Am J Clin Dermatol 2011; 12 (4): 233-245

REVIEW ARTICLE 1175-0561/11/0004-0233/$49.95/0

ª 2011 Adis Data Information BV. All rights reserved.

Drug-Induced Acneiform Eruption

Aurélie Du-Thanh, Nicolas Kluger, Houdna Bensalleh and Bernard Guillot
Department of Dermatology, University of Montpellier I, Saint-Eloi Hospital, Montpellier, France

Contents

Abstract. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 233
1. Diagnostic Criteria . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 234
2. Causative Agents. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 234
2.1 Hormones . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 234
2.1.1 Corticosteroids and Corticotropin (ACTH) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 234
2.1.2 Androgens and Anabolic Steroids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 235
2.1.3 Hormonal Contraceptives . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 235
2.1.4 Other Hormones . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 236
2.2 Neuropsychotherapeutic Drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 236
2.2.1 Tricyclic Antidepressants . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 236
2.2.2 Lithium . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 237
2.2.3 Antiepileptic Drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 237
2.2.4 Aripiprazole . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 237
2.2.5 Selective Serotonin Reuptake Inhibitors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 237
2.3 Vitamins B1, B6, and B12 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 237
2.4 Cytostatic Drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 237
2.4.1 Dactinomycin (Actinomycin D) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 237
2.4.2 Other Cytostatic Drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 237
2.5 Immunomodulating Molecules . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 238
2.5.1 Cyclosporine (Ciclosporin) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 238
2.5.2 Sirolimus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 238
2.5.3 Other Immunosuppressants . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 238
2.6 Antituberculosis Drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 238
2.6.1 Isoniazid . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 238
2.6.2 Rifampin (Rifampicin). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 238
2.6.3 Ethionamide . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 238
2.7 Halogens. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 238
2.7.1 Iodine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 239
2.7.2 Bromine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 239
2.7.3 Chlorine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 239
2.7.4 Other Agents. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 240
2.8 Miscellaneous Drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 240
2.9 Targeted Therapies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 241
3. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 242

Abstract Drug-induced acne is a specific subset of acne that usually has some specific features, namely a mono-
morphic pattern, an unusual location of the lesions beyond the seborrheic areas, an unusual age of onset,
a resistance to conventional acne therapy and, of course, the notion of a recent drug introduction. Many
drugs can be responsible for such a clinical pattern. Corticosteroids, neuropsychotherapeutic drugs,
234 Du-Thanh et al.

antituberculosis drugs, and immunomodulating molecules are the more classical drugs associated with
induced acne. Recently, new drugs, mainly targeted therapy in the field of oncology, such as epidermal
growth factor receptor inhibitors, have been associated with an increased frequency of this adverse effect.
Disruption of the culprit drug is rarely mandatory in cases of drug-induced acne. Close cooperation between
the dermatologist and medical staff in charge of the patient is an important challenge to achieve optimal
management of the initial disease.

Acne is defined as a chronic disease of the pilosebaceous Table I. ‘Old’ and ‘new’ drugs involved in acneiform eruptions
follicle and is a frequent motive for referral in dermatology. Hormones
Whereas hormone-dependent juvenile acne is the more frequent Local and systemic corticosteroids
subset, some cases are related to a specific etiology especially
Corticotropin (ACTH)
during adulthood, including mechanical and drug-induced acne,
Androgens and anabolic steroids
with the latter being defined by the occurrence of an acne-like
Hormonal contraceptives
eruption arising after medication intake. Numerous drugs have
Other hormones (thyroid-stimulating hormone, danazol)
been classically involved or at least associated with this subset
Neuropsychotherapeutic drugs
of acne. The development of new molecules, especially among
Tricyclic antidepressants (amineptine, maprotiline, imipramine)
the so-called targeted therapies in the field of oncology, has also
been associated with an increased observation of such adverse Lithium

events (table I). Antiepileptic drugs

We review the clinical characteristics of drug-related acne Aripiprazole

and their possible specificity as to the involved triggering Selective serotonin reuptake inhibitors
molecules. A literature search was conducted to retrieve these Vitamins
data in PubMed, using the keywords ‘drug-induced acne’ and Vitamins B1, B6, B12
‘drug-induced acneiform rash or eruption.’ Cytostatic drugs
Dactinomycin (actinomycin D)
Azathioprine, thiourea, thiouracil
1. Diagnostic Criteria
Immunomodulating molecules
There are no specific criteria to define drug-induced acne. Cyclosporine (ciclosporin)
However, several characteristics that are summarized in table II Sirolimus
may be of help to support a potential relationship between drug Others: topical tacrolimus, topical pimecrolimus
ingestion and acne.[1,2] Taken one by one, these criteria are not Antituberculosis drugs
enough to make the diagnosis as, for instance, some drugs may Isoniazid
be responsible for retentional acneiform lesions. However, Rifampin (rifampicin)
taken all together, these criteria may shed light on the imput-
Ethionamide
ability of a treatment. Diagnosis may sometimes be difficult
Halogens
and a rigorous search for a causative drug must be conducted in
Iodine
all suspected cases.
Bromine
Chlorine
2. Causative Agents Others: halothane gas, lithium
Miscellaneous
2.1 Hormones
Dantrolene

2.1.1 Corticosteroids and Corticotropin (ACTH) Quinidine

Corticosteroid-induced acne was first described during the Antiretroviral therapy

1950s.[3,4] This subset of acne may be observed after topical Continued next page
corticosteroid application,[5] systemic oral or intravenous

ª 2011 Adis Data Information BV. All rights reserved. Am J Clin Dermatol 2011; 12 (4)
Drug-Induced Acneiform Eruption
Table I. Contd
Targeted therapies
EGF inhibitors
cetuximab, panitumumab
Multitargeted tyrosine kinase inhibitors
gefitinib, erlotinib, lapatinib
sorafenib, sunitinib
imatinib
VEGF inhibitor: bevacizumab
Proteasome inhibitor: bortezomib
TNFa inhibitors
lenalidomide
infliximab
Histone deacetylase inhibitor: vorinostat
EGF = epidermal growth factor; TNFa = tumor necrosis
VEGF = vascular endothelial growth factor.
intake,[6] and even after inhaled administration.[7,8] Acne has
also been reported after treatment with corticotropin.[3,9] The
eruption begins after a variable delay, from shortly after the
introduction of topical or oral therapy (usually 2–4 weeks) to
several months. Dosage, duration of administration, and in-
dividual susceptibility play a role in the clinical presentation.
The clinical pattern is classically a monomorphic eruption of
small, flesh-colored or pink-to-red, dome-shaped inflamma-
tory papules and pustules of the seborrheic areas (face, trunk),
and a potential extension to the upper extremities (figure 1 and
figure 2). After this initial phase, the inflammatory papules
resolve, while closed and open comedones or small keratin cysts
appear on the same areas several months later. If corticosteroid
dosage is low, the eruption may consist only of comedones.
Inhaled and topically applied corticosteroids may be respon-
sible for perioral dermatitis, which often occurs in patients re-
ceiving excessive doses or very protracted treatment (2–18 years’
duration).[7,8,10]
2.1.2 Androgens and Anabolic Steroids
The effect of androgens on sebaceous glands is responsible
for the development of adolescent acne. Therefore, any androgens
or anabolic steroids with androgenic activity will inevitably
affect sebaceous glands because of their structural analogy with
endogenous androgens. Fyrand et al.[11] performed a com-
parative, retrospective study in 176 Norwegian boys (mean age
14 years), 90 of them having being treated with an injectable
testosterone blend for premature closure of epiphysial growth
zones, and a prospective study in 23 boys over a 24-month
period. They observed a clear increase in acne incidence in the
ª 2011 Adis Data Information BV. All rights reserved.
235
treated group. Some boys developed severe papulopustular and
nodulocystic acne, including four cases of acne fulminans. Acne
appeared on the face and the trunk from 1 week to 2 months
after initiation of androgen injections.[11]
Acne in young men should prompt the clinician to look for
any anabolic androgenic steroid (AAS) intake in the context of
fitness/body building practice (‘body building acne’) or any
another sport (‘doping acne’).[12-14] Indeed, approximately 50%
of AAS abusers present with acne. Clinical presentation ranges
from exacerbation of seborrhea to papulopustules, acne con-
globata, or acne fulminans.[13] Acne may have appeared de novo
or pre-existing acne may be found while taking the medical
history. Furthermore, acne may be more difficult to treat if
AASs are being taken. Concomitant vitamin abuse (vitamin B6
and B12) should also be considered as it may also potentially
factor-a;
trigger acne (see section 2.3). Other symptoms that suggest AAS
abuse include gynecomastia, striae, edema, increased body
mass index, and a decrease in testicular volume. Treatment is
the immediate withdrawal of AAS followed by conventional
management of acne.[13]
2.1.3 Hormonal Contraceptives
Hormonal contraceptives can worsen pre-existing acne
or induce it. The molecules responsible for such effects are
Table II. Characteristics supporting a relationship between drug introduction
and acneiform eruption
Anamnesis
1. Unusual age of onset: before or after teenage and early adulthood
(aged >30 years)
2. Abrupt onset of acne in the absence of past history of acne vulgaris
or
Unusual severity of an acne flare in a patient with a past history of ‘classic’
mild acne vulgaris
or
Aggravation of pre-existing acne
Clinical presentation of acne
1. Monomorphic, inflammatory clinical pattern of the lesions
2. Lack of comedones and cysts or their late appearance secondary to
inflammatory lesions
3. Unusual localization of acne: extension beyond the seborrheic area,
such as the arms, trunk, lower back, and genitalia
Resistance to conventional acne therapy
Time relationship
1. Delay of onset after recent drug implementation
2. Improvement after drug withdrawal
3. Recurrence after drug reintroduction
Am J Clin Dermatol 2011; 12 (4)
236 Du-Thanh et al.

features. Indeed, they were predominantly women, mainly aged

Fig. 1. Corticosteroid acne: monomorphic inflammatory papules on the
face.
progestogens with androgenic activity or low-dose estrogens.
Recently, cases of acne induced by etonogestrel implants (Im-
planon; Schering-Plough, Kenilworth, NJ, USA) have been
reported in up to 26.8% of women using this contraceptive
device.[15] However, acne incidence related to contraceptive
implants varies according to clinical studies.[16-18] Moreover,
several patients with new-onset acne after the placement of a
levonorgestrel-releasing intrauterine system were reported to
have developed inflammatory papules localized to the jawline
and/or the back 1–3 months after insertion.[19,20]
>40 years, with a severe psychiatric background (depression,
schizophrenia, etc.).[23,34] They all disclosed a strikingly abrupt
onset of monomorphic lesions composed of microcysts, mac-
rocysts, and comedones of varying size. Inflammatory lesions
were usually absent. Lesions were located mainly on the face
and auricles but could also extend to the neck, chest, back, and
genitalia. Eruption occurred many months or years after ini-
tiation of the treatment and severity was related to high-dose,
long-term amineptine intake. The use of supratherapeutic
dosage (up to 100 tablets a day![22]) was often reported and
revealed a trend for toxicomania. On some rare occasions, the
patient denied amineptine intake.[24] Amineptine and its by-
products could be detected in serum, urine, and also within the
skin lesions. Histologic examination was usually nonspecific,
but on some rare occasions involvement of the eccrine sweat
glands with keratinizing syringometaplasia and areas of neu-
trophilic eccrine hidradenitis were observed, and the term ‘ad-
nexal drug eruption’ was proposed for this subset of lesions.[29]
Treatment included the complete withdrawal of amineptine,

2.1.4 Other Hormones

Rare cases of drug-induced acne have been reported with
thyroid hormone and gonadotrophins.[9] Danazol (2,3-isoxazole-
17b-ethinyltestosterone) is a known antigonadotropin used in
the management of hereditary angioedema and endometriosis.
It has been shown in studies and case reports to induce acne in
female patients.[21]

2.2 Neuropsychotherapeutic Drugs

2.2.1 Tricyclic Antidepressants

Amineptine
In 1988, Thioly-Bensoussan et al.[22] published striking ob-
servations of a new subset of drug-induced acne after amineptine
intake. Rapidly, a large number of similar cases were reported
in 1988 during the French Congress of Dermatology.[22-26]
Since then, over 30 cases have been reported.[27-34] Amineptine
is a non-halogenated tricyclic antidepressant that was widely
used before its withdrawal in January 1999 because of the
high level of severe adverse events in France. Patients with
amineptine-induced acne presented with some characteristic Fig. 2. Corticosteroid acne: widespread inflammatory papules on the back.

ª 2011 Adis Data Information BV. All rights reserved. Am J Clin Dermatol 2011; 12 (4)
Drug-Induced Acneiform Eruption
surgical removal of macrocysts, and treatment with isotretinoin
(0.5–1 mg/kg/day).
Maprotiline
Maprotiline is also a tricyclic antidepressant. Only one case
of induced acne has been described with this molecule.[35]
Imipramine
In 1974, Ossofsky [36]
reported two cases of imipramine-
induced acne in a study of five patients that investigated the role
of imipramine in amenorrhea and endogenous depression. To
date, there have been no additional reports of imipramine-
induced acne.
2.2.2 Lithium
Acneiform eruption with lithium was reported during the
beginning of the 1970s.[37-39] Lithium-induced acne is more
frequent in men and among allergic patients.[40,41] The lesions
are often inflammatory, occur abruptly, and involve the face
but also the axilla, groin, arms, and buttocks.[37,42] There is no
obvious dose-effect relationship and acne may appear even with
normal serum lithium concentrations, although high concen-
trations of lithium may be observed in the skin, suggesting that
the drug can accumulate in the skin, which might result in lesion
occurrence.
2.2.3 Antiepileptic Drugs
Many antiepileptic drugs are responsible for drug-induced
acne, including, by order of frequency, phenytoin, pheno-
barbital, primidone, carbamazepine, and lamotrigine.[43-48] The
genuine liability of these drugs in acne remains controversial
and imputability must be cautiously documented. Indeed,
Greenwood et al.[49] did not observe any difference in acne se-
verity and sebum excretion rate between patients receiving
anticonvulsants and healthy control subjects. They concluded
that the association between acne and anticonvulsants was a
‘myth.’ However, several reports favor a significant role for anti-
epileptic drugs in acne occurrence.[43-48] Classically, the acne is
inflammatory with widespread papulopustules. One case of
keloidal acne of the scalp has been described during treatment
with phenytoin and carbamazepine.[46] A case of SAPHO
syndrome (synovitis, acne, pustulosis, hyperostosis, and ostei-
tis) after barbiturate initiation was reported and the authors
speculated on a potential link that could not be proved.[48]
2.2.4 Aripiprazole
Aripiprazole is a quinolinone antipsychotic acting as a partial
agonist at the dopamine D2 and serotonin 5-HT1A receptors
ª 2011 Adis Data Information BV. All rights reserved.
237
and antagonist at the 5-HT2A receptors. An Indian patient
developed a papulopustular eruption on the forehead and nasal
bridge 10 days after initiation of aripiprazole. Drug withdrawal
and local treatment allowed complete resolution of skin
symptoms within 10 days.[50]
2.2.5 Selective Serotonin Reuptake Inhibitors
Acneiform eruption occurs as folliculocentric pustules,
usually without comedones, on the face, chest, and upper aspect
of the back. This may occur with all the selective serotonin
reuptake inhibitors.[51]
2.3 Vitamins B1, B6, and B12
The first descriptions of vitamin B12-induced acne were
made during the 1950s.[52] Acne is predominantly observed in
women.[52-56] The eruption develops abruptly and shortly after
initiating vitamin B12 injections, usually after the first or second
injection (8–10 days).[53,55] The lesions consist of 10-40 in-
flammatory, monomorphous, voluminous papules and pus-
tules that are mainly located on the face. There are no
comedones or cysts, but hyperseborrhea may be noted. Lesions
usually heal quickly after vitamin B12 withdrawal. The cause is
still unclear. Acne is considered to be a clue for vitamin over-
load. Dupré et al.[55] suggested that iodine particles, which are
used for vitamin B12 extraction, would still be present in some
commercial lots.
Many pharmaceutical preparations of vitamin B12 also
contain vitamin B1 (thiamine) and/or vitamin B6 (pyridoxine),
but their role in acne development remains hypothetical.[55-57]
2.4 Cytostatic Drugs
2.4.1 Dactinomycin (Actinomycin D)
Acne induced by dactinomycin has been mainly reported in
men treated for testicular cancer,[58] most likely because of the
androgenic properties of the molecule. Moreover, dactinomycin
has a tricyclic chemical structure similar to some antidepressive
drugs. The lesions are most often inflammatory and appear in
the classical areas of acne vulgaris, usually after the fifth day of
treatment, and they are dose dependent. Comedones may occur
later on.
2.4.2 Other Cytostatic Drugs
Acne has been sparsely described with azathioprine, thiourea,
and thiouracil,[9,59] but the level of evidence for their imput-
ability is poor because of the lack of documented cases.
Am J Clin Dermatol 2011; 12 (4)
238
2.5 Immunomodulating Molecules
2.5.1 Cyclosporine (Ciclosporin)
Cyclosporine (ciclosporin) is an inhibitor of T-lymphocyte
activation that is used routinely during the management of solid
organ transplants and can also be used for the treatment of
various autoimmune and inflammatory diseases. Most of the
cutaneous adverse effects of cyclosporine involve the piloseb-
aceous unit, including hypertrichosis, epidermal cysts, keratosis
pilaris, folliculitis, and sebaceous hyperplasia.[60-67] Acne oc-
curs in approximately 15% of patients.[60] Acne may be severe
with a nodulocystic presentation[61,65,66] or may occur as acne
keloidalis.[64] Treatment includes isotretinoin therapy, with an-
ecdotal reports confirming its safety in transplant patients,[65-67]
and possible cessation of cyclosporine with a switch to another
immunosuppressive therapy.[61] Of note, coadministration of
isotretinoin and cyclosporine should prompt careful monitor-
ing of serum lipid levels.[66]
2.5.2 Sirolimus
Sirolimus is an immunosuppressive macrolide that is in-
creasingly used in post-transplantation immunosuppression. It
inhibits the mammalian target of rapamycin (mTOR), a protein
kinase involved in cytokine and growth factor signaling path-
ways. The frequency of acne is estimated to be from 15% to
25%.[68] However, a French prospective study revealed that an
acneiform eruption was present in 46% of the 80 consecutive
recipients of renal transplantation who were taking sirolimus.[69]
Acne occurs predominantly in male patients, especially those
with a history of severe acne vulgaris. There is no significant
correlation between acne severity and the sirolimus daily dose
or blood concentrations.[68] Sirolimus-induced acne is different
from acne vulgaris, with inflammatory papulopustules dis-
tributed on the seborrheic regions. Comedones and cysts are
absent. Lesions can extend to the forearms, arms, cervical area,
and scalp. Conventional local and oral treatments for acne
vulgaris can be proposed. Again, lipid levels should be moni-
tored when coadministering isotretinoin and sirolimus. Severity
of the acne may also lead to withdrawal of sirolimus treatment,
with an improvement of the symptoms.[68]
Sirolimus might induce acne because of its direct inhibi-
tion of epidermal growth factor (EGF) activity by inhibiting
the mTOR pathway, in a similar fashion to other specific EGF
inhibitors currently used in oncology (gefitinib, cetuximab, etc.).[68]
Of note, Lübbe et al.[70] successfully treated a patient who pre-
sented with a sirolimus-induced acneiform eruption associated
with an acquired reactive perforating collagenosis with hy-
droxychloroquine. The authors chose this treatment because of
ª 2011 Adis Data Information BV. All rights reserved.
Du-Thanh et al.
a predominantly lymphocytic infiltrate with perivascular and
perifollicular distribution and no neutrophilic folliculitis on
the biopsy.[70]
2.5.3 Other Immunosuppressants
Tacrolimus (FK-506) is another immunosuppressive macro-
lide that blocks the calcineurin-dependent pathway inside
T cells. Interestingly, there are to date no case reports of acne
with oral tacrolimus. However, there are anecdotal case reports
of facial acne induced by topical application of tacrolimus[71]
and pimecrolimus,[72] another calcineurin inhibitor.
2.6 Antituberculosis Drugs
2.6.1 Isoniazid
In 1959, Bereston[73] reported for the first time cases of
isoniazid-induced acneiform eruption in 16% of 2600 patients
receiving a combination of isoniazid and aminosalicylic acid.
Most of these patients were aged between 40 and 70 years,
which is beyond the average age for acne vulgaris. Acne pres-
ents as a sudden, extensive, efflorescence of lesions consisting
of open and closed comedones and inflammatory papules/
pustules or only inflammatory lesions. A slow acetylating pheno-
type among patients may be responsible for the isoniazid-
induced acne.[74] However, such a slow inactivation profile is
most likely not the sole factor, as the incidence of isoniazid-
induced acne remains low.[74] Acneiform eruption may occur
late (up to 18 months) after initiation of isoniazid, and can
improve with disruption of isoniazid.[74-77]
2.6.2 Rifampin (Rifampicin)
In 1974, Nwokolo[78] reported a case series of African patients
who started to develop chronic papular acneiform eruption on
the face, neck, and shoulders approximately 5 weeks after ini-
tiating combined tuberculosis treatment. Withdrawal of only
rifampin (rifampicin) led to the disappearance of the lesions
within 3 weeks.
2.6.3 Ethionamide
Ethionamide, a third-line drug for tuberculosis, was also
mentioned as a cause of acneiform rash.[79]
2.7 Halogens
Iodide, bromide, and chloride salt-containing drugs, which
are perhaps eliminated by sebaceous glands, are associated with
specific eruptions called iododerma, bromoderma, and chloracne,
respectively. Iododerma and bromoderma can present as large
Am J Clin Dermatol 2011; 12 (4)
Drug-Induced Acneiform Eruption
Fig. 3. Inflammatory papules and pustules on the nose during erlotinib
treatment for metastatic non-small-cell lung carcinoma.
violaceous and inflammatory nodules,[80] or sometimes as veg-
etating or bullous lesions, occasionally mimicking pyoderma
gangrenosum or ecthyma. Lesions may sometimes present only
as severe inflammatory acne of the face and trunk. However,
lesions may occur on any part of the body and are not specif-
ically located on sebaceous areas.
2.7.1 Iodine
Iododerma refers to the wide range of skin eruptions that
occur as a consequence of oral, parenteral, or topical iodine
administration. It has been reported extensively in the literature
since 1854.[81-97] The lesions may present as papules, vesicles,
and pustules but also as erythematous, urticarial, furuncular,
carbuncular, bullous, and sterile vegetating lesions that may
ulcerate. Lesions appear on the seborrheic regions (face, neck,
and back), but they may be more widespread and involve the
whole body.[85] Iododermas occur mostly in patients with renal
insufficiency as iodine is cleared by the kidneys. They have been
reported after various situations including intravenous injection
of iodinated contrast medium,[89] cardiac catheterization,[93]
urography,[84] lymphography,[85] iodized salt consumption,[82]
potassium iodide intake for thyroid protection,[86] and amio-
darone intake.[92] Histology shows a dense inflammatory in-
filtrate composed of neutrophils and eosinophils in the dermis.
In long-standing lesions, pseudoepitheliomatous hyperplasia
develops with epidermal abscesses.[86,93] Iodine serum levels are
above the normal range. Discontinuation of iodine intake is
sufficient to improve the patient’s symptoms, but local or systemic
corticosteroids may be necessary. The pathogenesis of iododerma
remains unclear. Various hypotheses have been suggested as
follows: cell-mediated immune reaction, inflammatory mech-
ª 2011 Adis Data Information BV. All rights reserved.
239
anism, and idiosyncratic reaction. Patients with such reactions
should be warned to avoid any contact or injection with iodine
products as recurrence may occur.[82]
2.7.2 Bromine
Bromoderma, defined as a skin eruption occurring in the
context of bromide intoxication, is infrequent nowadays.[98-101]
However, some drugs containing bromide are still available and
used for their sedative, antiepileptic, spasmolytic, and ex-
pectorant properties.[101] Moreover, some preparations are also
available as non-prescription compounds on the French mar-
ket.[100] The clinical cutaneous presentation is rather similar to
iododerma. Bromide intoxication is also responsible for hy-
perpigmentation, photosensitivity, and macular eruption.[98]
Diagnosis is confirmed by an elevated bromide level in serum
and urine.[98,100] Withdrawal of the culprit drug and conven-
tional acne treatments resolve the cutaneous symptoms.
2.7.3 Chlorine
Chloracne was first described in 1899 by Herxheimer.[102] It
is defined as an acneiform eruption secondary to a systemic
toxicity of exogenous exposure to polyhalogenated aromatic
hydrocarbons (dioxins, naphthalenes, biphenyls, dibenzofurans,
azobenzenes, and azoxybenzenes).[103] Exposure to chloracnegens
may be due to occupational exposure,[104] or to non-occupational
exposures to local environmental contamination[105] or environ-
mental hazards such as the Seveso accident.[103] Exposure may
also be familial or even as a result of a poisoning attempt.
The clinical presentation is rather different from acne vul-
garis and other halogenodermas. Patients present with come-
dones on the face, the malar crescent especially, and the
retroauricular folds but also on the forearms, back, chest, lower
Fig. 4. Papulopustular lesions on the seborrheic areas of the face during
gefitinib treatment.
Am J Clin Dermatol 2011; 12 (4)
240 Du-Thanh et al.

but, in this case, the patient presents an unusual clinical worsen-

Fig. 5. Severe acneiform eruption with disseminated hemorrhagic and
yellow crusts on the face during therapy with cetuximab for metastatic
colon cancer.
limbs, and genitalia. Interestingly, the nose is highly resistant
and therefore is spared by the eruption, giving an ‘‘island in
a sea aspect.’’ The axilla is also a specific area affected by
chloracne.[103] Lesions appear 6–12 weeks after first exposure.
In more severe cases, cysts may occur on the face and neck,
sometimes giving the appearance of plucked chicken skin.
Other cutaneous symptoms include folliculitis/follicular hyper-
keratosis, xerosis, and hyperpigmentation. There is no pustule
formation, in contrast to acne vulgaris.[104] Lesions may last up
to 15–30 years after chloracnegen exposure.[103] Treatment is
rather difficult as conventional treatments are often dis-
appointing in this indication.
ing of acne. Dantrolene-induced acne mainly consists of black-
heads, comedones, cysts, pustules, and abscesses. One specific
aspect is the elective localization of the lesions on the site of
chronic trauma, friction, or pressure. Patients are often con-
fined to their bed or a wheelchair because of their neurologic
condition and can consequently display lesions on the back,
extensor aspect of the forearms, axillae, buttocks, and perineum.
Isotretinoin is not recommended because of a cumulative
hepatotoxicity with dantrolene. If possible, a dose reduction or
switch from dantrolene to another treatment such as baclofen
should be proposed.[111] The physiopathology is unclear but
dantrolene is an hydantoin derivative and chemically similar to
phenytoin, which is known to be a cause of iatrogenic acne (see
section 2.2.3).
Acne has been observed with quinidine. Burkhart[112] reported
the case of a 57-year-old man who developed papulopustules on
the trunk and back within the first year of quinidine treatment.
Antiretroviral therapy has been associated with the devel-
opment of acne vulgaris and rosacea.[113] This phenomenon
may be interpreted as an immune restoration syndrome.

2.7.4 Other Agents

Halothane, a halogenated anesthetic gas, may trigger acne in
nurses or practitioners using this molecule.[106,107] Eruption
occurs within hours after exposure and recurs after each exposure
to halothane gas. It initially affects the face and then may be
more widespread.
Lithium was reported in two cases of halogenoderma-like
presentations.[108] The authors postulated on a potential
interaction between lithium intake and iodine metabolism.
Such an hypothesis has not been explored so far.

2.8 Miscellaneous Drugs

Dantrolene is a myorelaxing drug used to treat spasticity.

The first cases of dantrolene-induced acne were reported by
Joynt[109] in 1976. The eruption occurs from 6 months[110] to
4 years[111] after initiation without any correlation with daily Fig. 6. Inflammatory papules extending to the back during cetuximab
dosage. A past medical history of acne vulgaris may be noted[109,111] therapy.

ª 2011 Adis Data Information BV. All rights reserved. Am J Clin Dermatol 2011; 12 (4)
Drug-Induced Acneiform Eruption 241

This acneiform rash complies with the previously mentioned

Fig. 7. Histology of an acneiform lesion during cetuximab therapy: super-
ficial and florid neutrophilic suppurative folliculitis (original magnification ·10).
2.9 Targeted Therapies
Targeted therapies interact with specific key molecules in-
volved in the pathophysiology of inflammatory or tumoral
diseases. This therapeutic group includes specific and multi-
targeted tyrosine kinase inhibitors, such as gefitinib, erlotinib,
and imatinib; monoclonal antibodies, such as cetuximab,
panitumumab, and infliximab; soluble receptors, such as
etanercept; transcription modulators, such as vorinostat; and
proteasome inhibitors, such as bortezomib.
Acneiform eruption has quickly become a hallmark of some
of these molecules. For antitumoral therapies, such a rash is
classically reported as a prognostic factor for a good response
to treatment,[114] although such adverse effects may sometimes
lead to disruption of therapy.
criteria of drug-induced acne (see table II). The first and most
frequently reported cases are related to EGF receptor inhibitors
(EGFRIs). Monoclonal antibodies directed against EGF re-
ceptors (EGFRs) [e.g. cefuximab and panitumumab] and in-
hibitors of the EGFR-associated tyrosine kinases (e.g. erlotinib
and gefitinib) share similar cutaneous adverse effects.[115-119]
We chose to describe here the typical acneiform rash, independent
of the related drug. Targeted therapies previously reported as
acneiform rash inducers are summarized in table I.
The highest incidence of this rash concerns EGFRIs, affect-
ing 60–100% of patients according to published series.[117,120]
Monoclonal antibodies may be more frequently involved than
tyrosine kinase inhibitors. Patients with a past history of juvenile
acne or folliculitis are not more susceptible to development of
this adverse effect. Lesions usually appear after the first course
of treatment, and reach their maximal incidence between the
third and fourth weeks. Worsening of the lesions can be observed
after each course of the treatment. Spontaneous regression has
sometimes been described, but telangiectasia and hyperpig-
mentation have been described at the site of previous lesions.
After the 24th week of treatment, the rash is still ongoing in
only 37.5% of the patients, even if untreated.[121]
The typical acneiform rash consists of inflammatory papules
and pustules located on seborrheic areas of the face (figure 3 and
figure 4), although they can rapidly spread to the scalp, trunk,
and, more rarely, the limbs. Palms and soles are classically spared.
The lack of comedones is characteristic.[117,118] The rash can be
pruriginous. Crusted or hemorrhagic lesions have been described
in more severe forms, along with Sweet-like lesions (figure 5 and

Table III. National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events, version 4.03[122]
NCI grade Grade 1 Grade 2 Grade 3 Grade 4 Grade 5
Criteria for rash Papules and/or pustules Papules and/or pustules Papules and/or pustules Papules and/or pustules Death
acneiform covering <10% BSA, which covering 10-30% BSA, which covering >30% BSA, which covering any % BSA, which
may or may not be may or may not be associated may or may not be may or may not be
associated with symptoms with symptoms of pruritus or associated with symptoms associated with symptoms
of pruritus or tenderness tenderness; associated with of pruritus or tenderness; of pruritus or tenderness
psychosocial impact; limiting limiting self-care ADL; and are associated with
instrumental ADL associated with local extensive superinfection
superinfection with oral with IV antibacterials
antibacterials indicated indicated; life-threatening
consequences
Suggested Cosmetics Topical antibacterials: erythromycin, clindamycin, If treatment fails, decrease
management metronidazole, or benzoyl peroxide dosage or interrupt
Oral doxycyline 100 mg/d for 4 wk + topical corticosteroids for treatment of causative drug
5 d/wk
ADL = activities of daily living; BSA = body surface area; IV = intravenous.

ª 2011 Adis Data Information BV. All rights reserved. Am J Clin Dermatol 2011; 12 (4)
242 Du-Thanh et al.

Table IV. New targeted therapies involved in acneiform eruption

Molecule Target No. of reported cases or Mean delay of Evolution References
proportion of patients if occurrence
available
Imatinib C-kit, bcr-abl, PDGFR 1 2 mo NA 127
Sorafenib VEGFR-1, -2, and -3, 3 1 mo Spontaneous resolution within 2 wk 128-130
PDGFR, c-kit, RAF, etc. after sorafenib dosage decrease
Sunitinib VEGFR-2, PDGFR, etc. 6/116 (5% of the patients with NA NA 131
cutaneous manifestations)
Lapatinib EGFR, ErbB2 8? (probable acneiform rash) NA NA 132
Lenalidomide TNFa 1 3 mo Resolution with doxycycline 133
100 mg/d after 3 mo, no cessation
of lenalidomide therapy
Bevacizumab VEGFR 1 NA NA 134
Selumetinib MEK 35/59 (60%) NA NA 135
(AZD-6244)
Infliximab TNFa 7 1–5 mo Resolution with tetracyclines, no 136-138
cessation of infliximab therapy
Vorinostat Histone deacetylase 1 (but patient had also 5 wk after the end NA 139
received cetuximab) of treatment
Bortezomib Proteasome 6/25 (24%) 1 mo Resolution with prednisone, no 140
disruption of bortezomib therapy
EGFR = epidermal growth factor receptor; MEK = MAP kinase; NA = data not available; PDGFR = platelet-derived growth factor receptor; TNFa = tumor necrosis
factor-a; VEGFR = vascular endothelial growth factor receptor.

figure 6). Histologically, the lesions display a poorly specific
neutrophilic folliculitis along with perifolliculitis (figure 7),[117,118]
while no bacterial infection is detected on skin swabs.
The National Cancer Institute established Common Terminol-
ogy Criteria for Adverse Events (CTCAE) version 4.03, which
includes criteria for grading acneiform rash (table III).[122] Both
incidence and severity of rash seem dose dependent. Treatment
depends on the severity grading and guidelines have been es-
tablished. Tetracyclines are used to control severe lesions in
association with topical corticosteroids, but their efficiency is
sometimes limited. In a randomized, double-blind trial, oral
minocycline appears useful in an attempt to decrease the severity
of the eruption during the first month of treatment, whereas
tazarotene is not recommended.[123] The CYTAR study showed
that preventive treatment with oral doxycyline 100 mg/day
during erlotinib treatment for non-small-cell bronchopulmon-
ary cancer did not decrease the incidence of acneiform rash but
reduced its severity grade and did not influence the efficacy of
erlotinib.[124]
The underlying pathophysiologic mechanisms remain un-
clear, but the major tropism of EGFRIs for the skin and skin
appendages is obvious. This rash is a d-type adverse effect
(cross reaction) according to the classification of the im-
munobiologic drug adverse effects proposed by Pichler.[125]
There are EGFRs on keratinocytes that could become involved
with apoptosis, forming vesicles and then pustules.[126]
Acne has also been reported in association with other newer
targeted therapies, although the incidence and severity seem less
important so far than with the EGFRIs (table IV). Interestingly,
not all drugs from this family appear to be responsible for acnei-
form eruption. For instance, among the tumor necrosis factor-a
antagonists, only infliximab has been reported to cause acne thus
far. Lenalidomide, derived from thalidomide, has major anti-
tumor necrosis factor-a activity and has been described to be
responsible for an acneiform rash by Michot et al.[133]
3. Conclusions
Drug-induced acne is a frequent adverse effect. The increased
use of new targeted therapies in oncologic patients has been
associated with an increased incidence of acneiform eruption.
Medical history data may provide clues as to the potential role
of a newly introduced drug in the development of these erup-
tions, as do unusual clinical features, i.e. high age at onset,
atypical location, resistance to conventional therapy, and a
monomorphic clinical pattern. Moreover, some drug-related

ª 2011 Adis Data Information BV. All rights reserved. Am J Clin Dermatol 2011; 12 (4)
Drug-Induced Acneiform Eruption
eruptions are erroneously called induced ‘acne’; however, the
lack of comedones does not favor such a designation. There-
fore, the terms ‘acneiform eruption’ or ‘induced folliculitis’
should probably be considered instead.
Preventing drug-induced acne is often challenging. The main
issue in management remains whether the culprit drug should
be withdrawn. Direct discussion with the medical staff in charge
of the patient is mandatory in making this decision.
Acknowledgments
No funding sources or financial disclosures/conflicts of interest to report.
Aurélie Du-Thanh and Nicolas Kluger contributed equally to this work.
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Correspondence: Prof. Bernard Guillot, Service de Dermatologie, Université
Montpellier I, Hôpital Saint-Eloi, CHU de Montpellier, 80 avenue Augustin
Fliche, FR-34295 Montpellier Cedex 5, France
E-mail: b-guillot@chu-montpellier.fr
Am J Clin Dermatol 2011; 12 (4)