D2.355 - Treatment-refractory chronic spontaneous urticaria: a diagnostic pitfall

Chronic spontaneous urticaria (CSU) is usually responsive to guideline-based therapies, including high-dose antihistamines, omalizumab, and immunosuppressants. However, a small subset of patients shows profound treatment resistance, necessitating reconsideration of the underlying diagnosis, including autoinflammatory conditions. We report the case of a 25-year-old woman with a long-standing history of CSU since adolescence and mild atopic dermatitis. Extensive diagnostic work-up, including provocation testing (cold, heat, pressure), methacholine challenge, and autologous serum skin testing, was negative. Helicobacter pylori eradication and multiple antihistamines up to fourfold dosing failed to control symptoms. Subsequent therapies with omalizumab (300 mg every 4 weeks, later escalated to 450 mg every 2 weeks), dupilumab, cyclosporine A (5 mg/kg), and mepolizumab were ineffective. A subsequent skin biopsy revealed a predominantly neutrophilic infiltrate. Based on this result dapsone was initiated without satisfactory response.

Given the marked therapeutic resistance, a comprehensive re-evaluation was performed, including repeated histopathological assessment, autoimmune diagnostics, and extended laboratory testing. 

While no monoclonal gammopathy or paraproteinemia was detected, serum amyloid A was markedly elevated (199.0 mg/L; reference 0–6.4 mg/L). In the absence of systemic symptoms such as recurrent fever or arthralgia, the findings were consistent with a paraprotein-negative IL-1–mediated inflammatory dermatosis (PANID), considered a potential precursor of Schnitzler syndrome. Targeted therapy with the subcutaneous IL-1 receptor antagonist anakinra (100 mg daily) was initiated. Anakinra led to rapid and near-complete symptom resolution within days, accompanied by a significant decrease in serum amyloid A levels. However, due to delayed-type injection site reactions, therapy was switched to monthly subcutaneous canakinumab, which has been well tolerated and remains effective.

This case highlights the importance of considering IL-1–mediated autoinflammatory dermatoses in patients with treatment-refractory CSU and neutrophilic histology, even in the absence of paraproteinemia or systemic symptoms. Early recognition may prevent prolonged ineffective treatments and disease progression.