A case of symmetrical drug-related intertriginous and flexural exanthema triggered by Chinese Herbal Medicines

Dear Editor, Symmetrical drug-related intertriginous and flexural exanthema (SDRIFE) is an uncommon adverse drug reaction (ADR) characterized by erythematous lesions in intertriginous areas without systemic involvement. Increasingly, studies have found that traditional Chinese medicine (TCM), widely used in East Asian countries, can cause adverse reactions. We present a case of SDRIFE with erythematous papules that broke out following ingestion of Chinese herbal pills, highlighting the diverse clinical spectrum of SDRIFE and the need to consider TCM as a potential trigger. A 39-year-old female presented with a severe, itchy rash on her trunk and extremities for 5 days. She had no systemic symptoms, recent infections, or insect bites but reported consuming Chinese herbal pills for constipation 6 days prior, after which the rash abruptly appeared. A similar episode had occurred 2 years earlier after she ingested similar Chinese herbal pills prescribed by the same clinic. During the previous episode, skin lesions were predominantly localized to the axillary and inguinal areas and resolved promptly upon discontinuation of the medicine. This time, the rash initially appeared in the axillae and inguinal area and spread within 2 days despite cessation of the suspected medication. Examination revealed numerous 1–2 mm erythematous papules symmetrically involving the axillary and inguinal folds and bilateral popliteal and antecubital fossae [Figure 1a-f] but no involvement of the scalp, face, palms/soles, knee/elbows, or mucosa. Laboratory investigations were unremarkable. Skin biopsy indicated epidermal spongiosis with prominent papillary edema and perivascular lymphocytic infiltrates with eosinophils in the upper dermis [Figure 1g]. Based on clinical features and histopathology, the patient was diagnosed with SDRIFE. Treatment included systemic hydrocortisone at 200 mg/day for 4 days, tapered to 100 mg/day for an additional 4 days, followed by prednisolone at 15 mg/day for 2 days, then tapered to 5 mg/day for 5 days. Diphenhydramine and topical steroids were also administered. This regimen resolved the rash within 10 days. The patient discontinued the use of herbal medicine to prevent recurrence and exhibited complete resolution at the last follow-up.Figure 1: Patient clinical presentations as viewed from the front (a), back (b), and axillae (c and d). Numerous symmetrical erythematous monomorphic papules are present in the axillary and inguinal folds of the antecubital (e) and popliteal (f) fossae, with no involvement of extensor sites. (g) Histopathological findings from a skin biopsy indicated epidermal spongiosis with prominent papillary edema and perivascular infiltrates of lymphocytes with scattered eosinophils (×40 view of H and E staining, scale bar = 200 μm).SDRIFE is an infrequent manifestation of type IV hypersensitivity reactions to drugs, with characteristic skin lesions typically localized in intertriginous regions. Diagnostic criteria include exposure to a systemically administered drug, either at initial or subsequent administration; demarcated erythema in the gluteal/perianal or V-shaped erythema in the inguinal/perigenital regions; involvement of at least one additional flexural area; symmetry of affected regions; and absence of systemic symptoms or signs.[1] Our patient met all of these criteria. Antibiotics, biologics, and nonsteroidal anti-inflammatory drugs (NSAIDs) have been implicated in SDRIFE,[2,3] with TCM increasingly recognized as a potential trigger.[4,5] The complex composition of TCM, which include medicinal plants, animal materials, and minerals, and its diverse formulations, such as creams, inhalants, powders, decoctions, and honey/paste pills, poses challenges in examining drug reactions. Furthermore, contamination of herbal products with incorrect plant constituents, heavy metals, or Western medications (such as NSAIDs or steroids) has been reported, increasing the risk of ADRs affecting the skin and internal organs. This issue is a major public health concern, particularly in East Asian regions.[6] Although drug provocation tests are considered the gold standard for diagnosis, patient willingness and the risk of triggering severe reactions must be considered. Patch testing, intradermal injection, and lymphocyte transformation tests can assist in diagnosis, but their sensitivity is limited.[4,5] The pathogenesis of SDRIFE remains unclear. A combination of type IV hypersensitivity and a recall phenomenon triggered by reactivation of tissue toxicity at predilection sites within intertriginous regions may contribute to SDRIFE.[7] Furthermore, direct interactions of drugs with immunoreceptors and anatomical peculiarities of large folds, such as an abundance of eccrine sweat glands, may play a role.[4] Several cases of SDRIFE associated with TCM have been reported, including reactions to Xi-Huang capsules,[5] Chinese herbal balls of unknown composition,[4] and Berberine[8] [Table 1]. These cases involved diverse clinical presentations, such as macular erythematous rashes and scaly patches primarily affecting intertriginous areas, resolving after discontinuation of the suspected herbal products within 1–2 weeks. Notably, three of the four cases, including ours, exhibited no or mild involvement of the intergluteal region, an area typically affected by SDRIFE, suggesting an atypical distribution pattern associated with TCM. However, this observation requires further cases for a more definitive conclusion. Furthermore, our patient was unique in presenting with erythematous papules, highlighting the diverse manifestations of SDRIFE. These findings emphasize the necessity of considering TCM as a potential trigger for SDRIFE and conducting further research to elucidate its pathogenesis, improving prevention and management strategies.Table 1: Summary of previously reported symmetrical drug-related intertriginous and flexural exanthema cases caused by traditional Chinese medicineDeclaration of patient consent The authors certify that they have obtained all appropriate patient consent form. In the form, the patient has given her consent for her images and other clinical information to be reported in the journal. The patient understands that her name and initials will not be published and due efforts will be made to conceal identity, but anonymity cannot be guaranteed. Data availability statement All data generated or analyzed during this study are included in this published article. Financial support and sponsorship Nil. Conflicts of interest There are no conflicts of interest.