A RANDOMIZED, CONTROLLED TRIAL OF RITUXIMAB VERSUS AZATHIOPRINE AFTER INDUCTION OF REMISSION WITH RITUXIMAB FOR PATIENTS WITH ANCA-ASSOCIATED VASCULITIS AND RELAPSING DISEASE

Background: Rituximab (RTX) is an effective therapy for induction of remission in ANCA-associated vasculitis (AAV). However, the effect of RTX is not sustained, and subsequent relapse rates are high, especially in patients with a history of relapse. Objectives: The RITAZAREM trial is an international, multi-center, open-labelled, randomized, controlled trial of patients with AAV with relapsing disease comparing the efficacy, after induction of remission with RTX, of two relapse-prevention strategies: repeat dosing of RTX or daily oral azathioprine (AZA). Methods: Patients with AAV were recruited at the time of relapse and received induction therapy with RTX and glucocorticoids. If remission was achieved by month 4, patients were randomized in a 1:1 ratio to receive either RTX (1000 mg every 4 months for 5 doses) or AZA (2 mg/kg/day) as maintenance therapy. Patients were followed for a minimum of 36 months, with the primary outcome being time to disease relapse. Results: 190 patients were enrolled and 170 randomized at 4 months (85 to RTX; 85 to AZA). The data are complete on all patients up to at least month 24. Median age was 59 years (range 19-89), with a prior disease duration of 5.3 years (0.4-38.5). 123/170 (72%) patients had a history of testing positive for anti-proteinase 3 ANCA; 47/170 (28%) for myeloperoxidase ANCA; 104/170 (61%) were enrolled having suffered a major relapse, and 48/170 (28%) received a pre-specified higher dose glucocorticoid induction regimen ( Table 1 ). Table 1. Baseline characteristics of patients enrolled in RITAZAREM trial Rituximab (N=85 ) Azathioprine (N=85 ) Total (N=170 ) Age, years: median (range) 57 (18-89) 61 (27-83) 59 (18-89) Female, number (%) 42 (49.4%) 44 (51.8%) 86 (50.6%) Disease duration, years: median (range) 5.8 (0.4-38.5) 4.9 (0.4-25.8) 5.3 (0.4-38.5) Prior cyclophosphamide therapy Number of patients (%) 67/85 (78.8%) 66/85 (77.6%) 133/170 (78.2%) Cumulative dose, grams (g): median (range) 7.1 g (0.2-301) 12 g (1.0-146) 10 g (0.2-301) Prior rituximab therapy Number (%) patient 33/85 (38.8%) 27/85 (31.8%) 60/170 (35.3%) Cumulative dose, grams (g): median (range) 3.2 g (2.0-16.0) 5.4 g (1.5-14.0) 3.9 g (1.5-16.0) Glucocorticoid induction regimen 1mg/kg/day starting dose 24/85 (28.2%) 24/85 (28.2%) 48/170 (28.2%) 0.5mg/kg/day starting dose 61/85 (71.8%) 61/85 (71.8%) 122/170 (71.8%) ANCA type Anti-proteinase 3 61/85 (71.8%) 62/85 (72.9%) 123/170 (72.4%) Anti-myeloperoxidase 24/85 (28.2%) 23/85 (27.1%) 47/170 (27.6%) Relapse type upon entry into trial Severe 52/85 (61.2%) 52/85 (61.2%) 104/170 (61.2%) Non-severe 33/85 (38.8%) 33/85 (38.8%) 66/170 (38.8%) RTX was superior to AZA in preventing disease relapse with a preliminary overall hazard ratio (HR) estimate of 0.36 (95% CI 0.23-0.57, p <0.001) and a during-treatment HR estimate of 0.30 (95% CI 0.15-0.60, p<0.001) ( Figure 1 ). After adjustment, none of the randomization stratification covariates (ANCA type, glucocorticoid induction regimen, or relapse severity) had a significant differential effect on the primary outcome. By 24 months after entry, 20 months after randomization, 11/85 (13%) patients in the RTX group had experienced a relapse compared to 32/85 (38%) patients in the AZA group. 19/85 (22%) patients in the RTX group and 31/85 (36%) patients in the AZA group experienced at least one severe adverse event (SAE). 25/85 (29%) and 42/85 (49%) patients in the RTX group developed hypogammaglobulinaemia (IgG <5g/l) and non-severe infections respectively, compared to 21/85 (25%) and 41/85 (48%) in the AZA group. Figure 1. Relapse-free survival in RITAZAREM trial: rituximab versus azathioprine Conclusion: In the RITAZAREM trial, following induction of remission with RTX, RTX was superior to AZA for preventing disease relapse in patients with AAV with a prior history of relapse. There were no new major safety signals for use of these medications in this population. Disclosure of Interests: Rona Smith Grant/research support from: Roche, David Jayne Grant/research support from: ChemoCentryx, GSK, Roche/Genentech, Sanofi-Genzyme, Consultant of: Astra-Zeneca, ChemoCentryx, GSK, InflaRx, Takeda, Insmed, Chugai, Boehringer-Ingelheim, Peter A. Merkel Grant/research support from: AstraZeneca, Bristol-Myers Squibb, Boeringher-Ingelheim, Celgene, ChemoCentryx, Genentech/Roche. Genzyme/Sanofi, GlaxoSmithKline, InflaRx, Kypha, TerumoBCT., Consultant of: AbbVie, AstraZeneca, Biogen, Bristol-Myers Squibb, Boeringher-Ingelheim, Celgene, ChemoCentryx, Genentech/Roche, Genzyme/Sanofi, GlaxoSmithKline, InflaRx, Insmed, Jannsen, Sparrow, Kiniksa. Citation: Ann Rheum Dis, volume 79, supplement 1, year 2020, page 19Session: Vasculitis (Oral Presentations)