329. Successful use of cyclosporin A and interleukin-1 blockers in VEXAS synome: a single-centre case series

Background/objectives: VEXAS synome is a recently recognized autoinflammatory disease induced by somatic mutations of the UBA1 gene. While the number of diagnosed patients is rapidly increasing, management of VEXAS is still unclear and no successful therapeutic option has been identified yet. Aim of our study is to report the successful use of a combination therapy of cyclosporin A (CsA) and interleukin-1 blockers in 3 VEXAS patients. 

Methods: VEXAS patients followed up at our Autoinflammatory Diseases Clinic were identified.  VEXAS diagnosis was confirmed by the identification of mutated UBA1 gene (p.Met41Val variant, n=2; p.Met41Thr, n=1). Demographics, disease features and previous treatments were reviewed. Clinical and laboratory responses, defined by change of inflammatory markers and variation of systemic manifestations, were recorded. Dose modification of concomitant steroid therapy was also evaluated.

Results: Three VEXAS patients were identified. All patients were male, with a median age of 69 (IQR, 68-70) years, and were initially treated with high-dose systemic prednisone, with rapid benefit. Two patients were originally diagnosed with adult-onset Still disease and one patient with relapsing polychonitis; median diagnostic delay was 30 (IQR, 29-57) months. Baseline features and previous therapies are summarized in Table 1. In all three cases, disease relapsed after reducing prednisone dose below 20 mg daily. Before combination therapy start, all patients failed monotherapy with 2 biologic or targeted steroid-sparing agents. Combination of canakinumab and CsA was started in one patient who did not tolerate anakinra monotherapy due to extensive cutaneous reaction. Combination of anakinra and CsA was started in one patient who failed canakinumab monotherapy and in one patient who did not tolerate anakinra monotherapy due to extensive cutaneous reaction. Notably, this last patient had a good tolerance to anakinra when administered together with CsA. At combination therapy start, all patients were on prednisone therapy at intermediate dosage. At month 6 after combination therapy start, prednisone was safely reduced to 5 mg daily in all patients. In this time course, no patient experienced a clinical or laboratory flare and no patient needed a temporary increase of steroid therapy. Combination therapy was well-tolerated by all patients. Two patients experienced significant neutropenia (800 and 900 cells/mm³) but this adverse event was not associated with infectious events and did not require therapy suspension. One case of upper respiratory tract infection was observed in the patient who did not experience neutropenia.

Conclusions: Interleukin-1 blockers and CsA combination therapy could be an effective steroid-sparing treatment option in VEXAS patients. Treatment-induced neutropenia does not seem to be associated with increased risk of infections. Longer follow-up and replication of these preliminary results in larger cohorts are required.

Disclosures: CC, GC, GDL and LD received honoraria and speaking fees from SOBI and Novartis