World Clinics (Acne) PDF

World Clinics
Dermatology
Acne
Prelims_ACNE.indd 1 30-11-2013 17:37:29

World Clinics
Dermatology
Acne
Editor-in-Chief Guest Editor

Neena Khanna MD Raj Kubba MBBS MRCP (UK) FRCP (Canada)
FRCP (Edinburgh)
December 2013 Volume 1 Number 1
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the drug or device.
Cover images: (Left) Mixed inflammatory, non-inflammatory lesions at lower face and chin. Courtesy: Alison M Layton and
Rebecca L Mawson. (Middle) Inflammatory acne and scarring. Courtesy: Alison M Layton and Rebecca L Mawson. (Right)
Lower face acne aggravated by topical pimecrolimus. Courtesy: Raj Kubba.
World Clinics Dermatology: Acne

December 2013, Volume 1, Number 1
ISSN: 2347-7156
ISBN: 978-93-5090-976-8
Printed in India

Contributors
Editor-in-Chief
Neena Khanna MD
Professor, Department of Dermatology and Venereology
All India Institute of Medical Sciences
Guest Editor
Raj Kubba Mbbs Mrcp (UK) Frcp (Canada) Frcp (Edinburgh)
Diplomate American Board of Dematology
Delhi Dermatology Group, New Delhi 110 066, India
Department of Dermatology, Boston University School of Medicine, Boston,
MA, USA
Contributing Authors
Ma Flordeliz Abad-Casintahan MD FPDS
Vice Chairman & Training Officer
Department of Dermatology, Jose R Reyes Memorial Medical Center
Manila, Philippines
Craig G Burkhart MD MPH

Clinical Professor, Department of Medicine
The University of Toledo College of Medicine
Clinical Assistant Professor, Department of Medicine
Ohio University College of Medicine
Toledo, Ohio, USA
Craig N Burkhart MD
Associate Professor, Department of Dermatology
University of North Carolina
Chapel Hill, North Carolina, USA

Acne
Vandana Chatrath MBBS MSc (USA) Fellowship Derm Surgery (USA)

Consultant Dermatologist
Delhi Dermatology Group
New Delhi, India
Goh Chee-Leok MBBS MD MMed FRCPE FAMS

Senior Consultant and Clinical Professor, National Skin Centre
Singapore
Wenchieh Chen MD PhD

Department of Dermatology and Allergy, Technische Universität München
Munich, Germany
Soyun Cho MD PhD

Associate Professor
Department of Dermatology
Seoul National University
Seoul, Korea
Melissa S Crites MD
Transitional Year Resident
Mercy St. Vincent Medical Center
Toledo, Ohio, USA
Federica Dall’Oglio MD PhD

Dermatology Clinic, University of Catania
Catania, Italy
Brigitte Dréno MD PhD

Professor, Department of Dermatology and Skin Cancer
University Hospital, Nantes
France
Pan Jiun-Yit MBBS FRCP FAMS

Consultant, National Skin Centre
Singapore
Goknur Kalkan MD
Department of Dermatology, Gaziosmanpasa University, School of Medicine
Taşlıçiftlik yerleşkesi, 60250
Tokat, Turkey
vi

Contributors
Sewon Kang MD
Noxell Professor and Chairman
Department of Dermatology
Johns Hopkins University, MD, USA
Ayşe Serap Karadağ MD

Department of Dermatology, Istanbul Medeniyet University
Göztepe Researh and Training Hospital
Kadıköy, Istanbul, Turkey
Yi-Tin Lin MD
Department of Dermatology, Chang Gung Memorial Hospital
Chang Gung University College of Medicine
Taipei, Taiwan
Alison M Layton MB ChB FRCP

Consultant Dermatologist, Harrogate and District NHS Foundation Trust,
Lancaster Park Road
Harrogate, HG2 7SX, UK
Munisamy Malathi MD
Senior Resident
Jawaharlal Institute of Postgraduate Medical Education and Research
( JIPMER)
Puducherry, India
Rebecca L Mawson MB ChB Bsc DRCOG

Flat 1, 21 Cold Bath Road
Harroagte, HG2 0NA, UK
Bodo C Melnik MD
Department of Dermatology, Environmental Medicine and Health Theory
University of Osnabrück, Germany
Giuseppe Micali MD
Professor and Chairman, Dermatology
Director, Residency Program in Dermatology
University of Catania
Catania, Italy
vii

Acne
Dae Hun SUH MD PhD

Professor, Department of Dermatology
Seoul National University College of Medicine
Acne Research Laboratory
Seoul National University Hospital
Seoul, South Korea
Aurora Tedeschi MD PhD

Dermatology Clinic, University of Catania
Catania, Italy
Devinder Mohan Thappa MD DHA MNAMS

Professor and Head, Department of Dermatology and STD
Jawaharlal Institute of Postgraduate Medical Education and Research
( JIPMER)
Puducherry, India
Christos C Zouboulis MD PhD

Professor, Departments of Dermatology, Venereology, Allergology and
Immunology
Dessau Medical Center
Dessau, Germany
viii

Contents
Editorial......................................................................................................... xi
Neena Khanna
Abbreviations................................................................................................. xiii
What’s New in Acne Pathogenesis................................................................. 1

Soyun Cho, Sewon Kang
The Role of Microbiology and Biofilms in Acne............................................ 31

Melissa S Crites, Craig G Burkhart, Craig N Burkhart
The Sebaceous Gland and Its Role as an Endocrine Organ........................... 37

Christos C Zouboulis, WenChieh Chen
Nutrient and Growth Factor Signalling in

Acne Sensed by FoxO1 and mTORC1.......................................................... 52
Bodo C Melnik
Acne and PCOS............................................................................................. 89

Ma Flordeliz Abad-Casintahan
Acne Expression and Management in Indians.............................................. 105

Raj Kubba, Vandana Chatrath
Adult Acne .................................................................................................... 128

Alison M Layton, Rebecca L Mawson
Acne Syndromes............................................................................................ 144

Pan Jiun-Yit, Goh Chee-Leok
Acne Comorbidities....................................................................................... 155

Raj Kubba
Update of Oral Isotretinoin in Acne Treatment............................................. 169

Ayşe Serap Karadaǧ ,Goknur Kalkan, Yi-Tin Lin, WenChieh Chen

Acne
Current Role of Light and Laser Therapy in Acne......................................... 201

Dae Hun Suh
Evaluation and Management of Acne Scars.................................................. 210

Brigitte Dréno
Acneiform Drug Eruptions............................................................................ 218

Devinder Mohan Thappa, Munisamy Malathi
The Role of Dermocosmetics in Modern Acne Treatment............................ 234

Giuseppe Micali, Federica Dall’Oglio, Aurora Tedeschi

World Clin Dermatol. 2013;1(1):xi-xii.
Editorial
Neena Khanna MD
Editor-in-Chief
Acne is an extremely complex disease with elements of pathogenesis involving

defects in epidermal keratinzation, androgen secretion, sebaceous function,
bacterial growth, inflammation and immunity. In the past 30 years, much has been
worked out, and we now have a fairly detailed understanding of the events that
result in an acne pimple, although there is also much left to be discovered.
Occurrence of adolescent acne is so universal that it is almost considered physiological
is an old dermatological adage and this is more true today, than ever. So acne
could well be the commonest skin disease for which advice is sought. Hence, the
inaugural issue of World Clinics is dedicated to this ubiquitous condition. In this
issue, which is a culmination of efforts of an international team of experts who are
leaders in their own field, we have reviewed some of the latest developments in the
pathogenesis and management of acne.
The contents cover a wide range of aspects of acne, each covering the most
relevant literature with personal insights from the authors, wherever and whenever
necessary. The issue begins with a discussion on the pathogenesis of acne including
the role of P. acnes biofilms and the all important molecular and cell biological
aspects of sebocytes and sebaceous glands. Nutrition and acne are strange partners,
their relationship blowing sometimes hot, sometimes cold. Recent evidence
has tilted the balance in favor of a pathogenic role of insulinotropic Western
(now ubiquitous!) diet in the induction and aggravation of acne. So an article on
nutrient signaling … in acne. There is also a growing body of evidence on systemic
associations of acne, so a look at these aspects as well in a couple of articles. The
clinical aspects of acne are discussed in articles on adult acne and acneiform
eruption. Therapeutic aspects of acne are covered in sections on isotretinon
(a favorite for the past few decades and likely to remain so for the next few too,
thanks to the gratifying response of acne to it) and on light and laser therapy. And
© 2014 Jaypee Brothers Medical Publishers. All rights reserved.

Acne
of course, no account of acne is complete, if acne scars are not discussed. Then
there is an article on acne in Indian patients- ironically, India, which probably
has the largest population of acne patients has very little data available on acne,
including antibiotic resistance pattern of P. acnes.
Neena Khanna MD
Professor, Department of Dermatology and Venereology
All India Institute of Medical Sciences
Email: neena_aiims@yahoo.co.in
xii

Abbreviations
13cRA 13-cis-retinoic acid CD2BP1 Chromosome 15q encoding
17-OHP 17-hydroxyprogesterone CD2-binding protein 1
21-OH 21-hydroxylase CFUs Colony forming units
24OHase D-24-hydroxylase CGRP Calcitonin gene-related peptide
4E-BP Eukaryotic initiation factor CHG Chlorhexidine gluconate
4E-binding protein CMC-Lys Carboxymethyl cysteine-lysine
5FU 5-fluorouracil c-MET Proto-oncogene c-met product
5-LOX 5-lipoxygenase CO2 Carbon dioxide
5α-DHT 5α-dihydrotestosterone COX Cyclooxygenase
9cRA 9-cis-retinoic acid COX2 Cycloxygenase-2
α-MSH Alpha-melanocyte-stimulating CP Clindamycin phosphate
hormone CPA Cyproterone acetate
AAD American Academy of CRABP-2 Cellular retinoic acid binding
Dermatology protein-2
AAS Anabolic androgenic steroid CRH Corticotropin-releasing
AchR Acetylcholine receptors hormone
ACTH Adrenocorticotropic hormones CRH-R Corticotropin-releasing
ADL Activities of daily living hormone receptor
ADSC Adipose-derived stem cells CRM1 Chromosomal region
Akt Akt-kinase (protein kinase B) maintenance protein-1
AMP Adenosine monophosphate (exportin-1)
AMPK Adenosine monophosphate- CSL Casual sebum level
activated protein kinase CT Clinical trial
AMPs Antimicrobial peptides CTCAE National Cancer Institute
AN Acanthosis nigricans Criteria for Adverse Events
AP-1 Activator protein-1 CYP1A1 Cytochrome P-450 1A1 gene
AR Androgen receptor CYP21 Steroid 21-hydroxylase gene
ASI Acne Severity Index δ-ALA Delta-aminolevulinic acid
ATP Adenosine triphosphate D Day
AtRA all-trans-retinoic acid DHC Dehydrocholesterol
AzA Azelaic Acid DHEA Dehydroepiandrosterone
BMD Bone mineral density DHEA-S Dehydroepiandrosterone sulfate
BMI Body mass index DHT Dihydrotestosterone
Bnip3 Bcl-2/adenovirus E1B 19-kDa- DLE Discoid lupus erythematosus
interacting protein 3 DLQI Dermatology life quality index
BPO Benzoyl peroxide DNA Deoxyribonucleic acid
BSA Body surface area DPNs Dermatosis papulomis nigra
CAH Congenital adrenal hyperplasia ECCA Echelle d’Evaluation clinique
CAMP Christie, Atkins, Munch- des Cicatrices d’acné scale
Petersen EGCG Epigallocatechin-3-gallate
CBR Cannabinoid receptors EGF Epidermal growth factor
CCR7 C-C chemokine receptor 7 EGF-R Epidermal growth factor
CD Clusters of differentiation receptor

Acne
eIF Eukaryotic initiation factor IGF-1R Insulin-like growth factor-1

ER Estrogen receptors receptor
ERK Extracellular signal-regulated IGFBP-3 Insulin-like growth factor-
kinase binding protein 3
ER-α Estrogen receptor-alpha IL Interleukin
ESHRE European Society for Human iNOS Inducible nitric oxide synthase
Reproduction and Embryology IPL Intense pulsed light
FBS Fasting blood sugar IR Insulin receptor; insulin
FDA Food and Drug Administration resistance
FGF-R Fibroblast growth factor IRAA Insulin Resistance-associated
receptor acne
FGFs Fibroblast growth factors IRS Insulin receptor substrate
FoxO Forkhead box class O I-V IPL I to V interpeak latency
transcription factor JNK Jun N-terminal kinase
FSH Follicle-stimulating hormone K6 Markers of keratin
fT3 Free triiodothyronine Klf2 Krüppel-like factor 2
G6Pase Glucose-6-phosphatase KTP Potassium titanyl phosphate
GA Glycolic acid LA Lactic acid
GAP GTPase-activating protein LAT Low-affinity transport
GDP Guanosine diphosphate LED Light-emitting diode
GEF Guanine nucleotide exchange LH Luteinizing hormone
factor LKB Liver kinase B
GH Growth hormone LL-37 Cathelicidin
GHR Growth hormone receptor LMB Leptomycin B
GI Gastrointestinal LPS Lipopolysaccharide
GIP Glucose-dependent LTB4 Leukotriene-B4
insulinotropic polypeptide LXR Liver X receptor
GSH-Px Glutathione peroxidase LXR-α Liver X receptor-alpha
GSK Glycogen synthase kinase MA Malic acid
GTP Guanosine triphosphate MAL Methyl-ALA
H-1R Histamine-1 receptors MAPK Mitogen-activated protein
H2O2 Hydrogen peroxide kinase
HA Hyperandrogenism MAT Moisture accumulation test
HAIRAN Hyperandrogenic, insulin- MC-1R Melanocortin-1 receptor
resistant and acanthosis MC-5R Melanocortin-5 receptor
nigricans MCP-1 Monocyte chemoattractant
hBD-1 Human β-defensin 1 protein-1
HCL Hydrochloride salt MCs Melanocortins
HO-1 Heme oxygenase-1 MDA Malondialdehyde
HOMA-IR Homeostasis model assessment MIF Macrophage migration
for insulin resistance inhibitory factor
IBD Inflammatory bowel disease MMP Matrix metalloproteinase
ICAM-1 Intercellular cell adhesion MN Myrtacine + nicotinamide
molecule type-1 mRNA Messenger ribonucleic acid
ICG Indocyanine green MS Metabolic syndrome
IF Inflammatory MST1 STE20-like protein kinase-1
IFN-γ Interferon gamma mTOR Mammalian target of
IgE Immunoglobulin E rapamycin
IGF Insulin-like growth factor MUFAs Monounsaturated fatty acids
IGF-1 Insulin-like growth factor-1 N Nicotinamide
xiv

Abbreviations
NAD(P)H Nicotinamide adenine PSTPIP1 Proline-serine-threonine-

dinucleotide phosphate phosphatase-interactive
hydrogen protein 1
Nd:YAG Neodymium:yttrium- PTEN Phosphatase and tensin
aluminum-garnet homolog deleted on
NES Nuclear export signal chromosome 10
NESs Nuclear export signals PUVA Psoralen-ultraviolet A
NF-κB Nuclear factor-kappa B Rag Ras-related GTP-binding
NGAL Neutrophil gelatinase- protein
associated lipocalin RAL Retinaldehyde
NIF Non-inflammatory RALGA Diacneal (retinaldehyde and
NLS Nuclear localization signal glycolic acid)
NOX NAD(P)H oxidase Raptor Regulatory associated protein
NP Nicotinamide + panthenol of mTOR
NS Non-specified RAR Retinoic acid receptor
NY Neuropeptide Y RARE Retinoic acid response element
OCPs Oral contraceptive pills RCT Randomized controlled trial
OPR µ-opiate receptors RF Radiofrequency
OTC Over-the-counter Rheb Ras homolog enriched in brain
PA Pyruvic acid Rictor Rapamycin-insensitive
PAK1 p21-activated kinase-1 companion of mTOR
PAMPs Pathogen-associated molecular RNA Ribonucleic acid
patterns ROS Reactive oxygen species
PAPA Pyogenic arthritis, pyoderma RSK Ribosomal S6 kinase
gangrenosum and acne RXR Retinoid X receptor
syndrome S6K p70 S6 kinase
PAR-2 Proteinase-activated receptor 2 SA Salicylic acid
Pck1 Phosphoenolpyruvate SAPHO Synovitis, acne, pustulosis,
carboxykinase 1 hyperostosis and osteitis
PCOS Polycystic ovarian syndrome SC Stratum corneum
PDGF Platelet-derived growth factor SCD Stearoyl CoA desaturase
Pdk4 Pyruvate dehydrogenase kinase SCL-90-R Symptom check list
isoenzyme 4 SCTT Stratum corneum turnover time
PDL Pulsed dye laser SD Standard deviation
PDT Photodynamic therapy SER Sebum excretion rate
PEM Polymorphic epithelial mucin SFAs Saturated fatty acids
PG Pyoderma gangrenosum SG Sebaceous gland
PI3K Phosphoinositide-3-kinase SHBG Sex hormone-binding globulin
PP Postprandial Shh Sonic hedgehog
PPARs Peroxisome proliferator- SI Severity index
activated receptors SIBO Small intestinal bacterial
PPAR-γ Peroxisome proliferator- overgrowth
activated receptor-gamma SNPs Single nucleotide
PPBS Postprandial blood sugar polymorphisms
PR Progesterone receptor SOD Superoxide dismutase
PRRs Pattern recognition receptors SORT Strength of recommendation
PS Phytosphingosine taxonomy B criteria
PS-HCL Phytosphingosine - SREBP Sterol regulatory element
hydrochloride binding protein
xv

Acne
SREBP-1 Sterol regulatory element- TOR Target of rapamycin

binding protein-1 Trb3 Tribbles3
SSL Skin surface lipids TRH Thyrotropin-releasing
STRA8 Stimulated by retinoic acid 8 hormone
T2DM Type 2 diabetes mellitus TSC Tuberous sclerosis complex
TBARS Thiobarbituric acid reactive TSC1 Hamartin
substances TSC2 Tuberin
TC Triclosan TSH Thyroid-stimulating hormone
TCA Trichloroacetic acid UK United Kingdom
TCF T cell factor USA United States of America
TES Triethyl citrate + ethyl linoleate UV Ultraviolet
+ salicylic acid UVA Ultraviolet A
TEWL Trans epidermal water loss UVB Ultraviolet B
TGF-β Transforming growth factor- VDR Vitamin D receptor
beta VEGF Vascular endothelial growth
TGs Triglycerides factor
Th2 T-helper type-2 VIP Vasoactive intestinal
TIMP Metalloproteinase inhibitor polypeptide
TLC Total lesion count Vit Vitamin
TLR Toll-like receptor VNTR Variable number of tandem
TNFR2 Type 2 tumor necrosis factor repeat
receptors VR Vanilloid receptor
TNF-α Tumor necrosis factor-alpha W Week
xvi

World Clin Dermatol. 2013;1(1):1-30.
What’s New in Acne Pathogenesis

*,1Soyun Cho MD PhD, 2Sewon Kang MD MPH
1
Department of Dermatology, Seoul National University, Seoul, Korea
2
Department of Dermatology, Johns Hopkins University, Baltimore, MD, USA
ABSTRACT
In recent years, our knowledge on the classic pathogenic factors of acne, i.e.,
androgenic control of sebaceous gland, infundibular retention hyperkeratosis,
Propionibacterium acnes and inflammatory events, attained a new depth.
This article summarizes newer information, including the importance
of altered lipid and oxidant/antioxidant ratio in sebum composition, the
crucial role of P. acnes as the primary elicitor of host’s innate and adaptive
immune responses, and the likely involvement of matrix metalloproteinases
in scar formation. Furthermore, polymorphisms of genes that function
in the steroid hormone metabolism, innate immunity-related genes and
fibroblast growth factor receptor 2 (FGFR2) found to be associated with
acne are discussed. Emerging evidence demonstrates that dietary triggers,
especially the high glycemic load diet and milk consumption, may aggravate
acne vulgaris by raising insulin and insulin-like growth factor 1 (IGF‑1)
levels. Paradigm shifting data show that subclinical inflammation may be
the initial driver of follicular hyperkeratinization and hyperproliferation,
indicating that our understanding of acne pathogenesis will continue to
evolve in the future.
INTRODUCTION
Acne, an exclusively human disease, is a very common skin condition which affects
as many as 85% of teenagers and 3% of those aged 35–44 years.1 Its pathogenesis is
complex and multifactorial, with pubertal androgenic stimulation of the sebaceous
gland playing a major role while follicular hyperkeratosis, increased colonization
with Propionibacterium acnes, inflammatory events, and dietary and lifestyle
factors contributing additionally in variable proportions in genetically susceptible
*Corresponding author
Email: sycho@snu.ac.kr

Cho and Kang
individuals. The current body of evidence indicates that the relationship between
sebum production, hyperkeratosis, P. acnes and inflammation is more complex
than thought previously, with data even suggesting that inflammatory events may
precede microcomedone formation and that the plug formation is at least partially
influenced by inflammation produced by P. acnes.2 It is clear that these processes
are all interrelated since sebum is necessary for P. acnes colonization of the skin and
P. acnes is essential in switching on the innate and adaptive immune system leading
to the inflammation. Currently, acne is considered primarily an inflammatory skin
disease of the pilosebaceous unit, and the precise mechanism by which P. acnes
contributes to the pathogenesis of acne remains unknown.
Regarding the role of diet in acne, there is a general perception that non-
Western populations have a lower incidence of acne, and that this incidence
increases when a Western dietary pattern is adopted, implying that genetic
predisposition is not the only relevant factor in the development of acne.3 In
this article, we provide a comprehensive review of these notable factors in the
pathogenesis of acne.
PATHOGENIC FACTORS
Role of Sebaceous Gland and Androgens
Sebaceous Gland
The function of the sebaceous gland, a holocrine gland, is to excrete sebum and
sebum excretion occurs in parallel with acne development. Sebum contains
triglycerides (TGs) and fatty acid breakdown products, wax esters, squalene,
cholesterol esters and cholesterol.4 The sebaceous gland is a steroidogenic
organ that possesses all the enzymes required for sex-hormone synthesis and
metabolism. It can synthesize androgens de novo from cholesterol or by locally
converting weaker circulating androgens to more potent ones.5 Functional
studies on sebocytes have been conducted mainly with cell culture models using
mammalian sebocytes, human sebocyte-like cells (human, mouse, hamster and rat)
and human sebaceous gland cell lines (SZ95, SEB-1, Seb-E6E7).5,6 Identification
of functional receptors for neuropeptides such as corticotropin-releasing hormone
(CRH), melanocortins (MCs), b-endorphin, vasoactive intestinal polypeptide,
calcitonin gene-related peptide and substance P7,8 gave rise to the notion that
human sebaceous gland is like the “brain of the skin”.9 Since CRH is expressed in
human sebocytes, stress may affect inflammatory changes in early acne lesions.10
In SZ95 cells that are not stressed, CRH promotes lipogenesis in autocrine
fashion.11 However in acne lesions, CRH expression was strongly enhanced, and
this further stimulated the release of interleukin (IL)-6 and IL-8 from sebocytes by
an IL-1b-independent manner.7 Excessive sebum production is one of the major
2
factors in the pathogenesis of acne. Among the MC receptors [melanocortin-1

receptor (MC-1R) and melanocortin-5 receptor (MC-5R)] that are expressed in
human sebocytes, MC‑1R is expressed in both undifferentiated and differentiated
sebocytes, whereas MC-5R is expressed only in the differentiated lipid-containing
cells at the center of sebaceous glands,12 and is therefore associated with sebocyte
differentiation and sebum production.13 MC-1R expression was shown to be
increased in the sebaceous glands of acne lesion in vivo.14 Treatment of cultured
sebocytes with substance P led to enhanced IL-1, IL-6, tumor necrosis factor alpha
(TNF-a) and peroxisome proliferator-activated receptor gamma (PPARg) gene
and protein expression, further supporting the role of stress in acne development.15
The pilosebaceous unit is an immunocompetent organ, the infundibular
keratinocytes and sebocytes being fully equipped with the capacity to elicit innate
immune responses.16 The keratinocytes and sebocytes may be activated by P. acnes,
via toll-like receptors (TLRs) and cluster of differentiation (CD) 14, recognize
altered lipid content in sebum, and produce inflammatory cytokines.17
Among the components of sebum, the TG fraction appears to be responsible
for acne development;18,19 bacteria can hydrolyze sebaceous TGs and liberate
fatty acids which can penetrate the follicular wall and become incorporated
into the surrounding epidermis.20 The application of free fatty acids on rabbit
ears or hairless mice was shown to induce hyperkeratinization and epidermal
hyperplasia similar to the process of comedogenesis.18,21 Research has shown that
among the fatty acids only monounsaturated fatty acids (MUFAs) stimulate the
morphological changes in comedo formation whereas TGs and saturated fatty
acids (SFAs) have little effect.18 Presumably, MUFAs of sebum interfere with the
intracellular calcium dynamics of follicular keratinocytes and the intercellular
lipid bilayer structure of epidermal barrier.18 Sebum contains a high proportion
of MUFAs, with a characteristic double bond at the D6 position19 instead of
the standard D9 position. Sebum itself is not a direct cause of acne since not
everybody gets acne, rather, the compositional changes that occur with increasing
sebum production seem to affect events involved in comedo formation.22 Sebum
alterations associated with acne include: (1) decrease in linoleic acid which
affects the composition of sphingolipids, which may be involved in the follicular
hyperkeratosis crucial in comedogenesis;22 (2) incorrect activity of specific
desaturase enzymes altering the ratio between D6 and D9 unsaturated fatty acids,
with resultant compositional changes that can drive toward acne development;23
and (3) lipid peroxidation byproducts, such as squalene peroxide, which lead to
follicular hyperkeratinization, increased proliferation of sebaceous glands, and
upregulation and release of inflammatory mediators such as IL-6.23 When sebum
was analyzed in individuals with and without acne, subjects with acne had more
(59%) sebum than controls, and free fatty acids were reduced in the sebum of acne
subjects whereas squalene was upregulated 2.2-fold in acne subjects,24 suggesting
3
Cho and Kang
potential utility of squalene amount as a lipid marker to diagnose acne-prone

skin. Sebaceous gland lipids demonstrate direct proinflammatory and anti-
inflammatory properties; specifically the induction of 5-lipoxygenase (5-LOX)
and cycloxygenase-2 (COX2) pathways in sebocytes leads to the synthesis of
proinflammatory lipids.25 Conversely, the proinflammatory cytokine TNF-a can
induce lipogenesis in SZ95 sebocytes through the Jun N-terminal kinase ( JNK)
and phosphoinositide-3-kinase/Akt (PI3K/Akt) pathways,26 providing rationale
for anecdotal reports of dramatic improvement in acne following administration
of etanercept, a soluble TNF-a receptor antibody.
Fatty acids also act as ligands of nuclear hormone receptors such as the
PPARs, which are transcription factors involved in lipid metabolism and energy
homeostasis. Activation of PPARg and PPARa by their respective specific ligands
was found to stimulate lipid droplet accumulation in cultured immature sebocytes
but not in keratinocytes, with 5a-dihydrotestosterone (DHT) exhibiting an
additive effect only with combination of DHT and PPARg. This demonstrates
that PPARg influences a step in sebocyte differentiation that is distinct from that
influenced by androgen.27 In another study, PPARb/d messenger ribonucleic acid
(mRNA) was overexpressed in both inflammatory and noninflammatory acne in
vivo.28
The sebaceous gland also expresses antimicrobial peptides such as human
b-defensin 1 (hBD-1), hBD-2 and cathelicidin (LL-37).29 Although hBD‑2
has no direct antimicrobial effects on P. acnes,30 it acts synergistically with
cathelicidin.31 Sebum free fatty acids have antibacterial activity against Gram-
positive bacteria. When human sebocytes were incubated with free fatty acids, the
expression of hBD-2 was dramatically enhanced, suggesting that free fatty acids
may provide direct antibacterial activities against P. acnes and enhance the skin’s
innate antibacterial defense.32
SZ95 sebocytes express liver X receptor (LXR) a and LXRb, which belong to
the nuclear receptor superfamily and play a critical role in cholesterol homeostasis
and lipid metabolism.33 Among the two receptors, only LXRa expression was
enhanced and lipid synthesis increased by LXR ligands. Furthermore, LXR
ligands decreased lipopolysaccharide (LPS)-induced proinflammatory factors
COX2 and inducible nitric oxide synthase (iNOS), suggesting the important
roles of LXRa in differentiation and inflammatory signaling in the sebaceous
gland.34
Acetylcholine receptors (AchR) are also expressed in sebocytes and
infundibulum. Stimulation of the receptors by acetylcholine can promote
infundibular epithelial hyperplasia and follicular plugging, possibly linking an
etiological role of nicotine uptake from smoking in comedonal acne characteristic
of smokers.35
4
Androgens
Hormones are undeniably the initiating factor in the pathogenesis of acne. With
the surge of androgens in puberty, sebaceous gland is known to mature and begin
secreting sebum actively. Androgen receptors (ARs) are expressed in the basal
layer of the sebaceous gland and in the outer root sheath keratinocytes of the hair
follicle.36 When free testosterone enters the cell, it is quickly reduced to DHT by
the 5a-reductase enzyme, whose activity is increased in proportion to the size of
the sebaceous gland.37 In primary human sebocyte culture, androgens testosterone
and DHT only stimulate sebocyte proliferation38 through sterol-response
element-binding proteins (SREBPs), whereas PPAR ligands are required for
differentiation and lipogenic activity.39 Exogenous administration of testosterone
and dehydroepiandrosterone sulfate (DHEA-S) increases sebaceous gland size
and sebum production.40 Serum androgen levels, however, do not correlate with
acne severity. Therefore androgens may only serve as a prerequisite for acne
development.17 Despite the clinical evidence that androgens stimulate sebaceous
gland, the in vitro effect of androgens on the proliferation and differentiation of
sebocytes vary in different experiments and cell types.17 The mechanisms by which
androgen/AR regulate sebocyte activity in acne vulgaris are still unclear. Androgens
might cross talk with IGF-1 activities in controlling acne development.41 At
puberty, IGF-1 induces synthesis of androgens and enhances 5a-reductase activity
in the skin.42 In addition, IGF‑1/PI3K/Akt activity stimulates phosphorylation of
FoxO1, an AR corepressor. Upon phosphorylation, FoxO1 translocates from the
nucleus to the cytosol and releases its inhibition on AR transactivation.41 Recently,
in human sebocyte culture, addition of DHT upregulated IL-6 and TNF-a gene
and protein expression, suggesting that DHT may participate in inflammatory
acne process as well.43 In addition to affecting sebaceous gland activity, androgens
also influence keratinization of follicular corneocytes.44
Role of Follicular Epithelial Cells

The initial plugging of the pilosebaceous canal is thought to be from a mechanical
effect27 because electron microscopic findings show retention hyperkeratosis with
increased number and size of keratohyaline granules and pressure-induced folding
of retained squames on themselves.27 Androgen stimulates ductal keratinocytes
to multiply; the proliferating keratinocytes are propelled toward the center of the
sebaceous duct, which expands to accommodate the increasing volume of lipid
droplets until the inelastic “glassy membrane” that encloses the pilosebaceous duct
can expand no further. Further accumulation of keratinocytes in this closed system
causes an increase in intraluminal pressure, leading to hypoxia in the central part
of the duct.27 This produces an anoxic environment that favors intraductal P. acnes
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colony formation, which leads to rupture of the duct walls with release of luminal
antigens and resultant inflammation. This was the classic theory of how acne
develops. Recent studies using clinically normal follicles from uninvolved skin
of acne patients show that vascular endothelial cell activation and inflammatory
responses occur prior to and act as possible causal factors in the hyperproliferative
changes of acne, as opposed to a secondary event, with increased IL-1 activity
occurring prior to follicular hyperproliferation around uninvolved follicles,
triggering the “keratinocyte activation cycle”.45
Although the exact cause of follicular hyperkeratinization is still to be
elucidated, IL-1a seems to play an important role since it was reported to induce
infundibular hyperkeratinization in vitro and in vivo.40 In addition to this change,
dysregulated terminal differentiation with increased filaggrin expression46 and
follicular keratinocytic hyperproliferation with the hyperproliferative markers of
keratin [K6 and K16] was observed.47 Besides IL-1a, increased DHT,44 relative
deficiency of linoleic acid and peroxides in sebum,48 and P. acnes extracts46 may
all contribute to abnormal hyperkeratinization of infundibular keratinocytes. To
elucidate the pathogenesis of closed and open comedo formation, studies have
been performed on nevus comedonicus, and the results show association of gain-
of-function mutation of fibroblast growth factor receptor 2 (FGFR2), which is
also the causative mutation of acne in Apert’s syndrome.49,50 This will be dealt
with in more detail later in this article.
Role of Propionibacterium Acnes

Propionibacterium acnes is a normal commensal in the pilosebaceous units, found
to be present in nearly 100% of adults.51 Its population density rises in puberty
with an increased sebum excretion rate, keeps increasing until the age of 25
years, and remains constant thereafter through middle age with a declining trend
after age 70 years, regardless of race.52 Not everyone gets acne, and there is no
relationship between acne severity and follicular population density of P. acnes.53
Therefore, a question rises as to whether P. acnes is a true etiological pathogen
or not in acne. There is at present no definitive proof that microorganisms,
particularly P. acnes, initiate either comedogenesis or inflammation in
acne.54 What exists is circumstantial evidence that a proportion of normal
pilosebaceous follicles are colonized by P. acnes; a favorable microenvironment
leads to increased colonization of microcomedone by P. acnes which may further
aggravate comedogenesis; and an inflamed lesion may further provide an
enriched environment for the colonization as well as proliferation of P. acnes. P.
acnes can intensify the inflammatory process but is dispensable for its initiation.
Nevertheless, we will overview the evidence of the role that P. acnes plays in
comedogenesis and inflammation.
6
Recently, acne was suggested to be an IGF-1-mediated disease.55 IGF-1 and

IGF-1 receptor (IGF-1R) were overexpressed in acne lesions, and P. acnes extracts
elevated IGF-1 and IGF-1R expression in the epidermis and induced keratinocyte
proliferation, demonstrating that P. acnes can help induce the formation of
comedone by stimulating the IGF/IGF-1R system.56 In addition, P. acnes
extracts can directly modulate the differentiation of keratinocytes by inducing
transglutaminase, K17, integrin (b1, a3, a6x and aVb6) and filaggrin expression,46
while decreasing K1 and K10 expression.57 Also P. acnes was shown to increase
the CRH expression in the epidermis, thereby modulating the differentiation of
keratinocytes and increasing local inflammation, hence possibly playing a role in
the formation of early microcomedo.58 Furthermore, P. acnes has been shown to
form biofilms, a biological glue, that may lead to the increased cohesiveness of
corneocytes in acne, leading to comedone.2 A biofilm is a complex aggregation
of microorganisms within an extracellular polysaccharide lining, and it is secreted
after adherence to a surface.2 The biofilm confers P. acnes increased resistance to
antimicrobial agents with enhanced production of virulence factors.59 Indeed, the
genome sequence of P. acnes revealed immunogenic and surface-associated genes,
confirming the existence of the acne biofilm.60
P. acnes produces various exogenous proteases, and these proteases at least
partially elicit cellular responses via proteinase-activated receptor 2 (PAR-2), a
sensor for exogenous danger molecules. Increased protease activity and PAR-2
expression was demonstrated in acne lesions. P. acnes induced calcium signaling and
stimulated IL-1a, IL-8, TNF-a, hBD-2, LL‑37, and matrix metalloproteinase
(MMP) 1, 2, 3, 9, and 13 in keratinocytes through PAR‑2, indicating that PAR-2
plays an important role in acne pathogenesis by inducing inflammation, innate
immune responses and matrix degradation.61
P. acnes is important in the induction and maintenance of the inflammatory
phase of acne. The evolving concept of immune response includes microbial
invasion, subsequent activation of innate immune system followed by recovery
from the microbial infection, or in case this direct recovery is not feasible,
secondary activation of adaptive immune system which results in recovery and
immune memory with further activation of innate immune system. TLRs are the
best studied transmembrane pattern recognition receptors (PRRs) that sense and
bind with certain pathogen-associated molecular patterns (PAMPs) such as LPS
and CpG DNA and activate the innate immune system. The intracellular portion
of TLR has homology with the cytoplasmic domain of the IL-1 receptor; the
intracellular portion may trigger a Myd88-dependent pathway that leads to the
nuclear translocation of the transcription factor nuclear factor kappa B (NF-kB)
and ultimate transcription of many immune response genes.62 TLRs are mainly
located in blood and tissue immune cells. Ten TLRs have been identified in
humans so far.63 TLR4 is highly specific for LPS from Gram-negative bacteria,
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while TLR2 mediates the recognition of lipopeptides from Gram-positive

bacteria.64 TLR2 was expressed on the surface of macrophages surrounding
pilosebaceous follicles, and P. acnes, Gram-positive anaerobic bacilli, induced
cytokine (IL-1b, IL-8, IL‑12 and TNF-a) production in monocytes through a
TLR2-dependent pathway.65 The IL-8 produced by the activated monocytes is a
potent T cell chemoattractant and neutrophil activator, and as a result, neutrophils
release proteins including defensins. Among the six different a-defensins and two
b‑defensins identified in humans, human neutrophil proteins (HNP) 1-3,66 and
hBD 1 and 229 have been found in acne lesions. Interestingly HNPs were expressed
only in inflammatory acne lesions suggesting that they may contribute to the
development of inflammatory lesions.66 Contrary to the earlier dogma, it has been
shown that the initial infiltrating cells in developing inflammatory acne lesions
are mononuclear cells which are predominantly CD4+ “memory/effector skin
homing”T cells and that neutrophils appear later in the course of inflammation.67,68
Inflammatory events, consisting of IL-1a and increased CD4+ T cells occur in the
very earliest stages of acne development, before hyperproliferation or abnormal
differentiation of follicular epithelium.69 Once neutrophils infiltrate into the acne
lesion, neutrophil a‑defensins, in addition to their antimicrobial effects, induce
selective chemotaxis of CD45RA/CD4 cells, CD8 T cells and immature dendritic
cells at nanomolar concentrations,70 amplifying chronic inflammatory responses.
Normal keratinocytes express TLR1, 2, 4 and 5.71,72 When keratinocytes from
acne patients are exposed to P. acnes extract ex vivo, the expressions of TLR2, TLR4
and MMP9 are increased.73 Only certain strains of P. acnes were found to induce
selective IL-8 and hBD-2 expression in human keratinocytes via TLR2 and TLR4
and induce keratinocyte growth in vitro.74 P. acnes GroEL (a heat-shock protein)
is able to upregulate the proinflammatory cytokine production of keratinocytes.75
In inflammatory acne, the early interaction between keratinocytes and bacteria
appears crucial since keratinocytes produce reactive oxygen species (ROS) and
proinflammatory cytokines in response to the bacteria.76 SZ95 sebocytes also
constitutively express TLR2, TLR4, CD14, IL-1a, IL-1b, IL-6 and IL-8. When
exposed to LPS of Gram-negative bacteria and lipoteichoic acid of Gram-
positive bacteria,30 SZ95 sebocytes increase the production of IL-6 and IL-8, in
addition to antimicrobial lipids48 and antimicrobial peptides (hBD-2, psoriasin
and cathelicidin).30,31,77 Therefore, innate immunity can be induced directly
in keratinocytes and sebocytes without involving the inflammatory cells, and
recruitment of inflammatory cells to the involved sites amplifies the inflammatory
process in acne.78 Once the adaptive immune response takes over the innate
immunity, the inflammatory reaction is augmented dramatically. However, the
magnitude of this response is not related to the amount of bacteria.76 Rather, acne
severity is related to the capacity of various P. acnes strains to induce inflammation,
and to the host’s genetic capacity to respond to P. acnes immunologically.76
8
Colonization of pilosebaceous unit by P. acnes is the main event that leads

to inflammation. Recently a higher prevalence of follicular P. acnes colonization
was actually visualized, with greater number of follicles containing P. acnes and
the greater numbers of bacteria in macrocolonies/biofilms than in controls.79
P. acnes also directly augments intracellular lipid formation in hamster sebocytes
by increasing the de novo synthesis of triacylglycerols.80 LPS directly increases
inflammation in sebaceous glands in vivo by augmenting COX2, PGF2a and
PGF2a-mediated pro-MMP2 productions.81 The production of pro-MMP2 was
augmented by P. acnes-derived factors in hamster sebocytes and dermal fibroblasts,
suggesting that the bacteria may participate directly in acne scar formation.82
In summary, P. acnes is capable of inducing inflammation by: (1) releasing
lytic enzymes and lipases that trigger the rupture of follicular epithelium and
inflammatory reaction; (2) producing chemotactic factors that recruit neutrophils
through the epithelial wall;83,84 (3) activating the innate immune system
through the TLR2 and TLR4 mentioned above; (4) stimulating the formation
of C5a by activation of the classical and alternative complement pathways;85
and (5) triggering the adaptive immune response evidenced by the presence of
activated T helper 1 (Th1) cells in early inflamed acne lesions.86 In acne vulgaris
patients, high serum antibody titers87 directed to several putative surface proteins88
of P. acnes were detected. Infiltrating neutrophils destroy the P. acnes, but the
bacteriolysis results in the production of hydrolases that add to further disruption
of follicular epithelium and enhanced inflammation. Recently P. acnes was shown
to secrete Christie Atkins Munch-Petersen (CAMP) factor, a virulence factor that
was cytotoxic to keratinocytes and macrophages in a synergistic manner with the
host acid sphingomyelinase. Such observation has led to the possibility of applying
vaccine technology that targets both the secreted P. acnes CAMP factor and host
acid sphingomyelinase to locally suppress inflammatory acne.89
Gene array expression profiling in acne lesions was conducted for the first
time in 2006 and revealed marked upregulation of genes involved in inflammation
and matrix remodeling, including MMP1 and 3, IL-8, hBD4, and granzyme B.90
An emerging picture is the chronic inflammatory nature of acne triggered by a
pathogen, P. acnes.
Role of Immune Mediators

Clearly, inflammatory cytokines, chemokines and other proteins including IL-1,
IL-8 and certain MMPs mediate acne.91 In normal unstressed sebocyte culture,
cytokines such as IL-1a, TNF-a, IL-6 and IL-8 are present.25 Treatment of
cultured sebocytes with P. acnes and LPS significantly upregulates the expression
of proinflammatory cytokines, with P. acnes stimulating IL-8 and TNF-a and
LPS stimulating IL-8, TNF-a and IL-1a.30
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P. acnes-stimulated keratinocytes also play an important role in the

inflammatory reaction, producing a number of proinflammatory cytokines
and chemokines such as IL-1a, IL-1b, IL-8, GM-CSF, TNF-a and hBD-2
through the TLR2 and TLR4 signaling pathways in vitro.65,73 P. acnes activates
NF-kB and mitogen-activated protein kinase (MAPK) pathways92 and recruits
macrophages and immune cells to the site of infection.
When stimulated by P. acnes surface proteins, keratinocytes were shown
to rapidly produce ROS, and especially superoxide anions93 by NAD(P)H
(nicotinamide adenine dinucleotide phosphate hydrogen) oxidase (NOX) pathway
through activation of the scavenger receptor CD36. The superoxide anions combine
with nitric oxide to form peroxynitrites which in turn, activate p38 and extracellular
signal-regulated kinase (ERK), MAPKs, leading to IL-8 production. IL-8
production is also activated through P. acnes-induced TLR2 signaling pathway.93
Furthermore, P. acnes-induced superoxide anions abrogated P. acnes growth and
were involved in the lysis of keratinocytes through formation of peroxynitrites.
Retinoic acid derivatives prevent superoxide anion production, IL-8 release and
keratinocyte apoptosis, demonstrating the relevance of this pathway in vivo.
Leukotriene B4 (LTB4), a proinflammatory mediator synthesized from
arachidonic acid by 5-LOX, is also implicated in the pathogenesis of acne because
systemic treatment with a specific LOX inhibitor resulted in 60% decrease in
acne severity index within 3 weeks and 70% reduction in inflammatory lesions at
3 months, with 65% reduction in sebum total lipids.94 LTB4 is also a natural ligand
for PPARa; therefore, PPAR regulation can modulate the tissue inflammation
in acne lesions by inhibiting the expression of proinflammatory genes.95 On the
other hand, COX-2 expression and PGE2 production are increased by PPARg
agonists.81
A decrease in the body’s antioxidant activity may also play a role in the
pathogenesis of acne. The superoxide dismutase (SOD) levels were significantly
lower in leukocytes from acne patients96 in a dose-dependent manner; the
more severe the acne, the lower the SOD activity in tissues and blood. Other
parameters of oxidative stress such as serum malondialdehyde (MDA) level and
xanthine oxidase activity were higher, and serum catalase and SOD activity was
lower in acne patients.26 MDA is an end-product of lipid peroxidation induced by
oxygen free radicals and is well correlated with the degree of lipid peroxidation.12
When stratum corneum samples from involved and normal skin of acne patients
and healthy controls were compared for quantity of glutathione, a component
of endogenous antioxidant system, both samples from acne patients contained a
significantly lower amount.97 Whether the oxidative stress is the cause or outcome
of the inflammatory events is yet to be determined. All these data suggest that
P. acnes could modulate host genes, which might in turn influence the inflammatory
reaction.
10
Genetic Factors
Genetic factors, which play a role in the pathogenesis of acne, were initially
demonstrated by twin studies and community-based studies.36,98-101 In these
studies, the occurrence and severity of acne symptoms showed a strong
concordance in identical twins and a familial tendency. In a large British female
twin study of 458 monozygotic and 1,099 dizygotic pairs, 47% of acne twins had
a family history of at least one non-twin sibling affected with acne compared
with 15% in non-acne twins; acne in either parent was reported in 25% of
acne twins and 4% of non-acne twins; 41% of acne twins had at least one child
affected with acne, in contrast to 17% of controls.99 The authors of this study
showed that acne is one of the most heritable skin disorders with 81% of the
variance in acne liability attributed to additive genetic factors and only 19% to
environmental factors.99
Genes Involved in Steroid Metabolism

Serious search for specific genetic susceptibility factors only began in the
1990s.102-104 At that time studies involved genes affecting steroid hormone
metabolism, including human cytochrome P-450 1A1 gene (CYP1A1),102
steroid 21-hydroxylase gene (CYP21)103 and AR gene polymorphisms.104 Since
cytochrome P-450 enzymes are involved in the metabolism of a wide range of
endogenous and foreign compounds and CYP1A1 is involved in vitamin A
and endogenous retinoid metabolism, polymorphisms in the regulatory sites
of CYP1A1 may impair the biological efficacy of natural retinoids due to their
rapid metabolism to inactive compounds, with resultant abnormal sebocyte
differentiation and hyperkeratinization of follicular canal, initiating acne in
some patients.102 Several years later, two Chinese studies investigated CYP17-34
(T > C) single nucleotide polymorphisms (SNPs) and found that CC homozygote
Chinese male patients were at a significantly increased risk of developing severe
acne105 and that this mutation increased the risk of postadolescent acne in Chinese
female patients with increased androgen levels.106 CYP17 encodes cytochrome
P-450c17a which is a key enzyme in androgen biosynthesis, mediating both
steroid 17a-hydroxylase and 17,20-lyase activity.107 Therefore, this SNP may result
in a higher level of androgen in serum, followed by enhanced sebum production
and follicular keratosis. An inadequate activity of steroid 21-hydroxylase, as well
as CYP21 mutation, is the most common defect in late-onset congenital adrenal
hyperplasia which presents with symptoms of androgenicity including acne.
Although a CYP21 mutation was more common in acne patients, there was a poor
correlation between the mutation and either elevated steroids or acne, suggesting
other factors for the variable phenotype of hyperandrogenism.103
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Androgen works by binding to nuclear ARs which are localized in the basal
layer of sebaceous gland and outer root.108 When androgen activates the receptor,
the ligand-receptor complex is translocated to the nucleus and transactivation of
androgen-regulated genes occurs. The modulatory domain of AR gene includes a
polymorphic CAG triplet repeat coding for a polyglutamine tract whose number
is inversely correlated with AR’s transcriptional activity.109 AR polymorphism of
CAG repeat length did not exhibit a correlation with acne in Caucasians,104 but
in Chinese Han population the CAG repeat length was significantly shorter in
male acne subjects,110 suggesting this variable number of tandem repeat (VNTR)
polymorphism as a candidate genetic marker for male acne susceptibility and
hinting at genetic differences in each ethnic group.
Since elevated levels of serum IGF-1 correlate with overproduction of sebum
and acne55,111 and functional relationship between IGF-1 (CA) 19 polymorphism
and circulating IGF-1 levels is known,112 IGF-1 (CA) 19 polymorphism was
investigated in Turkish acne patients and a significant association was found
between this polymorphism and acne severity regardless of gender.113 The varying
frequency of IGF-1 (CA) 19 among different populations, with the highest
frequency in Caucasian (65.5%) followed by Asian (33.3%) and African-American
(15.6%) population,114 may offer a partial explanation for different susceptibility
to acne in each race.
Innate Immunity Genes

More recently, a handful of reports on genetic polymorphisms in the innate
immunity genes were added.102,103,105,106,110,113,115-123 In the innate immune system,
external danger signals including microbes activate pathogen recognition receptors
such as TLRs, which leads to the release of early response cytokines including
IL-1a and TNF-a. The resultant increased expression of various downstream
target genes such as those of adhesion molecules, secondary cytokines and
chemokines, and infiltration of professional immune cells, can lead to uncontrolled
inflammation.124
Two mutations in the TLR2 gene, Arg677Trp and Arg753Gln, and two SNPs
causing Asp299Gly and Thr399Ile changes in the TLR4 gene were investigated
in 101 Central European subjects, but no association was found between these
mutations and acne, suggesting that carriage of TLR2 or TLR4 SNP allele may
not affect susceptibility of patients for acne vulgaris.125 More recently, the carriage
of the above SNPs of TLR4 was shown to be protective against the development
of acne conglobata in Greek subjects, implying the possibility of modulating
TLR4 for therapeutic purposes.115
The gene IL1A encoding IL-1a, a central molecule in cutaneous inflammatory
reactions, was also investigated for a relevant mutation in Central Europeans, and
12
a positive association was found between IL1A +4845 (G > T) SNP and acne.
The severity of inflammatory acne symptoms correlated with the percentage of
subjects carrying the homozygote T/T genotype.116 IL-1a is synthesized as pre-
IL-1a and processed into mature IL-1a by enzymatic cleavage.55 The IL‑1A
SNP causes an alanine to serine substitution close to the proteolytic cleavage
site and might lead to enhanced cleavage, causing elevated ratio of cytoplasmic/
secreted IL-1a to nuclear pre-IL-1a and hence uncontrolled inflammatory
reactions and acne symptoms.116 This, together with the same researchers’ report
on TNF-a regulatory SNP,121 suggests that genetic variations in proinflammatory
cytokines contribute to acne development by causing dysregulation of epidermal
homeostasis. IL-1A-889 (C > T), but not IL-8-21 (T > A), polymorphism was
also a predisposing factor for acne in Polish patients.117 In Saudi population,
IL-4R Q551R (A > G) polymorphisms were significantly associated with acne
susceptibility but not severity.118
There are several reports on the association of acne and SNPs in TNF-a gene
promoter: TNF-a-308 (G > A) in Turkish patients,119 Central Europeans121 and
Saudi subjects.122 Interestingly, TNF-a-857 (C > T) minor T allele was found
to act as a protective factor against acne in the Central European study.121 The
function of TNF-a is mediated mainly by type 2 TNF receptors (TNFR2).
TNFR2 M196R (676 T > G) SNPs were associated with acne vulgaris in Han
Chinese population,120 further supporting the role of inflammatory cytokines in
the pathogenesis of acne.
MUC1 Gene
Polymorphisms of genes with antiinflammatory properties were also investigated.
Polymorphic epithelial mucin (PEM) or MUC1 is a cell surface glycoprotein
secreted from various epithelial gland tissues, including sweat glands and
sebaceous glands of the skin. During pathogen infection, the mucins initiate
active protection mainly by interfering with the NF-kB signal transduction.
VNTR polymorphisms are present in the extracellular domain of MUC1, and
compared to controls, a higher percentage of longer length alleles were seen in
severe Japanese acne patients.123 Long alleles may be more efficient in pathogen
binding and hence result in enhanced bacterial colonization and susceptibility to
various infectious diseases in the carriers.126
Fibroblast Growth Factor Receptor 2 Gene

Evidence for the role of FGFR2 signaling in the pathogenesis of acne has
been provided by confirming FGFR2 gain-of-function mutations in unilateral
acneiform nevus49 and nodulocystic acne seen in Apert’s syndrome, a dominantly
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inherited condition with craniosynostosis and syndactyly.127 FGFR2 Ser252Trp or

Pro253Arg mutations cause epidermal thickening seen in epidermal nevi,128 and
androgen-dependent dermal-epithelial FGFR2 signaling seems to be important
in acne development; fibroblasts, in response to DHT, synthesize FGF7 and
FGF10, which are ligands for FGFR2b found on suprabasal keratinocytes and
sebocytes.129 FGFR2b binding causes transcription of IL-1a, which stimulates
follicular hyperkeratinization and in sebocytes, proliferation and fatty acid
synthesis. Importantly, FGFR2b shares with IGF1R common downstream
signaling cascades,130 which are MAPK and PI3K/Akt, sonic hedgehog (Shh)
and MC-5R pathways.131
Genes Involved in Autoinflammatory Syndromes

Acne may also be a manifestation of autoinflammatory syndromes such as
PAPA (pyogenic sterile arthritis, pyoderma gangrenosum and acne) and
SAPHO (synovitis, acne, pustulosis, hyperostosis and osteitis) syndromes. In
PAPA syndrome a heterozygous point mutation in proline-serine-threonine-
phosphatase-interactive protein 1 (PSTPIP1) gene on chromosome 15q encoding
CD2-binding protein 1 (CD2BP1) has been verified.132 PSTPIP1 and pyrin
are coexpressed as part of nucleotide-binding domain and leucine-rich repeat
containing protein 3 (NLRP3) inflammasome in granulocytes and monocytes,
and the mutation leads to increased binding of PSTPIP1 to pyrin and resulting in
reduced free pyrin. Pyrin is an inhibitor of the inflammatory process that recruits
caspase-1. Consequent increased recruitment of caspase-1 leads to increased IL-1
production,133,134 leading to inflammation in the joint and skin. In conclusion,
multiple genes are involved in the development of acne.
Environmental Factors
In addition to genetic propensity, varying prevalence of acne in different countries
and cultures may reflect different lifestyles including dietary factors, smoking, face
washing and sunlight exposure.
Diet
For several decades, there has been a general consensus in the dermatology
community that diet plays no role in the pathogenesis of acne. Earlier small,
uncontrolled studies looking into the effects of chocolate, milk or peanuts found no
effect of these foods on acne.28,135,136 These few, old, poorly designed studies have
been referenced time and again to support the non-association of diet and acne in
the literature. In the last decade, however, the general thinking regarding diet and
14
acne has been revisited following a large cross-sectional study of acne in native,
non-Westernized New Guinean and Paraguayan populations3 in whom acne is
nonexistent, in contrast to the prevalence of acne in Western populations. The diet
of these indigenous people has low glycemic index (GI), consisting of fresh fruits
and vegetables, lean protein and healthy fats. The GI is the potential of various
foods to increase blood glucose, and glycemic load is calculated by multiplying
the GI by the carbohydrate content/serving size.137 Western diet characterized
by high GI, i.e. high carbohydrate diet (> 55% of energy from carbohydrates),
leads to reactive hyperinsulinemia and results in increased androgens and IGF‑1,
which are involved in acne pathogenesis.138 Since then, several studies have been
conducted that directly implicate diet as the most likely environmental factor
underlying pathogenesis of acne.
In the last two decades, a growing body of evidence has shown that the course
of acne corresponds more closely to plasma growth hormone (GH) and IGF-1
levels than the traditionally associated androgen levels.139 GH, secreted by the
anterior pituitary, binds to GH receptor expressed on most peripheral cells of the
body140 and induces hepatic synthesis and secretion of IGF-1, the key regulator
of growth. During puberty, GH-driven rise in IGF-1 stimulates 5a-reductase,141
adrenal and gonadal androgen synthesis, AR signal transduction,142 and sebocyte
proliferation and lipogenesis,42 thereby potentiating peripheral androgen
signaling. In human sebocytes, IGF-1 is most strongly expressed in maturing
sebocytes and suprabasal cells of sebaceous ducts,143 suggesting its role as a
sebaceous mitogen and morphogen. More than 90% of circulating IGFs are
bound to IGF-binding protein 3 (IGFBP-3), the rest to IGFBP-1, 2, 4, 5 and
6, and less than 1% of IGFs circulate as free IGFs. IGF signal transduction is
mediated by IGF1R and IGF2R. IGF1R is a tyrosine kinase receptor which
can form heterodimers with insulin receptor (IR). Insulin and IGFs overlap
substantially in signal transduction due to their receptor cross-reactivity.140,144
Insulin and IGF-1 increase SREBP-1 expression, and this transcription factor
in turn stimulates lipogenesis.145 Endocrine or nutritional conditions including
puberty, precocious pubarche, polycystic ovary syndrome, acromegaly, insulin
resistance, high glycemic food and skim milk consumption which cause increased
insulin and IGF-1 serum levels are frequently associated with acne.42 Furthermore,
individuals with congenital deficiency of IGF-1 (Laron syndrome) were found
to be almost free of acne,146 and in male acne patients receiving a low-glycemic-
load diet, IGFBP-1 and IGFBP-3 increased significantly, reflecting reduced free
IGF-1 activity and bioavailability.147 Increased insulin/IGF-1 signaling activates
PI3K/Akt pathway, reducing the nuclear content of the transcription factor
FoxO1, the key nutrigenomic regulator of acne target genes. In the absence of
GH, nuclear FoxO1 suppresses nuclear receptors (AR, PPARg), key genes and
transcription factors of cell proliferation (cyclin D2), matrix breakdown (MMPs),
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lipid biosynthesis (SREBP-1) and inflammatory signaling (NF-kB). Nuclear

FoxO1 deficiency results in AR transactivation, increased follicular proliferation,
increased sebaceous lipogenesis and follicular inflammation, all of which occur in
acne development.41
The first randomized controlled trial (RCT) to demonstrate a therapeutic
effect of dietary intervention on acne came from Australia in 2007 and reported
that a 12-week low-glycemic-load diet in male patients aged 15–25 years led to
a decrease in total acne lesion counts, body weight and free androgen index with
an increase in IGFBP-1 compared to control group.148 This dietary intervention
was also high in protein and fiber, and test diet group lost more body weight
and body mass index (BMI) at the end of the 12 weeks. As part of this dietary
intervention trial, skin surface lipids were collected from 31 subjects; at 12 weeks
the experimental diet group showed increased ratio of SFAs to MUFAs of skin
surface TGs compared to controls, and this increase correlated with decreased
acne lesion counts.20 As MUFAs, but not SFAs and TGs, have been shown to
induce abnormal keratinization and epidermal hyperplasia seen in comedo
formation,18 improvement of acne following this dietary intervention seems
relevant. MUFAs presumably led to an influx of calcium through N-methyl-D-
aspartate glutamate ionic channels on the cellular membrane of keratinocytes and
cause hypercornification.149 Although the precise mechanism by which dietary
glycemic load influences the sebum composition is unknown, it is possible that
low-glycemic-load diet may both decrease the glycogen stores in sebaceous glands,
which may be a limiting factor in sebaceous lipogenesis, and lower insulin levels,3
thereby reducing testosterone bioavailability and DHEA-S concentrations.148
A recent study from Korea showed beneficial effects of a low-glycemic-load
diet of 10 week duration in both noninflammatory and inflammatory acne
lesions assessed clinically and histopathologically.150 Clinical improvement was
accompanied by histologic reduction in sebaceous gland size, less inflammation
and lowered expression of SREBP-1 and IL-8, demonstrating for the first time
objective evidence for decreased lipogenesis and inflammation following a low-
glycemic-load diet. In another Australian study of low GI and high GI parallel
design for 8 weeks, there was no significant difference between the two groups
in the improvement of acne, and the authors suspected that probably 8 weeks is
too short a time to see any difference.151 The results of these studies indicate that
future trials would need to be designed with at least a 10 week duration.
Milk is an exception to the seemingly beneficial effects of food with low GI.
Milk has low GI of 15–30 and yet produces high insulinemic index of 90–98.152
This disproportionately high insulinotropic effect of milk was attributable to the
whey fraction which comprises 20% of milk protein; casein which accounts for
80% of protein fraction of cow’s milk had a stronger IGF-1 stimulating effect
than whey.153 Two cohort studies from the US demonstrated association of milk
16
consumption, especially skim milk, with acne in teenage girls and boys,154,155 and
a recent Italian case-control study reached the same conclusion, with the risk
increasing with more than three portions per week milk consumption and the
association more marked for skim than for whole milk.155 The higher association
of skim milk with acne indicates that the hydrophilic protein fraction, not the
lipophilic androgenic steroids in milk fat, might have a stronger influence on
aggravation of acne.143 A recent Malaysian case-control study also confirmed a
higher dietary glycemic load and frequency of milk and ice-cream consumption
in cases compared to controls.156 Cow’s milk contains active IGF-1 and IGF-2.157
High levels of IGF-1 are detected after homogenization and pasteurization of
milk, and there is evidence that IGFs in milk may survive digestion and remain
bioactive in the plasma after intake.143 Since bovine and human IGF-1 shares the
same amino acid sequence, bovine IGF-1 binds to the human IGF1R.143 Milk
consumption has been shown to increase serum IGF-1 levels,158-161 with increased
ratio of IGF-1/IGFBP-3,159 leading to increased bioavailability of IGF-1. In
addition, milk contains androgens, 5-alpha reduced steroids and other growth
factors that may affect the pilosebaceous unit. The results of these studies may
justify recommending restriction of milk to acne patients.
In the above mentioned Italian study, the risk was reduced in people with
lower BMI and people who consumed fish.162 As high BMI has been identified
as a risk factor for acne development,163,164 the beneficial effects of lowered BMI
can be expected. Since fish oil, high in omega-3 fatty acids, is known to inhibit
LTB4, this inhibition may lead to reduced sebum production and improved
inflammatory acne.165 Polyunsaturated fats, and omega-3 from fish oil in
particular, are inversely correlated with androgen levels.166 A Korean case-control
study showed protective effects of vegetable and fish intake and exacerbating
effects of a high-glycemic-load diet, dairy food, high fat and iodine consumption
and irregular intermeal intervals in acne patients.167 Notably Korean diet has
traditionally included seaweed consumption, which is high in iodine, and iodine
intake is well known to aggravate acne.168 Another community-based case-control
study from Italy demonstrated a protective effect of Mediterranean diet toward
acne.169 In contrast, familial hypercholesterolemia, diabetes and hypertension
were strong risk factors for acne.169 Nonetheless, further elucidation on the roles
of omega-3 fatty acids, antioxidants, zinc, vitamin A and dietary fiber in acne
vulgaris remains.170
Based on the existing body of data, convincing evidence exists that high GI
foods and dairy products play an important role in the exacerbation of acne.
Considering the simultaneous protective effects of low-glycemic-load diet against
cardiovascular diseases, type II diabetes and even obesity, there is no reason not to
recommend it to acne patients.
17
Cho and Kang
Cigarette Smoking
Regarding smoking and acne, conflicting results have been reported101,171-179 with
six studies demonstrating a negative171-173 or no association101,175,176 and four studies
observing a positive association.174,177-179 In the largest cohort study conducted to
date in which 27,083 young Israeli men were interviewed and acne diagnosed
by dermatologists, an inverse dose-dependent relationship between severe acne
prevalence and daily cigarette consumption (21 or more cigarettes a day) was
found.171 The negative association or protective effect of smoking against acne may
possibly be due to the anti-inflammatory180 and immunosuppressive181 action of
nicotine. Therefore, smoking is more likely to inhibit the inflammatory acne than
the comedonal acne. This may be an explanation for the so called “smoker’s acne”
which is characterized by predominantly noninflammatory microcomedones and
macrocomedones in mostly adult female smokers.182 Keratinocytes have nicotine
AchR, and they induce cutaneous hyperkeratinization at high concentration.183 In
addition, through production of ROS, smoking was shown to increase the grade
of sebum peroxidation with an associated reduction in vitamin E.182 Squalene
peroxides are comedogenic and can cause hyperproliferation of keratinocytes.184 In
a German study of smoking and acne, positive correlation was seen only when the
entire age range was considered (up to 87 years).175 When analysis was restricted
to patients between 15 years and 40 years of age no association was found. In a
retrospective case-control study of Hong Kong and Indian subjects, smoking was
correlated with acne only in men.178 In a cross-sectional study of 17,345 Chinese
subjects acne was correlated with smoking in adolescents (< 25 years of age) but
not in adults.174 Recently benzo(a)pyrene, a major environmental contaminant in
cigarette smoke, was found to induce oxidative stress-mediated IL-8 production
in human keratinocytes via the aryl hydrocarbon receptor signaling pathway,
providing a plausible partial explanation for correlation of smoking and acne
severity.185 The conflicting results of the previous studies may be due to the
different ways of recruiting study subjects, subject gender/age, sample size and
ascertainment of smoking and/or acne.
Sunlight (Seasonal Influence)

There is no consensus regarding the influence of sunlight on acne. In a survey
of 139 acne patients, one-third of patients reported aggravation in winter, one-
third in summer, and the remaining one-third saw no seasonality,186 but this
retrospective study is subject to recall bias. Potential beneficial effects of sunlight
may be inferred from encouraging results of clinical trials performed using
artificial light sources such as ultraviolet B (UVB), UVA, blue, red, green, violet
and full-spectrum light;187-190 however, lack of blinding or control in these studies
limits the credibility of their acne-ameliorating effects. In view of the sun’s well-
18
established harmful effects on the skin and the lack of convincing evidence of its
beneficial effects on acne, advocating light therapy as treatment for acne cannot
be justified.
Stress
There is a dearth of research on the effects of stress on acne. In the only cohort
study that investigated the relationship between stress and acne exacerbation,
increased acne severity was significantly correlated with increased stress levels
during examinations in 22 university students,191 and this association remained
significant even after controlling for changes in diet and sleep habits during
the test period. Increased levels of glucocorticoids and adrenal androgens that
are released during periods of emotional stress,192 and secretion of neuroactive
substances within the epidermis activating cutaneous inflammatory processes193
have been proposed as mechanisms of stress-induced aggravation of acne.
Skin Hygiene
Personal hygienic factors may also affect the progression of inflammatory acne.
However, existing studies are scarce in this area. In an RCT, the effects of
chlorhexidine gluconate skin cleanser and 5% benzoyl peroxide in acne were
similar at 8 weeks and 12 weeks, whereas chlorhexidine cleanser led to significantly
less acne lesions compared to vehicle placebo.194 In contrast to chlorhexidine,
povidone-iodine cleanser showed no significant superiority to control.195 In
another study of mild-to-moderate acne in men, the effect of face washing
frequency of 1, 2 or 4 times a day with a mild cleanser was evaluated over a 6 week
period. Significant improvements in total noninflammatory lesions was observed
in the group washing twice a day, whereas worsening of acne with increases in
erythema and total inflammatory lesions was observed in the group washing once
a day; excessive face washing 4 times daily did not improve or worsen acne.196
This study was limited by the fact that clinical assessment was performed without
blinding of the treatment groups and that non-wash control arm was lacking. In
a cross-sectional study of 2,300 Turkish subjects, daily facial washing of 3 times
or more significantly lowered risk for acne.197 Despite their limitations, the results
of these studies offer some evidence to recommend face washing at least twice
daily for acne patients. In a different study, when two groups of patients with a
similar degree of mild inflammatory acne were compared after 4 weeks of twice
daily use of an acidic syndet bar or a conventional alkaline soap bar, the number
of inflammatory lesions decreased in the former group, whereas it increased in
the latter group. Symptoms of irritation were seen in 2% of syndet group and
40% of soap group,198 suggesting associated irritation caused by alkaline soap may
aggravate inflammatory acne.
19
Cho and Kang
ACNE SCAR FORMATION

Although our understanding of acne pathogenesis has increased substantially in
recent years, it is in the area of its scar formation that significant advances have been
made. Classic teachings had included, based on strong clinical impression, that the
more inflamed acne lesions are, the more likely acne scars will result. However,
how inflammation may lead to scar formation was considered “unknown”.
The first report of dermal matrix degradation in inflamed acne lesion was
published in 2005.199 Compared to uninvolved facial skin from acne patients,
involved lesions were found to contain markedly elevated levels of matrix
degrading MMPs of several types—1, 3, 8 and 9. MMP8, also known as neutrophil
collagenase, was due to significant number of neutrophils that had infiltrated acne
lesions. Three other MMPs (1, 3 and 9) are known to be activator protein-1 (AP‑1)
transcription factor-regulated genes. Coincident increase in c-Jun protein (a key
element of AP-1) in cells lining the sebaceous follicles and in some dermal cells
implicated the participation of MAPK. In the same report, in vivo demonstration
of NF-kB activation (nuclear translocation of p50/p65), and consistent elevation
of primary proinflammatory cytokines (IL-1B, TNF-a, etc.) suggested the likely
involvement of TLRs in initiating the signaling cascade.
Applying computer software program to accurately superimpose high quality
clinical photographs over time has allowed investigators to follow the natural
history of acne lesions.200 In one study, development of atrophic scars was carefully
documented every 2 weeks, in over a 12 week observation period. About 20%
of atrophic scars arose from acne lesions, mostly from inflammatory lesions, but
also from large comedones. Remarkably, about half of the atrophic scars arose in
previously normal appearing skin. These findings suggest that aggressive and rapid
treatment plans should be implemented to reduce scar formation.
CONCLUSION
The classic pathogenic factors of acne, i.e. androgenic control of sebaceous
gland, infundibular retention hyperkeratosis, P. acnes and inflammatory events,
undoubtedly play a major role in the breakout of this common cutaneous disorder.
They withstood the test of time and still provide a foundational framework in
thinking about acne pathogenesis. In the last few years however, we have gained
refined insight into the role of these classic factors, as well as additional potential
triggers (such as genetic and dietary) through molecular studies and well-designed
prospective RCTs.
Sebaceous gland is crucial in the initiation of acne since it possesses all the
enzymatic machinery for the production of hormones and cytokines.201 We now
appreciate that more than seborrhea, it is the altered lipid composition and the
oxidant/antioxidant ratio that are important in acne pathogenesis.
20
Colonization of the pilosebaceous unit by P. acnes is the primary event that

elicits both innate and adaptive immune responses in the host. Interaction of
P. acnes in the skin’s microflora with keratinocytes, sebocytes and other cells that
comprise of the cutaneous immune system must be important in acne. Recent
research that suggests a link between the clinical severities of acne, the host’s ability
to neutralize ROS generated by P. acnes is consistent with this view.93 Therefore,
the use of antioxidants to mitigate this process may be a novel treatment option
in the future.
Complementing molecular studies that looked at genetic risk factors
(investigating polymorphisms of genes that function in the steroid hormone
metabolism, innate immunity-related genes and FGFR2), epidemiologic inquiry
revealed important lifestyle factors (such as diet and smoking) that impact the
development of acne. Compelling evidence that high-glycemic-load diet and
milk consumption contribute to aggravation of acne vulgaris by raising insulin
and IGF-1 levels allow us to recommend behavior modifications to improve the
outcome of acne. The influence of dietary fatty acids, vitamin A, antioxidants,
iodine and dietary fiber on acne is less clear and warrant further investigation.
Since diet is an important factor which influences one’s hormonal, inflammatory
and oxidation status, assessing diet history should be included in the evaluation
of acne patients.17 The existing literature on the effects of smoking and sunlight is
controversial and no conclusions can be drawn at this time.
In the classic theory on acne development, inflammation is considered a
late stage event. Emerging body of evidence however, points to inflammation
(subclinical) as an early, almost necessary step in driving follicular hyper
keratinization and hyperproliferation, supporting the notion that even comedonal
acne is an inflammatory skin disease. Such evidence-based assessment of acne
has implications on treatment strategy. Treating uninvolved skin in acne patients
becomes important, as well as the choice of pharmacologic agents. Inclusion of
medications that possess antiinflammatory properties may reduce or even prevent
the appearance of visible acne lesions. Improved clinical outcome of our acne
patients can be realized through continued research into its pathogenesis.
Editor’s Comment
Knowing acne pathogenesis is an essential prerequisite to understanding acne and
managing it well in the clinical setting. Dr Soyun Cho and Dr Sewon Kang have
succeeded admirably, in my opinion, in providing an account that is not only current
but also lucid, well articulated, and with unambiguous interpretations of complex
scientific data.
21
Cho and Kang
This is an information-dense article. I had to read it three times to cull facts

and information that I hope to apply to my acne practice forthwith. There are
precious statements throughout. The authors quote a study which proposes that 81%
of the variance in acne liability is attributable to genetic factors and only 19% to
environmental factors. Serum androgen levels do not correlate with acne severity
but androgens are necessary for acne development. P. acnes is important in the
induction and maintenance of the inflammatory phase of acne thereby contributing
to its chronicity. Increased insulin/IGF-1 signaling activates PI3K/Akt pathway,
reducing the nuclear content of Fox01, the key nutrigenomic regulator of acne target
genes. Milk has low GI of 15-30 and yet produces high insulinemic index of 90-98.
About half of the atrophic acne scars arise in previously normal appearing skin.
These are but a few of the words of knowledge that await the reader of this
article.
Raj Kubba
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30
The Role of Microbiology and

Biofilms in Acne
1
Melissa S Crites MD, *,2Craig G Burkhart MD MPH
3
Craig N Burkhart MD MSBS
1
Mercy St. Vincent Medical Center, Toledo, Ohio, USA
2
Department of Medicine, The University of Toledo-College of Medicine and Life Sciences,
Toledo, Ohio, USA
3
Department of Dermatology, University of North Carolina at Chapel Hill,
Chapel Hill, North Carolina, USA
ABSTRACT
Propionibacterium acnes has been shown to form biofilms both in vitro and
within the pilosebaceous unit in vivo. Biofilms are complex communities
of bacteria encased in a protective polysaccharide matrix and are capable of
altering their growth, metabolism, and phenotypes based on environmental
cues and stressors. These complex interactions lead to increased antibiotic
resistance and thus, persistence of the immunologically active P. acnes. The
biofilm model helps to explain the pathogenesis of acne and current aspects
of acne therapy to elaborate why prolonged antibiotic therapy is needed.
Further studies on the microbiologic principle of the acne biofilm could
lead to future changes in the assessment and treatment of acne.
INTRODUCTION
Acne vulgaris is one of the most common skin disorders, affecting nearly 80% of
teenagers. The etiology of acne is multifactorial and includes hypercornification
of the pilosebaceous duct, increased sebum production, and colonization of
the pilosebaceous unit with Propionibacterium acnes. Many models have been
generated about the correct sequence of events in the pathogenesis of acne, with no
consensus among experts. Still, P. acnes has been implicated in acne since as early
as 18961 and the microbiology of the pilosebaceous unit with its immunologic
consequences is a key factor in the production of inflammation in acne.2
Email: cgbakb@aol.com
World Clinic Dermatology (Acne).indd 31 30-11-2013 17:04:47

Crites et al
P. acnes is the predominant organism in the pilosebaceous unit, residing in the

anaerobic infundibulum, where the inflammatory reaction in acne occurs. As many
as 107 viable organisms have been isolated from a single pilosebaceous unit.3‑5
P. acnes is serologically and biochemically identical to Corynebacterium parvum, a
potent stimulator of the humoral and cell-mediated reticuloendothelial system,
complement, and cytotoxins.2,6-8 Indeed, P. acnes displays inflammatory effects via
complement, chemotactic properties, cell-mediated immunity, and its interaction
with humoral factors.2 Interestingly, these inflammatory effects occur regardless of
whether the organism is alive or dead.7
Still, P. acnes is not infectious by normal standards, as there is no correlation
between the number of bacteria and severity or type of acne. P. acnes is present
in both healthy and diseased skin, as well as in the mouth, conjunctiva, and
gastrointestinal tract. Conceivably, P. acnes may be a symbiote to humans, with
the human host providing food and lodging in the pilosebaceous unit, while the
bacteria provides immunomodulatory benefits, such as protection against rabies
and other infections.9,10 This relationship is similar to other human symbiotic
relationships, including those of the human papillomavirus (HPV) and herpes
virus.11,12
THE PROPIONIBACTERIUM BIOFILM

In the past, the microcomedone theory was the cornerstone for the pathogenesis
of acne, stating that a keratinaceous plug forms in the upper infundibulum of
the follicle by the retention and accumulation of corneocytes in the lumen. The
accumulation of shed keratinocytes and sebum then leads to the expansion of
the follicle and eventual rupture of the wall, causing immunogenic keratin and
sebum to extrude into dermal tissues. This theory is devoid of any explanation
for the increased cohesiveness of keratinocytes. Exploring the concept of biofilms
and specifically, the P. acnes biofilm, helps explain the increased cohesiveness, thus
leading to a better understanding of the pathogenesis and treatment of acne.
Firstly, biofilms are very common in nature, with most bacteria existing as
biofilms and not as free-floating plankton.13-15 These 2 bacterial states differ in
their physiology, gene expression, and morphology, which is of significance since
clinical microbiology characterizes bacteria in the planktonic state and not the
natural biofilm state.16 Biofilms have been shown to form on a variety of natural
and biological surfaces, as well as non-biological surfaces. Classic examples include
dental plaques, prosthetic device infections, and urinary catheter infections, though
biofilms are also present in a number of dermatologic conditions, including acne.17
Biofilm formation is a dynamic process determined by the intrinsic genetic
profile of the microbial cells and extrinsic environmental factors. First, bacteria
attach to the environmental surfaces or host tissues, such as the lining of a
32

The Role of Microbiology and Biofilms in Acne
pilosebaceous unit. Tighter binding of the bacteria to host tissues is achieved by

proteins called adhesins. As the bacteria multiply, they encase themselves in a
polysaccharide matrix. This extracellular matrix comprises 66% of the biofilm and
acts as a protective exoskeleton and physical barrier. The community of bacteria
continues to increase in complexity, forming multiple microenvironments and
communicating via a form of cell-to-cell communication, known as quorum
sensing.18,19 The same species of bacteria live in diverse niches within the biofilm
with varying rates of metabolism, replication, and responsiveness to antibiotics.
By expanding the microcomedone theory to include the P. acnes biofilm,
the increased cohesiveness of keratinocytes can be explained by the attachment
of the P. acnes biofilm to the pilosebaceous unit and secretion of the glue-like
polysaccharide matrix.20 The P. acnes biofilm has been visualized both in vitro21,22
and in vivo in connection with the pilosebaceous unit.23 The complete genome of
P. acnes also supports the existence of the biofilm, as clusters of genes involved in
the biosynthesis of the polysaccharide capsule were identified.24,25
THE BIOFILM MODEL AND ASPECTS OF

ACNE THERAPY
One reason that biofilms are so prevalent in the world is that they convey a
survival benefit to the bacteria. In fact, in vitro studies have shown that bacteria in
biofilms are 50–500 times more resistant to antibiotics than planktonic bacteria.26
The first defense is the polysaccharide matrix encasing the biofilm, which creates
a physical barrier against diffusion of antibiotics. Within the biofilm, many
microenvironments exist, each with different rates of growth and metabolism. The
center of the biofilm is less metabolically active due to decreased nutrients and
oxygen; therefore, most antibiotics, which work on actively dividing cells, have a
minimal effect on the center of the biofilm.27,28 Also, bacteria within the biofilm
are capable of phenotypic changes to more tolerant phenotypes in response to
environmental stressors, such as a lack of nutrients, change in pH, or increased
population density.29 Increased mutation frequency and gene transfer in biofilm
bacteria may explain the quick development of multidrug resistance. Finally,
biofilms often contain spore-like cells, known as ‘persistor cells’, that produce
proteins capable of shutting down antibiotic targets; thus, making it extremely
difficult to eradicate the bacteria.30-32 All of these mechanisms lead to increased
antibacterial resistance and could explain why prolonged antibiotic treatment is
required in acne and why P. acnes is never eliminated from the pilosebaceous unit.
Current acne therapies include medications that alter the physical,
biological, and chemical microenvironment of the pilosebaceous unit. With the
adaptability of the biofilm bacteria to its environment, this multiphasic approach
is, conceivably, the best option. Both topical and oral antibiotics are commonly
33

Crites et al
used in the treatment of acne. A study tested 4 oral antibiotics (erythromycin,

minocycline, oxytetracycline, and doxycycline) in the acne biofilm and found
that the tetracycline derivatives, specifically minocycline, were most successful in
reducing the biofilm mass and cell viability.33 Minocycline is more fat-soluble
than other antimicrobials, perhaps leading to an increased penetration into the
biofilm and thus, better efficacy.
Interestingly, antimicrobials can display paradoxical effects in biofilms.
Some antibiotics in subminimum inhibitory concentrations have been shown
to enhance biofilm formation.34 Also, antibiotics may work in normal bacterial
culture of planktonic organisms, but not when tested in the biofilm setting. These
nuances in biofilm microbiology make choosing the correct antibiotic and dose
very important factor in the treatment. Additionally, accutane therapy that greatly
diminishes sebaceous gland size, should dramatically affect the P. acnes biofilm by
decreasing its nutrient base.
Common topical therapies in acne were also studied in the acne biofilm.
Azaleic acid, triclosan, and benzoyl peroxide when combined with erythromycin
or clindamycin were found to be the most successful at reducing the biofilm.
Salicylic acid and benzoyl peroxide alone were not as successful.33 With the
increased survivability of bacteria in the biofilm community, maximizing the
efficacy of all available medications is the key. Benzoyl peroxide is universally
applied in a crystalline state, but solubilizing it with an organic base or by adding
side chains increases its antibacterial properties by approximately tenfold. Both
clindamycin and erythromycin contain tertiary amines, which act as solubilizing
agents, thus explaining the increased success in topical benzoyl peroxide or -mycin
combinations.35
CONCLUSION AND FUTURE APPROACHES

Currently, culture and sensitivity tests for bacteria are performed on planktonic
bacteria, which differ in their physiology, gene expression, and morphology from
biofilms. In order to accurately determine antibacterial resistance and extrapolate
this to clinical outcomes, testing needs to be performed on in vitro biofilms and
not planktonic bacteria. The crystal violet assay and fluorescence as measured with
resazurin have been used in the research lab to assess the biofilm mass and cell
viability, respectively.33
As more information becomes available about the structure and microbiology
of the biofilm, future therapies can be developed to target specific components
of the biofilm. Inhibiting the adherence of bacteria to the pilosebaceous unit
or using a mechanical or biochemical force, such as sonication or enzymes, to
dislodge bacteria from the pilosebaceous unit would stop biofilm formation at the
very first step. Additionally, treatment modalities must be able to penetrate the
34

The Role of Microbiology and Biofilms in Acne
polysaccharide matrix to reach the bacteria within the biofilm. Continued interest
and exploration into the biofilm model of acne can lead to a better understanding
of the pathogenesis of acne and lead to the development of future treatments.
Editor’s Comment
Propionobacteria spp is central to pathogenesis of acne and though P. acnes has been
the focus of most if not all attention, its lesser known siblings like P. granulosum
may be equally important. P. acnes is known to form biofilms which give the microbe
a survival advantage by virtue of the physical protection they offer as also due to
alteration of growth, metabolism and phenotypes of P. acnes based on environmental
pressures created by the biofilm. Biofilms have been used to explain the discordance
of in vitro antibiotic sensitivity and the clinical response to antibiotics. In this
article, Drs M S Crites, C G Burkhart and CN Burkhart have lucidly provided a
simple insight into the complicated yet fascinating world of biofilms. Efforts should
be now made to formulate products which can initially penetrate or dismantle the
biofilm in acne prone areas by altering its physical and biochemical properties and
subsequently prevent or substantially reduce its reformation.
Neena Khanna
REFERENCES
1. Unna PG. The histopathology of disease of the skin. New York, USA: Macmillan and Co; 1896.
2. Burkhart CG, Burkhart CN, Lehmann PF. Acne: a review of immunologic and microbiologic factors. Postgrad
Med J . 1999;75:328-31.
3. Marples RR. The microflora of the face and acne lesions. J Invest Dermatol. 1974;62:326-41.
4. Nishijima S, Kurokawa I, Katoh N, Watanabe K. The bacteriology of acne vulgaris and antimicrobial
susceptibility of Propionibacterium acnes and Staphylococcus epidermidis isolated from acne lesions.
J Dermatol. 2000;27:318-23.
5. Leyden JJ. Propionibacterium levels in patients with and without acne vulgaris. J Invest Dermatol.
1975;65:382-9.
6. Adlam C, Scott MT. Lymphoreticular stimulatory properties of Corynebacterium parvum and related bacteria.
J Med Microbiol. 1973;6:261-5.
7. Burkhart CG, Cantrill J, Lehmann P. P. acnes: Interaction with complement and development of an enzyme-
linked immunoassay for the detection of antibody. Int J Dermatol. 1999;38:200-3.
8. Senaldi G, Yin S, Shaklee CL, Piguet PF, Mak TW, Ulich TR. Corynebacterium parvum and Mycobacterium
bovis Bacillus Calmette-Guerin-induced granuloma formation is inhibited in TNF receptor I knockout mice
and by treatment with soluble TNF-RI. J Immunol. 1996;157:5022-6.
9. Megid J, Kaneno R. Natural killer activity in mice infected with rabies virus and submitted to Propionibacterium
acnes as immunomodulator. Comp Immunol Microbiol Infect Dis. 2000;23:91-7.
10. Megid J, Peraçolli MT, Curi PR, Zanetti CR, Cabrera WH, Vassao R, et al. Effect of vaccination and immuno
modulators bacillus of Calmette-Guerin, avridine and Propionibaterium acnes on rabies in mice. Comp
Immunol Mivrobiol Infect Dis. 1998;4:305-18.
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11. Burkhart CG. The endogenous, exogenous, and latent infections with human papillomavirus. Int J Dermatol.
2004;43:548-9.
12. Burkhart CG. Herpes acquisition and transmission. J Drugs Dermatol. 2005;4:378-82.
13. Donlan RM, Costerton JW. Biofilms: survival mechanisms of clinically relevant microorganisms. Clin
Microbiol Rev. 2002;15:167-93.
14. Sutherland IW. The biofilm matrix – an immobilized but dynamic microbial environment. Trends Microbiol.
2001;9:222-7.
15. Wolcott RD, Ehrlich GD. Biofilms and chronic infections. JAMA. 2008;299:2682-4.
16. Burkhart CN, Burkhart CG, Gupta AK. Dermatophytoma: recalcitranceto treatment due to existence of fungal
biofilm. J Am Acad Dermatol. 2002;47:629-31.
17. Landini P, Antoniani D, Burgess JG, Nijland R. Molecular mechanisms of compounds affecting bacterial
biofilm formation and dispersal. Appl Microbiol Biotechnol. 2010;86:813-23.
18. Sutherland IW. Biofilm exopolysaccharides: a strong and sticky framework. Microbiol. 2001;147:3-9.
19. Whitchurch CB, Tolker-Nielsen T, Ragas PC, Mattick JS. Extracellular DNA required for bacterial biofilm
formation. Science. 2002;295:1487.
20. Burkhart CG, Burkhart CN. Expanding the microcomedone theory and acne therapeutics: Propionibacterium
acnes biofilm produces biological glue that holds corneocytes together to form plug. J Am Acad Dermatol.
2007;57:722-4.
21. Bayston R, Ashraf W, Barker-Davies R, Tucker E, Clement R, Clayton J, et al. Biofilm formation by
Propionibacterium acnes on biomaterials in vitro and in vivo: impact on diagnosis and treatment. J Biomed
Mater Res. 2007;81:705-9.
22. Holmberg A, Lood R, Mörgelin M, Söderquist B, Holst E, Collin M, et al. Biofilm formation by Propionibacterium
acnes is a characteristic of invasive isolates. Clin Microbiol Infect. 2008;15:787-95.
23. Jahns AC, Lundskog B, Ganceviciene R, Palmer RH, Golovleva I, Zouboulis CC, et al. An increased incidence
of Propionibacterium acnes biofilms in acne vulgaris: a case-control study. Br J Dermatol. 2012;167:50-8.
24. Brüggemann H, Henne A, Hoster F, Liesegang H, Wiezer A, Strittmatter A, et al. The complete genome
sequence of Propionibacterium acnes, a commensal of human skin. Science. 2004;305:671-3.
25. Burkhart CN, Burkhart CG. Genome sequence of Propionibacterium acnes reveals immunogenic and
surface-associated genes confirming existence of the acne biofilm. Int J Dermatol. 2006;45:872.
26. Mah TF, O’Toole GA. Mechanisms of biofilm resistance to antimicrobial agents. Trends Microbiol. 2001;9:34‑9.
27. Werner E, Roe F, Bugnicourt A, Franklin MJ, Heydorn A, Molin S, et al. Stratified growth in Pseudomonas
aeroginosa biofilms. Appl Environ Microbiol. 2004;70: 6188-96.
28. Vlassova N, Han A, Zenilman JM, James G, Lazarus GS. New horizons for cutaneous microbiology: the role
of biofilms in dermatological disease. Br J Dermatol. 2011;165:751-9.
29. Novick RP. Autoinduction and signal transduction in the regulation of staphylococcal virulence. Mol Microbiol.
2003;48:1429-49.
30. Driffield K, Miller K, Bostock JM, O’Neill AJ, Chopra I. Increased mutability of Pseudomonas aeroginosa in
biofilms. J Antimicrob Chemother. 2008;61:1053-6.
31. Molin S, Tolker-Nielsen T. Gene transfer occurs with enhanced efficiency in biofilms and induces enhanced
stabilization of the biofilm structure. Curr Opin Biotechnol. 2003;14:255-61.
32. Lewis K. Persister cells and the riddle of biofilm survival. Biochemistry (Mosc). 2005;70:267-74.
33. Coenye T, Peeters E, Nelis HJ. Biofilm formation by Propionibacterium acnes is associated with increased
resistance to antimicrobial agents and increased production of putative virulence factors. Res Microbiol.
2007;158:386-92.
34. Dunne WM. Effects of subinhibitory concentrations of vancomycin or cefamandole on biofilm production boy
coagulase-negative staphylococci. Antimicrob Agents Chemother. 1990;34:390-3.
35. Burkhart CG, Burkhart CN. Antibacterial properties of soluble benzoyl peroxide. Int J Dermatol. 2008;47:301‑2.
36

The Sebaceous Gland and

Its Role as an Endocrine Organ
*,1
Christos C Zouboulis MD PhD, 2WenChieh Chen MD PhD
1
Departments of Dermatology, Venereology, Allergology and Immunology,
Dessau Medical Center, Dessau, Germany
2
Department of Dermatology and Allergy, Technische Universität München,
Munich, Germany
ABSTRACT
Hormones influence development and function of the sebaceous gland,
which on the other hand, produces and releases hormones. Recently,
attention has been drawn in identifying and understanding complex
endocrine properties of the sebaceous gland such as expression and
function of specific hormone receptors, synthesis of hormones from major
classes of compounds used by the body for general purposes, organized
metabolism, activation, inactivation, and elimination of the hormones in
sebaceous gland cells, exertion of biological activity, and release of tissue
hormones in the circulation. Indeed, hormones exert their biological effects
on the sebaceous gland through interaction with high-affinity receptors.
Steroid hormones, phospholipid hormones, retinoids and nuclear receptor
ligands as well as the so-called stress hormones play pivotal roles in
controlling the development of the pilosebaceous units and sebaceous
lipogenesis, whereas the sebaceous gland produces, activates or deactivates
metabolically numerous hormones, which are probably important not only
for skin functions, but also for functions of the entire human organism.
Among them, androgens and retinoids are most extensively studied and
of highest clinical significance. These steps are overtaken in a coordinated
way indicating the endocrine autonomy of the organ. The sebaceous gland
fulfills major requirements for being an important peripheral endocrine
organ.
Email: christos.zouboulis@klinikum-dessau.de

Zouboulis and Chen
INTRODUCTION
Sebaceous glands are found in the skin of all mammals except whales and
porpoises.1 They are holocrine glands composed of acini attached to a common
excretory duct.2 These glands are present throughout the skin except on the
palms and soles. Sebaceous gland cells or sebocytes are the cells of the sebaceous
gland, which synthesize and accumulate lipid droplets. The amount and quality of
sebaceous gland research has significantly increased in the last years by using newly
emerged cell culture models and molecular techniques, and the results obtained
have improved our understanding of the pathogenesis of sebaceous gland diseases
and the determination of targets for future drug development,3 meanwhile leading
to a rapid reduction of the use of animals in acne and sebaceous gland research.
Maintenance of human sebocytes in certain culture conditions has helped in
investigating the physiology and in understanding the endocrinological role of
sebaceous gland (Table 1).
Nowadays, the human sebaceous gland is regarded as the target for several
hormones, whose effects have long been recognized and in some instances well
characterized.4 For example, sebaceous glands are the targets for androgen steroids
secreted by the gonads and the adrenal cortex.5 In the widest sense, the sebaceous
gland is the target as well as the producer of hormones. For example, the circulating
androgens dehydroepiandrosterone (DHEA) and androstenedione are converted
in the sebaceous gland to testosterone and further to the more potent androgen
5a-dihydrotestosterone (5a-DHT) in the periphery.6
THE SEBACEOUS GLAND AS HORMONE TARGET

Hormone Receptors and Their Biologic Activity
Hormones exert their biological effects on the sebocytes through binding and
interaction with high-affinity receptors (Table 2).7 Human sebocytes express
Table 1: Endocrine Functions of Sebaceous Glands

• Regulation of independent endocrine function of the skin
• Expression of all enzymes required for steroidogenesis from circulating lipids
• Regulation of local androgen synthesis
• Substantial involvement in the hormonally induced skin ageing process
• Modification of lipid synthesis by combined androgens and peroxisome proliferator-
activated receptor ligands, estrogens and the insulin-like growth factor-1 (IGF-1)/IGF-1
receptor complex
• Expression of vitamin D (Vit D) receptor (VDR) and Vit D-metabolizing enzymes
• Expression of retinoid-metabolizing enzymes
• Selective control of the action of hormones and xenobiotics on the skin
• Exhibition and influence by a regulatory neuropeptide program
38

The Sebaceous Gland and Its Role as an Endocrine Organ
Table 2: Hormone Receptors Expressed in Human Sebocytes

Receptors Natural ligands Effect on sebocytes
Peptide hormone and neurotransmitter receptors
Serpentine (seven transmembrane domain) receptors
Corticotropin-releasing CRH, urocortin • ↓ proliferation
hormone (CRH) receptors • ↑ ∆5-4 3β-hydroxysteroid
1 and 2 (CRH-R1 dehydrogenase (CRH)
> CRH-R2) • ↑ lipid synthesis (CRH)
• ↑ interleukin (IL)6 and IL8 release
(CRH)
Melanocortin-1 and α-melanocyte- • ↑ proliferation (MC-1R)
5 receptors (MC-1R and stimulating hormone • ↓ IL1-induced IL8 synthesis
MC-5R) (α-MSH) (MC-1R)
• ↑ lipid synthesis (MC-1R in the
presence of testosterone)
• Marker of differentiation (MC-5R)
• ↑ lipid synthesis (MC-5R)
µ-opiate receptors (OPR) β-endorphin • ↓ epidermal growth factor (EGF)-
induced proliferation
• ↑ lipid synthesis
VPAC receptors Vasoactive intestinal ↑ IL6 and IL8 release (NY)
polypeptide (VIP),
receptors for
neuropeptide Y (NY)
and calcitonin gene-
related peptide (CGRP)
Cannabinoid receptors Endogenous • Marker of differentiation (CBR1)
(CBR1 and CBR2) cannabinoids • Marker of undifferentiated
sebocytes (CBR2)
• ↑ differentiation, lipogenesis and
apoptosis (via CBR2)
Histamine receptor 1 Histamine • ↓ squalene synthesis
(H1 antihistamines)
Single-transmembrane domain receptors with intrinsic tyrosine kinase activity
Insulin-like growth factor-1 IGF-1, insulin ↑ lipogenesis
(IGF-1) receptor
EGF receptor EGF • ↓ sebaceous differentiation and
lipogenesis
• ↑ IL1 excretion
Single-transmembrane domain receptors without intrinsic tyrosine-kinase activity
Growth hormone (GH) GH • ↑ differentiation
receptor • ↑ 5α-DHT-induced lipogenesis
Continued
39

Zouboulis and Chen
Continued
Table 2: Hormone Receptors Expressed in Human Sebocytes
Receptors Natural ligands Effect on sebocytes
Nuclear receptors
Steroid receptors
Androgen receptor (AR) Testosterone • ↑ proliferation
5α-dihydrotestosterone • ↑ lipogenesis (with PPAR ligands)
(5α-DHT)
Estrogen receptors 17β-estradiol • ↑ polar lipid production
(ER-α and -β) • Marker of undifferentiated and
early differentiated sebocytes
(ER-α and -β)
Progesterone receptor (PR) Progesterone ?

Thyroid receptors
Retinoic acid receptors all-trans-retinoic acid ↓ proliferation
(RAR-α and -γ) (atRA)
Retinoid X receptors 9-cis-retinoic acid Regulate lipogenesis (?)
(RXR-α, > PXR-β, -γ) (9cRA)
Vitamin D (Vit D) receptor Vit D3 Regulates cell proliferation, cell
cycle, lipid content and IL6 and IL8
secretion
Peroxisome proliferator- Linoleic acid (PRARδ, γ) • ↑ lipogenesis (PPARγ)
activated receptors Leukotriene-B4 (LTB4) • ↓ lipogenesis (PPARα
(PPARα, PPARγ > PPARd) (PPARα) ligand/5‑lipoxygenase inhibitor)
• ↓ IL6 release (PPARα
ligand/5‑lipoxygenase inhibitor)
• ↑ prostaglandin E2 release
• ↑ IL6 release (PPARγ ligand)
• ↓ IL8 release (PPARγ ligand)
• ↑ cyclooxygenase 2 (COX2)
synthesis
• ↓ apoptosis (PPARγ)
Liver X receptors 22(R)-hydroxy • ↓ proliferation
(LXR‑α and -β) cholesterol • ↑ lipogenesis
• ↓ lipopolysaccharide-induced
COX2 and inducible nitric oxide
synthase
receptors for peptide hormones and neurotransmitters, which are mostly aligned
on the cell surface, and those for steroid hormones, which are found in the
cytoplasm or nuclear compartments.8,9
40

Peptide Hormone and Neurotransmitter Receptors

Three of four groups of peptide hormone and neurotransmitter receptors are
expressed in human sebocytes. To the first group, the so-called serpentine or
“seven-transmembrane domain receptors”, belong the:
• Corticotropin-releasing hormone (CRH) receptors (CRH-R) 1 and 2, whereas
CRH-R1 is more abundant and seems to regulate CRH activity in human
sebaceous glands in vivo and in vitro.10-12 Through binding to CRH-R1,
CRH and urocortin reduce sebocyte proliferation. CRH upregulates D5-4
3b-hydroxysteroid dehydrogenase expression and enhances synthesis of
neutral lipids and interleukin (IL)6 and IL8 release
• Melanocortin (a-melanocyte stimulating hormone)-1 and 5 receptors (MC-
1R and MC-5R), which bind a-melanocyte stimulating hormone and are
located at the cellular surface of sebocytes.13,14 MC-1R mediates the induction
of proliferation as well as regulation of inflammation in SZ95 sebocytes15
and exhibits a stronger expression in acne-involved sebaceous glands.13
Melanocortin was shown to increase MC-1R immunoreactivity and lipid
synthesis in SZ95 sebocytes in the presence of testosterone.16 The expression
of MC-5R is weaker than that of MC-1R but has been shown to be a marker
of human sebocyte differentiation, since it is only expressed in differentiated,
lipid-containing sebocytes and can induce lipogenesis in sebocytes in vitro14,17
• µ-opiate receptors (OPR), which bind b-endorphin. b-Endorphin inhibits
the proliferation of sebocytes induced by epidermal growth factor (EGF) and
stimulates lipogenesis, specifically increasing the amount of C16:0, C16:1,
C18:0, C18:1 and C18:2 fatty acids to an extent similar to linoleic acid in
sebocytes18
• VPAC receptors, which bind vasoactive intestinal polypeptide, receptors for
neuropeptide Y (NY) and calcitonin gene-related peptide (CGRP).19 NY
activates cytokine synthesis. CGRP is often co-localized with substance P
(SP).20 SP is released from cutaneous nerve fibers or mast cells, which are
located around the sebaceous gland in the extracellular space or at the cell
surface, and promotes both proliferation and differentiation of sebaceous
glands.21 Mast cell-derived IL6 and tumor necrosis factor-a, followed by SP-
stimulated degranulation, have the potential to induce nerve growth factor
expression in sebaceous cells which result in the promotion of innervation
and in the expression of E-selectin, respectively. Undifferentiated germinative
sebocytes were shown to produce high amounts of neutral endopeptidase
in order to inactivate SP in vitro and in acne-involved sebaceous glands in
vivo.22 Interestingly, SZ95 sebocytes express further neutral ectopeptidases
such as dipeptidyl peptidase IV and aminopeptidase N, and their inhibition
suppressed proliferation, enhanced terminal differentiation and slightly
41

Zouboulis and Chen
decreased total neutral lipid production in SZ95 sebocytes. Moreover,

the antiinflammatory and differentiation-restoring cytokine IL1 receptor
antagonist was significantly upregulated23
• Cannabinoid receptors (CBR) 1 and 2 are expressed in SZ95 sebocytes and
sebaceous glands.20,24 CBR1 was found in the differentiated sebocytes and
CBR2 in the undifferentiated cells, whereas endocannabinoids enhance
sebocyte differentiation, lipogenesis and apoptosis via CBR2
• Histamine 1 receptor binds histamine and is expressed in SZ95 sebocytes.25
Histamine 1 receptor inhibitors reduce squalene synthesis in SZ95 sebocytes.
The insulin-like growth factor (IGF)-1 receptor (IGF-1R) and the EGF
receptor (EGFR) belong to the second group, the single-transmembrane domain
receptors that harbor intrinsic tyrosine-kinase activity.
IGF-1R is expressed on SZ95 sebocyte cell surface and can be activated by
IGF-1 and high concentrations of insulin.26 The activation of IGF-1R by IGF-1
amplifies lipid accumulation in SZ95 and SEB-1 (immortalized human) sebocytes
in a dose-dependent manner by sterol response element-binding protein-
dependent and independent pathways.26,27 IGF-1 also stimulates proliferation
and differentiation of rat preputial gland cells, which resemble sebocytes, especially
under the combined treatment with growth hormone (GH).28 Interestingly,
epigallocatechin-3-gallate suppresses IGF-1-induced lipogenesis and cytokine
expression in SZ95 sebocytes.29
The EGFR contributes to the final cell number, size and lipid output
of mouse, and hamster sebaceous glands30,31 but does not regulate human
sebocyte proliferation in vitro.32 On the other hand, its ligand, EGF, inhibits
sebaceous differentiation and lipogenesis,33 and induces IL1 secretion in human
sebocytes,32,34 a finding being associated with initiation of comedogenesis and
follicular hyperkeratosis in vivo and ex vivo.
The third group, which is functionally similar to the second group, does not
possess intrinsic tyrosine-kinase activity but appear to function through interaction
with soluble transducer molecules which do possess such activity. In human
sebocytes, they are represented by the GH receptor,8,9 whose regulation by GH
upregulates sebocyte differentiation and augments the effect of 5a-DHT on sebum
synthesis.28 On the other hand, GH does not affect sebocyte proliferation in vitro.
The effects of the GH/IGF-1 axis are addressed toward a homeostatic
regulation of cell proliferation and differentiation. GH activity is mainly mediated
by the IGFs but GH has also direct effects on human skin cells.28 GH is likely
to be involved in sebaceous gland development. Moreover, GH is able to switch
the predominant CRH-R1 messenger ribonucleic acid (mRNA) expression to
a sole CRH-R2 mRNA expression in human sebocytes10 indicating a possible
interaction of the GH/IGF-1 axis with the hypothalamus-pituitary-adrenal-like
axis in human skin.
42

Nuclear Receptors
The nuclear receptors are soluble molecules, and employ transcriptional regulation
as a means of promoting their biological effects. Thus, though some receptors
are compartmentalized in the cytoplasm while others are defined to the nucleus;
they all operate within the nucleus chromatin where they bind a hormone-specific
“hormone response element”. These receptors are expressed in human sebocytes
and can be grouped into two major subtypes based on shared structural and
functional properties.
In the first group, the steroid receptor family, the androgen receptor (AR),
the estrogen receptors (ER), the glucocorticoid receptor and the progesterone
receptor (PR) are present in human sebocytes, in basal and early differentiated
ones.6,35
• Androgen receptor is stabilized und upregulated by ligand binding, while its
downregulation reduces sebocyte proliferation.36 The biological activity of
androgens in the skin is induced in large part by its conversion to 5a-DHT,
which is the most potent AR ligand. Five intracellular enzymes—all of
them expressed in sebocytes6—are involved in the activation (before binding
to AR) and inactivation of androgens. DHEA-sulfate is metabolized by
the stearoyl CoA desaturase (SCD) to DHEA. DHEA and androsterone
are converted to testosterone and later to 5a-DHT by 5a-reductase.6,37
Akamatsu et al. showed a dose dependent induction of sebocyte proliferation
by testosterone treatment.38 In addition, the effect of androgens on human
sebocyte proliferation depends on the area of skin from which the sebaceous
glands are obtained; facial sebocytes are mostly affected.39 However, no effect
of testosterone, as a single agent, on lipid synthesis in SZ95 sebocytes could
be detected40 but the combination with the peroxisome proliferator-activated
receptor (PPAR) ligand linoleic acid exhibited the expected lipogenic effect.41,42
Interestingly, c-myc, an inducer of sebaceous differentiation, triggers a p53-
dependent deoxyribonucleic acid damage response, leading to accumulation
of proliferative sebaceous gland progenitors and inhibition of AR signaling.
Conversely, testosterone treatment or p53 deletion activated AR signaling and
restored c-myc-induced differentiation43
• Estrogen receptors (ER; a- and b-isotypes):44-46 ER-b is expressed in basal
and partially differentiated sebocytes, whereas ER-a is expressed in basal and
early differentiated sebocytes. One of the natural estrogens, 17b-estradiol, as
in the testosterone metabolic pathway, is generated by oxidative reduction of
4-androsten-3, 17-dione. Treatment of sebocytes with 17b-estradiol showed
an effect on polar lipid production but did not affect neutral lipids.47 Current
evidence indicated that although sebocytes express ERs making them directly
susceptible to estrogens,48 a cross-talk between estrogen and IGF-1 signaling
43

Zouboulis and Chen
pathways obviously takes place.47 Moreover, like testosterone, estradiol is able

to regulate corticotropin-releasing hormone receptor (CRH-R) mRNA levels
in sebocytes, whereby in an opposite way.10 Phytoestrogens such as genistein,
probably regulate sebocyte differentiation through upregulation of PPARg
expression49
• Glucocorticoid receptors: The expression of glucocorticoid receptors in
sebaceous glands has barely been investigated, although glucocorticoids
stimulate sebocyte proliferation32 and lipogenesis50
• Progesterone receptor was found in the nuclei of basal sebocytes in sebaceous
glands.44,51
In the second group, the thyroid receptor family, the following receptors are
expressed in human sebocytes:
• Retinoic acid receptors (RAR; isotypes a and g) and retinoid X receptors (RXR;
isotypes a, b, g):52,53 RARa and g and RXRa are the predominant retinoid
receptors in human sebocytes, whereas RAR regulate cell proliferation.52 The
natural ligands for RAR and RXR are all-trans-retinoic acid (atRA) and
9-cis-retinoic acid (9cRA), respectively. 13-cis-retinoic acid (13cRA) inhibits
proliferation in SZ95 sebocytes, whereas 13cRA was found to be metabolized
intracellularly to the RAR ligand atRA. RXR agonists are stimulating
sebocyte differentiation and proliferation. The RXR agonists rexinoids in
combination with the specific PPAR agonists, WY 14643, troglitazone and
cabaprostacyclin, affected differentiation and growth of cultured primary
sebocyte-like rat preputial cells54
• Vitamin D (Vit D) receptor (VDR):55 SZ95 sebocytes express VDR
but also all major enzymes of vitamin D3 (calcitriol) metabolism, namely
vitamin D-25-hydroxylase, 25-hydroxyvitamin D-1a-hydroxylase and
1,25-dihydroxyvitamin D-24-hydroxylase (24OHase), the latter being an
established indicator for calcitriol presence.56 Calcitriol induces time- and
dose-dependent modulation of cell proliferation, cell cycle regulation and lipid
content in cultured sebocytes as well as IL6 and IL8 secretion. RNA expression
of VDR and 24OHase was upregulated along with calcitriol treatment
• PPAR are expressed in the human sebaceous gland,49,57,58 whereas PPARa
and g are the predominant subtypes. PPAR are present in mitochondria,
peroxisomes and microsomes of sebocytes and regulate multiple lipid
metabolic genes. PPARa seems to predominantly regulate inflammation,59
while PPARg is necessary for sebocyte differentiation and lipogenesis.42,60
Linoleic acid, a natural PPARg ligand, induces accumulation of neutral lipids
in undifferentiated human sebocytes and reduces spontaneous IL8 secretion.61
PPAR activation may protect human sebocytes from apoptosis.62
44

Eicosanoids such as prostaglandins, prostacyclines and leukotrienes are fatty

acid derivatives, whose synthesis can be induced in human sebocytes by several
proinflammatory signals.57 Leukotriene B4 (LTB4), a natural ligand for PPARa, is
synthetized in human sebaceous glands. The axis arachidonic acid/LTB4/PPARa/
lipid synthesis and inflammation in acne was confirmed by a clinical study; systemic
treatment of acne patients with zileuton, a selective 5-lipoxygenase inhibitor, led
to a 70% reduction in inflammatory acne lesions, an approximately 65% reduction
in total sebum lipids as well as a substantial decrease in proinflammatory lipids
at 3 months.57 In vitro, zileuton reduced lipogenesis and IL6 release.63 The
oxidative stress-mediated prostaglandin E2 production is mediated by PPARg.64
On the other hand, estradiol induces the metabolism of prostaglandin D2 to D12-
prostaglandin J2, a natural ligand for PPARg.65
• Liver X receptors (LXR, -a and -b isotypes) are expressed in SZ95 sebocytes
at the mRNA and protein levels.66,67 The application of natural 22(R)-
hydroxycholesterol or synthetic ligands significantly inhibited sebocyte
proliferation and increased lipogenesis. The expression of known LXR targets
such as fatty acid synthase and sterol regulatory element-binding protein 1,
was induced by the synthetic LXR ligand TO901317, which also decreased
the expression of cyclooxygenase 2 and inducible nitric oxide synthase that
was induced by lipopolysaccharide treatment.67
Other Receptors
Other receptors being identified in human sebocytes are:

• The vanilloid receptor (VR), which belongs to the transient ion channels, is
expressed in differentiating sebocytes.68 VR ligand capsaicin was shown to
reduce SZ95 sebocyte proliferation
• The fibroblast growth factor receptors (FGFR), which comprises a family
of related but individually distinct tyrosine-kinase receptors.69 Four FGFRs
designated as FGFR1 to FGFR4 have been identified, two splice variants of
FGFR2 are designated FGFR2b and FGFR2c. FGFR2b is localized mainly
in the suprabasal spinous layer of the epidermis and sebocytes and plays a
crucial role in controlling epithelial proliferation and differentiation. Increased
fibroblast growth factor receptor-2 (FGFR2) signaling has been proposed to
be involved in the pathogenesis of acne and explains acne in Apert syndrome
and unilateral acneiform nevus associated with gain-of-function point
mutations of FGFR269
• The proto-oncogene c-met product, which is a tyrosine-kinase receptor and
functions as a receptor for hepatocyte growth factor70
45

Zouboulis and Chen
• Cluster of differentiation (CD) 14, toll-like receptor (TLR) 2, TLR4

and TLR6 are expressed in human sebocytes,71,72 indicating that human
sebocytes are immunologically active cells capable of TLR- and CD14-
mediated bacterial recognition and play an important role in initiating and
perpetuating the activation of both innate and adaptive immune responses.72,73
Interestingly, SCD is regulated by TLR2 ligands in human sebocytes74
while 11b-hydroxysteroid dehydrogenase type 1, being expressed in human
sebaceous glands, can regulate glucocorticoid-induced lipid synthesis and
TLR2 expression in SZ95 sebocytes50
• Leptin is expressed in SZ95 sebocytes.75 It affects sebaceous lipid formation
and intracellular distribution and induces proinflammatory signaling.
Activation and Inactivation of

Hormones in the Sebaceous Glands
In addition to its capacity to respond to hormone signals the sebaceous gland is able
to metabolize hormones in order to activate and inactivate them. Characteristic
examples for this kind of cutaneous endocrine function are the metabolic pathways
of sexual steroids and retinoids.
Steroidogenesis
Human sebocytes express the steroidogenic acute regulatory protein which is
essential for cholesterol translocation from the outer to the inner mitochondrial
membrane and thus the initiation of steroidogenesis.76 They also express P450
side chain cleavage enzyme which catalyzes the conversion of cholesterol into
pregnenolone, cytochrome P450 17-hydroxylase that leads to precursors of cortisol
and DHEA, and steroidogenic factor-1 which maintains these reactions. DHEA
can be further converted into androstenedione. The most important metabolic
steps of DHEA are not only its conversion to testosterone, but also directly to
the tissue active 5a-DHT in human sebocytes77,78 through 3a-hydroxysteroid
dehydrogenase-D5-4 isomerase.10 Sebocytes are able to regulate the balance of
testosterone and androstenedione bidirectionally through the expression and
action of 17b-hydroxysteroid dehydrogenase isotypes 2 and 3.
The Retinoid Pathway

Human sebocytes in vitro regulate the levels of the intracellularly active atRA.
Isomerization of atRA prevents its intracellular accumulation. In contrast to atRA,
13cRA is not able to regulate its own metabolism.79 Human sebocytes in vitro
rapidly take up and convert atRA initially to 13cRA. Retinoid metabolism in
46

human skin is likely to be a cell-specific event, since sebocytes exhibit a distinct

metabolic pattern compared to epidermal keratinocytes.
Conclusion
The human sebaceous gland can respond to, synthesize, metabolize and activate
several hormones, which can function in a paracrine, autocrine and intracrine
pathway. There exist several diverse hormone receptors in the sebaceous gland
to take up and interact with the circulating hormonal messages released from
other endocrine organs. Therefore, the human sebaceous gland can work as an
ideal model for dermato-endocrinological studies. In correlation with clinical
observations, further molecular studies are needed to understand the function
and interaction of the various identified hormones/hormone receptors in the
pathogenesis of sebaceous gland-associated skin diseases.
Editor’s Comment
The sebaceous gland, which for decades had been portrayed as the target organ for
other hormones (read androgens), has itself emerged as an important peripheral
endocrine organ which itself synthesizes hormones like androgens which target
not only the skin but other organs as well. Hormones exert their biological effects
on the sebocytes through binding and interaction with high-affinity receptors. In
the present article, Dr CC Zouboulis and Dr WC Chen have succinctly discussed
the plethora of hormone receptors present on sebocytes including those for peptide
hormones and neurotransmitters on the cell surface, and for steroid hormones either
in the cytoplasm or nucleus. In addition to its capacity to respond to hormone signals,
the sebaceous gland is able to synthesize and metabolize hormones (like androgens
and retinoids) in a coordinated way. Though several molecular mysteries have been
unraveled in the sebaceous gland, in future there is immense scope for correlating
these with pathogenesis of sebaceous gland-associated skin diseases.
Neena Khanna
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lized sebocyte cell line (SEB-1). J Invest Dermatol. 2003;120:905-14.
77. Samson M, Labrie F, Zouboulis CC, Luu-The V. Biosynthesis of dihydrotestosterone by a pathway that does
not require testosterone as intermediate in the SZ95 sebaceous gland cell line. J Invest Dermatol. 2010;
130:602-4.
78. Chen W, Tsai SJ, Sheu HM, Tsai JC, Zouboulis CC. Testosterone synthesized in cultured human SZ95
sebocytes mainly derives from dehydroepiandrosterone. Exp Dermatol. 2010;19:470-2.
its specific activity on human sebocytes through selective intracellular isomerization to all-trans-retinoic acid
and binding to retinoid acid receptors. J Invest Dermatol. 2000;115:321-7.
51

Nutrient and Growth Factor Signalling in

Acne Sensed by FoxO1 and mTORC1
Bodo C Melnik MD
Department of Dermatology, Environmental Medicine and Health Theory,
University of Osnabrück, Germany
ABSTRACT
Accumulating evidence underlines the impact of Western diet in the
induction and aggravation of acne. This article elucidates the pathogenic
role of exaggerated nutrient signalling of Western diet. Both high glycemic
load and dairy protein consumption increase insulin and insulin-like
growth factor-1 (IGF-1) signalling, which is superimposed on elevated
IGF-1 serum levels of puberty. Important sensors of the cell’s nutritional
status are the forkhead box class O transcription factor-1 (FoxO1) and the
kinase mammalian target of rapamycin complex 1 (mTORC1). Insulin/
IGF-1 signalling inactivates FoxO1 by Akt kinase (protein kinase B)
(Akt)-mediated nuclear extrusion of FoxO1. FoxO1 inhibits the expression
of hepatic growth hormone receptor (GHR), thus links nutritional status
to the regulation of IGF-1-driven somatic growth. FoxO1 is an androgen
receptor (AR) cosuppressor, thus links nutritional status to androgen-
dependent growth. FoxO1 inhibits the activity of mTORC1, thus links
nutrient availability to mTORC1-mediated protein and lipid synthesis,
cell proliferation and differentiation. FoxO1 induces heme oxygenase-1
(HO‑1), which inhibits nuclear factor kappa B (NF-kB)-mediated
inflammation, thus links nutritional status to inflammation and regulation
of oxidative stress. FoxO1 directly interacts with AR, peroxisome
proliferator-activated receptor-g (PPARg), liver X receptor-a (LXRa),
tuberous sclerosis complex-2 (TSC2), b-catenin and glycogen synthase
kinase-3 (GSK3), thus orchestrates crucial signalling pathways important
for sebaceous gland (SG) development and homeostasis. Intriguingly, all
major antiacne drugs appear to function by nuclear FoxO accumulation.
Thus, antiacne treatment increases FoxO-dependent gene transcription
and attenuates the activity of mTORC1, thus counteracts the adverse
effects of enhanced insulin/IGF-1 signalling of Western diet.
Email: melnik@t-online.de

Nutrient and Growth Factor Signalling in Acne Sensed by FoxO1 and mTORC1
INTRODUCTION
The proper functioning of the pathways that are involved in sensing and
management of nutrients is central to metabolic homeostasis, and is therefore
among the most fundamental requirements for survival.1 It is the purpose
of this article to highlight the role of nutrient signalling of Western diet, a
fundamental environmental factor in the pathogenesis of acne and other
epidemic nutrient-dependent diseases of civilization.2-6 Western style nutrition
is characterized by high calorie uptake, high glycemic load, high fat intake and
increased dairy protein and meat consumption. Metabolic signals of Western
diet are predominantly sensed by the forkhead box class O transcription factor-1
(FoxO1) and the nutrient-sensitive serine/threonine kinase, mammalian target
of rapamycin complex 1 (mTORC1), which integrate signals of cellular energy,
growth factors like insulin and insulin-like growth factor-1 (IGF-1) and
protein/amino acid-derived signals, predominantly provided by the essential
branched-chain amino acid leucine.7-12 Both the metabolic regulations mediated
by FoxO1 and the activity of mTORC1 depend on upstream activation of the
insulin/IGF-1/phosphoinositol-3 kinase (PI3K)/Akt signalling cascade, which
is required for metabolic control and adaptive nutrient homeostasis as well as
endocrine growth regulation in mammals.13
EXAGGERATED INSULIN/IGF-1 SIGNALLING OF

WESTERN DIET
The major endocrine changes of puberty primarily depend on activated GH-
mediated hepatic secretion of IGF-1 (somatomedin C), the principal mediator
of somatic growth in most tissues including SGs, where IGF-1 promotes growth,
cell proliferation and sebaceous lipogenesis.5,14-19 Western diet composed of high
fat, high glycemic load and dairy proteins significantly increases insulin and
IGF‑1 serum levels and thus exaggerates already upregulated IGF-1 signalling
of puberty.6,20
The role of diet in the pathogenesis of acne is a topic of intensive research
and clinical evidence has been reviewed elsewhere.21-27 Convincing evidence from
placebo-controlled studies demonstrated that high glycemic load diets aggravate
acne.28-36 High glycemic load diets result in postprandial hyperinsulinemia and
increased serum levels of free IGF-1.30,31 Epidemiological as well as accumulating
clinical evidence demonstrates that bovine milk and other insulinotropic dairy
protein-enriched milk products are important nutritional compounds that also
have the ability to induce or aggravate acne.3,32,33,37-41 It has been recognized
recently that mammalian milk functions as an endocrine growth-promoting
signalling system.42 Whey proteins by increasing serum levels of leucine and
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Melnik
glucose-dependent insulinotropic polypeptide (GIP) raise postprandial insulin

levels. Casein intake increases hepatic synthesis of IGF-1 and persistently elevates
serum IGF-1 levels.42 Increased growth factor signalling by insulin and IGF-1
provides a fundamental mechanism of all mammals, which suppresses FoxO1 and
promotes mTORC1-driven neonatal growth (Figure 1).42
IGF-1, insulin-like growth factor-1; Akt, Akt kinase (protein kinase B); FoxO1, Forkhead box class O
transcription factor-1; TSC1, hamartin; TSC2, tuberin; mTORC1, mammalian target of rapamycin complex 1,
Rheb, Ras homolog enriched in brain; AMPK, adenosine monophosphate-activated protein kinase; GIP,
glucose-dependent insulinotropic polypeptide; GHR, growth hormone receptor; GH, growth hormone;
IR, insulin resistance; LAT, L-type amino acid transporter; IRS, insulin receptor substrate; IGF‑1R, IGF-1
receptor; PI3K, phosphoinositol-3 kinase; 4E‑BP‑1, eukaryotic initiation factor (eIF) 4E-binding protein;
S6K1, p70 S6 kinase.
Figure 1: Increased insulin/IGF-1 signalling of Western diet results in Akt-mediated

phosphorylation and inhibition of FoxO1 by nuclear extrusion. Akt-mediated phosphorylation of
TSC2 attenuates the inhibitory effect of TSC1/TSC2 on Rheb, thus promotes mTORC1 activation.
In contrast, nuclear activation of FoxO1 stimulates the expression of Sestrin3, which activates
AMPK and thereby inhibits mTORC1 activation by enhancing the inhibitory function of TSC2
toward Rheb. Increased insulin/IGF-1 signalling of Western diet is superimposed on enhanced
IGF-1 signalling of puberty, thereby promotes the development of acne.
54

FOXO1 INTEGRATES NUTRIENT SIGNALLING

Forkhead box O (FoxO) transcription factors FoxO1, FoxO3a, FoxO4 and
FoxO6 are important regulatory proteins that modulate the expression of genes
involved in cell cycle control, DNA damage repair, apoptosis, oxidative stress
management, cell differentiation, glucose and lipid metabolism, inflammation and
immune function.43-47 FoxO transcription factors are expressed ubiquitously in all
mammalian tissues including androgen-dependent glands like the prostate.48,49
FoxO1 protein has recently been detected by immunohistochemistry in human
SGs (Zouboulis CC, personal communication).
Accumulating evidence from human and animal studies points to the pivotal
role of FoxO1, the predominant FoxO isoform, in the regulation of metabolism.50
Genome-wide analysis of FoxO1 binding to the 5’GTAAACA3’ binding
sequence in mouse hepatic chromatin exhibited 401 FoxO1-binding locations.51
Gene ontology analysis has demonstrated a significant role of FoxO1 in metabolic
processes, especially for carboxylic acids, fatty acids, steroids and retinoids.51
FoxO1 has been recognized to function as a key regulator in the pathogenesis of
acne as FoxO1 integrates external nutrient and internal growth factor signals at
the level of gene regulation.7
Central to the regulation of FoxO transcription factors is a shuttling system,
which confines FoxO factors to either the nucleus or the cytosol. Shuttling of
FoxO1 requires protein phosphorylation of nuclear FoxO1 by activated PI3K
and Akt kinase (protein kinase B, PKB). Activated Akt translocates into the
nucleus for FoxO phosphorylation. Phosphorylated FoxO1 leaves the nucleus,
thereby modifies FoxO1-dependent target gene expression.43,44,47 Diet-induced
nuclear export of FoxO1 by insulin, IGF-1 or other growth factors [fibroblast
growth factors (FGFs)] modifies the transcriptional activity of key target genes
and nuclear receptors involved in the pathogenesis of acne.7-10 The PI3K-Akt
signalling cascade is physiologically suppressed by the tumor suppressor PTEN
(phosphatase and tensin homolog deleted on chromosome 10). PI3K and PTEN
are major positive and negative regulators, respectively, which control cell growth,
survival and proliferation.52 Increased IGF-1 signalling is an endocrinological
hallmark of puberty as well as insulinotropic Western nutrition characterized by
increased consumption of insulinotropic dairy proteins and carbohydrates with
high glycemic index (Figure 1).7-10
FOXO1 REGULATES THE SOMATOTROPIC AXIS

Organisms adjust their rate of growth depending on the availability of nutrients.The
insulin/IGF-1 receptor pathway together with the FoxO family of transcription
factors plays a crucial role in this process. FoxOs are able to integrate the cell’s
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Melnik
responses to growth and proliferation in relation to nutrient availability.11 The

most important FoxO1 isoform mediating metabolic regulation in response to
nutrient availability and insulin/IGF-1 signalling is FoxO1. Nuclear FoxO1 is
highly upregulated during fasting and is the transcription factor of starvation. In
contrast, in the postprandial state and conditions of abundance or overnutrition
insulin and IGF-1 downregulate FoxO1 by Akt-mediated phosphorylation.50,53,54
From a mechanistically point of view it should be expected that FoxO1 interferes
with the regulation of somatic growth, which should be suppressed in the absence of
nutrients. The key regulator of somatic growth is the mitogenic hormone IGF-1.5
Most circulating IGF-1 is synthesized and secreted by the liver. The liver responds
to GH secreted in increased amounts in the pituitary gland during puberty.
Notably, untreated individuals with Laron syndrome, a primary GH resistance
due to a genetic defect of the GHR, exhibit diminished congenital IGF-1 serum
levels, are of short stature and do not develop acne.55,56 IGF-1 deficient serum
of Laron individuals increased nuclear FoxO levels and inhibited mTORC1.56
In contrast, increased IGF-1 serum levels promote acne. IGF-1(CA)19 gene
polymorphism with elevated IGF-1 serum levels has recently been detected in
acne patients.57 There is an interesting mouse model mimicking Laron syndrome,
the DKO-mouse, which exhibits impaired insulin/IGF-1 signalling. DKO-mice
with a double knock out of insulin receptor substrate 1 (IRS1) and IRS2 in the
liver are shorter and exhibit 20% less body mass than control mice.13 Reduced
hepatic Akt signalling with increased nuclear FoxO1 levels in DKO-mice resulted
in decreased expression of GHR, IGF-1 and sterol regulatory element binding
protein-1c (SREBP-1c) and increased the expression of IGF binding protein-1
(IGFBP-1).13 It has recently been confirmed by mouse hepatic chromatin analysis
that GHR and IGFBP-1 are FoxO1 target genes.51 FoxO1-mediated inhibition of
GHR expression in the liver attenuates GH-mediated synthesis and secretion of
hepatic IGF-1, the main source of IGF-1 in the circulation.13 Furthermore, FoxO1
induces hepatic expression of circulating IGFBP-1, a mechanism that reduces
the availability of free IGF-1 for IGF-1 receptor binding.13,58,59 Both decreased
hepatic secretion of IGF-1 and reduced bioavailability of IGF-1 attenuate
IGF‑1-mediated growth signalling including IGF-1-dependent growth of SGs
and sebaceous lipogenesis.15-19 Importantly, FoxO1 activates the expression of the
cell cycle inhibitors p21 and p27.60-65 Moreover, FoxO1 activates transcription of
the eukaryotic initiation factor (eIF) 4 binding protein-1 (4E-BP-1), which is a
major substrate of mTORC1 and functions as a potent translational inhibitor and
growth suppressor.66,67 FoxO1 not only controls protein synthesis and cell growth,
but also lipid metabolism. The key transcription factor of lipid synthesis SREBP‑1c
is controlled by FoxO1 (Table 1).68 IGF-1-induced SREBP-1 expression and
lipogenesis in SEB-1 sebocytes via activation of the PI3K/Akt pathway.19 In
contrast, isotretinoins therapeutic mode of action has recently been linked to
56

Table 1: Important FoxO1-regulated Target Genes in the Pathogenesis of Acne

Growth hormone receptor (GHR) Suppression of GHR expression, downregulation of
hepatic IGF-1 synthesis
IGF-binding protein-1 (IGFBP-1) Upregulation of IGFBP-1 expression, reduction of
circulating free IGF-1
Eukaryotic initiation factor (eIF) Activation of 4E-BP-1 expression, inhibition of mRNA
4 binding protein-1 (4E-BP-1) translation
p21 Activation of p21 expression, cell cycle inhibition,
growth inhibition
p27 Activation of p27, cell cycle inhibition, growth inhibition
Sestrin3 Activation of Sestrin3 expression, activation of AMPK-
mediated phosphorylation of TSC2 activating the
inhibitory function of TSC1/TSC2, thus suppressing
mTORC1
Heme oxygenase-1 (HO-1) Activation of OH-1 expression, inhibition of
mitochondrial function and ROS formation, inhibition of
NF-kB, inhibition of inflammation
IGF-1, insulin-like growth factor-1; mRNA, messenger ribonucleic acid; AMPK, adenosine monophosphate-
activated protein kinase; TSC1, hamartin; TSC2, tuberin; mTORC1, mammalian target of rapamycin
complex 1; ROS, reactive oxygen species; NF-kB, nuclear factor kappa B.
upregulated nuclear expression of FoxO1.69 It is conceivable that suppression of

GHR by isotretinoin-induced FoxO1 would lead to decreased hepatic synthesis
of IGF-1. In fact, Karadag et al. have demonstrated a significant decrease of serum
IGF-1 levels during systemic isotretinoin treatment.70
FOXO1 REGULATES LIPOGENESIS AND

CELL CYCLE CONTROL
FoxO1 plays a fundamental role in the regulation of lipid metabolism. In skeletal
muscle FoxO1 antagonizes retinoid X receptor-a (RXRa)/LXRa-upregulated
expression of SREBP-1c.68 A low glycemic load diet in comparison to a high
glycemic load Western diet reduces insulin signaling and thus increases nuclear
levels of FoxO1.6 Thus, it should be expected that a low glycemic load diet via
increasing nuclear FoxO1 levels in sebocytes would suppress SREBP-1 expression
and would reduce the growth and proliferation of SGs. In fact, Kwon et al. provided
recent evidence that a 10-week low glycemic load diet reduced SREBP‑1-
expression in the skin of acne patients, reduced the size of SGs, reduced cutaneous
inflammation and improved acne.34 The transcription factors PPARg and LXRa
play a costimulatory role for sebaceous lipogenesis.71-76 In contrast, FoxO1 either
directly by protein-protein interaction or at the promoter level of PPARg repressed
the function of PPARg and LXRa.68,77-79
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Melnik
Table 2: FoxO1-interaction with Regulatory Proteins and Transcription Factors

Androgen receptor (AR) Suppression of AR transactivation
PPARg Suppression of PPARg and PPARg-mediated lipogenesis
LXRa Suppression of RXR/LXRg-mediated activation of SREBP-1
TSC2 Akt-phosphorylated cytoplasmic FoxO1 dissociates and
thereby inhibits the TSC1/TSC2 heterodimer
b-catenin Augmentation of nuclear FoxO1 signalling
GSK3 Modulation of GSK3-TSC2-mTORC1 signalling
CRM1 Nuclear FoxO1 export
FoxO1, forkhead box protein O1; PPARg, peroxisome proliferator-activated receptor-g; LXRa, liver X
receptor-a; RXR, retinoic acid receptor; SREBP-1, sterol regulatory element binding protein-1; TSC1,
hamartin; TSC2, tuberin; GSK3, glycogen synthase kinase-3; mTORC1, mammalian target of rapamycin
complex 1; CRM1, chromosomal region maintenance protein-1 (exportin-1).
Taken together, the metabolic sensor FoxO1 is involved in nutrient-dependent

regulation of IGF-1 synthesis, IGF-1 bioavailability, the expression of the most
critical cell cycle inhibitors p21 and p27, the transcriptional inhibitor of protein
synthesis 4E-BP-1 and important transcription factors of lipid biosynthesis like
SREBP-1, PPARg and LXRa (Table 2). Thus, FoxO1 is a key transcription factor,
which orchestrates the impact of nutritional status to the pathogenesis of acne.7
FOXO1 INHIBITS ANDROGEN SIGNALLING

Sebaceous gland growth is androgen-dependent and acne is believed to be an
androgen-dependent disease.80 Androgens are growth factors of androgen-
responsive tissues. The AR is a transcription factor of androgen/AR-responsive
target genes.81 It is conceivable that general IGF-1-mediated growth should be
linked to and coordinated with androgen signalling. IGF-1 stimulates gonadal
and adrenal androgen synthesis and intracutaneous conversion of testosterone to
10‑fold more active dihydrotestosterone, the most potent AR ligand.5 As discussed
above, high nutrient availability via increased insulin signalling reduces nuclear
FoxO1 in the liver and thereby increases hepatic GH-GHR-signal transduction
resulting in increased synthesis of circulating IGF-1, which promotes androgen
synthesis. Furthermore, the functional significance of FoxO1 in the regulation of
steroid metabolism has recently been confirmed.51
However, only a few patients with acne exhibit hyperandrogenemia, an
observation, which points to the predominance of peripheral tissue-dependent
androgen sensitivity for the manifestation of acne.80 Notably, high nutrient
availabilty modifies the magnitude of peripheral AR signal transduction because
FoxO1, the integrator of nutrient signalling, functions as an AR cosuppressor.82-84
High nutrient availability with increased insulin/IGF-1 signalling leads to Akt-
58

mediated nuclear extrusion of FoxO1 into the cytoplasm and thereby releaves
FoxO1-mediated suppression of AR transactivation. Thus, suppression of FoxO1
by high insulin/IGF-1 signalling of Western diet appears to increase AR signal
transduction and links Western diet to increased androgen responsiveness of
peripheral androgen-dependent tissues.
Both AR signalling like IGF-1 signalling synergistically increase SREBP-1-
mediated lipogenesis resulting in a coordinate upregulation of the entire program
of lipogenic pathways.85 In contrast to FoxO1, which upregulates the expression
of the cell cycle inhibitor p27, AR signalling rapidly reduced p27 by increasing its
proteasome-mediated degradation.86 Thus, IGF-1 and androgen signalling both
decrease p27, IGF-1 via induction of a nuclear FoxO1 deficiency with decreased
expression of p27 and androgens by increased degradation of the p27 protein.
These findings exemplify the intimate nutrient-dependent molecular crosstalk
between androgen and IGF-1 signalling.
FOXO1 LINKS NUTRITIONAL STATUS TO

IMMUNE REGULATION
FoxO family members play critical roles in the suppression of T cell activation.87
FoxO1 deficiency in vivo resulted in spontaneous T cell activation and effector
differentiation.88 Notably, increased CD4+ T cell infiltration and enhanced
interleukin-1 (IL-1) activity have been detected in acne-prone skin areas prior
to follicular hyperkeratinization and comedo formation.89 FoxO1 not only plays
a conserved role in the adaptation of cells and organisms to nutrient and growth
factor availability, but is also crucial for the regulation of T cell homeostasis.90 In
naive T cells, FoxO1 controls the expression of the adhesion molecule L-selectin,
the chemokine receptor CCR7 (C-C chemokine receptor 7) and the transcription
factor Krüppel-like factor 2 (Klf2) involved in the regulation of lymphocyte
trafficking.91 Furthermore, FoxO1 deficiency resulted in a severe defect in
interleukin 7 receptor a-chain (IL-7Ra). Finally, growth factor withdrawal
induced a FoxO1-dependent increase in Sell, Klf2 and IL-7R expression. These
data support the view that FoxO1 regulates the homeostasis and life span of naive
T cells by sensing growth factors and nutrient availability and regulates T cell
homing and survival signals.91
In Drosophila flies the dfoxo transcription factor controls the expression of
several antimicrobial peptides (AMPs) in various tissues including skin.92 AMP
induction is lost in dfoxo null mutants but enhanced when dfoxo is overexpressed. In
Drosophila, AMP activation can be achieved independently of immunoregulatory
pathogen-dependent pathways by dfoxo, indicating the existence of cross-
regulation of metabolism and innate immunity at the promoter level of dfoxo-
activated AMP genes.92 In contrast, insulin and IGF-1-dependent signalling with
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Melnik
Akt-mediated translocation of dfoxo from the nucleus into the cytosol reduced the
expression of AMPs. It is conceivable that insulinotropic Western diet may affect
the balance and activity of AMPs. Thus, it is likely that insulinotropic Western diet
provides an AMP-deficient cutaneous microenvironment, which may promote
Propionibacterium acnes growth and hypercolonization. In this regard, Western
diet with increased insulin/IGF-1 signalling would not only provide increased
lipid nutrients of sebaceous origin for P. acnes growth, but might also diminish
AMP-mediated host responses against P. acnes.9
Furthermore, FoxO1 at the promoter level induces HO-1, the rate-
limiting enzyme of heme degradation important for mitochondrial oxidation
and mitochondrial generation of reactive oxygen species (ROS).50,93 HO-1 has
been recognized to exert important immunomodulatory and antiinflammatory
properties dependent on PI3K/Akt/FoxO1 signal transduction.94 HO-1
downregulates the IkB kinase (IKK)/NFkB signalling pathway.95 Induced HO-1
is cleaved at its N-terminal fragment and translocates into the nucleus where it
interacts with AP-1 and NFêB sites of the IL-23p19 promoter, which prevents
proinflammatory IL-23p19 transcription.96
FOXO1 REGULATES OXIDATIVE STRESS RESPONSES

Overnutrition is associated with increased oxidative stress.97 Increased oxidative
stress has been observed in patients with acne vulgaris.98,99 Anabolic states
with increased activity of mTORC1 induce oxidative stress.100 In contrast,
FoxO transcription factors regulate defense mechanisms against accumulating
ROS through HO-1-mediated inhibition of mitochondrial ROS formation,
activation of Sestrin3 gene expression, which functions as a ROS scavenger
and FoxO target gene expression of ROS-degrading enzymes like manganese
superoxide dismutase and catalase.101-103 On the other hand, ROS regulates FoxO
activity in many ways through an elaborate combination of activating as well as
repressing posttranslational modifications, including phosphorylation, acetylation,
ubiquitinylation and methylation. Hence, FoxOs are key players of redox signalling
and link nutritional status to metabolic oxidative stress, a characteristic feature of
acne vulgaris.98,99,103
REACTIVE OXYGEN SPECIES INCREASE

NUCLEAR FOXO LEVELS
The topical standard therapy of acne vulgaris is benzoyl peroxide (BPO), which
is applied in high concentrations commonly ranging from 3% to 10%.104 BPO’s
major mode of action is believed to reduce the growth of P. acnes. However,
BPO-mediated extinction of P. acnes is a matter of minutes, whereas clinical
60

improvement of acne takes several weeks of continued BPO treatment. Thus,

there appears to be another overlooked mode of action of BPO in the treatment
of acne. This most likely involves ROS-mediated activation of FoxO1-signalling.
It is most conceivable that BPO activates oxidative stress-inducible kinases
like Jun N-terminal kinase ( JNK) and STE20-like protein kinase 1 (MST1),
which increase nuclear levels of FoxOs.43 Remarkably, the activation of FoxOs,
initiated by the phosphorylation by JNK and MST1 is dominant to the inhibitory
phosphorylation of FoxOs by Akt.105 Thus, BPO/hydrogen peroxide (H2O2)/
JNK/MST1-activated FoxO-signalling may be the operative effector mechansim
of BPO in acne, which couteracts nutrient/Akt-mediated inactivation of FoxO
transcription factors.
TORC1: CONVERGENCE POINT OF

NUTRIENT SIGNALLING IN ACNE
Mammalian target of rapamycin complex 1 is an evolutionarily conserved nutrient
sensing protein kinase that regulates growth and metabolism in all eukaryotic
cells including keratinocytes and sebocytes.100 mTORC1 belongs to a conserved
group of serine/threonine kinases from the phosphoinositol-3-kinase (PI3K)-
related kinase (PIKK) family. mTORC1 signalling serves as a “growth checkpoint”
surveying the extracellular and intracellular milieu of growth factors and nutrient
conditions to mediate growth accordingly.100,106 mTORC1 signalling stimulates
gene transcription, translation, ribosome biogenesis, protein synthesis, cell growth,
cell proliferation, lipid synthesis but suppresses mechanisms of autophagy.107-112
mTOR is a multidomain protein of approximately 300 kDa exhibiting a
protein kinase domain at its C-terminus related to PI3Ks. In mammalian cells,
two functionally different mTOR complexes exist: mTORC1 and mTORC2.
Among other functional proteins, mTORC1 contains the important partner
protein Raptor (regulatory associated protein of mTOR), which interacts with
substrates for mTORC1-mediated phosphorylation. mTORC1 controls the
G1/S transition and G2/M progression of the cell cycle.109 The mTORC1-
signalling network connects various signalling modules sensing and relaying
diverse inputs, especially nutrient, growth factor and cellular energy status, to a
central “signalling core” that consists of the serine/threonine kinase Akt, the TSC
proteins TSC1 and TSC2, the Ras-like small GTPase (guanosine triphosphate)
Rheb and mTORC1 itself (Figure 1).100 In contrast to mTORC2, which contains
the partner protein Rictor (rapamycin-insensitive companion of mTOR), only
mTORC1 plays a special role in sensing cellular nutrients, amino acids and
energy [adenosine triphosphate (ATP)] levels important for cell growth and
proliferation. Liver kinase B1 (LKB1) and adenosine monophosphate (AMP)-
activated protein kinase (AMPK) are critical regulators of mTORC1.113 Most
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Melnik
functions of mTORC1 are inhibited by rapamycin, a triene macrolide antibiotic

synthesized by Streptomyces hygroscopicus.112
mTORC1 has to be regarded as a pivotal convergence point in cell signalling,
because it integrates many intracellular and extracellular signals such as growth
factors (insulin, IGF-1), energy-sensing signals (glucose, the AMP/ATP-ratio
regulating AMPK), and most importantly the availability of sufficient amounts
of amino acids, especially of the branched-chain essential amino acid leucine for
mTORC1 activation (Figure 1).114
Recent advances in molecular biology have elucidated two parallel mechanisms
of mTORC1 activation: (1) the upstream activation of the small GTPase Rheb
by growth factor signals and high cellular energy levels; and (2) the amino acid-
dependent translocation of inactive mTORC1 to active Rheb localized at late
endosome or lysosome compartments.115-117 The activity of Rheb is tightly
regulated by the tuberous sclerosis proteins TSC1 (hamartin) and TSC2 (tuberin),
which form a functional heterodimeric complex. Intriguingly, loss-of-function
mutations of either the TSC1 or TSC2 gene cause the hamartoma syndrome
tuberous sclerosis. TSC1 stabilizes TSC2 that possesses a GTPase-activating
protein, which hydrolyses GTP to guanosine diphosphate (GDP). The TSC1/
TSC2 complex provides this function to Rheb leading to inactivation of Rheb.
Insulin and IGF-1, which both activate the kinase Akt as well as other growth-
related kinases such as mitogen activated protein kinase (ERK) and ribosomal
S6 kinase (RSK) phosphorylate TSC2, thereby inhibit the function of the
TSC1/TSC2 complex. This inhibition leads to the activation of Rheb and finally
activation of mTORC1.118-120
Besides the important input of growth factor signalling on mTORC1
activation, AMPK, an essential energy sensor, plays a key role in energy-dependent
mTORC1 regulation. During states of energy-deficient conditions like glucose
deprivation, ATP levels fall and AMP levels rise, resulting in AMPK activation.
AMPK phosphorylates TSC2 and Raptor, thereby suppressing mTORC1
activity.121,122 Abundant cellular energy provided by hypercaloric Western diet
with high glycemic load, thus reduces AMPK activity and stimulates mTORC1
signalling.
Remarkably, in response to amino acid depletion, mTORC1 activity is rapidly
abolished.123 Amino acid starvation impairs binding of mTORC1 to Rheb.124
From all essential amino acids, leucine exerts the greatest effects on mTORC1
signalling.109,112,123 Recent evidence has been provided that amino acids and
especially leucine promote the cellular translocation of inactive mTORC1 to
lysosomal compartments enriched in activated Rheb.115,116 This spatial regulation
of inactive mTORC1 by amino acids is mediated by an active Rag (Ras-related
GTP-binding protein) heterodimer and is of utmost biological importance as
it explains the complete mechanism of nutrient sensing of mTORC1. Recently
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mechanistic insights into amino acid sensing of mTORC1 have been elucidated.125
Unlike the GTPases that rely on a lipid moiety for their subcellular localization,
the pentameric Ragulator complex comprised of p18, p14, MP1, HBXIP and
C7 or f59 acts as a scaffold for the Rag GTPases and mTORC1 at the lysosomal
membrane. Amino acid and especially leucine accumulation in the lysosomal
lumen generates an activating signal that is transmitted in a v-ATPase-dependent
fashion to activate the guanine nucleotide exchange factor (GEF) activity of
Ragulator toward RagA. Upon RagA-GTP loading, the Rag-Ragulator interaction
weakens and mTORC1 is recruited to the lysosomal surface where it interacts
with Rheb and becomes activated.125 Thus, mTORC1 integrates not only growth
factor/energy-derived signals to Rheb, but requires parallel amino acid (leucine)-
dependent activation of mTORC1. These two independent major pathways of
mTORC1 activation explain why either insulin/IGF-1 signalling or amino acid
signalling alone is not sufficient to reach maximal mTORC1 activation. Insulin
is not able to activate the mTORC1 pathway when cells are deprived of amino
acids.126 In fact, recent experimental evidence confirmed that both insulin- and
amino acid signalling are required for maximal mTORC1 activity (Figure 1).126
Western diet promotes mTORC1 activity by stimulating all major mTORC1-
activating pathways: (1) by abundance of milk- and meat protein-derived essential
amino acids; (2) by increased insulin/IGF-1 signalling provided by dairy protein
consumption and high glycemic load; and (3) decreased AMPK activity by
availability of high cellular energy (high glycemic load).
After integration of nutrient signals, growth factors and energy status,
mTORC1 conducts the downstream cellular signalling symphony.127 As
protein and lipid biosynthesis, cell growth and proliferation are coordinated by
mTORC1 in all mammalian cells, it is obvious that mTORC1 plays a key role
in the pathogenesis of acne, which is characterized by increased proliferation
of acroinfundibular keratinocytes, SGs hyperplasia and increased sebaceous
lipogenesis.10
Activated mTORC1 phosphorylates important substrates involved in
the regulation of the translational machinery, the S6 kinases (S6Ks), which
phosphorylate ribosomal protein S6, and 4E-BPs, which control the activity of the
translation factor eIF4E that binds to the 5’-cap structure of eukaryotic mRNAs,
thereby facilitating ribosome recruitment. Intriguingly, the downstream target
of mTORC1, S6K1, phosphorylates insulin receptor substrate proteins (IRS),
mediating an important feed back mechanism, which downregulates insulin/
IGF-1 signalling. This is the molecular basis for S6K1-mediated insulin resistance
(IR), a characteristic feature of the metabolic syndrome.128
Cell growth not only requires increased amounts of protein but also adequate
amounts of lipids, an important issue for SGs. It is thus not surprising that the
key transcription factor of lipid biosynthesis SREBP is dependent on mTORC1
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activation.129 mTORC1 phosphorylates lipin-1, which controls the access of

SREBP-1 to the promoter region of SREBP-1-dependent genes. Recent evidence
points to a direct role of dietary fatty acids for amino acid-independent activation
of S6K1, the downstream target of activated mTORC1.130
As both the key regulatory kinase mTORC1 and the nutrient-sensing
transcription factor FoxO1 integrate nutrient- and growth factor signals, it should
be expected that they might intimately interact with each other to coordinate
cellular responses according to nutrient availability.
FOXO1 IS A RHEOSTAT REGULATING TORC1

Recent progress in cell signalling has highlighted the pivotal interplay between
FoxOs, mTORC1, and Akt in mammalian cell systems.131 FoxO transcription
factors are pivotal inhibitors of mTORC1 signalling (Table 3).131 Increased
insulin/IGF-1 signalling and activation of the PI3K/Akt-pathway results in Akt-
mediated nuclear extrusion of FoxO proteins. Intriguingly, FoxOs have emerged
as important rheostats that coordinate the activity of Akt and mTORC1.131
Activated FoxOs (FoxO1, FoxO3, FoxO4) induce the expression of Sestrin3,
which activates AMPK to inhibit mTORC1 in a TSC2-dependent manner
(Figure 1).101 TSC1-TSC2 negatively regulates the mTORC1 pathway by acting
as a GTPase-activating protein (GAP) for Rheb1, a small GTPase that when
bound to GTP is an essential activator of mTORC1 kinase activity.118-120,125
Table 3: Impact of Nuclear and Cytoplasmic FoxOs in the Regulation of mTORC1

nFoxO1↑ GHR↓, hepatic IGF-1↓, Akt↓ mTORC1↓
nFoxO1↑ IGFBP-1↑, free IGF-1↑, Akt↑ mTORC1↓
nFoxO1↑, nFoxO3↑, nFoxO4↑ Sestrin3↑, AMPK↑, TSC2↑ mTORC1↓
nFoxO1↑ AR↓, mTORC2↓, Akt↓ mTORC1↓
AR↓, LAT↓, Ragulator↓
nFoxO1↑ 4E-BP-1↑ mTORC1↓
nFoxO1↑ Rictor↑, mTORC2 assembly↑ mTORC1↓
nFoxO1↑ Trb3↑, Akt↓ mTORC1↓
nFoxO3↑ Bnip3↑, Rheb↓ mTORC1↓
nFoxO3↑ FoxO1↑ mTORC1↓
TSC1↑
cFoxO1↑ TSC1/TSC2↓, Rheb↑ mTORC1↑
nFoxO, nuclear FoxO; GHR, growth hormone receptor; IGF-1, insulin-like growth factor-1; Akt, Akt kinase
(protein kinase B); mTORC1, mammalian target of rapamycin complex 1; IGFBP-1, IGF binding protein-1;
AMPK, adenosine monophosphate-activated protein kinase; TSC2, tuberin; AR, androgen receptor; LAT,
L-type amino acid transporter; 4E-BP-1, eukaryotic initiation factor (eIF) 4E-binding protein-1; Rictor,
rapamycin-insensitive companion of mTOR; Trb3, tribbles3; Bnip3, Bcl-2/adenovirus E1B 19-kDa-
interacting protein 3; Rheb, Ras homolog enriched in brain; TSC1, hamartin; cFoxO, cytoplasmic FoxO.
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Activated AMPK has been shown to phosphorylate FoxO3 and facilitates its
nuclear localization.132 Furthermore, Akt-phosphorylated cytoplasmic FoxO1
binds to TSC2 and thereby dissociates the TSC1/TSC2 complex, which activates
mTORC1.133 Thus, activated Akt inhibits FoxO1, FoxO3 and FoxO4 through
direct phosphorylation, and indirectly activates mTORC1, which in turn elevates
protein and lipid synthesis. mTORC1 and its downstream effector, the kinase
S6K1, elicit negative feedback loops to inhibit Akt. FoxO1 also induces insulin/
IGF-1 receptors and IRS2, a feedback mechanism, which increases insulin
sensitivity.131,134 FoxO1 elevates the expression of Rictor, leading to increased
mTORC2 activity that consecutively activates Akt. The elevation of Rictor by
FoxO increases mTORC2 assembly and activity at the expense of mTORC1
assembly, thereby activating Akt while inhibiting mTORC1.
Taken together, FoxOs act as a rheostat that maintains homeostatic balance
between Akt and mTOR complexes’ activities (Table 3).101 Furthermore, FoxO1
elevates the expression of 4E-BP-1, a major substrate of TORC1, which functions
in its unphosphorylated form as a potent repressor of mRNA translation and
suppressor of cell growth.66,67 Furthermore, FoxO1 suppresses the expression of
the pseudokinase tribbles 3 (Trb3), which inhibits insulin signalling by blocking
Akt activity.135,136 FoxO3 elevates the expression of the autophagy-related gene
Bnip3 (Bcl-2/adenovirus E1B 19-kDa-interacting protein 3).137 Bnip3 inhibits
mTORC1 activity by direct binding to Rheb thereby decreasing Rheb GTP
levels.138 Moreover, FoxO1 has been shown to induce apoptosis in skeletal
myotubes in a DNA-binding-dependent manner.139 Finally, it has been reported
that FoxO3 induces transcriptional expression of TSC1 and thereby inhibits
mTORC1 (Table 1).140
In summary, FoxO transcription factors interact directly or indirectly with the
mTORC1 signalling cascade at multiple regulatory levels: (1) FoxO1 suppresses
hepatic GHR expression and thereby attenuates IGF-1/PI3K/Akt/mTORC1
signalling; (2) FoxO1 suppresses AR/mTORC2/Akt/mTORC1 signalling,
thus reduces the impact of androgens on mTORC1 activation; (3) FoxO1
via stimulated Sestrin3 expression increases AMPK activity, which inhibits
mTORC1 via AMPK-mediated TSC2 phosphorylation, thus links FoxO1 to
energy-dependent regulation of mTORC1; (4) FoxO1 stimulates the expression
of Rictor, which favors the assembly of mTORC2 at the expense of mTORC1
formation; (5) cytoplasmic Akt-phosphorylated FoxO1 associates with TSC2
and thereby dissociates the inhibitory TSC1-TSC2 complex resulting in Rheb-
mediated activation of mTORC1, thereby interfering with growth factor/PI3K/
Akt/TSC1-TSC2/Rheb/mTORC1 signalling; (6) FoxO1 controls the expression
of 4E-BP-1, the most important suppressor of translation, thus interferes with
upstream and downstream regulatory events of mTORC1 signalling cascade
(Table 3).
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Thus, ample evidence underlines the inhibitory role of enhanced FoxO1 on

mTORC1 signalling, which is in contrast to deficient nuclear FoxO activity
induced by persistently enhanced insulin/IGF-1 signalling of Western diet.6
FOXO1 REGULATES KERATINOCYTE AND

SEBOCYTE PROLIFERATION
In countries consuming insulinotropic Western diet, acne is an epidemic,
hyperproliferative disorder of the pilosebaceous follicle characterized by exaggerated
proliferation of acroinfundibular keratinocytes and increased sebocyte growth
with enhanced sebum production.141,142 The PI3K/Akt/mTORC1 pathway has
been shown to stimulate keratinocyte proliferation.143 Loss-of-function of either
the TSC1 or TSC2 gene leads to persistent activation of mTORC1 resulting in
the hamartoma syndrome tuberosus sclerosis complex.144 It is thus not surprising
that in folliculocystic and collagen hamartoma of TSC multiple comedones and
keratin-containing cysts lined by infundibular epithelium have been described.145
Acne has recently been proposed to be a visible mTORC1-driven disease of
civilization promoted by exaggerated diet-induced insulin/IGF-1-signalling with
decreased expression of FoxO1-regulated genes.7-10
FoxO1/p21 interaction: Comedogenesis, the primary lesional change of acne, is
associated with increased proliferation of acroinfundibular keratinocytes.141
The comedo is the morphological result of keratinocyte hyperproliferation and
obviously of impaired keratinocyte differentiation. Cell proliferation is controlled
by two major cell cycle inhibitors: p21 and p27.146 Withdrawal from the cell cycle
and growth arrest are an intrinsic part of the keratinocyte terminal differentiation
program.147,148 It is well established that induction of p21 is the earliest regulatory
step associated with epidermal keratinocyte differentiation.149 Notably, p21 is a
FoxO1 target gene and FoxO1 induces the expression of p21.60 Thus, high insulin/
IGF-1 signalling of Western diet may reduce FoxO1-mediated p21 expression
of acroinfundibular keratinocytes and may thus allow uncontrolled proliferation
of already growth factor (androgen, IGF-1)-stimulated acroinfundibular
keratinocytes during the pubertal growth period. Isotretinoin, the most potent
systemic antiacne drug, inhibits proliferation of epidermal keratinocytes.150-152
This may already point to a therapeutic isotretinoin-FoxO1-p21 interaction. In
fact, isotretinoin-induced apoptosis and growth arrest of SEB-1 sebocytes has
been associated with increased expression of p21.153 Thus, accumulating evidence
supports the hypothesis that isotretnoin’s phamacological mode of action is
primarily linked to isotretinoin-mediated upregulation of nuclear FoxO1 levels.69
Sebocytes are highly specialized, sebum-producing epithelial cells that
release their content by rupture of the cell membrane and cellular degradation
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(holocrine secretion).154 Sebocytes are most commonly found in the skin in

association with hair follicles, where they arise from hair follicle keratinocytes.154-156
Sebocyte formation is controlled by multiple molecular pathways. The transcription
factors Sox9, Blimp1, BMP, sonic hedgehog, c-myc and Wnt/b-catenin play most
important roles in the regulation of SG development.154
FoxO1/c-myc-interaction: Overexpression of c-myc in transgenic mice results in
enlarged and more numerous SGs at the expense of the hair follicle lineage.157,158
Furthermore, skin-specific deletion of c-myc negatively affects SG development.159
Remarkably, recent evidence points to the role of FoxO proteins as regulators
of p21-activated kinase-1 (PAK1) expression.160 Both PAK1 and PAK2 are
known to inhibit c-myc by specific phosphorylation.161,162 Thus, high insulin/
IGF-1 signalling of Western diet with low nuclear FoxO levels may result in less
PAK-mediated c-myc inhibition, thereby promoting c-myc-stimulated sebocyte
proliferation. As demonstrated, FoxO1 may not only link nutritional status to the
regulation of keratinocyte, but also to sebocyte growth and proliferation.
FoxO1/b-catenin-interaction: Wnt/b-catenin signalling blocks differentiation
toward the sebocyte phenotype, since inhibition of Wnt target genes promotes
sebocyte development.163-165 Induction of b-catenin degradation in the skin
of developing mice by forced expression of Smad7 perturbed hair follicle
morphogenesis and differentiation but accelerated SG morphogenesis.165 In skin,
c-myc and b-catenin appear to exert opposing effects on sebocyte differentiation.
Analysis of transgenic mice with simultaneous activation of c-myc and b-catenin
revealed mutual antagonism: c-myc blocked b-catenin-mediated formation
of ectopic hair follicles and b-catenin reduced c-myc-stimulated sebocyte
differentiation.166,167 Thus, the question arose whether FoxO1 may modify
b‑catenin signalling and vice versa.
Intriguingly, it has been demonstrated in mammalian cells that b-catenin
strongly interacts with FoxO1 and FoxO3a.168 This interaction requires armadillo
repeats 1 to 8 of b-catenin and the C-terminal half of FoxO proteins.168
Importantly, binding of b-catenin to FoxO enhances the transcriptional activity
of FoxO.168 Thus, increased Wnt/b-catenin-signalling with enhanced nuclear
FoxO1 activity may suppress c-myc-dependent sebocyte growth via activation of
the FoxO1-PAK1 pathway. This is compatible with the fact that high nuclear
levels of â-catenin bind to FoxO3a and FoxO1 and augment their transcriptional
proapoptotic effects.43,44,47 Furthermore, it has been demonstrated that FoxOs and
T cell factor (Tcf ) factors compete for the limited nuclear pool of b-catenin.169,170
These observations confirm the pivotal role of the evolutionarily conserved FoxO/
b‑catenin interactions and provide new insights into the complex signalling
network of FoxO1, c-myc and Wnt/b-catenin signalling in SG development and
homeostasis (Table 2).
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Akt/GSK3/FoxO1/mTORC1-interaction: Increased insulin/IGF-1 signalling via

activation of Akt triggers not only inhibitory phosphorylation of FoxO1, but also of
GSK3.171,172 When active under fasting conditions GSK3 is dephosphorylated.173
Active GSK3 directly phosphorylates and activates TSC2 when primed by
AMPK-dependent phosphorylation and inhibits mTORC1 activation.174 In the
postprandial state, i.e. conditions of high glucose availability and high insulin
signalling, Akt-driven inactivation of GSK3 alleviates TSC2-driven inhibition
of Rheb, and thus results in mTORC1 activation.174 Recently, direct interaction
between FoxO1 and GSK3b has been observed.175 Overexpression of GSK3b
augmented FoxO1-mediated glucose-6-phosphatase (G6Pase) promoter
activation in a manner dependent on its kinase activity, whereas GSK3 inhibition
abolished the G6Pase promoter activation by FoxO1 (Table 2).175
Taken together, substantial evidence underlines the central role of the nutrient-
sensitive transcription factor FoxO1 as a relaying system orchestrating nutrient
signalling in the pathogenesis of acne. FoxO1 activity is primarily regulated by
insulin/IGF-1 signalling, interacts at multiple regulatory levels with mTORC1
signalling and modifies pivotal pathways important for sebocyte proliferation and
homeostasis. Not only by chance, FoxO1 maintains a close molecular crosstalk
with canonical growth-regulating pathways, modifies the expression of FoxO1
target genes, and physically interacts with PPARg, LXRa, AR, b-catenin and
GSK3b (Table 2).77,78,83,84,168,175
ENHANCED FOXO1 SIGNALLING

INDUCED BY ISOTRETINOIN
Insulinotropic and IGF-1 enhancing Western diet obviously decreases FoxO1-
mediated metabolic regulation and gene transcription.7 In contrast, accumulating
evidence derived from studies of isotretinoins therapeutic and adverse effects
is consistent with the proposed hypothesis that isotretinoin exerts its major
therapeutic mode of action by upregulation of nuclear FoxO1 levels (Figure 2).69
Isotretinoin undergoes significant and selective all-trans-isomerization to all-
trans-retinoic acid (ATRA) in cultured sebocytes and has been considered as a
prodrug mediating its activity through isomerization to ATRA.176-178 Binding of
ATRA initiates changes in interactions of RARs/retinoid X receptors (RXRs)
with corepressor and coactivator proteins, activating transcription of primary
target genes. Importantly, ATRA/RAR-signalling induces secondary responses
in gene expression encoding transcription factors and signalling proteins that
further augment a whole cascade of gene expression.179 FoxO proteins, especially,
are transcription factors of the secondary retinoid response.179 They transcriptionally
activate their target genes to generate the whole spectrum of retinoid-mediated
transcriptional regulation.179 For instance, ATRA increased the expression
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FoxO, forkhead box class O transcription factor; ATRA, all-trans-retinoic acid; STRA8, stimulated by retinoic acid
8; CRM1, chromosomal region maintenance protein 1 (exportin-1); JNK, Jun N-terminal kinase; MST1, STE20-like
protein kinase-1; ROS, reactive oxygen species.
Figure 2: Synopsis of the common mode of action of all antiacne agents: the upregulation of nuclear
FoxO1. Oral isotretinoin after isomerization to ATRA enhances the expression of FoxO3, an important
inducer of FoxO1 expression. ATRA enhances the expression of STRA8, which binds to CRM1 and
interferes with nuclear FoxO1 export. Doxycycline inhibits the expression of CRM1, thereby impairs
FoxO1’s nuclear export. Benzoyl peroxide (BPO) generates oxidative stress and activates JNK and MST1,
which by specific phosphorylation promote nuclear FoxO import.
of FoxO3a in neuroblastoma cells and FoxO3a has been identified as a key

regulator for ATRA-induced granulocytic differentiation and apoptosis in acute
promyelocytic leukemia.180,181 Furthermore, treatment of acute promyelocytic
leukemia cells with ATRA reduced FoxO3a phosphorylation and translocated
FoxO3a into the nucleus. Notably, FoxO3a is a strong inducer of the transcription
factor FoxO1.47 FoxO1 expression is stimulated by activated FoxO3a at the FoxO1
promoter in a positive feed back loop.47 Thus, systemic isotretinoin trreatment
appears to activate FoxO1-dependent target genes by induction of the ATRA/
RAR/FoxO3a/FoxO1 signalling cascade (Figure 2).69
Support for the isotretinoin-FoxO1-hypothesis comes from a recent genome-
wide analysis of FoxO1 binding in mouse hepatic chromatin.51 It is well known that
Pck1 (phosphoenolpyruvate carboxykinase 1) and Pdk4 (pyruvate dehydrogenase
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kinase isoenzyme 4) are retinol and ATRA-reponsive genes.182-186 At the promoter

level these genes are not only regulated by retinoic acid response elements, but also by
FoxO1.50,51,60 Pck1 and Pdk4 gene expression of retinol and ATRA-stimulated cells
were significantly reduced when FoxO1 was deleted.51 Thus, maximal induction
of Pck1 and Pdk4 appears to require promoter activation of both the retinoic acid
response elements as well as FoxO1-binding sequences. This view is compatible
with isotretinoin/ATRA/FoxO1-stimulated activation of Pck1 and Pdk4, which
appears to be reduced when FoxO1 is deleted. This mechanism explains increased
gluconeogenesis with elevated glucose serum levels in patients systemically treated
with higher doses of isotretinoin.10,69 Thus, upregulation of FoxO1 by isotretinoin
not only induces proapoptotic responses, but may also inhibit mTORC1 resulting
in enhanced autophagy and explains the suppressive effects of isotretinoin on
keratinocyte and sebocyte growth, cell proliferation and sebum production.10,69
DO RETINOIDS AND DOXYCYCLINE

INHIBIT NUCLEAR FOXO EXPORT?
The transport of FoxO proteins through the nuclear pore is dependent on active-
transport mechanisms.44,187 Transport across the nuclear-pore complex requires
adaptor proteins that mediate either import or export. These adaptors are importin
or exportin receptors, respectively.188 Importins and exportins recognize specific
nuclear localization signals (NLSs) and nuclear export signals (NESs) present
in the protein to be exchanged. Previous studies of FoxO1 have identified an
NLS in the C-terminal basic region of the DNA-binding domain, and a leucine-
rich, leptomycin-sensitive NES located further downstream of FoxO1. The
evolutionary conserved protein exportin 1, also called CRM1 (chromosomal
region maintenance protein 1) recognizes several NESs including those of FoxO
proteins.44,189 Therefore, FoxO1 binding to CRM1, is a requirement for FoxO1
nuclear export (Figure 2).189-191 Remarkably, the herbal fungicide leptomycin B
(LMB) is a specific inhibitor of the nuclear export factor CRM1.192,193
Furthermore, LMB specifically inhibits CRM1-FoxO1 interaction by binding
to the LMB-sensitive NES motif of FoxO1.194 Thus, FoxO proteins accumulate
in the nucleus after treatment with LMB.189-191 The fact that LMB enhances
nuclear FoxO accumulation allows the prediction that topical treatment with
LMB might be a most powerful new antiacne therapy. LMB has been shown to
exert antiinflammatory action in contact dermatitis and inhibited the expression
of cyclooxygenase-2 (COX-2) and matrix metalloproteinases (MMP)-9 and
MMP‑3.195-197 Notably, increased expression of COX-2 and MMP-9 have been
observed in SGs of acne patients.198,199 Isotretinoin treatment has been shown to
reduce the expression of COX-2 and MMP-9.198-200
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The relation bewteen LMB-mediated inhibition of CRM1, the nuclear

FoxO exporter, with decreased expression of MMP-9 allows the assumption that
LMB-induced inhibition of MMP-9 expression may be mediated by increasing
nuclear FoxO levels. Indeed, MMP-9 expression is known to be activated at the
MMP-9 promoter level by FoxO4.201 The fact that isotretinoin, the prodrug of
ATRA, reduces MMP-9 expression in a comparable fashion to LMB allows the
speculation that isotretinoin or ATRA may interfere with the regulation of the
nuclear export machinery, most likely with CRM1 or other CMR1-interacting
proteins of the nuclear core complex.202 In this regard it is most exciting that the
ATRA-induced protein STRA8 (stimulated by retinoic acid 8) has been found to
interact with CRM1.203 The retinoid-responsive STRA8-CRM1 interaction may
thus be another regulatory mechanism of retinoids that modifies the localization
and nuclear distribution of retinoid-responsive transcription factors including
FoxO proteins (Figure 2).
A mainstay of systemic treatment of moderate-to-severe inflammatory acne
is doxycycline, the most commonly prescribed oral antibiotic in the treatment of
acne.204 It is known for a long time that doxycycline not only inhibits bacterial
growth, but most importantly also exerts antiinflammatory effects even when
administered in sub-antibacterial doses.205 Evidence has recently been provided
in a bitransgenic mouse lung tumor model that in mice treated with doxycycline
(500 µg/mL in the drinking water for 9 months) CRM1 expression decreased
dramatically in comparison to untreated mice.206 From this observation it can be
concluded that doxycycline may exert its antiinflammatory action by decreasing
the expression of CRM1, which would enhance nuclear levels of FoxO proteins.
As outlined above, FoxO proteins exert pivotal antiinflammatory and immune
modulatory effects, which would explain the antiinflammatory potential of
doxycycline in the treatment of acne and rosacea. In this regard, both retinoids
and doxycycline may function is a similar fashion by upregulation of nuclear FoxO
levels and stimulation of FoxO-dependent genes (Figure 2).
BENZOYL PEROXIDE: AN ACTIVATOR OF

NUCLEAR FOXO IMPORT
Benzoyl peroxide is the mainstay for the external therapy of acne vulgaris.207
BPO is an organic compound of the peroxide family and penetrates into all skin
layers and structures of the pilosebaceous follicle in a concentration-dependent
fashion.208,209 Topical H2O2 has been shown to be as effective as BPO in reducing
both inflammatory and noninflammatory lesions of acne vulgaris in patients with
mild-to-moderate disease.210,211 The activation of the oxidative stress-inducible
kinases JNK and MST1 by ROS with upregulation of nuclear FoxO levels appears
to be the predominant pharmacological mode of action of peroxide treatment in
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acne, which may counterbalance Western diet-induced nuclear FoxO deficiency

(Figure 2). Upregulated FoxO1 will finally attenuate downstream mTORC1
signalling. Thus, it should be expected that BPO treamtent would reduce
mTORC1-dependent growth and proliferation of keratinocytes and sebocytes. In
fact, it has been shown 30 years ago by Gloor et al. that BPO treatment decreased
the size of gold hamster ear SGs and the number of sebocytes entering the
S-phase of the cell cycle.212 Similar results have been obtained in autoradiographic
studies of human SGs.213,214 Although less efficient than ATRA, BPO decreased
the size and number of corneocytes and reduced comedo formation in the rabbit
ear microcomedo prevention assay.215,216 Recent evidence derived from follicular
granulosa cells confirmed that H2O2 stimulated FoxO1 nuclear translocation.217
Thus, BPO is most likely a cutaneous FoxO1 inducer with inhibitory action on
mTORC1-driven keratinocyte and sebocyte growth and proliferation. Future
research should substantiate the impact of “old” BPO in modern concepts of
FoxO1-mTORC1 regulation in acne.
METFORMIN ATTENUATES TORC1

The old antidiabetic drug metformin in combination with either spironolactone
or simvastatin has recently been shown to improve acne, especially in females with
polycystic ovary syndrome (PCOS).218,219 Treatment of PCOS with metformin
improves overweight, IR and clinical signs of hyperandrogenism including
acne.220 Remarkably, acne has been associated with increased body mass index.40
Metformin reduces body weight and activates AMPK resulting in mTORC1
inhibition (Table 4).113,122
Intriguingly, a second AMPK-independent mechanism of metformin-
mediated mTORC1-inhibition has recently been identified. Metformin inhibited
the leucine-induced translocation of inactive mTORC1 to Rheb-enriched
lysosomal membrane compartments and thereby reduced mTORC1 activation by
amino acid stimulation.221 Thus, metformin counterbalances the adverse growth-
promoting effects of Western diet mediated by high insulin/IGF-1 and leucine
signalling. However, metformin and other AMPK agonists suppress FoxO1
activity.222,223 In contrast to FoxO1, AMPK-mediated phosphorylation of FoxO3a
resulted in activated FoxO3a expression and stimulation of FoxO3a-dependent
genes coding for tumor suppressors and cell cycle arrest.181,223,224 FoxO3a binds
and transactivates the TSC1 promoter, indicating a key role for FoxO3a in
regulating TSC1 expression and mTORC1 signalling.140 Notably, FoxO1 itself is
a FoxO3a-target gene, which demonstrates the complexity of the FoxO-mediated
feedforward and feedback regulatory circuits.47
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Table 4: Action of Commonly Used and Potential New Antiacne Drugs Correcting
Imbalanced FoxO1/mTORC1 Signalling
Isotretinioin ATRA↑, FoxO3↑, FoxO1↑ mTORC1↓
ATRA FoxO3↑, FoxO1↑ mTORC1↓
STRA8↑, CRM1↓, FoxO1↑
BPO ROS↑, JNK↑, MST1↑, FoxO1↑ mTORC1↓
Doxycycline CRM1↓, FoxO1↑ mTORC1↓
Leptomycin? CRM1↓, FoxO1↑ mTORC1↓
Metformin AMPK↑, TSC2↑ mTORC1↓
Leucine-Rag-Ragulator↓
Resveratrol PI3K↓, Akt↓, TSC2↑ mTORC1↓
TOR kinase↓
EGCG AMPK↑, TSC2↑ mTORC1↓
PI3K↓, Akt↓, TSC2↑
Rapamycin (sirolimus)? Rapamycin-FKB12-complex↑ mTORC1↓
Rapalogs (everolimus)? Rapalog-FKB12-complex↑
Synthetic TOR kinase TOR kinase↓ mTORC1↓
inhibitors?
Antiandrogens mTORC2↓, Akt↓, TSC2↑ mTORC1↓
LAT↓, leucine-Rag-Ragulator↓
ATRA, all-trans-retinoic acid; FoxO, forkhead box class O transcription factor; mTORC1, mammalian target
of rapamycin complex 1; STRA8, stimulated by retinoic acid 8; CRM1, chromosomal region maintenance
protein-1 (exportin-1); BPO, benzoyl peroxide; ROS, reactive oxygen species; JNK, Jun N-terminal kinase;
MST1, STE20-like protein kinase-1; EGCG, epigallocatechin-3-gallate; AMPK, adenosine monophosphate-
activated protein kinase; TSC2, tuberin; PI3K, phosphoinositol-3 kinase; Akt, Akt kinase (protein kinase B);
TOR, target of rapamycin; LAT, L-type amino acid transporter; Rag, Ras-related GTP-binding protein.
ATTENUATION OF TORC1 BY NATURAL INHIBITORS

There is recent evidence that plant-based Mediterranean diet in contrast to typical
Western diet improves acne.35 Notably, acne is absent in populations consuming a
palaeolithic diet excluding sugar, grains and dairy proteins like the Kitava islanders
who exhibit nearly 50% reduced basal insulin levels compared with age-matched
Europeans.2,225 Higher consumption of vegetables, predominantly cruciferous
vegetables in association with green tea consumption may antagonize increased
mTORC1 signalling induced by Western diet. Thus, diets emphasizing vegetables
and fruits and restricting dairy products, isolated sugars and cereal grains are
associated with reduced insulin/IGF-1-signalling. Higher intake of plant-derived
natural mTORC1 inhibitors appears to have an additional favorable effect in
the treatment of acne, and has been shown to have a protective effect in the
development of prostate cancer.42 Intriguingly, prostate cancer patients exhibited
an increased incidence of more severe acne.226
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Resveratrol
Resveratrol, a polyphenolic flavonoid from grapes and red wine with potential
antiinflammatory, antioxidant, neuroprotective and anticancer properties, down
regulates PI3K/Akt/mTORC1-signalling.227-231 Resveratrol has been shown
to directly inhibit PI3K by targeting the class IA PI3K ATP-binding site in a
competitive and reversible fashion.232 Thus, resveratrol acts as a direct and indirect
inhibitor of mTORC1. These insights imply that resveratrol may exert beneficial
therapeutic effects in the treatment of acne. In fact, resveratrol has been shown to
inhibit the proliferation of P. acnes and topical treatment of facial acne vulgaris in
20 patients with a resveratrol-containing gel (0.01% weight/volume) significantly
reduced the number of microcomedones, papules and pustules compared to
vehicle control.233,234
Epigallocatechin-3-Gallate
Epigallocatechin-3-gallate (EGCG), the major green tea catechin, is regarded
as the active antiinflammatory and antiproliferative compound of green tea
extracts.235-238 It has been demonstrated that topical 2% green tea lotion was
effective in the treatment of mild-to-moderate acne vulgaris.239 After 6 weeks,
the mean total lesion count and mean severity index of acne showed significant
reductions of 58% and 39%, respectively.239 Furthermore, a 3% green tea emulsion
significantly reduced sebum production in 10 healthy male volunteers after 8 weeks
of treatment.240 Most recently, it has been demonstrated that topical application of
EGCG to rabbit auricles reduced the size of the SGs. When applied to cultured
human SZ95 sebocytes, EGCG strongly suppressed cell sebocyte proliferation
and lipogenesis.241 EGCG in physiologically relevant concentrations has been
shown to function as an ATP-competitive inhibitor of both PI3K and mTORC1,
respectively.242 Both resveratrol and EGCG are thus natural PI3K and mTORC1
lipid kinase inhibitors. In accordance, EGCG has been shown to activate AMPK
and to suppress mTORC1 and 4E-BP-1.243 Notably, the PI3K inhibitor EGCG
upregulated nuclear FOXO levels in Caenorhabditis elegans and attenuated TOR
signalling, thus explaining the worm’s life span extension.244
TORC1 INHIBITION BY RAPAMYCIN AND

TOR KINASE INHIBITORS
Future drug research and development in acne should focus on topical mTORC1
inhibitors. These may include the topical use of the immuno-suppressant
allosteric mTORC1 inhibitor rapamycin, rapalogs like everolismus as well as
specific competitive inhibitors of the ATP-dependent kinase domain of target of
74

rapamycin (TOR). Effective inhibition of growth and proliferation of androgen-

dependent prostate epithelial and carcinoma cells by TOR inhibitors has been
demonstrated and reviewed elsewhere.42
FOXO1-TORC1 SIGNALLING OF WESTERN VERSUS

PALAEOLITHIC DIET
Acne is a disease of Western civilization with prevalence rates in adolescence of
over 85% in the USA and European countries.2,245,246 According to the Indian
Acne Alliance, acne in India is believed to be as common.247 Insulinotropic and
IGF-1-enhancing Western diet appears to be the fundamental environmental
factor promoting the acne epidemic.6,8,10 Acne is absent in populations consuming
less insulinotropic palaeolithic diets like the Kitava islanders.2,225 Palaeolithic diets
do not contain grains and dairy proteins, and are thus much lower in total insulin/
IGF-1 signalling.6
It has been demonstrated in this article that the nutrient-sensitive transcription
factor FoxO1 relays nutrient-derived growth signalling of insulin and IGF‑1 to
FoxO1-mediated transcriptional programs of gene expression. At various levels of
interaction, FoxO1 inhibits mTORC1, the central hub of metabolism controlling
protein and lipid synthesis, cell proliferation, cell differentiation and autophagy.
The insulin/IGF-1 signalling of palaeolithic diets is low and comparable to
low insulin/IGF-1 signalling of individuals with Laron syndrome who exhibit
congenital IGF-1 deficiency and elevated nuclear FoxO levels.6,55,56 Notably,
untreated patients with Laron syndrome never develop acne and are protected
from cancer and type 2 diabetes.55,56
DIETARY INTERVENTION IN ACNE

Less insulinotropic plant-based diets containing natural mTORC1 inhibitors
may be most promising in the treatment of acne as well as topical treatment of
acne with natural mTORC1 inhibitors like resveratrol and EGCG.239-244
However, it should be appreciated that deviated FoxO1/mTORC1 signalling
is not only an acne-specific medical problem, but also reflects the predominance
of adverse prolonged nutrient signalling promoting other common mTORC1-
driven age-related diseases. Epidemic acne thus shares the same deviations of
mTORC1 signalling found to be of critical importance in the development of
obesity, type 2 diabetes and cancer.10 In contrast, FoxO1 polymorphisms with high
nuclear FoxO binding affinity appear to be associated with longevity and reduced
prevalence of age-related diseases.248,249 In this regard Kapahi and co-workers
have recently proposed “with TOR less is more”.100 In fact, there is convincing
evidence from recent concepts of molecular medicine that less mTORC1-
75

Melnik
activity is most favorable and delays the onset of aging and common diseases
of cilvilization.106,250-254 Chronically enhanced mTORC1 links growth signal
integration to cancer, diabetes and ageing.254 Dermatology should recognize that
acne is a visible indicator disease of exaggerated diet-induced mTORC1 signalling
with long-term adverse health effects.10
The population of India, especially, appears to be exposed to a higher risk
as India’s major source of animal-derived proteins are the growth-promoting
insulinotropic proteins of bovine lactation. From all animal proteins, the whey
proteins, components of milk and yoghurt, exert the highest insulinotropic
response.255,256 Young male adolescents visiting the fitness and bodybuilding
environment have an increased risk for acne when they consume daily amounts
of 60–80 g of whey protein concentrates to enhance muscle mass.41,257 In fact,
high whey protein intake of young adult men has been shown to increase skeletal
muscle mTORC1 activity and downstream 4E-BP-1 phosphorylation.258
CONCLUSION
Insulinotropic Western diet appears to be the fundamental cause for impaired
FoxO1-mediated gene regulation in acne. FoxO1 has been identified as a key
regulator in acne.7 FoxO1 controls the somatotropic axis, modifies the magnitude of
AR signalling, interacts with important regulators of SG homeostasis (b-catenin),
of metabolism and lipogenesis (PPARg, LXRa, SREBP-1) and most importantly
determines the activity of mTORC1.
Acne is thus a skin disease featuring exacerbated mTORC1 signalling and
belongs to the family of mTORC1-driven diseases of civilization.10 Dietary
intervention in acne is just not an adjunctive treatment option but rather the
causal measure to treat and prevent the most common human skin disease.10
Remarkably by various mechanisms, all effective antiacne drugs appear either
to enhance nuclear FoxO1 or attenuate mTORC1 activity, thus counteract the
signalling imbalances induced by insulinotropic Western diet.
Dermatologists counselling children and adolescents with acne should not
only prescribe antiacne drugs, but should take responsibility to emphasize the
causal diet-acne relationship not only to improve acne but most importantly to
prevent mTORC1-driven chronic diseases of civilization.
Nutrition therapy of acne should: (1) normalize total calorie intake; (2) lower
glycemic load; and (3) restrict total dairy protein consumption and should condemn
whey protein abuse.10 Future studies of clinical dermatology in cooperation with
nutritional sciences have to elaborate appropriate dietary regimens for a save and
efficient nutrition therapy of acne.10 By appreciating the nutrient signalling of
Western diet dermatology comes closer than ever to understand Hippocrates of
Kós who stated about 2400 years ago “your diet should be your medicine, and your
medicine should be your diet”.
76

Editor’s Comment
The role of diet in pathogenesis of acne has always generated debate, with interest
in its importance waxing and waning. Recent evidence has tilted the balance in
favour of a pathogenic function of insulinotropic Western (now ubiquitous!) diet
in the induction and aggravation of acne. Dr. BC Melnik in this article elucidates
the importance of exaggerated nutrient signalling of high glycemic foods and dairy
proteins (which are predominant in modern diets) through increased insulin
and insulin-like growth factor-1 (IGF-1) signalling. Reduced FoxO1 (which
plays an important role in regulation of gluconeogenesis and glycogenolysis)
activity and enhanced mTORC1 (which controls protien synthesis) function are
central to this loop. FoxO1, which is also an androgen receptor cosuppressor, links
nutritional status to androgen dependent growth and also inhibits activity of
mTORC1. Interestingly, many antiacne drugs induce accumulation of nuclear
FoxO and reduce activity of mTORC1, thereby, countering the adverse effects
of enhanced insulin/IGF-1 signalling of Western diet. So apart from prescribing
specific therapy, dermatologists should give patients with acne dietary advice
including suggestions on normalizing total calorie intake, lowering glycemic load
and restricting total dairy protein consumption and condemning excessive use of
whey protein.
Neena Khanna
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258. Farnfield MM, Carey KA, Gran P, Trenerry MK, Cameron-Smith D. Whey protein ingestion activates mTOR-
dependent signalling after resistance exercise in young men: a double-blinded randomized controlled trial.
Nutrients. 2009;1:263-75.
88

Acne and PCOS

Ma Flordeliz Abad-Casintahan MD FPDS
Department of Dermatology, Jose R Reyes Memorial Medical Center,
Manila, Philippines
ABSTRACT
Polycystic ovarian syndrome (PCOS) is a worldwide problem regarded to
be the most common endocrinopathy among women, with about 4–12%
of women in their reproductive age, diagnosed with the condition clinically
and through laboratory examinations. The syndrome has variety of clinical
signs of which none is pathognomonic. Persistent acne that is resistant
to conventional treatments is one of the known manifestations of PCOS.
Obviously, it is a cosmetic concern for most patients; however, what is more
significant than aesthetic are the underlying causes of the condition. These
causes could eventually lead to comorbidities such as diabetes mellitus,
hypertension and other medical conditions which would eventually
influence the overall quality of life of the affected individual. Therefore, it
is of importance to emphasize the need for prompt identification of this
medical condition which if done would lead to timely intervention and
hence, would halt the whole disease process.
The purpose of this article is to shed light on clinicians, particularly the
dermatologists, regarding the diagnosis of PCOS at the background of
resistant acne, as well as the proper management of the condition.
INTRODUCTION
Polycystic ovarian syndrome (PCOS) is a complex and heterogenous disorder
which is widely accepted as the most common cause of anovulatory fertility.1,2 It
affects around 4–12% of women of reproductive age, and an even slightly higher
incidence among adolescents with approximately 11–26%.1,3 Several underlying
etiologies have been enumerated in the past including congenital adrenal
hyperplasia (CAH), ovarian and adrenal tumors, drugs such as anabolic steroids,
progestins, danazol and lastly, androgenic excess secondary to chronic anovulation.
It was the last one where majority of the cases are being attributed.
Email: lizkcmd@yahoo.com

Abad-Casintahan
Resistant acne vulgaris is one of the hallmarks of this condition, and

perhaps the initial symptom that would lead the patient to seek medical
attention. Studies have shown that among women who suffer from acne past
the puberty stage, 10–20% of which would later be diagnosed with PCOS.1 The
complicated nature of this condition makes the diagnosis and eventually the
provision of solution to this problem a real challenge. Several diagnostics and
methods of treatment have been suggested by a number of studies; however, a
specific consensus seems to be missing, or if at all, unknown to most clinicians.
Therefore, this article aims to clarify these issues and makes emphasis on
the importance of early diagnosis and treatment, in order to avoid future
complications associated with PCOS.
PATHOPHYSIOLOGY
Polycystic ovarian syndrome has a number of manifestations which is discussed
in the following sections. These signs and symptoms are the results of two major
underlying pathophysiologic processes namely, hyperandrogenemia and insulin
resistance.
In hyperandrogenemia, what comprises this process is the primary androgen,
dehydroepiandrosterone sulfate (DHEA-S), a hormone which is equal in both
men and women, and is said to regulate sebum production. This is converted into
more potent forms of androgen via intracellular enzymes present in sebocytes.
These are testosterone and dihydrotestosterone (DHT) which are then taken
up in a cell where they bind to a cytoplasmic androgen receptor, and wander
into the nucleus. In the nucleus, they bind into specific gene sequences where
the androgen-receptor complex that is formed affects the reading rate of the
target genes. Whereas, peripherally active androgens control cellular functions
directly or indirectly leading to stimulation of keratinocyte proliferation and the
volume of sebaceous glands as well as the sebum secretion rate. The resulting
follicular obstruction and increased sebum production, respectively along with
Propionibacterium acnes colonization lead to the development of acne lesions.4
On the other hand, recent evidences have been shown linking hyper
androgenemia with insulin resistance, wherein an increase in the level of insulin
leads to elevation of androgen hormones. To begin with, genetic predisposition
determines one’s susceptibility to insulin resistance.5 Here, there is a subnormal
biological response to insulin by a cell, tissue or an organ wherein a greater
than normal amount of the said substance is required to elicit an appropriate
response.2,5 The normal response is increased insulin secretion by b-cells in which
the resulting compensatory hyperinsulinemia has bearing on almost every organ
in the body, from the skeletal muscle to liver, adipocytes and ovaries. In adipose
tissues, there is an observed bidirectional relationship. Insulin has been proven
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Acne and PCOS
to stimulate lipogenesis and inhibit lipolysis at the same time.6 The decrease in
sex hormone-binding globulin (SHBG) from an increase in insulin levels leads
to increased body fat.2 The resulting obesity in return causes insulin resistance
among the affected individuals, as most studies have shown. Another, insulin is
synergistic with gonadotropins in increasing androgen production in the ovaries.
The elevated levels of insulin potentiate the effect of luteinizing hormone (LH) on
ovarian theca cells to cause androgen excess, because the theca cells from PCOS
women are intrinsically programmed to overproduce androgens.7 In the hepatics,
hyperinsulinemia results in a decreased production of SHBG with consequent
increase in the delivery of free androgens to target tissues, leading to an elevated
free testosterone fraction.8 Whereas in the adrenals, there is collaboration with
adrenocorticotropic hormones (ACTH) causing the eventual increase in adrenal
androgens. Lastly, in pilosebaceous glands there is a resulting heightened response
to androgen hormones leading to the development of the characteristic resistant
acne vulgaris.
In summary, insulin resistance along with the subsequent hyperinsulinemia
aids in ensuing the major factor in the initiation of PCOS which is hyper
androgenemia. Suffice to say that every manifestation of this condition is a
consequence of the rise in androgen levels in the affected organ systems.
CLINICAL FEATURES
Acne Vulgaris
Acne vulgaris is a chronic inflammatory disease of the pilosebaceous follicles,
characterized by comedones, papules, pustules, nodules and often, scars.9
Moderate-to-severe inflammatory acne primarily located around the perioral
area and along the jawline (above and below) that is persistent and resistant to
conventional treatment, should alert the dermatologist to the possible presence
of PCOS. Approximately 11–43% of PCOS patients manifest with acne vulgaris
wherein 93% of them experience premenstrual flares.10
Hirsutism
Hirsutism is defined as excessive hair growth in women where the hair growth
is most androgen sensitive. These sites include upper lip, chin, chest, upper
abdomen and back. It should not be confused with hypertrichosis, a condition
characterized by general increase in hair including nonsexual areas such as trunk
and extremities.11
Hirsutism can be found in 60–70% of women with PCOS.1 Genetic variances
exist due to differences in 5a-reductase activity wherein its incidence among
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Abad-Casintahan
Case Study
A case of an 18 year-old female presented with a history of moderate to severe
inflammatory acne, mostly located along the jawline area as well as the back area,
persistent and resistant to treatment, with noted pre-menstrual flares. On physical
examination, patient presented with central obesity and thickened, pigmented,
velvety skin over the neck (Figures 1–3). Pelvic ultrasound was requested revealing
presence of polycystic ovaries.
Figure 1: Multiple erythematous papules and pustules

over the forehead, malar and jawline and neck.
Figure 2: Multiple erythematous and hyperpigmented

papules on the back. Note also the presence of truncal
obesity.
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Acne and PCOS
Figure 3: Acanthosis Nigricans.
Caucasian patients seem to be higher than Asian women.12,13 Around 40–92%

of PCOS patients in Europe and USA have hirsutism while only 10–20% of
Japanese women with PCOS do so.14,15 In addition, it is important to remember
that hirsutism in the setting of PCOS is slow and chronic, therefore, a rapid onset
and high levels of androgen should alert the dermatologist to the presence of
ovarian or adrenal neoplasm.
Seborrhea
The presence of oily skin among acne patients with PCOS and those women with
acne but without PCOS has been found to be of no significant difference.16
Acanthosis Nigricans
Acanthosis nigricans is characterized by thickened, pigmented, velvety skin lesion,
most often found in the vulva and may be present on the axilla, over the nape of
the neck, below the breast and on the inner thigh; it is a reliable marker of insulin
resistance in hirsute women. It is said to occur in only 1–3% of women with
PCOS, comprised mostly by adolescent girls.17,18
Male Pattern Alopecia

It is defined as diffuse pattern of hair thinning over the vertex of the scalp with
frontal hairline preservation, with less than 10% of women diagnosed with PCOS
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Abad-Casintahan
experiencing it. Whereas, 20% of women having androgenetic alopecia were

shown to have polycystic ovaries on ultrasound.18
Other Clinical Features

As mentioned, the effect of PCOS spans almost every organ in the body producing
a domino effect which therefore explains the wide variety of manifestations seen
in different patients.
The insufficiency of follicle-stimulating hormone (FSH) causes anovulation
among women with PCOS; hence there is secondary amenorrhea, infertility and
menstrual alterations in about 66% of the patients. In addition, as mentioned
in the pathophysiology, there is increased body fat production due to decreased
SHBG levels. This in turn is manifested as truncal obesity in 30–75% of the
patients. Other features of the syndrome include insulin resistance with metabolic
syndrome, with 40–45% of PCOS women affected, and cardiovascular problems
such as the consequent increase risk of atherosclerosis.
DIAGNOSIS
Historically, combination of androgen excess and anovulation has been considered
the hallmark of PCOS. Ultrasonographic evidence of polycystic ovaries was
considered “suggestive” of PCOS but was not required for the diagnosis.19 However,
due to the consistent finding of polycystic ovaries in women demonstrating clinical
and biochemical evidence of the syndrome, the European Society for Human
Reproduction and Embryology (ESHRE) amended a new consensus criteria now
known as the Rotterdam criteria. According to this criteria, the diagnosis of PCOS
requires presence of two of the following criteria: oligoovulation (fewer than eight
menses per 12-month period) and/or anovulation, clinical hyperandrogenism and/
or biochemical signs of hyperandrogenism, and polycystic ovaries (> 12 follicles)
in each ovary measuring 2–9 mm in diameter and/or increased ovarian volume
(> 10 mL) by ultrasonography, with exclusion of all other disorders that can
result in menstrual irregularity and hyperandrogenism.20 Biochemical and/or
imaging studies must be done to rule out other possible disorders and ascertain
the diagnosis.
Exclusion of Related Disorders

In order to make a diagnosis of PCOS, it is important to rule out other disorders
that can mimic it. Disorders that may have similar clinical presentations are
listed in table 1 along with the laboratory tests used to adequately assess these
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Acne and PCOS
Table 1: Differential Diagnoses of PCOS and Screening Tests22

Diagnosis Laboratory test
Late-onset CAH 17-hydroxyprogesterone
Cushing’s syndrome 24-hour urine cortisol
Adrenal tumor Dehydroepiandrosterone sulfate (DHEA-S)
Ovarian tumor Total testosterone
Hyperprolactinemia Prolactin
Hypothyroidism Thyroid-stimulating hormone
Syndromes of severe insulin resistance Fasting blood sugar and insulin level
(HAIR‑AN syndrome)
HAIR-AN, hyperandrogenemia, insulin resistance and acanthosis nigricans; PCOS, polycystic ovarian
syndrome; CAH, congenital adrenal hyperplasia.
possibilities. These tests should be obtained in the luteal phase of the menstrual
cycle (within 2 weeks before the onset of menses).21
However, there are several issues in the interpretation of laboratory tests that
can affect diagnosis.1
24-Hour Urine Cortisol

Mild elevations can be observed in PCOS; values reaching more than double
the upper limit of normal is more consistent with Cushing’s syndrome. A
dexamethasone-suppression, corticotropin-releasing hormone stimulation test is
needed to distinguish true Cushing’s syndrome from pseudotypes.
Dehydroepiandrosterone Sulfate
In a subset of patients, DHEA-S may be normal or slightly elevated in PCOS.
Values more than 800 µg/dL warrant consideration of an adrenal tumor.
Testosterone
Testosterone values may be normal in PCOS. In patients taking oral contraceptive
pills (OCPs), it is best to get the total testosterone level after 3 months off the
medication as OCP tend to lower total testosterone. Most testosterone values in
PCOS will be less than or equal to 150 ng/dL (≤ 5.2 nmol/L). A virilizing tumor
is suspected if values exceed 200 ng/dL (≥ 6.9 nmol/L).
Prolactin
Mild hyperprolactinemia has been reported in 5–30% of patients with PCOS.
Most cases are transient with only 3–7% of patients having persistently elevated
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Abad-Casintahan
prolactin levels. Moreover, patients with prolactinomas may have polycystic ovaries
on ultrasound.
Assessment of Oligo- or Anovulation

Menstrual irregularities in PCOS result from anovulation. Menstrual history
is important in the clinical evaluation of anovulation. Oligomenorrhea is
characterized by fewer than eight episodes of menstrual bleeding per year or
menses that occur at intervals greater than 35 days. However, ovulatory dysfunction
can be present in patients with regular menses so laboratory investigation is still
needed.
The initial work-up for patients presenting with oligo- or anovulation includes
measuring LH and FSH levels. It is clear that a significant number of women with
PCOS have elevated LH. A LH/FSH ratio of greater than or equal to 2.0 may
be found in 95% of patients with PCOS but is not highly sensitive or specific. In
one study, the ratio was elevated in 35 out of 63 (55.6%) patients with PCOS.9
Ovulation can be confirmed by obtaining serum progesterone level greater than
10 nmol/L taken at any random time during the luteal phase.19
Assessment of Hyperandrogenism
Excess androgens may be produced by either the adrenal gland or the ovary.
Suspicion of hyperandrogenism may be aided by clinical symptoms. Hirsutism
is present in 60–70% of women with PCOS and is considered the most common
clinical manifestation of hyperandrogenism in women. Acne is present in one-
third of patients, particularly in younger women. Alopecia is also recognized as a
symptom of PCOS as it is an androgen-mediated process.19 However it appears
to be a poor predictor of biochemical excess androgen unless present in the oligo-
ovulatory patient.22
Total testosterone assay is the recommended first-line approach in the
investigation of hyperandrogenism in women. As mentioned earlier, most total
testosterone in PCOS will be less than or equal to 150 ng/dL (≤ 5.2 nmol/L)
and will exceed 200 ng/dL in an androgen-secreting adrenal or ovarian tumor.
If the testosterone level is twice the upper limit of the normal, DHEA-S assay
may be performed. If DHEA-S is normal, the diagnosis could be either ovarian
hyperthecosis (associated with insulin resistance), or an androgen-secreting
ovarian tumor. DHEA-S level of more than 600 µg/dL (16,000 nmol/L) connotes
an androgen-secreting adrenal cortical adenoma.23
Normal testosterone levels in patient with signs of hyperandrogenism such as
hirsutism and seborrheic acne must be handled carefully. If there is any suspicion
of PCOS, SHBG assay must be performed. SHBG is normally reduced in PCOS,
increased weight, metabolic syndrome, or in family history of diabetes. Rarely,
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Acne and PCOS
elevated testosterone is associated with marked increase in SHBG, possibly

because of the estrogenic effects of drugs (tamoxifen, raloxifene), hyperthyroidism,
or liver disease.
Assessment of Polycystic Ovaries

Transvaginal ultrasound in the evaluation of polycystic ovaries has a sensitivity
and specificity of 75% and 99%, respectively.24 Modern imaging techniques have
shown cysts in about 80% of women over the age of 21 years who complained of
severe acne. The current ultrasonographic guidelines define polycystic ovary as
containing 12 or more follicles in each ovary measuring 2–9 mm in diameter, and/
or increased ovarian volume of more than 10 mL. Ultrasound should be performed
in the early follicular phase (cycle days 3–5) in regularly menstruating women, and
at random or between days 3 and 5 after a progestin-induced withdrawal bleeding
in oligo- or amenorrheic women. Whenever possible, the transvaginal approach
should be utilized, especially in obese patients.22
Computed tomography scan of the adrenal glands may be done to rule out an
adrenal tumor.
Other Tests
Insulin Resistance
Understanding of the link between PCOS and insulin resistance has been growing.
Though it is not required for diagnosis or before starting insulin-sensitizers, serum
levels of insulin may be determined. Some suggest using oral glucose tolerance
test and 2-hour glucose level after a 75 g oral glucose challenge to evaluate risk
of diabetes or for calculating glucose-to-insulin ratio (< 4.5 suggests insulin
resistance).22
Relevance of Diagnosis of PCOS

Left untreated, PCOS can lead to increased risk of diabetes mellitus, metabolic
syndrome, infertility, endometrial cancer, hypertension and hereditary cardio
vascular disease in relatives. Although the genetics of PCOS remain unclear, a
strong familial relationship exists. In a large family study of 336 women with
PCOS and 307 probands, indicators of hyperinsulinemia were found more in
sisters of women with the syndrome than in controls and hyperandrogenemia was
established as the major predictor of insulin resistance.25 This predisposes relatives
to metabolic and cardiovascular diseases. Therefore, the diagnosis of PCOS should
initiate review of family members.26
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TREATMENT
The goals in the medical management of PCOS can be divided into short-term
goals (control of acne, hirsutism, obesity and menstrual irregularities) and long-
term goals (restoration of ovulation and fertility, and prevention of diabetes
mellitus, cardiovascular disease and endometrial cancer).
Specifically, hormonal therapy in the management of acne in PCOS is geared
toward opposing the effects of androgens on the sebaceous gland and probably
follicular keratinocytes.21 This can be achieved with the use of estrogens, agents
designed to suppress the endogenous production of androgens by the ovary or
adrenal gland, or antiandrogens (androgen receptor blockers). Increasing sensitivity
to insulin with the use of insulin-sensitizers indirectly improves acne.
Ovarian Androgen Production Inhibitors

The most common form of ovarian suppression is treatment with combined
OCPs. Estrogens are commonly used to treat acne, usually in combination with
a progestin to avoid the risk of endometrial cancer associated with unopposed
exposure to estrogens. The estrogen component suppresses the ovarian production
of androgens by suppressing gonadotropin release and stimulating hepatic SHBG
production, thereby decreasing the bioavailability of serum testosterone.21 On
the other hand, the progestin component lowers the local androgen effect by
inhibiting 5a-reductase activity in the hair follicle or by competitively inhibiting
the androgen receptor. All combined OCPs reduce free testosterone and have
a positive effect on acne with respect to number of total lesions, inflammatory
lesions, and global assessment. A recent Cochrane database review of 25 trials
concluded that combined OCPs worked better than placebo in controlling acne.
Formulations containing more androgenic progestins such as levonorgestrel and
norgestrel may be less effective.27 Available combined OCPs are the following:
ethinyl estradiol 35 µg + cyproterone acetate (CPA) 2 mg (diane-35), ethinyl
estradiol 30 µg + drospirenone 3 mg (Yasmin), and ethinyl estradiol 20 µg +
drospirenone 3 mg (Yaz). There is no clear consensus regarding the maximum
duration of hormonal therapy but giving for 6–12 months is associated with good
outcomes.28
The risk of thromboembolism, considered the most serious side effect of OCPs,
is tripled particularly in women of older age and those with hypercoagulable states
or deep venous thrombosis. OCPs are also not advised in women over 35 years
old who smoke. Associated mortality doubles in women aged 35–44 years
compared with younger women. Hypertriglyceridemia may possibly be worsened
prompting determination of fasting lipid profile prior to initiation of therapy.
Breast examination, Pap smears and referral to an obstetrician-gynecologist is
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Acne and PCOS
recommended if subjecting patient to chronic estrogen therapy. In general, OCPs

are well-tolerated by most women. More common adverse effects are nausea,
vomiting, breast tenderness, headache, spotting and weight gain.21
Antiandrogens or Androgen Receptor Blockers

Spironolactone
An aldosterone antagonist, spironolactone acts both as an androgen receptor
blocker and an inhibitor of 5a-reductase activity. In a retrospective study
of low-dose spironolactone therapy in 85 patients with acne, 28 (33%) had
marked improvement, 23 (27.4%) had partial improvement and 6 (7%) had no
improvement. Therapeutic dose for acne is 50–100 mg twice a day and has been
shown to reduce sebum production and improve acne. Duration of treatment can
span 6–12 months and may be given up to 12 weeks with tolerable side effect.29
Spironolactone may also be used in combination with OCPs in women who have
limited response to OCPs alone. A higher dose is needed to reduce hirsutism,
ranging from 100 mg to 300 mg daily.30
Side effects are dose-dependent and include polydipsia, polyuria, nausea,
headache, fatigue, gastritis and menstrual irregularity (most common). Despite
its mild diuretic effect, spironolactone may potentially cause hyperkalemia.
Serum potassium is then checked 1–2 weeks after initiation of therapy or after
dose increase. Patients are also counseled regarding foods high in potassium.
Because spironolactone is an antiandrogen, there is risk of feminization of a
male fetus if it is taken during pregnancy. Thus, it is important for patients to
be on OCPs while on therapy or should be off medication for 3 months before
conception.21
Cyproterone Acetate
Cyproterone acetate is a progestational antiandrogen that competitively inhibits
testosterone and DHT at the level of androgen receptors. Administration of CPA
50–200 mg/day on days 5–15 and ethinyl estradiol 30–50 µg/day on cycle days
5–26 based on reverse sequential regimen given for 9–12 months showed decrease
in acne scores by 70–77% in 83–92% of patients.31
The most concerning side effect is hepatotoxicity, which appears to be related
to other hepatic diseases, and also tends to be dose-dependent.32 It should only be
used in women because like spironolactone, CPA can also result in feminization
in men. Other reported adverse effects are increased risk of thromboembolism,
decreased libido, breast tenderness, menstrual irregularity, fluid retention and
melasma.
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Flutamide
This drug is indicated and approved for the treatment of prostate cancer. It is
a nonsteroidal antiandrogen that acts after conversion of 2-hydroxyflutamide, a
potent competitive inhibitor of DHT binding to androgen receptor. Low doses of
62.5 mg or 125 mg/day are the recommended use for the treatment of mild-to-
moderate acne.33 However, in one study, 250 mg OD was seen to be as effective
as 250 mg BID with improvement of acne in 75% of patients treated for 1 year.34
One study revealed that combination of OCPs and flutamide is more efficacious
than flutamide alone.21 In hirsute women with acne who were treated with OCPs,
the addition of flutamide was significantly more effective than the addition of
spironolactone.35 Flutamide has also been used alone and in combination with
metformin and OCP in patients with PCOS to improve hyperandrogenic findings
in these patients.
The use of flutamide in the treatment of acne is very much limited by its side
effects. Serious adverse events include hepatotoxicity and anemia, leukopenia and
thrombocytopenia. Most importantly, cases of fatal drug-induced hepatitis have
been reported and monitoring of liver profile is required.36 It cannot be given to
pregnant women as it crosses the placenta and can produce a pseudohermaphrodite
condition of a male fetus. Therefore, flutamide should only be used cautiously and
in the most severe cases resistant to other forms of treatment.
Finasteride
Finasteride is a 5a-reductase inhibitor that acts by blocking the intracellular
conversion of testosterone to DHT. As a result, the amount of DHT available for
interacting with androgen receptors is decreased. It has a predominant effect on the
type 2 isoenzyme of 5a-reductase that specifically affects sebaceous gland activity,
explaining its action in decreasing acne.34 Given at 5–7.5 mg daily, it is reported
to be comparable to spironolactone in treating hirsutism. Use of finasteride has
been associated with gastrointestinal upset, but does not alter menstrual cyclicity.
Plasma levels of testosterone may increase during treatment, whereas DHT level
decreases. Most importantly, patients are also advised to avoid pregnancy due to
risk of having ambiguous genitalia in a male fetus.
Insulin-Sensitizing Agents
Metformin
Reduction in the symptoms of hyperandrogenism and improved menstrual
function has been documented with intake of metformin. Studies have indicated
that reducing plasma insulin levels substantially ameliorates hyperandrogenism in
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Acne and PCOS
Table 2: Dose Titration and Safety Issues with the Use of Metformin1
Dose titration example
Breakfast Supper Duration
X 500 mg 1 week
500 mg 500 mg 1 week
500 mg 1,000 mg 1 week
1,000 mg 1,000 mg Thereafter
Side effects Gastrointestinal in tolerance in 30% (nausea, abdominal pain and/
or diarrhea)
Precautions Hold for 48 hours prior to and after surgery and/or administration
of radiocontrast materials
Contraindications • Creatinine ≥ 1.4 mg/dL (for women)
• Liver disease (or risk thereof: alcohol abuse/binge drinking)
• Other risks for lactic acidosis: pulmonary disease, congestive
heart failure
PCOS.34 Metformin is an antidiabetic drug belonging to the biguanide class that

increases insulin sensitivity in both liver by inhibiting hepatic glucose production
and in the peripheral tissue by increasing glucose uptake and utilization. It
increases SHBG leading to improvement of insulin sensitivity causing a decrease
in free testosterone level. Aside from effects on insulin sensitivity, it also induces
resumption of normal ovulatory menstrual cycles in 40–90% of patients.1 Table 2
lists dosing/titration information as well as safety issues concerning metformin use.
No clear consensus has been established on how long to give metformin before it
is deemed ineffective at improving menstrual function but a 6-month trial seems
reasonable. On literature review, it was found that metformin, in comparison to
OCPs, is less effective in improving menstrual pattern, less effective in reducing
the serum total testosterone level weighted mean difference, and more effective in
reducing fasting insulin and decreasing fasting triglycerides levels.37
CONCLUSION
Polycystic ovarian syndrome is a metabolic syndrome that is prevalent around
the world presenting consistently with signs and symptoms of hyperandrogenism,
anovulation and insulin resistance. Interestingly, some patient will not have
excess body hair, obesity, or menstrual irregularities. It is commonly found among
women with resistant acne not responding to conventional treatment. Diagnosis
is mainly based on clinical grounds and biochemical tests to support the diagnosis.
Other diseases may exhibit the same symptoms as PCOS and it is important to
rule out these mimickers. The mainstay of treatment of acne in PCOS includes
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Abad-Casintahan
inhibition of ovarian androgen production, blocking of androgen action at the

level of androgen receptors and increasing sensitivity to insulin. Early diagnosis
is important as PCOS is associated with increased risk of developing diabetes,
cardiovascular diseases and endometrial cancer among other things. With the
increasing understanding of the link between PCOS and hyperinsulinemia, it is
recommended that initiation of review of relatives be started. This underscores the
fact that acne in PCOS is not merely skin deep.
Editor’s Comment
Polycystic ovarian syndrome (PCOS), a global problem, is the most common
endocrinopathy in women of the reproductive age, with a prevalence of 4–12%.
Though the syndrome has plethora of clinical manifestations, late onset persistant
acne vulgaris may be the earliest symptoms. The acne associated with PCOS is usually
moderate-to-severe, with predominantly inflammatory lesions located mainly
periorally and along the jawline and is often resistant to conventional treatment.
The other cutaneous clues to PCOS include slowly progressive hirsutism (60–70%),
patterned hair loss (10%) and acanthosis nigricans (1–3%). The gynaecological
manifestations include secondary amenorrhea, infertility and menstrual alterations
in about 2/3rd. Other manifestations include truncal obesity (30–75%), insulin
resistance with metabolic syndrome (40–45%) and increased risk of atherosclerosis.
Though not universally applied, diagnosis of PCOS is usually based on the Rotterdam
criteria viz presence of 2 of the following 3 criteria: oligoovulation (fewer than
8 menses/ year) and/or anovulation, clinical/biochemical hyperandrogenism and
polycystic ovaries (> 12 follicles) in each ovary measuring 2–9 mm in diameter
and/or increased ovarian volume (> 10 mL) by ultrasonography, with exclusion of
all other disorders that can result in menstrual irregularity and hyperandrogenism.
Dr Casintahan in this article has discussed these issues with emphasis on the
importance of early diagnosis and treatment, in order to avoid future complications
associated with PCOS. So acne may just be a clue to looking for deeper problems.
Neena Khanna
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edition. Philadelphia, PA, USA: Lippincott Williams & Wilkins; 2007. pp. 1069-1136.
12. Serafini P, Ablan F, Lobo RA. 5 alpha-Reductase activity in the genital skin of hirsute women. J Clin Endocrinol
Metab. 1985;60:349-55.
13. Lobo RA, Goebelsmann U, Horton R. Evidence for the importance of peripheral tissue events in the develop
ment of hirsutism in polycystic ovary syndrome. J Clin Endocrinol Metab. 1983;57:393-7.
14. Kopera D, Wehr E, Obermayer-Pietsch B. Endocrinology of hirsutism. Int J Trichology. 2010;2:30-5.
15. Aono T, Miyazaki M, Miyake A, Kinugasa T, Kurachi K, Matsumoto K. Response of serum gonadotropins
to LH-releasing hormone and oestrogens in Japanese women with polycystic ovaries. Acta Endocrinol
(Copenh). 1977;85:840-9.
16. Ojaniemi M, Pugeat M. An adolescent with polycystic ovary syndrome. Eur J Endocrinol. 2006;155:S149‑52.
17. Conway GS, Honour JW, Jacobs HS. Heterogeneity of the polycystic ovary syndrome: clinical, endocrine and
ultrasound features in 556 patients. Clin Endocrinol (Oxf). 1989;30:459-70.
18. Dunaif A, Thomas A. Current concepts in the polycystic ovary syndrome. Annu Rev Med. 2001;52:401-19.
19. Lujan ME, Chizen DR, Pierson RA. Diagnostic criteria for polycystic ovary syndrome: pitfalls and controversies.
J Obstet Gynaecol Can. 2008;30:671-9.
20. Azziz R. Controversy in clinical endocrinology: diagnosis of polycystic ovarian syndrome: the Rotterdam
criteria are premature. J Clin Endocrinol Metab. 2006;91:781-5.
21. Gollnick H, Cunliffe W, Berson D, Dreno B, Finlay A, Leyden JJ, et al. Management of acne: a report from a
Global Alliance to Improve Outcomes in Acne. J Am Acad Dermatol. 2003;49:S1-37.
22. Rotterdam ESHRE/ASRM-Sponsored PCOS consensus workshop group. Revised 2003 consensus on
diagnostic criteria and long-term health risks related to polycystic ovary syndrome (PCOS). Hum Reprod.
2004;19:41-7.
23. Pugeat M, Déchaud H, Raverot V, Denuzière A, Cohen R, Boudou P, et al. Recommendations for investigation
of hyperandrogenism. Ann Endocrinol (Paris). 2010;71:2-7.
24. Borgia F, Cannavò S, Guarneri F, Cannavò SP, Vaccaro M, Guarneri B. Correlation between endocrinological
parameters and acne severity in adult women. Acta Derm Venereol. 2004;84:201-4.
25. Legro RS, Bentley-Lewis R, Driscoll D, Wang SC, Dunaif A. Insulin resistance in the sisters of women with
polycystic ovary syndrome: association with hyperandrogenemia rather than menstrual irregularity. J Clin
Endocrinol Metab. 2002;87:2128-33.
26. Norman RJ, Dewailly D, Legro RS, Hickey TE. Polycystic ovary syndrome. Lancet. 2007;370:685-97.
27. Arowojolu AO, Gallo MF, Lopez LM, Grimes DA, Garner SE. Combined oral contraceptive pills for treatment
of acne. Cochrane Database Syst Rev. 2009;(3):CD004425.
28. Williams C, Layton AM. Persistent acne in women: implications for the patient and for therapy. Am J Clin
Dermatol. 2006;7:281-90.
29. Shaw JC. Low-dose adjunctive spironolactone in the treatment of acne in women: a retrospective analysis
of 85 consecutively treated patients. J Am Acad Dermatol. 2000;43:498-502.
30. Muhlemann MF, Carter GD, Cream JJ, Wise P. Oral spironolactone: an effective treatment for acne vulgaris
in women. Br J Dermatol. 1986;115:227-32.
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31. Carmina E, Lobo RA. A comparison of the relative efficacy of antiandrogens for the treatment of acne in
hyperandrogenic women. Clin Endocrinol (Oxf). 2002;57:231-4.
32. Savidou I, Deutsch M, Soultati AS, Koudouras D, Kafiri G, Dourakis SP. Hepatotoxicity induced by cyproterone
acetate: a report of three cases. World J Gastroenterol. 2006;12:7551-5.
33. Müderris II, Bayram F, Güven M. Treatment of hirsutism with lowest-dose flutamide (62.5 mg/day). Gynecol
Endocrinol. 2000;14:38-41.
34. Goodman NF, Bledsoe MB, Cobin RH, Futterweit W, Goldzieher JW, Petak SM, et al. American Association
of Clinical Endocrinologists medical guidelines for clinical practice for the diagnosis and treatment of
hyperandrogenic disorders. Endocr Pract. 2001;7:120-34.
35. Cusan L, Dupont A, Bélanger A, Tremblay RR, Manhes G, Labrie F. Treatment of hirsutism with the pure anti
androgen flutamide. J Am Acad Dermatol. 1990;23:462-9.
36. Brahm J, Brahm M, Segovia R, Latorre R, Zapata R, Poniachik J, et al. Acute and fulminant hepatitis induced
by flutamide: case series report and review of the literature. Ann Hepatol. 2011;10:93-8.
37. Costello MF, Shrestha B, Eden J, Johnson NP, Sjoblom P. Metformin versus oral contraceptive pill in polycystic
ovary syndrome: a Cochrane review. Hum Reprod. 2007;22:1200-9.
104

Acne Expression and Management

in Indians
*Raj Kubba MBBS MRCP (UK) FRCP (Canada) FRCP (Edinburgh),
1,2,
1
Vandana Chatrath MBBS MSc (USA) Fellowship Derm Surgery (USA)
1
Delhi Dermatology Group, New Delhi 110 066, India
2
Department of Dermatology, Boston University School of Medicine, Boston, MA, USA
ABSTRACT
Geographic and ethnic differences in acne are recognized. This article
highlights some such differences. In particular, acne in India is rarely
seen in isolation. There are companion morphologies and comorbidities.
Companion morphologies include benign hyperplasias, namely, acanthosis
nigricans, acrochordons, DPN’s, ephelides, lentigines, syringomata,
melanocytic nevi; physical signs of hormonal disturbances, such as,
hirsutism, alopecia, seborrhea; and skin manifestations of malassezia over-
colonization as folliculitis and seborrhoeic dermatitis. Insulin resistance
plays a much larger role in all aspects of acne in India than is generally
recognized and the term IRAA (insulin resistance associated acne) is
proposed for such patients. Acne management in India reflects the wide
availability of therapeutic modalities including generics, and the lack of
regulation permits varied therapeutic approaches.
IntroductIon
Indians are people with skin of color. However, they display considerable
heterogeneity in their skin color paralleling racial and ethnic assimilations
occurring over time and this is encountered more conspicuously in the border
states of the country. The majority of Indians belong to FST (Fitzpatrick skin
type) IV-V. There are some exceptions. There are pale complexioned Indians in
the northern states; some eligible for FST III. In this relatively small group those
Email: rajkubba@gmail.com

Kubba and Chatrath
inhabiting the north-west part of the country (Punjab, Jammu and Kashmir)
are more Caucasoid in their phenotypes whilst those in the north-east part
(Assam, Arunachal Pradesh, Manipur, Mizoram, Nagaland) are more Mongoloid.
Similarly, in the southern states there are some FST VI Indians also showing a
diversity, i.e., Aboriginal phenotype in the south-east (Tamilnadu) and Negroid in
the south-west (Kerala) (Figure 1).
There is a paucity of literature on the description of acne in Indians.1 Acne is
believed to be as common in Indians as it is noted elsewhere in other parts of the
developed and the developing world.1 But, more importantly, the clinical spectrum
of such acne along with its accompanying systemic and hormonal attributes yields
a profile that is believed by the authors to be sufficiently different and worthy of
documentation. Below is an account of acne seen in Indians with an attempt to
highlight features that are not recorded in the mainstream acne literature. Some of
these observations have already been described by one of us (Kubba R) in another
publication.2
A B
C D
Figure 1: Racial heterogeneity in Indians. A, North-West

Caucasoid. B, North-East Mongloid. C, South-West Negroid.
D, South-East Aboriginal.
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Acne Expression and Management in Indians
clInIcAl FEAturES
Although there are no published data, acne is believed to be the most common
skin disease in Indians.1 In our group practice, acne comprises 17% of all new
patients. Acne prevalence appears to be rising as also is the awareness to seek
treatment for acne. Even in the absence of much concerted efforts or organized
campaigns, knowledge of acne among the general population is reasonably good.
The age of onset, the chronic nature, and the natural course of the disease mostly
parallels that reported in the acne literature.
Preadolescent acne is increasingly being encountered in India. The perceived
explanation is Insulin resistance (IR), presumably through alterations in dietary
patterns, and a “westernized” lifestyle. Adoption of hyperinsulinemic diets has
caused acne to become more a “metabolic disease” driven by IR and it is clinically
marked by acanthosis nigricans (AN). Preadolescent acne is typically T-zone
in pattern and commences from forehead and nose (Figure 2). Seborrhea and
trichostasis over nose are commonly associated. Blackheads in conchal fossae are
unique in this age-group and when present portend more severe acne to follow
(Figure 3). Precocious puberty and adrenal hyperandrogenism, as measured by
elevated dehydroepiandrosterone sulfate (DHEA-S) level, are rare associations
although variable degree of hypertrichosis (on the forehead, cheeks including
zygomas, nape of neck, and adjacent upper back) is commonly noted (Figure 4).
Canities (premature graying of hair) and hair loss as crown thinning are occasionally
noted. Transverse neck creases (Figure 5) are early markers of IR more so when
accompanied by AN. Malassezia folliculitis (MF) is common in this age-group
and may masquerade as acne.3
Figure 2: Preadolescent Acne. T-zone

pattern. Note open and closed comedones
on nose and papulopustules on forehead
and chin in a boy, aged 13.
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Kubba and Chatrath
Figure 3: Blackhead in conchal fossa. Note

subtle hypertrichosis over tragus and ear
lobe.
Figure 4: Hypertrichosis involving forehead,

temples, zygomatic areas along with cheeks
and jaw areas in a case of adolescent
acne with onset in preadolescence.
Similar confluent hypertrichosis is often
encountered on the nape of neck extending
to adjacent upper back. Note dark circles
and shaded chin.
Adolescent acne in Indians is different in its clinical spectrum and its

associations. It conforms in being predominantly facial and females outnumbering
males 2:1 (in dermatology clinics). The perceived difference, however, is on account
of companion morphologies. The majority of Indian acne patients show a variable
mixture of companion morphologies2 that include, benign cutaneous hyperplasias
[acrochordons, dermatosis papulosis nigra (DPNs), syringomata, milia], skin
signs of androgen excess (seborrhea, hirsutism, patterned alopecia), pigmentary
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Figure 5: Transverse neck creases are

early marker of insulin resistance. Note
T-zone acne and hypertrichosis in a case of
preadolescent acne.
Figure 6: Companion morphologies in this

case of panfacial acne include DPN’s, milia,
and melanocytic nevi. Note shaded chin and
AHM’s.
disturbances (persistent tan, dark circles, shaded chin, shaded forehead, ephelides),2
and folliculitides2 (recurrent painful scalp and/or beard folliculitis, folliculitis
nuchae, recurrent deep folliculitis on buttocks and thighs, and MF on central face,
upper back and sternal area of chest). Whilst acne responds to well selected acne
treatment programs companion morphologies, especially benign hyperplasias
and melanocytic nevi, tend to persist unchanged (Figures 6 and 7). Bilateral
asymmetry (Figure 8) has been observed in almost 50% of acne patients in our
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Kubba and Chatrath
Figure 7: Melanocytic nevi are a common companion to acne.

Three or more melanocytic nevi were observed in 63% of a cohort
of 100 acne patients, slightly more common in adolescents than
mature adults over 25 years (36% vs 27%).
Figure 8: Bilateral asymmetry in acne is

noted in about 50% of all our acne patients.
In this case the asymmetry was fluctuating
as suggested by the scarring on the less
involved side.
clinic (unpublished); in some of them it was found to be fixed whilst in others

the asymmetry appeared to fluctuate between the two sides of the face during
the observation period. Adolescent acne in India onsets at or soon after puberty
and evolves in its extent and severity over the following 3±5 years. Increasingly
adolescent acne is persisting and is evolving into adult acne.
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Insulin resistance associated acne (IRAA) is the label increasingly being applied
to Indian acne patients based largely on frequently observing underlying IR which
in turn is assessed and validated by assaying fasting and postprandial (PP) serum
insulin along with fasting and PP blood sugar and glycated hemoglobin (HbA1c).
The clinical prompt for initiating IR assessment is the presence of AN, obesity,
companion morphologies (vide supra), and a strong family history of diabetes.
IRAA (Figure 9) tends to be milder, it is more comedonal, mostly confined to
the face, and is generally less responsive to standard acne treatments. IRAA
individuals tend to have suboptimal skin quality (SOSQ) and a general worsening
of skin color which reverses with successful treatment and this is readily apparent
in posttreatment photographs2 (Figures 10A and B). IRAA patients also show
variable expression of metabolic syndrome as evidenced by high or normal body
mass index (BMI), waist circumference, serum triglycerides, serum uric acid,
low-density lipoprotein (LDL), thyroid-stimulating hormone (TSH), and high-
density lipoprotein (HDL). Many such patients also have sonographic evidence of
fatty liver and occasionally show elevated liver transaminases. IRAA is more the
rule rather than exception in our current acne practice.
Adult acne (acne beyond age of 25 years) constitutes about 30% of all acne
and about 5% of all dermatology patients in our practice (Kubba R, unpublished).
In this group, 55% cases are of “persistent acne” and the rest of “late-onset”.
Adult acne, as generally noted, is milder, shows a predilection for chin/lower face
(V-zone acne), and is decidedly more common in females (Figure 11). Melasma-
like facial pigmentation (Figure 12) was noted in 22% of our adult acne cohort
and ephelides/lentigine-like pigmentation in 20% (Kubba R, unpublished).
Figure 9: Insulin resistance associated acne. Note preponderance

of comedones and associated DPN’s, shaded chin, and hirsutism.
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Kubba and Chatrath
A B
Figure 10: Insulin resistance associated acne. A, Before

treatment. B, Note improvement in skin color after treatment.
Figure 11: An example of mild chin acne

also called “V-zone” acne.
Companion morphologies are more common and whilst acne remits with
adequate anti-acne treatment companion morphologies require supplementary
treatment. Much of adult acne seen in India is believed to be IRAA. Furthermore,
the authors hypothesize that adult acne is a sign of metabolic syndrome whilst
adolescent acne is a marker of the same.
Hormonal acne is common amongst Indians. Mild forms of SAHA (seborrhea,
acne, hirsutism, alopecia) syndrome are common in both adolescent (Figure 13)
and adult acne and more so in IRAA. Polycystic ovarian syndrome (PCOS) is
112

Figure 12: Acne associated with melasma-like pigmentation.
Figure 13: SAHA syndrome. Note lower

face acne, seborrhoea and hirsutism.
frequently encountered in female acne patients and is suggested by menstrual

irregularity and physical signs of androgen excess. Both obese and non-obese
PCOS are seen. In a cohort of 62 adult acne patients where PCOS was assessed it
was confirmed in 27 patients (44%) (Kubba R, unpublished). In another 10 patients
(16%) there was equivocal/partial evidence of PCOS highlighting the existence of
a gray zone in this matter! Contrary to prevalent belief many PCOS patients have
mild acne (Figure 14) and come to light because of therapeutic unresponsiveness
and/or recalcitrant associated seborrheic dermatitis. Non-classic congenital
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Kubba and Chatrath
Figure 14: Mild acne in PCOS. The

association was suspected on the basis
of recalcitrant seborrhoeic dermatitis and
recalcitrant mild acne.
adrenal hyperplasia (NCAH) is often considered in cases of persistent adult acne

with a strong family history of acne but only occasionally confirmed by elevated
serum 17-hydroxyprogesterone (17-OHP). On the other hand, we encounter
many patients with clinical suspicion of NCAH but with borderline or mildly
elevated 17-OHP. IR is associated with PCOS and HAIR-AN (hyperandrogenic,
insulin-resistant and acanthosis nigricans) syndrome in women and APAAN.
(acne, patterned alopecia, acanthosis nigricans) syndrome in men. APAAN
syndrome is the counterpart of SAHA in females.2 It is commonly observed in
Indian men starting as early as adolescence (Figure 15). Clinically, besides acne,
these patients have Ludwig-type of male-pattern baldness, patterned or diffuse
AN (vide supra), and hyperinsulinemia (acute and chronic). We occasionally see
female acne patients with signs of IR, PCOS and NCAH suggesting an overlap
(Figures 16A and B).
Indians experience all grades of acne, both inflammatory and noninflammatory.
However, there is an impression that severe acne, nodulocystic acne, acne
corporis, acne conglobata, acne associated with hidradenitis suppurativa, and acne
syndromes such as SAPHO (synovitis, acne, pustulosis, hyperostosis, osteitis) are
less common or rare. The darkest skin phototype (FST V and VI), many of whom
also have IR, appear to be less liable to severe inflammatory acne. Postinflammatory
hyperpigmentation (PIH) and acne hyperpigmented macules (AHMs) are very
common, especially in IRAA (Figure 17). Indians scar as much and the scarring is
generally proportional to severity of the inflammation. Atrophic scars are mostly
seen on the cheeks and temples and include boxcar, icepick, and rolling. Papular
scars on the chin and body of the nose are common (Figure 18), and are sometimes
114

A B
Figure 15A-C: APAAN syndrome

– acronym for Acne, Patterned
C Alopecia, Acanthosis Nigricans.
Figure 16A: Persistent adult acne with

clinical, biochemical, and ultrasonological
features of IR, PCOS & NCAH.
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Kubba and Chatrath
Figure 16B: Schematic representation of overlap between insulin

resistance (IR), polycystic ovarian syndrome (PCOS) and non-classic
congenital adrenal hyperplasia (NCAH).
Figure 17: Postinflammtory hyper-

pigmentation, also known as AHM
(acne hyperpigmented macule).
mistaken for closed comedones. Hypertrophic scars/acne keloids are common, and
seen in typical seborrheic distribution on the torso, but are rarely also seen on the
jaw angles (Figure 19). Likewise, atrophic macular scars are occasionally observed
on the upper back (Figure 20).4 Perifollicular fibrosis (Figure 21) is commonly
seen on the sternal area and upper back as uniformly distributed 1±2 mm pale/
116

A B
Figure 18A and B: Acne papular scars. Chin is a common site.
Figure 19: Hypertrophic scars are rare on the face. They are rarely
encounterd over the jaw angles.
Figure 20: Extensive atrophic macular

scars on the back in a case of severe acne
corporis.
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Kubba and Chatrath
Figure 21: Perifollicular fibrosis as fleshy papules on the posterior

aspect of shoulder sequel to acne corporis. Sternal area is another
common site.
hypochromic dome-shaped persistent papules. There is a perception that atrophic

acne scars are less common in the darkest skin type (FST VI).
Malassezia overcolonization is a frequent comorbidity in Indian acne patients
and presents in a variety of ways including, stubborn dandruff, seborrheic
dermatitis as malar erythema and scaling, with occasional blepharitis and otitis
externa; MF as discrete superficial pustules on the nose, nasal folds, malar
areas, beard area in men, and on the upper back and upper chest (Figure 22);
and also as pityriasis versicolor. The MF is often confused with pustular acne
and it is the lack of response to antibiotics and a good response to antifungals
both topical and oral that helps recognize the nature and etiologic basis of such
recurrent asymptomatic pustules. Malassezia overcolonization and its clinical
manifestations sometime precede acne in preadolescent and adolescent subjects
and express as sandpaper comedones5 on the forehead, keratosis pilaris on the
upper arms, and trichostasis on the nose. Malassezia overcolonization is viewed as
a clue to IR and hypovitaminosis D (Kubba R, personal observation). Recurrent
crops of painful pustules in the scalp, beard area in men, in the bathing trunk area
(buttocks, pubic area, anterior, and posterior aspect of thighs) in both sexes is a
frequent association of acne. Clinically, it represents deep folliculitis (occasionally
there are overt furuncles) and responds only to systemic antibiotics. This too is
a clue to IR. Folliculitis nuchae is also common amongst Indian acne patients.
Bacterial folliculitis, as also impetigo, is sometimes encountered in acne patients
on oral isotretinoin, and beauty procedures such as threading or waxing are often
the trigger (Figure 23).
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Figure 22: Concomitant malassezia

folliculitis is a common occurrence in Indian
acne patients. It presents as superficial
pustules in paranasal area, glabella, along
the hairline on the forehead, on upper back
and sternal area of the chest.
Figure 23: Impetigo over jaw area following

waxing in a patient with acne being treated
with oral isotretinoin.
There is scant literature on quality of life (QoL) and acne from India. Active
acne seems to have much less impact on self-image, self-esteem, relationships, and
career prospects in dark skin people compared to the sequelae, especially PIH,
making prevention and treatment of the latter the focus of therapy. In India, acne
is relatively well tolerated, and causes some degree of psychological impairment;
however, the issue assumes great importance in the run up to marriage when
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Kubba and Chatrath
perfect skin is desired and preexisting acne is viewed as a great impediment to

finding a suitable match.
MAnAGEMEnt
Understanding the subtle differences in acne in skin of color is essential in order
to tailor therapy and individualize treatment. International guidelines6 have
made a major contribution and succeeded in creating a unified therapeutic vision.
However, acne treatments are also influenced by local beliefs and perceptions, by
local regulations (or lack of them), on the availability of drugs and devices, and
most of all by economic considerations. It is the authors view that acne is treated
differently in India as compared to Europe and the USA.7,8
In India all therapeutic modalities are freely available, many are generic and
relatively inexpensive, and even though there are local guidelines and treatment
algorithms,1 dermatologists are entirely free to treat acne as they choose. In India,
easy availability of over-the-counter medications and practice of alternate forms of
medicine such as homeopathy and Ayurveda, affect not only the clinical features
and severity of acne at the time of presentation, but also their response to standard
forms of therapy, steroid acne being one such example.
Topical retinoids are the mainstay of acne treatment and are recommended
in all types and all stages of acne and in acne prevention.6 However, it is known
that Indians are less tolerant of topical retinoids, and episodes of irritant contact
dermatitis are frequent, especially in the initial stages. In a study conducted at the
National Skin Center in Singapore, tolerance to topically applied retinoids was
compared between Chinese, Indian, Malay and European women; it was observed
that Indian and Chinese women were less tolerant of topical retinoids and
experienced more itching and burning.9 The dermatologists in India have been
aware of this fact and for this reason prior to introduction of adapalene, topical
retinoids were unpopular in India.1 Even today, it is a common practice to dilute
topical retinoids with moisturizers. However, the availability of newer formulations
of retinoids, such as microsponge delivery system, enabling controlled release of
tretinoin, has encouraged more enthusiastic use of retinoids as monotherapy and
as an adjunct to systemic acne treatments.
Antibiotics, topical and oral, are the most prescribed modalities in acne
treatment in India and generally work well. Topical clindamycin as cream, gel
and lotion and in fixed combination with benzoyl peroxide (BPO), tretinoin, and
adapalene, is readily available. The combining of clindamycin with BPO has the
threefold advantage of reducing development of bacterial resistance, increasing
efficacy with respect to either drug alone and decreasing the incidence of irritant
contact dermatitis that may occur when BPO is used alone in skin of color.10
Topical erythromycin has been withdrawn in India. Topical azithromycin and
120

clarithromycin are commonly used despite the absence of critical data assessing or
comparing their efficacy. Topical nadifloxacin has been available in India but has not
gained popularity. Antibiotic resistance is suspected from lack of clinical response
in some cases but no data are available. Oral antibiotics are inexpensive, readily
available, and are frequently employed to treat moderate-to-severe inflammatory
acne. Newer tetracyclines are preferred for their convenient dosing. Doxycycline
and minocycline are believed to be equal in efficacy. Minocycline is comparatively
more expensive in India. Macrolides in pulse dosing are very popular and are easy
to combine with matching topical preparations. A typical regimen is azithromycin
250 mg BID for 3 days every 2 weeks or 250 mg BID for 6 days every 4 weeks.
One advantage of macrolides is that they cover concomitant staphylococcal
folliculitis. Whether this use of antibiotics (without standardization of dose and
duration) impacts the development of antibiotic resistance in the future is yet to
be determined.
Antifungal agents, topical miconazole, ketoconazole and oral itraconazole, are
used in acne to treat dandruff, seborrheic dermatitis, and MF which are frequent
comorbidities. There is a perception that antifungal agents directly improve acne
raising the question whether Malassezia furfur has a direct etiological role in acne?
Oral itraconazole 100 mg BID for 14±28 days appears to have beneficial effect in
MF mimicking acne corporis (clinical experience of the authors).
Oral isotretinoin is generic, relatively inexpensive, and unregulated in India. It
is well tolerated and is very effective in all types of acne (including comedonal acne)
and for all age groups. Written informed consents are mandated but not enforced,
pretreatment and intratreatment pregnancy testing is not required. As yet there
are no reports of teratogenic complications from oral isotretinoin in India. There
is preference for lower dosages, typically below 0.5 mg/kg (perhaps due to the low
tolerance of dark skin toward retinoids?). Pulse dosing is favored in adult acne.11
There is freedom to create combinations and innovative regimens which allow for
greater individualizing of the treatment programs. Oral isotretinoin also addresses
sequelae of acne and improves the overall quality of skin. It improves the skin
complexion in dark skin acne patients, particularly FST IV-V (Figures 24A and B).
The very dark skin acne patients (FST VI) do not exhibit “retinoid glow” and rarely
there are instances of unexplained paradoxical darkening.2 These are temporary
effects typically lasting for 3±6 months. Adverse effect profiles match those stated
in the literature with a few exceptions. The susceptibility to Staphylococcal infections
increases in the form of impetigo, furuncles, and recurrent styes, especially during
hot summer months. Epistaxis, bleeding per rectum, reversible fibroadenomas of
the breasts (in both sexes), and a solitary case of vasculitis on the legs, are some of
the unusual adverse effects encountered by the authors. Serious psychiatric adverse
effects such as depression and suicidal tendency are rare. Overall, oral isotretinoin
is much liked by the patients and is popular with dermatologists in India.
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A B
Figure 24A and B: Improved complexion and “retinoid glow”

after oral isotretinoin.
Antiandrogens are the cornerstone of therapy for adult acne. Besides

resolving acne they correct other signs of androgen excess and improve
skin quality. Antiandrogens are readily available, are socially well accepted,
and dermatologists are free to prescribe them in India. Combination oral
contraceptive pills, Diane-35® (cyproterone 2 mg + ethinyl estradiol 35 µg) and
Yasmin® (drospirenone 3 mg + ethinyl estradiol 30 µg) are the popular choice
in acne patients with PCOS and androgen excess. Treatment is cyclical and
typically of 6±12 months duration. Beneficial effects are evident after three
cycles and are mediated through reduction of ovarian androgen production and
through elevation of serum sex hormone-binding globulin (SHBG). Diane-35®
and Yasmin® are comparable in efficacy and cost. In India, the generics
are available. Yaz® (drospirenone 3 mg + ethinyl estradiol 20 µg), a newer
introduction, offers low estrogen content and is preferred by some. Diane-35®
occasionally causes hypertension and is sometimes incriminated in weight gain.
Some dermatologists in India prefer Diane-35® for adolescents and Yasmin®
for mature adults. Spironolactone (SL) 25±50 mg BID is a good choice for
adult acne, especially those with female pattern hair loss (FPHL), melasma, and
hirsutism, but because it can cause virilization of the female fetus, it is often used
in conjunction with oral contraceptives that in turn add to its antiandrogenic
effect.12 SL is an androgen receptor antagonist and an inhibitor of 5á-reductase.
Bicalutamide, a nonsteroidal androgen receptor antagonist, is readily available
and is inexpensive; it is recommended for acne associated with hirsutism;13 the
dose is 50 mg OD and the typical treatment duration is 6 months. Finasteride,
inhibitor of 5a-reductase type 2, is routinely prescribed in APAAN syndrome,
and occasionally for female adult acne with recalcitrant androgenetic alopecia.
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Dutasteride, inhibitor of both type 1 and type 2 5a-reductase is sometimes

recommended for recalcitrant APAAN syndrome patients.
It has been estimated that a 50% reduction in acne requires 30±50%
reduction in sebum secretion.14 The sebosuppressive effect, especially of SL and
cyproterone acetate (CPA), is dose dependent. Oral isotretinoin is the most
sebosuppressive of them all. In India, we frequently combine antiandrogens to
limit dosages and toxicity and to enhance efficacy. CPA 50±100 mg OD for
the first 10 days of the Diane-35® cycle is another potent combination. Oral
antiandrogens are also combined with oral isotretinoin and/or oral antibiotics in
difficult and refractory cases and in acne associated with hormonal disturbances
(the therapeutic ladder).
Metformin is a first-line treatment for PCOS where it improves acne and
hirsutism besides correcting the irregular menstrual cycle even in non-obese
patients.15 Metformin is increasingly being used in India to treat acne associated
with insulin resistance (IRAA). The typical dose is 500 mg BID to start with
reaching an ideal dose close to 2 g/day in divided doses. The treatment duration
has to be individualized and greatly depends on ancillary factors pertaining to
lifestyle such as diet and exercise. We prefer slow release preparations for acne
patients with high fasting insulin (chronic hyperinsulinemia) or high HbA1c.
Slow release metformin is not recommended for individuals under 18 years of
age. Metformin is a biguanide and was first used in France in 1979.16 It improves
insulin sensitivity through improved binding of insulin to insulin receptors.
It also reduces hepatic gluconeogenesis, activates adenosine monophosphate
(AMP)-activated protein kinase, increases peripheral glucose uptake, and
reduces absorption of glucose from gastrointestinal tract.16,17 It reduces insulin
levels but does not cause hypoglycemia. Metformin can be combined with
antiandrogens, oral isotretinoin, and oral antibiotics with the exception of
cephalosporins. Metformin can be administered to individuals over 10 years of
age and is pregnancy category B.
Systemic steroids are prescribed to ameliorate scar-threatening acne
inflammation, and to prevent pustular flares in acne patients with closed comedones
or macrocomedones when oral isotretinoin is initiated.1 Methylprednisolone 8 mg
once in the morning suffices in most instances and the typical duration is 4±6
weeks. This is also helpful in preventing PIH. Suppressive dosages are required
for NCAH and nonspecific adrenal hyperandrogenism. In such cases, the typical
protocol is to commence with methylprednisolone 8 mg at bedtime till quiescence
is attained and then to taper in an individualized manner keeping in mind the
high probability of relapse.1 Dosages as low as 2 mg/day or 4 mg on alternate
days are sufficient for maintenance. Milder forms of inflammation is targeted with
topical pimecrolimus, the concomitant use of which not only allows dark skin acne
patients to tolerate topical retinoids, but also works as an adjunct prostaglandin
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Kubba and Chatrath
inhibitor, helping to ameliorate acne macules faster. Oral dapsone is another useful
adjunct to combat severe inflammation in nodulocystic acne, acne corporis, and acne
fulminans.1,18 It is freely available, very inexpensive, and Indian dermatologists are
very familiar with it from treating leprosy and other skin diseases. Dapsone gel,19
on the other hand, was found to be ineffective in India, where it has now been
withdrawn from the market. Another product, azelaic acid, a naturally occurring
dicarboxylic acid which is both antibacterial and anticomedonal in 10±20% cream
formulation and known to reduce hyperpigmentation failed to make a mark in
acne treatment in India. Nutritional supplements, namely, vitamin A, vitamin D3,
vitamin E, evening primrose oil, and oral zinc are popular adjuncts in acne
treatment in India. There are several mechanisms by which they are beneficial in
acne one of which is their ability to combat oxidative stress.20
Chemical peels, like topical retinoids, in skin of color address both acne and
PIH simultaneously. The safety and efficacy of chemical peels for acne in skin
of color is well established.21 However, there are a few precautions which when
exercised can improve the outcome and minimize the adverse effects. These include
starting with lower concentrations of peels, proper sun protection, pretreatment
with retinoids with or without hydroquinone, and stopping all topicals 2±3 days
prior to the treatment for better tolerance. Newer peels using salicylic-mandelic
acid combination (SMPs) give superior results compared to glycolic acid peels
both for active acne and PIH. Chemical peels for management of active acne are
infrequently utilized in India compared to Japan and Korea.
Lights and Lasers have been used in dark skin people7 to treat active
acne and acne sequelae (PIH and scars). Practice patterns for these vary from
country to country and reflect local conditions. In India, where unrestricted
medical treatments are available, physical devices such as blue light, red light,
photodynamic therapy (PDT), and diode laser are rarely used for active acne, the
exceptions being pregnant women and patients averse to medications. Acne scars,
on the other hand, are increasingly being treated with lasers. Newly developed
fractional lasers employ fractional thermolysis in which microscopic columns of
epidermal and dermal injury stimulate collagen remodeling and thus result in
dermal repair. There are several studies reporting beneficial effects of fractional
lasers in atrophic acne scars in dark skin people.22-24 Fractional lasers are color
blind (to some extent), therefore, especially suitable for dark skin people. There are
as yet no guidelines for lasers in acne due to the plethora of devices available across
the world and the fact that parameters are device specific making standardization
difficult. Nonablative fractional lasers are relatively less effective in darker skin
types possibly due to the limitation of using higher energy levels and increased
treatment density for the fear of risking pigment related side-effects. Ablative
fractional resurfacing lasers, on the other hand, are relatively more effective for
such patients with the advantage of needing one to two treatments (maximum)
124

but the disadvantage of having much longer downtime and higher risk of PIH. To
reduce the incidence of side-effects it is recommended that the treatment density
should be reduced and the number of treatments should be increased for both
nonablative and ablative fractional lasers.25 For boxcar scars and ice-pick scars
combination treatments with subcision, fractional lasers, and punch grafting offer
added advantage. Microneedling is yet another treatment for acne scars not biased
by the color of the skin and because of this, and the mild to moderate degree of
improvement that one can achieve at minimal cost, it is considered as a “poor
man’s laser” and it is, therefore, a popular treatment option in India either alone
or in combination.
Postinflammatory hyperpigmentation (PIH) is of major concern in acne in dark
skin people and warrants prevention as well as amelioration. The degree of PIH is
higher in prolonged and/or recurrent inflammation compared to short-term acute
inflammation7 and PIH in color of skin causes more psychological impact than
active acne itself warranting early and aggressive therapy. The use of sunscreens is
pivotal and we recommend their regular use. Topical retinoids are helpful in both
preventing and clearing PIH.7 Other topicals containing hydroquinone (2±4%),
and triple combination creams are also helpful and we use them cautiously in
selected patients. Superficial chemical peels and microdermabrasion are other
time tested beneficial options.8 Vascular lasers can be used to treat the “acne
macules” by treating the vascular component of inflammation, thereby promoting
early clearance and secondarily reducing the PIH risk.26 Pigment lasers such
as the Q-switched neodymium-doped yttrium aluminum garnet (Nd:YAG)
are increasingly being used to treat PIH but at low fluences.27 The concept of
“laser-toning” using large spot size, low fluence and multiple passes to achieve
an endpoint of mild erythema at variable intervals of 1±4 weeks is yet another
approach for post-acne hyperpigmentaion.28
With a rapid increase in IR in India the role of diet in the management of
acne has assumed much greater importance.29 We routinely discuss diet with
acne patients and in those with IRAA we emphasize the necessity to limit
consumption of glycemic foods, milk, and dairy products.30 India is presently
the world’s largest producer of milk and whereas the milk production is falling
globally in India it is going up 6% annually. Whey protein consumption is
rising amongst young men as is obesity in both sexes; both issues are routinely
discussed with acne patients.
concluSIon
In conclusion, this article is an attempt by the authors to profile acne as it is
observed in office practice in India, give an account of how it is managed, and to
compare and contrast it with acne as it is recorded in the English literature.
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Kubba and Chatrath
Editor’s Comment
Though Indians are considered to be people with skin of color, they display
considerable heterogeneity (ranging from Fitzpatrick skin type IV-VI) in their
skin color due to variation in their ethnicity. Though acne is probably the most
common dermatoses with which Indians present to the dermatologist, there is a
paucity of clinicoepidemiological data on acne. In this article, Drs V Chatrath
and R Kubba have not only delved into the scanty reports available in literature
on acne in Indians but also written from their extensive clinical experience. They
have rightly observed that acne is as common in Indians as it is elsewhere with
a spurt in preadolescent acne presumably related to a tilt towards Western diet
and lifestyle. Many patients of adolescent acne evolve into adult acne. The authors
have tried to compare the clinical profile of Indian acne patients with their
Western counterparts. Though antibiotics both topical and systemic are frequently
prescribed to treat acne in India, retinoids, especially the newer formulations
(to which Indian skin is more tolerant) have now become popular. The authors
rightly point out that there are no reports of antibiotic sensitivity pattern of
Propionibacterium spp from India. However, in a recently concluded study done
at the All India Institue of Medical Sciences, New Delhi, we observed that a
third of Propionibacterium spp strains were resistant either to erythromycin,
azithromycin or clindamycin.
Neena Khanna
rEFErEncES
1. Kubba R, Bajaj AK, Thappa DM, Sharma R, Vedamurthy M, Dhar S, et al. Acne in India: guidelines for
management - IAA consensus document. Indian J Dermatol Venereol Leprol. 2009;75:1-62.
2. Kubba R. Acne in dark skin people. In: Schwartz RA, Micali G (Eds). Acne. McMillan Medical Communications;
Gurgaon, India. 2013. pp. 39-50.
3. Ayers K, Sweeney SM, Wiss K. Pityrosporum folliculitis: diagnosis and management in 6 female adolescents
with acne vulgaris. Arch Pediatr Adolesc Med. 2005;159:64-7.
4. Cunliffe WJ, Gollnick HP. Acne: Diagnosis and Management. London, UK: Martin Dunitz; 2001.
5. Cunliffe WJ, Holland DB, Clark SM, Stables GI. Comedogenesis: Some new aetiological, clinical and
therapeutic strategies. Br J Dermatol. 2000;142:1084-91.
7. Davis EC, Callender VD. A review of acne in ethnic skin: pathogenesis, clinical manifestations, and
management strategies. J Clin Aesthet Dermatol. 2010;3:24-38.
8. Shah SK, Alexis AF. Acne in skin of color: practical approaches to treatment. J Dermatolog Treat. 2010;
21:206-11.
9. Goh CL. Data presented at the second Asian acne board meeting. Singapore: November 2006.
126

10. Eichenfield LF, Krakowski AC. Moderate to severe acne in adolescents with skin of color: benefits of a fixed
combination clindamycin phosphate 1.2% and benzoyl peroxide 2.5% aqueous gel. J Drugs Dermatol.
2012;11:818-24.
11. Goulden V, Clark SM, McGeown C, Cunliffe WJ. Treatment of acne with intermittent isotretinoin. Br J
Dermatol. 1998;137:106-8.
12. Krunic A, Ciurea A, Scheman A. Efficacy and tolerance of acne treatment using both spironolactone and a
combined contraceptive containing drospirenone. J Am Acad Dermatol. 2008;58:60-2.
13. Müderris I, Bayram F, Ozçelik B, Güven M. New alternative treatment in hirsutism: bicalutamide 25 mg/day.
Gynecol Endocrinol. 2002;16:63-6.
14. Janiczek-Dolphin N, Cook J, Thiboutot D, Harness J, Clucas A. Can sebum reduction predict acne outcome?
Br J Dermatol. 2010;163:683-8.
15. Tan S, Hahn S, Benson S, Dietz T, Lahner H, Moeller LC, et al. Metformin improves polycystic ovary syndrome
symptoms irrespective of pre-treatment insulin resistance. Eur J Endocrinol. 2007;157:669-76.
16. Bailey CJ, Turner RC. Metformin. N Eng J Med. 1996;334:574-9.
17. Musi N, Hirshman MF, Nygren J, Svanfeldt M, Bavenholm P, Rooyackers O, et al. Metformin increases
AMP-activated protein kinase activity in skeletal muscle of subjects with type 2 diabetes. Diabetes. 2002;
51:2074-81.
18. Prendiville JS, Logan RA, Russell-Jones R. A comparison of dapsone with 13-cis retinoic acid in the
treatment of nodular cystic acne. Clin Exp Dermatol. 1988;13:67-71.
19. Draelos ZD, Carter E, Maloney JM, Elewski B, Poulin Y, Lynde C, et al. Two randomized studies demonstrate
the efficacy and safety of dapsone gel, 5% for the treatment of acne vulgaris. J Am Acad Dermatol.
2007;56:439.e1-10.
20. Bowe WP, Logan AC. Clinical implications of lipid peroxidation in acne vulgaris: old wine in new bottles.
Lipids Health Dis. 2010;9:141.
21. Callender VD. Acne in ethnic skin: special considerations for therapy. Dermatol Ther. 2004;17:184-95.
22. Hasegawa T, Matsukura T, Mizuno Y, Suga Y, Ogawa H, Ikeda S. Clinical trial of a laser device called fractional
photothermolysis system for acne scars. J Dermatol. 2006;33:623-7.
23. Alster TS, Tanzi EL, Lazarus M. The use of fractional laser thermolysis for the treatment of atrophic scars.
Dermatol Surg. 2007;33:295-9.
24. Lee HS, Lee JH, Ahn GY, Lee DH, Shin JW, Kim DH, et al. Fractional photothermolysis for the treatment of
acne scars: a report of 27 Korean patients. J Dermatolog Treat. 2008;19:45-9.
25. Kono T, Chan HH, Groff WF, Manstein D, Sakurai H, Takeuchi M, et al. Prospective direct comparison study
of fractional resurfacing using different fluences and densities for skin rejuvenation in Asians. Lasers Surg
Med. 2007;39:311-4.
26. Ruiz-Maldonado R, Orozco-Covarrubias ML. Postinflammatory hypopigmentation and hyperpigmentation.
Semin Cutan Med Surg. 1997;16:36-43.
27. Eimpunth S, Wanitphadeedecha R, Manuskiatti W. A focused review on acne-induced and aesthetic
procedure-related postinflammatory hyperpigmentation in Asians. J Eur Acad Dermatol Venereol. 2013;27:
7-18.
28. Arora P, Sarkar R, Garg VK, Arya L. Lasers for treatment of melasma and post-inflammatory hyperpigmentation.
J Cutan Aesthet Surg. 2012;5:93-103.
30. Melnik BC, Schmitz G. Role of insulin, insulin-like growth factor-1, hyperglycemic food and milk consumption
in the pathogenesis of acne vulgaris. Exp Dermatol. 2009;18:833-41.
127

Adult Acne
*Alison M Layton MB ChB FRCP, Rebecca L Mawson MB ChB Bsc DRCOG
Harrogate and District NHS Foundation Trust, Lancaster Park Road,
Harrogate, HG2 7SX, London, UK
ABSTRACT
Acne remains as one of the commonest inflammatory dermatoses seen
worldwide. While teenage acne is still regarded as a ‘rite of passage’ by
many, it is increasingly acknowledged that acne is a chronic disease
extending beyond teenage years and in some cases, presents for the first
time well after adolescence. This article highlights key features of adult
acne including debate around the definition, prevalence of the problem,
underlying pathogenesis, and related epidemiological factors, as well as
therapeutic options specific to management and related outcomes.
Introduction
Acne represents a polymorphic inflammatory skin problem centered on the
pilosebaceous unit. It typically develops around adrenarche in association with
an increase in androgen-mediated sebum production. Over the last decade, it
has been recognized that acne is a chronic condition.1 The peak age of onset
for acne is 16–19 years in boys and 14–17 years in girls.2 Seventy percent of
cases resolve after 5 years of onset but in some cases, acne will either persist
as a continuum until 20–30 years of age or present for the first time well after
teenage years.3
DEFINING ADULT ACNE

Defining a specific age for the onset of late-onset or adult acne is challenging, as it
is dependent on individual maturity. A classification based on age of onset greater
Email: alison.layton@hdft.nhs.uk

Adult Acne
Figure 1: Moderate inflammatory

acne in a male of 26 years.
than 25 years, persistence beyond 21 years and/or relapse of acne post-adolescence

has been suggested in the literature (Figure 1).3
Given adolescent acne is said to peak at the latest around 19 years for males
and 17 years for females and the mean duration of adolescent acne is said to
be 5 years, the age of 25 years lies outside the expected time of resolution for
adolescent acne, so it is deemed a reasonable age to assume that the acne has
presented as a part of adulthood. However, it is acknowledged that each case needs
to be judged on its own merit and this interpretation remains open to debate and
in many cases, adult acne is a continuation from adolescence.
Implications Of Persistent Acne For

The Patient
Acne, at any age, can have a significant psychosocial impact, reducing self-esteem,
leading to lower socioeconomic achievement, as well as affecting social functioning
such as relationship formation and continuity. The psychosocial impact of acne has
been shown to be similar to other systemic diseases such as diabetes and epilepsy.4
Acne scarring correlates to the duration of acne5,6 and is also associated with
significant psychological morbidity in many patients.7
The chronic nature of acne and resultant scarring increases the likelihood
of psychological problems. It has been shown that adults with acne, have a 40%
prevalence of psychiatric co-morbidity.8 Effective therapy, started early in the
course of the disease, improves acne in the majority of patients and may avoid
resultant significant scarring.5
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Layton and Mawson
PREVALENCE OF ADULT ACNE

The prevalence of adult acne has been examined in many studies which have used
different definitions and variable modes of assessment including surveys, clinical
examination, patient-perceived assessment of acne, as well as community-based
vs. hospital-based evaluations. Inconsistent approach makes it challenging to
have a clear idea of the real prevalence of adult acne. Table 1 outlines the studies
that have been published.9-15 Goulden et al.9 noted that the mean age of facial
acne referred to the hospital department increased from 20.5 to 26.5 years over a
period of 10 years from 1989 to 1999. They questioned whether this was related
to an increased prevalence of acne in this age group or an increased awareness
of the disorder and knowledge of improved therapies. They conducted a survey
of 749 randomly selected volunteers with facial acne. Facial acne had persisted
since childhood in most adults and clinical acne was noted in 3% of males and
12% of females (Table 2).9 The prevalence of acne, in this UK study, only declined
significantly after 44 years of age. This contrasts with an Indian study which
showed that acne usually declines after 40 years of age but was still present in
2.1% of the studies’ population beyond 45 years.10 Other prevalence studies have
also confirmed increased prevalence in females with adult acne compared to the
males of the same age.
Table 1: Prevalence of Acne Reported by Age-group

Author No. of Age Country Study type Prevalence of acne
subjects (year)/Sex and year
Cunliffe 2,155 18–70 UK, 1979 Survey • 40–49 years: 3% males
et al.11 Males and and clinical and 5% females
females examination • 50–59 years: 6% males
and 8% females
Stern12 20,749 15–44 US, 1992 Survey of acne 15–44 years: 832,000
Males and conglobata females and 1,319,000
females and acne males. Male:female ratio
of atleast a for acne with cysts and
moderate scars 1.6:1
degree with
cysts and
scars
Poli 3,305 25–40 France, Survey • 41%
et al.13 Females 2001 || 17% clinical
only acne (mean 6.2
inflammatory lesions)
|| 24% physiologic
acne (mean 1.3

inflammatory lesions)
Continued
130

Adult Acne
Continued
Table 1: Prevalence of Acne Reported by Age-group
Author No. of Age Country Study type Prevalence of acne
subjects (year)/Sex and year
Goulden 200 25–55 UK, 1997 Clinical • >25 years:12% females
et al.9 Males and examination and 3% males acne
females • Beyond 45 years: 12.5%
Goulden 749 >25 UK, 1999 Community- >25 years: 54% females,
et al.14 Males and based study 40% males
females clinically
examined
Collier 1,013 >20 US, 2006 Survey Females vs. males:
et al.15 Males and • 20–29 years: 50.9% vs.
females 42.5%
• 30–39 years: 35.2% vs.
20.1%
• 40–49 years: 26.3% vs.
12.0%
• 50 years and older:
15.3% vs. 7.3%
Khunger 280 >25 India, Observational • The mean age of the
et al.10 Males and 2008 study patients was 30.5 years
females • Persistent acne was
observed in 73.2%,
while late-onset was
seen in 26.8%
Table 2: Prevalence of Acne According to Grade and Age in a Group of Caucasian

Volunteers Selected from University and Hospital Staff9
Type of acne Age (years) Prevalence male (%) Prevalence female (%)
Clinical 18 35 23
29–39 3 10
40–49 3 5
Mild acne 18 10 25
29–39 30 29
40–49 6 8
Perkins et al. studied the variable pattern of acne among different ethnic
groups, showing increased prevalence in African-American and Hispanic women
compared to Indian, Caucasian, and Asian women.16 The prevalence of different
subtypes of acne was similar through the ethnic groups, with the exception of Asian
women, who had more inflammatory lesions and Caucasians demonstrated more
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Layton and Mawson
comedonal acne. Hyperpigmentation, dyspigmentation, and atrophic scarring was

more common in African-American and Hispanic women.
Cunliffe et al. reported that acne was more prevalent in female patients of
age more than 23 years and that, men showed a gradual decline in their acne
with age.11 An Indian study\reported 82.1% of adult women above 25 years of
age were affected with acne when compared to 17.9% of men,10 and suggested,
like Goulden et al.,9 that this might relate to greater awareness in this group of
females. A survey of 1,013 respondents reported that of them, 73.3% had acne at
some point in their life. Acne was more common in females than males at all ages
after teenage years (p < 0.05).15
CLINICAL PRESENTATION OF ADULT ACNE

Classification of Adult Acne
Adult acne has been defined in the literature into the following suggested categories.3
• Late-onset, presenting for the first time over 25 years of age was found
to occur in 34% of the cases in 1 epidemiological study of adult females
with acne.17 Within the context of this group, clinical subtypes have been
described as
|| Chin acne either as a chronic inflammatory acne distributed on the chin
and perioral region typically with deep-seated, long-lasting nodules, and

cysts or
Hyperseborrhea with retentional lesions, mostly small, closed comedones
around the chin. Significant flares have been described premenstrually3
|| Sporadic acne occurring with no apparent reason or cause but may be
associated with other systemic disease17

• Persistent acne
This is a continuum of acne that begins in adolescence and may happen for a
variety of reasons. Patients might not have secured effective treatments; they
might not have used treatments correctly, or might have failed to respond
to treatments. Acne is frequently present most of the time but there may be
a significant premenstrual flare in women.18,19 A UK survey of adult acne
patients showed most patients had acne since teenage years (71%)11
• Relapse of adolescent acne in adult age
This can be difficult to identify from the history, as there is frequently no
clarity around when the patient was free from acne; however, it may be easier
to define when isotretinoin has been used successfully, as there will be a
period of time post-therapy, when the patient was free from any acne. A
study by Collier et al. suggested this might account for 4% of men and 13%
of women.15
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Adult Acne
DIFFERENCE IN CLINICAL PRESENTATION OF ADULT ACNE

Some authors have identified distinct morphological differences in the
characteristics of adult acne which may distinguish it from adolescent acne.
Unlike adolescent acne where males are affected more frequently than females,
adult acne is more prevalent in females. The classic presentation of adult acne is
of inflammatory lesions (in particular, papules, pustules, and nodules) which are
usually prominent over the lower chin, jawline, and neck (Figure 2).14,17,20
In contrast to this, an Indian study reported a predominance of lesions on the
cheeks, which raises the question of variable distribution based on ethnicity.10
Comedonal activity is rare, but if present, it is usually in the form of closed
comedones, retentional lesions, or microcysts around the lower face17 (Figure 3).
A B
Figure 2: A, Adult female inflammatory acne showing predilection to lower cheeks and
chin. B, Mixed inflammatory, non-inflammatory lesions at lower face and chin.
Figure 3: Adult female acne mixed inflammatory lesions and

macrocomedones around lower cheeks and chin.
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Layton and Mawson
Adult acne is mainly mild-to-moderate in severity and may be refractory to

treatment.3 However, cystic acne may occur and has been identified in up to 12%
of adults.11,14
Studies show a variation in the site involved, depending on where the
study has been conducted. Observational studies of community samples show
that persistent acne in women often involves non-facial skin, whereas studies
looking at those referred to a dermatology department, found a predominance
of facial distribution. This may be in part due to the fact that pure truncal
involvement is not deemed to be cosmetically distressing; hence, fewer patients
present for treatment. A survey of 942 adult females with acne in UK consulting
dermatologists, aged between 25 and 40 years, found chest and back involvement
in 28%.11
Underlying Pathogenesis And

Associated Epidemiological Factors
This area is extensively covered in other articles. Although there is a limited
evidence to suggest that the underlying pathophysiology of adult acne differs
significantly from adolescent acne, it is important to rule out a number of factors
as these may influence on-going management. As a larger proportion of females
suffer from adult acne, underlying hormonal imbalance should be considered
where history or other clinical features indicate this as a possible underlying
problem.
Hormonal Considerations
Women with adult acne often show clinical features suggestive of hyperandrogenism
such as hirsutism, premenstrual flare, and alopecia. Very few of these women
have raised laboratory markers of hyperandrogenism, but it raises the question of
their having an end-organ hypersensitivity, rendering them more susceptible to
circulating hormones.
Menstrual Cycle
There is an extensive evidence that adult acne in females relates to hormonal aspects
with flares occurring premenstrually.18,19 However, the prevalence varies. A self-
reported UK survey of 400 women found that 44% of women had premenstrual
flares, with women older than 33 years were more likely to have flare than those
between the age of 20 and 33 years.14 A smaller UK study found that 83% of
women with persistent acne reported premenstrual flare.20
134

Adult Acne
Dihydroepiandrosteronesulfate
Studies have looked at androgenic changes in women with acne. A study
examined women with adult-onset or hirsutism-associated acne compared with
an age-matched control group.21 Luteinizing hormone (LH), follicle-stimulating
hormone (FSH), total testosterone (T), dihydroepiandrosteronesulfate (DHEAS),
and sex hormone-binding globulin (SHBG) were measured and compared. Results
demonstrated that acne was associated with increased SHBG, free androgen
index, and DHEAS in females with hirsutism, but only DHEAS was increased in
women without hirsuitism.21
Androgens
There is also a suggestion of target tissue androgens in the skin having a pathogenic
role in women with adult acne.3,22 Androgens are produced locally in the sebaceous
glands and keratinocytes via DHEAS metabolism. Serum androgens, while
within the normal range, may increase tissue-derived androgens in females with
acne. This may be due to local, more sensitive tissue enzyme activity and more
sensitive receptors in the sebaceous gland and/or keratinocytes. Other studies
have confirmed that adrenal androgen secretion is only mildly elevated in patients
with adult acne and patients without acne, have similar hormone levels.23,24
Endocrinopathies and Genetic Factors

Late-onset Congenital Adrenal Hyperplasia
There is a link between adult acne and late-onset congenital adrenal hyperplasia
(CAH). One study identified 11.8% of patients with post-adolescent acne had
reduced activity of the enzyme 21-hydroxylase, in keeping with late-onset CAH.25
Polycystic Ovarian Syndrome

Symptoms of polycystic ovaries have been reported in 52–82% of patients with
adult acne, although hormonal profiles were not in accordance with the classical
polycystic ovary syndrome (PCOS).26
Genetic Factors
Familial links with acne including adult acne that has been well-documented
(Table 3).27 A large study of identical twins showed in 97.9% of individuals, both
had acne.28 Other studies, around the world, have shown high rates of family
members affected from 38 to 50%.13,16,28,29 Therefore, it seems that genetics might
have a significant role to play in acne development, persistence, and response to
treatment.
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Layton and Mawson
Table 3: High Frequency of Family History of Acne in Adult Women with Acne
Acne history Acne history Responses
positive negative
Father 49 (71%) 20 (29%) N = 69
Mother 51 (74%) 18 (26%) N = 69
Sibling 37 (54%) 32 (46%) N = 69
At least one 47 (67%) 23 (33%) N = 69
External Factors
Antibiotic Use
There has been a developing understanding of the role of P. acnes in adult acne and
the impact of evolving antibiotic resistant bacteria.1 Many patients suffering from
persistent acne have had many years of differing topical and/or oral antibiotic
therapy, without the adjuvant use of antimicrobials to prevent resistance. Some
adults with persistent acne may carry antibiotic resistant strains of P. acnes which
can contribute to or atleast result in some reduced efficacy to antibiotic therapies,
although it is acknowledged that the correlation between carriage of antibiotic
resistant P. acnes and response to therapy is complex.30 However, the judicial use of
antibiotics and concomitant use of an antimicrobial therapy alongside antibiotics,
when required, is advocated.1
No differences in bacterial flora have been observed between adolescents and
adults with acne; hence, it is unlikely that antibiotic resistant bacteria influence the
course of adult acne per se.31
Drug-induced Acne
A number of medications have been implicated in acne. Studies have linked
medications such as prednisolone, lithium, anabolic steroids, and phenytoin as
possible causative agents.32
Exposure to Ultraviolet Light

There is a suggestion that ultraviolet radiation may cause inflammation and
generate squalene peroxides which are highly comedogenic.33,34 This may play
a role in the persistence of acne in tropical countries, in addition to excessive
perspiring and increased humidity.33,35
Climate
There are various beliefs about the way that climate affects acne. Traditionally, in
the UK, it was thought that summer improved acne whereas winter aggravated
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Adult Acne
it. Indian studies found the opposite that sun exposure and summer seasons
aggravate acne. This may be explained by the relatively cool summers of the UK
when compared to hot tropical climates.35
Obesity and Food Intake

There is a suggestion of obesity and increased low-density lipoprotein (LDL)
cholesterol being linked to acne.36 Food intake has been associated with adult acne
in some studies.37 It is likely that this interplays with metabolic syndromes with
increased serum levels of insulin-like growth factor (IGF) also being positively
associated with acne lesions.38,39
Smoking
Smoking may play a role in acne severity and has been significantly related in a
dose-dependent manner to cigarette consumption.40,41 One variant common to
smokers has been described in post-adolescent acne. This embraces a paucity of
inflammatory lesions, but large prominent cyst-like comedones homogeneously
distributed on the whole face with a relative absence on the lower third of the face
and the jawline.40
Cosmetics
Cosmetics have been implicated in the development of acne in certain female
population groups.42 Others have reported no clear link between acne and
cosmetics, although there is thought to be an element of exacerbation by using oil
or greasy products.10
Stress
Chronic stress has been linked to adult acne and thought to be due to an increased
androgen secretion in females.43 Studies have linked stress and acne in up to 71%
cases.10,11,16 An association between increased levels of cortisol and emotional
stress has been reported.44 A study of 13 patients with late-onset adult acne
found no underlying abnormalities in levels of androgens but onset was related to
stress.45 These patients did not respond to antibiotics or isotretinoin, but 5 of the
patients had clearance of acne with an antidepressant.
Pregnancy
Pregnancy has a varied response on acne. Some women find there is a flare in acne
and some have improvement. Goulden et al. found a flare in 18%, improvement in
43%, and no effect in 39%.9
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Layton and Mawson
Related Outcomes
Psychosocial Impact
Acne at any age can have significant psychosocial impact on the patient leading to
reduced self-esteem, lower socioeconomic achievement, as well as negative impact
on social functioning, such as relationship formation and continuity.7 Adults with
acne have been shown to have a 40% prevalence of psychiatric co-morbidity.8 A
recent study from India confirmed that stress was a common associated issue in
female adults, with acne highlighting the need for an empathic and supportive
approach.45
Scarring and Post-inflammatory Hyper- or Hypopigmentation

Scarring is a distressing and disfiguring sequelae of acne (Figure 4) and is more
common in adults than in adolescents. This emphasizes the need for active,
aggressive early management of adult acne.
Two Indian studies46,47 demonstrated a high incidence of post-inflammatory
pigmentation (Figure 5) and scarring, with a predominance of icepick and rolling
atrophic scars.46,47 UK studies have also found a similar predominance of scarring,
A B
Figure 4: A, Subtle scarring in adult

male with acne. B, Significant scarring.
C C, ± inflammatory acne and scarring.
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Adult Acne
Figure 5: Post inflammatory pigmentation.
affecting 77.2% men and 58.5% women, with icepick scars representing the
commonest type.6,7 A French epidemiological study found that scars, with or
without pigmented macules, were a consequence in 49% of women with clinical
acne.13
There appears to be a clear correlation between acne in darker skin and
resultant pigmentary changes. A study looked at black Afro-Caribbean patients
seen for dermatologic consultation in Paris (skin types, V–VI). A prevalence of
29.2% in acne sufferers and dyschromia in more than 25% of cases was found.48
There is a suggestion of presence of an androgenic association in dark-skinned
individuals. African patients seeking dermatology consultation in Dakar, Senegal
found that acne was present in 75% of young females. The mean age of onset was
25.6 years. Acne was accompanied by hyperandrogenism in 19%, hirsutism in
94%, and artificial depigmentation 39%.47
MANAGEMENT OF ADULT ACNE

The specific management of acne is covered in other articles. Although there are
many similarities in management of adolescent and adult acne, there are also key
differences that need to be understood to achieve a holistic, tailored approach to
suit the individual patient’s needs and lifestyle.
There are patient-specific issues that need to be explored, including child-
bearing potential and whether treatments are acceptable to the individual, as
well as psychological support. Adults may have a skin that is more irritable and
sensitive, purely due to the aging process.49 Individuals may have failed with
139

Layton and Mawson
multiple courses of treatment in the past and response to new treatments might
be slower; therefore, patients need to be educated about the length of time
required for any treatment to demonstrate clinical improvement.1 Education
and counseling will improve adherence to therapy and has been shown to
improve clinical outcomes. Women are better at adhering to treatment regimens
as compared to men and adolescents.50 The uses of combination therapies and
discussion of side effects will also determine adherence. Simplifying regimens
with fixed-dose combinations can result in improved adherence.51 The clinician
must establish trust in a non-judgmental, empathetic way to encourage the
patients to express their self-perception of acne and how it affects their quality of
life.52 Engaging the patient in discussions and decisions regarding management
will aid adherence.
Cosmetic Use
Cosmetic usage is an important consideration when dealing with paients of adult
acne, especially women. It has been shown that the use of cleansers, moisturizers,
and make-up can have a positive effect on adherence and should be incorporated
into management regimens. Moisturizers should be aqueous, non-comedogenic,
and should contain minimal allergic ingredients.53 Due to the possible impact of
ultraviolet light on acne, it is recommended that patients use sunscreen. All of
these products should be anti-comedogenic and oil or grease-free.
Barriers For Adults Presenting And

Being Diagnosed With Adult Acne
The actual barriers for health-seeking behavior have not been explored in current
literature involving acne but potential issues could involve:
• Poor understanding that the condition can be treated but has a chronic course
• Lack of state healthcare availability to deal with a ‘cosmetic’ skin condition
• Female autonomy – in female adults with acne, there may be barriers to access
dermatology care, due to household and family needs, including healthcare
needs of their family taking priority over their own
• Rural areas having lack of access to dermatology clinics and in those areas,
isotretinoin therapy being difficult to be monitored safely
• Embarrassment about presenting with a ‘cosmetic’ or teenage issue
• Lack of self-esteem and poor psychological wellbeing, making it difficult to
present to a medical professional
• Issues related to men not wanting to seem feminine by wanting treatment to
improve their looks.
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Adult Acne
CONCLUSION
Clinicians managing adult acne need to be aware of specific features of adult
acne. Careful examination with appropriate lighting will help to identify subtle
lesions including macrocomedones and hence, facilitate the choice of targeted and
optimum treatment. External factors should be considered including underlying
endocrinopathies. Some adults have reportedly more sensitive skin which is easily
irritated. Therefore, the clinician should bear this in mind during the course of
treatment. Patients need to be fully informed regarding the speed and efficacy of
treatment and an empathic approach should always be adopted in support of the
psychosocial impact that adult acne can have.
Editor’s Comment
Acne, which was earler considered the bane only of adolescene, is now known to
often persist well beyond teenage years and in some cases, appear for the first time
in adulthood. Adult acne consists predominantly of inflammatory lesions, present
usually over the lower chin, jawline, and neck. About half these patients have
psychiatric comorbidities due to chronic nature of acne and resultant scarring.
This lucidly written article by Drs. LM Layton and RL Mawson highlights key
features of adult acne including the controversy about the definition, prevalence
of the problem in different geographic areas and related epidemiological factors
and the underlying pathogenesis. They also discuss the clinical features of adult
acne and how the condition differs from adlolescent acne, criteria for diagnosis,
the associated comorbidities and the therapeutic options available specific to
management and the related outcomes.
Neena Khanna
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6. Tan JKL. Current measures for the evaluation of acne severity. Expert Rev Dermatol. 2008;3:595-603.
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10. Khunger N, Kumar C. A clinic-epidemiological study of adult acne: Is it different from adolescent acne?
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12. Stern RS. The prevalence of acne on the basis of physical examination. J Am Acad Dermatol. 1992;26:931‑5.
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136:66-70.
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20 years and older. J Am Acad Dermatol. 2008;58:56-9.
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vulgaris among Caucasian, Asian, Continental Indian and African American Women. J Eur Acad Dermatol
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17. Dumont-Wallon G, Dreno B. Specificity of acne in women older than 25 years. PresseMed. 2008;37:585‑91.
18. Lucky A. Quantitative documentation of a premenstrual flare of facial acne in adult women. Arch Dermatol.
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19. Stoll S, Shalita AR, Webster GF, Kaplan R, Danesh S, Penstein A. et al. The effect of the menstrual cycle on
acne. J Am Acad Dermatol. 2001;45:957-60.
20. Shaw JC, White LE. Persistent acne in adult women. Arch Dermatol. 2001;137:1252-53.
21. Seirafi H, Farnaghi F, Vasheghani-Farahani A, Alirezaie NS, Esfahanian F, Firooz A, et al. Assessment of
androgens in women with adult onset acne. Int J Dermatol. 2007;46:1188-91.
22. Carmina E, Lobo RA. Evidence for increased androsterone metabolism in some normoandrogenic women
with acne. J Clin Endocrinol Metab. 1993:76:1111-4.
23. Chrousos GP, Peck GL, Gross EG, Cutler GB Jr, Loriaux DL. Adrenal function in women with idiopathic acne.
24. Thiboutot D, Gilliland K, Light J, Lookingbill D. Androgen metabolism in sebaceous glands from subjects with
and without acne. Arch Dermatol. 1999;135:1041-5.
25. Oslere LS, Richardson T, Caine S. The prevalence of late onset congenital adrenal hyperplasia in females
with post-adolescent acne. Br J Dermatol. 1993;129:25.
26. Betti R, Bencini PL, Lodi A, Urbani CE, Chiarelli G, Crosti C. Incidence of polycystic ovaries in patients with
late-onset or persistent acne: Hormonal reports. Dermatologica. 1990;181:109-11.
27. Goulden V, McGeown CH, Cunliffe WJ. The familial risk of adult acne: A comparison between first degree
relatives of affected and unaffected individuals. Br J Dermatol. 1999;141:297-300.
28. Bataille V, Snieder H, MacGregor AJ, Sasieni P, Spector TD. The influence of genetics and environmental
factors in the pathogenesis of acne: a twin study of acne in women. J Invest Dermatol. 2002;119:1317-22.
29. Herance MI, Ando I. Acne in infancy and acne genetics. Dermatology. 2003;206:24-8.
30. Coates P, Vyakrnam S, Eady EA, Jones CE, Cove JH, Cunliffe WJ. Prevalence of antibiotic resistant
propionibacteria on the skin of acne patients: 10-year surveillance data and snapshot distribution study.
Br J Dermatol. 2002;146:840-8.
31. Till AE, Goulden V, Cunliffe WJ, Holland KT. The cutaneous microflora of adolescent, persistent and late onset
acne patients does not differ. Br J Dermatol. 2000;142:885-92.
32. Zouboulis CC, Piquero-Martin J. Update and future of systemic acne treatment. Dermatology. 2003;
206:37‑53.
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33. Mills OH, Porte M, Klingman AM. Enhancement of comedongenic substances by ultraviolet radiation. Br J
Dermatol. 1978;98:145-50.
34. Motoyoshi K. Enhanced comedo formation in rabbit ear skin by squalene and oleic acne peroxides. Br J
Dermatol. 1983;109:191-8.
35. Sardana K, Sharma RC, Sarkar R. Seasonal variation in acne vulgaris – Myth or reality? J Dermatol.
2002;29:484-8.
36. Adulnaja KO. Changes in the hormone and lipid profile of obese adolescent Saudi females with acne vulgaris.
Braz J Med Biol Res. 2009;42:501-5.
37. Bowe WP, Joshi SS, Shalita AR. Diet and Acne. J Am Acad Dermatol. 2010;63:24-141.
38. Zouboulis CC, Eady A, Philpott M, Goldsmith LA, Orfanos C, Cunliffe WC, et al. What is pathogenesis of acne?
Exp Dermatol. 2005;14:143-52.
39. Cappel M, Mauger D, Thiboutot D. Correlation between sebum levels of insulin-like growth factor 1,
dehydroepiandrosterone sulfatedihydrotestosterone and acne lesion counts in adult women. Arch Dermatol.
2005;141:133-338.
40. Capitanio B, Sinagra JL, Bordignon V et al. Underestimated clinical features of post-adolescent acne. J Am
Acad Dermatol. 2010;63:782-8.
41. Schäfer T, Nienhaus A, Vieluf D, Berger J, Ring J. Epidemiology of acne in the general population: The risk of
smoking. Br J Dermatol. 2001;145:100-4.
42. Kligman AM, Mills OH. Acne cosmetic. Arch Dermatol. 1972:106:843-50.
43. Kligman AM. Post-adolescent acne in women. Cutis. 1992;48:75-7.
44. Laue L, Peck GL, Loriaux DL, Gallucci W, Chrousos GP. Adrenal androgen secretion in post adolescents acne:
Increased adrenocortical function without hypersensitivity to adrenocorticotropin. J Clin Endocrinol Metab.
1991;73:380-4.
45. Harrington CI. Post-adolescent acne and marital break-up. Br J Dermatol. 1997;137:478-9.
46. Adityan B, Thappa DM. Profile of acne vulgaris – A hospital based study from South India. Indian J Dermatol
Venereol Leprol. 2009;75:272-8.
47. Kane A, Niang SO, Diagne AC, Ly F, Ndiaye B. Epidemiologic, clinical and therapeutic features of acne in
Dakar, Senegal. Int J Dermatol. 2007;46:36-8.
48. Arsouze A, Fitoussi C, Cabotin PP, Chaine B, Delebecque C, Raynaud E, et al. Presenting skin disorders in
black Afro-Caribbean patients: a multicentre study conducted in the Paris region. Ann Dermatol Venereol.
2008;135:177-82.
49. Choi CW, Lee DH, Kim HS, Kim BY, Park KC, Youn SW. The clinical features of late onset acne compared with
early onset acne in women. J Eur Acad Dermatol Venereol. 2001;25:454-61.
50. Zaghoul SS, Cunliffe WJ, Goodfield MJ. Objective assessment of compliance with treatments in acne. Br J
Dermatol. 2005;152:1015-21.
51. Yentzer BA, Alikhan A, Teuschler H, Williams LL, Tusa M, Fleischer AB Jr, et al. An exploratory study of
adherence to topical benzoyl peroxide in patients with acne vulgaris. J Am Acad Dermatol. 2009;60:879‑80.
52. Thomas B, Tan JKL. Adherence optimization in acne management. Skin Therapy Letter. 2001;7:1-3.
53. Dréno B, Thiboutot D, Gollnick H, Finlay AY, Layton A, Leyden JJ, et al; Global Alliance to Improve Outcomes
in Acne. Large-scale worldwide observational study of adherence with acne therapy. Int J Dermatol.
2010;49:448-56.
143

Acne Syndromes
Pan Jiun-Yit MBBS FRCP FAMS,
*Goh Chee-Leok MD MBBS MMed FRCPE FAMS
National Skin Centre, Singapore
ABSTRACT
Acne is one of the most common skin disorders. However, it is also a
cardinal part of many syndromes with systemic manifestations. These
include congenital adrenal hyperplasia (CAH), seborrhea-acne-hirsutism-
androgenetic alopecia (SAHA) syndrome, polycystic ovary syndrome
(PCOS), hyperandrogenemia, insulin resistance and acanthosis nigricans
(HAIR-AN) syndrome, Apert syndrome, synovitis-acne-pustulosis-
hyperostosis-osteitis (SAPHO) syndrome, and pyogenic arthritis,
pyoderma gangrenosum and acne (PAPA) syndrome. The pathogenesis
of these conditions is diverse and varied, ranging from abnormalities in
androgen steroid metabolism, insulin resistance (IR), cell-cell signaling
and uncontrolled inflammation. It is important for clinicians to identify
the clinical features of these syndromes so that prompt and appropriate
investigations and treatment may be instituted.
INTRODUCTION
Acne vulgaris is one of the most common skin disorders seen in dermatology
and general practice. Its pathogenesis is due to excessive sebum production,
follicular hyperproliferation, inflammation and colonization of the skin by
Propionibacterium acnes.1-3 However, other pathogenetic factors also play a role in
acne syndromes in which patients present both with acne and a plethora of varied
systemic manifestations.4 In this article, seven distinct acne-associated syndromes
are highlighted, focusing on the diagnostic clinical features, pathogenesis,
investigations and recommended treatment.
Email: drgohcl@gmail.com

Acne Syndromes
CONGENITAL ADRENAL HYPERPLASIA—

AN INHERITED ENDOCRINOPATHY
In congenital adrenal hyperplasia (CAH), cortisol deficiency leads to oversecretion
of adrenocorticotropic hormone (ACTH) and adrenal overstimulation and
hyperplasia.5 The resulting androgen excess affects the pilosebaceous unit resulting
in androgenic alopecia, hirsutism and acne. The inheritance of CAH is autosomal
dominant and 95% of cases are due to 21-hydroxylase (21-OH) deficiency caused
by mutations in the 21-OH gene (CYP21, 6p21.3).6 The other 5% are usually
caused by 11b-hydroxylase deficiency or 3b-hydroxysteroid dehydrogenase
deficiency.7
Classical CAH is associated with complete loss of enzyme function presenting
in the neonatal period and is rare, occurring in 1/15,000 births. In classical
CAH, clinical manifestations (virilization, impaired fertility, short stature, early
appearance of facial/axillary/pubic hair, and acne) are caused by glucocorticoid
and mineralocorticoid deficiency and androgen excess.
Non-classical CAH (NCAH) or late-onset forms are milder and occur more
frequently, affecting 1% of the general population.8 NCAH may be associated
with hyperandrogenic symptoms such as acne, hirsutism, androgenetic alopecia,
or seborrhea. Severe cystic acne refractory to oral antibiotics and isotretinoin has
also been associated with NCAH.9
Non-classical CAH should be differentiated from PCOS, Cushing’s syndrome,
hyperprolactinemia and androgen-secreting tumors. The determination of
17-hydroxyprogesterone (17-OHP), the immediate substrate for 21-OH, is used
for biochemical diagnosis. For mild NCAH with normal basal adrenal steroids,
ACTH stimulation test is recommended. Genotype analysis of the 21-OH gene
(CYP21 genotyping) is available but not routinely used.7
Treatment of classical CAH reduces increased androgen production by
replacing cortisol with oral glucocorticoids, and if needed, aldosterone deficiency
with fludrocortisone. Treatment of NCAH depends on the main problem of
the patient such as acne or hirsutism. For the treatment of acne associated with
NCAH, oral glucocorticoids are administered in order to counteract adrenal
androgen production. Low-dose prednisolone or dexamethasone may be given
orally at bedtime. Serum dehydroepiandrosterone (DHEA) is monitored for
reduction or normalization to ensure that glucocorticoids are effective.7
SEBORRHEA-ACNE-HIRSUTISM-ANDROGENETIC
ALOPECIA SYNDROME
Seborrhea-acne-hirsutism-androgenetic alopecia (SAHA) syndrome in women
was defined in 1982.10,11 It includes the skin manifestations of androgen excess
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Jiun-Yit and Chee-Leok
in women, either due to hyperandrogenemia or increased sensitivity of the

pilosebaceous unit to normal circulating androgen levels. The SAHA syndrome is
classified into idiopathic, ovarian, adrenal and hyperprolactinemic types, and can
be associated with polycystic ovaries, cystic mastitis, obesity, IR and infertility.11
Androgen excess in women is common and can be caused by elevated androgen
production in adrenals and ovaries, decreased peripheral metabolism of androgens,
or activation of androgens in the skin.12 The sebaceous gland is an important organ
of active androgen formation and expresses all enzymes necessary for synthesis of
testosterone. Androgen excess can increase the size and number of lobules per
sebaceous gland as well as sebum excretion. However, most acne patients have
normal circulating androgen levels and acne severity does not correlate with serum
androgen levels.12
Hirsutism and oligomenorrhea are common symptoms associated with
hyperandrogenemia. Patients with hirsutism often exhibit increased 5a-reductase
activity and higher levels of androstenedione and dehydroepiandrosterone sulfate
(DHEA-S). Androgen excess induces shortening of follicular anagen phase and
progressive conversion of terminal hair to intermediate ones, leading to androgenic
alopecia.
The diagnosis of SAHA syndrome requires a complete history, physical
examination with emphasis on evidence of androgen excess and appropriate
laboratory investigations (including hormones such as DHEA-S, testosterone,
prolactin and 17-OHP) to exclude hyperandrogenemia.
Treatments for the dermatological manifestations of hyperandrogenism (HA)
include lifestyle modification, oral contraceptives, antiandrogens and insulin-
sensitizing medications.11
POLYCYSTIC OVARY SYNDROME

Polycystic ovary syndrome is a complex endocrine disorder characterized by
clinical or biochemical evidence of hyperandrogenison (HA) with oligo- and/or
anovulation, and polycystic ovaries.13 Hyperandrogenemia, altered gonadotropin
secretion as well as IR are involved in its pathogenesis.14,15 A new aspect in the
pathophysiology of PCOS is the involvement of vitamin D deficiency, which may
be related to insulin regulation disturbances.16
There is accumulating evidence for a strong genetic background of PCOS. The
related genes can be grouped into four categories: (1) those related to IR; (2) those
that interfere with the synthesis and the action of androgens; (3) those that code
for inflammatory cytokines; and (4) other candidate genes. A clear relationship
with obesity-associated genes has been shown recently.14,15
The disorder is frequently associated with IR accompanied by compensatory
hyperinsulinemia and an increased risk for the development of type 2 diabetes
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Acne Syndromes
mellitus. Women with PCOS frequently suffer from obesity, infertility, hirsutism,
acne and alopecia. PCOS appears more prevalent in women with severe acne, late-
onset acne, persistent acne and acne resistant to conventional therapies.
Clinical examinations including anthropometric measurements and hirsutism
score are required for diagnosis of PCOS. Determination of endocrinological
parameters including androgens is crucial for diagnosis. Other endocrine
disorders should be ruled out, e.g. CAH, Cushing’s disease, hyperprolactinemia
and hypothyroidism. To evaluate the metabolic risk of women with PCOS,
screening for diabetes mellitus, hyperlipidemia and obesity should be done.
Other investigations include ovarian ultrasound and tests for endometrial cancer,
ovulation and a menses calendar.
Lifestyle intervention, insulin sensitizers (e.g. metformin) and oral contra
ceptives are the most common therapeutic approaches for the management of
PCOS.17,18 Treatment should be individualized. Weight control is one of the first
interventions in obese women with PCOS, but its success is often limited and is
not applicable in lean patients with PCOS. Insulin sensitizers may not only be
helpful in weight loss, but also directly regulate IR and decrease androgen levels.
Vitamin D supplementation is recommended in the case of 25-hydroxyvitamin D
insufficiency, which may be also helpful in the correction of metabolic disturbances.
If patients are not planning pregnancy, oral contraceptives with an established
antiandrogen efficacy can help to control both androgen levels and skin symptoms
and hirsutism. Further, new therapeutic interventions might be helpful in the
future, including luteinizing hormone (LH)-releasing agents, for which clinical
studies are currently in progress.
HYPERANDROGENEMIA, INSULIN RESISTANCE AND

ACANTHOSIS NIGRICANS SYNDROME
Patients with HAIR-AN syndrome usually present with HA such as oily skin,
hirsutism, acne, menstrual irregularities, androgenic alopecia, deepening of voice,
clitorimegaly and changes in muscle mass, IR with diabetic symptoms, as well as
acanthosis nigricans (AN).19,20 Association with other autoimmune or endocrine
diseases has been observed such as Hashimoto’s thyroiditis, Graves’ disease, vitiligo,
Cushing’s syndrome, acromegaly and CAH.
Generally, these patients have markedly elevated insulin levels, elevated or
high-normal levels of testosterone and androstenedione but normal levels of LH
and prolactin. Adrenal function is normal, while pathological findings of ovarian
stromal hyperthecosis are commonly present.
The primary abnormality in patients with this syndrome is IR with a
compensatory elevation in insulin levels, which may have a direct short-term
effect on the regulation of steroidogenesis in ovaries, leading to a subsequent
147

overproduction of androgens. The severity of hyperinsulinemia correlates directly

with androgen levels. Hyperinsulinemia and hyperandrogenemia stimulate
epithelial proliferation and melanin accumulation, resulting in the cutaneous
manifestations of AN. A marked decrease in insulin receptors or mutations in the
receptor gene have been found in patients with HAIR-AN syndrome.21
For management of HAIR-AN syndrome, antiandrogens such as
spironolactone and flutamide may also be used, alone or in combination with
oral contraceptives. If medical treatment fails, a surgical biliopancreatic diversion
or bilateral wedge resection of ovaries may benefit certain patients, but in most
patients HA returns to preoperative status in a few months. Removal of the
ovaries fails to improve the IR as this is a genetic metabolic defect. Operation
in conjunction with hormonal gonadotropin suppression is the most effective
therapy available for recalcitrant cases.21
APERT SYNDROME
Apert syndrome (MIM 101200), also known as acrocephalosyndactyly, was first
described in 1906. Its birth prevalence is estimated to be 15/1,000,000 based
on a recent population-based study, making up approximately 4% of all cases
of craniosynostosis.22 Apert syndrome is inherited in an autosomal dominant
manner and is characterized by synostoses of extremities, vertebrae and skull,
with syndactyly of fingers and toes. In 1970, Apert syndrome became known as
Solomon described several patients with acne in an unusual distribution with
lesions extending to the surface areas of the forearms.23
Moderate-to-severe acne beginning in early puberty is a dermatological
hallmark of Apert syndrome.23 Patients with Apert syndrome often present with
oily skin and acne in the form of comedones, papules, pustules, nodules, cysts, or
scars.23,24 Plasma androgen levels and androgen receptor staining of sebaceous
glands show no difference between patients and controls.
Two specific heterozygous missense germline mutations of the fibroblast
growth-factor receptor 2 (FGFR2) gene have been identified. The mutations of
adjacent amino acid residues of FGFR2, either S252W or P253R, are localized
in the linker region between D2- and D3-immunoglobulin-like regions of the
FGFR2-ligand binding domain. Two major isoforms of FGFR2 because of splice
variants of FGFR2 are formed—FGFR2b is exclusively expressed on epithelial
cells, whereas FGFR2c is expressed only on dermal and mesenchymal cells.
Both receptor isoforms and their specific ligands are involved in mesenchymal
epithelial signaling, leading to downstream effects of activated FGFR2-signalling
on follicular keratinocyte proliferation, sebaceous lipogenesis and inflammatory
cytokine response. Increased FGFR2 signaling activity is seen in Apert syndrome,
which upregulates the activity of phosphoinositol-3 kinase (PI3K)/Akt and
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Acne Syndromes
mitogen-activated protein (MAP) kinase signal transduction pathways. This

results in a nuclear deficiency of the transcription factor forkhead box protein O1
(FoxO1), which is thought to be a key transcription factor in the pathogenesis of
acne vulgaris.24
Accumulating evidence supports the view that isotretinoin treatment restores
decreased nuclear levels of FoxO1, a new concept which is in accordance with the
excellent response of acne in Apert syndrome to oral isotretinoin treatment.23,24
Because of the persistently increased signaling of the mutated receptors, a lifelong
low-dose isotretinoin treatment is necessary to counterbalance the mutation-
induced FoxO1 deficiency. In order to minimize isotretinoin maintenance
dosage in Apert patients, dietary restriction of milk and dairy products, as well as
hyperglycemic carbohydrates has been proven to be most effective to reduce the
impact of diet-induced growth factors like insulin and insulin-like growth factor
(IGF)-1 on nuclear FoxO1 levels.
The genetic defects of the gain-of-function FGFR2 mutations of Apert
syndrome demonstrate that acne can be induced by increased growth factor
signaling. It has recently been suggested that anti-acne agents and especially,
retinoids attenuate FGFR2-signal transduction.4,10
SYNOVITIS-ACNE-PUSTULOSIS-
HYPEROSTOSIS-OSTEITIS SYNDROME
The SAPHO syndrome was first described in 1987. Three diagnostic criteria for
this syndrome have been proposed:
• Chronic recurrent multifocal osteomyelitis with or without skin manifestation
• Acute or chronic sterile arthritis associated with either pustular psoriasis or
palmoplantar pustulosis, or severe acne
• Sterile osteitis in the presence of one of the skin manifestations.
Any of the above three presentations is sufficient for diagnosis of this
syndrome.25
Synovitis-acne-pustulosis-hyperostosis-osteitis syndrome is considered as a
rare disease with an estimated prevalence, probably no greater than 1 in 10,000. It
is characterized by rheumatoid factor-negative osteoarthropathy associated with
various dermatological manifestations such as acne/hidradenitis suppurativa/
dissecting cellulitis of the scalp, psoriasis/pustular psoriasis/palmoplantar
pustulosis, Sweet’s syndrome, Sneddon-Wilkinson disease and pyoderma
gangrenosum (PG).26 The clinical presentation of acne varies greatly from mild-
to-severe type such as acne conglobata or acne fulminans. Bone involvement may
affect the anterior chest wall, sacroiliac joints and extremities. Sclerosis or osteolytic
changes can be observed in radiographic imaging, while bone scintigraphy shows
149

increased uptake in the involved bone. Whole body magnetic resonance imaging
assists early diagnosis by detecting multifocal osteitis lesions. Positron emission
tomography is useful for differentiation from multiple metastatic bone tumors.27
Synovitis-acne-pustulosis-hyperostosis-osteitis syndrome primarily affects
children and young adults. Association with inflammatory bowel diseases such as
Crohn’s disease and ulcerative colitis has been reported. In addition, recalcitrant
pyodermic lesions and neutrophilic dermatoses as seen in SAPHO syndrome are
often associated with myelodysplastic syndrome.26 The pathogenesis of SAPHO
syndrome remains poorly understood. Because of its involvement in acne and
sporadic isolation from a few osteitic bone lesions, P. acnes has been suspected
as an etiologic agent.28 However, prolonged antibiotic therapy is not effective. A
recent study suggested that interleukin (IL)-8 and tumor necrosis factor-alpha
(TNF-a) generated by purified polymorphonuclear neutrophils (PMN) were
higher in three patients with SAPHO syndrome than in the healthy controls.
The P. acnes-induced production of IL-8 and TNF-a in PMN was impaired in
the SAPHO group as compared to those with rheumatoid arthritis and psoriatic
arthritis, suggesting that SAPHO syndrome may be triggered by P. acnes-
induced infectious state, leading to strong humoral and cellular inflammatory
responses.28,29
Current therapy of SAPHO syndrome is mainly based on limited case series.
Several drugs, including nonsteroidal anti-inflammatory drugs, corticosteroids,
sulfasalazine, methotrexate, ciclosporin, leflunomide and calcitonin, have been
administered with differing results.30,31 The drug 13-cis-retinoic acid is useful
for treatment of severe acne and pustulosis. Recently, TNF-a blockers such
as infliximab have been reported to be effective for refractory cases.32 The
effectiveness of intravenous or oral bisphosphonate for SAPHO syndrome has
also been reported, which may be explained by their antiinflammatory activity
via suppression of IL-1b, IL-6 and TNF-a secretion.33 SAPHO syndrome is a
chronic disorder with intermittent exacerbations and remissions.
PYOGENIC ARTHRITIS-PYODERMA
GANGRENOSUM-ACNE SYNDROME
The clinical triad of pyogenic sterile arthritis, PG and acne conglobata was noted to
be familial and described with the acronym PAPA syndrome in 1997. In 2002, the
gene of CD2-binding protein 1 [CD2BP1; also called praline-serine-threonine-
phosphatase-interacting protein 1, (PSTPIP1)] on chromosome 15q24-25.1
was identified as the gene causing the syndrome. The CD2BP1 protein binds
pyrin, which is an inhibitor of the inflammatory process. In PAPA syndrome, the
mutated CD2BP1 protein has enhanced binding capacity to pyrin and prevents
the bound pyrin from acting. As pyrin is expressed on neutrophils, but not on T or
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Acne Syndromes
B cells, the decreased amount of unbound pyrin results in neutrophilic infiltration

in arthritis, acne, PG and other neutrophilic dermatoses.34-37
The manifestation of PAPA syndrome with its clinical triad varies in the
affected family members. Arthritis is the most consistent sign followed by acne
and PG.36,37 Arthritis occurs earliest between ages 1 year and 16 years. Being
aseptic and seronegative, the pauciarticular, non-axial arthritis of variable severity
commonly affects hands, elbows, knees and ankles. Axial joints were involved in a
few cases. At puberty, severe nodulocystic acne develops. PG occurs in adolescence
or adulthood, usually after the appearance of acne.
Association of PAPA syndrome with other diseases has been described such
as proteinuria, insulin-dependent diabetes mellitus, hypogammaglobulinemia,
idiopathic hepatitis and uveitis. Of the triad, PG and acne may be present for
decades. Sterile pyogenic arthritis is generally self-limiting, but prolonged
prominent arthritis can lead to joint destruction and deformity. Invasive surgery is
usually harmful and contraindicated.
Generally, the inflammatory condition of pyogenic arthritis, PG and acne
is responsive to systemic or locally administered glucocorticoids. Antimicrobial
therapy is normally not effective. Some disease modifying antirheumatic
drugs such as leflunomide or sulfasalazine may reduce joint flares and prevent
disease progression. Dapsone can be helpful in PAPA syndrome because of its
antineutrophilic effect.35 Biological therapy is a potential treatment of choice:
infliximab and recombinant human IL-1 receptor antagonist (anakinra) have
demonstrated efficacy in PAPA syndrome and other autoinflammatory diseases.38
CONCLUSION
The manifestation and involvement of acne in different syndromes highlight its
multifaceted nature. In CAH as well as SAHA, PCOS and HAIR-AN syndromes,
excessive hormones or an exaggerated hormone response via aberrant hormone
receptor expression or post-binding response induce the accelerated growth and
differentiation of pilosebaceous units and epidermal keratinocytes. Overlapping
cutaneous manifestations (acne, hirsutism, androgenetic alopecia and AN) among
different syndromes indicate the interplay of hormones (e.g. androgens, prolactin,
insulin and IGF) and common final pathways in the pathogenesis. The activated
downstream PI3K/Akt signal transduction and decreased nuclear levels of FoxO1
was hypothesized to be a potential pathway.39
Conversely, the differential expression of the skin syndrome complexes in
patients with the same or different syndromes can be explained by individual
predisposition of the involved patients and tissues (epidermis vs pilosebaceous
units) to hormone action. In daily practice, PCOS, SAHA syndrome and NCAH
should be excluded in patients with severe acne, acne associated with other
151

symptoms (alopecia, hirsutism and obesity) or acne resistant to various therapies,

especially in females. Familial acne accompanied by joint/bone involvement
or other neutrophilic dermatoses, may be an early sign for SAPHO or PAPA
syndrome.
More evidence is needed to prove whether adult acne or hidradenitis
suppurativa, particularly in women, can be considered as a skin index for metabolic
syndrome. The manifestation of acne in PAPA and SAPHO syndromes provides
evidence to the argument that acne is an inflammatory disorder. SAPHO syndrome
and acne fulminans may be a part of the same disease spectrum. The frequent
association between SAPHO syndrome and psoriasis in long-term follow-up
with sharing common features implies a link between SAPHO syndrome and
psoriatic arthritis.40-42
Acne is an interesting model for studying interactions among hormones,
innate immunity, inflammation and wound healing. Exploring mechanisms of
acne pathogenesis in acne-associated diseases/syndromes will be crucial in the
development of novel treatment options.
Editor’s Comment
That acne does not occur alone is well highlighted in this excellent account of acne
syndromes by Dr JY Pan and Dr CL Goh. SAHA syndrome, PCOS, and HAIR-
AN syndrome are frequently encountered in day to day acne practice. However,
assessment and management of these entities requires greater engagement with
the patient and a good knowledge of dermatoendocrinology. Alternatively, a
multidisciplinary approach involving gynecologists and endocrinologists may be
adopted. NCAH is common yet frequently overlooked. It should be considered in
all cases of persistent/relapsing acne especially in those with strong family history.
17‑OHP, the marker of NCAH, is best done on day 2 of the cycle (follicular
phase) on a sample drawn at 8.00 AM. Borderline results are common and in the
right context (good clinical laboratory correlation) a therapeutic test with steroid
suppression is helpful. SAHA, PCOS, NCAH often co-exist or overlap.
Apert syndrome, SAPHO and PAPA syndromes, are rare entities but clinically
distinctive and not difficult to recognize.
Raj Kubba
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3. Zouboulis CC. Propionibacterium acnes and sebaceous lipogenesis: a love-hate relationship? J Invest
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11. Orfanos CE, Adler YD, Zouboulis CC. The SAHA syndrome. Horm Res. 2000;54:251-8.
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13. Ehrmann DA. Polycystic ovary syndrome. N Engl J Med. 2005;352:1223-36.
14. Deligeoroglou E, Kouskouti C, Christopoulos P. The role of genes in the polycystic ovary syndrome:
predisposition and mechanisms. Gynecol Endocrinol. 2009;25:603-9.
15. Wehr E, Schweighofer N, Möller R, Giuliani A, Pieber TR, Obermayer-Pietsch B. Association of FTO gene
with hyperandrogenemia and metabolic parameters in women with polycystic ovary syndrome. Metabolism.
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16. Wehr E, Pilz S, Schweighofer N, Giuliani A, Kopera D, Pieber TR, et al. Association of hypovitaminosis D with
metabolic disturbances in polycystic ovary syndrome. Eur J Endocrinol. 2009;161:575-82.
17. Glueck CJ, Goldenberg N, Sieve L, Wang P. An observational study of reduction of insulin resistance and
prevention of development of type 2 diabetes mellitus in women with polycystic ovary syndrome treated with
metformin and diet. Metabolism. 2008;57:954-60.
18. Pasquali R, Gambineri A. Insulin-sensitizing agents in polycystic ovary syndrome. Eur J Endocrinol. 2006;
154:763-75.
19. Rager KM, Omar HA. Androgen excess disorders in women: the severe insulin-resistant hyperandrogenic
syndrome, HAIR-AN. ScientificWorldJournal. 2006;6:116-21.
20. Omar HA, Logsdon S, Richards J. Clinical profiles, occurrence, and management of adolescent patients with
HAIR-AN syndrome. ScientificWorldJournal. 2004;4:507-11.
21. Elmer KB, George RM. HAIR-AN syndrome: a multisystem challenge. Am Fam Physician. 2001;63:2385-90.
22. Freiman A, Tessler O, Barankin B. Apert syndrome. Int J Dermatol. 2006;45:1341-3.
23. Solomon LM, Fretzin DF, Pruzansky S. Pilosebaceous abnormalities in Apert’s syndrome. Arch Dermatol.
1970;102:381-5.
24. Steffen C. The acneiform eruption of Apert’s syndrome is not acne vulgaris. Am J Dermatopathol. 1984;
6:213-20.
25. Kahn MF, Khan MA. The SAPHO syndrome. Baillieres Clin Rheumatol. 1994;8:333-62.
26. Govoni M, Colina M, Massara A, Trotta F. “SAPHO syndrome and infections”. Autoimmun Rev. 2009;8:256‑9.
27. Kahn MF, Bouvier M, Palazzo E, Tebib JG, Colson F. Sternoclavicular pustulotic osteitis (SAPHO). 20-year
interval between skin and bone lesions. J Rheumatol. 1991;18:1104-8.
28. Colina M, Lo Monaco A, Khodeir M, Trotta F. Propionibacterium acnes and SAPHO syndrome: a case report
and literature review. Clin Exp Rheumatol. 2007;25:457-60.
29. Hayem G, Bouchaud-Chabot A, Benali K, Roux S, Palazzo E, Silbermann-Hoffman O, et al. SAPHO syndrome:
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Characterization of the immune response in the synovitis, acne, pustulosis, hyperostosis, osteitis (SAPHO)
syndrome. Rheumatology (Oxford). 2008;47:1160-7.
31. Olivieri I, Padula A, Palazzi C. Pharmacological management of SAPHO syndrome. Expert Opin Investig
Drugs. 2006;15:1229-33.
32. Iqbal M, Kolodney MS. Acne fulminans with synovitis-acne-pustulosis-hyperostosis-osteitis (SAPHO)
syndrome treated with infliximab. J Am Acad Dermatol. 2005;52:S118-20.
33. Amital H, Applbaum YH, Aamar S, Daniel N, Rubinow A. SAPHO syndrome treated with pamidronate: an
open-label study of 10 patients. Rheumatology (Oxford). 2004;43:658-61.
34. Tallon B, Corkill M. Peculiarities of PAPA syndrome. Rheumatology (Oxford). 2006;45:1140-3.
35. Renn CN, Helmer A, Megahed M. [Pyogenic arthritis, pyoderma gangrenosum and acne syndrome (PAPA
syndrome)]. Hautarzt. 2007;58:383-4.
36. Hong JB, Su YN, Chiu HC. Pyogenic arthritis, pyoderma gangrenosum, and acne syndrome (PAPA syndrome):
report of a sporadic case without an identifiable mutation in the CD2BP1 gene. J Am Acad Dermatol. 2009;
61:533-5.
37. Shoham NG, Centola M, Mansfield E, Hull KM, Wood G, Wise CA, et al. Pyrin binds the PSTPIP1/CD2BP1
protein, defining familial Mediterranean fever and PAPA syndrome as disorders in the same pathway. Proc
Natl Acad Sci U S A. 2003;100:13501-6.
38. Dierselhuis MP, Frenkel J, Wulffraat NM, Boelens JJ. Anakinra for flares of pyogenic arthritis in PAPA
syndrome. Rheumatology (Oxford). 2005;44:406-8.
39. Melnik BC. FoxO1 - the key for the pathogenesis and therapy of acne? J Dtsch Dermatol Ges. 2010;8:105‑14.
40. Chua SL, Angus JE, Ravenscroft J, Perkins W. Synovitis, acne, pustulosis, hyperostosis, osteitis (SAPHO)
syndrome and acne fulminans: are they part of the same disease spectrum? Clin Exp Dermatol. 2009;
34:e241-3.
41. Assmann G, Wagner AD, Monika M, Pfoehler C, Pfreundschuh M, Tilgen W, et al. Single-nucleotide
polymorphisms p53 G72C and Mdm2 T309G in patients with psoriasis, psoriatic arthritis, and SAPHO
syndrome. Rheumatol Int. 2010;30:1273-6.
42. Queiro R, Moreno P, Sarasqueta C, Alperi M, Riestra JL, Ballina J. Synovitis-acne-pustulosis hyperostosis-
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2008;26:125-8.
154

Acne Comorbidities
Raj Kubba Mbbs Mrcp (UK) Frcp (Canada) Frcp (Edinburgh)
Delhi Dermatology Group, New Delhi, India
Department of Dermatology, Boston University School of Medicine, Boston, MA, USA
ABSTRACT
Acne rarely occurs alone, certainly as it is seen in India. Companion
morphologies are frequent and include seborrhea, acne, hirsutism and
alopecia (SAHA syndrome), melasma-like facial pigmentations, acanthosis
nigricans (AN) and benign cutaneous hyperplasias (described elsewhere
in this publication). Acne comorbidities, hitherto underreported, include
insulin resistance (IR), hypovitaminosis D, hypovitaminosis B12, atopic
diathesis, hypothyroidism, hypovitaminosis A, hypovitaminosis E, zinc
deficiency, dyslipidemia, gastrointestinal (GI) dysfunction, and psycho
logical stress and depression.
INTRODUCTION
Acne is a cutaneous expression of a complex interplay of genetics, hormones,
metabolism, mind, environment and lifestyle. The clinical expression is wide
and varied and an acne patient is very likely to display a mixture of companion
morphologies and comorbidities. At least some of the variations in clinical
expression may be accounted for on ethnic and geographic basis.1
Comorbidity is not a term one hears often in acne symposia or reads in acne
literature. Comorbidity is defined in Wikipedia as “presence of one or more
disorders (diseases) in addition to a primary disease or disorder, or the effect
of such additional disorders or diseases” on primary disease.2 Mosby’s Medical
Dictionary defines comorbidity as “two or more co-existing medical conditions
that are additional to an initial diagnosis”.3 The American Heritage® Medical
Dictionary defines comorbidity as “a concomitant but unrelated pathological and
disease process”.4
Email: rajkubba@gmail.com

Kubba
In the quest for comprehensive acne management, it is imperative that acne

comorbidities be understood, identified and addressed. This requires awareness,
conviction and pursuit. It entails additional costs and requires additional resources,
but when viewed in the larger context of improved therapeutic outcomes and
improved general health and well-being, such additional costs are readily justified,
and in “pay for service system” readily borne by the patient.
INSULIN RESISTANCE
Acne is a recognized component of metabolic syndrome (MS) and its association
with insulin resistance (IR) is widely acknowledged.5 It is natural, therefore, to
look for signs of IR in acne patients and, where evident, to assess such patients
for both IR and MS (Table 1). This, in Indian acne population, is a rule rather
than exception. “Insulin resistance describes defective insulin stimulation of
glucose uptake by skeletal muscle, adipose tissue, liver and endothelial cells
resulting in compensatory hyperinsulinemia which is the fundamental metabolic
effect of IR.”5 IR is indicated by AN and by the presence of acrochordons.6 IR
is further suggested by companion morphologies, particularly those representing
benign cutaneous hyperplasias [dermatosis papulomis nigra (DPNs), ephelides,
syringomata, hypertrichosis, etc.] and by signs of androgen excess and polycystic
ovary syndrome (PCOS).7
Insulin resistance is validated by measuring fasting and postprandial (PP)
insulin levels along with fasting blood sugar (FBS) and PP blood sugar (PPBS),
and calculating HOMA-IR (homeostasis model assessment for insulin resistance),
a computer generated model in which FBS is multiplied with fasting insulin and
the product is divided by 405; [(FBS × F Insulin) ÷ 405]. A value of 4.5 or greater
confirms IR.
Table 1: Clinical Manifestations of IR (Metabolic Syndrome/Syndrome X)5

• Hypertension • Acanthosis nigricans
• Type II DM • Acrochordons
• Dyslipidemia (↑TG, ↓HDL) • PCOS
• Coronary artery disease • Acne
• Obesity • Male pattern baldness
• Hyperruricemia • Early menarche
• Abnormalities of fibrinolysis • ↓Stature
• Myopia
• Increased risk of epithelial cancers
(breast, prostate, colon)
IR, insulin resistance; DM, diabetes mellitus; TG, triglyceride; HDL, high-density lipoprotein; PCOS,
polycystic ovarian syndrome.
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Acne Comorbidities
There is scant literature on IR evaluation in acne population. There are

minor references to acne in literature emanating from obesity/metabolic
centers, and in PCOS studies from gynecology and endocrinology clinics.
Insulin assays are readily available but their interpretation remains problematic
because of a lack of consensus on normal values. Fasting insulin normal range is
8–11 µIU/mL (57–79 pmol/L);8 however, our laboratory in Delhi gives a range
of 2.5–30.0 µIU/mL. For PP insulin, there is no consensus internationally and
it is stated that the values should be interpreted in the context the test is being
performed, implying that clinical laboratory correlations are required.
In a cohort of 131 acne patients (female 70, male 41) assessed for IR in our
clinic in Delhi (a group of academic private practice catering to mostly self-
referred patients), following results were obtained (unpublished): fasting insulin
11.10 ± 6.51 [mean ± 1 standard deviation (SD)], the highest value 32.2 µIU/mL,
eight patients exceeded 20.0 µIU/mL, 50 patients exceeded normal cutoff of
11 µIU/mL. PP insulin 54.59 ± 35.92 µIU/mL (mean ± 1 SD), the highest value
170.20 µIU/mL, above 20.00 µIU/mL in 116 patients (88.54%). There was no
correlation between serum insulin levels and acne severity. HOMA-IR above 4.50
was observed in seven patients (5.34% of the cohort) and in another 30 patients
(39.33%); it was between 2.50 and 4.49. Our experience with insulin testing in
acne patients suggests that PP insulin levels are more helpful in substantiating IR.
This view, in fact, is in agreement with a Japanese study9 in which insulin levels
were compared between 30 women with acne with 13 age-matched controls with
no acne; the basal insulin levels were similar between the two groups whilst the
PP insulin levels were significantly higher in the acne group. PP insulin simulates
real life experiences as expressed in the following statement “Adolescents in
westernized societies may be repeatedly hyperinsulinemic due to their highly
glycemic diet. Hyperinsulinemia in turn may initiate an endocrine cascade that
affects the sebaceous gland and follicular keratinization and involves insulin-like
growth factor-1 (IGF-1), insulin-like growth factor-binding protein 3 (IGFBP 3),
androgens and retinoid signaling pathways”.10
Acne and IR are closely associated. However, the frequency of such an
association remains to be fully documented. The current yardsticks of IR validation
seemingly show low capture rates creating a large gray zone! It is reasonable to
hypothesize that IR is an evolutionary condition in which hyperinsulinemia is
initially intermittent (acute) and only identifiable by estimation of PP insulin, and
later, in more advanced stage of IR it is persistent (chronic hyperinsulinemia) and
is reflected as elevated fasting insulin. The recommended values for IR validation
are presumably generated from assessment of more advanced or more severe
expression of IR such as in PCOS and obesity. With the knowledge that dietary
restrictions, weight management and use of insulin-sensitizing medications
(metformin) are invaluable in IR associated acne; there is need to develop more
157

Kubba
sensitive and suitable criteria to improve capture and to justify opening of another
therapeutic front. In our practice, we pay full attention to skin signs of IR, are
alert to the possibility of PCOS in female patients, and perform fasting and PP
assays, along with tests to assess the full spectrum of MS, hormonal assays for
suspected PCOS and adrenal hyperandrogenism, and ultrasonography. We find
PP insulin more helpful and regard values greater than 20.00 µIU/mL to be
supportive of IR. However, the decision to initiate metformin treatment is based
on a combination of clinical signs of IR, hints of MS from clinical assessment and
biochemical findings, and elevated insulin levels. Higher the clinical laboratory
index of IR, the lower the threshold for incorporating metformin in our acne
treatment regimens.
ACNE AND VITAMIN D3

Hypovitaminosis D is increasingly being observed in populations the world over.
In urban India it is near universal and affects all age groups including the acne
susceptible populations. It may be safely assumed that acne and hypovitaminosis
D frequently coexist and they do.
In our aforementioned cohort of acne patients, hypovitaminosis D3 was
observed in 114 patients (87%). The mean values for the cohort were 18.40 ±
32.24 ng/mL (mean ± 1 SD). The normal range for serum 25(OH2) vitamin D3
is 25–100 ng/mL. In 47 patients (36%), vitamin D3 levels were below 10 ng/mL.
There was no correlation between vitamin D3 levels and acne severity.
Vitamin D3 has thus far not been incriminated in the pathogenesis of
acne. However it is known that sebocytes bear vitamin D receptors (VDRs)
and that they are vitamin D responsive target cells.11-13 In vitro, vitamin D is
sebosuppressive in a dose-dependent manner.14 Skin is also the site for vitamin D3
and 1,25-dihydroxyvitamin D3 synthesis.13 There is evidence for cross-talk between
VDR and retinoid X receptor (RXR)13 and VDR and peroxisome proliferator-
activated receptor (PPAR)-signaling pathways.14 Vitamin D3 is also known to be
involved in regulating keratinocyte growth and differentiation.13 Oral vitamin D
used to be a first-line treatment for acne in the 1930s.15-17 Vitamin D analogues
are currently being evaluated as topical therapy in acne.18
Vitamin D is essential for normal insulin secretion and hypovitaminosis D
causes hyporesponsive insulin secretion.19 Vitamin D deficiency impairs the
ability of pancreatic b-cells to compensate for prevailing IR resulting in higher
glucose levels.19 Raising vitamin D level from 10 ng/dL to 30 ng/dL improves
insulin sensitivity by 60% (vs troglitazone 54% and metformin 13%).19 Subjects
with hypovitaminosis D are at higher risk of IR and MS.19
In summary, it is evident that vitamin D3 is relevant to acne directly through
its effects on sebocytes and keratinocytes, and indirectly through its beneficial
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Acne Comorbidities
effect on insulin secretion and improved glucose tolerance. It thus becomes very
important to determine the vitamin D status of every acne patient and to correct
it wherever it is found to be deficient.
ACNE AND VITAMIN B12

Vitamin B12 is an essential vitamin to prevent anemia directly and through helping
folic acid and iron.20 It facilitates absorption of foods needed for deoxyribonucleic
acid (DNA) synthesis.20 It prevents nerve damage and helps maintain fertility.20
Vitamin B12 made first appearance in acne literature in 1976 when Braun-Falco and
Lincke,21 from Germany, reported worsening of acne or appearance of acneiform
exanthema in 14 patients being treated with vitamin B6 and/or vitamin B12.
Females were more frequently affected.21 The acneiform exanthema consisted of
loosely disseminated papules or papulopustules on the face, especially forehead
and chin, on the upper parts of the back and chest extending to the upper arms.21
The acneiform exanthema was transient and faded shortly after discontinuation of
treatment.21 This was corroborated by several other reports22,23 and later Sherertz24
pointed out the megadose basis for such eruptions.
The phenomenon of vitamin B12 deficiency in acne was recently observed in
the context of oral isotretinoin treatment.25 This was confirmed in a prospective
study26 in which it was observed that mean vitamin B12 levels in 66 study patients
dropped from 216.4 pg/mL pre-treatment to 170.2 pg/mL 4 months post-
treatment with oral isotretinoin. In the same study, levels of holotranscobalamin,
the transport system for vitamin B12 and folic acid also dropped, whereas the levels
of serum homocysteine rose significantly.26 Hyperhomocysteinemia is a known
effect of vitamin B12 and folic acid deficiencies, and is a risk factor for coronary
artery disease and cognitive functions of the brain.26 The study concluded that
oral isotretinoin treatment in acne caused decrease in vitamin B12 (vide supra)
and that this effect may explain some of the neuropsychiatric side effects of the
drug? Vitamin B12 deficiency is also recognized in the course of oral metformin
treatment,27 a drug increasingly being used to treat IR-associated acne (IRAA).
There is awareness for rising prevalence of vitamin B12 deficiency in the
community paralleling, perhaps, the rising prevalence of IR and type 2 diabetes
mellitus (T2DM). With our interest in IRAA, we routinely assess vitamin B12
levels prior to commencing acne treatment. The normal range of vitamin B12 for our
laboratory is 197–866 pg/mL. The mean values in our cohort (109 patients) were
289.66 ± 195.55 pg/mL (mean ± 1 SD). In 41 patients (37.61%), vitamin B12 levels
were low (below 197 pg/mL). In another 32 patients (29.36%), the vitamin B12
levels were low normal (under 300 pg/mL). We routinely supplement vitamin B12
deficient acne patients and have learnt that aggressive/rapid supplementation
(dosages > 1,000 µg/day) are counterproductive as they aggravate existing acne
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Kubba
A B
Figure 1A and B: Adolescent acne aggravated following oral

vitamin B12 supplementation for documented B12 deficiency.
The diagnosis was made on the basis of temporal relationship
and papulopustular nature of the flare.
and undermine patient confidence (Figure 1). We also monitor vitamin B12 levels
during metformin treatment which, as a rule, tends to be prolonged. Mention
needs to be made of functional vitamin B12 deficiency.28 Only about 30% of
circulating vitamin B12 is in the form of holotranscobalamin that represents
active B12. Clinical signs of vitamin B12 deficiency have been seen in individuals
with normal serum levels and this has been explained on the basis of elevated
methylmalonic acid and lowered holotranscobalamin.29
In conclusion, vitamin B12 deficiency may be more common in acne populations
than is generally recognized. An overlooked vitamin B12 deficiency makes the acne
patient more at risk for adverse drug effects of oral isotretinoin in the short-term,
and general health impairment, especially the effects on central and peripheral
nervous system, and on glucose tolerance/IR, in the long-term.
ACNE AND IMMUNOGLOBULIN E

Elevated serum immunoglobulin E (IgE) is a marker for atopic disorders, namely
asthma, hay fever, atopic dermatitis and urticaria, and also helminthiasis. IgE exerts
its biologic effects by binding to histamine-1 receptors (H-1R) that are widely
distributed throughout the body but especially the mast cells.2 Sebocytes too are
known to bear H-1R.20 H-1R blockers (antihistamines) are conventionally used
to prevent premenstrual flare of acne, typically for 7 days prior to the anticipated
date. H-1 antihistamines are believed to be useful in preventing inflammation
by modulating corticotropin-releasing hormone (CRH)-mediated mast cell
degranulation and by blocking the binding of released histamine,21,22 and also
160

Acne Comorbidities
Figure 2: Severe adult atopic dermatitis

with persistent panfacial adult acne. Note
blackheads on temple and forehead, and
inflammatory lesions and hypertrophic scars
in beard area and adjacent neck..
possibly, by their direct effect on sebocytes through reducing the squalene content
of the sebum.23
Acne patients often display atopic manifestations and/or have elevated IgE
levels (Figure 2). Clinically this finding is noted and considered when planning
acne treatment. For example, it is widely recognized that atopic individuals
have lower threshold for contact irritancy and lower tolerance for topical and
oral retinoids; in such cases, escalating regimens of topical retinoids and lower
dosages of oral retinoids are recommended. As much as 50% of acne patients
report itching on the face.24 The itching is independent of the severity of acne
and responds to oral antihistamines.24 There is no formal documentation of acne-
atopy association. Atopy as a comorbidity in acne has not received any recognition
to the best of author’s knowledge.
In our aforementioned cohort, elevated IgE was recorded in 57 of 131
acne patients (43.18%). The mean values for the cohort were 322.12 ±
1205.35 IU/mL (normal range 5–100 IU/mL). Six patients had values in excess
of 1,000 IU/mL. When these were taken out, the mean values dropped to
157.80 ± 170.80 IU/mL. There was no correlation between total IgE levels and
acne severity. Our observation raises several questions. Are these elevated IgE
levels indicative of a possible causal relationship between two common chronic
diseases or is their co-occurrence merely coincidental? There is some evidence
to link them.25 There is epidemiologic data to link acne (as a marker of sex
hormone/testosterone status) with asthma and atopy in females and males.25 It
is hypothesized that high levels of testosterone may promote T-helper type-2
(Th2) cell responses which are associated with higher antibody production.26 An
161

Kubba
overlap between metabolic and endocrine disorders, in the context of asthma,

has also been proposed.27
In summary, clinical experience shows overt atopic manifestations and
elevated IgE levels in substantial number of acne patients. There is some
published evidence to support a link between acne, atopy and IgE. Acne and
atopic dermatitis share “chronic disease” status and rising prevalence28 and both
are influenced by environment and lifestyle. It is worthwhile to assess acne
patients for atopy and it is rewarding to include antihistamines in acne therapy
where justifiable.
ACNE AND GASTROINTESTINAL DYSFUNCTION

Acne patients are more likely to experience constipation, halitosis, gastric reflux
and abdominal bloating.30 Acne patients often report GI distress, particularly
in respect to their previous drug intolerances making them adopt a negative
stance toward any future systemic therapy. This aversion, sometimes amounting
to phobia, imposes an unwarranted constraint in treatment planning. A recent
scholarly review31 has not only provided invaluable insight into this important
phenomenon, but also drawn attention to published literature that actually
links acne with GI system and opens a whole new therapeutic front. The notion
that acne may be linked to GI tract was first reported in 1930 by Stokes and
Pillsbury29 as a part of a larger hypothesis proposing that “emotional states
may alter the normal intestinal microflora, increase intestinal permeability,
and contribute to systemic inflammation”.31 Gut microbes may thus influence
acne through a systemic effect on inflammation, oxidative stress, glycemic
control, tissue lipid levels, pathogenic bacteria, neuropeptides and mood-
regulating neurotransmitters.31 A case has been made for therapeutic value of
probiotics, particularly Lactobacillus acidophilus, in acne through correction of
small intestinal bacterial overgrowth (SIBO) associated with hypochlorhydria
which in turn has been associated with acne.30 Adjunctive probiotics were
associated with improved outcomes32,33 and better tolerance and compliance
with oral antibiotics.32 Lastly, acne may be linked to inflammatory bowel disease
(IBD).34 More importantly, particularly with medicolegal connotation, systemic
isotretinoin has been incriminated in IBD.35
ACNE AND PSYCHOLOGICAL IMPAIRMENT

Psychological disability as a comorbidity in acne is well recognized. Acne is
stated to evoke greater impairment of mental health than many other chronic
medical conditions including epilepsy and diabetes.36 It is hypothesized that
pathophysiological pathways involved in promoting susceptibility to acne may
162

Acne Comorbidities
also promote a greater generalized risk of mental health disorders.37 It is further

hypothesized that mood-related symptoms may predate or even set the stage for
a higher propensity to acne.37 There are several possible mechanisms to explain
association of acne with depression and/or anxiety. The first and foremost is the
oxidative stress theory mediated by lipid peroxidation which not only links acne
and psychological disturbances, but is also incriminated in the pathogenesis of
both.37 Oxidative stress within the pilosebaceous unit oxidizes sebum which in turn
alters the oxygen tension in the follicle resulting in microaerophilic environment
making it more suitable to harbor anaerobic bacteria such as Propionibacterium
acnes.38 Systemic oxidative stress, supposedly through changes in mitochondrial
function, membrane fluidity, changes in enzymes and ion channel functioning,
and compromised brain growth factors, may explain depression and anxiety.37
Oxidative stress also increases blood insulin levels, which is relevant to both
acne and depression.37 Insulin increases oxidative stress within the skin and steps
up demand for superoxide dismutase (SOD).39 Low levels of platelet-derived
monoamine oxidase (MAO) have been reported in mental health disorders
including depression and anxiety and also in acne patients providing yet another
mechanism for their association.40
Oxidative stress is validated by low serum levels of glutathione peroxidase
(GSH-Px) and SOD,41,42 two key intracellular antioxidant enzymes, and elevated
levels of thiobarbituric acid reactive substances (TBARS) and malondialdehyde
(MDA)43 representing end products of lipid peroxidation. Patients with severe
acne have the lowest SOD levels compared to those with mild acne and healthy
controls;44 conversely, MDA levels are elevated in patients with severe acne.44 The
upshot of this new insight is that antioxidants may be considered as additional
therapeutic intervention in acne patients where oxidative stress is suspected
on the basis of clinical picture and more so where it is proven by laboratory
validation. There is historical precedence for such treatments.37 Vitamins A and
E have documented synergistic efficacy in acne45 and were advocated as far back
as 1978, as means to attenuate lipid peroxidation. Vitamin D has antioxidant
properties and can increase SOD and GSH-Px activity.46,47 Interestingly,
hypovitaminosis D is associated with depression and anxiety,48 and similarly,
vitamin A deficiency can result in depressive behavior.49,50 Vitamin C, zinc and
selenium are similarly placed, and also work both ways.37 SOD is now available
as nutritional supplement (plant derived) and is being evaluated as an adjunctive
treatment in severe acne as also in acne associated with psychological impairment
and GI distress.
In summary, oxidative stress appears to be an important upstream mechanism
in the pathogenesis of acne, perhaps “a starter gun” or “a match that lights the
fire”,37 providing insights into systemic nature of acne and affording additional
therapeutic options.
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Kubba
ACNE, THYROID, LIPIDS, ZINC, VITAMIN A, VITAMIN E

There is no known association between acne and thyroid, except, however, both
are recognized components of MS. Hypothyroidism was detected in 4% of our
acne cohort (unpublished). Dermatologists may, by such awareness, facilitate
early detection of thyroid dysfunction and help contain comorbidity and prevent
secondary effects on acne.
Dyslipidemias are commonly encountered in acne population, in a few as a
pretreatment finding where it becomes a contraindication for oral isotretinoin
(especially the hypertriglyceridemia), and more commonly as an adverse effect
of oral isotretinoin treatment. Awareness and diligent monitoring prevents
dyslipidemias and their consequent ill-effects, namely, acute pancreatitis and
cardiovascular disease. Dyslipidemias and acne are also linked through MS.
Zinc deficiency has been implicated in acne since a long time.51,52 A recent
study from Turkey53 reiterates the point and reports low zinc levels in acne
subjects compared to age- and sex-matched controls but finds no correlation with
acne severity. On the other hand, both oral and topical zinc have been deemed
therapeutically beneficial in acne more so in inflammatory acne.54-56 Zinc has
antibacterial and antiinflammatory effects and may decrease sebum production
[SORT (strength of recommendation taxonomy B criteria)].57 Zinc is also
a mild antiandrogen and is known to inhibit 5a-reductase, (type 1).58 Zinc is
bacteriostatic against P. acnes59 and inhibits toll-like receptor 2 (TLR-2) surface
expression by keratinocytes in vitro.60 IGF-1 and insulin-like growth factor-1
receptor (IGF‑1R) are overexpressed in acne prone skin and whilst P. acnes extracts
(membrane fraction) increased such overexpression along with increase in Ki-67
and filaggrin, zinc was observed to downregulate IGF-1/IGF-1R expression.61 A
PubMed search at the time of writing this work yielded 169 citations for “acne and
zinc” covering many aspect of the subject. The message here is that zinc deficiency
is well documented particularly from Asia and in vegetarians, and zinc being an
essential trace element, such a deficiency may constitute an important comorbidity
in acne patient population. Assay for serum zinc levels is widely available and may
be considered in the appropriate clinical setting.
Vitamins A and E have been reported to be low in acne patients compared
to age-matched controls.53,62 Further, there is correlation between the severity
of acne and levels of vitamins A and E.53,62 Vitamins A and E have traditionally
been used to treat acne and are believed to be synergistic in their therapeutic
effect.45,63 This knowledge may be helpful when managing dietary manipulations
in acne patients, and may justify oral vitamins A and E as adjunctive therapy
in recalcitrant cases even in the absence of documented deficiency of either of
them.
164

Acne Comorbidities
CONCLUSION
An attempt has been made, and evidence presented, to link acne to several
important systemic occurrences by way of comorbidities. There is very likely
much more to it. Acne comorbidities imply systemic nature of the condition, offer
insights into acne pathogenesis and provide additional therapeutic approaches.
Multiple comorbidities are usual. There is much to gain by recognizing acne
comorbidities and addressing them.
Editor’s Comment
Acne often coexists with seborrhea, acne, hirsutism and alopecia (SAHA syndrome),
melasma-like facial pigmentation and acanthosis nigricans. However, acne,
especially one which is persistant and that which is resistant to treatment is often
more than skin deep. Psychological disability as a comorbidity in acne is well
established and acne is known to impact the patient’s quality of life more than
many other chronic medical conditions including epilepsy and diabetes. Acne
is itself a recognized association of metabolic syndrome and insulin resistance.
Some comorbidities like hypovitaminosis A, D, E and B12, atopic diathesis,
hypothyroidism, zinc deficiency, dyslipidemia, gastrointestinal dysfunction though
reported have not been extensively studied. In this article, Dr R Kubba has lucidly
presented evidence to link acne to several important systemic associations of acne,
which imply that acne is more than a cosmetic problem. Moreover the presence
of these associations offers new insights into pathogenesis of acne and provide
additional therapeutic strategies.
Neena Khanna
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168

Update of Oral Isotretinoin in

Acne Treatment
1
Ayşe Serap Karadaǧ MD, 2Goknur Kalkan MD,
3
Yi-Tin Lin MD, *,4WenChieh Chen MD
1
Department of Dermatology, Istanbul Medeniyet University,
Göztepe Researh and Training Hospital, Istanbul, Turkey
2
Department of Dermatology, Gaziosmanpasa University,
School of Medicine, Tokat, Turkey
3
Department of Dermatology, Chang Gung Memorial Hospital,
Chang Gung University College of Medicine, Taipei, Taiwan
4
Department of Dermatology and Allergy,
Technische Universität München, Munich, Germany
ABSTRACT
Systemic isotretinoin remains so far the most efficacious treatment for
severe acne, targeting all the crucial factors in the pathogenesis of acne.
A great progress in the understanding of its mode of action has been
made over the past 10 years. Most important is the secondary response
to all-trans-retinoic acid (ATRA)/retinoic acid receptor (RAR)-signaling
involving many transcription factors and coregulators. Isotretinoin-
mediated upregulation of the forkhead box O (FoxO) pathway, especially
FoxO1, can (1) activate their target genes to generate the retinoid-mediated
transcriptional regulation; (2) regulate lipogenesis via interaction with
androgen receptor (AR), peroxisome proliferator-activated receptor gamma
(PPARg) as well as PPARg/retinoid X receptor alpha (RXRa) and liver X
receptor (LXR)/RXRa heterodimers; and (3) oppose the inflammation
through regulation of the innate and adaptive immunity. Neutrophil
gelatinase-associated lipocalin (NGAL) is another potential mediator
of the action of isotretinoin, hypothecally through NGAL- and insulin-
like growth factor binding protein (IGFBP)-33-mediated apoptosis in
sebocytes. Other beneficial effect of isotretinoin may include (1) inhibition
of the motility and cutaneous migration of neutrophils; (2) reduction of
matrix metalloproteinases; (3) downregulation of the formation of reactive
Email: wenchieh.chen@lrz.tum.de

Karadaǧ et al
oxygen species (ROS); and (4) inhibition of proinflammatory nuclear

factor-kappa B (NF-kB)-mediated cytokine signaling.
The long-term therapeutic effect of oral isotretinoin is mainly dependent
on the total cumulative dose taken, which so far remains at 120–150 mg/kg
as the target doses. The current recommendation is to begin at a low-dose
regimen at less than or equal to 0.3 mg/kg to avoid acute flare and the
dose-dependent side effects. Patients showing unsatisfactory response and
higher relapse rates may include those with macrocomedonal disease, severe
nodulocystic acne, truncal lesions, women with untreated hyperandrogenism
and smokers. Little is known about the absolute advantages of different
dosing schedules and the long-term remission rate of more than 5 years.
Among the side effects, it is shown in small-scale studies to cause mild
suppression of many pituitary hormones, cortisol and thyroid hormones.
The effect of isotretinoin on insulin resistance and lipid metabolism seems
more dependent on the treatment duration and cumulative doses. Most
studies fail to demonstrate negative impact on bone mineralization, bone
marrow density, premature epiphyseal closure or hyperostosis. The cardiac
adverse effects have rarely been reported in the treated juveniles or adults. A
transient change of the hearing function may occur acutely after treatment
commencement. Isotretinoin can influence neurogenesis, dopamine
functioning and brain metabolism. Diverse psychiatric changes such as
depression, obsessive compulsive disorders, psychosis, bipolar disorders are
observed only in a minority of treated individuals. Better controlled studies
are needed to clarify the gastrointestinal effect of isotretinoin, especially
its association with inflammatory bowel diseases (IBD). Oral isotretinoin
can cause multiple ophthalmologic adverse effects and many of them are
serious.
Overall, well-stratified studies with an adequately large sample size and
an extensive long-term follow-up of the therapeutic efficacy and adverse
effects of oral isotretinoin are limited. A regular checkup of the adverse
effects is warranted and should not be overlooked. A better understanding
of the action of isotretinoin at the molecular level will help develop novel
treatment modalities with greater benefit-risk ratios and longer remission
time.
INTRODUCTION
Acne is one of the most common human-specific skin diseases. It is characterized
by (1) complex etiopathogenesis involving interactions of hormones, infection,
immunity, inflammation and wound healing; (2) major involvement of the most
apparent body region, namely, the face and neck; (3) frequent formation of
everlasting unpleasant scars; and last but not least (4) high prevalence rates in the
young generation with particularly great concern about self-image. Modern acne
treatment began in 1930s with the introduction of topical benzol peroxide, 1950s
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Update of Oral Isotretinoin in Acne Treatment
oral tetracycline, 1960s topical tretinoin and oral cyproterone acetate, in 1980s
oral isotretinoin [13-cis-retinoic acid (13cRA)] and 1990s topical adapalene.1
Development of novel treatment modalities has been hampered mainly due to
the lack of ideal animal models. No essential progress has been made in the past
30 years after the introduction of oral isotretinoin. For mild-to-moderate acne,
patients must wait at least 4 weeks for a noticeable improvement and 12 weeks
for an optimal effect. For moderate-to-severe acne, 4–8 weeks are usually required
for the clinical effect of systemic antibiotics, which must then be extended to
3–6 months for an optimal long-lasting control.2
Oral isotretinoin remains the most effective treatment for severe acne, although
its acting mechanism is still incompletely understood. It is the only medication that
can clinically improve all the cardinal features of acne: comedogenesis, excessive
sebum production, colonization of Propionibacterium acnes and inflammation. On
the other hand, oral isotretinoin is no longer considered as a panacea for acne,
with the relapse rates estimated to be over 20% within the first 2 years following
sufficient isotretinoin treatment.3,4
In this article, we will present and discuss the recent understandings of the
acting mechanisms of isotretinoin as well as important factors associted with the
relapse and details of the side effects.
MECHANISM OF ACTION OF ISOTRETINOIN

Isotretinoin, a vitamin A (Vit A) derivative and among the first generation of
retinoids, is so far the most potent inhibitor of sebum production, one of the
key components in the pathophysiology of acne. However, its exact molecular
mechanism of action remains incompletely understood. Oral isotretinoin is
the only therapy targeting all the implicated aspect of acne etiopathogenesis. It
directly suppresses sebaceous gland activity leading to a significant reduction
in sebaceous lipogenesis, normalizes the pattern of keratinization within the
sebaceous gland follicle, inhibits comedogenesis and inflammation, and indirectly
reduces the growth of P. acnes.5 In addition, it normalizes the expression of tissue
matrix metalloproteinases and their inhibitors.6 There is no evidence to propose
that isotretinoin affects the metabolic activity of the keratinocytes.7
Although isotretinoin is not an antimicrobial, it effectively reduces the total
numbers of P. acnes population by modifying the follicular microenvironment
by dramatically reducing sebum excretion rate and the size of the pilosebaceous
duct. The result is a log3 decrease in P. acnes and suppression much superior to
that seen with oral and topical antibiotics.7 Clinically, the sebum excretion rate
is evidently diminished (80%) after a few weeks.7,8 The number and dimensions
of cysts decreased significantly and a maximum improvement is maintained at
post‑treatment period.7-10 Isotretinoin also has direct and indirect antiinflammatory
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properties such as inhibition of the motility and migration of neutrophils into

the skin, reduction of matrix metalloproteinases and a decrease in the P. acnes
population.
At the molecular level, isotretinoin achieves this remarkable efficacy by
influencing the cell-cycle progression, cell differentiation, cell survival and
apoptosis in sebaceous glands. It activates nuclear (retinoid) receptors and regulates
transcription, decreases the proliferation, differentiation and activity of basal
sebocytes (cell-cycle arrest).7,8 Isotretinoin also induces apoptosis in the sebocytes
by a retinoid acid receptor-independent mechanism, meanwhile, it normalizes
follicular keratinization and inhibits comedogenesis.9,10
Pharmacodyamically, unlike all-trans-retinoic acid (ATRA), isotretinoin
has little or no ability to bind to the cellular retinol-binding proteins (CRBP)
or retinoic acid nuclear receptors (RARs and RXRs), but may act as a prodrug
being intracellularly converted to metabolites that are agonists for RAR or RXR
nuclear receptors.7 Isotretinoin has at least five biologically important metabolites:
(1) 13-cis-4-oxo-retinoic acid (4-oxo-isotretinoin); (2) ATRA; (3) all-trans-4-
oxo-retinoic acid (4-oxo-tretinoin); (4) 9cRA and (5) 9-cis-4-oxo-retinoic acid.
Isotretinoin undergoes significant and selective all-trans-isomerization to ATRA
in cultured sebocytes.11-13 Binding of ATRA to RARs initiates changes in the
interactions of RARs/RXRs with corepressor and coactivator proteins, leading
to activation in transcription of primary target genes. However, the multifaceted
effects of isotretinoin on acne imply that there must be a primary mechanism
of action at the regulatory level of gene transcription which cannot be clarified
by the pathways mediated by ATRA.12,13 It has been shown that ATRA/RAR-
signaling can induce secondary responses in the gene expression encoding
transcription factors and signaling proteins that amplify a complete cascade of
gene expression.12 Particularly FoxO proteins, the transcription factors of the
secondary responses, can transcriptionally activate their target genes to create the
spectrum of retinoid-mediated transcriptional regulation.12,14 In mechanism of
action of isotretinoin, the secondary responses to ATRA with their transcription
factors and coregulators seem to be essential.14
FoxO-Transcription Factors
Forkhead box O (FoxO) transcription factors are significant proteins transforming
the gene expression in cell-cycle control, DNA damage and repair, apoptosis,
oxidative stress, cell differentiation, glucose metabolism, inflammation, immune
functions and regulation of stem cell homeostasis.14-23 FoxOs are expressed in
mammalian tissues, especially adipose tissue, brain, heart, liver, lung, ovary,
pancreas, prostate, skin, skeletal muscle, spleen, thymus and testis.23 FoxO3a is
a strong inducer of the transcription factor FoxO1. The transcription of FoxO
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genes is stimulated by FoxO3 and repressed by growth factors like insulin and
insulin-like growth factor-1 (IGF-1) increasing at puberty. Many acne-associated
syndromes display insulin resistance such as polycystic ovary syndrome, HAIR-
AN (hyperandrogenism, insulin resistance and acanthosis nigricans) syndrome,
congenital adrenal hyperplasia, acromegaly and Apert’s syndrome.15,16 Acne in
Apert’s syndrome and acneiform nevus reply wonderfully to isotretinoin treatment;
therefore, it is suggested that acne can be induced by a growth factor-induced
nuclear deficiency of FoxO1. Isotretinoin increases nuclear FoxO1 levels and
reverses acne-related imbalances of FoxO homeostasis.13,17 All the isotretinoin-
mediated effects on sebocyte apoptosis, sebaceous lipogenesis, antiinflammatory
activity, downregulation of ROS can be elucidated by an upregulation of the
nuclear levels of FoxO transcription factors. Most adverse and teratogenic effects
of isotretinoin can also be clarified by FoxO-mediated proapoptotic signaling.14-23
Consequently, there is evidence from translational research for a relationship
between retinoid signaling and FoxO1-mediated gene regulation.17
Androgen Receptor Transactivation

Androgen receptor (AR)-mediated signal transduction plays a crucial role
in stimulation of the size of sebocytes and sebum production in addition to
keratinocyte proliferation.24,25 Androgens stimulate the expression of sterol
regulatory element binding protein (SREBP), the most important transcription
factor of lipogenesis.26 Increased AR protein levels have been determined in the
skin of acne patients. FoxO1 is an important AR corepressor being metabolically
regulated and can bind to the N-terminal transcription activation domain which
is most important for AR transcriptional activity.24 The AR repressive function
of FoxO1 is attenuated by increased growth factor signaling, leading to an
upregulation of AR transcriptional activity and an increase in the expression of
AR-responsive target genes.27 FoxO1 regulation of AR activity at the genetic
level explains the functional relation of insulin/IGF-1 and androgens in acne.27
Oral isotretinoin treatment has recently been shown to decrease serum IGF-1
levels, which may decrease AR-mediated gene expression.28 These data imply that
isotretinoin may downregulate the transcriptional activity of AR by increasing the
nuclear concentration of the AR cosuppressor FoxO1.24-28
Lipogenesis and Sebum Production

The sebaceous gland belongs to the type of glands with most active lipid
biosynthesis. Isotretinoin is the most successful retinoid in reducing sebaceous
gland size (up to 90%), by diminishing proliferation, disturbing differentiation of
the basal sebocytes and suppressing sebum production in vivo.7 The peroxisome
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proliferator-activated receptors (PPARs) are a family of transcription factors

that regulate energy balance by promoting either energy deposition or energy
dissipation. Under normal physiological conditions, PPARg is mainly expressed in
adipose tissue and regulates diverse functions such as the development of fat cells
and their capacity to store lipids, insulin sensitivity, as well as glucose and lipid
homeostasis.29 PPARg is also expressed in sebocytes, and together with its natural
ligand prostaglandin J2 are very essential in the regulation of differentiation and
lipid metabolism in sebaceous gland.30,31
Peroxisome proliferator-activated receptor-g like AR can be suppressed by
FoxO1.32,33 It has been shown in adipocytes that growth factor signaling with
reduced nuclear FoxO1 concentrations augments PPARg activity required for
terminal differentiation and prevents FoxO1-PPARg interaction to rescue the
transrepression of genes involved in lipogenesis.34 Growth factor signaling inhibits
the transrepressive effect of FoxO1 on AR and PPARg/RXRa heterodimers, thus
augmenting the entire program of sebaceous lipogenesis.34,35 Clinically, serum
IGF-1 levels correlate with facial sebum excretion.35
Liver X receptors like PPARs play a critical role in lipid metabolism. Expression
of LXRa and LXRb has been detected in SZ95 sebocytes while LXR ligands
enhance the expression of LXRa in stimulating lipid synthesis.36 LXRs directly
control the expression of SREBP-1.37 Verification from translational research
sustains the basic impact of nuclear FoxO1 on the regulation and expression
of SREBP-1c, the key transcription factor of multiple lipogenic target genes
expressed in adipocyte, hepatocyte, skeletal muscle and sebocyte.38
To summarize, FoxO transcription factors play a critical role in metabolism
and lipogenesis of sebaceous gland. The suppressive regulatory effect of nuclear
FoxO1 is exerted via a direct transcriptional regulation of AR and PPARg in
addition to the coregulation of PPARg/RXRa and LXR/RXRa heterodimers.34,36
Cell Proliferation and Apoptosis

Isotretinoin is superior to other retinoids with regard to decreasing sebocyte
proliferation and suppressing sebum production.39 The antiproliferative effect is
dose- and time-dependent, as observed in SEB-1 sebocytes and immortalized
SZ95 sebocytes.10,11 Moreover, the isotretinoin-induced cell-cycle arrest and
apoptosis seems specific to sebocytes.10 This may be explained by the delayed
initiation of retinoid inactivation under incubation of sebocytes with isotretinoin,
a fact leading to higher intracellular concentrations of ATRA.40 In contrast,
incubation with ATRA causes rapid enhancement of cellular retinoic acid binding
protein-2 (CRABP-2) expression in cultured sebocytes, which reduces the free
intracellular concentration of ATRA through promotion of its metabolism
by cytochrome P450 enzymes and induction of CYP1A1 expression, a major
metabolizing enzyme.11
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Recent studies on isotretinoin-induced changes in gene expression and

apoptosis focus primarily on the regulatory role of RAR and RXR.40 CRABP-2,
a related intracellular lipid binding protein for ATRA, was found to strongly
express in sebocytes compared to epidermis in the isotretinoin-treated patients,
promoting a preferential transport of ATRA to RARs in sebocytes. Proapoptotic
actitivies of ATRA are mediated predominantly by RAR.41
The protein neutrophil gelatinase-associated lipocalin (NGAL) has recently
been identified as another mediator of the apoptotic effect of isotretinoin on
sebocytes.42 It functions in the innate immune response to Gram-negative
bacteria. NGAL is increased 2.4-fold in patients’ skin within 1 week of beginning
isotretinoin. The increase in NGAL precedes the decrease in both sebum and
P. acnes, indicating that NGAL is an important mediator of the early response to
isotretinoin. This provides a rationale for the investigation of agents that activate
NGAL expression in the skin as potential therapeutic alternatives to isotretinoin
in the treatment of acne.
However, as NGAL-mediated apoptosis is not a specific mechanism of
isotretinoin-induced sebocyte apoptosis, mediators of apoptosis other than NGAL
deserves further study.42 During isotretinoin treatment a 3.43-fold increased
expression of IGFBP-3 was exclusively observed in sebocytes but not in the whole
skin.42 Nuclear IGFBP-3 is a potent inducer of apoptosis.43 The interaction of
RXRa-I and GFBP-3 modulate the transcriptional activity of RXRa to mediate
the effects of IGFBP-3 on apoptosis.43 A common unifying mechanism of
NGAL- and IGFBP-3-mediated apoptosis in sebocytes can be speculated.42,43
Isotretinoin-induced nuclear overexpression of FoxO1 and IGFBP-3 might also
mediate the anticomedogenic effects of isotretinoin as upregulation of IGFBP-3
suppresses the proliferation of transient amplifying keratinocytes.44
Antiinflammation
Although isotretinoin is per se not antimicrobial, it effectively reduces the total
numbers of P. acnes (antibiotic-resistant species likewise) by modifying the
follicular microenvironment.45,46 Isotretinoin also has direct antiinflammatory
properties such as inhibition of the motility and migration of neutrophils into the
skin, and other indirect effects, including reduction of matrix metalloproteinases,
downregulation of ROS formation, inhibition of proinflammatory NFkB-
mediated cytokine signaling, and modulation of acquired and innate immunity.6,47
Metalloproteinases
Isotretinoin is recognized to reduce scarring in acne and influence dermal tissue
remodeling. Expression of NF-kB and activator protein-1 is activated in acne
lesions with consequently elevated levels of inflammatory cytokines and matrix
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degrading metalloproteinases (MMPs), which have been shown in vivo to be

molecular mediators of inflammation and collagen degradation in acne lesions.47
Sebum contains pro-MMP-9 and MMP-13, which is decreased following
treatment with isotretinoin in parallel to the clinical improvement of acne.
Isotretinoin inhibits the arachidonic acid-induced secretion of pro-MMP-2/-9
and their mRNA expression in both sebocytes and HaCaT keratinocytes, but
only MMP-13 in keratinocytes.6 In ultraviolet A (UVA) or ultraviolet B (UVB)-
irradiated fibroblasts, the expression of FoxO1a mRNA decreases significantly,
as well as the expression of type I collagen. Addition of FoxO1a-peptide induces
an increase in type I collagen expression and a decrease in MMP-1 and MMP-2
expression.48 This can explain why topical ATRA-treatment for aged, UV-damaged
skin can increase collagen synthesis and reduce the activity of matrix degrading
MMPs.49 To summarize, isotretinoin’s suppressive effect on MMP expression can
be well explained by the isotretinoin-induced upregulation of FoxO1 and FoxO3a
in modifying MMP promoter activity.47-49
Immunity
There is a functional link between upregulated toll-like receptor 2 (TLR-2)
signaling in acne with increased interleukin-1a (IL-1a) production and T-cell-
mediated acquired immunity.50 ATRA has been shown to downregulate the
expression and function of TLR-2.51 An increase in CD4+ T cell infiltration
and IL-1 activity has been detected in acne-prone skin areas prior to follicular
hyperkeratinization and comedo formation.
An increase in the T helper 2 (Th-2)/Th-1 ratio following retinoid treatment
has also been demonstrated in in vitro and in animal models.52 In a study on the
effects of isotretinoin on T-cell differentiation markers in patients with acne, tumor
necrosis factor-alpha (TNF-a), IL-4, IL-17 and interferon gamma (IFN-g) levels
were found to decrease significantly after treatment,53 indicating the suppression
of all of the effector CD4+ T cell types Th-1, Th-2 and Th-17.54 Inflammation is
considered to be a key element of acne since the cytokines TNF, IL-1b, IL-8 and
IL-10 are considerably upregulated in acne-involved skin compared with normal
adjacent skin.54 An abnormal colonization by P. acnes has been detected by the
induction of inflammatory mediators.54 Isotretinoin treatment may change the
inflammatory response within the skin by modifying T-cell functions.
Metabolism and growth factor status can regulate the activity of genes involved
in innate immunity, which may play a role in P. acnes hypercolonization.55,56 A
recent study emphasizes the crucial role of FoxOs in the regulation of innate
immunity. It shows that FoxO transcription factor in Drosophila flies controls the
expression of several antimicrobial peptides (AMPs) in various tissues including
skin.56 AMP induction is lost in FoxO null mutants but augmented when FoxO
is overexpressed. AMP activation can be accomplished by FoxO, representing the
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existence of crossregulation of metabolism and innate immunity at the promoter

level of FoxO-activated AMP genes in Drosophila.56
On the contrary, insulin and IGF-1-dependent signaling with Akt-mediated
translocation of FoxO from nucleus into the cytosol reduces the expression of
AMPs. Therefore, insulinotropic Western diet (milk, dairy and hyperglycemic
carbohydrates) may affect the balance and activity of AMPs and impairs innate
immunity of the pilosebaceous follicle. Both isotretinoin-induced upregulation of
FoxO1 with reduced sebaceous lipogenesis and isotretinoin-induced stimulation of
the AMP response act synergistically in suppression of the sebaceous lipogenesis,
P. acnes growth and bacterial follicular colonization.43,44,56
To summarize, FoxOs may play an essential role in the control of lymphocyte
homeostasis involving the termination and resolution of an immune response.57
A nuclear deficiency in FoxOs induced by growth factors such as insulin, IGF‑1
and fibroblast growth factor (FGF) would activate T-cell proliferation and
decreases expression of AMPs. A decrease of AMPs would increase the number of
pathogens (P. acnes) stimulating TLR-induced proinflammatory genes. In contrast,
isotretinoin-mediated upregulation of FoxO1 may exert antiinflammatory effects
by downregulation of T-cell responses and upregulation of innate immunity.21-23
More studies are needed to demonstrate these scenarios in acne.
Suppression of Oxidative Stress

Isotretinoin treatment suppresses the formation of ROS. Patients with inflam
matory acne show a considerably higher level of hydrogen peroxide produced by
neutrophils as compared to patients with comedonal acne or healthy controls.58
In several recent studies, significantly lower levels of superoxide dismutase and
catalase were measured in polymorphonuclear neutrophils, while higher serum
levels of malondialdehyde and xanthine oxidase activity were found in the patients
with acne than in controls.59,60 It suggests that oxidative stress plays a role in the
pathogenesis of acne vulgaris, but it remains to be determined whether oxidative
stress is a reason or a result of inammation.
Isotretinoin exerts an antioxidant activity against the superoxide anions.
Activated FoxO proteins enhance stress resistance by binding to the promoters
of the genes encoding manganese superoxide dismutase and catalase, which
may facilitate oxidative detoxification in mammals.16,61,62 FoxO-mediated
oxidative-stress resistance is predisposed by other pathways like b-catenin.
Besides, upregulation of FoxO1 downregulates the synthesis of heme and various
cytochromes of the mitochondrial respiratory chain involved in ROS formation.63
Briefly, isotretinoin-induced upregulation of FoxO1 may clarify the suppression
of mitochondrial ROS generation and increase in ROS catabolism leading to
normalization of applified ROS generation in acne.15,61-63
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LONG-TERM THERAPEUTIC EFFECTS AND

RELAPSE RATES
Since its introduction in the United States of America (USA) in 1982 and in
Canada the following year, long-term clinical experience with isotretinoin has
confirmed its therapeutic effectiveness. According to the European evidence-based
guidelines, oral isotretinoin is highly recommended as monotherapy for patients
with severe papulopustular acne, moderate-to-severe nodular acne and conglobate
acne.64,65 The Food and Drug Administration (FDA) recommends isotretinoin for
severe, recalcitrant nodular cystic acne unresponsive to other first-line therapies
(topical medications and/or antibiotics).66 It is recommended in the more recent
American Academy of Dermatology (AAD) guidelines to use oral isotretinoin
for the management of patients with acne that is either treatment-resistant or
producing physical scarring or psychological disturbance.67
There is still an ongoing debate about the choice of the most beneficial dosage
of oral isotretinoin and treatment plan in acne patients. Attempts to determine
the cumulative dose necessary to obtain an optimal treatment response and low
relapse rate have so far yielded insufficient evidence,64 because most studies are
retrospective and well-defined criteria for relapse are lacking. Other possible
explanations for the discrepancy in the results and relapse rates may include
(1) insufficient sample size; (2) variable dosage regimen used; (3) different length
of follow-up; (4) mixed study population with discrepant degrees of acne severity;
or (5) other confounding factors such as nutrition and smoking.3,68-70
Relapse Rate
Relapse of severe nodulocystic acne after oral isotretinoin treatment continues to be
a problem, with the relapse rates estimated to vary between 10% and 60%.3,4,7,65,71‑78
In a study of 237 patients receiving a total cumulative dose between 75 mg/kg
and 150 mg/kg for nodulocystic acne, acne resistant to conventional therapy or
with relapse immediately after discontinuation of conventional therapy, or acne
persisting beyond 25 years of age treated by isotretinoin for the first time, the
estimated rate of relapse at 1 year, 3 years and 5 years is 14%, 40% and 48%,
respectively.73 In a 10-year follow-up of 88 patients with moderate-to-severe acne
after isotretinoin treatment at doses of 0.5–1 mg/kg/day for 16 weeks or until
reaching 85% clinical improvement with variable total cumulative doses between
56 mg/kg and 112 mg/kg, a relapse rate at 39% was observed, with 16% requiring
oral antibiotics and 23% a second course of isotretinoin for the therapy. Ninety-six
percent of the relapse occurred within 3 years after stopping therapy,66 while 82%
of the relapse was on a cumulative dose of less than 120 mg/kg, as compared with
30% who were given a larger cumulative dose of greater than 120 mg/kg.66
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Recent studies published in 1999–2007 have tried to determine the relapse

rates of acne after completion of isotretinoin therapy on 0.5–1.0 mg/kg/day with
a variable follow-up period of 6 months to 6 years.3,73,78,79 The relapse rates in
these studies were similar (40–48%) and became significant as cumulative dose
fell below 120–150 mg/kg.
Cumulative Dose
The dose of isotretinoin was initially suggested to be given at 0.5–1.0 mg/kg/day in
a single course, leading to a total cumulative treatment dose of 120–150 mg/kg over
a 5–6-month period.67,80-83 Early studies indicate a higher relapse rate associated
with a lower total cumulative dose (< 120 mg/kg/day).10,75 However, subsequent
studies with a follow-up period ranging from 2 years to 9 years suggested that
the relapse of acne vulgaris was related less to the cumulative dose and more to
the length of sebaceous gland suppression.76,84 Severe nodulocystic acne seems
to benefit more from an average dose of 1.5 mg/kg/day for 5–6 months (a total
cumulative dose of 290 mg/kg) with the advantage of a lower relapse rate, as
compared to the standard dose regimen with a relapse rate of more than 20%
within 2 years after treatment.85
It is now recognised that isotretinoin induces apoptosis in a dose- and time-
dependent manners, not only of human sebocytes, but also of sebaceous gland
stem cells.81,86 This results in the prolonged suppression of sebaceous gland
activity, even after discontinuation of the drug. Based on this finding, smaller
doses of 0.1 mg/kg/day are not able to induce the same degree of apoptosis of
sebaceous gland stem cells.86,87 Recovery of sebaceous gland from the isotretinoin-
driven apoptosis occurs more quickly with lower doses.68,86,87 In other words,
1.0 mg/kg/day for 16 weeks suppresses sebaceous glands more effectively in a
shorter period of time than would 0.1 mg/kg/day, given for the same number of
weeks of treatment. Note that the total cumulative dose at the endpoint of treatment
is different. It remains to be determined that, with the same total cumulative dose
of 120–150 mg/kg, whether the degree of apoptosis in sebaceous gland stem
cells is different between treatment with a higher daily dose (0.5–1 mg/kg/day)
for a shorter period and treatment with a lower daily dose (< 0.5 mg/kg/day)
continuously or intermittently in a longer period.
Daily Dose of Isotretinoin

The first published study of isotretinoin for acne used a dosage range of
1.0–3.3 mg/kg/day. However, subsequent dose-ranging studies with a dose
range of 0.1–3.0 mg/kg/day for various follow-up periods (4–12 months)
after discontinuation of treatment showed no difference, regarding both the
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rate of improvement and the total clearance of acne during and at the end of
treatment.10,87-99 For treatment of moderate acne, it seems that the dose effect of
oral isotretinoin is insignificant with regard to the rate of improvement and the
clearance of acne. With the same total cumulative dose, it is better to prescribe
higher daily dose of isotretinoin for a shorter period in patients with nodulocystic
acne and lower daily dose for a longer duration in patients with moderate acne.
Due to many dose-dependent mucocutaneous and systemic side effects, a lower
daily dose of isotretinoin (< 0.5 mg/kg/day) for a longer period of treatment has
been recommended to reduce the risk and severity of side effects and to increase
patient compliance.72,93-102
In a recent interventional study on 60 patients with moderate acne according
to the global acne grading system score, three dose ranges of isotretinoin were
used: (1) 0.5–0.7 mg/kg/day (standard dose) for 24 weeks (a cumulative dose of
84–118 mg/kg); (2) 0.25–0.4 mg/kg/day (low dose) for 24 weeks (a cumulative
dose of 48–67 mg/kg); and (3) an intermittent regimen of 0.5–0.7 mg/kg/day for
1 out of every 4 weeks for a total of 6 cycles (a cumulative dose of 21–30 mg/kg).95
At 24 weeks, reduction in global acne grading and inflammatory/noninflammatory
lesion counts was significantly greater in the standard dose/low-dose groups than
that in the intermittent regimen. Patient’s satisfaction was higher in the low-dose
group, while dose-related known side effects were more frequent in the standard
dose group. Relapse rates at 1 year after the end of treatment were significantly
lower in the standard (13%) and lower dose group (18%), as compared with the
intermittent group (56%), respectively.
Many side effects of sysetimc isotretinoin treatment are reversible and depend
on the daily doses. In a retrospective study on 1,743 patients commenced on
isotretinoin over a 6-year period, cheilitis was reported to be the most common
side effect during the course of therapy (78%), followed by eczema and tiredness
(12% each).103 However, these were clearly dose-dependent, as the group treated
with doses less than or equal to 0.25 mg/kg/day reported cheilitis in 47%, eczema
7% and tiredness 5%, as compared with 96%, 16% and 18%, respectively, in the
high-dose treatment group at 0.76–1.0 mg/kg/day.103 A further advantage of
using a lower dose is the differential effect on acne scarring. At 1 mg/kg/day there
is a well-established risk of excessive scarring, yet at doses of 0.1 mg/kg/day acne
scarring is generally much less.68 Another problem of higher dosage isotretinoin
is the flare of acne after 3–6 weeks of treatment, which can largely be avoided by
using doses less than or equal to 0.2 mg/kg/day.104-106
Duration of Treatment
The duration of treatment is closely related to the daily dose and the cumulative
dose of isotretinoin. Duration of treatment may represent a further therapeutic
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disadvantage for patients concerning side effects or the wish for pregnancy in
women at child-bearing age. In contrast to most studies addressing the association
between cumulative doses and relapse rates, little is known about the most
appropriate duration of treatment to clear acne.72,93-95,97,99,102 Furthermore, what
is still unclear is the association between treatment duration and adverse effects in
acute, long-term or irreversible form.
Other Prognostic Factors

In addition to the cumulative dose and daily dose, other factors shown to influence
a relapse, slow response or treatment failure may include early cessation of
treatment before complete remission of acne, androgen excess, polycystic ovarian
syndrome, younger age (< 16 years), a family history of acne, a macrocomedonal
pattern of acne, acne extended to the trunk, severity of acne, excessive seborrhoea
at the end of the treatment and smoking.3,63,68,69,74-76,106-109
Strategies for Preventing Relapse

In the case of a significant relapse recalcitrant to conventional treatment, a new cycle
of treatment with oral isotretinoin can be repeated, with no evidence of increased
adverse effects.67,82 In a retrospective study on 30 subjects who have received three
or more courses of isotretinoin (median time 24.5 months with a median total
cumulative dose of 350 mg/kg), no correlation was found between cholesterol or
triglyceride concentration in the final treatment course and the total cumulative
dose.108 If a second course of therapy is needed, it should not be initiated until at
least 8 weeks after completion of the first course, because experience has shown
that patients may continue to improve while off isotretinoin.109 However, further
studies are required to know whether the second or further session of treatment is
as effective as the first or previous treatment with regard to (1) the effective dose
for acne clearance; (2) time to achieve acne clearance; (3) length of remission time;
and (4) long-term relpase rates.
NEW FINDINGS ABOUT THE SIDE EFFECTS OF

ISOTRETINOIN
Isotretinoin is now widely used for treatment of several skin diseases including
acne vulgaris, rosacea and seborrhea. The main concern of isotretinoin use is its
potential side effects.68 The vast majority of these classic adverse effects have been
described for a long time; however, certain side effects are newly described or are
still debating. Hereby, an update of the side effects of isotretinoin will be presented,
in the following classifications:
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• Endocrinological side effects

• Metabolic side effects
• Osteogenic side effects
• Cardiac side effects
• Otologic side effects
• Psychiatric side effects
• Gastrointestinal side effects
• Ophthalmologic side effects
• Rare new side effects.
Endocrinological Side Effects

Pituitary Hormones
Several hormones affecting sebaceous gland activity have been linked to acne.
These may include androgens, estrogens, growth hormone (GH), insulin,
IGF‑1, corticotropin-releasing hormone (CRH), melanocortins such as adreno
corticotropic hormone (ACTH) and melanocyte-stimulating hormone, and
glucocorticoids.110 On the other hand, it has recently been found that isotretinoin
treatment induces several changes in the hormonal status of acne patients: cortisol,
ACTH, luteinizing hormone (LH), total testosterone and prolactine levels decline
significantly after 3 months of treatment.111 Retinoids can induce dopamine
receptor type 2 (D2R) gene transcriptions in cultured pituitary cells, which is
linked to the presence of a functional retinoic acid response element (RARE) in
the D2R promoter.112 Prolactine reduction induced by isotretinoin may be related
to an increase in central dopaminergic tonus.112
Thyroid Hormones
Isotretinoin has been controversially shown to cause reversible hypo- and
hyperthyroidism.113-116 The effects of Vit A derivatives on thyroid function still
remain debating. Bexarotene, with a different structure to isotretinoin, can cause
hypothyroidism through central mechanism by activation of nondeiodinase-
mediated pathway leading to enhanced peripheral degradation of thyroid
hormones.117 In a study on seven patients with severe rosacea treated with
isotretinoin 1 mg/kg/day for 12 weeks, serum triiodothyronine and thyroxine levels
were significantly lower following treatment, but the response to thyrotropin-
releasing hormone (TRH) stimulation was not declined.114 In another study,
mild reduction in thyroid function was demonstrated after administration of
0.8 mg/kg isotretinoin for 3 months in 18 patients. These changes were reversible
after discontinuation of the therapy.113 Further, study showed a significant
decrease of free triiodothyronine (fT3), thyroid-stimulating hormone (TSH)
182

and TSH receptor antibody levels after 3-month treatment with isotretinoin.111
Decrease in TSH and fT3 levels may be caused by central hypothyroidism due to
RXR-mediated suppression of TSHb gene expression, as previously shown for
bexarotene.118
Growth Hormone and IGF-1

Recent studies show evidence of a connection between acne and IGF-1.35,119-123
Limited information is available for the effect of isotretinoin on GH physiology.
A remarkable decline in serum GH levels has been demonstrated in 23 patients
treated with isotretinoin for 3 months (daily dose and cumulative dose are
unavailable).124 The GH level was found to decrease to 6.4 ng/mL (after clonidine
stimulation test) and 9.7 ng/mL (after arginine stimulation test) in an 11-year-
old girl presenting with growth failure after long-term isotretinoin treatment
at 40 mg/day due to bone marrow transplantation for neuroblastoma.125 Other
side effects related to isotretinoin treatment can be seen in GH deficiency as
well, including reduced bone mineral density (BMD), depressed affection,
dyslipidaemia and myalgia.126 In a recent study, a significant decrease in IGF-1
and IGFBP3 levels has been observed following 3 months of treatment with dose
at 0.5–0.75 mg/kg/day, indicating isotretinoin may have a negative influence on
the GH/IGF-1 axis.28
Metabolic Side Effects

Adipose tissue is the main storage site for Vit A derivatives and plays a crucial role
in its metabolism. Retinoid places a key role in thermogenesis and adipose tissue
metabolism. It may involve control of adiposity and potentially provides treatment
option for obesity and type 2 diabetes.127 In an experimental study, remarkable
alteration in rat epididymal adipose tissue was observed following 10 days of
isotretinoin treatment. Meanwhile adipocyte fatty acid binding protein, PPARd,
glucose transporter type 4 and leptin levels were found to increase and TNF-a
gene transcription to decrease at the end of the study. Based on these findings,
isotretinoin may stimulate new adipocyte formation and may improve insulin
sensitivity of fat tissue.128 Conflicting results exist regarding the role of isotretinoin
in insulin sensitivity. Isotretinoin can increase serum cholesterol level and can
decrease serum high-density lipoprotein cholesterol-C, which can be related to
impaired glucose metabolism or hyperglycemia.124,129,130 Hypertriglyceridemia
caused by retinoid may be as a result of failure in the clearance of triglyceride
particles.127 Short-term isotretinoin treatment (1 mg/kg/day for 5 days) usually
does not affect insulin sensitivity,127 but long-term treatment (0.5 mg/kg/day for
4–6 months) can cause insulin resistance in patients with acne.129 It has been
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demonstrated that oral isotretinoin at dose of 0.5–0.75 mgDkg/day for more than
4 months significantly increased the levels of cholesterol, low-density lipoprotein
cholesterol-C, triglyceride and very low-density lipoprotein cholesterol-C at the
end of the period. Based on these findings, the effect of isotretinoin on glucose
and lipid metabolism seems time- and dose-dependent.131
Osteogenic Side Effects

Oral retinoids can affect bone mineralization,132,133 which has been demonstrated
in many previous studies on acitretin. Studies investigating the effect of isotretinoin
on bone physiology and BMD measurements show that isotretinoin can cause
osteoporosis and hyperostotic alterations mimicking diffuse idiopathic skeletal
hyperostosis.132 In a prospective multicenter clinical trial, a roentgenographic
survey of patients showed that chronic, very-low-dose isotretinoin (approximately
0.14 mg/kg/day for 3 years, cumulative dose ca. 150 mg/kg) can stimulate
hyperostotic axial skeletal changes comparable to those reported in patients on
higher doses.134 However, not any significant effect was observed in patients
treated with isotretinoin 0.89 mg/kg/day for 20 months (cumulative dose ca.
530 mg/kg) regarding the bone mineralization at L2–4 vertebrae, the femoral
neck and the proximal femur.135 The effect of short-term isotretinoin therapy on
BMD is inconclusive. Some studies show that even a single isotretinoin treatment
course might cause a decrease in BMD, which is not supported in other studies.133
In an animal study, BMD, bone mineral content and diameter as well as cortical
thickness of the femur were found to reduce in rats treated daily with 10–15 mg/kg
ATRA or 30 mg/kg isotretinoin.136 No considerable roentgenological changes or
outcomes on BMD were detected in a study of 11 patients on isotretinoin therapy
starting at 0.71 mg/kg/day and then altered to 0.88 mg/kg/day for 1–3 months.137
Another recent multicenter study reported no change in BMD of 217 adolescents
(including 81 girls) with severe, recalcitrant, nodular acne on isotretinoin at a mean
dose of 1 mg/kg/day for 4 months (cumulative dose of 120 mg/kg). Hyperostosis
was not observed in any patient.138 Isotretinoin treatment of 36 patients
(15 males/21 females) with severe nodulocystic acne at 1 mg/kg for 4–6 months
(cumulative dose 120 mg/kg) did not generate any significant differences in the
BMD of lumbar spine and femur.139 In a study of 21 patients (14 male, 7 female)
treated with isotretinoin for 6 months at a cumulative dose of 120 mg/kg, there
was no any statistically significant difference in the BMD for posteroanterior/
lateral lumbar spine and hip between the mean baseline and at 6 months.140 The
use of isotretinoin at 0.4 mg/kg/day for 6 months (cumulative dose 72 mg/kg)
did not exert important impact on BMD at posteroanterior lumbar spine in male
patients.141
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Isotretinoin therapy can rarely cause premature epiphyseal closure. A few single
case reports mentioned premature epiphyseal closure with progressive anterior
pain in both knees, or bone marrow edema in the distal tibia after isotretinoin
treatment,142,143 but detailed information about the dose and duration were not
available. An epiphyseal injury itself may cause premature epiphyseal closure,
independent of isotretinoin treatment.144 In a large-scale, population-based, case-
control study involving 124,655 patients with fractures (cases) and 373,962 age-
and sex-matched controls, no association could be established between any kind
of fracture (hip, forearm, or spine) and the dose or duration of treatment with
systemic Vit A analogues including isotretinoin and acitretin.145
There are limited data about the effect of isotretinoin on vitamin D (Vit D)
and its metabolism. A 4-month course of daily isotretinoin treatment in 11 male
patients was reported to cause significant decrease in the level of 1,25-(OH)2-
Vit D, increase in the molar ratio of 24,25-(OH)2-Vit D to 25-OH-Vit D,
and no change in the levels of 25-OH-Vit D or 24,25-(OH)2-Vit D, serum
calcium, phosphorus, alkaline phosphates, or parathyroid hormone.146 Another
study investigating 20 patients who received 0.89 mg/kg/day isotretinoin for
acne showed a statistically significant fall in the level of 1,25(OH)2-Vit D but
insignificant change in the levels of parathyroid hormone, 25-OH-Vit D, serum
calcium, serum phosphate, or urine calcium.141 In a recent study on 50 patients
(35 female, 15 male patients), the levels of 25-OH-Vit D and serum calcium
levels decreased remarkably, whereas 24,25-(OH)2-Vit D, parathyroid hormone
and bone alkaline phosphates levels increased significantly following 3 months of
0.80 mg/kg/day isotretinoin treatment (cumulative dose ca. 80 mg/kg). Vitamins
A and D have opposite effects on bone metabolism and excessive amount of Vit A
can antagonize the effect of Vit D on Ca+2 homeostasis.147 The reduction in BMD
following isotretinoin treatment may be related to osteomalacia rather than real
osteoporosis.147,148
Cardiac Side Effects

Some isomers of RA such as ATRA, 9cRA and isotretinoin, may be critical for
cardiac biological activities,149 but the incidence seems very low. Reported cases
include right bundle branch block and sinus tachycardia in an 18-year-old man,150
and atrial tachycardia in a 16-year-old boy.151 However, other studies fail to show
any significant side effects, including QT interval prolongation, QT dispersion
increment,152 cardiac arrhythmias, or electrocardiogram abnormalities.153,154
Intrauterine exposure to retinoids can cause congenital heart diseases.155
Isotretinoin can also lead to cardiac hypertrophy with concentric-type heart
modeling, which may be due to its effects on cellular growth and differentiation
mediated by RAR and RXR receptors acting as DNA transcription factors.156
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Karadaǧ et al
The activation of the RXR-PPARg complex has been shown to cause cardiac
hypertrophy in the animal model as well.156 Physician should be aware of the
potential cardiac side effects in patients treated with higher doses of isotretinoin.
Otologic Side Effects

Little is known about the effects of retinoid on hearing function.157 A 15-year-
old boy developed hypoacusia and tinnitus after treated with isotretinoin for
6 weeks that quickly resolved after discontinuation of isotretinoin.158 In another
case report, the infant presented hearing loss, congenital external auditory canal
stenosis and cholesteatoma after prenatal exposure to isotretinoin.159
In a recent study, no clinically evident adverse reactions were detected after
isotretinoin treatment. However, there was a significant increase in the third
and fifth peak latency of both ears, and a significant increase of the first peak
latency and the wave I to V interpeak latency (I–V IPL) of the auditory brain-
stem response in the left ear.160 In a study of 38 patients on oral isotretinoin, the
hearing level of the patients was found to improve in all audiometric frequencies
in a 1-month follow-up.161 As an antioxidant, retinoids may play a role in the
regeneration of cochlear hair cells in the damage induced by ototoxic drugs.162-164
Psychiatric Side Effects

Acne is frequently reported to show comorbidity with depression, anxiety
disorders, social phobia and somatoform disorders.165,166 Eighteen to forty-four
percent of acne patients has depression and anxiety disorders in need of treatment
and should be cautious for higher suicidal risk.166,167 On the other hand, many
adverse psychiatric effects, including depression, psychosis, mood swings, violent
behavior, obsessive compulsive disorder, suicide and suicide attempts, have been
ascribed to isotretinoin since its introduction to the market.168,169 Isotretinoin
is the only nonpsycotropic drug listed in the FDA’s top 10 drugs associated
with depression and increase in suicidal thoughts.170 However, the overall lack
of concrete scientific data limits any conclusion to be drawn about a causal
relationship.168
Action of Isotretinoin on the Brain System

Retinoids can bind to retinoid receptors in the brain to exert effects on gene
transcription.171 Retinoid receptors are concentrated in limbic areas associated
with depression, including the amygdala, prefrontal cortex and hippocampus.
Retinoids also influence neurochemical systems implicated in anxiety disorder
and depression, in particular dopamine, but to some extent also serotonin and
186

norepinephrine.171,172 Administration of retinoids causes changes in dopamine

receptors, while genetic mutations of retinoid receptors are associated with deficits
in dopamine receptors as well as mesolimbic dopamine functioning. Isotretinoin
is supposed to affect mesocortical tract causing dopamine release in orbitofrontal
and prefrontal cortices. Isotretinoin treatment is shown to cause decline in brain
metabolism in the humanorbitofrontal cortex, which might lead to emotional
disturbances.172 Retinoids are associated with an inhibition of neurogenesis in the
hippocampus brain area with connections to prefrontal cortical area, including
the orbitofrontal cortex. Inhibition of neurogenesis in the hippocampus has been
hypothesized to play a role in depression.171
Depression and Suicide

There are conflicting results concerning depressive disorders induced by isotretinoin.
In spite of the findings about decline in depressive symptoms, some reports refer
to no change in depression symptomatology during isotretinoin treatment.173-175
A review analysis of nine studies about the effects of isotretinoin on depression
and suicidal behavior does not confirm their correlation.176 Some studies even
show that depression score may improve after isotretinoin treatment. Isotretinoin
may rarely cause idiosyncratic psychological reaction due to plausible biological
mechanisms induced by retinoids.169,177,178 In an important retrospective cohort
study from Sweden in 1980–1990, the ratio of attempted suicide in patients on
isotretinoin was calculated 3 years before, during and up to 15 years following
the treatment. The risk of suicide attempts gradually increased the year before the
isotretinoin treatment, peaked 6 months following the treatment and return to
anticipated level 3 years after treatment.178 The increased risk of suicide within 6
months was not only linked to isotretinoin, because it started even before treatment.
Interestingly, patients with a history of suicidal attempts before treatment had
even fewer suicidal attempts than those whose behavior started during treatment.
Therefore, isotretinoin can be considered as an alternative treatment in patients
with severe acne with a history of attempted suicide.179 The brain imaging study
detected a decrease in orbitofrontal function in patients with isotretinoin-induced
headache. In another study, headache was found to be associated with depression
in patients treated with isotretinoin.180 It raises the possibility that subjects who
develop isotretinoin-induced headache may have higher risks to develop other
neural side-effects such as depression.181
Obsessive Compulsive Disorder

The effects of isotretinoin on obsessive compulsive disorder are shown in animal
and molecular studies, which may be due to the change in serotonin and dopamine
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Karadaǧ et al
levels.169,172 Relevant data are lacking in human, except in a case report about the
occurrence of obsessive compulsive disorder following isotretinoin treatment,182
which may be explained by its association with higher orbitofrontal metabolism
and dopaminergic system.171 In a study on 38 acne patients using symptom check
list (SCL-90-R), significant increase in obsessive compulsive scores was found
after a daily dose of 0.5–1 mg/kg/day for an average of 24 weeks.182
Psychotic Changes
Isotretinoin has been shown to cause psychotic changes in some case reports
and schizophrenia-like symptoms in animal models by affecting dopaminergic
system.163,165,178 These results cannot be confirmed in later studies.183
Bipolar Disorder
There are only three case reports about bipolar disorder induced by isotretinoin.
In a study involving 500 soldiers treated with isotretinoin for acne, five of them
without past history of bipolar disorder developed “manic psychosis”. Three among
them had a family history of bipolar disorder in their first-degree relatives.184 It is
found that isotretinoin can cause worsening of mood symptoms including suicidal
behavior in some patients with bipolar disorders.185
In a comprehensive analysis of the studies on psychiatric effects associated
with retinoids and isotretinoin published between 1960 and 2010, the
consensus is isotretinoin induces psychiatric effects only in a minority of
treated individuals.181 These patients should be closely followed up and they
and their families should be fully informed about the risks and benefits of the
medication.177,181,186,187 Particularly, patients with increased risk of suicidal
behavior should be closely monitored up to 12 months after discontinuation of
isotretinoin as its effects on suicidal behavior can persistent up to 6 months after
cessation of treatment.179
Gastrointestinal Side Effects

There is still a debate about the isotretinoin-induced gastrointestinal side effects.
The association between acne treatment and inflammatory bowel disease (IBD) or
acne itself and IBD remains unclear.188-193 Clarification of this complicated issue is
quite challenging because endoscopic evaluation of healthy control subjects can be
problematic leading to difficulties in performing prospective studies. Furthermore,
conducting randomized controlled trials or prospective cohort studies is not
practical due to low incidence of IBD. Two recent population-based case-control
studies conclude that there is insufficient evidence to confirm or refute causality
188

between isotretinoin and IBD.189,190 In one study, no association between IBD and
isotretinoin was found,189 while ulcerative colitis was associated with isotretinoin
in another study. No association between isotretinoin and Crohn’s disease was
observed in both studies.189,190 In comparing these two studies, it is concluded
that the absolute risk of isotretinoin-induced IBD is low. Further prospective or
well-designed retrospective pharmacoepidemiological studies are warranted to
better understand the causality between isotretinoin and IBD.188 Dermatologists
should be aware of these potential side effects, and when patients treated with
isotretinoin develop persistent gastrointestinal symptoms, they should be referred
to gastroenterologists for further investigation.193
Ophthalmologic Side Effects

Oral isotretinoin can cause changes in exposed and unexposed conjunctiva,
including increase in cell-to-cell contact, nucleus-to-cytoplasm ratio and goblet
cell density.194 The ocular adverse effects related to isotretinoin can be categorized
into “certain”, “probable/likely”, “possible”, “unlikely”, “conditional/unclassified”
and “inaccessible/unclassifiable” according to the World Health Organization
classification.194-196 The “certain” drug adverse effects are abnormal meibomian
gland secretion and atrophy, intracranial hypertension with optic disc edema,
ocular sicca, corneal opacities, keratitis, myopia and decreased dark adaptation.
The “probable/likely” drug adverse effects are reversible decreased color vision,
giant cobblestone-like papillae, corneal shield ulcer and permanent loss of dark
adaptation. The “possible” side effects are permanent sicca, corneal ulcers, diplopia
and eyelid edema. The “unlikely” side effects are exophthalmos, keratoconus,
glaucoma, activation of herpes simplex and pupil abnormalities. Not enough data
are present for “conditional/unclassified” and “inaccessible/unclassifiable” side
effects.195-198
Clinically isotretinoin can cause eye dryness, decreased eye tear, conjunctivitis
and increased Staphylococcus aureus colonization.197 Isotretinoin can cause
significant alterations in most anterior segments during the treatment.199 In an
extreme example, a 19-year-old female developed premacular hemorrhage and
consequent loss of vision in the left eye following oral isotretinoin.200 Corneal
steepening and significant visual drop following oral isotretinoin for seven and a
half weeks was reported as well.195
Patients treated with isotretinoin should be closely monitored for ocular side
effects. Dermatologists and primary care physician can prescribe ocular lubricants
(such as preservative-free artificial tears) to treat eye dryness. If ocular symptoms
progress or persist, patients should be referred to ophthalmologists for detailed
investigation.196
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Karadaǧ et al
Rare New Side Effects

A recent study investigating 30,496 patients treated with isotretinoin showed
rare side effects such as stroke, phlebitis/thrombophlebitis, myocard infarctus
and thrombosis.201 A 17-year-old white man treated with systemic isotretinoin
for recalcitrant acne presented with central retinal vein occlusion in one eye.197
Another recent case report described terminal hematuria after 1-month isotretinoin
treatment, which was postulated to be due to its xerotic mucosal alteration causing
increased bleeding risk.202
CONCLUSION
An ideal acne therapy should simultaneously target and interfere all four
pathogenic factors and their interactions effectively. Although the trend moves
toward using antiinflammatory agents for primary acne treatment, the available
experimental data and limited clinical evidence indicate that antiinflammation
therapy may benefit mainly acne of mild-to-moderate grades. The clinical
experience with current treatment options so far suggests that only inhibition of
sebaceous gland secretion and normalization of the keratinisation in sebaceous
follicles can decisively change the course of acne. Systemic isotretinoin remains
the most efficacious treatment for severe acne as well as moderate disease
unresponsive to other treatment modalities. New understandings about its
mode of action may include (1) secondary responses to ATRA/RAR-signaling;
(2) upregulation of the FoxO pathway; predominantly FoxO1; (3) interaction
with AR, PPARg, PPARg/RXRa and LXR/RXRa heterodimers; (4) regulation
of the innate and adaptive immunity; (5) sebocyte apoptosis mediated by
NGAL; (6) inhibition of neutrophil chemotaxis; (7) reduction of matrix
metalloproteinases; (8) downregulation of ROS formation; and (9) inhibition of
proinflammatory NF‑kB-mediated cytokine signaling.
The long-term therapeutic effect of oral isotretinoin is mainly dependent
on the cumulative dose taken but is probably limited to less than 5 years. It
remains to be determined whether a higher dose at greater than or equal to
120 mg/kg can bring additional benefit considering long-term remission. It is
unknown if the ideal cumulative dose should be given without interruption in
one session or can be administered in multiple sessions without interference
of the efficacy. A low-dose regimen at less than or equal to 0.3 mg/kg seems
as effective as the high-dose regimen at greater than or equal to 0.7 mg/kg to
achieve a short-term clearance of acne, with a significantly fewer side effects
and better tolerance. Higher doses are indicated in patients with significant
macrocomedonal disease, acne of greater severity, truncal lesions, women with
untreated hyperandrogenism and smokers.
190

Recent studies on the adverse effects of oral isotretinoin raise the discussions
again if the treatment may cause (1) suppression of GH, IGF-1, ACTH, LH,
prolactin, thyroid hormones, cortisol and total testosterone; (2) insulin resistance
and lipid metabolism; (3) osteogenic effect such as bone mineralization, BMD
change, premature epiphyseal closure and hyperostosis; (4) psychiatric changes
such as depression, obsessive compulsive disorders, psychosis, bipolar disorders;
(5) association with IBD; and (6) rare side effects in the cardiac and hearing
system. Short-term treatment for 3–6 months seems safe and, if at all, with only a
slightly increased but reversible risk of adverse effects. Long-term safety must be
reexamined in better stratified studies with an adequately large sample size. Due to
the growing wish of patients for a smooth skin without acne scar and the reluctance
to take prolonged oral antibiotics, the trend is going toward to prescribing oral
isotretinoin earlier in the treatment decision. The multiple potential adverse effects
cannot be underestimated and a regular checkup is warranted. Development of
new dosing schedules with fewer adverse effects and better tolerance but without
impairment of the therapeutic efficacy is worth trying. A better understanding
of the acting mechanism of isotretinoin at the molecular level will help design
novel medications with greater therapeutic index, lower relapse rates and longer
remission time.
Editor’s Comment
Systemic isotretinoin is the most gratifying therapy for management of moderate
to severe acne. It targets several factors in the pathogenesis of acne. In this artile,
Drs Karadag, Kalkan, Lin and Chen have discussed the recent advances in the
mechanism of action of retinoids including the secondary responses to all-trans-
retinoic acid (ATRA)/retinoic acid receptor (RAR)-signaling involving many
transcription factors and coregulators. They have further considered the various
dosing schedules, emphasizing that optimum long term therapeutic effect depends on
consumption of a total cumulative dose of 120–150 mg/kg. Though several dosages
are used, little is known about the absolute advantage of different dosing schedules
and the long-term remissions induced by them. Patients showing unsatisfactory
response and higher relapse rates may include those with macrocomedonal disease,
severe nodulocystic acne, truncal lesions, women with untreated hyperandrogenism
and probably smokers. Among the side effects, this article discusses the lesser known
(and lesser discussed!) adverse effects of retionoids suggesting that a more clear
understanding of the action of isotretinoin at molecular level will help develop novel
treatment modalities with greater benefit-risk ratios and longer remission time.
Neena Khanna
191

Karadaǧ et al
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isotretinoin. J Am Acad Dermatol. 2001;45:515-9.
171. Bremner JD, McCaffery P.The neurobiology of retinoic acid in affective disorders. Prog Neuropsychopharmacol
Biol Psychiatry. 2008;32:315-31.
172. Bremner JD, Fani N, Ashraf A, Votaw JR, Brummer ME, Cummins T, et al. Functional brain imaging
alterations in acne patients treated with isotretinoin. Am J Psychiatry. 2005;162:983-91.
173. Ng CH, Tam MM, Celi E, Tate B, Schweitzer I. Prospective study of depressive symptoms and quality of life
in acne vulgaris patients treated with isotretinoin compared to antibiotic and topical therapy. Australas J
Dermatol. 2002;43:262-8.
174. Hahm BJ, Min SU, Yoon MY, Shin YW, Kim JS, Jung JY, et al. Changes of psychiatric parameters and their
relationships by oral isotretinoin in acne patients. J Dermatol. 2009;36:255-61.
175. Ferahbas A, Turan MT, Esel E, Utas S, Kutlugun C, Kilic CG. A pilot study evaluating anxiety and depressive
scores in acne patients treated with isotretinoin. J Dermatol Treat. 2004;15:153-7.
176. Marqueling AL, Zane LT. Depression and suicidal behavior in acne patients treated with isotretinoin: a
systematic review. Semin Cutan Med Surg. 2005;24:92-102.
177. Magin P, Pond D, Smith W. Isotretinoin, depression and suicide: a review of the evidence. Br J Gen Pract.
2005;55:134-8.
178. Sundstro/m A, Alfredsson L, Sjo/lin-Forsberg G, Gerdeìn B, Bergman U, Jokinen J. Association of suicide
attempts with acne and treatment with isotretinoin: retrospective Swedish cohort study. BMJ. 2010;341:
c5812.
179. Simpson RC, Grindlay DJ, Williams HC. What’s new in acne? An analysis of systematic reviews and clinically
significant trials published in 2010-11. Clin Exp Dermatol. 2011;36:840-3.
180. Wysowski DK, Swartz L. Relationship between headache and depression in users of isotretinoin. Arch
Dermatol. 2005;141:640-1.
181. Bremner JD, Shearer KD, McCaffery PJ. Retinoic acid and affective disorders: the evidence for an
association. J Clin Psychiatry. 2012;73:37-50.
182. Fornaro M. Obsessive-compulsive disorder with bipolar diathesis following isotretinoin therapy remitting
upon treatment with olanzapine and fluvoxamine. Neuropsychiatr Dis Treat. 2010;6:719-22.
183. Karadag AS, Bilgili SG, Selvi Y, Tutuncu R, Aydýn A, Calka O, et al. Effects of isotretinoin treatment on
general psychiatric symptoms, quality of life and social phobia in acne vulgaris patients. J Eur Acad
184. Barak Y, Wohl Y, Greenberg Y, Bar Dayan Y, Friedman T, Shoval G, et al. Affective psychosis following
Accutane (isotretinoin) treatment. Int Clin Psychopharmacol. 2005;20:39-41.
185. Schaffer LC, Schaffer CB, Hunter S, Miller A. Psychiatric reactions to isotretinoin in patients with bipolar
disorder. J Affect Disord. 2010;122:306-8.
186. Brasiæ JR. Monitoring people treated with isotretinoin for depression. Psychol Rep. 2007;100:1312-4.
187. Fea A. Medicine and mental health: the isotretinoin issue. N Z Clin Psychol J. 2008;18:8-14.
188. Crockett SD, Gulati A, Sandler RS, Kappelman MD. A causal association between isotretinoin and
inflammatory bowel disease has yet to be established. Am J Gastroenterol. 2009;104:2387-93.
189. Bernstein CN, Nugent Z, Longobardi T, Blanchard JF. Isotretinoin is not associated with inflammatory bowel
disease: a population-based case-control study. Am J Gastroenterol. 2009;104:2774-8.
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190. Crockett SD, Porter CQ, Martin CF, Sandler RS, Kappelman MD. Isotretinoin use and the risk of inflammatory
bowel disease: a case-control study. Am J Gastroenterol. 2010;105:1986-93.
191. Alikhan A, Henderson GP, Becker L, Sciallis GF. Acne treatment and inflammatory bowel disease: what is
the evidence? J Am Acad Dermatol. 2011;65:650-4.
192. Mostow EN. Include discussions and review of systems regarding inflammatory bowel disease in patients
starting isotretinoin therapy: comment on “Isotretinoin therapy and inflammatory bowel disease”. Arch
Dermatol. 2011;147:729-30.
193. Popescu CM, Popescu R. Isotretinoin therapy and inflammatory bowel disease. Arch Dermatol. 2011;
147:724-9.
194. de Queiroga IB, Antônio Vieira L, Barros Jde N, Melo Diniz Mde F, de Morais LC. Conjunctival impression
cytology changes induced by oral isotretinoin. Cornea. 2009;28:1009-13.
195. Santodomingo-Rubido J, Barrado-Navascués E, Rubido-Crespo MJ. Drug-induced ocular side-effects with
isotretinoin. Ophthalmic Physiol Opt. 2008;28:497-501.
196. Neudorfer M, Goldshtein I, Shamai-Lubovitz O, Chodick G, Dadon Y, Shalev V. Ocular adverse effects of
systemic treatment with isotretinoin. Arch Dermatol. 2012;148:803-8.
197. Labiris G, Katsanos A, Karapetsa M, Mpanaka I, Chatzoulis D. Association between isotretinoin use and
central retinal vein occlusion in an adolescent with minor predisposition for thrombotic incidents: a case
report. J Med Case Rep. 2009;3:58.
198. Rosen E, Raz J, Segev F. Giant cobblestone-like papillae during isotretinoin therapy. Ocul Immunol Inflamm.
2009;17:312-3.
199. Cumurcu T, Sener S, Ozsoy E, Doganay S. Changes in anterior chamber parameters with the Pentacam
rotating Scheimpflug and axial length measurements by ultrasound in patients who use isotretinoin. Curr
Eye Res. 2012;37:395-8.
200. Onder HI, Turan H, Kilic AC, Kaya M, Tunc M. Premacular hemorrhage due to isotretinoin use. Cutan Ocul
Toxicol. 2013;32:170-2.
201. Bérard A, Azoulay L, Nakhai-Pour HR, Moussally K. Isotretinoin and the risk of cardiovascular, cerebrovascular
and thromboembolic disorders. Dermatology. 2011;223:45-51.
202. Sarifakioglu E, Yilmaz AE, Erpolat S. Terminal hematuria associated with oral isotretinoin treatment in a
patient with acne vulgaris. Pediatr Dermatol. 2012;29:668-9.
200

Current Role of Light and

Laser Therapy in Acne
Dae Hun Suh MD PhD
Department of Dermatology, Seoul National University College of Medicine,
Acne Research Laboratory, Seoul National University Hospital, Seoul, South Korea
ABSTRACT
Acne treatment must be convenient for patients because acne is a chronic
disease. Cost-effectiveness is another important issue. With technological
development, light and laser therapy with better efficacy and safety offer
ideal treatment not only adjunctively, but also alternatively. Light and
laser-based treatment equipment for acne is relatively new and reasonably
expensive, but several types of light-based therapy and lasers have been
successfully tried for acne treatment. Although the number of randomized
controlled studies is not many, the effectiveness of laser and light-based
therapy for acne has been proved in clinical practice.
INTRODUCTION
Acne is a chronic disease, wax and waning in nature. Large epidemiological study
showed acne persisted over 2 years in more than 70% of patients.1 Prolonged
management is required in acne. There are several requisites for long-term
management in general. First of all, treatment must be well-tolerated and have
minimal discomfort. Convenience and cost-effectiveness is another important
issue. With technological advancement, light and laser therapy with better efficacy
and safety offer ideal treatment not only adjunctively, but also alternatively.
Though light and laser-based treatment equipment for acne is relatively new
and reasonably expensive, total cost for treatment is similar to other treatment
methods considering long-term course of acne.
When light hits the skin, skin-light interaction occurs. Part of the light
is reflected, absorbed or penetrates the skin. The absorbed light interacts with
Email: daehun@snu.ac.kr

Suh
biomolecules and elicits various biological responses. Light penetration depth

varies according to wavelength. There are several chromophores in skin such
as melanin, hemoglobin, bilirubin and beta-carotene.2 Each chromophore has
different absorption spectra. The density of the chromophores in human skin varies
from individual to individual. Skin thickness and the density of the chromophore
vary throughout the body. The intensity of radiation and concentration of
chromophores is related to the intensity of biological response. Inactivation of
Propionibacterium acnes and photothermal effect in pilosebaceous unit are believed
to be the main targets of this biological reaction.
LIGHT THERAPY IN ACNE

Blue Light Therapy
Many current acne treatments focus on P. acnes. P. acnes is considered to play a
role in acne pathophysiology.3 Blue light inactivates P. acnes. Porphyrin produced
by Propionibacterium species is associated with the efficacy of light therapy.
Protoporphyrin, uroporphyrin and coproporphyrin III are main porphyrins
produced by P. acnes.4 Light is absorbed by chromophore and transferred into
heat. The peak of absorption spectra of the porphyrin is at 415 nm (Soret band).
Thus wavelength of blue light is ideal for photoactivation of porphyrin.4 Blue
light excites porphyrin in P. acnes, ultimately reactive oxygen species (ROS) is
generated. This energy transfers and ROS lead to structural damages to membranes
in P. acnes. Antimicrobial effect of blue light (407–420 nm) against P. acnes was
confirmed through in vitro study.5 Significant reduction of acne grade was
observed following 4-week intense blue light treatment (ClearLightTM, Lumenis,
Yokneam, Israel) for 14 minutes twice a week in recent clinical study.6 There was
significant reduction in inflammatory lesion but decrease in the noninflammatory
lesion failed to reach statistical significance. This intrinsic photodynamic therapy
(PDT) appears to have direct effect on only P. acnes. Significant improvement
was observed in 8 out of 10 patients in another study done with flexible optical
light in Japan.7 Several studies show significant reduction in inflammatory
acne as much as 67% with eight or 10 sessions of blue light therapy.8 The more
significant improvement in inflammatory lesion than in noninflammatory lesion
is a consistent finding in blue light therapy.
Red Light Therapy

Red light may have several advantages over blue light. Red light may have some
effect on deeper structures with better penetration. Porphyrin is photoactivated by
red light (Q band) and can cause lethal effect on P. acnes as with the blue light.4
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Current Role of Light and Laser Therapy in Acne
Longer exposure time is required to activate the equal amount of porphyrin in red
light than in blue light. Reduced colonization of P. acnes may be associated with
reduction of inflammation. Though only negligible porphyrins are accumulated
in sebocyte, there was a previous report shows that red light can affect the sebum
secretion and keratinocyte.9 Red light can also have antiinflammatory activity
through influence on macrophage and cytokines from dermis.10
Combination of Blue and Red Light

There are several clinical trials revealed that combination of blue and red light
(415 nm and 660 nm) had therapeutic effect on acne.11,12 It appears that mixed
red-blue light improves inflammatory lesions better than benzoyl peroxide or
blue light single therapy, resulting in 76% reduction of lesions with 3 months
treatment.12 Though there was no statistical significance, the improvement of
noninflammatory lesion achieved by mixed red-blue light was superior to that
of benzoyl peroxide.12 No severe adverse events were reported. Combination
of red and blue light may have synergistic effect on acne by antibacterial and
antiinflammatory action.
Intense Pulsed Light

Intense pulsed light (IPL) is an incoherent high-intensity pulsed light with wide
range of wavelength (500–3,200 nm) targeting various chromophores in the
skin. IPL can photoactivate porphyrins and induce selective photothermolysis
of blood vessels supplying sebaceous glands.13 In clinical trial, IPL-reduced acne
lesion by 66% after four sessions with 2-week interval.14 But there was a little
rebound observed after 8 weeks. Efficacy of IPL for inflammatory lesion showed
comparable results to even benzoyl peroxide. IPL may provide additive benefits to
red macules, irregular pigmentation.
LASER THERAPY IN ACNE

Unlike light, laser emits focused coherent light with single wavelength. Laser
affects relatively small area and selective structures in the skin. Several lasers
have been used for acne treatment. Treatment effect on acne may be related to
photothermal effect of laser on sebaceous gland, P. acnes and vessels in the skin.
Some of the lasers are especially beneficial in post-acne scarring rather than
acne itself. Acne scar becomes easier to manage with the development of laser
instruments. Though ablative lasers have lots of adverse effects, they showed good
efficacy to treat atrophic acne scar. Fractionated devices are designed to reduce
adverse effects from laser treatments.
203

Suh
Diode Laser
Sebaceous glands are believed to be easily destroyed by heat. There are several
studies that show improvement of inflammatory acne and shrinkage of the
sebaceous glands by the 1,450 nm laser treatment. However, most of studies are
lacking in enough clinical evidence because of their small scale and uncontrolled
design.15 In recent split-face study, three sessions of treatments were done with
Smoothbeam® (Candela, UK). No significant difference was observed between
diode laser treated side and control side in lesion count and grade at 4 weeks and
12 months after the last treatment.16 However, the role of diode laser for acne
treatment remains unclear because studies have used small sample size and have
shown contradictory results.
Potassium Titanyl Phosphate Laser

Potassium titanyl phosphate (KTP) laser emits 532 nm green light. Several trials
reported varying degree of efficacy of KTP laser on acne treatment as much as
35.9%.17 Simple comparison is impossible due to different number of sessions and
periods among them. KTP laser with longer wavelength is believed to penetrate
deeper than blue light. The mode of action is basically same as other light or laser
therapy such as reduction of P. acnes by free oxygen radicals or thermal effect on
circumferential sebaceous glands.
Pulsed Dye Laser

In comparison with IPL and blue-red combination light-emitting diode (LED),
pulsed dye laser (PDL) required less average number of treatment sessions
reaching a more than 90% clearance. After four sessions of PDL treatment for
8 weeks, both inflammatory and noninflammatory lesions showed reduction to
38% and 41% of baseline, respectively.14 These improvements were sustained even
at 8-week follow-up after last treatment. Authors suggested that these findings
may be associated with transforming growth factor beta (TGF-b) level change
in the lesion.14 In the other study, there was no significant improvement in
with nonpurpuric dye laser in 12-week clinical trial.18 These tentative results are
associated with the wavelength of the light (585 nm) that PDL emit. The 585-nm
light is heavily absorbed by hemoglobin. PDL does not inhibit main pathogenesis
of the acne but induce antiinflammatory effect by targeting vessels in the skin.
Nd:YAG Laser
The classic Q-switched 1,064 nm neodymium:yttrium-aluminum-garnet (Nd:YAG)
laser has been used for pigment disorder or tattoo. However, Nd:YAG laser has
204

different biological effects according to pulse duration. Unlike Q-switched Nd:YAG,

long pulse Nd:YAG causes diffuse heating of dermal tissue. Heat transfer to dermis
can affect collagen remodeling which may improve acne scar. Furthermore, the long
pulse Nd:YAG affords greater depth of penetration than Q-switched Nd:YAG. A
clinical trial showed additional effect of long pulse Nd:YAG on acne when combined
with long pulse KTP laser.19
Carbon suspension serves as a photoenhancer when combined with Nd:YAG
laser. Carbon as an exogenous chromophore assists penetration of heat transfer.
In recent study, inflammatory and noninflammatory acne lesions were improved
by 58.6% and 52.4%, respectively after three sessions of quasi-long pulse and
Q-switched Nd:YAG laser treatment assisted with a topically applied carbon
suspension (dual mode, 7-mm diameter spot, 300 ms with 1.8–2 J/cm2 followed
by 5 ns with 1.8 J/cm2).20
Combined 585/1,064 nm Laser

Combined 585/1,064 nm laser emits PDL and long pulse Nd:YAG sequentially.
Both inflammatory and noninflammatory lesions are effectively treated by PDL
and a combined laser in a 12-week split-face study for comparison of PDL and
a combined 585/1,064 nm laser (Cynergy, Cynosure Inc., Westford, MA, USA).
Reduction of inflammatory lesion was 86% on the PDL side and 89% on the
combined laser side after three sessions of treatments.21 Corresponding reductions
of 69% and 64% were shown in noninflammatory acne lesion, respectively.
Combined 585/1,064 nm laser was found to ameliorate acne scar after four sessions
of treatments. Combined 585/1,064 nm laser was more effective for deep boxcar
scar than single long pulse Nd:YAG laser therapy.22 Long pulse Nd:YAG has been
reported to promote significant neocollagenesis.23 PDL targets oxyhemoglobin
in blood vessel and induces oxidized form of hemoglobin as methemoglobin.
Methemoglobin can absorb more energy by 4.75 times than oxyhemoglobin
by irradiation from Nd:YAG laser. Thus, combined laser can transfer heat more
effectively and deeply than single use of each laser.
Radiofrequency
Radiofrequency (RF) is getting popularity for medical application involving tissue
heating in the field of dermatology. Delivery of heat to dermal tissue leads to
nonsurgical tissue lifting and tightening with tolerable discomfort. Synergism
is expected when RF combines with optical device which lowers impedance.
Lowered impedance enhances selectivity and enables to transfer heat effectively.
Furthermore, lower levels of both types of energy obtain reasonable efficacy with
minimal adverse effect. Combination of bipolar RF and 915 nm diode laser
205

Suh
showed significant improvement of acne scar after three sessions of treatments

and improvements persisted for at least 12 weeks24 although this study is lacking
in control group.
PHOTODYNAMIC THERAPY IN ACNE

Acne is one of the dermatologic indications that PDT can be a valuable treatment
option. Light therapy in acne uses porphyrin produced by P. acnes, thus light
therapy without exogenous photosensitizer could be called intrinsic PDT. With
the exogenous photosensitizer, additive effect other than reduction of P. acnes can
be expected such as damage to sebaceous gland. Moreover, antiinflammatory effect
of PDT was shown by in vitro study. Intercellular cell adhesion molecule type-1
(ICAM-1) and major histocompatibility complex II in the dendritic cells were
decreased after PDT.25 Another mechanism of downregulation of inflammatory
cell infiltration by PDT through toll-like receptor-2 (TLR-2) is suggested.26
Heat shock protein released by PDT is considered as mediator of TLR-2
signaling. However, the mechanism of PDT has not been precisely established.
There are several contradictory results. Transient reduction in mean density of
Propionibacterium species was observed.25 In another clinical trial, there was no
bacterial reduction, only sebum production was decreased.27 Furthermore, PDT
promotes inflammation by inducing proinflammatory cytokines such as tumor
necrosis factor-alpha (TNF-a), interleukin (IL)-6, IL-1.28
Various Factors that Affect the Efficacy of

Photodynamic Therapy
There are several factors that can be related to the efficacy of PDT. Micro
environment including oxygen supply, exogenous photosensitizer, light source and
dosimetry is associated with the result of PDT. There was no significant difference
in a 12-week clinical study comparing the efficacy of PDT using topical 20% delta-
aminolevulinic acid (d-ALA) with that of PDT using 16% MAL (methyl‑ALA)
in a split-face study.29 After one session of PDT, the median percentage decrease
in numbers of inflammatory lesions was 59% in both MAL and ALA treated
sides of the face.
Indocyanine green (ICG) is a cyanine dye and has a peak spectral absorption
at 800 nm. Significant improvement was showed after three sessions of PDT with
ICG and 805 nm diode laser in controlled, split-face study.30
Optimal incubation time between photosensitizer application and light
exposure is lack of consensus for acne treatment. In general, incubation time was
10–30 minutes up to 4 hours. Prolonged suppression of sebum secretion was
confirmed only by long incubation (over 3 hours).31,32 Wavelength and dosimetry
206

of the light is another important factor. It is plausible that long-term damage of

sebaceous gland is observed histologically only after PDT using light with long
wavelength.31,32 ALA-PDT for acne with different source of light has studied.32,33
Comparing about efficacy according to dosimetry among studies is not possible
because of their various light source and design.
CONCLUSION
In conclusion, various methods of laser and light-based therapy have been performed
for acne treatment. Although there are only a few randomized, controlled studies;
these treatment methods are increasingly used because dermatologists seem to be
aware of their effectiveness.
Editor’s Comment
Medical treatment of acne is often prolonged and is totally dependent on patient’s
adherence and compliance to therapy. So any therapeutic modality which circumvents
these (by reducing the period of active therapy and being physician delivered),
is received with euphoria. In this article, Dr D Suh discusses the technological
advancements in light and laser therapy of acne. With the availability of more
efficacious and safe light equipment and lasers it is suggested that they may be the
almost ideal treatment modalities not only adjunctively, but also alternatively. And
though reasonably expensive, they have been cost effectively used for acne treatment.
Even if the number of randomized controlled studies are few, the effectiveness of
laser and light-based therapy for acne has been established in clinical practice.
Neena Khanna
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14. Choi YS, Suh HS, Yoon MY, Min SU, Lee DH, Suh DH. Intense pulsed light vs. pulsed-dye laser in the
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15. Jih MH, Friedman PM, Goldberg LH, Robles M, Glaich AS, Kimyai-Asadi A. The 1450-nm diode laser for
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a randomized split-face, investigator-blinded clinical trial. Br J Dermatol. 2011;165:1256-62.
17. Yilmaz O, Senturk N, Yuksel EP, Aydin F, Ozden MG, Canturk T, et al. Evaluation of 532-nm KTP laser treatment
efficacy on acne vulgaris with once and twice weekly applications. J Cosmet Laser Ther. 2011;13:303-7.
18. Orringer JS, Kang S, Hamilton T, Schumacher W, Cho S, Hammerberg C, et al. Treatment of acne vulgaris
with a pulsed dye laser: a randomized controlled trial. JAMA. 2004;291:2834-9.
19. Jeon HC, Cho SY, Lee JH. Does long-pulsed neodymium:yttrium-aluminum-garnet work on acne lesions?:
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20. Jung JY, Hong JS, Ahn CH, Yoon JY, Kwon HH, Suh DH. Prospective randomized controlled clinical and
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22. Min SU, Choi YS, Lee DH, Yoon MY, Suh DH. Comparison of a long-pulse Nd:YAG laser and a combined
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29. Wiegell SR, Wulf HC. Photodynamic therapy of acne vulgaris using 5-aminolevulinic acid versus methyl
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209

Evaluation and Management of

Acne Scars
Brigitte Dréno MD PhD
University Hospital, Nantes, France
ABSTRACT
Scars are a major concern for the acne patient. They are even more
important than acne lesions themselves. This fear can be explained by the
fact that the patient is aware of the difficulty to which the physician who
wants to treat acne scars is confronted. Treatments of acne lesions remain
indeed still often difficult, requiring the combination of several techniques
often with a partial result. It is therefore essential to discuss the prevention
of acne scars.
Introduction
Acne is the only facial inflammatory dermatosis inducing scars: why?
This can be explained by the fact that acne is a disorder of the pilosebaceous
follicle, and thus, the inflammation is deeply located, often in the intermediate
dermis and the deep dermis, or in the hypodermis. Scar frequency is highly variable
in the literature depending on the evaluation method, recruitment and definition
itself of the scars, in particular whether or not pigmentations and erythema are
included.1,2 Thus, the percentages vary between 25% and 95%. It is not always easy
to predict, when a patient is seen in consultation, whether or not he/she will have
acne scars, including hypertrophic scars. However, one can remember that they
occur more likely due to severe, nodular, or superficial expanded papulopustular
acnes, and especially when acne evolution duration is long.3 Layton et al. has
shown that after a 3-year mean acne duration, 95% of scars were found on the
face.4
Email: brigitte.dreno@wanadoo.fr

Evaluation and Management of Acne Scars
SCAR PATHOPHYSIOLOGY
The phenomena taking place in the healing of an acne lesion include:
• An inflammatory phase with vasodilation and presence of granulocytes,
lymphocytes and macrophages around the pilosebaceous follicle. Many
cytokines are released, associated with a vasodilation
• Thereby, this leads to the healing phase of the scar with collagen formation,
mainly type III collagen, in the dermis. The main cytokines involved at this
level are the insulin-like growth factor-1 (IGF-1) and the transforming growth
factor-beta (TGF-b) as well as the platelet-derived growth factor (PDGF)
• A third phase of remodeling follows these two first phases, which is sustained
over several months and where metalloproteinases play a central role. Indeed, it
is believed that an imbalance between the metalloproteinase/metalloproteinase
inhibitor (TIMP) ratios would be at the origin of the formation of these scars.5
DIFFERENT TYPES OF ACNE SCARS

According to the Jacob classification, three types of atrophic scars can be
distinguished: (1) icepick or V-shaped scars; (2) boxcar or U-shaped scars with
vertical edges and (3) rolling or M-shaped scars.6
There are also two types of hypertrophic scars: hypertrophic scars delineated
to the inflammatory lesion area and that can regress spontaneously, and keloid
scars that extend beyond the inflammatory lesion area and usually evolve for more
than 2 years.
Erythema and pigmentation, which can be reversible, must not be considered
as pigmentations.
SCAR EVALUATION
Regarding the scar evaluation scales, two are more often used: the ECCA (Echelle
d’Evaluation clinique des Cicatrices d’acné) scale (Figure 1) and the Goodman
scale. The first one is semiquantitative and uses the different types of atrophic
scars proposed by Jacob.7,8 The second one is more quantitative, thus longer and
more adapted for clinical research. A recent article has shown, however, how
difficult was it to find an agreement on the evaluation of acne scars. Thus, a good
classification of acne scars is important due to the impact on the therapeutic
approach and global alliance is actively working toward recommendations for
the classification and assessment of acne scars, as well as strategies to prevent
and treat scars.9
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Dréno
Figure 1: Acne scars assessed by the ECCA

(Echelle d’Evaluation clinique des Cicatrices d’acné) grading scale.7
ACNE SCAR TREATMENT

Acne scar treatment (Figure 2) is complex and difficult and this is mainly due to
two facts:
• Their depth, because of the localization in the pilosebaceous follicle
• The presence of an underlying fibrosis.
In any case, before offering a treatment for acne scars, it should be specified
to the patients that complete correction is not possible, the aim being therefore to
improve scars, and above all to well associate the risks.10
212

CO2, carbon dioxide; 5FU, 5-fluorouracil; TCA, trichloroacetic acid.
Figure 2: Treatment options for acne scars. Non-ablative lasers for mild disease; ablative and fractional
lasers for moderate scarring.10
ATROPHIC SCARS
Surgical Techniques
There are four types of surgical techniques:
• The simple punch excision followed by a suture.
• The scar elevation takes place in three stages: (1) punch excision; (2) elevation
of the fragment above the adjacent skin with forceps to avoid retraction and
(3) fixation of the fragment with a steristrip or a fixed thread.
• The micrografts that are particularly interesting for U-shaped scars.
Microdermal grafts can also be offered under deep linear scars after using the
tunneling technique with a cannula.
• The subcisions with needle when a significant fibrosis is present or need for
flattening epithelial tunnels of acne congoblata.11
Resurfacing Techniques
Peels
• Superficial peels are essentially interesting to reduce superficial pigmentations,
tighten the pores and thus result in a more homogeneous appearance of the
213

Dréno
skin. They are essentially made of fruit acid, glycolic acid, salicylic acid and
liposoluble salicylic acid
• Intermediate peels are peels using resorcinol paste of Unna. They have mainly
been used in the past. This technique requires 8–10-day eviction period that
is more and more abandoned. Intermediate trichloroacetic acid (TCA) 30%
peels are more frequently used
• Deep peels, mainly with resorcinol, are reserved for experimental dermatologists.
Indeed, they have a significant risk of side effects.
A special mention for high concentration TCA peel that consists in applying
TCA ranging from 65% to 100% at the bottom of the V-shaped scar for about
10 seconds with a sharp stick. This induces a neocollagenesis and elevates the scar
bottom.12
Mechanical Grindings
• Microdermabrasion is performed by projecting pressurized aluminium oxide
crystals but it usually gives the modest results. It is comparable to the use of
needles or tattoo guns13
• Dermabrasion with a grindstone is a bloody method, indicated for shallow
scars. For the whole face, a general anesthesia is necessary or at least a local
or locoregional anesthesia. The healing takes about 8 days. An erythema may
persist for several weeks. Grindings with microneedles exist today, they are very
interesting in rolling-shaped scars and have only few side-effects
Lasers
Different types of lasers are offered:
• Pulsed dye laser and intense pulsed light: The intense pulsed light (IPL) is
particularly interesting for erythematous and pigmented macules. Resurfacing
lasers [pulsed dye laser 585 nm, neodymium:yttrium-aluminum-garnet
(Nd:YAG) laser 1,064 nm and 1,320 nm, iodine laser 1,450 nm] give partial
results and are used recently for very superficial atrophic scars
• Nonablative lasers: Nonablative fractional lasers are represented by the Fraxel®
1,500 nm. The impacts are extremely small and cause photocoagulation
columns by thermolysis. Consequences are minor with erythema, sometimes
a discreet edema that lasts for 3 or 4 days without social eviction. It has also
been noted an improvement in scar hypopigmentation
• Ablative lasers: They are mostly used for the treatment of atrophic acne scars.14
|| The continuous ablative lasers having been demonstrated to be the more
effective are the carbon dioxide (CO2) 10,600 nm and radium YAG
2,050 nm. As with the mechanical dermabrasion, the papillary dermis
214

must not be passed. Consequences are serious with scarring from the
pilosebaceous annexes, in 8 days for the CO2 laser and 5 days for the
erbium laser. The erythema lasts for several weeks, sometimes with a
transient pigmentation
|| Ablative fractional lasers are more recent; they include CO2 or erbium
lasers that have broader impacts, and spray dermo-epidermal columns

causing a thin cutaneous cut. They have postoperative consequences, less
severe than ablative lasers, but nevertheless greater than with nonablative
fractional lasers with oozing and crusting for about 5 days. The treatment
only requires a topical local anesthetic. A recent review has compared
ablative and nonablative fractional lasers by reviewing the literature.
It demonstrates that ablative fractional lasers are the most effective
(between 26% and 83% for ablative lasers vs 26% and 50% for nonablative
lasers). However, the side effects are higher with ablative fractional lasers
(erythema, pigmentation, pain).15
Filling
The filling can only be done if the scars are flexible enough to allow lifting by a
filling agent. It is indicated in M-shaped scars. The most frequent filler is hyaluronic
acids with different forms but in the future, an interesting approach could be
the use of stem cells that are undifferentiated cells, which have the important
properties of self-renewal and differentiation. Among them, adipose-derived stem
cells (ADSC) have relative advantages in accessibility and abundance compared
to other stem cell types. ADSC were shown to have antioxidant, whitening and
wound healing effects in the skin through secretion of growth factors and by
activating fibroblasts. Subcutaneous injection of ADSC significantly increased
collagen synthesis in hairless mice, dermal thickness, collagen density and
fibroblast number. In addition, procollagen type I increased. Thus, these results
suggest that ADSC could be of interest in the future for acne scars in addition of
ageing.16
HYPERTROPHIC SCAR TREATMENT17

For both hypertrophic and keloid scars, the care is identical to that of hypertrophic
scars from other origins, including:
• Compression, with notably silicone plates, or in the extended forms, a
compressive dressing
• Delayed intralesional steroid or bleomycin injections
• Cryotherapy and cryosurgery are only moderately effective. Cryosurgery is
especially useful on the face
215

Dréno
• Intense pulsed light seems to give good results

• Pulsed dye laser is only interesting in simply hypertrophic scars by targeting
their vascular components
• Surgical excision of keloids can be discussed. It is here usually associated
with either a brachytherapy or the implementation of an immunomodulatory
treatment, imiquimod.
Regarding topical treatments, retinoids are suited and in particular for post-
inflammatory pigmentation.18 Finally, it is important to remember that the
best scar treatment to date remains prevention by an early treatment. Acne scar
treatment remains indeed most often complex.19
CONCLUSION
In conclusion, acne scars are primarily linked to the inflammation size and
duration at the pilosebaceous follicle level. They are the primary reason for patient
consultation. The outcome remains often partial, justifying their prevention
through an early acne treatment.
Editor’s Comment
Acne causes scarring and severe and persistent acne causes more scarring is succinctly
brought out by Professor Brigitte Dreno who is an undisputed expert in this field.
She has admirably classified acne scars and enumerated all the treatment approaches
possible. However, I would like to draw attention to a few points that may interest
clinicians.
Acne scars frequently co-exist with active acne; this impacts majorly on the timing
when to initiate scar treatment and also on the selection of treatment modalities. In
general, there is a tendency to defer scar treatment till the condition has been brought
well under control, a desirable situation that is increasingly becoming elusive as can
be imagined from the rising prevalence of adult acne most of which is persistent
adolescent acne. An acne patient may have more than one type of scar often in the
same anatomic site. Atrophic scars are peculiar to the face and the hypertrophic scars
to the torso (shoulders, upper back, and sternal area). There are exceptions though,
namely, hypertrophic scars occurring over jaw angles and atrophic scars occurring on
the torso (macular atrophy). There are acne scars that defy Jacob classification; these
include follicular pits (common), stellate and honeycomb scars (rare), and papular
scars (peculiarly on the chin, nose and sternal area).
Time is a good healer for many acne scar patients! Lastly, skin color often comes
in the way when choosing the treatment modality.
Raj Kubba
216

REFERENCES
1. Chivot M, Pawin H, Beylot C, Chosidow O, Dreno B, Faure M, et al. [Acne scars: epidemiology, physiopathology,
clinical features and treatment]. Ann Dermatol Venereol. 2006;133:813-24.
2. Goodman GJ. Management of post-acne scarring. What are the options for treatment? Am J Clin Dermatol.
2000;1:3-17.
3. Baum CL, Arpey CJ. Normal cutaneous wound healing: clinical correlation with cellular and molecular
events. Dermatol Surg. 2005;31:674-86.
4. Layton AM, Henderson CA, Cunliffe WJ. A clinical evaluation of acne scarring and its incidence. Clin Exp
Dermatol. 1994;19:303-8.
degradation mediated by activated transcription factors nuclear factor-kappa B and activator protein-1 in
inflammatory acne lesions in vivo. Am J Pathol. 2005;166:1691-9.
6. Jacob CI, Dover JS, Kaminer MS. Acne scarring: a classification system and review of treatment options.
J Am Acad Dermatol. 2001;45:109-17.
7. Dreno B, Khammari A, Orain N, Noray C, Mérial-Kieny C, Méry S, et al. ECCA grading scale: an original
validated acne scar grading scale for clinical practice in dermatology. Dermatology. 2007;214:46-51.
8. Goodman GJ, Baron JA. Postacne scarring—a quantitative global scarring grading system. J Cosmet
Dermatol. 2006;5:48-52.
9. Finlay A, Torres V, Kang S, Bettoli V, Dreno B, Goh CL, et al. Classification of acne scars is difficult even for
acne experts. J Eur Acad Dermatol Venereol. 2012. [Epub ahead of print].
10. Thiboutot D, Gollnick H, Bettoli V, Dréno B, Kang S, Leyden JJ, et al. New insights into the management
of acne: an update from the Global Alliance to Improve Outcomes in Acne group. J Am Acad Dermatol.
2009;60:S1-50.
11. Batra RS. Surgical techniques for scar revision. Skin Therapy Lett. 2005;10:4-7.
12. Lee JB, Chung WG, Kwahck H, Lee KH. Focal treatment of acne scars with trichloroacetic acid: chemical
reconstruction of skin scars method. Dermatol Surg. 2002;28:1017-21.
13. Bhalla M, Thami GP. Microdermabrasion: Reappraisal and brief review of literature. Dermatol Surg. 2006;
32:809-14.
14. Alster T, Zaulyanov L. Laser scar revision: a review. Dermatol Surg. 2007;33:131-40.
15. Ong MW, Bashir SJ. Fractional laser resurfacing for acne scars: a review. Br J Dermatol. 2012;166:1160-9.
16. Kim JH, Jung M, Kim HS, Kim YM, Choi EH. Adipose-derived stem cells as a new therapeutic modality for
ageing skin. Exp Dermatol. 2011;20:383-7.
17. Leventhal D, Furr M, Reiter D. Treatment of keloids and hypertrophic scars: a meta-analysis and review of
the literature. Arch Facial Plast Surg. 2006;8:362-8.
18. Elson ML. The role of retinoids in wound healing. J Am Acad Dermatol. 1998;39:S79-81.
19. Kang WH, Kim YJ, Pyo WS, Park SJ, Kim JH. Atrophic acne scar treatment using triple combination therapy:
dot peeling, subcision and fractional laser. J Cosmet Laser Ther. 2009;11:212-5.
217

Acneiform Drug Eruptions

*Devinder Mohan Thappa MD DHA MNAMS, Munisamy Malathi MD
Department of Dermatology and STD, Jawaharlal Institute of
Postgraduate Medical Education and Research ( JIPMER), Puducherry, India
ABSTRACT
Acneiform eruptions are acute-onset cutaneous eruptions resembling
acne vulgaris but associated with the absence of comedones usually. These
eruptions can arise due to a host of causes with iatrogenic or drug-induced
acneiform eruptions being the most common cause. An extensive list of
drugs has been implicated to either exacerbate acne or induce acneiform
eruptions, and this list is never ending with the introduction of newer
drugs for various diseases. The classical description of acneiform drug
eruptions is monomorphic papulopustular eruption involving seborrheic
and non-seborrheic areas, with resistance to conventional therapies and
characteristically resolving with cessation of therapy. Hence, acneiform
drug eruptions need to be considered in all cases of refractory acne and a
detailed drug history including over-the-counter medications is essential
in evaluating such patients. The treatment of this condition is challenging,
as the decision to withdraw the drugs should be based on risk-benefit
assessment with an equal consideration given to the psychosocial impact
of the disease.
INTRODUCTION
Acne vulgaris is one of the most commonly encountered cutaneous eruptions
by the dermatologists. Acne-like eruptions known as acneiform eruptions are
used to describe eruptions that typically begin with inflammatory lesions like
papulopustules, cysts or nodules, completely bypassing the comedo stage in their
pathogenesis, in most of the cases.1 They can be associated with a wide spectrum
of disorders ranging from infections to drug eruptions to malignancies to growth
anomalies. Hence, the therapeutic modalities designed to modify the pathogenesis
Email: dmthappa@gmail.com

of acne vulgaris would be of little value in acneiform eruptions, necessitating an

accurate diagnosis.
Acneiform drug eruptions, accounting for about 1% of all drug-induced skin
eruptions,2 represent the most common differential diagnosis of acneiform
eruptions and a variety of medications have been implicated in causing these
eruptions.
ETIOPATHOGENESIS OF ACNEIFORM DRUG ERUpTIONS

A wide variety of drugs have been implicated to cause acneiform eruptions
(Table 1) but the list is exhaustive and practically any drug can cause acneiform
Table 1: Drugs Reported to Cause Acneiform Eruptions2-4

Drug group Drugs implicated
Hormones • Steroids: Topical, systemic, inhaled
• ACTH
• Growth hormone
• Synthetic androgens and anabolic steroids: Danazol, stanozolol,
nandrolone
• Hormonal contraceptives: Progesterone, levonorgestrel5
Psychotropic Lithium, amineptine, chlorpromazine, maprotiline, escitalopram,6
medications aripiprazole,7 olanzapine, pimozide, risperidone, selective serotonin
reuptake inhibitors
Biologically targeted • EGFR inhibitors:8 Cetuximab, panitumumab, matuzumab,
chemotherapeutic nimotuzumab
agents • Tyrosine-kinase inhibitors:8 Gefitinib, erlotinib, canertinib,
lapatinib, sorafenib, sunitinib, vemurafenib,9 imatinib
• VEGF inhibitor: Bevacizumab
• Proteasome inhibitor: Bortezomib
• TNF-a inhibitors: Lenalidomide, infliximab
• Histone deacetylase inhibitor: Vorinostat
Anticonvulsants Phenytoin, phenobarbitone, primidone, carbamazepine, valproate,
lamotrigine,10 troxidone, gabapentin, topiramate
Antitubercular drugs Isoniazid, rifampicin, ethionamide, pyrazinamide
Vitamins Vitamins B1, B6, B12 and D
Halogens Bromides and iodides in cough preparations and other over-the-
counter preparations
Immunomodulators Tacrolimus, pimecrolimus, cyclosporine, sirolimus
Cytostatic drugs Cyclophosphamide,11 azathioprine, capecitabine,12 dactinomycin,
thiouracil, thiourea, pentostatin
Miscellaneous Dantrolene,13 celecoxib,14 naproxen, chloroquine, disulfiram,
quinidine, ritonavir, ganciclovir, itraconazole, quinine, ramipril,
buserelin, cabergoline, isosorbide, famotidine, clofazimine,
mesalazine, nilvadipine, nimodipine, PUVA therapy
ACTH, adrenocorticotropic hormone; EGFR, epidermal growth factor receptor; VEGF, vascular endothelial
growth factor; TNF-a, tumor necrosis factor alpha; PUVA, psoralen-ultraviolet A.
219

Thappa and Malathi
eruptions, and newer drugs (for example, targeted therapies used in oncology) are
continuously being added to the list (Figures 1–5).
In general, the postulated mechanism of drug-induced acneiform eruptions
is injury to the follicular epithelium, with subsequent rupture of the follicular
contents into the dermis, resulting in an inflammatory reaction forming the initial
inflammatory papule clinically.1 However, individual drugs can have specific
mechanisms playing a role in the pathogenesis of acneiform eruptions, the most
common and important ones—steroids, lithium and epidermal growth factor
inhibitors will be discussed.
A B
Figure 1A and B: Lower face acne aggravated by topical

pimecrolimus – a rare occurrence. Courtesy of Dr Raj Kubba,
Delhi Dermatology Group, New Delhi, India.
Figure 2: Panfacial inflammatory acne

attri
buted to Lamotrigine being given for
epilepsy. Courtesy of Dr Raj Kubba, Delhi
Dermatology Group, New Delhi, India.
220

Figure 3: Sebaceous hyperplasia and

sporadic acne on account of prolonged
testosterone supplements (over 40 years)
following testicular torsion in early adult life.
Courtesy of Dr Raj Kubba, Delhi Dermatology
Group, New Delhi, India.
Figure 4: V-zone acne and melasma-like

hyperpigmentation triggered by Ormeloxifene,
a selective estrogen receptor modulator,
given for fibroids and dysfunctional uterine
bleeding (DUB). Courtesy of Dr Raj Kubba,
Delhi Dermatology Group, New Delhi, India.
Steroid acne is reported to occur with topical, inhaled and oral steroids. It
has been suggested that glucocorticoids enhance toll-like receptor-2 expression
in human keratinocytes stimulated by Propionibacterium acnes or proinflammatory
cytokines, resulting in acne.15 Pityrosporum ovale infection of pilosebaceous unit
has also been proposed to be associated with steroid acne.16
In patients taking lithium, a ten-fold higher content of lithium has been
demonstrated in the acneiform lesions along with pathological findings of
neutrophilic infiltration in the epidermis in these lesions. Thus acneiform eruptions
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Thappa and Malathi
Figure 5: Adult acne triggered by HRT

given for primary ovarian failure. Courtesy
of Dr Raj Kubba, Delhi Dermatology Group,
New Delhi, India.
may be the result of increase in circulating neutrophils and neutrophil chemotaxis

associated with lysosomal release from leukocytes.17,18
Epidermal growth factor receptor (EGFR) inhibitors used for the treatment
of advanced stages of solid malignancies are frequently associated with acneiform
eruptions as their most common side effect. The severity of eruptions parallels
the tumor response and patient survival, especially with cetuximab and erlotinib.
Thus acneiform eruptions in these cases can be used as surrogate markers of tumor
inhibition and also as a yardstick to determine the optimal biologic dose based on
a dose-to-rash strategy. EGFR plays an important role in normal skin homeostasis
and direct EGFR inhibition results in upregulation of cell-cycle inhibitor p27 that
causes alterations in cell growth and differentiation resulting in changes in the
stratum corneum of the follicular infundibulum, causing hyperkeratosis, abnormal
desquamation, follicular plugging with bacterial overgrowth, with the clinical
development of acne-like lesions.8,19-21
CLINICAL FEATURES
Drug-induced acneiform eruptions usually manifest as abrupt onset of mono
morphic lesions in the form of papules, pustules, nodules and very rarely comedones,
on unusual body sites extending beyond the seborrheic regions, at quite an unusual
age (usually adulthood). There will be history of lesions occurring after drug intake
and history of resistance to conventional anti-acne therapy. Comedones, which are
pathognomonic of acne vulgaris, are not the primary lesions in acneiform eruptions
and they can occur as secondary lesions subsequent to the inflammation.2,3
222

Du-Thanh et al.3 have proposed certain characteristics of acneiform drug

eruptions that would aid in making a diagnosis by establishing the potential
relationship between drug ingestion and acne, which are as follows:
• Anamnesis
Unusual age of onset: before or after adolescence and early adulthood
||
(age > 30 years)

|| Abrupt onset of acne in the absence of past history of acne vulgaris or
unusual severe flare in a patient with a past history of mild acne vulgaris or
exacerbation of preexisting acne
• Clinical presentation of acne
|| Monomorphic, inflammatory lesions with papules, pustules, nodules as
primary lesions
|| Absence of comedones and cysts or their late appearance as secondary to
inflammatory lesions
|| Atypical sites of occurrence: extending beyond the seborrheic area such as
the arms, trunk, lower back and even genitalia

• Resistance to conventional acne therapy
• Time relationship
|| Onset after recent drug implementation
|| Improvement after drug withdrawal
|| Recurrence after drug reintroduction.
Steroids (topical/systemic) can induce as well as worsen acne and usually

present within 2–4 weeks of starting steroids or after several months. Factors
that were found to promote the development of steroid acne with topical steroids
include high concentrations, continuous occlusion, young adults below age of
30 years, whites in preference to blacks, history or signs of acne and applications
to acne prone areas of face and upper back.22 Acneiform eruptions related to
systemic and inhaled steroids are dose related.23 Steroid acne manifests as multiple
minute folliculocentric papules and pustules on an erythematous base with most
of them at the same stage of development. The scalp, trunk, shoulders and upper
arms are often involved and the face is often spared. Comedones, scars, nodules
and cysts are uncommon, while itching and postinflammatory hyperpigmentation
are common.16,23
“Doping acne” or “body building acne” should be suspected in young athletic
men who abuse both oral and intramuscular anabolic androgenic steroid (AAS).
AAS-induced acne includes the face, shoulders, chest and back. The lesions of
AAS-induced acne do not always respond to routine therapy and may persist for
weeks to months following discontinuation of the drugs. However, continued use
of AASs even after acne develops can delay its resolution or can precipitate acne
fulminans and acne conglobata.24
223

Thappa and Malathi
Lithium causes both flares of acne as well as acneiform eruption within

few weeks of starting treatment and these are the most commonly encountered
cutaneous adverse effects of lithium. These eruptions are dose-dependent and
more common in males, in younger patients between 20 years and 30 years of
age, and in those with a personal or family history of severe acne. The lesions are
persistent, noncyclical pustules with characteristic absence of comedones or cysts,
predominantly occurring over the limbs and trunk. These lesions usually regress
in 1 month after dose adjustment and sometimes may even subside with ongoing
therapy with lithium.17,18
Epidermal growth factor receptor inhibitors associated acneiform eruptions
classically have an onset between 1 week and 3 weeks of treatment and the onset
can extend up to a maximum of 5 weeks. They usually resolve within 4 weeks
after withdrawal of treatment, but may have a waxing and waning course. The
typical rash presents as inflammatory papules and pustules without comedones on
seborrheic areas of the face. It can rapidly spread to the scalp, trunk, buttock and,
more rarely, the limbs in a cephalocaudal progression. Palms, soles and mucosa
are classically spared. The rash can be pruriginous, crusted or hemorrhagic. The
reaction is well tolerated and is usually associated with minimal discomfort or
pruritus. There are no reports of scarring but residual hyperpigmentation has been
noted in some patients. Spontaneous improvement with progressive resolution
or stabilization of the rash can occur with continued treatment, and with long-
term administration, there may also be a decrease in the severity of subsequent
lesions. Both incidence and severity of rash are dose-dependent but there is no
relationship of the rash to treatment duration.8,19-21
The acneiform rash of EGFR inhibitors is graded based on the National
Cancer Institute Criteria for Adverse Events (CTCAE) version 4.03 as follows:25
• Grade 1: Papules and/or pustules covering less than 10% body surface area
(BSA), which may or may not be associated with symptoms of pruritus or
tenderness
• Grade 2: Papules and/or pustules covering 10–30% BSA, which may or may
not be associated with symptoms of pruritus or tenderness; associated with
psychosocial impact; limiting instrumental activities of daily living (ADL)
• Grade 3: Papules and/or pustules covering greater than 30% BSA, which may
or may not be associated with symptoms of pruritus or tenderness; limiting
self-care ADL; associated with local superinfection with oral antibiotics
indicated
• Grade 4: Papules and/or pustules covering any percent BSA, which may or may
not be associated with symptoms of pruritus or tenderness and are associated
with extensive superinfection with intravenous antibiotics indicated; life-
threatening consequences
• Grade 5: Death.
224

Although this criterion allows for quick severity estimation of a patient, yet
it is not suitable for monitoring the severity of the skin lesions over time. Hence
a new scoring tool with score ranging between 0 and 100 has been proposed by
Wollenberg et al.,26 which is calculated from body involvement, facial involvement
and clinical grading of the skin features like erythema, papulation, pustulation
and scaling/crusts. This score might be useful in clinical practice to follow-up the
clinical course of patients during the different therapeutic approaches.
Halogenodermas are rare dermatoses that develop following exposure to
bromides, fluorides and iodides and they may present as acneiform eruptions
with papulopustules or pustules in the seborrheic areas. These eruptions are dose
related and usually occur within a few weeks of ingestion of iodides but may
take a very long interval as late as 8–12 months. Halogenodermas may persist
for weeks after drug withdrawal because of the slow elimination rates but there
is complete disappearance of the lesions after cessation of drugs. Rarely, it may
warrant systemic steroids in persistent cases.27,28
DIFFERENTIAL DIAGNOSIS
Drug-induced acneiform eruptions need to be differentiated from other conditions
for two main reasons: first, the decision to withdraw the drug is challenging and
second, the approach to treatment is different. The differential diagnosis for
acneiform eruptions is extensive and the distribution of the lesions and the age
of the patient are the main characteristics that may provide strong clues to the
etiology.
• Acne vulgaris: It is characterized by pleomorphic lesions, ranging from
comedones to inflammatory papules, pustules and nodules, usually affecting
boys and girls around puberty, but may arise or persist in adulthood. It involves
the pilosebaceous units of the face and trunk and microcomedo formation is
the initial pathology, subsequently resulting in inflammation. Table 2 compares
and contrasts the features of acne and acneiform drug eruptions29-32
• Rosacea: It is a chronic acneiform disorder of the facial pilosebaceous unit
coupled with capillary hyper-reactivity, resulting in episodic facial flushing
and telangiectasias with a female predilection and a peak incidence between
40 years and 50 years of age. Absence of comedones and involvement of central
face differentiate the papulopustular lesions from acne29-32
• Perioral dermatitis: It is acneiform eruption of unknown etiology common
in young women manifesting as asymptomatic micro-papulo-pustules and
micro-papulo-vesicles with erythematous bases predominantly located around
the mouth, characteristically sparing the vermilion border of the lip. It may
also affect the perinasal and periorbital areas (periorificial dermatitis). They are
225

Thappa and Malathi
Table 2: Differentiation between Acne and Acneiform Drug Eruptions

Features Acne Acneiform drug eruptions
Onset Gradual Rapid
Age at onset Adolescence Adulthood or later
Morphology of lesions Pleomorphic Monomorphic
Primary lesion Comedones Inflammatory papules and pustules
Secondary lesion Inflammatory papules, Postinflammatory comedones
pustules, nodules, cysts
Scar Common Absent to minimal
Site Pilosebaceous units of Atypical locations
face and trunk
Treatment Respond well to Resistant to conventional anti-
conventional anti-acne acne therapy; resolve when drugs
therapy withdrawn
Course Prolonged Resolution immediately on withdrawal;
sometimes can persist for few months
after withdrawal
usually associated with the use of fluorinated topical or inhaled corticosteroids,

moisturizers and contact irritants or allergens29-32
• Infections and infestations:
|| Staphylococcal folliculitis: They present as abrupt onset of small, well
circumscribed, dome-shaped, often monomorphic pustules in clusters on

beard area, trunk and buttock. Sycosis barbae or deep follicular infections
present as painful erythematous nodules involving the beard area and
healing with scarring29-31
|| Gram-negative folliculitis: It commonly presents as sudden deterioration of
the acne or a persistent papulopustular eruption in patients on prolonged

antibiotics for acne, more commonly in males. The organisms implicated
include Escherichia coli and Klebsiella, Enterobacter and Proteus species29-31
|| Pityrosporum folliculitis: It presents as follicle-based pustules primarily
on the trunk and upper extremities of late adolescents and young adults
associated with pruritus and responds to appropriate antifungal therapy
rather than to antibiotics29-31
|| Secondary syphilis: Pustular acneiform secondary syphilis has been reported
manifesting as generalized acne-like skin eruption on the trunk, extremities

and face33
|| Sporotrichosis: The fixed variety of sporotrichosis can manifest as acneiform
eruptions localized to the point of inoculation that may involve the face,
apart from nodular, ulcerated or verrucous lesions34,35
226

|| Cutaneous coccidiodomycosis: Lesions in primary cutaneous or disseminated

coccidiodomycosis can present as acneiform papules, rosacea-like lesions
apart from the classical verrucous plaques or granulomatous lesions36
|| Atypical mycobacterial infections: Mycobacterium chelonae infection has been
reported to present with atypical acneiform lesions, characterized by

pustules, nodules and scattered hemorrhagic crusts in a immunosuppressed
patient (on oral steroids) after laser resurfacing and acne conglobata-like
lesions in an immunocompetent patient37,38
|| Demodicidosis: It occurs in immunocompetent middle-aged or older
women who use excessive facial cosmetics, and in immunocompromised

individuals as papulopustular eruptions, resembling rosacea or perioral
dermatitis and pityriasis folliculorum. They commonly involve the
seborrheic regions such as the nose, temporal regions, nasolabial folds,
periorbital areas and less commonly the upper and medial region of the
chest and back39,40
• Eosinophilic pustular folliculitis: It is a disease of unknown etiology, probably
due to allergic hypersensitivity, manifesting as recurrent, pruritic, follicular
papulopustular eruption on the face, trunk and proximal extremities29,30
• Pseudofolliculitis barbae: It is a foreign body reaction to the ingrowth of
obliquely cut, tightly curled hair presenting with erythematous papules in the
beard area29,30
• Autoimmune diseases:
|| Behçet’s disease: Acneiform eruptions are the second common cutaneous
manifestations of Behçet’s disease next to erythema nodosum, and they

are more common in males, unlike erythema nodosum which is common
in females. The papulopustular eruptions are more common in trunk,
upper and lower extremities, and genitalia. One of the minor criteria of
the international study group criteria for diagnosing Behçet’s disease
includes pseudofolliculitis or papulopustular lesions; or acneiform nodules
observed by the physician in a postadolescent patient who is not receiving
corticosteroid treatment41,42
|| Lupus erythematosus: An unusual variant of discoid lupus erythematosus
(DLE) can manifest with comedones and inflammatory papules on the face
or with acneiform pattern of pitted scarring. Systemic lupus erythematosus
has been reported to present as treatment-resistant acne characterized by
inflammatory follicular papules and hypopigmented macules on the face
and neck43
• Infiltrative disorders:
|| Follicular mucinosis: It can present as chronic eruption with multiple small
discrete papules, reminiscent of acne while the classical presentation is

grouped follicular papules associated with alopecia44
227

Thappa and Malathi
Lipoid proteinosis: It can manifest as papulonodular lesions and acneiform

||
icepick scars, located on the cheeks, forehead and chin, easily mistaken
for persistent acne. The lesions are waxy deposits prominently seen in the
face and eyelid margin as beaded eyelids, and in areas prone to trauma and
movements like knees, elbows, hands and feet45
• Malignancies:
|| Primary cutaneous follicle center lymphoma: It has been reported to present
as multiple folliculocentric, pseudo-pustules on the forehead, cheeks and

chin as an unusual acneiform presentation in two reports46,47
|| Folliculotropic mycosis fungoides: It can present as acneiform lesions,
comedones, cysts, pustules, keratosis pilaris-like lesions, follicular

mucinosis-like plaques and alopecia, more commonly in elderly males,
involving the head and neck areas48
• Developmental anomalies:
|| Nevus comedonicus: It is a rare type of nevus presenting with aggregated
open comedones consisting of dilated follicular or eccrine orifices plugged

with keratin29,35
|| Acneiform nevus: It is a variant of nevus comedonicus presenting as unilateral
segmental nevus with multiple comedones as well as inflammatory papules

and pustules in linear or whorled pattern along the lines of Blaschko49
|| Becker’s nevus: It is an androgen sensitive acquired epidermal nevus with
onset at puberty characterized by hairy, hyperpigmented macule associated

with acneiform eruptions localized to the nevus50
|| Apert’s syndrome: It is rare malformation syndrome characterized by
craniosynostosis, symmetric severe syndactyly and cutaneous manifestations

like acneiform eruptions, hyperhidrosis, plantar hyperkeratosis, excessive
forehead wrinkling. The acneiform lesions are diffuse follicular papules
involving the face, upper trunk, forearms, buttocks, and thighs and tend to
be unusually resistant to pharmacologic therapy. Acneiform lesions have
also been reported to occur in a nevoid distribution pattern51
|| Eruptive vellus hair cysts: They are hereditary anomalous vellus hair follicles
presenting as flesh-colored papules usually on the face, chest, neck, thighs,

groin, buttocks and axillae. They may undergo spontaneous regression, form
a connection to the epidermis, or undergo degradation with a resultant
foreign body granulomatous formation29,35
• Diet-related acneiform eruptions:
|| Kelp acne: “Kelp”, a large sea weed commonly used in Thai, Chinese, Japanese
cuisines and in hair loss supplements, results in acneiform eruptions due to

its 20 times higher concentration of iodine than in other foods4,52
|| Japanese oil disease or Yusho: An outbreak of this disease characterized by
acne-like eruptions, pigmentation of the skin and increased eye discharge
228

due to consumption of rice bran oil contaminated by Kanechlor occurred

in western part of Japan53
|| Iodized salt: Prolonged administration of a small dose of iodide may
provoke an acneiform eruption which needs to be considered while

evaluating refractory postadolescent acne54
• Post-facial beauty parlor treatment: Acneiform eruptions presenting with
predominantly deep-seated nodules and a few comedones occurring mainly
on the cheeks are common in postadolescent age group females after a facial
beauty treatment55
• Other subtypes of acne: Chloracne, tar acne, radiation acne, Favre-Racouchot
syndrome, acne aestivalis, tropical acne are important differentials for
acneiform eruptions51
• Miscellaneous conditions: Certain conditions that can be mistaken for acne
include lupus miliaris disseminatus faciei, papular sarcoidosis, adenoma
sebaceum in tuberous sclerosis, benign adnexal tumors such as syringoma and
multiple trichoepitheliomas.35
TREATMENT
Discontinuation of the implicated medication would result in resolution of the
acneiform eruptions in majority of the cases. But, stoppage of the drug may not
be possible practically, as benefits of the drug might outweigh the benign adverse
effect in the form of acneiform eruptions. On the other hand, the individual
patient’s cosmetic concern should be taken into consideration as acneiform
eruptions can be an important cause of poor compliance due to psychosocial
consequences, especially in young adults, jeopardizing the treatment of the
primary condition. Hence, these issues need to be discussed with the patient prior
to starting him/her on drugs commonly implicated in causation of acneiform
eruptions, to ensure compliance.
For steroid acne, therapy consists of discontinuing the causative drug
when medically feasible. Topical antibacterials are of not much use, while oral
antibacterials may speed up the resolution and topical benzoyl peroxide might
be beneficial. Topical retinoids may cause a slow (1–3 months) resolution of the
lesions despite continuation of steroids. If persistently unresponsive, a trial of
antifungals might be helpful owing to the association of pityrosporum folliculitis
with steroid acne. Treatment of acne induced by inhaled corticosteroids is
disappointing and alteration of dosage or tapering of the daily dosage may improve
the condition.16,23,24
For lithium-induced acne, various topical and oral treatments have been tried,
but none have been consistently effective and topical tretinoin may be beneficial.
Persistently poor response to anti-acne therapy may require dose reduction
229

Thappa and Malathi
or discontinuation of lithium. Tetracycline should be avoided because of the

interaction with lithium, with subsequent nephrotoxicity and elevation of lithium
levels to the toxic range.17,18
For amineptine associated acneiform eruptions, isotretinoin at a dose of
0.5–1 mg/kg/day for 6 months is recommended as a specific therapy along with
surgical removal of the macrocysts.56
Treatment of acneiform eruption associated with EGFR inhibitors depends
on the severity grading—except for Grade 1, intervention is required for the other
grades. Tetracyclines in combination with topical corticosteroids can be used to
control severe lesions but their efficiency can be limited. Oral minocycline has been
shown to be useful in decreasing the severity of the eruption during the first month
of treatment. Preventive treatment with oral doxycycline was found to reduce the
severity with no effect on the incidence of acneiform rash as well as on the efficacy
of EGFR inhibitor.8,19-21 Traditional acne medications, including isotretinoin, can
be used successfully but with caution until further research on EGFR signaling
pathways in tumors is delineated. A colloidal solution, containing finely milled
oatmeal (avena rhealba) particles in suspension with antiinflammatory properties
has been shown to be effective in the management of acneiform eruptions caused
by these agents.57
CONCLUSION
Acneiform drug eruptions should be suspected in cases of monomorphic acne-like
eruptions which are acute in onset, arising in atypical locations, in the absence
of comedones, at an unusual age at onset for acne and refractory to conventional
anti-acne therapy. These eruptions usually resolve when the implicated drug is
withdrawn, but sometimes can last up to several months after withdrawal. The
challenging issue in the management is the decision to continue or withdraw the
implicated drug which should be left to the discretion of the physician treating
the primary condition.
Editor’s Comment
Acneiform eruptions are often misdiagnosed as acne (but remember age, unusual
sites, monomorphicity and absence of comedones are clinchers!)and pityrosporum
folliculitis. They are most commonly iatrogenic, being triggered by drugs. Professor
DM Thappa and Dr M Malathi have looked at acneiform eruptions in an organised
way, dwelling on their etiology, clinical features, classification and then discussing
in details the differential diagnosis. And this is probably the longest discussion
I have seen recently in the management of acneiform eruption. So happy reading!
Neena Khanna
230

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233

The Role of Dermocosmetics in

Modern Acne Treatment
*Giuseppe Micali MD, Federica Dall’Oglio MD PhD,
Aurora Tedeschi MD PhD
Dermatology Clinic, University of Catania, Italy
ABSTRACT
Cosmetic treatment for acne, if correctly prescribed and used, may have
a synergistic effect with standard dermatological treatment. The cosmetic
approach for acne includes hygiene and cleansing, with a non-comedogenic,
non acnegenic, non-irritating and non-allergenic cleanser. In addition,
the use of sebum controlling agents may be considered to minimize
excessive sebum production. Topical corneolytics induce a comedolytic
effect and may also facilitate skin absorption of topical drugs. Cosmetics
with antimicrobial and antinflammatory properties may enhance clinical
outcome, whereas moisturizers specifically designed for acne patients may
counterbalance xerosis caused by other treatments. The use of specific
photoprotective agents and shaving products should also be encouraged.
Finally, tailored camouflage make-up technique using non-comedogenic
products may minimize the esthetic problem associated with acne and
improve patients’ self-esteem and adherence to treatment.
INTRODUCTION
The use of cosmetics plays an important role in the management of acne, and if
correctly prescribed, may contribute to clinical improvement, whereas their misuse
may aggravate the disease.1,2 In order to avoid cosmetics and/or procedures that may
worsen acne, it is necessary to teach patients to use the most appropriate cosmetics,
chosen in consideration of ongoing pharmacological therapy as well as acne type
and severity. Recent data have shown that many cosmetic products previously
thought to be inert have effects on the skin and the term “cosmeceuticals”, has been
Email: cldermct@nti.it

The Role of Dermocosmetics in Modern Acne Treatment
introduced. They “may have little pharmaceuticals activity and minimal potential
side effects and would be prescribed for those indications in which cosmetics are
usually indicated”.3 The Federal Food, Drug and Cosmetic Act does not recognize
the “cosmeceutical” term, for these reasons cosmeceuticals are still classified either
as drugs or cosmetics. In this article, we will discuss about cosmetics for acne,
highlighting for each substances any evidence in the literature either as citation
or review, article or book chapter, or as results from in vitro and in vivo studies.
The cosmetic approach for acne includes hygiene and cleansing products, topical
sebum controlling, corneolytics, antimicrobial, antiinflammatory and moisturizers
agents specifically designed for acne patients. The use of specific photoprotective
agents and shaving products should also be encouraged. Finally, tailored camouflage
makeup technique using noncomedogenic products may minimize the esthetic
problem associated with acne and improve patients’ self-esteem and adherence to
treatment.
MATERIALS AND METHODS

A thorough revision of the literature on matched electronic databases (PubMed,
MEDLINE) using the keywords “cosmetic and acne” or “cleanser” or “sebum”
or “antimicrobial” or “antiinflammatory” or “corneolytic” or “moisturizers” or
“photoprotective”, “shaving” and “camouflage” and “agents word” and “acne”
and “placebo”, “comparative”, “double-blind”, “single-blind”, and “in vivo” and
“in vitro” studies were performed. In vitro studies were cited only if the tested
substance showed in vivo evidence of clinical efficacy. Trials on efficacy of drugs
or over-the-counter (OTC) agents were not considered, with the exception of
those few evaluating cosmetics versus drugs or OTCs. Retrieved studies were
classified based on the following evidence levels: IA = systematic review or meta-
analysis; IB = randomized controlled trial (RTC); IIA = controlled trial without
randomization; IIB = another type of experimental study; III = nonexperimental
descriptive studies, e.g. comparative studies, correlation studies and case-control
studies; IV = Expert committee reports or opinions or clinical experience of
respected authorities. Data from eligible studies then pooled and summarized in
synoptic tables. Substances with only in vitro evidence were not considered.
HYGIENE AND CLEANSING

Skin cleansing is an essential part of skin care. It consists of a procedure that
removes liposoluble, hydrosoluble and insoluble dirt through natural or synthetic
surfactants.1 Several types of cleansers are available with different mechanism
of action including surfactants, makeup remover, astringent cleanser and abrasive
cleanser. Surfactants could be natural (from animal or vegetal fats and divided
235

Micali et al
into anionic, cationic, ampholytic and nonionic) or synthetic (syndet) and are
commercially available as soaps, dermatologic bars or cakes, liquid or gel or foam
cleansers, superfatted soaps and lipid-free cleanser.
How to choose the most appropriate cleanser? It is important to note that
the use of aggressive and strong cleansers, often used to remove the typical acne
patient’s skin oiliness, can cause a paradoxal form of acne called “acne detergicans”.
Clinically characterized by papules, pustules and comedones, it is related to a
paradoxal sebaceous hypersecretion that in turn may result in increased chance for
growing pathogenic bacteria.
The ideal cleanser for acne patients should be noncomedogenic, non-
acnegenic, nonirritating and nonallergenic. The so-called “natural soap” (solid
or liquid natural anionic cleansers) should be avoided in acne patients because
of their strongly alkaline pH. The uses of syndet cleansers are preferred because
of their pH close to normal skin that provide a mild cleansing. Dermatologic
bars and specifically designed liquid, gel or foam cleansers for acne, are generally
synthetic surfactants, chemically different from natural soaps, obtained through
a sophisticated manufacturing process in which weak organic acids are added to
formulations in order to obtain a pH close to normal skin so as to provide a mild
cleansing. They may be enhanced with anti-acne agents such as benzoyl peroxide
(BPO), sebum controlling or corneolytics substances as well as moisturizers
and soothing agents.4 They are more expensive than natural soaps. Among the
different formulations, liquids are generally preferred to the solid ones because
they are milder and nonirritating; gel and foam formulations are in general well
appreciated by youngsters.
Other syndets are suitable for acne skin include superfatted soaps, rich in lanolin,
almond oil and glycerol, suggested by some authors, to improve the typical xerosis
observed during retinoid treatments and lipid-free cleansers characterized by no
fragrances, colorants and preservatives substances, best if used at the beginning of
therapy in order to facilitate cutaneous adaptation to treatments.5
Among makeup removers, cleansing milk is the most indicated for acne patients,
reminding that they require rinse with water or the subsequent use of astringent
lotions. Recent makeup remover formulations for acne include water solutions
enhanced with corneolytic or soothing agents. They are well-tolerated and do not
require rinse.5 Astringents or toners are lotions containing alcohol or propylene
glycol. They are used after lipid-free or milk cleanser to remove other cleanser
residues. The so-called “earth-based mask” containing absorbent products such
as clay, bentonite or kaolin, belongs to this category of cleanser. Finally, abrasive
cleansers are mechanical exfoliants, including vinyl masks and scrubs that remove
insoluble dirt or induce a comedolytic effect.6
Eight clinical trials (CTs) on cleansers (Level IB = 4; Level IIA = 1; Level III
= 3) listed in Table 1 have been found.7-14
236

Table 1: Cleansers for Acne
Agent In vitro studies In vivo studies
Author Author Study design Comments
Azelaic acid (1%) + – Choi Double-blind, placebo, RCT: • Level IB
World Clinic Dermatology (Acne).indd 237

Salicylic acid (1%) + 20107 1% azelaic acid (AzA) +1% salicylic acid (SA) + • Limited number of pts
Triclosan (0.04%) 0.04% triclosan (TC) cleanser vs placebo (twice • Biopsy proven clinical results
daily for 8w)
Benzoyl peroxide – Brummitt Double-blind, placebo, CT: • Level IIA
(4%-5%- 5.3%-6%- 19848 5% BPO solution wash vs 10% BPO solution wash
9.8%-10%) vs placebo (30s once daily for 4w)
Del Rosso Single-blind, crossover, RCT: • Level IB
20099 6% BPO foaming cloth cleanser switched to • High risk of bias
6% BPO cleanser switched to 4% BPO washes
(5’ single application)
Leyden 1) Open, CT: • Level III
201210 9.8% BPO foam “non leave-on” formulation (once
daily for 2w);
2) Open, comparative, CT:
9.8% BPO foam “non leave-on” vs 5.3% BPO
foam “leave-on” formulation (once daily for 2w)
Chlorhexidine – Stoughton 1) Comparative, RCT: • Level IB
gluconate 198711 4% chlorhexidine gluconate (CHG) cleanser vs 5%
(4%) BPO cleanser (twice daily for 12w)
2) Double-blind, placebo, RCT:
4% CHG cleanser vs placebo (twice daily for 12w)
Clay (% NS) + – Meier Prospective, CT: • Level III
Jojoba (% NS) 201212 clay jojoba facial mask (2–3 times/w for 6w)
Salicylic acid – Bettley Placebo, RCT: • Level IB
(2%) 197213 2% SA cream wash vs placebo (twice daily for 2 m)
Shalita Open, crossover, CT: • Level III
237
198914 2% salicylic acid (SA) cleanser for 2w switched
to 10% benzoyl peroxide (BPO) cleanser (once or
twice daily for 2w)
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Micali et al
SEBUM-CONTROLLING AGENTS
Sebum is the results of androgen-driven secretion by sebaceous glands. An
overproduction of sebum is frequently seen in acne patients. Drugs such as
systemic retinoids, birth-control pills and spironolactone are indicated to regulate
the overproduction of sebum. Topical sebum-controlling agents are cosmetic
products, which are used to absorb and retain sebum. Their action seems mostly
due to the presence of so-called “matifiant” agents like methacrylate copolymer
microsphere.1 Their role on 5a-reductase or on sebaceous glands activity has been
claimed, but this issue still needs to be confirmed.15
Among the various sebum controlling agents, two studies in vitro and nine
CTs (Level IB = 5; Level IIA = 2; Level III = 2) listed in Table 2 have been
identified.15-24
ANTIMICROBIAL AGENT
Topical antibiotic are commonly used for the management of moderate-to-
severe acne vulgaris. In order to optimize efficacy and to reduce the emergence of
Propionibacterium acnes resistance, topical antibiotics are most commonly used in
combination with antimicrobial-controlling agents.
Five studies in vitro and four CTs (Level IB = 3; Level IIA = 1) are listed in
Table 3.25-31
ANTIINFLAMMATORY AGENTS
Recent understanding in the pathogenesis of acne has suggested a pilot role of
inflammatory (IF) events in the development of acne lesions. Most of topical or
systemic pharmacological therapies for acne have also an antiinflammatory action
and the use of cosmetics with antiinflammatory properties may seems reasonable.
Ten studies in vitro and 19 CTs (Level IB = 10; Level II4 = 5; Level III = 4)
listed in Table 4 have been identified.20,23,24,28,32-53
CORNEOLYTICS
Corneolytics are cosmetics that cause intercorneocyte cell detachment so as to
induce a comedolytic effects. They include a-hydroxyacids such as glycolic acid
(GA), lactic acid (LA) and citric acid; b hydroxyacids like salicylic acid (SA) and
a-ketoacids such as pyruvic acid in concentrations varying from 2% to 7% and up
with GA as well as retinaldehyde (RAL) and retinol, at concentration of 1% or
less.4 This group of cosmetics is particularly indicated for comedonal acne, making
comedones more superficial and at the same time smoothing the skin. They
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Table 2: Sebum Controlling Agents
Green tea Mahmood Mahmood Open, CT: • Level III

(3%) 201016 201016 3% tea emulsion (twice daily for 8w)
Nicotinamide – Draelos Multicentre, double-blind, placebo, RCT: • Level IB
(2%) + Panthenol 200617 2% nicotinamide + 1% panthenol gel (NP) vs • Biophysical only assessment
(1%) placebo (twice daily for 4w)
Retinaldehyde – Poli Multicentre, double-blind, placebo, RCT: • Level IB
(0.1%) + Glycolic 200518 0.1% retinaldehyde (RAL) + 6% glycolic acid (GA) • Biophysical only assessment
acid (6%) (RALGA) emulsion vs placebo (once daily for 12w)
Serenoa repens Raynaud Dobrev Open CT: • Level III
(2%) 200715 200719 2% Serenoa repens cream-gel (twice daily for 4w)
Silicic acid – Lassus Double-blind, placebo, CT: • Level IIA

(%NS) 199620 Silicic acid gel vs placebo (20m twice daily for 6w)
Fernandez Double-blind, placebo, RCT: • Level IB
200521 silicic acid emulsion vs placebo (twice daily for 8w) • Biophysical, clinical and self-
assessment evaluation
Tetranoic acid (TA) – Burton Controlled, CT • Level IIA
(2%) 197022 2% TA solution vs no treatment (twice daily for 8 w)
Triethyl citrate – Charakida Double-blind, placebo, RCT: • Level IB

(% NS) + Ethyl 200723 triethyl citrate + ethyl linoleate + 0.5% salicylic acid • Biophysical only assessment
linoleate (% NS) + (TES) lotion vs placebo (twice daily for 12w
Salicylic acid (0.5%)
Zinc pyrrolidone – Capitanio Double-blind, placebo, RCT: • Level IB
(0.1%) + Laminaria 201224 0.1% zinc pyrrolidone + seaweed Laminaria digitata • Biophysical only assessment
digitata (% NS) extract cream vs placebo (twice daily for 8w)
239
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Micali et al
240

Table 3: Antimicrobials Agents
Ethyl lactate Prottey Prottey Placebo, RCT: • Level IB
(10%) 198425 198425 10% ethyl lactate alcohol lotion vs placebo (twice • Limited number of patients
daily for 2w) • In vitro and in vivo study
• Microbiologic and biophysical
assessment
Phytosphingosine Pavicic Pavicic Placebo, RCT: • Level IB
(0.2%) 200726 200726 0.2% phytosphingosine (PS) emulsion vs 0.2% • Limited number of patients
PS-hydrochloride salt (HCL) vs triclosan (NS % and • In vitro and in vivo study
formulation) vs placebo (twice daily for 8w)
• Microbiologic only
assessment
Tea tree oil Raman Enshaieh Double-blind, placebo, RCT: • Level IB
(5%) 199527 200728 5% tea tree oil gel vs placebo (twice daily for 6w)
Triclosan Lee 200329 Franz Double-blind, placebo, CT: • Level IIA

(0.1%) Dominguez- 197831 0.1% triclosan (TC) cream vs 0.1% TC + 0.75%
Delgado 201130 propylene phenoxetol cream vs placebo (twice
daily for 8w)
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Table 4: Antinflammatory Agents
Benzoyl peroxide – Mills Double blind, placebo CT: • Level IIA

(2.5%-5%-10%) 198632 1) 2.5% BPO gel vs placebo (twice daily for 8 w)
2) 2.5% BPO gel vs 5% BPO gel (twice daily for 8 w)
3) 2.5% BPO gel vs 10% BPO gel (twice daily for 8 w)
Green tea – Elsaie Open, uncontrolled, CT: • Level III
(2%) 200933 2% tea lotion (twice daily for 6 w)
Lactic acid Pasricha Garg Open, uncontrolled, CT: • Level III
(5%) 197934 200235 5% lactic acid (LA) solution (twice daily for 48w)
Myrtacine Fiorini-Puybaret Veraldi Multicenter, prospective, placebo, CT: • Level IIA
(0.2%) + 201136 201237 0.2% myrtacine + 4% nicotinamide (MN) emulsion vs
Nicotinamide (4%) placebo (twice daily for 4w)
Nicotinamide (4%) Grange 200938 Shalita Multicentre, double-blind, comparative, RCT: • Level IB
Padula 201039 199540 4% nicotinamide (N) gel vs 1% clindamycin gel (twice
daily for 8w)
Nicotinamide (4%) – Morganti Multicentre, double-blind, placebo RCT: • Level IB
+ Linoleic acid - rich 201141 4% Nicotinamide + linoleic acid- rich • Biophysical and clinical
phophatidylcoline phoshatidylcoline (N-PHCL) emulsion vs 1% evaluation
(4%) clindamycin phosphate emulsion + placebo
(once daily for 12w)
Nicotinamide (4%) – Emanuele Prospective, CT: • Level III
+ Retinol (1%) + 201242 4% Nicotinamide + 1% retinol + 0.5% • Biopsy proven clinical
Dehydrocholesterol dehydrocholesterol (DHC) in a moisturized base results
(0,5%) (twice daily for 6 w)
Resveratrol Gao 200343 Fabbrocini Single-blind, placebo, CT: • Level IIA
(0.01%) 201144 0.01 mg/ml resveratrol hydrogel vs placebo • Biopsy proven clinical
(daily for 8w) results
241
Continued
30-11-2013 17:05:06
Continued
Micali et al
Table 4: Antinflammatory Agents
242

39
Salicylic acid Padula 2010 Shalita Double-blind, placebo, RCT: • Level IB
(0.5%) 198145 0.5% salicylic acid (SA) in alcohol-solution vs placebo
(twice-daily for 12w)
Silicic acid Chen 201246 Lassus Double-blind, placebo, CT: • Level IIA
(% NS) 199620 Silicic acid gel vs placebo (20m twice daily for 6w)
Tea – Sharquie Single-blind, placebo, RCT: • Level IB
(2%) 200647 2% tea lotion vs placebo (twice daily for 8w)
Sharquie Single-blind, comparative, RCT: • Level IB
200848 2% tea lotion vs 5% zinc sulphate solution
(twice daily for 8w)
Tea tree oil Khalil 200449 Bassett Single blind, RCT: • Level IB
(5%) Koh 200250 199051 5% tea tree oil gel vs 5% BPO lotion (once daily for )
Enshaieh Double-blind, placebo, RCT: • Level IB
200728 5% tea tree oil gel vs placebo (twice daily for 6.4w)
Triethyl citrate – Charakida Double-blind, placebo, RCT: • Level IB
(NS %) + Ethyl 200723 0.5% TES lotion vs placebo (twice daily for 12w)
linoleate
(NS %) + Salicylic
acid (0.5%)
Zinc pyrrolidone – Capitanio Double-blind, placebo, RCT: • Level IB
(0.1%) + Laminaria 201224 0.1% zinc pyrrolidone cream vs placebo
digitata (NS %) (twice daily for 8w)
Zinc sulphate Jarrousse Cochran Double-blind, placebo CT: • Level IIA
(2%) 2007 52 198553 2% zinc sulphate solution vs placebo
(three time daily for 12w
Sharquie Single-blind, comparative, RCT: • Level IB
200848 2% tea lotion vs 5% zinc sulphate solution
30-11-2013 17:05:06
represent a valid and useful option for patients that do not tolerate prescription
topical retinoids and during maintenance therapy.5
There are three studies in vitro and 11 CTs on corneolytic agents (Level
IB = 7; Level IIA = 1; Level III = 3) listed in Table 5.18,25,45,51,54-63
MOISTURIZERS
Moisturizers are cosmetics designed to hydrate the stratum corneum and make
the skin soft and sooth. The hydration is an important issue in acne patients
considering that many treatments, such as topical and systemic retinoids as well as
BPO, may cause skin xerosis. Moisturizers for acne patients are mostly humectants
and emollients.2 Specific lines of moisturizers indicated for patients receiving oral
isotretinoin are available. Some of them are designed to improve cheilitis, dry eyes
or nose bleeding.
There are four CTs (Level IB = 1; Level III = 3) that have been listed in
Table 6.52-55
SUNSCREEN PRODUCTS
Ultraviolet (UV) radiation may have a mild antiinflammatory effect, but it
also promotes infundibular hyperkeratosis. For these reasons acne tends to get
worse after returning from summer holidays.56 Therefore, it is important to
educate patients to avoid lengthy midday sun exposure and the use of products
containing vegetables oils, considered as comedogenic.57 Photoprotection is
strongly recommended in all acne patients, especially in those taking oral/topical
retinoids, oral antibiotics and oral contraceptive pill (OCP) or birth-control pills
as a combination of an estrogen and a progestin. A wide range of products are
specifically designed for acne; all oil free as evanescent emulsions O/A, gels and
spray, some of them also containing sebum-controlling agents is available.
No in vitro or in vivo studies in acne patients are available for this product
category.
SHAVING PRODUCTS
In male patients with inflammatory acne, daily shaving should not be recommended.
Specific nonirritating foams or gels enhanced by antibacterial agents such as
triclosan (TC) and zinc, along with the use of noncomedogenic and soothing after
shave products should be suggested,56 in order to prevent or minimize irritations
or infections.
No in vitro or in vivo specific studies have been performed.
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Micali et al
Table 5: Corneolityc Agents
244

Acetylcysteine - Montes Double-blind, placebo, CT: • Level IIA
(5%) 201254 5% acetycysteine gel vs placebo (twice day for 8 w)
Glycolic acid Xhauflaire- Abels Double-blind, placebo, RCT: • Level IB
(10%) Uhoda 200855 201156 10% glycolic acid (GA) emulsion vs placebo • Clinical and self-
(once daily for 12w) assessment evaluation
Gluconolactone – Hunt Double-blind, placebo, RCT: • Level IB
(14%) 199257 14% gluconolactone lotion vs 5% benzoyl peroxide • Clinical and self-
lotion vs placebo (NS application number for 12w) assessment evaluation
Lactic acid – Scherdin Placebo, RCT: • Level IB
(2%) 200458 1) 2% lactic acid (LA) cream-gel vs 2% salicylic acid • Biopsy proven results
(SA) cream-gel vs placebo (twice daily for 6w)
2) 2% LA cleansing gel vs 2% LA cleansing gel +
2% SA cream-gel vs 2% LA cleansing gel + 2% LA
tonic + 2% SA cream-gel (twice daily for 6w)
Malic acid – Baldo Multicentre, comparative, CT: 2% malic acid (MA) • Level III
(2%) 201059 cream vs MA cream + topic antibiotics or retinoids
or BPO (twice daily for 8w)
Retinaldehyde Tran 200560 Poli Multicentre, double-blind, placebo, RCT: • Level IB
(0.1%) + Bordat 200561 200518 0.1% RAL + 6% GA emulsion • Clinical and self-
Glycolic acid (6%) (RALGA) vs placebo (once daily for 12w) assessment evaluation
Dréno Multicentre, CT: • Level III
200562 0.1% retinaldehyde (RAL) + 6% glycolic acid (GA)
(RALGA) emulsion (once daily for 12w)
Dréno Multicenter, CT: • Level III
200963 0.1% RAL + 6% GA (RALGA) emulsion
(once daily for 12w)
Continued
30-11-2013 17:05:06
Continued
Table 5: Corneolityc Agents

Salycilic acid – Shalita Double-blind, placebo, RCT: • Level IB
(0.5%-2%) 198145 0.5% salicylic acid (SA) in alcohol-solution vs
placebo (twice-daily for 12w)
Silicic acid – Fernandez Double-blind, placebo, RCT: • Level IB
(% NS) 200525 silicic acid emulsion vs placebo (twice daily for 8w)
Tea tree oil – Bassett Single blind, RCT: • Level IB
(5%) 199051 5% tea tree oil gel vs 5% BPO lotion
(once daily for 8w)
245
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Micali et al
246

Table 6: Moisturizer Agents
Ceramide – Zeichner Open, CT; • Level III
(%NS) 201252 ceramide lotion + 2.5% BPO gel (morning) +
ceramide lotion + 0.05% tretinoin (evening) vs
ceramide lotion + 1.2% CP/2.5%BPO (morning) +
ceramide lotion + 0.05% tretinoin (evening) (for 12 w)
Glycerin – Laquieze Controlled, RCT: • Level IB
(% NS) 200653 1) glycerin cream (on one half of the face) and • Clinical, biophysical, and
systemic isotretinoin (10 to 20 mg daily) vs systemic self-assessment evaluation
isotretinoin (twice daily for 2m)
2) glycerin cream (on one half of the face) and topic
0.05% tretinoin cream vs topic 0.05% tretinoin cream
(daily for 2w)
Urea (10%) in – Gold Multicenter, comparative, CT: • Level III
Benzoyl peroxide 200654 10% urea in 4.5% BPO or 8.5% BPO cleanser/
(4.5%/8.5%) cream/gel vs 10% urea in 4.5% BPO or 8.5% BPO
cleanser/cream/gel + minocycline vs 10% urea
in 4.5% BPO or 8.5% BPO cleanser/cream/gel +
systemic doxycycline (once daily for 4w)
Witch hazel (% NS) – Bartenjev Open, uncontrolled, CT: • Level III
+ Glycerin (NS %) 201155 glycerin and witch hazel extracts emulsion
30-11-2013 17:05:06
CAMOUFLAGE
Camouflage, or corrective maquillage, is a makeup technique able to minimize
some unaesthetic postinflammatory disorders such as hyperpigmentations typical
of acne.5,6 The benefit of covering inflammatory lesions with designed corrective
cosmetics has scientifically been proven. Generic and commercial cosmetic
makeup is not indicated for acne patients because of its potential comedogenic
role. The approach to corrective cover cosmetics (CCC) consists of two steps.
The first one is a preliminary clinical evaluation, in order to evaluate need and
realistic expectations for CCC.2 The second one consists in the application of
green or yellow undercover, used, respectively to minimize inflammatory lesions
and brownish hyperpigmented spots. The most appropriate foundation color
(liquid or creamy formulations) is then applied and after this a powder is gently
pressed.2,51,64 Lastly, additional colored facial cosmetics, including eye shadow,
eyeliner and mascara may be applied to improve final appearance.
No in vitro or in vivo CTs are available, although several studies confirm the
beneficial cosmetic and psychological improvement of camouflage technique in
acne patients.64-68
DISCUSSION
The use of cosmetics plays an important role in the management of acne, and
there are a growing number of scientific papers suggesting their in vitro and/
or in vivo efficacy. Although, preliminary investigational in vitro results have
seldom been confirmed in vivo and for many substances active in vitro, there is a
stringent need for CTs. Moreover, a major pitfall is that cosmetics usually contain
multiple different active principles, whose efficacy should be tested both as single
ingredients and as combination treatment. In fact, positive clinical results are
likely to be due to a synergistic action of multiple agents, or even depend on the
vehicle used. Yet, only a few agents fulfill the concept of evidence-based medicine.
In particular, for cleansers, a double-blind, placebo-controlled RCT has shown
that the use of a cleanser containing a mixture of 1% azelaic acid (AzA), 1% SA
and 0.04% TC decreases inflammatory lesions (evaluated by facial photographs
and skin biopsy), and also downsizes the rebound effect at the end of treatment.7
Some studies also confirmed that in inflammatory acne, concurrently treated with
topical antibiotics, the use of a BPO cleanser should be encouraged because this
agent is able to reduce the development and the proliferation of P. acnes-resistant
strains69 even when used in short-contact therapy.10
Among the various sebum-controlling agents, nicotinamide has shown the best
efficacy profile, according to one placebo-controlled RCT, in reducing the sebum
excretion rate (SER) of facial acne skin after 4 weeks of treatment (21.85% vs 10.7%
in placebo group). As regards antimicrobial agents, ethyl lactate and phytosphingosine
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Micali et al
(PS) have been proven to effectively reduce P. acnes growth both in vitro and
in vivo.25,26 In particular, the antimicrobial action of PS, previously investigated
in vitro by evaluating the inhibitory effect of PS on growth of Gram-positive and
negative bacteria, was then confirmed in vivo by a test on unwashed hands calculating
the total microbial count, and in a placebo-controlled RCT on acne patients.26
Among the antiinflammatory agents, the use of nicotinamide and resveratrol
should be encouraged, according to studies that have shown their efficacy evaluated
by skin biopsy at the beginning and end of treatment.42,44
Corneolytic agents have shown to be effective in preventing and treating post-
acne scarring70 and/or include improve postinflammatory hyperpigmentation
without causing any overt blanching effect, and are thus suitable for extensive use
in dark skin patients.70,71
Available studies on moisturizers for acne confirm that they can be used in
affected patients without inducing a comedogenetic effect.
CONCLUSION
Cosmetics are part of the therapeutic armamentarium in dermatology and many
patients along with an appropriate pharmacologic treatment ask for cosmetological
advices. If not provided, and patients left free to choose the cosmetics they like,
the risk of compromising the ongoing prescription treatment is high and the onset
of irritant/allergic contact dermatitis, photodermatitis and/or xerosis should be
taken into consideration. A cosmetics correct choice may enhance the therapeutic
outcome as well as patient’s compliance.
Editor’s Comment
Cosmetics are part of the therapeutic armamentarium in the management of acne
and many a pretty handsome face marred by acne has benefitted dramatically with
clever use of cosmetics. On the flip side, the incorrect use of inappropriate cosmetics is
known to aggravate the disease, largely due to presence of comedogenic ingredients
in many cosmetics. In this article, Drs Micali, Dall’Oglio and Tedeschi have
discussed the use of cosmetics in patients with acne. Based on extensive literature
search and their personal experience, they have highlighted the use of appropriate
cleansers, sebum controlling agents, corneolytics, antimicrobial products, anti-
inflammatory and moisturizing agents specifically designed for acne patients. They
also emphasize the importance of using appropriate photoprotective agents and
shaving products. Finally, they discuss personalized camouflage makeup techniques
using noncomedogenic products so as to minimize the esthetic problem associated
with acne and improve patients’ self-esteem and adherence to treatment.
Neena Khanna
248

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World Clinics

Prelims_ACNE.indd 1 30-11-2013 17:37:29

Editor-in-Chief Guest Editor

December 2013 Volume 1 Number 1

Jaypee Brothers Medical Publishers (P) Ltd.

Prelims_ACNE.indd 3 30-11-2013 17:37:30

World Clinics Dermatology: Acne

Prelims_ACNE.indd 4 30-11-2013 17:37:30

Craig G Burkhart MD MPH

Prelims_ACNE.indd 5 30-11-2013 17:37:30

Vandana Chatrath MBBS MSc (USA) Fellowship Derm Surgery (USA)

Goh Chee-Leok MBBS MD MMed FRCPE FAMS

Wenchieh Chen MD PhD

Soyun Cho MD PhD

Federica Dall’Oglio MD PhD

Brigitte Dréno MD PhD

Pan Jiun-Yit MBBS FRCP FAMS

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Ayşe Serap Karadağ MD

Alison M Layton MB ChB FRCP

Rebecca L Mawson MB ChB Bsc DRCOG

Prelims_ACNE.indd 7 30-11-2013 17:37:30

Dae Hun SUH MD PhD

Aurora Tedeschi MD PhD

Devinder Mohan Thappa MD DHA MNAMS

Christos C Zouboulis MD PhD

Prelims_ACNE.indd 8 30-11-2013 17:37:30

What’s New in Acne Pathogenesis................................................................. 1

The Role of Microbiology and Biofilms in Acne............................................ 31

The Sebaceous Gland and Its Role as an Endocrine Organ........................... 37

Nutrient and Growth Factor Signalling in

Acne and PCOS............................................................................................. 89

Acne Expression and Management in Indians.............................................. 105

Adult Acne .................................................................................................... 128

Acne Syndromes............................................................................................ 144

Acne Comorbidities....................................................................................... 155

Update of Oral Isotretinoin in Acne Treatment............................................. 169

Prelims_ACNE.indd 9 30-11-2013 17:37:30

Current Role of Light and Laser Therapy in Acne......................................... 201

Evaluation and Management of Acne Scars.................................................. 210

Acneiform Drug Eruptions............................................................................ 218

The Role of Dermocosmetics in Modern Acne Treatment............................ 234

Prelims_ACNE.indd 10 30-11-2013 17:37:30

Acne is an extremely complex disease with elements of pathogenesis involving

© 2014 Jaypee Brothers Medical Publishers. All rights reserved.

Prelims_ACNE.indd 11 30-11-2013 17:37:31

Prelims_ACNE.indd 12 30-11-2013 17:37:31

Prelims_ACNE.indd 13 30-11-2013 17:37:31

eIF Eukaryotic initiation factor IGF-1R Insulin-like growth factor-1

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NAD(P)H Nicotinamide adenine PSTPIP1 Proline-serine-threonine-

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SREBP-1 Sterol regulatory element- TOR Target of rapamycin

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What’s New in Acne Pathogenesis

© 2014 Jaypee Brothers Medical Publishers. All rights reserved.

factors in the pathogenesis of acne. Among the MC receptors [melanocortin-1

potential utility of squalene amount as a lipid marker to diagnose acne-prone

Role of Follicular Epithelial Cells

Role of Propionibacterium Acnes

Recently, acne was suggested to be an IGF-1-mediated disease.55 IGF-1 and

while TLR2 mediates the recognition of lipopeptides from Gram-positive

Colonization of pilosebaceous unit by P. acnes is the main event that leads