Bellebonelli.com.br

Drug-Induced Acneform Eruptions: Definitions and Causes saira Momin, do; Aaron Peterson, do; James Q. del rosso, do
Several drugs are capable of producing eruptions that may simulate acne vulgaris, clinically, histologi-cally, or both. These include corticosteroids, epidermal growth factor receptor inhibitors, cyclosporine, anabolic steroids, danazol, anticonvulsants, amineptine, lithium, isotretinoin, antituberculosis drugs, quinidine, azathioprine, infliximab, and testosterone. In some cases, the eruption is clinically and his-tologically similar to acne vulgaris; in other cases, the eruption is clinically suggestive of acne vulgaris without histologic information, and in still others, despite some clinical resemblance, histology is not consistent with acne vulgaris. Drugs are a relatively common cause of involvement; and clearing of lesions when the drug cally, histologically, or both. With acne vulgaris, the primary lesion is com- CortiCosteroids
It has been well documented that high levels of systemic nification, with inflammation leading to formation of corticosteroid exposure may induce or exacerbate acne, papules and pustules. In drug-induced acne eruptions, as evidenced by common occurrence in patients with the initial lesion has been reported to be inflammatory Cushing disease.2 Systemic corticosteroid therapy, and, with comedones occurring secondarily. In some cases in some cases, exposure to inhaled or topical corticoste-where biopsies were obtained, the earliest histologic roids are recognized to induce monomorphic acneform observation is spongiosis, followed by lymphocytic and lesions.2-4 Corticosteroid-induced acne consists predomi-neutrophilic infiltrate. Important clues to drug-induced nantly of inflammatory papules and pustules that are acne are unusual lesion distribution; monomorphic small and uniform in size (monomorphic), with few or lesions; occurrence beyond the usual age distribution no comedones. Anti-inflammatory effects of topical cor-of acne vulgaris; sudden onset within days; widespread ticosteroids may initially suppress inflammatory papules and pustules and decrease erythema; however, patients Dr. Momin is Dermatology Resident and Dr. Peterson is may experience dramatic flare-ups when the topical agent Traditional Rotating Intern, Valley Hospital Medical Center, Touro University College of Osteopathic Medicine, Las Vegas. Percutaneous absorption of corticosteroid after topical Dr. Del Rosso is Dermatology Residency Director, Valley Hospital application varies among individuals, vehicle formula- Medical Center, and Clinical Associate Professor, Dermatology, tions, and anatomic locations. The groin, neck, and face Touro University College of Osteopathic Medicine, Henderson, absorb increased amounts of topical corticosteroids and Nevada, and University of Nevada School of Medicine, Las Vegas. are more likely to develop local side effects.5 Variable The authors report no conflicts of interest in relation to percutaneous absorption is caused by the thickness of the stratum corneum and its lipid composition.5,7 Facial skin is more permeable, has a thin stratum corneum, and has 28 Cosmetic Dermatology® • jAnuAry 2009 • Vol. 22 no. 1
natural distribution shunts because of numerous seba- preventing autophosphorylation and subsequent activation ceous follicles, which allow more of the drug to penetrate of signaling cascades. Cetuximab, trastazumab, and panitu- to subepidermal structures.8 There is a defective epider- mumab (ABX-EGF) are monoclonal antibodies that bind to mal barrier in atopic dermatitis, and the penetration of the extracellular domain of the EGF-r, blocking activation topical corticosteroids is 2 to 10 times greater than that and signal transduction of the receptor.16,17 through healthy skin.5 Cases have been reported of acneform eruptions in lesions of corticosteroid-induced acne and acne vulgaris patients receiving EGF-rIs. During trials, acneform erup- appear to evolve differently based on histologic evaluation. tions were seen in 66% of patients with use of gefitinib, In acne vulgaris, an observed early pathologic change is 75% of patients with erlotinib, and 86% of patients with abnormal keratinization of the follicular epithelium. In cetuximab. These reactions generally appeared after 7 to acneform eruptions associated with corticosteroid use, 14 days of treatment, with acneform eruptions occurring early histologic changes are necrosis and rupture of a seg- on seborrheic areas such as the face, neck, retroauricular ment of the follicular epithelium, leading to perifollicular area, shoulders, upper trunk, and scalp.16,17 The skin abscess that presents clinically as monomorphic inflam- lesions consist of erythematous follicular papules and matory papules and pustules.9,10 In acne vulgaris, the pustules that may coalesce to form lakes of pus that primary lesion is the comedone; however, comedones may evolve to form yellow crusts. The skin lesions are not also be present in corticosteroid-induced acne. It has been preceded by visible comedones, and, in contrast to acne-suggested that topical corticosteroids induce comedone form eruptions caused by other drugs, EGF-rI–induced formation by rendering the follicular epithelium more skin lesions may be accompanied by pruritus. Some-responsive to the comedogenesis.9-12 Comedone forma- times, spontaneous improvement can be seen even tion occurs during a period of months and may evolve when treatment with the EGF-rI is continued, but the into the dominant lesion in the late stages of corticosteroid- patient may exhibit a flare-up following each subsequent induced acne.10,12 Topical application of corticosteroids administration.17 Some studies have reported that there leads to increased concentration of free fatty acids in skin is a positive correlation between the presence and grade surface lipids and increased numbers of bacteria in the of cutaneous eruption and survival time.16 Patients who pilosebaceous duct.13,14 Free fatty acids, formed in pilose- presented with this type of acneform eruption had a sig- baceous ducts by breakdown of triglycerides in the seba- nificant increase in survival time than did those with no ceous secretion, may contribute to comedogenesis.13 cutaneous reaction. Also, increase in the severity of the Tagami15 reported a case of an acneform eruption that acneform eruption seemed to correlate with an increase appeared unilaterally on the face of a middle-aged woman in survival time.16,17 Acneform eruptions have not been approximately one month after the start of oral corticoste- reported with inhibitors of other EGF-r family members roid therapy for facial paralysis. It was proposed that the such as trastuzumab, a monoclonal antibody against the resultant lack of facial muscle movement due to Bell palsy HEr2 receptor.17played a role in the pathogenesis of acneform lesions. Histopathologic evaluation of the acneform eruption normal facial movement, which would promote a con- seen with EGF-rIs is not consistent with that seen in acne stant outflow of sebum from the lumen of the sebaceous vulgaris, demonstrating suppurative neutrophilic follicu-follicles, was lacking on the paralyzed side.
litis and perifolliculitis preceded by early infiltration with T lymphocytes that surround the follicular infundibulum. ePiderMAl Growth FACtor
Intraepidermal acantholysis is sometimes present. no reCePtor inhibitors
Epidermal growth factor receptor inhibitors (EGF-rIs) are The pathogenic mechanism of acneform eruptions a group of medications used for therapy of advanced stages associated with EGF-rIs has not been firmly established. of several forms of cancer. Epidermal growth factor recep- The cell-cycle inhibitor p27 may play a role because tors (EGF-rs), also known as HEr1 or ErbB1, are overex- p27 is unregulated by the use of EGF-rIs.16 Cell-cycle pressed in many tumors and play a role in the development inhibitor p27 is a regulator that inhibits the actions of and progression of cancer, especially solid tumors of the cyclin-dependent kinase CDK2, preventing progression head and neck, lung, breast, ovary, prostate, and colon. In from G1 phase to S phase in the cell cycle. Increased cutaneous locations, including epidermal keratinocytes, expression of p27 results in alterations in cell growth sebocytes, and the outer root sheath of hair follicles, and differentiation, leading to changes in the stratum EGF-rs are expressed normally and are involved in nor- corneum of the follicular infundibulum and resulting mal cell growth and differentiation.16 Gefitinib and erlo- in hyperkeratosis, abnormal desquamation, follicular tinib are small-molecule EGF-rIs that selectively inhibit plugging with bacterial overgrowth, and development the tyrosine kinase activity of the intracellular domain, of acnelike lesions.16 Although Propionibacterium acnes Vol. 22 no. 1 • jAnuAry 2009 • Cosmetic Dermatology® 29
Drug-InDuceD Acneform eruptIons
has not been found in the follicles of the patients with closed comedones. Both patients had a predominance EGF-rI–induced eruptions, other microorganisms have of noninflammatory acne lesions, and one patient also been found in the plugged infundibulum, which may pos- exhibited inflammatory lesions. The clinical appear- sibly induce an inflammatory response.16 It is also possible ance differed from that of monomorphic papules of that monoclonal antibody inhibitors themselves may induce corticosteroid-induced acneform lesions.22 one case of a an inflammatory reaction by the activation of neutrophils teenaged boy with Crohn disease who developed severe and complement through the binding of its Fc domain.16 nodulocystic acne after 3 perfusions of infliximab has yalçin et al18 reported a patient with non–small-cell been reported.22,23 There was only one case of acneform lung carcinoma who developed an acneform eruption on eruption reported in a retrospective review of side effects the face, trunk, and upper extremities, sparing the region in 73 infliximab-treated patients with psoriasis.22,24 The exposed to previous radiotherapy while on erlotinib mechanism of induced anti–TnF-a acneform eruption is treatment. Skin biopsies were performed from the spared unknown. Interleukin-1a, TnF-a, and interferon-g may previously irradiated skin and from neighboring affected play a role in hypercornification of the infundibulum nonirradiated skin. Histologic examination revealed sup- and/or innate immune response leading to inflammatory purative folliculitis destroying follicular epithelium and acne lesions, and, therefore, anti–TnF-a effects would be
adnexal structures in the nonirradiated skin specimens. expected to improve rather than promote development of
Although eccrine glands and piloerector muscles were acneform lesions.22
normal, there were no follicular structures identified in
the previously irradiated skin specimens. no differences siroliMus
were noted between irradiated and nonirradiated skin in Sirolimus is an immunosuppressive drug used after organ
EGF-r expression with staining for EGF-rs.
transplantation. The most common dermatologic side Imatinib (ST1571), a tyrosine kinase inhibitor, is well effects of sirolimus are pathologies of the pilosebaceous tolerated and has a significant antileukemic activity in apparatus, chronic edema, angioedema, and mucous patients with chronic myelogenous leukemia. Martin membrane disorders.25,26 Mahé et al25 described acneform et al19 reported a similar cutaneous eruption with imatinib eruptions in 45% of 80 patients soon after starting siroli-treatment to those associated with other EGF-rIs.
mus, predominantly in men. In sirolimus-induced acne-form eruptions, only inflammatory lesions that primarily GrAnuloCyte Colony-
involved the sebaceous regions were observed; however, stiMulAtinG FACtor
lesions also frequently extended to the forearms, inner Granulocyte colony-stimulating factor (G-CSF), a potent surface of the arms, cervical area, and scalp. A few stimulator of neutrophils, is an important treatment for patients were observed to have severely painful, nodular, significant neutropenia, especially in patients with cancer edematous lesions on the neck and face.25,26 Histologic who are receiving chemotherapy. It has been reported examinations suggested nonspecific folliculitis.25 that both G-CSF and granulocyte-macrophage colony- The role of sirolimus in the cause of acne may be due stimulating factor (GM-CSF) cause localized and general- to direct toxic effects on follicles or its chemical toxic ized cutaneous eruptions mediated by neutrophils, and modification of sebum. The mechanism of acneform lesion GM-CSF has been reported to cause widespread erythem- development secondary to use of sirolimus is not known; atous macules and papules.20 Horn et al21 showed that a however, it may be due to its effects on EGF and testoster-perivascular infiltrate developed in skin from a patient one synthesis. Sirolimus inhibits EGF action by inhibiting undergoing chemotherapy that was incubated with the mTor pathway. Testosterone upregulates EGF receptor GM-CSF. lee and Dover20 reported a case of a teenage synthesis, and sirolimus downregulates testosterone syn-boy who had a mixed germ cell tumor of the testis with thesis. Therefore, sirolimus might induce acneform lesions metastasis, who underwent radical orchiectomy and was because of its direct inhibition of EGF action and may do given chemotherapy and G-CSF. The patient experienced so predominantly in men because of the downregulation of exacerbation of preexisting acne vulgaris correlating with the EGF-r by testosterone suppression.25 the administration of G-CSF.20 CyClosPorine
Anti–tuMor neCrosis FACtor-a
The development of acneform lesions in organ-transplant Infliximab is a chimeric (mouse-human) monoclonal recipients is common and has usually been attributed to antibody targeting tumor necrosis factor (TnF)-a. Bassi the use of corticosteroids. Cyclosporine (CsA) is a potent et al22 reported 2 cases where the patients receiving in- immunosuppressive agent used after organ transplanta- fliximab for Crohn disease and ankylosing spondylitis tion. There have been reports of cyclosporine-induced developed papules, pustules, nodules, and open and acneform eruptions. Highly lipophilic, one of CsA’s 30 Cosmetic Dermatology® • jAnuAry 2009 • Vol. 22 no. 1
Drug-InDuceD Acneform eruptIons
possible routes of elimination may be via the sebaceous ovarian endometriosis, sexual precocity, and hereditary gland, which is the major cutaneous site for the elimina- angioedema. Danazol is a derivative of 17a-ethinyl testos- tion of lipids through sebum, and the drug may modify terone (ethisterone). It suppresses the pituitary-gonadal the pilosebaceous follicles.27 axis by diminishing the output of both follicle-stimulating El-Shahawy et al28 reported a case of severe nodulo- hormones and luteinizing hormones from the pituitary cystic acne that rapidly and significantly improved after gland. It does not seem to influence the secretion of other complete withdrawal of CsA. Azurdia et al29 reported trophic pituitary hormones.36 3 white male patients who were treated with cyclosporine Greenberg36 reported a young woman who developed following organ transplantation, who developed acne nodulocystic acne while being treated for endometriosis keloidalis nuchae of the occipital scalp and nuchal neck.
with danazol. There have been other reported cases of acneform eruptions induced by danazol.36 AndroGens And
AnAboliC-AndroGeniC druGs
levonorGestrel iMPlAnts And
The use of anabolic-androgenic steroids in the united intrAuterine deviCes
States has increased markedly among athletes and those Studies show increased acne development in women
who want to rapidly build muscle. These agents initially using levonorgestrel implants and in women using intra-
produce a sense of euphoria, diminish fatigue, increase uterine devices. The tendency to notice increased acne
protein synthesis in skeletal muscle cells causing hypertro-
eruptions was more pronounced for women who had phy of striated muscle, and increase lean body mass.30,31 previous problems with acne. The results of androgen Androgens stimulate the sebaceous glands, which leads to determinations in women complaining or not complain-increased follicular keratinization resulting in comedone ing of increased acne during treatment with levonor-formation. High dosages of testosterone and anabolic- gestrel implants is not a result of increased plasma levels androgenic steroids can increase skin surface lipids, includ- of androgens, but rather a reflection of a different skin ing cholesterol and free fatty acid levels, and increase the metabolism of and/or sensitivity to androgens among the P acnes organism population. Skin biopsy specimens after susceptible women.37 anabolic-androgenic steroid use show significant enlarge-ment of sebaceous glands, especially with intramuscu- vAlProAte
lar anabolic-androgenic steroids.30,31 The amount of free Valproate is an antiepileptic drug used to treat epilepsy, androgen in serum may have an important association with bipolar disorder, and migraine cephalgia in reproductive- development of acne lesions, suggested by stronger enzy- aged women. In women, many valproate users are matic conversion to the more active dihydrotestosterone reported to have isolated polycystic ovarian syndrome, or increased receptor sensitivity toward androgens in the such as elevated serum testosterone or luteinizing hor-skin.32 Administration of testosterone induced synthesis of mone concentrations.38 joffe et al38 reported that new-androgen receptors in the sebaceous glands of the Syrian onset oligomenorrhea with hyperandrogenism developed hamster and resulted in an increase in sebum production.33,34 in 10.5% of women with bipolar disorder who were Cutaneous signs are often the first clinical manifesta- treated with valproate. The clinical features of hyperan- tions of anabolic-androgenic steroid use or abuse. Induc- drogenism are hirsutism, acne, male pattern alopecia, and tion and worsening of acne is a commonly observed elevated androgen concentrations.38complication.35 Anabolic-androgenic steroids can induce cystic acne, with onset sometimes months following ces- AMinePtine
sation of drug intake.30 Heydenreich35 reported a case of Cases of acneform eruption have been reported in asso-acne fulminans caused by misuse of testosterone, anabolic ciation with use of amineptine, a tricyclic antidepres-steroids, or both. Traupe et al, 33 reported 3 cases of acne sant.39,40 Amineptine may induce a florid, retentional fulminans in tall boys following testosterone therapy.33 acnelike eruption with multiple comedones, microcystic oral preparations include methandrostenolone, ethyl- lesions, and macrocystic lesions involving the face, ears, estrenol, stanozolol, fluoxymesterone, oxymetholone, and neck, trunk, and pubic area. Many reported cases involve oxandrolone. Parenteral steroids include nandrolone phen- adult women, and the severity of the cutaneous lesions is ylpropionate, nandrolone deconoate, testosterone enanthate, usually related to accumulated amineptine after chronic testosterone cypionate, and testosterone propionate.30,31 intake. Inflammatory lesions are usually absent or scarce, occasionally presenting as apparent secondary infection or inflammation associated with cystic lesions.39 An antigonadotropic agent with mild androgenic prop- Histologically, there is cystic dilatation in the ducts erties, danazol is useful in the treatment of pelvic and of the sebaceous glands with formation of keratin-filled Vol. 22 no. 1 • jAnuAry 2009 • Cosmetic Dermatology® 31
Drug-InDuceD Acneform eruptIons
comedones. other changes observed with acneform A young white male was reported to develop acne eruption associated with amineptine occur in eccrine keloidalis–like lesions on the central scalp while on sweat glands, showing keratinizing syringometaplasia treatment with diphenylhydantoin (phenytoin) and with areas of neutrophilic eccrine hidradenitis.39 carbamazepine.46 Firm, red papules, 0.5 cm in diam- The mechanism of action of amineptine-induced acne- eter, some coalescing into longitudinal plaques with form eruption is unknown but likely the result of drug scattered sterile pustular foci, were present clinically. accumulation in the cutaneous glands.39,40 Fazio et al41 Initial biopsy taken from a papule showed dense inflam-extensively studied skin lipids in a case of amineptine- matory infiltration composed of polymorphonuclear induced acneform eruptions and demonstrated an elevated cells, lymphocytes, histiocytes, and plasma cells in the reduction of sebaceous lipid fractions in both cysts and dermis. A subsequent biopsy showed marked fibrotic skin surface lipids. Amineptine and its metabolites have changes in the dermis. Withdrawal of carbamaze-been found in sebaceous and eccrine sweat glands.40,42 pine with continuation of diphenylhydantoin for one Because of the amphetaminelike properties of aminep- year resulted in slowly progressive worsening of the tine, it is abused by some patients, including the elderly. skin disorder, despite treatment with topical cortico-The abuse is facilitated by rapid tolerance to the drug and steroids. Progressive improvement was noticed only to the onset of withdrawal symptoms (eg, moodiness, when diphenylhydantoin was also discontinued. rein-agitation, insomnia) in the days immediately following stitution of treatment with carbamazepine alone did not discontinuation. usually, the acneform eruption disap- Although apparently rare, other tricyclic antidepres- lithiuM CArbonAte
sants, such as maprotiline and imipramine, occasionally lithium has been associated with various cutaneous side have been known to trigger acneform eruptions.40,43 effects including acneform eruptions. It has been reported that nearly one half of male patients who were on lithium dACtinoMyCin
complained of acne as a secondary cutaneous reaction.47 Dactinomycin, used in the treatment of solid tumors, It appears that lithium may aggravate some cutaneous has been associated with occasional development of an conditions that are associated with a prominence of neu-acneform eruption. Blatt and lee44 reported a case of a trophilic infiltration and predisposes particularly to the prepubertal girl who received dactinomycin in combina- development of acne vulgaris. lithium may act as a trig- tion with other chemotherapeutic agents that have not gering or aggravating factor.47 been implicated in the development of acne lesions. Two cases of acne papules and pustules on the face, They noted a rise and fall of serum androstenedione, neck, chest, groin, and axillae after treatment with dehydroepiandrosterone, and testosterone levels over the lithium were reported.48 In another report, 18 patients period of time, defined by 2 courses of therapy inclusive developed lithium-induced folliculitis located on the of dactinomycin. A gradual improvement of the acneform arms and legs.49 In 4 female patients, exacerbation of acne eruption was noted as hormone levels diminished, which on the face and neck was noted after lithium treatment.50 supports a relationship between drug exposure, the pres- A young female patient was reported to develop a severe ence of the eruption, and hormone levels.44 acneform eruption on her face, chest, and back soon after Interestingly, dactinomycin shares a similar tricyclic she started taking lithium; however, comedone formation structure with amineptine.44 It is not clear whether was not observed. Histopathologic examination revealed dactinomycin directly stimulates androgen production neutrophilic folliculitis, which was more consistent with or leads to an increase in adrenocorticotropic hormone folliculitis than with acne vulgaris.51production by inhibiting activity of an enzyme along the cortisol synthesis pathway.44 dAntrolene
Two cases of an acneform eruption, comprising primar-
hydAntoin
ily of open comedones, were reported in middle-aged A case of facial neonatal acne was reported in an infant women being treated with dantrolene for spasticity.52 with fetal hydantoin syndrome.45 Hydantoin, which Histology of the skin showed keratin-filled cysts commu-crosses the placenta, is reported to cause numerous skin nicating with the epidermal surface. Besides the face, acne reactions including hypertrichosis of extensor surfaces of in both cases favored sites of chronic trauma and friction. the limbs and worsening of acne, which improves when Acneform eruptions in patients receiving dantrolene have the treatment is stopped. Treatment of pregnant women been reported to exhibit a predilection for areas subject with systemic halogens and corticosteroids may result in to pressure, such as the back and extensor aspect of neonatal acne vulgaris.45 32 Cosmetic Dermatology® • jAnuAry 2009 • Vol. 22 no. 1
Drug-InDuceD Acneform eruptIons
orAl isotretinoin
acne. A second biopsy specimen showed spiny follicular Tretinoin is known to be effective for the topical treatment plugs consisting of Demodex folliculorum organisms, colo-of acne probably by decreasing retention hyperkeratosis nies of Corynebacterium acnes (P acnes), and an absence and comedone formation and through downregulation of inflammatory infiltrate. The third biopsy from a later of receptor-2, which is toll-like.54 Isotretinoin (13-cis- phase of the eruption exhibited prominent inflammatory retinoic acid) is a vitamin A analogue that has been shown infiltrate, no comedones, and hyperplastic follicular epi-to be remarkably effective in treating cystic acne and thelium, which are features compatible with those seen acne conglobata and has a profound suppressive effect on in the resolving phase of acne vulgaris.61 The following sebum secretion.54,55 factors should be considered in the diagnosis of isoniazid- Adverse cutaneous reactions to isotretinoin have been induced acne: occurrence in older persons, absence of reported, including ulceration, hemorrhagic crusting, and recent or remote history of acne vulgaris, and sudden, tenderness of preexisting acne lesions.55 The appearance extensive efflorescence of lesions.61of excess granulation tissue may resemble pyogenic gran- Chronic papular acneform lesions of the face, neck, ulomas underlying many of the crusts. The ulceration and shoulders have been observed in 8 of 24 men with and crusting that occurred in these patients are similar genitourinary tuberculosis who were receiving rifampi-to those seen in acne fulminans, but none of the patients cin. Withdrawal of the medication led to disappearance experienced fever or arthralgias. Histologic evaluation of the skin lesions within 3 weeks. Ethionamide, thiacet-showed foci of epidermal ulceration and a dense inflam- azone, and prothionamide have also been reported to matory cell infiltrate in the middle and upper dermis, cause acneform eruption.62
consisting of numerous lymphocytes, plasma cells, and
moderate numbers of neutrophils and eosinophils. In the Quinidine
middle and lower dermis, the connective tissue became A case of numerous papules and pustules was reported to
denser and less infiltrated with inflammatory cells, but occur on the chest and back of a 57-year-old man who
numerous fibroblasts were seen. The underlying patho-
had a history of premature ventricular contractions soon physiologic mechanism of the reaction is unknown. Skin after the initiation of quinidine therapy.63 Quinidine ther-
fragility may occur in patients during treatment with apy was continued, and excellent resolution of the erup-
isotretinoin and is associated with the loss of desmosomes tions occurred within 4 weeks of topical treatment with
and desmosomal attachments and with the accumulation erythromycin solution and benzoyl peroxide. The lesions
of an amorphous material within the epidermis.55 At sites reappeared when his acne therapy was discontinued.63
of inflammation, this fragility may result in frank ulcer-
ation with subsequent crust formation.55 A case of acne tACroliMus
fulminans with severe myalgia believed to be precipitated Tacrolimus is a macrolide derivative that acts by blocking
by isotretinoin therapy has been reported.56 Acne fulmi-
the calcineurin-dependent signal transduction pathway nans and bilateral seronegative sacroiliitis reported to be with strong T-cell–specific immunosuppressive activ-triggered by isotretinoin has also been described.57 ity.64,65 Primarily used for treatment of atopic dermatitis, Cystic acne and comedonal acne as side effects it has been used to treat other inflammatory and immu- of etretinate therapy for psoriasis have also been nologic skin disorders, including vitiligo. A case of focal reported.58,59 Etretinate alters keratinization and cel- acne was reported during topical tacrolimus therapy for lular differentiation but appears to have little effect on vitiligo.64 rosaceiform dermatitis has also been reported sebum production.58,59 during treatment of facial inflammatory dermatoses with tacrolimus ointment.65 AntituberCulosis druGs
In 1959, isoniazid-induced acneform eruptions were betA-bloCker
reported to occur in 16% of 2600 patients receiving Dermatologic side effects from beta-blockers are reported
a combination of isoniazid and aminosalicyclic acid; to be extremely rare.66 Facial acne was reported in a young
11% of these acne patients were slow inactivators of the adult with no history of dermatologic disease after start-
isoniazid.60 In another report, 7 patients were noted to ing propranolol for migraine prophylaxis.66 The acne did
develop acneform eruptions associated with isoniazid not improve with treatment but resolved completely after
therapy.61 Five of these patients who had extensive erup-
discontinuing the propranolol. Facial acne reappeared a tions were slow inactivators of isoniazid. Histologically, few weeks after starting nadolol for migraine prophylaxis one case showed open and closed comedones and an and again resolved completely on discontinuation of the absence of inflammatory infiltrate, which is reported to beta-blocker. The mechanism of acne of the beta-blocker– be characteristic of the early phase of isoniazid-induced associated acneform eruption is not clear.66 Vol. 22 no. 1 • jAnuAry 2009 • Cosmetic Dermatology® 33
Drug-InDuceD Acneform eruptIons
orAl dAPsone
acneform eruption on the chest and back that consisted Acne fulminans and hemolysis were reported in a young mainly of small, red, dome-shaped papules and a few female patient treated with oral dapsone.67 This patient comedones and pustules. A biopsy specimen of a papular had preexisting mild acne vulgaris of the face and was lesion showed a dilated pilosebaceous follicle filled with given dapsone after poor response to oral tetracyclines. inflammatory debris and keratin.71 Perioral dermatitis one week after starting oral dapsone, she had worsening was reported in 4 of 80 patients treated with PuVA, and of the lesions and developed facial pain and a low-grade 2 of these cases also had acneform eruptions localized to fever. Some of the lesions had excoriated to form ulcers, the forehead.72others were crusted, and some were hemorrhagic. Com- Acnelike eruptions on the face, induced by light, edones were not observed. Additionally, the patient was were first described using the term light-sensitive sebor-
later diagnosed with dapsone-induced hemolysis. Dapsone rhoid.72,73 The designation acne aestivalis (Mallorca acne)
was immediately stopped, and high doses of vitamin C is used for a papular eruption occurring after intense sun
and intravenous methylene blue were given, along with exposure in an anatomic distribution characteristic of
oral prednisone, and dramatic improvement of the facial acne vulgaris.72,74
acneform lesions was noted.67
Acne usually improves during the summer with exposure to sunshine, although it may be aggravated in AzAthioPrine
some patients, particularly in a hot and humid climate, one case of azathioprine-induced acneform drug eruption possibly related to marked eccrine sweating. Patients during treatment of multiple sclerosis was reported.68 undergoing PuVA treatment are usually irradiated in enclosed cabinets and cubicles in rather confined areas. lAMotriGine
Despite powerful extractor fans and fans incorporated lamotrigine is used for the treatment of some forms in the cabinets and modules used, the temperature of seizure disorder and bipolar disorder.69 Two cases and humidity in these units are often high, and some of lamotrigine-induced acneform eruption have been patients sweat profusely. other factors including the reported.69 Acneform lesions developed on the back in uVA light itself may contribute to the development of both cases within a few months after the target dose of acneform eruption.71lamotrigine had been reached and while the patients received no other drugs. resolution was noted with- vitAMins b6 And b12
out therapy when lamotrigine was discontinued. The A case of facial acneform eruption due to a megadose 2 patients had prior treatment with lithium, but the erup- of vitamins B6 and B12 has been reported.75 Histologic tions did not develop until 1 to 2 months after lithium evaluation of a facial lesion was reported to show para-was discontinued. The possibility that the preceding keratosis overlying a focally spongiotic epidermis. There treatment with lithium may be a related causative factor was a mononuclear inflammatory infiltrate in the papil-cannot be ruled out.69 lary dermis and in a perivascular location. When the patient was instructed to discontinue use of the nutri- tional supplement, there was dramatic improvement in A patient with rheumatoid arthritis first developed an the eruption.75 eruption consistent with lichen planus and, subsequently, Exacerbation or onset of inflammatory acne related to acneform lesions on the face and trunk after gold sodium vitamins B2 (riboflavin), B6 (pyridoxine), and B12 (cyano-thiomalate treatment.70 Gold is retained in the body for a cobalamin) have been reported in European literature.75 prolonged duration and is especially bound in the kidneys, The lesions of vitamin B–induced acne may occur as liver, and skin.70 Excretion of gold can be demonstrated in exacerbations of preexisting acne vulgaris, as new onset the urine for up to 12 months after discontinuing the treat- of multiple papules and papulopustules, or as an explo- ment.70 The patient had not taken any other drugs and did sive pustular eruption involving the face. The pathogen-not come into contact with acnegenic materials; therefore, esis is unknown, although it has been postulated that the his acne was most likely provoked by gold.70 origin of B6 /B12-induced acne may be similar to that of isoniazid-induced acne.75,76 PsorAlen–uv-A
oral and topical methoxsalen (8-methoxypsoralen) with tetrACyCline
long-wave uVA is commonly used to treat psoriasis. A case A tetracycline-induced acneform eruption was first
of acne believed to be induced by psoralen–uV-A (PuVA) described in 1969.77,78 A 30-year-old male patient was
treatment has been reported.71 The patient, with exten-
reported to develop an acneform eruption from tetra- sive psoriasis on PuVA treatment, had developed an cycline.78 The patient was on tetracycline for infected 34 Cosmetic Dermatology® • jAnuAry 2009 • Vol. 22 no. 1
Drug-InDuceD Acneform eruptIons
seborrheic dermatitis of the face and scalp and on pred- white PetrolAtuM
nisone for an unknown disease of the central nervous White petrolatum–induced unilateral acne developed in system. Multiple red, superficial follicular pustules of a young woman attempting to relieve the effects of Bell the neck, chest, back, and upper arms were noted. The palsy by massaging her face nightly.83 White petrolatum eruption slowly resolved when both prednisone and is thought to be noncomedogenic and safe to use in acne-tetracycline were discontinued. Although corticosteroid- prone skin. However, it may be occlusive and could cause induced acne may have been considered, one month later a pustular reaction.83
the patient was again started on tetracycline, and a similar
eruption appeared on the same areas and slowly subsided sunsCreens
after tetracycline was discontinued. Subsequent readmin-
Fourteen of 29 sunscreen formulations, including sun- istration of tetracycline one month later also provoked a tan promoters, were found to be comedogenic when similar eruption.78 applied to the external ear canal of albino rabbits.84 It was reported that uV exposure enhanced the comedogenic tetrAethylthiurAM disulFide
effect. The vehicles, rather than the uV-absorbing com- Tetraethylthiuram disulfide has been used extensively in pounds, seemed to be responsible.84
the treatment of alcoholism. A repeated cystic acneform
eruption of the face, anterior chest, and back, coincident Cow udder ointMent
with the ingestion of tetraethylthiuramdisulfide has been Two cases of widespread and atypical acneform eruptions
reported.79 With each recurrent episode of acneform were reported to be associated with use of cow udder
lesions, withdrawal of the drug repeatedly resulted in ointment.85 Cow udder ointment contains boric acid and
subsiding of the eruption.79
starch in a wax and oil base. The patients were using the cow udder ointment for treatment of atopic eczema hAloGens
Iodides and bromides have been reported to induce a
flare of inflammatory acne.80 The mechanism is unknown ConClusion
but may relate to stimulation of neutrophil function. It is important to consider drug-induced acneform erup-
The most common sources of halogens are some thyroid tions whenever a patient is being treated pharmacologi-
medications, expectorants containing potassium iodide, cally and recent onset or worsening of acne is apparent.
contrast medium, iodized salt, vitamin and mineral Several medications have a proven causal relationship,
preparations, and some sedatives.80,81 The inflammatory with the percentage of patients affected exceeding 80%,16,17
eruption occurs in the typical acne areas (face and upper whereas other medications may have only a few reported
trunk), as well as elsewhere, commonly in an asymmetri-
cases. It can be concluded that nearly any medication cal distribution pattern. Initial lesions are often follicular used to treat almost any disease is a possible culprit, and pustules, and later, comedonal lesions can emerge as a with new medications being developed and implemented hyperkeratotic reaction to chronic inflammation.81 constantly, it is vital to recognize acneform eruptions Chloracne is an acneform eruption resulting from and be able to differentiate them from other possibly marked exposure to halogenated aromatic compounds. unrelated eruptions. Although the mechanisms may vary The condition is a symptomatic marker for systemic considerably, the responsibility of dermatologists and the poisoning.82 It is difficult to treat and can last for long practitioners prescribing the medications is to familiarize periods without known additional exposure to chlor- themselves with the common offenders, recognize the acnegens. The most sensitive areas of the human skin common presentation and appearance of such an erup-
to chloracnegens are inferior to and lateral to the eye tion, and determine if the side effect is acceptable in the
(malar crescent) and behind the ear. The genitalia, both overall success of the treatment desired. To better educate
penis and scrotum, are also sensitive regions. If sufficient the medical community, every practitioner should assume
exposure and toxic reaction have occurred, lesions may the responsibility to report future cases with medications
appear on the shoulders, chest, back, and, eventually, the previously unknown to cause such eruptions.
buttocks and abdomen. The axillary regions have been
commonly involved only in those patients who have reFerenCes
ingested or inhaled the chloracnegens as the sole or major 1. Plewig G, jansen T. Acneiform dermatoses. Dermatology.
route of exposure. The primary lesion of chloracne is the
2. Monk B, Cunliffe Wj, layton AM, et al. Acne induced by inhaled comedone. In the most severe cases, the patients also corticosteroids. Clin Exp Dermatol. 1993;18:148-150.
manifest inflammatory lesions. Dioxins are also included 3. Hughes jr, Higgins EM, du Vivier AW. Acne associated with on the list of halogenated compounds.82 inhaled glucocorticosteroids. BMJ. 1992;305:1000.
Vol. 22 no. 1 • jAnuAry 2009 • Cosmetic Dermatology® 35
Drug-InDuceD Acneform eruptIons
4. Smith Mj, Hodson ME. Effects of long term inhaled high 28. el-Shahawy MA, Gadallah MF, Massry SG. Acne: a potential side dose beclomethasone dipropionate on adrenal function. Thorax. effect of cyclosporine A therapy. Nephron. 1996;72:679-682.
29. Azurdia rM, Graham rM, Weismann K, et al. Acne keloidalis in 5. Hengge ur, ruzicka T, Schwartz rA, et al. Adverse effects of topi- caucasian patients on cyclosporin following organ transplantation. cal glucocorticosteroids. J Am Acad Dermatol. 2006;54:1-15.
Br J Dermatol. 2000;143:465-467.
6. Wells K, Brodell rT. Topical corticosteroids ‘addiction’. a cause of 30. Scott Mj jr, Scott Mj 3rd. Dermatologists and anabolic-androgenic perioral dermatitis. Postgrad Med. 1993;93:225-230.
drug abuse. Cutis. 1989;44:30-35.
7. Feldmann rj, Maibach HI. regional variation in percutaneous 31. Scott Mj III, Scott AM. Effects of anabolic-androgenic steroids on penetration of 14C cortisol in man. J Invest Dermatol. 1967;48: the pilosebaceous unit. Cutis. 1992;50:113-116.
32. Fyrand o, Fiskaadal Hj, Trygstad o. Acne in pubertal boys under- 8. Cohen Hj. Perioral dermatitis. J Am Acad Dermatol. 1981;4: going treatment with androgens. Acta Derm Venereol. 1992;72: 9. Kaidbey KH, Kligman AM. The pathogenesis of topical steroid 33. Traupe H, von Mühlendahl KE, Brämswig j, et al. Acne of the acne. J Invest Dermatol. 1974;62:31-36.
fulminans type following testosterone therapy in three excessively 10. oliet Ej, Estes SA. Perianal comedones associated with chronic tall boys. Arch Dermatol. 1988;124:414-417.
topical fluorinated steroid use. J Am Acad Dermatol. 1982;7: 34. luderschmidt C, Eiermann W, jawny j. Steroid hormone receptors and their relevance for sebum production in the sebaceous gland 11. Mills oH, Kligman AM. Acnegenicity of corticosteroids; mode of ear model of the Syrian hamster. Arch Dermatol Res. 1983;275: action. Clin Res. 1974;22:330.
12. Kligman AM, Mills oH. Steroid acne. Dermatol Allergy. 1979;2: 35. Heydenreich G. Testosterone and anabolic steroids and acne fulmi- nans. Arch Dermatol. 1989;125:571-572.
13. Gloor M, Mildenberger KH. on the influence of an external 36. Greenberg rD. Acne vulgaris associated with antigonadotropic therapy with dexamethasone-21-sodium-m-sulfobenzoate on the (Danazol) therapy. Cutis. 1979;24:431-433.
amount of free fatty acids in the skin surface lipids. Arch Dermatol 37. olsson SE, odlind V, johansson E. Androgen levels in women using norplant implants. Contraception. 1986;34:157-167.
14. Gloor M, Funder H, Franke M. Effect of topical application of 38. joffe H, Cohen lS, Suppes T, et al. Valproate is associated with dexamethasone on propionibacteria in the pilosebaceous duct. Eur new-onset oligoamenorrhea with hyperandrogenism in women J Clin Pharmacol. 1978;14:53-56.
with bipolar disorder. Biol Psychiatry. 2006;59:1078-1086.
15. Tagami H. unilateral steroid acne on the paralyzed side of the face. 39. De Gálvez Aranda MV, Sánchez PS, Alonso Corral Mj, et al. Acne- iform eruption caused by amineptime. a case report and review of 16. DeWitt CA, Siroy AE, Stone SP. Acneiform eruptions associated the literature. J Eur Acad Dermatol Venereol. 2001;15:337-339.
with epidermal growth factor receptor-targeted chemotherapy. J 40. Bettoli V, Trimurti S, lombardi Ar, et al. Acne due to amineptine Am Acad Dermatol. 2007;56:500-505.
abuse. J Eur Acad Dermatol Venereol. 1998;10:281-283.
17. Segaert S, Van Cutsem E. Clinical signs, pathophysiology and man- 41. Fazio M, Afa G, Sacerdoti G, et al. Acne iatrogena da amineptina: agement of skin toxicity during therapy with epidermal growth osservazioni cliniche e biochemiche. G Ital Dermatol Venereol. factor receptor inhibitors. Ann Oncol. 2005;16:1425-1433.
18. yalçin S, Dizdar o, yalçin B, et al. Sparing of previously irradiated 42. Vexiau P, Gourmel B, julien r, et al. Severe acne-like lesions caused skin from erlotinib-induced acneiform rash. J Am Acad Dermatol. by amineptine overdose. Lancet. 1988;1:585.
43. Farella V, Sberna F, Knöpfel B, et al. Acne-like eruption caused by 19. Martin jM, jordá E, Monteagudo C, et al. Follicular acneiform amineptine. Int J Dermatol. 1996;35:892-893.
eruption induced by imatinib. J Eur Acad Dermatol Venereol. 44. Blatt j, lee PA. Severe acne and hyperandrogenemia following dactinomycin. Med Pediatr Oncol. 1993;21:373-374.
20. lee PK, Dover jS. recurrent exacerbation of acne by granulocyte 45. Stankler l, Campbell AG. neonatal acne vulgaris: a possible fea- colony-stimulating factor administration. J Am Acad Dermatol. ture of the fetal hydantoin syndrome. Br J Dermatol. 1980;103: 21. Horn TD, rest EB, Karp jE, et al. Interleukin 2 and granulocyte- 46. Grunwald MH, Ben-Dor D, livni E, et al. Acne keloidalis-like acrophage colony-stimulating factor induce a perivascular lym- lesions on the scalp associated with antiepileptic drugs. Int J phocytic infiltrate in a skin explant model. Arch Dermatol. 47. Chan HH, Wing y, Su r, et al. A control study of the cutaneous 22. Bassi E, Poli F, Charachon A, et al. Infliximab-induced acne: report side effects of chronic lithium therapy. J Affect Disord. 2000;57: of two cases. Br J Dermatol. 2007;156:402-403.
23. Pandya K, Babar r. Severe nodulocystic acne vulgaris in a patient 48. Kusumi y. A cutaneous side effect of lithium: report of two cases. on infliximab. J Am Acad Dermatol. 2006;52(suppl 2):126.
Dis Nerv Syst. 1971;32:853-854.
24. Krathen rA, Berthelot Cn, Hsu S. Sustained efficacy and safety of 49. rifkin A, Kurtin SB, Quitkin F, et al. lithium-induced folliculitis. infliximab in psoriasis: a retrospective study of 73 patients. J Drugs Am J Psychiatry. 1973;130:1018-1019. 50. yoder FW. letter: acneiform eruption due to lithium carbonate. 25. Mahé E, Morelon E, lechaton S, et al. Acne in recipients of renal Arch Dermatol. 1975;111:396-397.
transplantation treated with sirolimus: clinical, microbiologic, his- 51. Kanzaki T. Acneiform eruption induced by lithium carbonate. J tologic, therapeutic, and pathogenic aspects. J Am Acad Dermatol. 52. Pembroke AC, Saxena Sr, Kataria M, et al. Acne induced by dan- 26. Mahé E, Morelon E, lechaton S, et al. Cutaneous adverse events trolene. Br J Dermatol. 1981;104:465-468.
in renal transplant recipients receiving sirolimus-based therapy. 53. joynt rl. Dantrolene sodium: long-term effects in patients with Transplantation. 2005;79:476-482.
muscle spasticity. Arch Phys Med Rehabil. 1976;57:212-217.
27. Bencini Pl, Montagnino G, Sala F, et al. Cutaneous lesions in 54. Gomez EC. Actions of isotretinoin and etretinate on the pilo- 67 cyclosporin-treated renal transplant recipients. Dermatologica. sebaceous unit. J Am Acad Dermatol. 1982;6(4 Pt 2 Suppl): 36 Cosmetic Dermatology® • jAnuAry 2009 • Vol. 22 no. 1
Drug-InDuceD Acneform eruptIons
55. Exner jH, Dahod S, Pochi PE. Pyogenic granuloma-like acne 70. Hjortshoj A. lichen planus and acne provoked by gold. Acta Derm lesions during isotretinoin therapy. Arch Dermatol. 1983;119: 71. jones C, Bleehen SS. Acne induced by PuVA treatment. Br Med J. 56. Huston nr, Mules r. Acne fulminans with severe myalgia precipi- tated by isotretinoin therapy. N Z Med J. 1985;98:821.
72. nielsen EB, Thormann j. Acne-like eruptions induced by PuVA- 57. Elías lM, Gómez MI, Torrelo A, et al. Acne fulminans and bilat- treatment. Acta Derm Venereol. 1978;58:374-375.
eral seronegative sacroiliitis triggered by isotretinoin. J Dermatol. 73. Frumess GM, lewis HM. light-sensitive seborrheid. AMA Arch 58. Menter A, Boyd A. Cystic acne in psoriatic patients undergoing 74. Hjorth n, Sjolin KE, Sylvest B, et al. Acne aestivalis–Mallorca acne. etretinate therapy. J Am Acad Dermatol. 1988;18:751-752.
Acta Derm Venereol. 1972;52:61-63.
59. lowe l, Herbert AA. Cystic and comedonal acne: a side effect of 75. Sherertz EF. Acneiform eruption due to “megadose” vitamins B6 etretinate therapy. Int J Dermatol. 1989;28:482.
and B12. Cutis. 1991;48:119-120.
60. Bereston ES. reactions to antituberculous drugs. J Invest Dermatol. 76. Braun-Falco o, lincke H. [The problem of vitamin B6/B12 acne. a contribution on acne medicamentosa]. MMW Munch Med 61. Cohen lK, George W, Smith r. Isoniazid-induced acne and pel- Wochenschr. 1976;118:155-160.
lagra. occurrence in slow inactivators of isoniazid. Arch Dermatol. 77. Weary PE, russell CM, Butler HK, et al. Acneform eruption result- ing from antibiotic administration. Arch Dermatol. 1969;100: 62. Holdiness Mr. Adverse cutaneous reactions to antituberculosis drugs. Int J Dermatol. 1985;24:280-285.
78. Bean SF. Acneiform eruption from tetracycline. Br J Dermatol. 63. Burkhart CG. Quinidine-induced acne. Arch Dermatol. 79. Barefoot SW. Acneiform eruption produced by use of tetraethyl- 64. Bakos l, Bakos rM. Focal acne during topical tacrolimus therapy thiuramdisulfide. JAMA. 1951;147:1653.
for vitiligo. Arch Dermatol. 2007;143:1223-1224.
80. Webster GF. Pustular drug reactions. Clin Dermatol. 1993;11: 65. Antille C, Saurat jH, lübbe j. Induction of rosaceiform dermatitis during treatment of facial inflammatory dermatoses with tacroli- 81. Fisher AA. Drug eruptions in geriatric patients. Cutis. 1976;18: mus ointment. Arch Dermatol. 2004;140:457-460.
66. Bajwa ZH, Sami n, Flory C. Severe acne as a side effect of propran- 82. Tindall jP. Chloracne and chloracnegens. J Am Acad Dermatol. olol and nadolol in a migraineur. Headache. 1999;39:758-760.
67. Ismail r. Acne fulminans with dapsone induced haemolysis: a case 83. Frankel EB. Acne secondary to white petrolatum use. Arch Dermatol. report. Med J Malaysia. 1987;42:124-126.
68. Schmoeckel C, von liebe V. [Acneiform exanthema caused by 84. Mills oH jr, Kligman AM. Comedogenicity of sunscreens. azathioprine]. Hautarzt. 1983;34:413-415.
experimental observations in rabbits. Arch Dermatol. 1982;118: 69. nielsen jn, licht rW, Fogh K. Two cases of acneiform erup- tion associated with lamotrigine. J Clin Psychiatry. 2004;65: 85. o’Brien Tj. Acneiform eruption associated with the use of a cow udder ointment. Australas J Dermatol. 1990;31:119. Vol. 22 no. 1 • jAnuAry 2009 • Cosmetic Dermatology® 37

Source: http://www.bellebonelli.com.br/cursos/biblioteca/DrugInducedAcneform.pdf