Drug and acneiform eruptions – Introduction, Chemotherapeutics, Corticosteroids, Hormones and Central nervous system agents
Acneiform eruptions are skin conditions that resemble acne. The extent to which an eruption resembles acne depends on the clinician’s aptitude and experience. Misclassification of distinct clinical entities such as gram-negative folliculitis, pseudofolliculitis barbae, acne fulminans, and rosacea fulminans, renamed so by Plewig et al. in 1992 (1), is reviewed in other posts.
Acne medicamentosa, or drug-induced acne, is the prototypic acneiform eruption. Although classical acne treatments may alleviate disease, the presence of a causative agent differentiates acneiform eruptions from garden-variety acne vulgaris as identification and withdrawal of said agents are critical in treatment.
The first documented use of the term acneiform eruption came from All-worthy in 1917. He described young girls who worked as “doffers” or those who cleaned machines and were exposed to dirt, sweat, and sperm oil used in machinery. He rightfully postulated that follicular plugging lead to inflammatory changes that produced the eruptions (2).
Acneiform eruptions originate in the follicles, much like acne vulgaris. Histologically, spongiosis followed by rupture of follicular epithelium and spillage of glandular contents into dermis results in neutrophilic inflam-mation (3,4). The clinical features of acneiform eruptions are reviewed in Table 1.
The diagnosis may be confirmed with improvement after discontinuation of offending agent. Many categories of systemic therapies have a long and well-documented history of causing acneiform eruptions, which should assist clinicians in choosing agents to discontinue when possible.
Table 1 Signs and Symptoms of Acneiform Eruptions
|Sudden onset, within daysMonomorphic lesions with papules and pustules in the same stage of development as opposed to acne vulgaris
Involvement of high sebaceous gland density areas, with potential extension to nonclassic areas as well
Development of inflammatory papules prior to comedones
Association with a new oral or topical therapeutic
Epidermal Growth Factor Receptor Inhibitors
Epidermal growth factor receptor inhibitors (EGFR-I) are the most recently identified and most reported on acneiform eruption. The tyrosine kinase inhib-itors include gefitinib, erlotinib, lapatinib, and canertinib, while monoclonal antibodies against the receptor include cetuximab, panitumumab, and matuzu-mab. Their use has been widespread from glioblastoma, head and neck squamous cell carcinoma, non small cell lung cancer to pancreatic and colorectal cancer. Many reports have noted that incidence of acneiform eruption on this class of medication actually portends better clinical efficacy. In fact, the association has prompted some to consider a “treatment to rash” approach to therapy. However, the impact on quality of life has also required dose reduction, treatment holidays, and total discontinuation. Recently, an expert consensus group of cutaneous toxicities reported an overall acneiform eruption frequency of 60% to 80% (5).
EGFR-I-induced acneiform eruptions show increased inflammation at the dermoepidermal junction, accompanied by neutrophils and damage to the hair follicles. Further testing reveals high levels of p53 in the basal keratinocytes (6). It has been reported that mild cases of acneiform eruption respond well to topical anti-inflammatory acne therapy, whereas oral tetracyclines are needed to treat moderate to severe cases (7). The pathophysiology of EGFR-I in the develop-ment of acneiform eruptions is yet to be elucidated (8); the mechanism is likely to be complicated given the broad range of potential cutaneous side effects reported to EGFR-I: xerosis, eczema, fissures, telangiectasia, hyperpigmentation, hair changes, and paronychia with pyogenic granuloma (7).
Thalidomide and Lenalidomide
Thalidomide and lenalidomide are immunomodulating agents believed to decrease levels of tumor necrosis factor-oc. Currently, lenalidomide is used in the treatment of multiple myeloma and myelodysplasic syndromes. Additionally, it may be used as part of a multitherapy regimen for systemic amyloidosis. Thalidomide has the above indications and is also used to treat erythema nodosum leprosum.
Lenalidomide is associated with an overall skin complication rate of 29% in patients with multiple myeloma and 43% in patients with systemic amyloi-dosis in one study. A relatively low rate of acneiform eruptions, 3% of all patients, was reported (9). Thalidomide has been reported to cause acneiform eruptions as well, although there is no estimate of its incidence (10). Of the two reports cited, no case was biopsied. Although the time of onset after treatment initiation and time of resolution with discontinuing treatment were described for urticarial rashes, the same was not done for acneiform eruptions.
Actinomycin-D binds to deoxyribonucleic acid and inhibits ribonucleic acid transcription. It has been used as chemotherapy against testicular and uterine cancers, Ewing’s sarcoma, Wilms’ tumor, and rhabdomyosarcoma. Additionally, it has been used as an antibiotic, although mostly in laboratory settings. A single case report of an eight-year-old girl with embryonal rhabdomyosarcoma describes an acneiform eruption within 10 days of treatment initiation. Her physicians monitored and documented rises in androstenedione, dehydroepian-drosterone, and testosterone that coincided with courses of actinomycin-D. The authors concluded that these observations support a relationship between drug, dermatitis, and hormone levels. Further, the authors identified structural simi-larity between actinomycin-D and amineptine, a tricyclic antidepressant not available in the United States. Amineptine, when in use, was also a causative agent of acneiform eruptions. It is unclear if this can be seen as a general side effect of central dopamine enhancement, due to the inhibitory effect of dopamine on prolactin, with the subsequent increase in testosterone output or through direct simulation of androgen production (11).
Steroid-induced acne is well documented. Classically, it presents with mono-morphic inflammatory papules and pustules. Few to no comedones are apparent. Although short-term use of topical corticosteroids may actually decrease inflammation and shorten the duration to clearance of a single inflammatory papule, extended use has routinely demonstrated the association with subsequent onset and/or worsening of acne. Furthermore, discontinuation of long-standing topical corticosteroid can lead to a severe flare. The situation of steroid-induced acne that flares with discontinuation of the offending agent is a clinical quagmire most dermatologists choose to avoid.
Plewig and Kligman first reported steroid-induced acne in 1973 (12). Kligman and Leyden went on to describe three distinct clinical entities that resulted from months of indiscriminate use of topical steroids: steroid rosacea, perioral dermatitis, and steroid-induced acne. They also reported that occlusive application of fluorinated steroids to the back creates, within three weeks, an acneiform eruption identical to the one that follows systemic corticosteroids. Treatment recommendations included discontinuation of the offending agent and oral tetracycline (13). Beyond causing acneiform eruptions, topical steroids are associated with atrophy, striae, rosacea, perioral dermatitis, and purpura (14).
Kaidbey and Kligman studied the natural history of topical steroid use in a prisoner volunteer population. Fluocinolone acetonide cream 0.01% was applied under occlusion to the upper back three times a week for three weeks. Not all patients developed acneiform eruptions. Patients with a history of acne vulgaris were more likely to develop steroid-induced acne. Serial biopsies revealed that the earliest changes were evident by day 4. A focus of swollen, poorly stained, necrotic epithelial cells with shrunken nuclei appeared deep in the follicle, often localized to one side. The degenerated nests subsequently sloughed and could be found free in the lumen of the follicle at higher levels. By day 6, neutrophils were present in both the spongiotic degenerated zones and in adjacent tissue. The largest sebaceous follicles were the most susceptible, with vellus follicles not being involved at all. At 10 to 15 days of treatment, epithelial disorganization was complete, with neutrophils forming intrafollicular abscesses. At completion of therapy, foreign-body giant cells and comedones were not identified (15).
Both systemic and inhaled corticosteroids (16) have been associated with acneiform eruptions. Often, the illness being treated is associated with such significant morbidity and mortality that using a corticosteroid is indicated in spite of the cutaneous effects.
Anabolic-androgenic steroids (AAS) cause sebaceous gland hypertrophy along with increased sebum excretion, increased production of skin surface lipids, and an increased population of Propionibacterium acnes (17). AAS vary in their affinity to the androgen receptor and their interaction with various steroid-metabolizing enzymes and transport proteins such as sex hormone binding globulin, thus altering each androgen’s specific mechanism of action. Regarding interactions of AAS with intracellular steroid receptor proteins, different binding affinities are known (18).
In 1987, a 12-week strength-training program with self-AAS administra-tion followed the sebum secretion rate and profile. After four weeks of AAS, the sebum excretion rate increased significantly from 0.989 f 0.191 g/cm2/min to 1.171 f 0.076 g/cm2/min. The relative distribution of the main lipid classes of sebum (free fatty acids, squalene, triglycerides, wax esters) on the forehead showed no statistically significant difference with AAS use. However, a sig-nificant increase in cholesterol from the initial level of 2.4 f 0.1% to 4.2 f 0.7% was reported (19). Beyond effects of androgens on the androgen receptor, other nuclear receptors, specifically the nuclear hormone peroxisome proliferator activated receptors (PPARs), are involved in development, proliferation, and differentiation of sebocytes. AAS increase sebum synthesis directly by binding to the androgen receptor of the sebocyte and indirectly by induction of the PPAR-,y1 (20,21).
The cutaneous side effects of topical and systemic AAS have been described in both men and women (22). Estimated in 2010 by the National Institute on Drug Abuse at 2.5% of all 12th-grade males (23), use of AAS has been difficult to quantify. Older sources estimate the range to be 11% (24,25). Further, various studies show the incidence of acne in AAS users to be between 43% and 50% (18,26). It has been documented to cause both acne conglobata and acne fulminans (26).
Androgen-induced acne can be difficult to diagnose since the patient rarely reports illicit androgen use voluntarily and the acne is in no way different from normal acne. Treatment involves eliminating the androgen and therapy appro-priate to the severity of the acne.
Progestins and Intrauterine Devices
Levonorgestrel-based implants and intrauterine devices are approved for use as a contraceptive and for the treatment of heavy menstrual bleeding. They are promoted as a local source of progestin with minimal systemic adverse effects. However, there is evidence of elevated serum and tissue levels of levonorgestrel. Some have reported high discontinuation and dissatisfaction rate (27,28). Additionally, oily skin and acne have been observed in some, which is postulated to be a direct effect of progestin, although this area of investigation remains controversial (29).
CENTRAL NERVOUS SYSTEM AGENTS
Although used to treat conditions that may have a slightly higher baseline incidence of acne vulgaris, several central nervous system agents have the propensity to induce acneiform eruptions. These agents are difficult to categorize as they have multiple indications. Some are antiepileptics, mood stabilizers, antipsychotics, antidepressants, or any combination thereof.
Lamotrigine is used to treat seizure disorders and bipolar disorder. In a report of two cases, two patients developed an acneiform eruption on the back one to two months after starting the medication. Discontinuation of lamotrigine lead to clearance without need for further treatment. Of note, both patients had pre-viously been on lithium but had been discontinued from it one to two months prior to the onset of the eruption. Therefore, lithium as a causative agent could not entirely be excluded (30).
Aripipazole is used as an antipsychotic and antidepressant. It is a partial agonist of the dopamine-2 and 5-hydroxytryptamine-1A receptors; it acts as an antag-onist of the 5-hydroxytryptamine-2A receptor. A single case report of a patient who developed papulopustules with few comedones subsequent to initiation of aripipazole therapy exists. The patient required both discontinuation of the medicine with topical tretinoin therapy to achieve clearance (31).
Valproate is a histone deacetylase inhibitor believed to block voltage-gated channels and affect the function of the y-aminobutyric acid (GABA) receptor. It is used as an antiepileptic, antipsychotic, antidepressant, and as a therapeutic option in the treatment of bipolar disorder and migraine headaches. Although acneiform eruptions have been noted in patients taking valproate, a recent study showed no statistical difference in rates of acne between two cohorts of patients with epilepsy at a tertiary endocrine referral center in Israel. Although the study was not prospective and randomized, data from a total of 88 patients were collected. Even though no increase in acne with valproate was identified, the treated postmenarcheal subgroup had a higher mean testosterone level than the untreated postmenarcheal controls (32).
Although previous reports of its cutaneous side effects (33) exist, lithium was first noted to cause acneiform eruptions in the dermatology literature in 1975. Four female patients experienced new-onset acneiform eruptions after initiating lithium treatment. One had worsening of previous acne. All patients improved with discontinuation of medicine (34).
Recent reviews have shown an estimated overall cutaneous reaction rate ranging from 3.4% to 45%, with acne and psoriasis being the most common dermatoses. Lithium tends to exacerbate any skin condition with pathophysiol-ogy driven by the action of neutrophils (35). Given that control of mental illness reduces mortality, some continue with therapy in spite of cutaneous side effects. For these patients, oral isotretinoin has been used concomitantly (36).
Chloracne is a long-observed cutaneous eruption predominantly of comedones with sparse inflammatory papules on forehead, ears, neck, and genitals. Patients tend to be photosensitive as well. Although seen in laborers and those with exposure to industrial materials, the exact chemicals and route of exposure were debated for over half a century. The causative agents are halogenated aromatic compounds, such as chlorinated dioxins and dibenzofurans; inhalation is suffi-cient to provoke the eruption, although direct contact is the most common route of exposure. Histopathologic examination reveals either a superficial or a deep cystic structure with complete loss of sebaceous glands (37). Presence of com-edones, usually open comedones, after exposure to “toxic chlorine,” is what brought about the current terminology. Recently, the recognition that cyto-chrome p450 enzymes in the skin produce toxic metabolites has lead some to suggest renaming this entity “metabolizing acquired dioxin-induced skin hamartomas” (MADISH) (38); however, this term has not yet gained use.
The most widely known case of chloracne was a poisoning attempt on Ukrainian President, Viktor Yuschenko, during his 2004 campaign (39). Chloracne responds best to discontinuation of exposure. Clearance can be extended, with some cases taking years to decades to respond. Attempts have also been made to increase excretion of the toxic chemical as well. Both topical tretinoin and oral isotretinoin have been used with reasonable efficacy.
Agent Orange is the name given to an herbicide used during the Vietnam War. It was, and continues to be, a source of controversy both politically and medically (40). It is a 1:1 mixture of 2,4-dichlorophenoxyacetic acid and 2,4,5- trichlorophenoxyacetic acid, which contains minute traces of 2,3,7,8-tetra-chlorodibenzo-p-dioxin (41). The U.S. government, along with the Institutes of Medicine, has shown a positive association between chloracne and dioxin exposure through Agent Orange in reports released in 1994 and updated four times to 2004 (42). The 2004 report concluded it was unlikely, given the envi-ronmental dissipation of dioxins, little bioavailability, properties of the herbi-cides, and application methods, that veterans without direct contact could have experienced clinically meaningful exposure. The report also concluded that those who handled or otherwise had direct contact with the dioxins, as opposed to incidental exposure from spraying under field conditions, could have sustained appreciable accumulation of the toxins (43). Although it has been suggested that there are fewer than 4000 persons with chloracne worldwide (40), there has been considerable debate over the incidence in exposed veterans and even the clinical features of exposure (44 46).
BIOLOGICS AND ANTI–TUMOR NECROSIS FACTOR-α AGENTS
Biologic agents are a relatively new class of medication utilized in the treatment of many inflammatory and autoimmune diseases. A case series of three patients being treated with anti tumor necrosis factor (anti-TNF)-a therapy for psoriasis developed acneiform eruptions (47). Another case documents the use of different anti-TNF-a products in the same patient. The patient had both psoriasis vulgaris and acne vulgaris. Each disease responded differently to each treatment. Efali-zumab, a monoclonal antibody that binds CD11 leukocyte surface antigen and has now been withdrawn from the market, gave mild improvement in the Pso-riasis Area and Severity Index (PASI) score with severe worsening of Acne Intensity Score (AIS). Etanercept, which binds and inhibits TNF-a, improved the acne. However, the psoriasis persisted with a high PASI even with a dose of 50 mg subcutaneously twice weekly. After 15 weeks of therapy, the decision was made to switch to infliximab, an intravenous chimeric monoclonal antibody preventing TNF-a from binding its receptor. The PASI reduced rapidly within six weeks, and the AIS continued to improve. It was postulated that since P. acnes activates toll-like receptors, therapeutics that either stimulate or inhibit these receptors could cause or treat acne, respectively. Toll-like receptors also stimulate the production of TNF-a, which, through positive feedback, increases the expression of toll-like receptors. The authors further postulated that TNF-a inhibitors decreased activation of mononuclear cells, also implicated in the pathogenesis of acne (48).
In 2006, a single case entered the literature describing a 22-year-old male who had failed years of standard therapies for acne vulgaris. He had been treated unsuccessfully with topical treatments (benzoyl peroxide, erythromycin, azelaic acid, and retinoids), systemic antibiotics (minocyclin: 200 mg/day for 6 months, lymecycline: 300 mg/day for 3 months, and azithromycin: 500 mg/day for 3 consecutive days per month for 3 months), and oral isotretinoin (0.5 1 mg/kg/ day for an overall period of 18 months). He was started on etanercept 25 mg subcutaneously twice weekly. The patient and physician noted an improvement within 2 weeks, with complete resolution of disease in 24 weeks. During a 12- week follow-up period when the patient was discontinued from medication, no recurrence was observed (49).
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