P024 Paradoxical exacerbation of Sweet-like dermatosis following tumour necrosis factor inhibition unmasking VEXAS syndrome

Abstract

VEXAS (vacuoles, UBA1, X-linked, autoinflammatory, somatic) syndrome is an adult-onset autoinflammatory disorder caused by somatic mutations in the UBA1 gene. It is characterized by systemic inflammation, cytopenias and neutrophilic dermatoses, frequently mimicking idiopathic Sweet syndrome. Optimal management remains uncertain, with variable responses to conventional immunosuppressants and biologic agents, and the impact of tumour necrosis factor (TNF) inhibition is poorly defined. A 77-year-old man had a 6-year history of severe, steroid-dependent biopsy-proven Sweet syndrome refractory to methotrexate, colchicine and ustekinumab. This was complicated by drug reaction with eosinophilia and systemic symptoms secondary to dapsone. Three weeks after initiation of adalimumab, he developed a significant flare characterized by widespread erythematous plaques, arthralgia, myopathy, auricular chondritis, periorbital oedema, sicca symptoms, fever and pulmonary infiltrates requiring hospitalization. Laboratory investigations demonstrated markedly elevated inflammatory markers, hyperferritinaemia, thrombocytopenia and lymphopenia. A peripheral blood film revealed vacuolated myeloid precursors, and targeted UBA1 sequencing on peripheral blood confirmed a diagnosis of VEXAS. Treatment with daily prednisolone 30 mg, ruxolitinib and tocilizumab resulted in sustained clinical and biochemical remission. This case illustrates a paradoxical exacerbation of VEXAS following TNF inhibition, unmasking the underlying diagnosis. A potential mechanistic explanation is that TNF blockade removes physiological suppression of type I interferon signalling, thereby amplifying interferon-driven inflammation in an already interferon-dominant disorder. Clinicians should maintain a high index of suspicion for VEXAS syndrome in older men with steroid-dependent neutrophilic dermatoses and systemic inflammation, particularly when paradoxical worsening occurs following TNF inhibition. Early recognition, avoidance or cautious use of TNF inhibitors, and consideration of Janus kinase inhibition, represent a rational and potentially effective therapeutic strategy in this setting.