Drug-induced acne

Jana Kazandjieva MD, PhD, N. Tsankov MD, PhD

PII: S0738-081X(16)30268-1
DOI: doi: 10.1016/j.clindermatol.2016.10.007
Reference: CID 7105

To appear in: Clinics in Dermatology

Please cite this article as: Kazandjieva Jana, Tsankov N, Drug-induced acne, Clinics in
Dermatology (2016), doi: 10.1016/j.clindermatol.2016.10.007

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 ACCEPTED MANUSCRIPT

Drug-induced acne

Jana Kazandjieva, MD, PhD1, N. Tsankov, MD, PhD2

1
Department of Dermatology and Venereology - Medical University, Sofia, Sofia, Bulgaria
2
Department of Dermatology and Venereology – Tokuda Hospital, Sofia, Bulgaria

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+35925230511
janaderm@abv.bg

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need tel, fax, and e-mail

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Abstract
A variety of drugs may provoke acne with drug induced acne (DIA) often

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having some specific clinical and histopathologic features. DIA is characterized
by a medical history for drug intake, sudden onset, and an unusual age of onset,
with a monomorphous eruption of inflammatory papules or papulo-pustules. The
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location of the acne lesions is beyond the seborrheic zone. Corticosteroids,
anabolic steroids, testosterone, halogens, isoniazid, lithium and some new
anticancer agents are drugs with undoubted causal relationship to acne. The
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diagnosis of DIA is made by a detailed history with a record of drug onset,

dosage regimen and therapy duration, absence of additional triggering factors,
clinical relationship between the introduction of the drug ,and the onset of an
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acne-like eruption. In all cases, the withdrawal of the drug should be followed
by improvement of the acne lesions.
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Drug-induced acne (DIA) is a common skin condition whose classic signs

resemble true acne. DIA is provoked by a variety of drugs and has some
specific clinical and histopathologic features. The culprit drug can be one orally
administered, topically applied, or even inhaled. The earliest report of DIA
dates from 1928, when acne-like lesions were described with the use of iodides
and chlorinated hydrocarbons1.

Drug induced acne (DIA) is very similar to common acne; yet, there are a
number of differences to distinguish its clinical picture. DIA is characterized by:
medical history for drug intake; sudden onset; unusual age of onset; appearance
on the face and neck, and an unusual location of the lesions beyond the
seborrheic areas. The eruption consists of inflammatory papules or papulo-
pustules; comedones, if present, are secondary lesions2(Table I).

Table I. Differences between DIA and Acne vulgaris

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Clinical signs Acne vulgaris DIA

Medical history no history for drug history of present illness
intake and/or drug intake

Onset onset during teenaged Sudden onset

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years, or late onset (occurrence often away
beginning after the age from acne age)

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of 25 years (adult acne)

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Acne localisation appearance on the face, appearance on the face

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chest, and back and neck, unusual
location of the lesions
beyond the seborrheic

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areas
Acne lesions polymorphous monomorphous
eruption: comedones, eruption: inflammatory
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papules, pustules, papules or papulo-
nodules, and cysts pustules; no comedones
or if present, they are
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secondary lesions

Therapy conventional acne resistance to

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therapy conventional acne

therapy
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Prognosis Acne can almost always Lesions disappear with

be controlled with the discontinuation of
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medication; however, the inducing drug

results may not be seen
for weeks or months.

The number of patients with DIA is currently rising. Considering their acne
inducing capacity, drugs related to acne fall into the following categories:
- Drugs with undoubted causal relationship to acne
- Drugs about which there are considerable, though insufficient data
- Drugs occasionally reported to be associated with acne (Table II)3

Table II. Drugs with acne inducing potential

Drugs with Drugs with Drugs occasionally

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undoubted causal considerable, but associated with acne

relationship to insufficient data
acne

Corticosteroids Cyclosporine A Vitamin B6

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Anabolic steroids Tacrolimus, Vitamin B1

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Sirolimus
Testosterone Vitamin B12 PUVA

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Isoniazid Vitamin D2 Propylthiouracil
Halogens (Iodines, Phenobarbiturates Anticancer agents

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Chlorides, Bromides) (VEGFi, anti-TNF-α)
Anticancer agents Disulfiram Voriconazole

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(EGFRi, BRAFi
MEKi,)
Lithium Azathioprine Dactinomycin
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Quinidine Rifampicin
Amoxapine Etanbutol
TNF-alpha inhibitors Sertraline
Tetraethynilthiuram Muscle relaxant
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(Dantrolene)
Tricyclic
antidepressants
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(Amineptine)
Thireostatica
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(Thiouracil)

Corticosteroids
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Systemic corticosteroids, inhaled steroid therapy, or use of huge amounts of

topical corticosteroids are often culprit for the induction and exacerbation of
acneiform lesions. Steroid induced acne often appears in patients with collagen
vascular diseases or with neurologic pathology that requires protracted courses
of oral corticosteroids. Steroid acne has become more common, following the
advent of organ transplant surgery and chemotherapeutic regimens4.

Factors predisposing to steroid acne are high concentration of the drug,

application under occlusion, young adults below age 30, whites in preference to
blacks, and application to acne-prone areas of face and upper part of the back5.
The exact pathogenesis of steroid acne is still uncertain. The accelerated
chronologic progression of infundibular spongiosis, hyperkeratosis,
microcomedo formation, and hair follicular rupture is significant for the
development of the papules and papulo-pustules in steroid acne4 Several reports
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have shown that steroid-induced TLR2 together with P. acnes play an important
role in the exacerbation of acne vulgaris6.
The severity of the acne eruption seems to depend on the dose, the treatment
duration, and the medical history of acne. The eruption usually starts, following
several weeks of treatment. It is located predominantly on the trunk and

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extremities with less involvement of the face. It is possible that the use of a
facial mask may concentrate the exposure to inhaled corticosteroids, thus

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leading to acneiform eruptions in the midfacial region7.

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The clinical picture consists of a monomorphous papulo-pustular eruption.

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Comedones may be present predominantly in cases with topical steroid
application. Nodules and cysts are rarely observed. Steroid acne has been
described with a similar clinical picture to Pityrosporum folliculitis8.

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Steroid acne usually resolves after discontinuation of the drug. Conventional
treatment for acne vulgaris is recommended, if the steroid drug should be
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continued. Tretinoin topically is often preferable9.

Anabolic steroids
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Anabolic-androgenic steroids (AAS) represent a class of synthetic steroid

hormones related to the testosterone. The use of self-administered AAS by
recreational bodybuilders is a well-recognized phenomenon. Acne is one of the
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most frequent adverse effects of these drugs, but for many users it has been an
acceptable one10. DIA occurs in about 50 % of AAS abusers11 after use of large
doses of both human and veterinary preparations. ‘Sus’ and ‘Deca’ are terms
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usually used for Sustanon, a preparation of four testosterone esters and for
nandrolone decanoate.
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Androgens are also used as anabolic reagent to treat muscle wasting.

Attenuated androgens (Stanozolol - 0.5 - 2.0 mg daily) are also helpful in the
treatment of hereditary angioedema.

High dosages of testosterone and anabolic-androgenic steroids increase skin

surface lipids, the cutaneous population of Propionibacterium acne and the
cholesterol and free fatty acids of the skin surface lipids. Examination of skin
biopsy specimens from persons using AAS demonstrates dramatic hypertrophy
of the sebaceous glands12. The mechanism of action of AAS may differ between
compounds due to variations in the molecule and affinity to androgen receptors.

The clinical picture of AAS induced acne consists of aggravation of preexisting

acne vulgaris, male pattern hair loss, and hirsutism. Acne fulminans and acne
conglobata have also been described as induced by anabolic steroids.
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Therapy is difficult, because the patients are often unwilling to admit using
AAS. It is important to advise them to stop these drugs. Standard acne treatment
determined by the severity of the clinical picture is helpful in the majority of
AAS induced acne.

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Testosterone
For most clinical applications, testosterone is administered as longer acting

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esters through intramuscular injections, surgical implantation for implants and

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pellets, or transdermal delivery, such as patches and gels. In general, these
routes of administration are not very convenient and are sometimes associated

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with fluctuation in serum testosterone level followed by testosterone induced
acne and hirsutism13. Testosterone induced acne may be observed in both sexes.
In men, testosterone is used to treat hypogonadism and excessively tall stature.

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Hormone replacement therapy in aging men has also been reported to improve
body composition, plus bone and cartilage metabolism. High dose testosterone
treatment seems to trigger acne fulminans14. Patients asking for hormonal height
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reduction should be aware of this rare but serious side effect. Аcne fulminans
may be observed in 1-2% of adolescent boys treated for excessively tall stature
with testosterone15.
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In women, late onset acneiform eruptions are observed after testosterone

replacement therapy following ovariectomy. Testosterone administration to
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postmenopausal women is controversial but still practiced. Some studies

indicate acne and/or hirsutism after use of methyltestosterone replacement
therapy in up to 38% and 36% of the patients, respectively; other studies suggest
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a much lower incidence of approximately 5%16. Postmenopausal women have

been treated with testosterone patches, due to a newly described 'hypoactive
sexual desire disorder.” Acne, hirsutism, hair loss, and deepening of the voice
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occurrs more frequently in women using testosterone patches than in women on

placebo. In about 30% to 60% of the affected women, these adverse effects
failed to resolve on treatment cessation17.

In both sexes, testosterone is used for the treatment of protein wasting diseases
associated with cancer, burns, traumas, AIDS, anemia secondary to chronic
renal failure, aplastic anemia, and hereditary angioedema. In all the above-
mentioned instances, testosterone induced acne is noted as a side effect.

Generally, retinoids are the treatment of choice, when therapy with testosterone
is to be continued.

Lithium
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Lithium is used in psychiatry in the form of lithium citrate and lithium

carbonate, mainly for treatment and prophylaxis of affective psychic disorders.
Long term lithium therapy causes a variety of dermatologic problems, such as
DIA and psoriasis18. Men taking lithium are more susceptible to developing
cutaneous reactions,19.

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Lithium works not through an androgen receptor mechanism, but through direct,

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sometimes toxic effects, on the follicular epithelium20. It is questionable

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whether, as in other dermatoses, the serum level of lithium plays a role in the
provocation of DIA. Lithium induced acne is probably caused by neutrophilic

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chemotaxis and their degranulation inducing the inflammatory cascade (as in
psoriasis). Follicular plugging due to direct influence of lithium on the follicular
keratinocytes adds to the mechanism of action19.

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Acne lesions due to lithium appear 2-6 months after the start of the therapy1,21.
The clinical pictures consist of monomorphic, papulopustular eruption of the
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face, trunk, and extremities. Severe forms, such as acne conglobata and
hidradenitis supporativa, have been described22. Usually, postinflammatory
scarring is present.
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Therapy is extremely difficult. Oral retinoids are not the appropriate treatment
for this type of acne, as depression is a known side effect in about 1 percent of
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patients taking it. Also, the interaction between lithium and tetracycline must
be recalled; co-administration may result in elevated lithium levels. Some
psychiatrists suggest discontinuation of lithium and switching to alternative
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drugs.

Other drugs used in psychiatry and neurology such as Sertraline23,

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Ethosuximide24, Escitalopram oxalate25 and Quetiapine26 have also been

described to induce acneiform eruptions.,

Isoniazid
Considering the various types of skin eruptions induced by antituberculous
drugs, acneiform eruptions are mild and less common 27. Isoniazid has been
reported as a cause for acneiform eruptions - alone or in combination with
rifampicin and ethambutol28, 29. The frequency of isoniazid induced acneiform
eruption is estimated at 1.42% - 2.5%8,30. Isoniazid may induce acne and
pellagra due to slow inactivators of the drug31.???

The skin lesions develop after long-teerm treatment with isoniazid. The clinical
picture consists predominantly of inflammatory follicular papules. Usually, the
eruption is mild, but there are some reports describing more severe forms of
acne including SAPHO syndrome32.
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Isoniazid induced acne resolves after the discontinuation of the drug.

Halogens (Iodines, Chlorides, Bromides)

Chemicals that contain iodines, bromides, and other halogens can also induce an

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acneiform eruption similar to that of steroid acne. Iodines and bromides

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frequently cause acne-like eruptions or exacerbate pre-existing acne. Fluoride in

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toothpaste has also been implicated in acne-like eruptions, but this is
questionable.

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Iodines are found in many asthma preparations, expectorants, and kelp
containing supplements and tees??, combined mineral and vitamin supplements,

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contrast dyes. There is a debate linking iodine containing milk and acne,33
which raises three questions: whether levels of iodine in milk are too high and
therefore contribute to acne; what is the source of the iodine; whether there is a
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valid link between iodine and acne vulgaris, per se.

Sedatives, analgesics and cold remedies may still contain bromides in some
countries and in rare cases and long-time therapy can cause acne-like eruption.
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Herxheimer full name and dates. This contradicts the introductory

paragraphfirst described chloracne in 1899. Since then, the history of chloacne
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tends to mirror the technologic advances of the twentieth century. The main
group of chloracnegens includes dioxins, naphthalenes, biphenyls,
dibenzofurans, azobenzenes ,and azoxybenzenes. Usually, chloracne is due to
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dioxins and systemic poisoning most often in occupational settings. Dioxin is

the common name for dibenzo-p-dioxins and dibenzofurans, contaminants
nearly ubiquitous in the environment and highly resistant to chemical and
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biological degradation34. An industrial accident in a reactor producing 2,4,5-

trichlorophenol resulted in the release of a gaseous cloud containing
chlorophenols in Seveso, Italy, in 1976. In 193 of 5000 exposed people, signs of
chloracne were seen 30–60 days after acute exposure. The main chloracnegen
was believed to be 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), absorbed35. An
outbreak of chloracne among seven discovery chemists has been reported. The
chemists synthesized novel polycyclic halogenated chemical compounds, which
were classified as triazoloquinoxalines36.

Chloacnegens exert their biologic effects by binding to an intracellular receptor,

the aryl hydrocarbon receptor. Activation of this receptor leads to the induction
of cytochrome p450 1A1. Expression of cytochrome p450 1A1 in human skin is
a key marker for the activation of aryl hydrocarbon receptor, and it may induce
comedogenesis resulting in acne-like lesions known as chloracne/metabolizing
acquired dioxin-induced skin hamartomas (MADISH)37.
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The clinical picture consists of diffuse acneiform lesions distributed commonly

on the face and on body areas not usually affected by acne. Very characteristic
for this type of acne are the comedo-like lesions and yellowish cysts on the face.
Such skin changes can spread to the trunk and other body regions. The color of

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the skin is grayish. Chloracne is sometimes associated with hypertrichosis and
areas of folliculitis. Internal changes involving the ophthalmic, nervous, and

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hepatic systems may also occur.

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Treatment consists of discontinuation of the culprit drug or food additive.

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Vitamins B6 and B12
There are only a few studies discussing the role of vitamins B6 and B12 in the

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induction or aggravation of acne38.Exacerbation or onset of DIA has been seen
with high doses of B12 (5 to 10 mg/week). There is not an established dose
concerning vitamin B6. There are reports of development of acneiform lesions
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following intramuscular or oral vitamin B12 supplementation. Diagnosis in all
case reports was based on a positive time relationship, with an average duration
of 2 weeks between the start of supplementation and the onset of signs39.
Confirmation of the diagnosis by a positive provocation test was performed in
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one case40. In another case, the authors found a positive time relationship
between doubling of the multivitamin supplementation and the onset of the
acneiform lesions39.
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The exact mechanism of DIA by vitamin B6 and B12 is not certain. 41 Possibly,
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prolonged excretion of vitamin B12 might cause an irritation of the follicular

epithelium and produce an inflammatory reaction. In addition, sorbitol or iodine
present in some ampoules of B12 might be involved in the pathogenesis.
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The incubation period varies from the immediate appearance of skin lesions
after the first injections to 13 days following it. The acneiform eruption is a
monomorphic one42.The clinical picture consists of disseminated small follicular
papules or papulopustules on the face (especially on the forehead and chin), on
the upper parts of the back and chest and upper arm43. A single case of severe
acne rosacea, temporally associated with a daily ingestion of 100 mcg of B12
(with 100 mg of B6) has been reported. The rash resolved upon discontinuation
of both drugs and recurred upon readministering half the doses44.

This acneiform rash fails to respond to the usual treatment but generally fades
within a short time after vitamin B6 or vitamin B12 treatment has been stopped.
Characteristically, the skin lesions disappear within 8 to 10 days after stopping
Vitamin B therapy.
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New anticancer agents

Epidermal growth factor receptor inhibitors
Epidermal growth factor receptor (EGFR, also known as ErbB-1 or HER-1)
inhibitors are either tyrosine kinase inhibitors or monoclonal antibodies that
slow down or stop cell growth.

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EGFR inhibitors used in oncology often cause drug induced acne. About 85% of

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treated patients develop more or less extent acneiform eruption 45. Acneiform

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eruptions may occur during treatment with various kinase inhibitors, such as
erlotinib, dovitinib, imatinib, lapatinib, sorafenib, and sunitinib. Some authors46

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believe that terms as acne, acne-like, or acneiform drug eruptions should be
avoided and suggest papulo-pustular rash as a correct diagnosis for this skin
changes. Also the term 'late acneiform toxicity of EGFR inhibitors (LATE)

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syndrome' has been proposed47.

The pathogenic mechanism is unclear and differs from acne vulgaris. EGFRI
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can block the normal development, differentiation, and functioning of the
keratinocytes and thus cause occlusion of the hair follicles. In addition, EGFRI
can lead the sebaceous glands to increase production of inflammatory mediators.
EGFRI induced acne is dose-dependent48 and occurs one week to several months
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after the initiation of the treatment. Usually, the skin eruption is mild to
moderate in severity. It consists of follicular papules and sterile pustules, which
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affect the face and upper part of the trunk 49 . Distribution of the eruption is
similar to acne vulgaris, but unlike acne, might affect areas such as the legs and
dorsal surface of the arms. Comedones are rarely found50, but there are some
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reports describing comedonal acneiform eruption following sorafinib and

dovitinib therapy51. Association with severe pruritus and Staphylococcus aureus
superinfection has been described.
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The histologic findings reveal increased numbers of inflammatory cells and

debris in the superficial dermis, varying degrees of oedema and vasodilation,
keratin plugs in dilated follicular infundibula and ruptured follicles.

Treatment options are not well standardized. Most reports52 indicate that topical
anti-acne products, oral tetracyclines, and oral corticosteroids constitute an
effective therapy. Clindamycin phosphate-benzoyl peroxide gel may be an
effective and safe option in the treatment of cetuximab-
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associated acneiform eruptions . .A promising treatment with vitamin K3
(menadione) has been proposed. Successful treatment with oral isotretinoin has
also been reported54. Topical Recombinant Human Epidermal Growth Factor is
proposed as an effective treatment option for EGFR inhibitor-
induced acneiform eruptions55.
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Curiously, EGFRI induced acne may even have a positive relation to survival56.

BRAF inhibitors (BRAFi) and MEK inhibitors (MEKi)

These inhibitors increase survival in BRAF mutant metastatic melanoma
patients. MEK inhibitor Trametinib has been the most extensively tested in

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metastatic melanoma and shows an overall survival benefit over standard
chemotherapy in this disease57. Trametinib frequently

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induces acneiform eruptions. In one study, 10 of 13 patients developed

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acneiform eruptions during the trial with trametinib alone (77%), while only,
three of 30 developed acneiform lesions in the combination trial (10%). Acne

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lesions developed within the first 2 weeks of the treatment. The clinical picture
is presented by multiple small inflamed pustules and papules that crusted very
quickly, with no conspicuous comedones58. A conventional regimen for acne

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treatment for 3–6 weeks has been found to be effective in such cases. DIA from
trametinib seems to diminish when dosed in combination with dabrafenib59.
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Vascular endothelial growth factor (VEGF) inhibitors
Bevacizumab is currently used to treat various neoplasms, including colorectal,
lung, breast, kidney cancer, and glioblastoma. Development of follicular
acneiform skin eruption has been reported in the literature60.
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Tumor necrosis factor α antagonists

Tumor necrosis factor α antagonists are potent biologics used to treat a variety
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of autoimmune diseases including rheumatoid arthritis, Crohn’s disease,

psoriasis, and psoriatic arthritis. These medications are recognized to have many
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side effects (eg, infusion reactions, cytopenia, risk for infection, heart
failure).;however, only a few cases of DIA have been associated with the use of
tumor necrosis factor α antagonists. A small number of DIA cases caused by
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infliximab61, adalimumab62 and etanercept are reported in the liteature63. These

cases emphasize a paradoxical reaction very similar to the occurrence of anti-
TNF-α-induced psoriasis.

Chemotherapeutics
Capecitabine is a chemotherapeutic agent, which converted following
administration to fluorouracil by thymidine phosphorylase. It is one of the
commonly used agents for colorectal and metastatic breast malignancies. The
most frequently observed adverse effect from capecitabine is hand-foot
syndrome, but acneiform drug eruptions have also been described64.
In most of the cases, DIA by anticancer agents is reversible after drug
discontinuation.

Immunosupressants
An Italian study on the incidence of cutaneous manifestations among kidney
transplant recipients showed that 54% of patients developed acneiform eruptions
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of the face, upper aspects of the trunk, or arms65. A patient with acneiform
eruption on the breast66 has been described. This patient was with renal
transplant and taking three immunosuppressant, namely tacrolimus, leflunomide,
and prednisone. Upon discontinuation of tacrolimus, there was a significant
decrease in the development of new acneiform lesions, supporting the diagnosis

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of immunosuppressant-induced acneiform eruption.

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An acneiform eruption was the fourth most common (36%) mucocutaneous side

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effect in 50 renal transplant recipients receiving sirolimus-based
immunosuppressive therapy, where therewas no correlation between the daily

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dose of sirolimus and the development of DIA67.

A patients have developed a cyclophosphamide associated acneiform eruptions68

Diagnosis
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There are four points to be considered for making the diagnosis of DIA3
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1. Detailed history with a record of drug onset, dosage regimen, and therapy
duration
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2. Absence of additional triggering factors (hormonal levels, occupation)

3. Clinical relationship between the introduction of the drug and the onset of
an acne-like eruption
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4. Withdrawal of the drug followed by improvement of the dermatological

status
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Differential diagnosis of DIA

Some conditions mimic DIA. The most common differential diagnosis is

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Pityrosporum folliculitis produced by an overgrowth of the Malassezia species,

often secondary to oral or systemic corticosteroids or secondary to broad-
spectrum antibiotics such as the tetracyclines. This is often misinterpreted as
'tetracycline-resistant acne'. Other folliculitides from bacterial origin,
eosinophilic ustulosis, and some clinical forms of rosacea should be considered.

Conclusions
DIA is a well-established subgroup of acne. Distinguishing acne from DIA is
often a difficult task. Dermatologists easily identify different forms of acne such
as acne conglobata or acne fulminans ,but DIA may often present a pitfall for
clinical diagnosis. The clinical picture often resembles true acne; however, the
list of drugs causing or precipitating acne is daunting with new agents,
especially chemotherapeutic agents being added every year. For these reasons,
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a detailed history and the relationship between the introduction of the drug and
the onset of acne-like eruption are important..

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