Evaluating the Efficacy of Cytokine-Directed Therapies in the Management of VEXAS Syndrome.

Abstract

Objective: To evaluate the efficacy of cytokine-directed therapies in VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory somatic) syndrome using previously proposed treatment response criteria.

Methods: All patients with genetically confirmed VEXAS syndrome who received targeted therapies with JAK inhibitors (JAKi), tumor necrosis factor α inhibitors (TNFαi), or interleukin-1 (IL-1) or IL-6 inhibitors were identified. Clinical and biochemical data were recorded for patients at time of targeted therapy initiation, and at 3-, 6-, and 12-month follow-up time points. Treatment response was labeled as complete response (CR; normalization of C-reactive protein [CRP], prednisone <10 mg/day, and resolution of disease activity), partial response (PR; >50% improvement in CRP, >50% prednisone dose reduction, improvement or resolution of disease features), treatment failure (TF; worsening CRP, increasing prednisone, worsening of disease features), or no response (not meeting criteria for CR, PR, or TF).

Results: Overall, 52 patients received an IL-1i, IL-6i, or JAKi therapy. At six-month follow-up, 3 of 19 IL-6i patients experienced CR, 4 of 19 experienced PR, and 7 of 19 experienced TF. 2 of 17 patients receiving JAKi experienced CR, 3 of 17 experienced PR, and 6 of 17 experienced TF. No patients receiving IL-1i or TNFαi experienced CR, and only 1 of 5 IL-1i patients experienced PR. Among those still receiving biologic therapy at 12 months, only 1 of 11 receiving IL-6i and 0 of 7 receiving JAKi experienced CR.

Conclusion: IL-6i and JAKi therapies demonstrated limited, unsustained efficacy for management of VEXAS syndrome. IL-1i and TNFαi therapies were not efficacious. Useful application of previously reported treatment response criteria was demonstrated, but future incorporation of hematologic parameters may be beneficial.