Unmasking Macrophage Activation Syndrome in Vexas Syndrome: A Diagnostic Challenge

Vacuoles, E1 Enzyme, X-linked, Auto-inflammatory, Somatic (VEXAS) syndrome is a late-onset autoinflammatory disease caused by somatic mutations in the UBA1gene. Macrophage activation syndrome (MAS) is a rare but life-threatening hyperinflammatory condition whose association with VEXAS syndrome remains poorly described.

We report three cases of MAS occurring in men aged 65 to 72 years with genetically confirmed VEXAS syndrome. In all cases, MAS was characterized by fever, recent-onset cytopenias, marked hyperferritinaemia, and a high probability of MAS according to the H-score (>93%). Bone marrow examination demonstrated haemophagocytosis in two patients and numerous activated macrophages in one. Extensive investigations failed to identify infectious, malignant, or drug-related triggers. In one patient, MAS preceded the diagnosis of VEXAS syndrome by several years. In the two others, MAS occurred during the course of established VEXAS disease and was considered a manifestation of disease flare. Treatment included high-dose corticosteroids, with additional anakinra in one patient and etoposide in another, resulting in rapid clinical and biological improvement. One patient experienced MAS relapse following granulocyte colony-stimulating factor exposure during azacitidine treatment, whereas no recurrence was observed in the other two patients during follow-up.

MAS appears to be an underrecognized and potentially severe complication of VEXAS syndrome that may occur in the absence of an identifiable infectious or malignant trigger. Diagnostic overlap between both conditions may delay recognition. MAS should be suspected in VEXAS patients presenting with acute cytopenias, marked hyperferritinaemia, and organ involvement. Early use of the H-score, bone marrow examination, and prompt immunosuppressive treatment are essential to improve outcomes.

Macrophage activation syndrome (MAS) may represent a severe flare manifestation of Vacuoles, E1 Enzyme, X-linked, Auto-inflammatory, Somatic (VEXAS) syndrome, even in the absence of an identifiable infectious, malignant, or drug-related trigger.The diagnosis of MAS can be challenging in VEXAS syndrome because both conditions share overlapping features, including systemic inflammation, cytopenias, hyperferritinaemia, and bone marrow abnormalities.Recent-onset cytopenias, marked hyperferritinaemia, and organ involvement in patients with VEXAS syndrome should prompt early assessment for MAS using the H-score and bone marrow examination, allowing rapid initiation of immunosuppressive therapy.