Dapsone-Induced Hypersensitivity Syndrome in a Patient with Dermatitis Herpetiformis: A Case Report

INTRODUCTION

Dermatitis herpetiformis (DH) is a chronic autoimmune blistering disorder characterised by intensely pruritic, symmetrical papulovesicular eruptions, most commonly affecting extensor surfaces and the trunk.¹ It represents the cutaneous manifestation of gluten sensitivity and is closely associated with celiac disease.^1,2 Diagnosis is classically confirmed by granular immunoglobulin A (IgA) deposition at the dermoepidermal junction on direct immunofluorescence, supported by circulating anti-epidermal transglutaminase (TG3) antibodies.^1,2 Dapsone is the cornerstone of pharmacological therapy for DH because of its rapid anti-inflammatory and anti-neutrophilic effects, often producing dramatic symptomatic relief within days.³ Despite its efficacy, dapsone is associated with both dose-dependent toxicities (such as haemolysis and methemoglobinaemia) and rare idiosyncratic reactions.^2,3 Among these, dapsone-induced hypersensitivity syndrome (DHS) is the most severe, typically presenting within 3–6 weeks of drug initiation and manifesting as fever, extensive cutaneous involvement and multi-organ dysfunction.^2,3

CASE REPORT

A 48-year-old female presented with progressively worsening pruritic, desquamating skin lesions involving the trunk, bilateral upper and lower extremities and oral mucosa for 20 days. Two months prior, she had developed intensely pruritic erythematous papulovesicular lesions predominantly over the trunk and extensor aspects of the limbs. Given the chronicity, symmetry and morphology of the lesions, an immune-mediated skin disorder was suspected. A perilesional skin biopsy for direct immunofluorescence demonstrated granular IgA deposition in the papillary dermis, confirming the diagnosis of DH. Serologic evaluation further supported the diagnosis, revealing elevated anti-tissue transglutaminase IgA antibody levels, consistent with underlying gluten-sensitive enteropathy.

Following diagnostic confirmation, the patient was initiated on oral dapsone therapy as per standard treatment guidelines for DH. Approximately 5 weeks after starting dapsone, the patient developed acute worsening of her cutaneous symptoms, accompanied by intense pruritus and systemic manifestations. The eruption rapidly progressed to diffuse erythema, scaling, erosions and haemorrhagic crusting, involving the trunk, abdomen and all four limbs [Figures 1 and 2]. She also developed painful oral mucosal erosions, resulting in difficulty with oral intake. Fever and malaise were noted during this period. Dermatological examination revealed extensive exfoliative dermatitis with tender erythematous erosions and crusting, involving a large body surface area. Mucosal examination showed multiple erosions over the buccal mucosa and lips. There was no prior history of adverse drug reactions. Given the temporal relationship between dapsone initiation and symptom onset, along with the presence of fever, widespread exfoliative dermatitis, mucosal involvement and systemic features, a diagnosis of DHS was considered. Laboratory investigations revealed evidence of multisystem involvement, including hepatic and renal dysfunction.

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Figure 1:

Diffuse erythema with extensive scaling, desquamation and areas of crusting over the anterior trunk and posterior torso, consistent with severe cutaneous involvement.

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Figure 2:

Bilateral involvement of both hands and legs with diffuse erythema, scaling, erosions, and crusting, highlighting widespread exfoliative dermatitis.

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Dapsone was immediately discontinued, and the patient was started on systemic corticosteroid therapy with intravenous dexamethasone (8 mg/day for 5 days), along with supportive care including intravenous fluids, antihistamines, topical antimicrobial agents (mupirocin 2%), meticulous dermatologic wound care, nutritional support with a high-protein diet and prophylactic broad-spectrum antibiotics to prevent secondary infection. Over the course of hospitalisation, the patient showed gradual clinical improvement, with a reduction in erythema, desquamation and mucosal involvement. Laboratory parameters progressively normalised. She was subsequently transitioned to oral prednisolone at 40 mg/day, which was tapered gradually over 4–6 weeks, and discharged with advice for strict lifelong avoidance of dapsone and other sulfone-containing drugs, along with close dermatologic follow-up.

DISCUSSION

DHS is a rare but potentially life-threatening idiosyncratic adverse drug reaction that typically occurs within 3–6 weeks of initiating dapsone therapy.¹ It is classically characterised by the triad of fever, cutaneous eruption and internal organ involvement, most commonly hepatitis.^1,2 The estimated incidence of DHS ranges from 0.5% to 3%, with higher prevalence reported in Asian populations, and mortality rates approaching 10% in severe or unrecognised cases.^2,3

Dapsone remains the first-line pharmacologic treatment for DH due to its rapid anti-inflammatory and anti-neutrophilic effects. In the present case, the diagnosis of DH was firmly established by direct immunofluorescence demonstrating granular IgA deposition in the papillary dermis, supported by elevated anti-tissue transglutaminase IgA antibodies, in keeping with current diagnostic standards.² Importantly, DH itself is confined to the skin and does not cause systemic illness, fever, or hepatic dysfunction. Therefore, the abrupt clinical deterioration with systemic involvement following dapsone initiation strongly favoured DHS rather than progression of the underlying disease.^2,3

The pathogenesis of DHS is complex and multifactorial. Dapsone undergoes hepatic metabolism via cytochrome P450 enzymes to form reactive hydroxylamine metabolites, which induce oxidative stress and act as haptens, triggering a T-cell-mediated delayed hypersensitivity reaction.³ Increasing evidence supports a strong genetic predisposition, particularly the HLA-B*13:01 allele, which has been shown to confer a markedly increased risk of DHS.⁴ Meta-analyses and functional studies demonstrate high sensitivity and specificity of this allele for predicting dapsone hypersensitivity, especially in Asian populations, highlighting the potential role of pharmacogenetic screening in the future.⁵

Clinically, DHS must be differentiated from other severe cutaneous adverse drug reactions, particularly Stevens– Johnson syndrome/toxic epidermal necrolysis (SJS/TEN) and drug reaction with eosinophilia and systemic symptoms (DRESS).⁶ Compared with SJS/TEN, DHS has a longer latency period, prominent hepatic involvement and less extensive epidermal necrosis. Although DHS shares overlapping features with DRESS, it has historically been regarded as a distinct entity due to its characteristic association with dapsone and predictable temporal onset.⁶ The cornerstone of management is immediate cessation of dapsone. Systemic corticosteroids are widely used in moderate to severe cases and are associated with favourable outcomes, particularly when initiated early.^6-8 Supportive care, close monitoring of organ function, prevention of secondary infections and long-term avoidance of dapsone and other sulfone-containing drugs are essential components of management.^7,8

CONCLUSION

Our case highlights the importance of maintaining a high index of suspicion for DHS in patients who develop fever, rapid cutaneous deterioration, or mucosal and systemic involvement within weeks of starting therapy. Early recognition, immediate withdrawal of dapsone, and timely initiation of systemic corticosteroids remain the most critical determinants of a favourable outcome. Clinicians should closely monitor patients during the initial weeks of treatment, provide counselling on early warning symptoms and ensure lifelong avoidance of dapsone and related sulfone drugs after recovery. Vigilance and prompt intervention can significantly reduce morbidity and prevent potentially life-threatening complications.