Symmetrical drug-related intertriginous and flexural exanthema: A little-known drug allergy

Symmetrical drug-related intertriginous and flexural exanthema is flexural eruption that occurs within few days of drug exposure. Antibiotics and iodinated contrast agents are the most frequent triggers. Skin testing has low sensitivity. Rechallenge identifies the culprit drug without serious manifestations. The symmetrical drug-related intertriginous and flexural ex-anthema (SDRIFE) is delayed flexural exanthema induced by systemic drug without previous cutaneous sensitization, typically presenting as a sharply defined symmetrical erythema of the gluteal area and in the flexural or intertriginous folds without systemic symptoms and 1 SDRIFE clinically resembles Baboon syndrome (BS); however, in BS, patients develop the exanthem after systemic exposure to an allergen to which they have been previously topically sensitized. 2 We retrospectively reviewed records from 2 French dermatology departments between 2006 and 2018 for adults with SDRIFE as defined by Hausermann et al 1 : (1) exposure to systemically administered drug either following the first or subsequent dose, (2) sharply demarcated erythema of the gluteal and/or inguinal area, (3) involvement of at least 1 other flexural localization, (4) symmetry of affected area, and (5) absence of systemic symptoms and signs. Twelve patients were excluded because of previous topical sensitization to the allergen (BS, n ¼ 2), diffuse maculopapular rash (MPR) with flexural reinforcement (n ¼ 7), other causes of flexural rash, for example, acute generalized exanthematous pustulosis (AGEP), toxic er-ythema due to chemotherapy (TEC) based on clinical and histological findings (n ¼ 2), and flexural erythema thought to be drug-induced but without relapse after reexposure (n ¼ 1). Patch tests (PTs) (IQ ultrachambers, Chemotechnique Diagnostics, Velinge, Sweden), skin prick tests (SPTs), and intradermal tests (IDTs) with delayed readings were performed following European guidelines 3 (Table I). We further reviewed all published cases of SDRIFE since Hausermann et al's publication (2004-2018). Eighteen patients were included, 10 females and 8 males, with mean and median ages of 57 years (range, 33-83 years). Erythematous patches or plaques affecting mean of 5 (range, 2-7) large or small skin folds (especially inguinal, gluteal, axillary, and mammary) (Figure 1, Table I) were observed. Four patients had localized skin vesicles or bullae and 1 (no. 16) had mucosal involvement. The eruption occurred shortly after drug exposure (median, 22 hours; mean, 34; range, 0.5-120). The causative drug was discontinued immediately in all patients, 10 were treated with topical steroids, and resolution of lesions was observed within median of 4 days (mean, 6.2; range, 1-18). Lymphopenia was found in 6 of 12 patients (50%; range, 350-1400/mm 3), not explained by distinct underlying condition. The most frequent histological pattern, found in 5 of 11 patients who had skin biopsy, was subepidermal edema with polymorphous perivascular and interstitial infiltrate of neutro-phils, eosinophils, and lymphocytes in the upper dermis. Four patients had spongiotic and/or lichenoid pattern on skin biopsy and 2 had nonspecific scant lymphocytic superficial peri-vascular infiltrate. There was no obvious relationship between histology and the clinical presentation and severity of the rash or timing of skin biopsy. The suspected drug was an antibiotic in 10 of 18 cases (56%), including amoxicillin AE clavulanate in 4 (22%), iodinated contrast agent (ICA) in 5 of 18 (28%), an analgesic in 2 of 18, and fluconazole in 1 of 18 (Table I). Fourteen patients had PT, 12 had SPT, and 11 IDT with delayed readings. Testing was performed within 1 month to 9 years of the original reaction, and most patients (13 of 16) were tested within 1 year of the reaction. Positive skin test results were obtained only in 5 patients, all with antibiotics: PT in 3 of 14 cases (21%): 1 with amoxicillin-clavulanate and 2 with pristinamycin; IDT in 2 of 11 cases (18%) with amoxicillin AE clavulanate. Skin test results remained negative in patient number 2 who also had SDRIFE due to amoxicillin confirmed by rechallenge test (RT). Results of all skin tests performed with ICAs (PT n ¼ 3, SPT and IDT n ¼ 5) were negative. The result of RT with the suspected causative drug, performed in 9 patients with negative skin test results, was always positive, without severe cutaneous or systemic manifestations. There was no obvious relationship between clinical presentation and positivity of skin test results. The median time for SDRIFE recurrence after reexposure to the drug (induced by RT [n ¼ 9] or skin tests [n ¼ 1]) was 12 hours (mean, 15 hours; range 2.5-30), shorter than during the first episode. SDRIFE is thought to involve type IV delayed-hypersensitivity immune response, because it occurs within few hours to few days after drug exposure, and there is evidence for T-cellemediated reaction, 1,4 though the precise physiopa-thology is not known. Antibiotics are common triggering agents in the literature (60% in Hausermann et al's 1 review, 33% in our literature review [2004-2018], n ¼ 51 [see Tables E1 and E2 in this article's Online Repository at www.jaci-inpractice.org]), especially beta-lactams (55% in Hausermann et al's review and 23% in our review), but only 5 cases of SDRIFE due to ICAs were reported. 5 In previously published cases, skin test results were positive more frequently than in our study, 40% of PTs, 11% of SPTs, and 70% of IDTs, for various drugs (antibiotics and others), possibly due to publication bias. Different methods for identifying the culprit drug might be necessary in SDRIFE. Skin testing on affected sites is one option; however, 3185