Acneiform Eruptions

[vc_row][vc_column][vc_column_text delay="0"]Drug-induced acne, which is more accurately called drug- induced acneiform eruption, is characterized by an eruption of papules and pustules arising after medication intake.  Often this can look like acne but is not true acne, as in it does not stem from a microcomedone.

So what symptoms present that may alert you that the cause of pustules and papules is actually a drug related phenomenon.

• Acne onset has occurred at an unusual age (i.e. before or after teenage and early adulthood), or there has been an abrupt onset of acne in the absence of a past history of acne vulgaris, an acne flare of unusual severity in a patient with a past history of mild acne vulgaris, or an aggravation of pre-existing acne.
• The clinical presentation of acne involves a pattern of monomorphic, inflammatory lesions, a lack or late appearance of comedones and cysts, and unusual localization (i.e. extension beyond the seborrhoeic area, such as the arms, trunk, lower back, and genitalia).
• Acne is resistant to conventional acne therapy (this is a big HINT).• There is a time relationship between acne and the potential causative drug, such as recent drug introduction, improvement in acne after drug withdrawal and recurrence after drug reintroduction

Acneiform eruptions are a hallmark of a number of targeted antitumoral or anti-inflammatory therapies, particularly monoclonal antibodies directed against epidermal growth factor receptors (EGFRs), such as cetuximab and panitumumab, and inhibitors of EGFR-associated tyrosine kinases, such as erlotinib and gefitinib.  Both the incidence and severity of targeted therapy-associated acneiform eruption appear to be dose dependent.

The typical acneiform rash induced by EGFR inhibitors consists of inflammatory papules and pustules located on seborrhoeic areas of the face, although they can rapidly spread to the scalp, trunk and, more rarely, the limbs.  The palms and soles are classically spared. The lack of comedones is characteristic.

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 reported, but telangiectasia and hyperpigmentation have been described at the site of previous lesions.

Acne has also been reported in association with other tar- geted therapies, including bevacizumab, bortezomib, imatinib, infliximab, lapatinib, lenalidomide, selumetinib, sorafenib, sunitinib and vorinostat, although its incidence and severity appear, to date, less important than that associated with EGFR inhibitors. Interestingly, not all of these newer targeted therapies appear to be responsible for acneiform eruption.[/vc_column_text][vc_empty_space][/vc_column][/vc_row][vc_row][vc_column delay="0" css=".vc_custom_1446806377031{border-top-width: 2px !important;border-right-width: 2px !important;border-bottom-width: 2px !important;border-left-width: 2px !important;border-left-color: #000000 !important;border-left-style: solid !important;border-right-color: #000000 !important;border-right-style: solid !important;border-top-color: #000000 !important;border-top-style: solid !important;border-bottom-color: #000000 !important;border-bottom-style: solid !important;}"][vc_column_text delay="0"]Table I. Association between acneiform eruptions and hormonal agents

Androgens and anabolic steroids
Any androgen or anabolic steroid with androgenic activity will inevitably affect sebaceous glands.  Clinical presentation: ranges from exacerbation of seborrhoea to papulopustules, acne conglobata or acne fulminans, with the acne preexisting.  In young men presenting with acne, consider whether acne is induced by anabolic androgenic steroid abuse (‘body building acne’ or ‘doping acne’); »50% of abusers of anabolic androgenic steroids present with acne.    Acne is more difficult to treat if anabolic androgenic steroids are being taken.

Corticosteroids and corticotropin
Acneiform eruptions may occur weeks or months after inhaled, intravenous, oral or topical corticosteroid administration.  Clinical presentation: classically a monomorphic eruption of small, flesh-coloured or pink-to-red, dome-shaped inflammatory papules and pustules of the seborrhoeic areas (face, trunk), and a potential extension to the upper extremities; the inflammatory papules then resolve, with closed and open comedones or small keratin cysts appearing on the same areas several months later.   Dosage, duration of administration and individual susceptibility play a role in clinical presentation (e.g. if the corticosteroid dosage is low, the eruption may consist only of comedones).  Inhaled and topical corticosteroids may be responsible for perioral dermatitis, which often occurs in patients receiving excessive doses or very protracted (2–18 y) treatment.

Hormonal contraceptives
Progestogens with androgenic activity or low-dose estrogens can worsen acne or induce acne.

Other agents
Thyroid hormone and gonadotropins have been associated with rare reports of drug-induced acne.  Danazol has been associated with inducing acne in women.[/vc_column_text][vc_empty_space][vc_single_image image="2185" alignment="center"][vc_empty_space][/vc_column][/vc_row][vc_row][vc_column delay="0" css=".vc_custom_1446809676989{border-top-width: 2px !important;border-right-width: 2px !important;border-bottom-width: 2px !important;border-left-width: 2px !important;border-left-color: #000000 !important;border-left-style: solid !important;border-right-color: #000000 !important;border-right-style: solid !important;border-top-color: #000000 !important;border-top-style: solid !important;border-bottom-color: #000000 !important;border-bottom-style: solid !important;}"][vc_column_text delay="0"]Table2. Association between acneiform eruptions and neuropsychotherapeutic agents

Antiepileptic agents
Antiepileptic agents responsible for drug-induced acne include (by order of frequency) phenytoin, phenobarbital, primidone, carbamazepine and lamotrigine.   Clinical presentation: classically inflammatory with widespread papulopustules, although keloidal acne of the scalp has been described.

Lithium
Lithium-induced acne more frequent in men and among allergic patients
Lesions are often inflammatory, occur abruptly, and involve the face but also the axilla, groin, arms and buttocks.  No obvious dose-effect relationship; acne may appear even with normal serum lithium concentrations, although high concentrations of lithium may be observed in the skin, suggesting drug accumulation resulting in lesion occurrence.

Selective serotonin reuptake inhibitors
Acneiform eruption occurs as folliculocentric pustules, usually without comedones, on the face, chest and upper aspect of the back.

Other agents
Isolated reports of drug-induced acneiform eruptions associated with tricyclic antidepressants (e.g. imipramine, maprotiline) and the partial dopamine D2 receptor agonist aripiprazole .[/vc_column_text][vc_empty_space][vc_column_text delay="0"]

Acne induced by vitamin B12 is predominantly observed in women, and is considered as a sign of vitamin overload.  The development of the eruption is abrupt and usually occurs after the first or second vitamin B12 injection.   Lesions consist of 10–40 inflammatory, monomorphous, voluminous papules and pustules that are mainly located on the face.  Hyperseborrhoea may be present, but comedones or cysts are lacking. After vitamin B12 is withdrawn, lesions usually heal quickly.

[/vc_column_text][vc_empty_space][/vc_column][/vc_row][vc_row][vc_column delay="0" css=".vc_custom_1446810987243{border-top-width: 2px !important;border-right-width: 2px !important;border-bottom-width: 2px !important;border-left-width: 2px !important;border-left-color: #000000 !important;border-left-style: solid !important;border-right-color: #000000 !important;border-right-style: solid !important;border-top-color: #000000 !important;border-top-style: solid !important;border-bottom-color: #000000 !important;border-bottom-style: solid !important;}"][vc_column_text delay="0"]Table III. Association between acneiform eruptions and halogens

Bromine
Bromoderma (occurs in the context of bromide intoxication) is now infrequent.  Clinical presentation: large violaceous (violet color)  and inflammatory nodules, or sometimes as vegetating or bullous lesions, occasionally mimicking pyoderma gangrenosum or ecthyma; lesions may occur on any part of the body.  Withdrawal of the culprit drug and conventional acne treatments resolve the cutaneous symptoms.

Chlorine
Chloracne (occurs secondary to systemic toxicity or exogenous exposure to polyhalogenated aromatic hydrocarbons) usually results from occupational exposure, or to non-occupational exposures to local environmental contamination/hazards.  Clinical presentation: comedones on the face and retroauricular folds, but also on the back, chest, forearms, lower limbs and genitalia, with the axilla specifically affected; the nose is spared by the eruption, giving an ‘island in a sea’ aspect.

No pustule formation; in more severe cases, cysts may occur on the face and neck (may give the appearance of plucked chicken skin) Lesions appear 6–12 wk after first exposure and last up to 15–30 y after chloracnegen exposure.  Treatment is rather difficult as conventional treatments are often disappointing.

Iodine
Iododerma includes a wide range of skin eruptions resulting from oral, parenteral or topical iodine administration.  Occur mostly in patients with renal insufficiency, as iodine is cleared by the kidneys, but have been reported after various situations including amiodarone intake, cardiac catheterization, intravenous injection of iodinated contrast medium, iodized salt consumption, lymphography, potassium iodide intake for thyroid protection.   Clinical presentation: papules, vesicles and pustules, but also erythematous, urticarial, furuncular, carbuncular, bullous and sterile vegetating lesions that may ulcerate; lesions appear on the seborrhoeic regions (face, neck and back), but may be more widespread and involve the whole body.

Patients with a history of iododerma should be warned to avoid any contact or injection with iodine products as recurrence may occur Discontinuation of iodine intake is sufficient to improve the patient’s symptoms, but treatment with local or systemic corticosteroids may be necessary.[/vc_column_text][vc_empty_space][/vc_column][/vc_row][vc_row][vc_column][vc_column_text delay="0"]Ciclosporin and sirolimus are associated with drug- induced acne in »15% and »15–25% of recipients of these drugs, respectively.  Ciclosporin-induced acne presents as severe acne with a nodulocystic presentation or acne ke- loidalis. Acne induced by sirolimus occurs predominantly in males (especially those with a history of severe acne vulgaris) and presents as inflammatory papulopustules distributed on the seborrhoeic regions, with an absence of comedones and cysts. There are no significant correlations between acne severity and the daily dose or blood concentration of sirolimus.

Dantrolene has been associated with acne eruption occur- ring from 6 months to 4 years after initiation.  There is no correlation between the dosage and the induction of acne, although patients may have a past medical history of acne vulgaris. Dantrolene-induced acne mainly consists of blackheads, comedones, cysts, pustules, and abscesses, with lesions localized to the site of chronic trauma, friction, or pressure.  Isotretinoin is not recommended to treat dantrolene-induced acne because of a cumulative hepatotoxicity with dantrolene. In- stead, if possible, consider reducing the dantrolene dosage or switching to another myorelaxing drug (e.g. baclofen).

Halogens
Bromide, chloride and iodide salt-containing drugs, which are perhaps eliminated by sebaceous glands, are associated with specific acneiform eruptions (table III).  Halothane, a halogenated anaesthetic gas, may trigger acne, with eruption occurring within hours of exposure and re- curring after each exposure to halothane gas.  It initially affects the face and then may be more widespread.

References
1. Du-Thanh A, Kluger N, Bensalleh H, et al. Drug-induced acneiform eruption. Am J Clin Dermatol 2011; 12 (4): 233-45

2. Common terminology criteria for adverse events (CTCAE), version
4.03. Bethesda (MD): U.S. Department of Health and Human Services, National Institutes of Health, National Cancer Institute, 2010 Jun 14

3. Perez-Soler R, Saltz L. Cutaneous adverse effects with HER1/EGFR- targeted agents: is there a silver lining? J Clin Oncol 2005; 23: 5235-46

4. Michot C, Guillot B, Dereure O. Lenalidomide-induced acute acnei- form folliculitis of the head and neck: not only the anti-EGF receptor agents. Dermatology 2010; 220: 49-50

5. Scope A, Agero AL, Dusza AL, et al. Randomized double-blind trial of prophylactic oral minocycline and topical tazarotene for cetuximab- associated acne-like eruption. J Clin Oncol 2007; 25: 5390-6

6. Deplanque G, Chavaillon J, Vergnenegre A, et al. CYTAR: a rando- mized clinical trial evaluating the preventive effect of doxycycline on erlotinib-induced folliculitis in non-small cell lung cancer patients [abstract no. 9019]. J Clin Oncol 2010 May 20; 28 (15 Suppl.): 9019[/vc_column_text][/vc_column][/vc_row]