Symmetrical Drug-Related Intertriginous and Flexural Exanthema

Etiology

Beta-lactam antibiotics, especially amoxicillin, are among the medications causing symmetrical drug-related intertriginous and flexural exanthema. These agents are the most common triggers.[4] However, there are reports of many other cases that included non-beta-lactam antibiotics such as pristinamycin, clindamycin, erythromycin, roxithromycin, and cotrimoxazole.[3][4][5] Other anti-infective agents such as nystatin, terbinafine, nystatin, fluconazole, metronidazole, and valacyclovir have also been incriminated.[5][6][7]

Finally, other reports exist of drugs as triggers of SDRIFE, including codeine, pseudoephedrine, cimetidine, allopurinol, heparin, hydroxyurea, oxycodone, naproxen, risperidone, ethyl loflazepate, antihypertensives, iodine radio-contrast media, chemotherapeutic agents and monoclonal antibodies such as infliximab.[4][5][7][8] Reports also implicate topical agents, including bufexamac and 5-fluorouracil.[5]

Epidemiology

Symmetrical drug-related intertriginous and flexural exanthema are not very common, and the literature documents a limited number of SDRIFE cases. However, since 1984, over 100 cases of drug-related baboon syndrome or SDRIFE have been reported.[9] SDRIFE affects patients of any age. According to reported cases, it can present at age 18 months to 84 years.[10] Both sexes are affected, with a male predominance.[4][10]

Pathophysiology

Real pathogenetic mechanisms of symmetrical drug-related intertriginous and flexural exanthema are still unclear. Still, it has been suspected to develop as a result of a type IV delayed hypersensitivity immune response.[11] This notion was supported by immunohistochemical evidence for CD4+ T cell infiltration and the increased endothelial and keratinocyte expression of CD26P-selectin, which recruits type 1 helper T cells to the sites of inflammation.[4]

According to some authors, SDRIFE likely involves a type IVa reaction involving CD4+ Th1 cells and macrophages and a type IVc reaction with cytotoxic CD4 and CD8 T cells.[12] Nevertheless, this does not explain the occurrence of SDRIFE after the first exposure to a given drug without prior sensitization.[3]

Pathophysiological mechanisms might also include a recall phenomenon due to the reactivation of tissue toxicity at the intertriginous predilection sites, direct interactions of the drugs with immunoreceptors, and anatomical particularities of the large folds (the abundance of eccrine sweat glands, the occlusion).[3][5]

Histopathology

The histological features of SDRIFE are not specific and are very variable. Typically, a superficial perivascular infiltrate of mononuclear cells is observed. It includes, in some cases, neutrophils and eosinophils.[4] However, other features were also reported, including subcorneal pustules, vacuolar changes, hydropic degeneration with subepidermal bullae, and necrotic keratinocytes.[13]

History and Physical

The latency of the onset of this condition varies from a few hours to a few days after the causative drug is removed. The basis of diagnosis is mainly on the highly characteristic and stereotypic appearance of the rash. The involvement of the gluteal and intertriginous areas and the symmetry of lesions are key diagnostic features.[9] The diagnostic criteria for symmetrical drug-related intertriginous and flexural exanthema are exposure to a systemically administered drug with the exclusion of contact allergens; characteristic well-demarcated erythema involving the gluteal, perianal, inguinal, or perigenital area; involvement of at least one intertriginous area; symmetry of the affected areas; and the absence of systemic symptoms.[3]

In the literature, skin lesions are often reported as maculopapular erythema or plaques. Atypical disease courses with pustules, papules, blisters, and descriptions of purpuric lesions also exist in rare cases.[9][10] SDRIFE typically does not present with mucosal involvement and involvement of the face and palmoplantar surfaces is very uncommon.[9]

Evaluation

The diagnosis relies mostly on clinical presentation, history, and exclusion of other causes for a rash. Laboratory investigations are performed to exclude systemic involvement (such as cytopenia and hepatic or renal involvement) but are otherwise not necessary for the diagnosis of SDRIFE.[9] Patch tests, lymphocyte transformation tests, and drug provocation tests (DPT) can be useful for diagnosis, but their outcomes are highly variable.

Skin patch tests are usually the preferred means of testing, applied to the previously affected areas. According to previous reports, a patch test gives only up to 50% of patients a positive reaction.[3][4][10] The explanation for these results may be that the systemic agent is not completely absorbed when applied to the skin during patch testing.[14]

Controlled drug-provocation testing is considered the gold standard clinical test and results positively in most patients with SDRIFE.[4] Positive drug provocation testing (DPT) has been reported for cases of SDRIFE with clindamycin, cimetidine, corticosteroids, turbine, and valacyclovir.[9]

Treatment / Management

Symmetrical drug-related intertriginous and flexural exanthema is a self-limiting disease, and treatment involves the withdrawal of the culprit agent and supportive management.[9][15] Systemic or topical steroids are usually prescribed to speed up the healing process, and antihistamines can be an option for symptomatic management of itching.[15](B3)

Differential Diagnosis

The differential diagnosis may include several conditions such as seborrheic dermatitis, intertrigo, allergic contact dermatitis, inverse psoriasis, granular parakeratosis, Darier disease, and Hailey-Hailey disease. All these dermatoses must be excluded before a drug eruption is to be diagnosed.[4][9]

SDRIFE can also mimic other specific drug reactions such as acute generalized exanthematous pustulosis (AGEP), drug reaction with eosinophilia and systemic symptoms (DRESS), and fixed drug eruption (FDE).[4][9][16] However, AGEP and DRESS characteristically demonstrate a widespread rash with accompanying systemic symptoms. FDE can be easily differentiated from SDRIFE as it characteristically presents asymmetrical acral, genital, and mucosal patches or plaques, usually round or oval, with residual hyperpigmentation.[13][15][16]

Prognosis

The prognosis of SDRIFE is good upon discontinuation of the offending drug.[5][9]

Complications

Symmetrical drug-related intertriginous and flexural exanthema is considered a benign rash due to its self-limited course, and complications are exceptional.[4]