PART IV SYSTEMIC IMMUNOMODULATORY AND ANTIPROLIFERATIVE DRUGS
20  Systemic retinoids
Timothy J. Patton and Laura K. Ferris
Questions
Q20-1 What are the various endogenous forms of vitamin
A, and what is the physiologic role of each form?
(Pg. 253x2)
Q20-2 How much time is needed for complete serum
elimination of (a) isotretinoin, (b) acitretin, and family of naturally occurring and biologic chemicals, rather
(c) bexarotene; what is the role of acitretin
re-esterification to etretinate in this issue? Early observations documented that vitamin A defi-
(Pgs. 254, 255, 260)
Q20-3 What are the primary retinoid nuclear receptors,
and how do heterodimers and homodimers of
these receptors affect regulation of various genes?
(Pg. 255)
Q20-4 What are the theoretical short- and long-term
benefits of systemic retinoid therapy in
combination with PUVA photochemotherapy? narrow therapeutic index of vitamin A, the engineering of
(Pg. 257)
Q20-5 How do (a) daily isotretinoin doses and
(b) cumulative isotretinoin doses affect the
likelihood of significant clinical recurrence of acne
vulgaris? (Pg. 257)
Q20-6 How significant is the evidence for a
chemopreventative effect of acitretin in (a) solid
organ transplantation patients, and (b) other
patients with frequent NMSC? (Pg. 258)
Q20-7 What are the primary components of the
retinoic acid embryopathy, and what timing in
relation to conception presents the greatest risk 1969 Kligman and colleagues first applied topical tretinoin
of these serious congenital malformations? for acne vulgaris.1
(Pg. 260)
Q20-8 How do the various systemic retinoids affect
triglyceride and cholesterol levels to varying
degrees? (Pg. 261)
Q20-9 How do epidemiologic studies of depression risk
from isotretinoin compare with case series
suggesting a possible idiosyncratic risk of
depression in occasional individuals on this drug?
(Pg. 262)
Q20-10 What does the preponderance of evidence
suggest regarding a possible causal role of
isotretinoin inducing inflammatory bowel disease?
(Pg. 262)
Q20-11 How does bexarotene-induced hypothyroidism
differ from most cases of hypothyroidism seen in
clinical practice? (Pg. 264)
Q20-12 What are the major components of the isotretinoin
checklist in therapeutic guidelines section (Box
20-8) prior to initiating therapy (see also Boxes
20-3 and 20-4)? (Pg. 267)
252
INTRODUCTION AND HISTORICAL
PERSPECTIVE
The term retinoids includes all synthetic and natural com-
pounds that have biologic activity like that of vitamin A,
whereas the term vitamin A is best used to characterize a
than one particular compound.
ciency induced epidermal hyperkeratosis, squamous meta-
plasia of mucous membranes, various keratinization
disorders, and certain precancerous conditions. These find-
ings provided the initial clue that vitamin A could play a
significant role in the field of dermatology.
The first dermatologic use of vitamin A dated back to
1943 by Straumfjord for acne vulgaris.1 Because of the
ideal synthetic retinoids having the highest therapeutic
activity with the lowest possible adverse effects was initi-
ated. Oral administration of all-trans retinoic acid (tretin-
oin) had initially shown promising results in the treatment
of certain disorders of keratinization.2 However, the oral
use of tretinoin for acne was not studied further owing to
its adverse effect profile, although oral tretinoin was sub-
sequently developed many years later for treatment of
acute promyelocytic leukemia. In 1962, Stüttgen reported
the therapeutic effectiveness of topical tretinoin in disor-
ders of keratinization such as ichthyosis and pityriasis
rubra pilaris, as well as actinic keratoses.2 Subsequently, in
Isotretinoin, first synthesized in 1955, had been studied
in Europe since 1971 (Table 20-1). Initially studied for dis-
orders of keratinization,3 isotretinoin was subsequently
studied for acne vulgaris and was noted to dramatically
improve acne in patients with severe disease, as well as to
induce prolonged remissions. In the late 1970s, isotretinoin
was confirmed to be highly effective for acne vulgaris and
cystic (conglobate) acne.4 Of the first-generation retinoids,
13-cis retinoic acid (isotretinoin; Accutane, and other
brands – see Table 20-1) was approved by the US Food and
Drug Administration (FDA) in 1982 to treat severe nodu-
locystic acne.
The aromatic retinoids were developed because they
appeared to be more effective in treating psoriasis and
other keratinizing dermatoses. In 1972, Bollag discovered
two aromatic retinoids, etretinate and acitretin, that pos-
sessed a favorable therapeutic index in chemically induced
rodent papillomas.5 In 1986, after more than a decade of
research, a second-generation retinoid, etretinate (Tegison),
was released in the United States for the treatment of pso-
riasis. In 1998, etretinate was phased out by Roche (because
of its very prolonged presence in subcutaneous fat) and
 Systemic retinoids
20 

Table 20-1  Systemic retinoids

Generic Tablet or capsule Special Standard dosage

Generic name Trade name available Manufacturer sizes formulations range

First-generation retinoids
Isotretinoin Accutane* Yes Roche 10, 20, 40 mg None 0.5–2 mg/kg/day
Claravis Barr 10, 20, 40 mg
Sotret Ranbaxy 10, 20, 30, 40 mg
Amnesteem Bertek 10, 20, 40 mg
Tretinoin Vesanoid None Roche 10 mg Topical gel, 45 mg/m2/day
(all-trans-retinoic acid)† cream, solution
Second-generation retinoids
Etretinate Tegison None Roche 10, 25 mg None 0.25–1 mg/kg/day
Acitretin Soriatane None Roche 10, 25 mg None 25–50 mg/day
Third-generation retinoids
Bexarotene Targretin None Ligand 75 mg None 300 mg/m2/day
Alitretinoin Toctino (EU) None Basilea 10, 30 mg None 30 mg/day

*Accutane brand of isotretinoin has been discontinued.

†
This systemic version of tretinoin is also known as ATRA (primarily used for hematologic malignancies).

Table 20-2  Key pharmacology concepts – systemic retinoids

Absorption and bioavailability Elimination

Drug name Category Peak levels (hrs) Bioavailable (%) Protein binding (%) Half-life Metabolism Excretion

Tretinoin First generation 1–2 – Albumin 99 40–60 min Hepatic Bile, urine

Isotretinoin First generation 3 25 Albumin 99 10–20 hrs Hepatic Bile, urine
Etretinate Second generation 4 44 Lipoprotein 99 80–160 days Hepatic Bile, urine
Acitretin Second generation 4 60 Albumin 95 50 hrs Hepatic Bile, urine
Bexarotene Third generation 2 No data Plasma proteins 99 7–9 hrs Hepatic Hepatobiliary

replaced by its acid metabolite, acitretin (Soriatane). This
process had already taken place in Europe about a decade
earlier. Because etretinate is no longer available (except in
Japan), less emphasis is placed on this agent in this chapter.
However, the majority of information on the mechanisms
of action of the second-generation retinoids is derived from
etretinate data. Alitretinoin (9-cis-retinoid acid) has been
approved in Europe for the treatment of chronic hand
eczema, although it is currently not available in the United
States.
PHARMACOLOGY
Table 20-2 lists key pharmacologic concepts for the sys-
temic retinoids.
VITAMIN A PHYSIOLOGY
 Q20-1  Vitamin A cannot be synthesized in vivo by the
human body, and so must be acquired through the diet. In
mammals, vitamin A exists in interconvertible forms as
retinol (vitamin A alcohol), retinal (vitamin A aldehyde),
and retinoic acid (RA; vitamin A acid). The details of
vitamin A physiology can be found in several complete
reviews.1,2,5,6
The precursors of vitamin A, such as β-carotene, are clas-
sified as carotenoids. They are synthesized by plants and
function as photosensitive structures. In animals, ingested
carotenoids are oxidized to vitamin A. Every molecule of
β-carotene is converted into two molecules of retinal in the
intestines before being absorbed.
The primary form of dietary vitamin A in humans is
retinyl ester derived from meat and animal products, such
as eggs and milk. In the intestines, the retinyl esters are
hydrolyzed to retinol, which is absorbed and initially
stored in the ester form (particularly as retinal palmitate)
in the liver. Retinol and retinal can be converted inter-
changeably, but retinol is irreversibly metabolized to RA.
 Q20-1  Retinal, as the 11-cis isomer and the 11-trans
isomer, is important in the biochemical reaction of visual
function, whereas retinol is essential to reproduction. Both
retinal and RA play an essential role in epithelial
253
20  PART IV    SYSTEMIC IMMUNOMODULATORY AND ANTIPROLIFERATIVE DRUGS

their therapeutic index shows no significant improvement

5HWLQRLG due to increased toxicity.7
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ABSORPTION AND DISTRIBUTION
The oral bioavailability of retinoids is enhanced with food
intake. The effect of fatty meals is especially great with
%LQGV5$5α β γ %LQGV5;5α β γ acitretin and bexarotene.8,9 In serum, natural and synthetic
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Figure 20-1  Retinoid mechanism figure. CRABP, cystosolic
retinoic acid-binding protein; RAR, retinoic acid receptor; RXR,
retinoid X receptor; RARE, retinoic acid response element. RARs
and RXRs are members of the superfamily of steroid receptors.
Binding of RAREs may lead to up- or downregulation of gene
activity. Retinoid effects are dependent on the specific genes
activated or inhibited in different tissues.
differentiation and normal growth. Carotenoids and
vitamin A may have a relatively small biologic role as
antioxidants.
STRUCTURE
All three forms of vitamin A, as well as all three genera-
tions of synthetic retinoids (see Table 20-1), come under
the heading of retinoids. β-Carotene, a precursor of retinal,
is not considered a retinoid. Non-selective retinoids
activate multiple pathways and are associated with a
higher incidence of adverse effects. To achieve the greatest
therapeutic index (highest therapeutic efficacy-to-lowest
toxicity ratio), it is logical to design receptor- and function-
specific retinoids that activate only desirable pathways
required for therapeutic efficacy under a specific clinical
condition.7
Manipulation of the polar end group and the polyene
side chain of vitamin A (Figure 20-1) forms the first-
generation retinoids. In addition, a large number of isomers
are synthesized. From this first generation of non-aromatic
retinoids, tretinoin (all-trans RA), isotretinoin (13-cis RA),
and alitretinoin (9-cis RA) gained experimental and clinical
importance in dermatology and oncology.1
Second-generation (monoaromatic) retinoids are synthe-
sized by replacing the cyclic end group of vitamin A with
various substituted and non-substituted ring systems.
Therapeutically important compounds include etretinate
(Tegison) and acitretin (Soriatane).
The third-generation (polyaromatic) retinoids include
the arotinoids and selected other retinoids. These agents,
formed through cyclization of the polyene side chain,
include the topical retinoids tazarotene (Tazorac) and ada-
palene (Differin), and the oral and topical retinoid bexaro-
tene (Tagretin). Although third-generation retinoids are
much more potent than earlier retinoids, unfortunately
254
retinoids are transported by plasma proteins (see Table
20-2). Similar to vitamin A, synthetic retinoids accumulate
in the liver,1 but with a lesser affinity than vitamin A for
storage in hepatocytes and in Ito stellate fibroblasts. When
retinoid absorption exceeds liver storage capacity, symp-
toms of hypervitaminosis A result.
Because isotretinoin and acitretin are relatively water
soluble, there is very little lipid deposition in adipose
tissue. However, etretinate is approximately 50 times more
lipophilic than its metabolite acitretin, resulting in increased
storage in adipose tissue, from which it is slowly released,
in some cases over a period of several years.9 This is one
of the presumed advantages of using acitretin over etreti-
nate in treating psoriasis, especially in women of childbear-
ing potential. The more water-soluble retinoids (i.e.,
isotretinoin, acitretin, and bexarotene) are undetectable in
serum within 1 month after stopping therapy. Less than
20% of the corresponding serum concentrations of acitretin
and its 13-cis isomer appear in breast milk. The estimated
amount of drug consumed by a suckling infant corre-
sponds to about 1.5% of the maternal dose, justifying its
avoidance in breastfeeding women.10 Based on analysis of
seminal fluid from 3 male patients treated with acitretin,
and 6 male patients treated with etretinate, the amount of
acitretin transferred in semen would be equivalent to
1/200 000 of a single 25-mg capsule.
METABOLISM AND EXCRETION
GENERAL ASPECTS
The metabolism of retinoids is mainly via oxidation and
chain shortening to biologically inactive, water-soluble
products in the liver. The oxidative metabolism is induced
mainly by retinoids themselves, and possibly also by other
agents known to induce hepatic cytochrome P-450 3A4
isoform.11,12
The major metabolite of isotretinoin is produced by oxi-
dation, which forms 4-oxo-isotretinoin. Acitretin metabo-
lism differs from isotretinoin metabolism primarily in the
initial metabolism, which involves isomerization instead of
oxidation. Within a few hours of dosing, isoacitretin pre-
dominates over acitretin in plasma.13 Subsequently, both
13-trans and 13-cis acitretin are transformed by demethoxy-
lation at the aromatic ring and are eliminated in the bile as
β-glucuronide derivatives, or through the kidneys as
soluble metabolites with shorter side chains.
There are important differences in the terminal elimina-
tion half-lives (T1/2) among the three generations of retin-
oids.8,14  Q20-2  Tretinoin has the shortest half-life, at 40–60
minutes, followed by bexarotene at 7–9 hours, then
isotretinoin at 10–20 hours, then acitretin at 50 hours. Etret-
inate has a prolonged half-life of 80–160 days. After etreti-
nate therapy is discontinued, the serum concentrations
quickly drop to very low levels; however, these levels may
persist for up to 2.9 years.9 Both isotretinoin and acitretin
are completely cleared from the body within 1 month after
the drug is stopped. Based on short T1/2 values, bexarotene
probably has a clearance profile similar to isotretinoin.
 Systemic retinoids
20 

All four drugs are excreted in the urine and feces.1,8 Glu-
curonide conjugated metabolites appear in the bile with Table 20-3  Ligand–receptor binding selectivity profiles of
available systemic retinoids
subsequent excretion in the feces.
RAR RXR
Generic
ACITRETIN RE-ESTERIFICATION (REVERSE METABOLISM)
name α β γ α β γ Comments
 Q20-2  Alcohol indirectly enhances the re-esterification of
acitretin to etretinate, which is detectable only after a few Tretinoin + + + − − − RAR-β > γ >> α
days of an acitretin regimen.10 Following 3-month admin- (all-trans-RA) RXR-β, γ > α
istration of acitretin (30 mg/day) in 10 patients with pso-
Alitretinoin + + + + + + RXR > RAR
riasis, steady-state plasma etretinate concentrations were
(9-cis-RA)
detected at 2.5–56.7 ng/mL. In another two-way crossover
study, all 10 subjects formed etretinate with concurrent Isotretinoin − − − − − − No clearly identified
ingestion of a single 100-mg dose of acitretin during a (13-cis-RA) affinity for any retinoid
3-hour period of ethanol ingestion. The formation of etreti- nuclear receptor
nate in this study was comparable to a single 5-mg Acitretin − − − − − − RAR (weak interaction)
oral dose of etretinate.15 Based on this fact, the recom-
mended period for contraception after acitretin therapy Bexarotene − − − + + + RXR-α, β, γ
has been lengthened from 2 months to 2 years in Europe.10 Adapalene − + + − − − RAR-β, γ > α
In the United States, the recommended period for contra- Does not bind to CRABP
ceptive use after cessation of acitretin is even longer, at 3
Tazarotene − + + − − − RAR-β, γ > α
years.15 No RXR
A study of 37 women of childbearing age exposed to
acitretin evaluated the levels of detectable etretinate con-
centration in 20 women who still used acitretin, and in 17
women who stopped therapy for up to 29 months. This
study revealed the prevalence of detectable etretinate con- MECHANISM AT THE NUCLEAR LEVEL
centrations to be respectively 45% and 83% in plasma and Retinoids exert their physiologic effects by binding to
subcutaneous tissue, among current acitretin users and receptors present in the nucleus (Table 20-3).  Q20-3  There
18% and 86% among those who had stopped acitretin are two families of retinoid receptors, a retinoic acid recep-
therapy.16 In another study, after 4–11 months of treatment tor (RAR) family and a retinoid X receptor (RXR) family,
with etretinate its concentration in the subcutaneous fat each having three isoforms (α,β, and γ) encoded by sepa-
attained equilibrium at a level of about 100 times that in rate genes.24 RAR are always paired with an RXR, whereas
plasma.17 Even though the drug concentrations in the fat RXR can exist as a homodimer with another RXR, or as a
compartment are much higher than those in serum or skin heterodimer with several other families of receptors, such
tissue, it is unknown whether these persistent levels are as vitamin-D3 receptor, thyroid hormone receptor, and per-
truly sufficient for toxicity. Regardless, inability to detect oxisome proliferator-activated receptor.25 Retinoid recep-
plasma etretinate is a poor predictor of the absence of etret- tors belong to the large superfamily of receptors consisting
inate in fat. also of glucocorticosteroid, thyroid hormone, and
vitamin-D3 receptors, all of which are DNA-binding pro-
teins and functioning as trans-acting transcription modu-
MECHANISM OF RETINOID ACTION lating factors. Acitretin activates but does not bind to
Retinoids are small-molecule hormones that elicit their bio- multiple RAR. Alitretinoin is a pan-retinoid receptor and
logic effects by activating nuclear receptors and regulating binds to all 6 known retinoid receptors (RAR-α, -β, -γ, and
gene transcription.7,18,19 RXR-α, -β, -γ).
The genes regulated by retinoids contain a retinoic acid
TRANSPORT OF RETINOIDS response element (RARE), which is a DNA sequence to
which the RAR–RXR heterodimer binds. Upon binding of
Physiologically, RA is predominantly in the all-trans form
a ligand, the RAR–RXR heterodimer acts a transcription
(ATRA). A small fraction is transported as 13-cis RA. Serum
factor, resulting in the expression of a number of proteins
transport is by albumin. The intracellular carrier known as
involved in growth and regulation.26 The retinoid–receptor
cytosolic retinoic acid-binding protein (CRABP) transports
complex can also act in an indirect fashion by antagonizing
RA to the cell nucleus.20 CRABP-I modulates the levels of
the action of other transcription factors, specifically AP-1.27
RA in various tissues. CRABP-II is the predominant form
The clinical effects of systemic retinoids in dermatology are
in human epidermis and is suggested to modulate the
related to their ability to affect pathways involved in
action of RA as a ‘morphogen.’21,22 In addition, epidermal
inflammation,28,29 cellular differentiation,30 apoptosis,31 and
differentiation is correlated with enhanced CRABP-II
sebaceous gland activity.32 In addition to their actions on
expression, and treatment with retinoids results in
the skin, retinoids exert broad effects in multiple tissues, a
increased CRABP-II expression.22
complete description of which is beyond the scope of this
CRABP is present in high levels in the epidermis, and is
chapter.
markedly elevated in lesional skin of psoriasis (by 800%
compared to non-lesional skin), lamellar ichthyosis, lesional
Darier’s disease, pityriasis rubra pilaris, and keratosis CLINICAL USE
pilaris.23 High levels of CRABP might indicate a greater
sensitivity of the lesions to retinoids. Unlike etretinate, Box 20-13,4,13,33–88 lists indications and contraindications for
acitretin competes with RA for CRABP.20 retinoids.
255
20  PART IV    SYSTEMIC IMMUNOMODULATORY AND ANTIPROLIFERATIVE DRUGS

Box 20-1  Systemic retinoids indications and contraindications3,4,13,33–88

FDA-approved indications
Psoriasis [acitretin – formerly etretinate] Acne vulgaris [isotretinoin]
Severe plaque-type psoriasis33–37 Nodulocystic acne 4,50–52
Pustular psoriasis – generalized38 Recalcitrant, especially if any scarring tendency53,54
Pustular psoriasis – localized39 Mycosis fungoides [bexarotene]
Combination therapy Resistant to at least one systemic therapy55–59
With UVB or PUVA40–46
With cyclosporine13,47
With biologic therapies48,49
Other dermatologic uses*
Follicular disorders Chemoprevention of malignancies
Acne related conditions Organ transplantation patients81–84
Gram negative folliculitis Syndromes with increased risk cutaneous malignancy
HIV-associated eosinophilic folliculitis Bazex syndrome
Acne with solid facial edema Nevoid basal cell carcinoma syndrome85
Rosacea60–62 Muir–Torre syndrome
Papulopustular (recalcitrant to other therapies) Xeroderma pigmentosa85
Granulomatous rosacea Frequent BCC or SCC (non-immunosuppressed)
Hidradenitis suppurativa63–65 Kaposi’s sarcoma
Dissecting cellulitis of scalp66–68 Other inflammatory dermatoses
Disorders of keratinization Lupus erythematosus (cutaneous features)86,87
Darier’s disease3,69 Lichen planus – oral erosive, palmoplantar94
Pityriasis rubra pilaris70–75 Lichen sclerosus et atrophicus
Ichthyosis spectrum3,76–80 Miscellaneous
Keratodermas Graft-versus-host disease
Human papillomavirus infections
Contraindications
Absolute Relative
Pregnancy or woman who is likely to become pregnant Leukopenia
Non-compliance with contraception Hypothyroidism (in bexarotene patients)
Nursing mothers Moderate-severe cholesterol or triglyceride elevation
Hypersensitivity to parabens (in isotretinoin capsules) Significant hepatic dysfunction
Significant renal dysfunction
Pregnancy prescribing status – Category X (for all 3 drugs)

*Not a comprehensive list of references for off-label uses – if no reference number listed above, see references 66 and 67 for pertinent
citations, as well as consulting various reviews in the Bibliography section.

PRACTICAL CONSIDERATIONS 3. Bexarotene (Targretin) for selected cases of mycosis

Concomitant vitamin A therapy should be limited to
< 5000 IU vitamin A daily. Oral administration with milk
or fatty foods (ideally in moderation) enhances retinoid
absorption. Patients should be advised to avoid an exces-
sively fatty diet. Women with childbearing potential must
not consume ethanol during and up to 2 months after ces-
sation of acitretin therapy. In female patients of non-
reproductive potential and in males, this conversion of
acitretin to etretinate is not a clinically important issue.
FDA-APPROVED INDICATIONS
Three dermatoses have FDA approval for systemic retinoid
use in severe subsets, as outlined in Box 20-1 and in the
sections that follow:
1. Acitretin (Soriatane) for psoriasis;
2. Isotretinoin (Claravis, Amnesteem, Sotret; formerly
Accutane) for acne vulgaris; and
256
fungoides.
PSORIASIS – RETINOIDS AS MONOTHERAPY
After etretinate was removed from the market in 1998
owing to concerns about its long half-life, it was replaced
by acitretin, which remains the only systemic retinoid to
receive FDA approval for the treatment of psoriasis. Mul-
tiple studies have demonstrated acitretin’s effectiveness
when used as monotherapy for the treatment of psoriasis.33-35
When different doses of acitretin were evaluated, higher
doses (50 and 75 mg) were found to be more effective than
lower doses (10 and 25 mg). A retrospective analysis was
performed on two of these studies, demonstrating Psoria-
sis Area and Severity Index (PASI)-50 and PASI-75 response
rates in more than 76% and 45% of patients, respectively.36
Clinical experience has shown that acitretin monotherapy
in chronic plaque psoriasis often leads to decreased thick-
ness, scaling, and itching of the plaques, without reducing

the body surface area involved. Patients should also be
aware that whereas the initial clinical effects are often seen
in 4–6 weeks, it may take up to 3–4 months or longer to see
the full clinical benefit.
Analysis of 385 cases of generalized pustular psoriasis
(GPP) revealed that retinoid treatment was effective in 84%
of patients, methotrexate in 76% of patients, cyclosporine
CsA in 71% of patients, and oral psoralen plus ultraviolet
A (PUVA) in 46% of patients.38 Localized pustular psoriasis
of the palms and soles also responds very well to retinoid
therapy.39
The optimal dosing strategy for acitretin therapy appears
to be initiation at a dose of 25 mg daily and increasing the
dose based on effectiveness and/or patient tolerance.37
Once satisfactory control of the disease is reached, attempt-
ing to reduce the acitretin dose to 10 mg daily or 25 mg
every other day is a reasonable plan for long-term
maintenance.
PSORIASIS – RETINOIDS IN COMBINATION THERAPY
 Q20-4  Combination therapy with systemic retinoids and
phototherapy is more effective than monotherapy with
either modality. In addition, combination therapy reduces
the long-term risks associated with ultraviolet light
(photoaging, skin cancer) by reducing the cumulative UV
doses necessary for an adequate clinical response to
phototherapy.
Acitretin with broadband UVB (ReUVB) has been evalu-
ated in randomized, controlled studies.40,41 Both of these
studies demonstrated significant improvement in patients
receiving acitretin plus UVB therapy compared to patients
receiving UVB therapy alone, with significantly shorter
total treatment times and UVB doses in the patients receiv-
ing acitretin. Similar findings were also seen in patients
receiving narrowband UVB and acitretin.42 Acitretin with
PUVA (RePUVA) has been shown in formal studies to
improve the efficacy of PUVA while reducing the PUVA
dose required for clearance.43,44 Acitretin has also been
evaluated in combination with commercial tanning bed
therapy, which demonstrated PASI-50 and PASI-75
response rates in 76% and 59% of patients, respectively.45
Current recommendations for combination acitretin–UV
therapy include instituting low-dose (25 mg) acitretin 2
weeks prior to the initiation of phototherapy. If skin-type
dosing is used, the initial dose of UV light and subsequent
increments should be adjusted downward to accommo-
date the acitretin effect. Alternatively, if a patient is on a
stable dose of UV, the UV dose should be lowered by 30–
50% approximately 7 days after starting acitretin.46
Acitretin can be used in combination with methotrexate
or cyclosporine in specific situations; however, every at­­
tempt should be made to limit the period for which patients
are taking both medications because of potential adverse
liver effects with the acitretin–methotrexate combination
and possible elevations in serum triglycerides that may
occur with patients taking both acitretin and cyclosporine.47
One specific setting in which combination therapy is
effective is a ‘sequential regimen,’ which can be used at the
onset of therapy. In this setting, a rapidly effective agent,
such as cyclosporine, is instituted initially. Once the patient
has responded to the cyclosporine, this drug is tapered off
over 3–4 months while an agent with better long-term
safety, such as acitretin, is added. This type of sequential
regimen takes advantage of cyclosporine’s rapid onset of
action and acitretin’s excellent long-term safety profile.13
Systemic retinoids
20 
RETINOIDS IN COMBINATION WITH
BIOLOGIC AGENTS
Because retinoids are generally not considered to be immu-
nosuppressive, they may be considered ideal candidates
for combination therapy with the biologic agents, and there
is an increasing body of evidence to support the benefits
of this combination.48 In a randomized trial comparing
etanercept 25 mg twice weekly, acitretin 0.4 mg/kg daily,
and the combination of etanercept 25 mg once weekly and
acitretin 0.4 mg/kg daily, the combination of acitretin with
etanercept 25 mg once weekly was superior to acitretin
alone and was equivalent to etanercept 25 mg twice weekly,
with similar safety profiles.49 However, randomized studies
of acitretin in combination with other biologic agents are
lacking.
ACNE VULGARIS
The only systemic retinoid that is FDA approved for the
treatment of acne is isotretinoin. Current FDA guidelines
state that isotretinoin is approved for the treatment of
severe recalcitrant nodular acne.89 ‘Recalcitrant nodular
acne’ is defined by the FDA as inflammatory lesions >5 mm
in diameter and unresponsive to conventional therapy,
including systemic antibiotics. ‘Severe,’ in this context, is
defined as ‘many’ lesions (as opposed to ‘few’ or ‘several’).
In view of this narrow definition that would limit the use
of isotretinoin to very select patients, some have suggested
that the indications be expanded.53 A recent consensus con-
ference defined severity in terms of the impact of the
disease on the patient, not on the number of lesions.54 The
first available version of isotretinoin, marketed as Accu-
tane, was withdrawn from the US market in 2009, but three
other forms of isotretinoin are still available on prescrip-
tion in the US (Table 20-1).
The first report documenting the effectiveness of
isotretinoin for the treatment of acne demonstrated 100%
improvement in 13 of 14 patients given the medication at
an average dose of 2 mg/kg daily for 4 months.4 The same
authors subsequently conducted a randomized placebo-
controlled trial confirming the dramatic effect of isotretin-
oin in treating acne, along with evidence of a decrease in
sebaceous gland size and sebum production.50  Q20-5  In a
dose-comparison study comparing 0.1, 0.5, and 1.0 mg/kg
daily for 20 weeks, clinical improvement was essentially
the same for all three groups at the end of 20 weeks, with
a higher percentage of patients requiring retreatment in the
0.1 mg/kg daily group.51 A retrospective study confirmed
a higher relapse rate with lower doses. In this study, 82%
of patients who had received 120 mg/kg cumulative dose
relapsed, compared to just 30% of patients who received a
larger cumulative dose of 150 mg/kg.52 An isotretinoin
dose in the range of 0.5–1.0 mg/kg daily until a total cumu-
lative dose of 120–150 mg/kg is reached, is a reasonable
therapeutic plan.
In terms of practical issues, patients should understand
that their complexion may worsen for the first 4–6 weeks
of isotretinoin therapy, after which time they are likely to
see improvement over the next few months, so that during
the fourth and fifth months of therapy many patients are
clear or almost clear. Patients should also understand that
if their acne does relapse, it is very likely that it will be
much more responsive to conventional therapy following
the course of isotretinoin. If a second course of isotretinoin
is necessary, the rate of success (clearance without relapse)
257
20  PART IV    SYSTEMIC IMMUNOMODULATORY AND ANTIPROLIFERATIVE DRUGS
is similar to that seen with initial courses, that is, approxi-
mately 70%.
CTCL – MYCOSIS FUNGOIDES AND
SÉZARY SYNDROME
In 1999, the FDA approved bexarotene for the treatment of
the cutaneous manifestations of cutaneous T-cell lym-
phoma (CTCL) in patients who were refractory to at least
one previous systemic therapy. Two open-label Phase II–III
trials (treating predominantly mycosis fungoides) demon-
strated overall response rates of 48%, with a complete
response rate of 4%, in patients who were taking 300 mg/
m2 daily, which was determined to be the optimal dose of
bexarotene balance effectiveness and toxicity.55,56 The
mechanism of action of bexarotene in CTCL has not been
fully elucidated, although two studies have suggested that
apoptosis of the malignant cells is induced.57,58 An algo-
rithm was recently proposed for the use of bexarotene in
the management of CTCL which addresses the dose, the
response to therapy, and adverse effects of bexarotene
(see below).59
OFF-LABEL DERMATOLOGIC USES
Only a selected group of off-label uses of systemic retinoids
are discussed here, and these conditions were chosen based
on reasonable literature support for clinical efficacy.
Reviews by Ellis and Voorhees90 and by Dicken91 are useful
sources for uncommon, anecdotal retinoid uses. Retinoid
use under these conditions should be considered experi-
mental. When pertinent, data on response of these derma-
toses to etretinate are presented when comparable studies
evaluating acitretin are not available.
ROSACEA
Compared to acne, rosacea tends to be a more chronic
disease that frequently flares when systemic therapy is
discontinued.92 For this reason, low-dose isotretinoin has
been studied for rosacea, with doses of 10 mg/day dem-
onstrating effectiveness in treating telangiectasia, ery-
thema, and papules and pustules.60 One study comparing
the treatment of rosacea with isotretinoin at doses of 0.1,
0.3, and 0.5 mg/kg/day with doxycycline 100 mg twice
daily found that isotretinoin at 0.3 mg/kg/day was as
effective as doxycycline, with a similar safety profile.61
Continuous ‘microdoses’ as low as 20–30 mg per week
after low daily doses of isotretinoin for 4–6 months also
prevented relapses in rosacea patients.62 However, with the
requirements of the iPledge system the long term use of
isotretinoin has become more challenging.
HIDRADENITIS SUPPURATIVA AND DISSECTING
CELLULITIS OF THE SCALP
Only a few reports describe the use of retinoids in hidrad-
enitis suppurativa (HS).63,64 The response of HS to isotretin-
oin therapy is less impressive than the response of acne
vulgaris or rosacea. Also, higher dosages in the range of
1–2 mg/kg daily are usually required. About 50% of HS
patients cleared or improved significantly with 0.7–1.2 mg/
kg daily of isotretinoin. Treatment is more successful in the
milder forms of HS. Monotherapy with isotretinoin usually
has a limited therapeutic effect. One retrospective study
found good long-term efficacy with acitretin therapy
of HS.65
258
Dissecting cellulitis of the scalp is a condition related to
HS for which there have been a few anecdotal reports of a
significant therapeutic response to isotretinoin.66,67 An
isotretinoin dosage range of at least 1 mg/kg daily is sug-
gested; higher doses up to 2 mg/kg daily may be required
for selected cases of dissecting cellulitis of the scalp. Com-
bining isotretinoin with rifampin has also been reported to
be effective in the treatment of this condition.68
DARIER’S DISEASE
In early studies involving patients with inherited ichthy-
osiform diseases, patients with Darier’s disease were also
studied and demonstrated improvement in response to
systemic retinoids.3 Both acitretin and isotretinoin are
effective in improving the appearance of the Darier’s
disease lesions.69 Clinical experience has shown that indi-
vidual patients may respond better to one of these agents
than to the other. Therefore, if the clinical response to one
agent is insufficient, a trial of the other is appropriate.
PITYRIASIS RUBRA PILARIS
Retinoid use in pityriasis rubra pilaris (PRP) has been
reported.70-73 Goldsmith and colleagues evaluated 45
patients with PRP treated with isotretinoin, the largest
study to date.73 A dosage of 1–1.5 mg/kg daily of isotretin-
oin or 1 mg/kg daily of etretinate induced significant
improvement in approximately 70% of the patients in this
study. A small but significant percentage of the patients
achieved a sustained remission with therapy. Acitretin in
combination with narrowband UVB74 and UVA175 therapy
has been reported in isolated cases. The doses used in these
studies were comparable to the doses of acitretin used to
treat psoriasis.
ICHTHYOSIFORM DERMATOSES
Although both vitamin A and retinoic acid showed some
therapeutic benefit in treating keratinizing disorders, the
hypervitaminosis-A syndrome evoked by these systemic
therapies limited their use. Following the development of
synthetic retinoids, open-label studies evaluating isotretin-
oin and etretinate were undertaken on several disorders of
keratinization.3,76,77 Of all the diseases studied, lamellar ich-
thyosis consistently responded very well to systemic retin-
oids, although relatively high doses tended to be required.
Acitretin was similarly evaluated and found to be just as
effective at an average dose of 0.47 mg/kg daily.78 Bullous
congenital ichthyosiform erythroderma (BCIE) and con-
genital ichthyosiform erythroderma (CIE) also responded
moderately well, although higher doses of the retinoids in
BCIE may lead to worsening skin fragility and a flare of
bullous lesions. Two recent studies evaluating the effec-
tiveness of acitretin included patients with inherited
ichythyosiform dermatoses.79,80 Both of these studies con-
firmed the effectiveness of and the tolerance to acitretin in
the treatment of these potentially severe disorders.
CHEMOPREVENTION OF MALIGNANCY
 Q20-6  Given the ability of retinoids to influence epider-
mal development and differentiation,93 various retinoids
have been studied in the treatment and prevention of non-
melanoma skin cancers in solid organ transplant recipients.
Some studies have supported the hypothesis that the
number of new SCCs that develop will be lower in patients
taking acitretin than in patients not taking acitretin.81,82

Another study found no difference in the incidence of new
skin malignancies when patients were taking acitretin,
although there did appear to be a reduction in the number
of actinic keratoses.83
Histologic and immunohistochemical studies performed
in these patients showed a decrease in epidermal thickness
and increase in the differentiation marker K10, whereas
parameters that measured epidermal proliferation, apop-
tosis, inflammation, and keratinocytic epidermal neoplasia
score were unchanged by acitretin therapy.84 All of the
trials were limited by the small number of patients studied
and the short treatment and follow-up periods. Most
patients had difficulty with drug tolerability.
Systemic retinoids have also been studied as preventa-
tive agents in patients with genetic susceptibility to skin
malignancies, including patients with xeroderma pigmen-
tosum and nevoid basal cell cancer syndrome.85 Although
higher doses of systemic retinoids are apparently effective
in reducing the number of lesions, upon discontinuation
this effect was lost.
There is some evidence indicating that retinoids may
prevent non-melanoma skin cancer (NMSC),81,82 but as the
preventative action of retinoids does not persist upon dis-
continuation, long-term therapy is necessary, and the risks
of long-term adverse effects as well as the likely need for
patients to continue therapy indefinitely must be consid-
ered. Hopefully, larger studies will help determine conclu-
sively whether the risk–benefit ratio of systemic retinoid
therapy in this population is favorable.
LUPUS ERYTHEMATOSUS
Both isotretinoin and etretinate have been used success-
fully by patients with various forms of cutaneous lupus
erythematosus.86,94 A good response occurs in the hyper­
keratotic variety of discoid lupus erythematosus. Patients
with generalized discoid lupus (without hyperkeratosis)
and subacute lupus erythematosus also responded. Both
isotretinoin and etretinate have been beneficial in the range
of 1 mg/kg daily, with response within 4 weeks in the
majority of patients. This response is typically not sustain-
able after discontinuation of the drug. The efficacy of
acitretin (50 mg/day; n= 528) was compared with that of
hydroxychloroquine (400 mg/day; n= 530) in patients with
cutaneous lupus erythematosus.87 After 8 weeks of therapy
an overall improvement occurred in 46% of patients treated
Box 20-2  Potentially serious adverse effects due to systemic retinoids
Teratogenicity
Retinoic acid embryopathy
Spontaneous abortions
Ocular
Reduced night vision
Persistent dry eyes
Staphylococcus aureus infections
Bone
Diffuse skeletal hyperostosis
Osteophyte formation
Premature epiphyseal closure
*Theoretically increased CAD risk with long-term therapy.
†
Primarily a risk with bexarotene (Targretin); pancreatitis also rarely reported with isotretinoin.
Systemic retinoids
20 
with acitretin and in 50% of patients treated with hydroxy-
chloroquine; however, the study was limited by small
sample size. The incidence of adverse effects was higher in
the acitretin group.
LICHEN PLANUS
Both isotretinoin and etretinate 1 mg/kg daily give medio-
cre results. Although many patients respond within 4
weeks, the majority have insufficient improvement to
warrant long-term retinoid therapy. Acitretin was evalu-
ated in a multicenter, double-blind, placebo-controlled
study (n= 65) for lichen planus. After 8 weeks’ therapy with
acitretin 30 mg daily, 64% of patients showed remission or
marked improvement compared with placebo (13%
improvement). During a subsequent 8-week open phase,
83% of previously placebo-treated patients responded
favorably to acitretin therapy.88 There may be a role for
systemic retinoids in patients with widespread, hyper-
trophic or oral erosive lichen planus, for which retinoids
alone or in combination with low-dose corticosteroids may
be beneficial. Combining a systemic corticosteroid ‘burst’
with a systemic retinoid is often more effective in control-
ling such severe cases.
CHRONIC HAND ECZEMA
Although not currently approved for this indication in the
United States, at the time this chapter was written alti-
tretinoin was undergoing Phase III studies for use in the
treatment of chronic hand dermatitis. Two large studies
have been done that have shown improvement in severe
chronic hand dermatitis using alitretinoin. The largest
study included 1032 patients and was a double-blind, ran-
domized, placebo-controlled study that looked at 2 doses
of alitretinoin, 10 mg daily and 30 mg daily. Response
rates, defined as a physician’s global assessment (PGA) of
clear or almost clear, of 28% and 48%, respectively, were
seen for these doses; the response rate for patients on
placebo was 17%.95 In another study of 319 patient, the
response rates to 10 mg, 20 mg, or 40 mg of alitretinoin
daily were 39%, 41%, and 53%, respectively, with a placebo
response rate of 27%.96
ADVERSE EFFECTS
Box 20-2 lists potentially serious adverse effects of systemic
retinoids. At high dosages, acitretin tends to cause more
Lipids Other endocrine effects
Hypercholesterolemia* Hypothyroidism (central)†
Hypertriglyceridemia Diabetes mellitus (controversial)
Gastrointestinal Hematologic
Inflammatory bowel disease flare Leukopenia†
Pancreatitis† (due to ↑ triglycerides) Agranulocytosis†
Hepatic Neurologic
Transaminase elevations Pseudotumor cerebri
Toxic hepatitis (rarely) Depression – suicidal ideation
Muscle
Myopathy
259
20  PART IV    SYSTEMIC IMMUNOMODULATORY AND ANTIPROLIFERATIVE DRUGS
discomfort than etretinate, particularly with regard to hair
loss, palmoplantar peeling, and minor musculoskeletal
complaints. Short-term use of isotretinoin in severe acne is
generally safe, and is associated with minimal, reversible
adverse effects provided pregnancy is avoided.
An imposing list of potential adverse effects should be
considered when the synthetic retinoids are prescribed. A
careful individualized assessment of risk–benefit ratio, fol-
lowed by diligent surveillance for adverse effects and
careful management of the adverse effects, when present,
is of paramount importance.
TERATOGENICITY – WOMEN EXPOSED TO RETINOIDS
Teratogenicity is the most important adverse effect of the
retinoids.  Q20-7  Common retinoid-induced malforma-
tions include defects in the cranium and face, cardiovascu-
lar defects, thymic abnormalities, and central nervous
system malformations. Just 3 years after isotretinoin was
licensed for the treatment of severe cystic acne, a summary
of retinoid-induced embryopathy demonstrated that these
defects were found in almost 50% of full-term pregnancies
in which there was first-trimester exposure to isotretin-
oin.97 Spontaneous abortions occurred in one-third of preg-
nancies, and there was an increased number of stillbirths.
Reports of acitretin- and etretinate-induced teratogenicity
are fewer,98 perhaps because patients receiving second-
generation retinoids are older, and because these drugs
were released much later than isotretinoin. The teratogenic
threshold has not been established for synthetic retinoids
in humans; therefore, there is no safe minimal dose for use
during pregnancy.
Women of childbearing potential should be counseled
on proper birth control prior to commencing retinoid
therapy (Box 20-3). It is extremely important that women
understand that:
1. They must not be pregnant at the time retinoid therapy
is initiated.
2. They must not become pregnant while taking a
retinoid.
3. They must not become pregnant for a defined period
after the systemic retinoid is discontinued.
For isotretinoin, approximately 10% of women exposed
to the drug during pregnancy were pregnant at the time
therapy was initiated.99 This emphasizes the fact that effec-
tive contraception or abstinence should commence 1 month
prior to starting therapy. In addition, effective contracep-
tion must be continued 1 month after discontinuation of
therapy, to ensure the drug has been completely cleared
from the system.
Acitretin is similar to isotretinoin in that contraception
or abstinence must be instituted 1 month prior to starting
therapy.  Q20-2  However, because of the ‘re-esterification’
to etretinate that can occur with concomitant alcohol and
acitretin use, there are current recommendations to con-
tinue contraception 3 years following the discontinuation
of acitretin, as etretinate has an exceptionally long elimina-
tion half-life.15 It is recommended that patients completely
avoid alcohol to try and minimize re-esterification, but one
must keep in mind that many ‘non-alcoholic’ edibles and
over-the-counter preparations (e.g., mouthwash, cough
syrup) actually contain some amounts of ethanol. It is not
clear what quantity of ingested alcohol is required for the
re-esterification of acitretin to etretinate, and the effect of
the timing of the ethanol ingestion is also unknown.
260
Box 20-3  Guidelines for pregnancy
monitoring
General requirements
Must have had 2 negative urine or serum pregnancy tests
with a sensitivity of at least 25  mIU/ml before receiving
the initial isotretinoin prescription.
The second pregnancy test should be done during the
first 5 days of the menstrual period immediately
preceding the beginning of isotretinoin therapy.
For patients with amenorrhea, the second test should be
done at least 11 days after the last act of unprotected
sexual intercourse (without using 2 effective forms of
contraception).
Each month of therapy, the patient must have a negative
result from a urine or serum pregnancy test.
Must commit to two forms of contraception (at least one
primary) for at least 1 month prior to initiation of
isotretinoin therapy, during isotretinoin therapy, and for
1 month after discontinuing isotretinoin therapy.
Additional guidelines
Effective forms of contraception include both primary and
secondary forms of contraception.
Primary forms of contraception include: tubal ligation,
partner’s vasectomy, intrauterine devices, birth control
pills, and injectable/implantable/insertable hormonal
birth control products.
Secondary forms of contraception include diaphragms,
latex condoms, and cervical caps; each must be used
with a spermicide.
Patients do not need to commit to two forms of
contraception if they are abstinent or have undergone
hysterectomy
A study conducted by the manufacturer of acitretin dem-
onstrated that the vast majority of offspring born to mothers
who had been exposed to acitretin within 2 years prior to
conception had no malformations typical of retinoid
embryopathy.100 There was no information about alcohol
use during acitretin therapy in these patients. Given the
above information, it is clear that there is a theoretical risk
of fetal malformation if conception occurs within 3 years
of discontinuing acitretin; however, the magnitude of the
actual risk is unknown, and appears to be small.
Data from the manufacturers of alitretinoin state that the
elimination half-life of the drug is 2–10 hours. In pharma-
cokinetic studies of patients receiving alitretinoin at doses
of 10 mg or 30 mg a day for 24 weeks, plasma concentra-
tions of alitretinoin and its metabolites returned to normal
2–7 days after the drug was discontinued.95
TERATOGENICITY – MALES EXPOSED TO RETINOIDS
The outcomes of 13 pregnancies in which the father was
taking acitretin at or around the time of conception was
reported.101 Only one pregnancy was associated with fetal
malformations, and in this single case none of the malfor-
mations described were consistent with retinoid-induced
embryopathy. This, combined with the low concentration
of acitretin demonstrated to be contained in the male ejacu-
late, makes any risk to the developing fetus unlikely. There

have been 4 reports of pregnancies in which the father was
taking isotretinoin at the time of conception and in which
the fetus had a malformation. However, none of the fetuses
had a constellation of findings consistent with a retinoid
embryopathy.89 Similar information is not available for
male patients taking bexarotene, and condom use is recom-
mended in these patients.8 In summary, it appears that
there is little, if any, risk of retinoid embryopathy in fetuses
fathered by men taking systemic retinoids.
THE ‘IPLEDGE’ REGISTRY REQUIREMENTS AND AN
UPDATE AFTER THE FIRST YEAR OF THE PROGRAM
Because of concerns about the number of pregnancies that
continued to occur while patients were taking isotretinoin,
beginning 1 March 2006, the four companies that manufac-
ture isotretinoin and the FDA agreed to establish a federal
registry in which it is mandatory that all patients receiving
isotretinoin are enrolled (Box 20-4). Wholesalers, pharma-
cies, prescribers, and patients are part of this registry, and
a certain set of requirements must be met before an
isotretinoin prescription can be filled. The program dictates
that women of childbearing potential should use two forms
of contraception while on isotretinoin. In year 1 of the
iPledge registry there were 122 confirmed pregnancies
among 91 894 women of childbearing potential who had
an isotretinoin prescription authorized through the
system.102 Most women who had pregnancies reported
became pregnant while taking isotretinoin (63.9%), were
over age 20 (79.7%), and reported oral contraceptives with
a secondary method of male condoms as their forms of
birth control (72.2%). Notably, 18.3% of pregnancies
occurred in women who reported abstinence as their
method of pregnancy prevention.
MUCOCUTANEOUS ADVERSE EFFECTS
Dry mucous membranes and skin is a common complaint
in patients taking isotretinoin and acitretin (Box 20-5).
Varying degrees of cheilitis, which are dose related, occur
in almost all patients taking isotretinoin, and similar levels
of dryness can occur in the nares as well. Cutaneous xerosis
occurs in less than one-half of patients taking isotretinoin,
but is more common in patients with a history of atopy.103
Topical emollients applied on a regular basis usually alle-
viate these adverse effects. Acitretin may also cause dose-
related cheilitis and nasal dryness, although at doses
currently used most patients do not have these symptoms.
Acitretin does cause cutaneous xerosis, and may also
induce a sensation of ‘sticky skin,’ especially on the
palms.104
An exuberant granulation tissue response has also been
reported to occur with systemic retinoids, and can occur in
previous acne lesions,105 around nail folds,106 and at sites of
trauma.107 Treatments include dose reduction or discon-
tinuation, curettage, silver nitrate, and pulsed dye laser.108,109
Acne fulminans can occur with isotretinoin use.110 It is
characterized by the abrupt onset of ulcerating acne lesions
with associated arthralgias, myalgias, fever, leukocytosis,
and elevated erythrocyte sedimentation rate. The treat-
ment consists of discontinuation or reduction of the
isotretinoin dose, along with systemic corticosteroids.110
LIPID EFFECTS
 Q20-8  The most common laboratory abnormality
observed in patients taking systemic retinoids is elevation
Systemic retinoids
20 
Box 20-4  Requirements of the
iPledge system
Prescribers of isotretinoin must be registered with iPledge.
Prescribers, patients, and pharmacists may access the
iPledge system via automated telephone system or via
the internet:
• Phone number 866–495–0654
• www.ipledgeprogram.com
All patients must be registered in the iPledge system by
the prescriber and must sign the iPledge informed
consent. Each patient will be issued a unique patient ID
number and card at the time of registration.
For women of childbearing potential, at the time of the
initial prescription and each subsequent prescription
specific information must be entered by the prescriber
into the iPledge system via one of the above methods:
• Confirmation of patient counseling
• Pregnancy test results
• Contraception methods used
For men or women not of childbearing potential, the
system must still be accessed at the time of each
prescription to confirm counseling.
Women of childbearing potential must also access the
iPledge system at the time of the first and each
subsequent prescription to answer specific questions
about the iPledge system and about their chosen form
of contraception.
After the patient and the prescriber have fulfilled the
above requirements, a Risk Management Authorization
(RMA) number can be issued to a registered pharmacy.
This number allows the registered pharmacy to fill a
single 30 day supply of isotretinoin within 7 days of the
most recent office visit (as documented in the iPledge
system).
• A list of registered pharmacies can be obtained on
the website or via the phone system.
A woman of childbearing potential is defined as a ‘non-
menopausal female who has not had a hysterectomy,
bilateral oophorectomy, or medically documented
ovarian failure.’
• Young women who have not yet started menstruating
are considered to be of childbearing potential
• Women who have had tubal ligations are considered
to be of childbearing potential
in serum lipids, especially triglyceride levels. The magni-
tude of this effect, in terms of both percentage of patients
affected and severity of elevation, is much greater with
bexarotene than with other systemic retinoids.
Isotretinoin, etretinate, and acitretin elevate triglycerides
in 50% of patients and cholesterol in 30%.98 Alitretinoin
elevates cholesterol in up to 27.8% of patients and triglyc-
erides in up to 35.4% of patients taking the 30 mg/day dose
of the drug.8 In patients taking bexarotene, elevations in
serum triglycerides and/or cholesterol were observed in
79% of patients and occurred within the first or second
week of therapy.56 Because of the high incidence of ele-
vated serum lipids in patients taking bexarotene, current
recommendations are to place all patients on lipid-lowering
261
20  PART IV    SYSTEMIC IMMUNOMODULATORY AND ANTIPROLIFERATIVE DRUGS

Box 20-5  Relatively common minor adverse effects due to systemic retinoids
Cutaneous Ocular Musculoskeletal
Xerosis Dry eyes with visual blurring Arthralgias
Palmoplantar, digital desquamation Blepharoconjunctivitis Myalgias
‘Retinoid dermatitis’ Photophobia Fatigue, muscle weakness
Photosensitivity Oral Tendinitis
Pyogenic granulomas Cheilitis – especially lower lip Neurologic
Stickiness sensation – palms, soles Dry mouth Headache
Staphylococcus aureus infections Sore mouth and tongue Mild depression
Hair Nasal Gastrointestinal
Telogen effluvium Nasal mucosa dryness Nausea
Abnormal hair texture, dryness Decreased mucus secretion Diarrhea
Nails Epistaxis Abdominal pain
Fragility with nail softening
Paronychia
Onycholysis

agents (LLA) prior to the initiation of therapy, and to
follow serum lipids closely during bexarotene therapy,
adjusting both the bexarotene dose and LLA as neces-
sary.111 Statins and fenofibrate, a fibric acid derivative, can
both be used in conjunction with bexarotene. Gemfibrozil,
another fibric acid derivative, is a potent inhibitor of the
cytochrome P-450 pathway, the same pathway responsible
for the metabolism of bexarotene. When administered
with bexarotene, gemfibrozil causes an increase in
bexarotene and triglyceride levels. Their use together is
contraindicated.8
Slight to moderate elevations in triglycerides (level >
300–500 mg/dL) are best managed with weight reduction,
increased physical activity, and a low-fat, low-carbohydrate,
low-alcohol diet. For triglyceride levels > 500 mg/dL more
definitive action is required, and physicians should con-
sider reducing the retinoid dose, adding an LLA (such as
an appropriate fibric acid derivative, a statin, or niacin),
and monitoring lipid levels more frequently. Because ele-
vations in triglycerides > 800–1000 mg/dL can cause pan-
creatitis,112 drug discontinuation should probably be
considered in these patients when conservative and medical
management fail. Lipid elevations are reversible on cessa-
tion of therapy.
DEPRESSION
Psychiatric adverse effects are primarily reported with
isotretinoin use; however, the exact nature and cause of
these adverse effects are not entirely clear.  Q20-9  Early
reports regarding psychiatric adverse effects of isotretinoin
focused on the benefits obtained with regard to both
anxiety and depressive symptoms following treatment of
acne.113 When observing large numbers of patients treated
for various disorders, there did appear to be a small number
of patients who developed clear signs of depression, which
improved rapidly upon discontinuation of isotretinoin.114
In 1998, following reports to MedWatch, the makers of
Accutane added an additional warning regarding possible
adverse effects of ‘depression, psychosis and rarely, sui-
cidal ideation, suicide attempts and suicide.’89 Following
the new labeling, larger studies have failed to demonstrate
a convincing link between isotretinoin and depression.115-117
262
More recent studies from Turkey118 and Sweden119 con-
firmed that there appears to be no direct link between
isotretinoin and depression or anxiety, with the larger
Swedish study suggesting that severe acne in and of itself
is a risk for depression and suicide. Contrary to these
studies was a case-crossover study suggesting that expo-
sure to isotretinoin was associated with an increased rela-
tive risk of depression of 2.68.120 A commentary on this
contrary study pointed out the fact that, assuming a base-
line incidence of depression of 3%, this risk would be asso-
ciated with a number needed to harm estimate for
depression of 20 patients,121 which is not consistent with
real world experience.
There have been no large well-designed studies that
have definitively proved or disproved that isotretinoin
causes or worsens depression. An idiosyncratic reaction is
possible in a very small number of patients without pre-
existing depression. With this possibility in mind, patients
and their families should be advised to watch closely for
any signs and symptoms of depression. The patient infor-
mation summary that accompanies prescriptions of
isotretinoin lists 9 separate symptoms or signs important
for patients or their families to report to the prescribing
physician.
The correct approach to patients with pre-existing
depression or a history of depression has not been clearly
defined. On the one hand, it is not clear whether these
patients are at increased risk for idiosyncratic isotretinoin-
induced worsening of depression; on the other hand, it is
known that many of these patients’ depressive symptoms
will improve as their acne resolves. Our own experience
has confirmed large-scale studies suggesting that isotretin-
oin used in patients being treated for depression is safe,
and is not associated with a worsening of psychiatric
symptoms. It is prudent to work closely with psychiatric
consultants in managing these patients.
INFLAMMATORY BOWEL DISEASE
 Q20-10  Isotretinoin has also been implicated as a cause
of inflammatory bowel disease (IBD), in the form of either
ulcerative colitis or Crohn’s disease. Recently, several large
studies have tried to ascertain whether this association is

more than what would be expected to occur as a result of
coincidence. One of the initial larger studies was an analy-
sis of the cases of IBD that occurred in association with
isotretinoin use that were reported to MedWatch from 1997
to 2002.122 In this study, the authors felt that there was a
‘probable’ or ‘highly probable’ likelihood that isotretinoin
was the cause of IBD in 68% and 5% of cases, respectively.
The authors do acknowledge, however, that the peak onset
of IBD occurs at the same age as when most patients would
be prescribed isotretinoin, and that coincidence could not
be ruled out in these cases. A case-control study demon-
strated that there was no difference in the incidence of IBD
in patients who were prescribed isotretinoin compared to
control patients within the same cohort.123 Another article
examined the reports of IBD and isotretinoin use that had
been published and applied the Hill criteria to evaluate
causation.124 These authors determined that the reports
were lacking in terms of strength, specificity, and consist-
ency, although they could not rule out causation either.
The same group subsequently performed a case-control
study and found that the risk of ulcerative colitis was
higher in isotretinoin patients (odds ratio of 4.36), whereas
there was no increased risk of Crohn’s disease.125
The data regarding isotretinoin use as a cause of IBD is
conflicting. Even in the report that demonstrated a possible
causal association, the overall risk of IBD in isotretinoin
patients would seem to be very small. As with depression,
patients need to be informed of the signs and symptoms of
IBD before starting isotretinoin, and to discontinue the
medication should these occur. In patients with a family
history of IBD or with a previous diagnosis of IBD, our
experience has demonstrated that therapy with isotretinoin
can still be initiated under the close supervision of a
gastroenterologist.
BONE EFFECTS
The potential for retinoid use to cause similar bone effects
to what is seen in chronic vitamin A toxicity (diffuse inter-
stitial skeletal hyperostosis [DISH], premature epiphyseal
closure, and lower bone mineral density),126,127 although
quite small, appears to be based on both the duration of
therapy and the dosage used.
For many patients, the only exposure to a systemic retin-
oid will be a relatively short course of isotretinoin for acne.
A recent study evaluated both BMD and development of
cervical hyperostosis in adolescents receiving a 16–20-
week course of isotretinoin for acne, and found no detri-
mental effect of isotretinoin on either parameter.128 In the
setting of the most common use for systemic retinoids,
there are virtually no adverse effects on bone or ligaments,
and no routine monitoring for bone changes is required.
Another consideration is that many patients, even if
taking retinoids for a prolonged period of time, are on rela-
tively low doses to control their disease. In a recent retro-
spective study, 26 of 41 patients taking an average dose of
acitretin of 25 mg for more than 1 year underwent X-ray
evaluation, and none of the patients studied demonstrated
any evidence of DISH.129 Only in the setting of worsening
arthritis or skeletal symptoms would X-rays need to be
performed in these patients.
On the other hand, a prospective study of patients taking
isotretinoin for disorders of keratinization demonstrated
the development of hyperostoses in 6 of 7 patients while
on therapy.130 Most of these hyperostoses were not
Systemic retinoids
20 
symptomatic, and because of the dramatic clinical benefit
to their skin disease, no patient chose to minimize or dis-
continue therapy.130 The doses in these patients ranged
from 1 to 3 mg/kg daily, and the course of therapy was 5
years.
It seems likely that high-dose systemic retinoids, if given
for long periods of time, do impart a risk of hyperostosis.
However, in the most common clinical settings (short
courses of relatively high-dose isotretinoin for acne and
long-term courses of low-to-moderate doses of acitretin for
psoriasis) there does not appear to be any significant risk
of skeletal effects. Thus, only in exceptional cases is it nec-
essary to consider monitoring asymptomatic patients for
these skeletal effects. In cases in which asymptomatic
skeletal effects are detected it is unclear whether cessation
of therapy is truly necessary, especially if the beneficial
effects on skin disease are dramatic. However, if DISH
involves the posterior longitudinal ligament, spinal cord
compression leading to neurological deficits can occur,131
and consideration should be given to discontinuing the
retinoid.
Premature epiphyseal closure has been reported in associa-
tion with retinoid therapy, but it is rare, occurring only
with higher doses.131 Because of this effect, the risks and
benefits of retinoid use in pre-adolescent children should
be carefully considered prior to therapy.
Osteoporosis as a consequence of long-term etretinate
therapy has been suggested; 132 however, the study design
in this report has been criticized.133 No prospective studies
have been performed to confirm the exact nature of the
relationship between osteoporosis and systemic retinoid
therapy. In studies of alitretinoin there were no dose-
dependent changes in bone mineralization by DEXA scan
pre and post treatment.8
OCULAR EFFECTS
Blepharoconjunctivitis is defined as a low-grade inflamma-
tion of the conjunctiva and lid margins, and has been
reported in patients taking the systemic retinoids isotretin-
oin134 and acitretin.135 This is most likely a result of decreased
meibomian gland secretion induced by the retinoids.136
Patients should be counseled about the possibility of devel-
oping dry eyes, and the possible need to discontinue
contact lens use while taking the medication should be
raised.137 Symptomatic patients can be treated with artifi-
cial tears.
Corneal opacities can also occur in patients taking sys-
temic retinoids. They occur in both the central and the
peripheral cornea and do not adversely affect vision.137
They are typically incidental findings on routine ophthal-
mologic examination.
Decreased night vision as an adverse effect of retinoid
therapy appears to be limited to isotretinoin use. In some
patients who have had complaints of poor night vision,
abnormalities could be detected in dark adaptation curves
or electroretinograms.138 Enzyme inhibition and competi-
tive binding with retinol are given as possible explanations
for this effect, although the exact mechanisms are
unknown.139 These abnormalities returned to normal fol-
lowing cessation of therapy.
Finally, bacterial conjunctivitis has been reported in clini-
cal trials in up to 7.3% of patients treated with isotretinoin,
although most clinicians find this adverse effect to be quite
uncommon.140
263
20  PART IV    SYSTEMIC IMMUNOMODULATORY AND ANTIPROLIFERATIVE DRUGS
LIVER EFFECTS
Elevated transaminases have been reported with both acitre-
tin and isotretinoin use. It has been assumed that these
elevations were hepatic in origin, although muscle as a
source of these elevations was not excluded. With isotretin-
oin these elevations are mild, occurring in 15% of patients,
and typically return to normal despite continued therapy.141
In a study of 128 patients taking acitretin for psoriasis,
elevated AST and ALT occurred in 30.5% and 27.3% of
patients, respectively.142 Pre- and post-treatment liver biop-
sies were performed in 83 patients, demonstrating improve-
ment in 24%, no change in 59%, and worsening in 17% of
patients. There was no correlation between hepatic
transaminase abnormalities and liver biopsy findings.
Most of these changes were mild, and were not considered
to be clinically significant. However, there have been cases
of severe hepatitis reported with acitretin use.143 Transami-
nase elevations as a result of bexarotene therapy occur less
frequently.55
Severe, fatal hepatitis as a result of retinoid therapy is rare
and most likely an idiosyncratic reaction.144 Taken together,
evidence suggests that the retinoids overall rarely induce
severe hepatotoxicity, other than these idiosyncratic reac-
tions, which seem to be most common with acitretin.
Monitoring of liver transaminases is advisable, with
discontinuation recommended only for severe (>3-fold)
elevations, although more frequent monitoring or dose
reductions should be considered for smaller transaminase
elevations.
THYROID EFFECTS
 Q20-11  Abnormalities in thyroid function have only been
reported for bexarotene and occurred in 80% of patients
taking the medication for CTCL.145 These abnormalities
represent ‘central hypothyroidism’ and include decreases
in both TSH and circulating thyroid hormone. Current rec-
ommendations include obtaining baseline TSH and free
thyroxine studies, starting low-dose levothyroxine in all
patients, monitoring the free thyroxine level during
therapy, and adjusting the dose as necessary.111 Alitretinoin
is also capable of causing central hypothyroidism, although
a low TSH was reported in only 8.4% of patients on the
30 mg/day dose of the drug.8 Nonetheless, TSH should be
checked at baseline and monitored in patients taking
alitretinoin.
CENTRAL NERVOUS SYSTEM EFFECTS
Changes of pseudotumor cerebri, although infrequent, are
the most important central nervous system adverse effects.
Transient headaches are relatively common early in
isotretinoin therapy. However, accompanying nausea,
vomiting, and visual changes should prompt further eval-
uation to exclude pseudotumor cerebri. In an early report
on pseudotumor cerebri associated with isotretinoin use,
half the patients were taking tetracycline or minocycline
concomitantly.146 Combined therapy with isotretinoin and
tetracycline, doxycycline, or minocycline should be
avoided.
MUSCLE EFFECTS
Myalgias are noted in roughly 15% of isotretinoin-treated
patients. An increased frequency and severity of these
264
myalgias can be seen in patients undergoing physical train-
ing programs involving heavy exertion, particularly when
new programs are being initiated. These symptoms have
been accompanied by markedly elevated creatine phos-
phokinase levels, but have not been accompanied by rhab-
domyolysis.1 These muscle effects are associated mostly
with isotretinoin therapy.
HAIR AND NAIL EFFECTS
The risk of telogen effluvium due to the systemic retinoids
has been reported to vary over a range of 10–75%.10,35,86 The
risk is greater for acitretin than for etretinate therapy, and
is much less common with isotretinoin and bexarotene.
Hair loss is a dose-related effect, and is reversible starting
2 months after either discontinuation of therapy or a sig-
nificant dose reduction. Women seem to have a more
noticeable hair loss, particularly if there is already a mild
baseline androgenic alopecia. In general, reassurance about
the reversibility of the hair loss is usually sufficient to
alleviate the patient’s concern. Dose reduction, or even
cessation of therapy, may be necessary in more severe
cases.
Nail fragility with onychorrhexis and onychoschizia is
common. Nail dystrophy and onycholysis occur infre-
quently, but with a higher incidence with acitretin than
with etretinate use.10,35,147
HEMATOLOGIC EFFECTS
In CTCL studies, up to 43% of patients receiving bexaro-
tene (300 mg/m2 daily) had reversible leukopenia (1000–
3000 WBC/mm3).8 The onset of leukopenia typically ranges
from 4 to 8 weeks. The leukopenia observed in most
patients was dose related and explained by neutropenia.
There was no febrile neutropenia or serious infections.
Leukopenia and neutropenia resolved within 30 days
after dose reduction or discontinuation. The incidence
of leukopenia and other hematologic abnormalities is
much less frequent with first- and second-generation
retinoids.98
DRUG INTERACTIONS
Formal studies of drug interactions with retinoids have
been limited. Table 20-4 lists both well-documented inter-
actions and interactions that can be anticipated based on
the CYP3A4 metabolism of retinoids.
MONITORING GUIDELINES
See Box 20-6 and Box 20-7. Most urine pregnancy tests have
a threshold detection limit of 20–50 mIU/mL. The serum
pregnancy tests are more sensitive and have a better
threshold detection limit of 1–5 mIU/mL. Urinary concen-
trations of β-human chorionic gonadotropin (β-HCG) vary
with the patient’s physiology, state of hydration, and urine
volume. Because of these factors, the urine pregnancy test
may not be sensitive enough until 6–8 days after concep-
tion, when the β-HCG level approaches 30 mIU/mL. If the
urine pregnancy test is used, the first void of the day
should be collected.
In general, implantable, injectable, and oral birth control
hormones are most effective (Box 20-3). Diaphragm, sper-
micide, and condom when used together can be highly
 Systemic retinoids
20 

Table 20-4  Systemic retinoids drug interactions

Interacting drug or group Examples and comments

The following drugs may increase the serum levels (and potential toxicity) of retinoids
Vitamin A Induces hypervitaminosis A-like toxicities
Tetracycline, doxycycline, Increased isotretinoin levels – pseudotumor cerebri risk when any of these drugs used in combination
minocycline with isotretinoin
Gemfibrozil Increased bexarotene levels due to CYP 3A4 inhibition – result is significantly increased risk for
bexarotene toxicity of various types
Macrolides, azoles, etc. Other CYP 3A4 inhibitors may increase retinoid drug levels and resultant potential for toxicity
The following drugs may reduce the serum levels of retinoids via CYP3A4 induction
Antituberculosis drugs Rifampin, rifabutin
Anticonvulsants Phenytoin, phenobarbital, carbamazepine
Retinoids may increase the drug levels (and potential toxicity) of the following drugs
Cyclosporine Increased cyclosporine levels via competition with retinoids for CYP 3A4 metabolism
Retinoids may reduce the drug levels of the following drugs
Progestin only contraceptives Reduced efficacy of these contraceptives when prescribed along with acitretin
Other potentially important drug interactions
Alcohol Acitretin ‘reverse metabolism’ to etretinate increased when acitretin used in combination with alcohol

Box 20-6  Isotretinoin and acitretin monitoring guidelines

Baseline
Examination
• Careful history and physical examination
• Identify those patients at increased risk for toxicity or
adverse effects
• Document concomitant medications that may interact with
retinoids (see Table 20-4)
Laboratory*
• Serum pregnancy test† (in women of childbearing potential)
• Complete blood count (CBC) with platelets
• Liver function tests (AST, ALT, alkaline phosphatase, bilirubin)
• Lipid profile during fasting‡ (triglycerides, total cholesterol,
LDL and HDL cholesterol)
• Renal function tests (blood urea nitrogen, creatinine)
• Optional urinalysis (if patients have renal disease,
proteinuria, diabetes or hypertension)
Special tests
• Consider baseline X-rays of wrists, ankles or thoracic
spine if plan long-term retinoid therapy
• Consider ophthalmologic examination if patients have a
history of cataracts or retinopathy
Follow-up
Examination
Clinical evaluation monthly for first 3–6 months, then every
3 months
• Assessment of patient response, improvement, and
complaints of adverse effects
• Routine physical examination of lesional skin
• Additional/focused physical examination of any reported
adverse effects
Laboratory*§
Monthly for the first 3–6 months, then every 3 months
• Complete blood count (CBC) with platelets¶
• Liver function tests (AST, ALT)
• Fasting lipid studies‡ (triglycerides, cholesterol – order LDL
and HDL cholesterol periodically)
• Renal function tests¶ (optional urinalysis)
• Serum or urine pregnancy test monthly for women of
childbearing potential (and at end of therapy)
Special tests
Periodically as indicated by symptoms
• Consider yearly X-rays of wrists, ankles or thoracic spine
with long-term retinoid therapy
• Radiographic studies of significantly symptomatic joints
with long-term therapy
• Complete ophthalmologic examination if patients report
visual changes (see text for components)

*More frequent surveillance is needed if laboratory parameters are abnormal or with high-risk patients.
†
Newer guidelines require two pregnancy tests before isotretinoin therapy – isotretinoin therapy should be initiated on the second day of next
normal menstrual cycle or ≥11 days after the last unprotected intercourse.
‡
Lipids should be drawn after a 12-hour fast and a 36-hour abstinence from ethanol.
§
When isotretinoin is used for 20-week acne course, it is reasonable to discontinue laboratory monitoring (other than pregnancy testing) after
8–12 weeks if laboratory results remain normal and the dose is constant.
¶
Renal function and hematologic tests are infrequently altered by retinoids; consider ordering these tests every other time the laboratory 265
evaluation is done.
20  PART IV    SYSTEMIC IMMUNOMODULATORY AND ANTIPROLIFERATIVE DRUGS
Box 20-7  Bexarotene monitoring guidelines
Baseline
Examination
• Careful history and physical examination
• Identify those patients at increased risk for toxicity or
adverse effects: liver disease or cirrhosis, biliary tract
disease, excessive alcohol consumption, prior
pancreatitis, thyroid disease, uncontrolled
hyperlipidemia, uncontrolled diabetes mellitus, HIV,
leukopenia, chronic infection, cataracts
• Document concomitant medications that may interact
with retinoids (see Table 20-4)
Laboratory*
• Serum pregnancy test (in women of childbearing
potential)
• Complete blood count (CBC) with platelets and
differential count
• Liver function tests (AST, ALT, alkaline phosphatase,
bilirubin)
• Lipid profile during fasting† (triglycerides, total
cholesterol, LDL and HDL cholesterol)
• Renal function tests (blood urea nitrogen, creatinine)
• Thyroid function tests: TSH, T4
• Optional urinalysis (if patients have renal diseases,
proteinuria, diabetes or hypertension)
Special tests
• Baseline ophthalmologic examination if patients have treatment if patients have a history of abnormal ocular
a history of cataracts
*More frequent surveillance is needed if laboratory parameters are abnormal or with high-risk patients.
†
Lipids should be drawn after a 12-hour fast and a 36-hour abstinence from ethanol.
‡
Renal function tests and urinalyses are infrequently altered by retinoids; consider performing them every other time when laboratory
evaluation is done.
Box 20-8  Therapeutic guidelines checklist
Risk–benefit analysis is best performed when
considering the following issues
• Patient age and gender – use particular caution for
children and for women of childbearing potential.
• Disease responsiveness – the most appropriate retinoid
drug choice, dose, and duration of therapy needs to be
chosen; whether a sustained remission of the disease
being treated is possible is of importance.
• Disease severity – systemic retinoids are best utilized
for conditions that are severe, involve large body
surface areas (over 10%), and/or a significantly
disabling on a physical or an emotional basis.
• Prior alternative therapies – it is important to consider
other topical and systemic therapies; systemic retinoids
may be the treatment of choice if other treatment
options are impractical, too costly, induce important
adverse effects, or have worrisome drug interactions.
• Adjunctive therapy – when possible, use systemic
retinoids in combination with other topical or systemic
266
Follow-up
Examination
Clinical evaluation every 2 weeks for first 4–8 weeks, then
monthly for the next 3 months; long-term clinical
evaluation every 2–3 months
• Assessment of patient clinical response and for adverse
side effects
• Additional/focused physical examination of any reported
side effects
Laboratory*
Every 1–2 weeks until the lipid response to Targretin is
established [usually 2–4 wks], then as below
• Lipid profile during fasting† (triglycerides, total
cholesterol, LD and HDL cholesterol)
Monthly for the first 3–6 months, then every 3 months
• Complete blood count (CBC) with platelets and
differential count
• Liver function tests (AST, ALT); if elevated can also
order bilirubin, alkaline phosphatase
• Renal function tests‡ (optional urinalysis)
• Serum or urine pregnancy test for women of
childbearing potential (continue monthly indefinitely)
• Thyroid function tests: TSH (at least), possibly T4 as well
(reasonable to follow-up just 1–2 times)
Special tests
• Repeat ophthalmologic examination periodically during
findings prior to retinoid therapy
therapies to enhance efficacy and/or reduce adverse
effects.
• Rotational or sequential therapy – using psoriasis as an
example, long-term adverse effects may be minimized
by alternating between retinoids and other therapeutic
options such as methotrexate, cyclosporine, PUVA or
UVB phototherapy, in addition to newer biologic therapy
options.
Additional issues to address to optimize systemic
retinoid therapy safety
• Dose and duration – a patient should take the lowest
possible retinoid dose for the briefest possible duration
that will be therapeutically beneficial; upon adequate
disease control, the dose can be tapered completely
or more ideally reduced to the lowest effective
maintenance dose to sustain disease control.
• Laboratory surveillance – this should be done as outline
in the Monitoring Guidelines boxes.
Continued
 Systemic retinoids
20 

Box 20-8  Therapeutic guidelines checklist—cont’d

• Patient education – this education should particularly
emphasize lipid, hepatic, teratogenic, psychiatric, and
musculoskeletal adverse effects.
• Management of adverse effects – maximum patient
compliance require patient efforts directed at minimizing
mucocutaneous adverse effects and awareness of
expected minor hair, nail, and systemic adverse effects.
Female patients should avoid pregnancy at all
costs when using systemic retinoid therapy. In
addition ‘new’ guidelines with the iPledge
system, the following guidelines are useful
reminders:
• Patient selection – the patient’s capacity to understand
the risk of serious teratogenicity and the importance of
complete compliance with pregnancy prevention
measures is a critical determinant in retinoid therapy
decision.
• Patient education – optimal patient education involves
both the physician’s careful explanation and information
handouts that address the important issues regarding
teratogenicity. After the patient has heard and read
these instructions, it is important to provide the patient
adequate opportunity to ask any questions she may
have. Mandatory participation in the iPledge program
(see Box 20-4) provides an ongoing reminder of the
teratogenicity potential.
• Informed consent documentation – for isotretinoin the
iPledge system is adequate from a medicolegal
perspective; thorough chart documentation of the
above discussion is important.
• Contraception and Exclusion of pregnancy – see Box
20-3.
• Anticipating options – the female patient should
consider available options if pregnancy occurs prior to
initiating retinoid therapy; it is helpful to document her
thoughts on this subject in the medical record.

effective. Other than abstinence, no method of birth control

is completely reliable. Women with a history of infertility Abbreviations used in this chapter
should use contraceptives, and women who have under-
gone tubal ligation should ideally use a second form of AP-1 Activating protein-1
contraception. ATRA All trans retinoic acid
BCIE Bullous congenital ichthyosiform erythroderma

THERAPEUTIC GUIDELINES β-HCG β-Human chorionic gonadotropin

 Q20-12  Box 20-8 contains a therapeutic guidelines check- BMD Bone mineral density
list for retinoid therapy. Two key issues influence the CIE Congenital ichthyosiform erythroderma
decision-making process regarding the selection of appro-
priate retinoids for therapy. First, retinoids are the single CRABP Cytosolic retinoic acid binding protein
most effective category of drugs available for acne vulgaris DEXA Dual energy x-ray absorptiometry
and many disorders of keratinization, and are strong con-
DISH Diffuse interstitial skeletal hyperostosis
tenders for therapy in severe presentations of dermatoses
such as psoriasis, pityriasis rubra pilaris, and mycosis fun- GPP Generalized pustular psoriasis
goides. Second, major systemic adverse effects such as tera- HS Hidradenitis suppurativa
togenicity and ocular, bone, lipid, and liver adverse effects
make careful patient selection and ongoing laboratory sur- IBD Inflammatory bowel disease
veillance critical. Even after thoroughly addressing the LLA Lipid-lowering agent
items in Box 20-8, there are still significant potential risks
NMSC Non-melanoma skin cancer
with synthetic retinoid therapy. Only physicians thor-
oughly familiar with the risks, monitoring guidelines, and PASI Psoriasis area severity index
elements of patient education should prescribe the sys- PGA Physician’s global assessment
temic retinoids, especially bexarotene. Properly monitored,
some of the most gratifying clinical results in dermatology PRP Pityriasis rubra pilaris
can be obtained through the appropriate use of systemic PUVA Psoralen and ultraviolet A
retinoids.
RA Retinoic acid
RAR Retinoic acid receptor

ACKNOWLDGMENT RARE Retinoic acid response elements

RePUVA Retinoid and psoralen plus ultraviolet A
The Editor would like to thank Matthew J. Zirwas for his
contribution to the second edition of this chapter. ReUVB Retinoid and ultraviolet B
RXR Retinoid X receptor
TSH Thyroid-stimulating hormone

267
20  PART IV    SYSTEMIC IMMUNOMODULATORY AND ANTIPROLIFERATIVE DRUGS
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Bone effects
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268.e3