Efficacy and Safety of Belimumab and Azathioprine for Maintenance of Remission in Antineutrophil Cytoplasmic Antibody-Associated Vasculitis: A Randomized Controlled Study

Abstract

Objective: To evaluate the safety and efficacy of belimumab as adjunctive therapy to maintain remission in antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV).

Methods: In this multicenter, double-blind, placebo-controlled study, patients with AAV (ages ≥18 years) were randomized 1:1 to receive azathioprine (2 mg/kg/day), low-dose oral glucocorticoids (≤10 mg/day), and either intravenous belimumab (10 mg/kg) or placebo, following remission induction with rituximab or cyclophosphamide along with glucocorticoids. The primary end point was time to first protocol-specified event (PSE), with first PSE defined as a Birmingham Vasculitis Activity Score (BVAS) of ≥6, presence of ≥1 major BVAS item, or receipt of prohibited medications for any reason, resulting in treatment failure (adjusted for ANCA type [proteinase 3 (PR3) or myeloperoxidase (MPO)], disease stage at induction, and induction regimen). Vasculitis relapse was defined as the PSE of either a BVAS activity score of ≥6 or receipt of prohibited medications for vasculitis. Changes in treatment practice led to truncation of the study population from ~300 patients to ~100 patients.

Results: The intent-to-treat population totaled 105 patients with AAV, of whom 52 (40 with PR3-ANCAs, 12 with MPO-ANCAs) received placebo and 53 (41 with PR3-ANCAs, 12 with MPO-ANCAs) received belimumab; 27 of the patients were in rituximab-induced disease remission, while 78 were in cyclophosphamide-induced disease remission at baseline. Compared with placebo, treatment with belimumab did not reduce the risk of a PSE (adjusted hazard ratio [HR] 1.07, 95% confidence interval [95% CI] 0.44-2.59; P = 0.884) or vasculitis relapse (adjusted HR 0.88, 95% CI 0.29-2.65; P = 0.821). The overall rate of PSEs was low (11 [21.2%] of 52 patients receiving placebo, 10 [18.9%] of 53 patients receiving belimumab). Vasculitis relapse in the placebo group (n = 8) occurred independent of the induction regimen, disease stage, or ANCA type. All vasculitis relapses in the belimumab group (n = 6) occurred in patients who had PR3-ANCA-associated vasculitis with cyclophosphamide-induced disease remission. Adverse events occurred in 49 (92.5%) of 53 patients receiving belimumab and 43 (82.7%) of 52 patients receiving placebo, with no new safety concerns.

Conclusion: Belimumab plus azathioprine and glucocorticoids for the maintenance of remission in AAV did not reduce the risk of relapse.

Trial registration: ClinicalTrials.gov NCT01663623.

Figure 1

Study design. BVAS = Birmingham Vasculitis Activity Score; IV = intravenous; R = randomization; PSE = protocol‐specified event.

Figure 2

Distribution of patients in the intent‐to‐treat (ITT) population. a = not all patients who withdrew due to lack of efficacy met the protocol‐specified event (PSE) criteria (n = 1 in the belimumab group and n = 2 in the placebo group did not meet the criteria), and in some cases in which patients experienced a PSE, the reason for discontinuation was reported as an adverse event rather than lack of efficacy. b = includes patients withdrawn from the study; patients who discontinued treatment with placebo or belimumab continued in the study until relapse, study withdrawal, or study completion. c = reasons for withdrawal included patient decision (n = 2), study termination (Italy) (n = 1), and protocol deviation (n = 1). d = reasons for withdrawal included patient decision (n = 3), study termination (Italy) (n = 1), protocol deviation (n = 3), and investigator decision (n = 2).

Figure 3

A, Kaplan‐Meier plot of time to first vasculitis relapse in each treatment group. Vasculitis relapse was defined as a Birmingham Vasculitis Activity Score (BVAS) of ≥6, presence of a major BVAS item, or receipt of a prohibited medication for vasculitis. B, Occurrence of vasculitis relapse, as defined in A, in patients according to disease status at screening (initial versus relapsing disease). RTX = rituximab; CYC = cyclophosphamide; PR3 = proteinase 3; MPO = myeloperoxidase.