Medications as well as chemical and food exposures have been causally linked to the development of pigmented purpuric dermatosis (PPD). We describe herein what is to our knowledge the first reported case of isotretinoin-induced PPD.
A woman in her 30s presented with purpura annularis telangiectodes of Majocchi on the lower extremities 2 months after initiating isotretinoin for the treatment of refractory nodulocystic acne.
Conclusions and Relevance
We believe isotretinoin was the most likely causative agent in this case because the lesions began after initiation of isotretinoin treatment and resolved shortly after its termination, and the pathologic findings were consistent with other described cases of drug-induced PPD. The lesions have continued to fade, and no new lesions have developed in a 3-month follow-up period. Drug-induced PPD is distinct from idiopathic PPD, and it is important to consider isotretinoin as a potential inciting agent.
The pigmented purpuric dermatoses (PPDs) are a group of histologically similar skin eruptions characterized by a perivascular lymphocytic infiltrate with extravasated eyrthrocytes that may exhibit evidence of small vessel lymphocytic vasculitis on occasion. Each entity presents with a unique clinical presentation of nonblanching, nonpalpable purpuric lesions that are often bilaterally symmetrical and present on the lower extremities.1 In addition to idiopathic cases attributed to various factors including exercise, gravitational dependence, venous hypertension, capillary fragility, and focal infections, medications and chemical exposures have been established in the literature as etiologic factors in PPD.1- 4 We report a case of purpura annularis telangiectodes of Majocchi (PATM) induced by isotretinoin and review the current literature on substance-induced PPD.
A woman in her 30s presented to the clinic for treatment of scarring nodulocystic acne that had been unresponsive to oral antibiotics (minocycline and doxycycline monohydrate), topical retinoids, and topical clindamycin. Treatment was started with isotretinoin at a dosage of 0.5 mg/kg/d (40 g/d), with the intent to increase the dosage to 70 mg/d. After the first month, the dosage was increased to 50 mg/d because the patient was experiencing uncomfortable xerosis. At about the end of her second month of treatment, mildly pruritic patches started to develop on the lower parts of her legs, which then spread upward to her thighs and buttocks. There was no associated edema.
Findings from a review of systems revealed that the patient experienced headaches and xerosis, but findings were otherwise negative. At examination, the patient had orange-brown annular macules with cayenne pepper–like nonblanching petechiae on both lower extremities, including her legs, thighs, and buttocks, which were clinically consistent with PATM (Figure 1).
The patient had several similar lesions on both lower extremities and buttocks. This red-brown lesion demonstrates the typical annular appearance of lesions in purpura annularis telangiectodes of Majocchi, with cayenne pepper–like punctate petechiae.
Laboratory results were normal, including complete blood cell count and results of a basic metabolic panel. A biopsy sample was taken from a representative lesion and showed a superficial perivascular lymphocytic infiltrate with extravasated erythrocytes (Figure 2A), and Perls stain revealed hemosiderin deposits within the papillary dermis (Figure 2B).
A, There is a superficial perivascular lymphocytic infiltrate with extravasated erythrocytes (hematoxylin-eosin, original magnification ×100). B, Perls stain reveals hemosiderin deposits within the papillary dermis. These histologic findings are consistent with a diagnosis of pigmented purpuric dermatosis (original magnification ×400).
The treatment with isotretinoin was discontinued, and spironolactone treatment was started for the patient’s acne after a week. Approximately 5 weeks after discontinuation of isotretinoin therapy (and still during spironolactone treatment), her lesions slowly began to fade. Three months after discontinuation of isotretinoin therapy, no new lesions have developed, and her old lesions continue to improve.
The PPDs, also referred to in the literature more broadly as purpura simplex4 and capillaritis, classically include 5 clinical entities: progressive pigmented purpura of Schamberg, pigmented purpuric lichenoid dermatosis of Gougerot and Blum, PATM, eczematoid-like purpura of Doucas and Kapetanakis, and lichen aureus.1,5 However, other entities have also been described, including itching purpura of Lowenthal, transitory PPD, unilateral linear PPD, and granulomatous PPD.1,6
The lesions of PPD typically present as solitary or multiple nonpalpable orange-brown purpuric macules, or, as in PATM, annular purpuric lesions with nonblanching punctate petechiae, often described as “cayenne pepper–like.”1,5,6 All of the PPDs are characterized by similar histologic findings of extravasated erythrocytes within the papillary dermis, hemosiderin deposition, and a lymphocytic infiltrate, and they rarely exhibit fibrinoid necrosis of small venules in the superficial dermis.3,4 Each PPD has characteristic clinical features and a demographic distribution.1 Most PPDs are considered more common in males, but PATM is more common in females.1 The lesions of PATM are usually distributed symmetrically on the legs and are sometimes symptomatic5; severe pruritus has been reported in drug-induced cases.4 In all the PPDs, hematologic findings, including platelet count and measures of coagulation time, are normal.1
The etiology of PPDs is unknown, but several contributing factors have been cited, including exercise, venous stasis, gravitational dependence, capillary fragility, hypertension, drugs, chemical exposure or ingestions, and contact allergy to dyes.1,2,7 Medications are frequently cited provocative factors, most commonly with presentations mimicking Schamberg disease. All subtypes of PPD have been described in drug-induced cases, with PATM the least common, matching the distribution pattern of non–drug-induced cases.1- 4
Both idiopathic and drug-induced classes of PPDs are described in the literature. Histologically, drug-induced cases lack epidermal involvement and a lichenoid infiltrate when compared with idiopathic PPDs. Clinically, these drug-induced cases are more likely to be generalized, but the majority still present classically with lower-extremity involvement, as in our patient.3,4 Furthermore, contrary to the classic description of PPDs as chronic, PPDs secondary to drug exposure is often more transient, with a reported mean duration of 3 to 4 months4 but with many cases resolving within a few weeks.6,7 In several studies, rechallenge has been used when possible to verify the causative agent and has induced PPDs within days to weeks.2,8,9 It has also been noted that patients may be taking the drug for months to years before PPD presentation, so a clear temporal relationship may not be easily elucidated.3
Pigmented purpuric dermatoses have been attributed to many different ingested substances (Table). Diuretics and nonsteroidal anti-inflammatory drugs are cited as common culprits,3 but a wide variety of substances are implicated, including sedatives, stimulants, antibiotics, cardiovascular drugs, dietary components, and vitamins.
The mechanism of drug-induced PPD is unknown, but it is believed that the culprit substance may act as a toxin and/or lead to an immunologic response in the capillary endothelium.3,12 A cell-mediated immune response is likely to be involved in the vascular damage.4,13 It has been proposed that the drug or substance may act as a hapten,7 leading to antigen formation with human protein, which then stimulates antibody formation and leads to immune system–mediated injury near the vascular endothelium, causing capillaritis and purpura.3 The underlying cell-mediated mechanism in drug-induced cases as well as cross-reactivity between different drugs has been proposed to explain the possibly more generalized presentation.3
Isotretinoin, an oral retinoid used for recalcitrant nodulocystic acne and probably the culprit drug in the present case, has been linked to many dermatologic adverse effects, including rare cases of palpable purpura and leukocytoclastic vasculitis.15 However, in reviewing the literature, we have found no other reports of isotretinoin causing a PPD.
Our patient’s lesions began approximately 2 months after the start of isotretinoin treatment and began to fade after isotretinoin was discontinued. Both the time course and the pathologic appearance of the lesions are consistent with other described cases of drug-induced PPD. Interestingly, because 13-cis-retinoic acid (isotretinoin) is present in normal serum as an isomer of naturally occurring all-trans-retinoic acid, it is less likely that this drug is acting as a hapten, which may suggest an alternate mechanism in this case.
Treatment of PATM includes topical corticosteroids and compression hose in mild cases, with the addition of oral ascorbic acid (vitamin C) or pentoxifylline in moderate cases, as well as possible use of colchicine and griseofulvin.5 In severe cases, psoralen–UV-A or narrowband UV-B phototherapy, cyclosporine, or methotrexate may be effective.5 In drug-induced cases, however, removal of the offending substance is often enough to clear the PPD.
Accepted for Publication: August 6, 2013.
Corresponding Author: Rachel Kaplan, MSEd, New York University School of Medicine, 160 E 38th St, Apt 20G, New York, NY 10016 (firstname.lastname@example.org).
Published Online: November 27, 2013. doi:10.1001/jamadermatol.2013.7371.
Author Contributions: Ms Kaplan and Dr Leger had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.
Study concept and design: Leger.
Acquisition of data: Kaplan, Leger.
Analysis and interpretation of data: All authors.
Drafting of the manuscript: Kaplan.
Critical revision of the manuscript for important intellectual content: All authors.
Administrative, technical, and material support: Kaplan.
Study supervision: All authors.
Conflict of Interest Disclosures: None reported.
Additional Contributions: We are indebted to Giselle Burgos for helping with the photography.
Kaplan R, Meehan SA, Leger M. A Case of Isotretinoin-Induced Purpura Annularis Telangiectodes of Majocchi and Review of Substance-Induced Pigmented Purpuric Dermatosis. JAMA Dermatol. 2014;150(2):182-184. doi:10.1001/jamadermatol.2013.7371