Rituximab versus Azathioprine for Maintenance in ANCA-Associated Vasculitis

S1. Rituximab for ANCA-associated vasculitis: The experience in the United States

Background and Aims Rituximab is an effective therapy for induction of remission in ANCA-associated vasculitis (AAV). However, the effect of rituximab is not sustained, and subsequent relapse rates are high, especially in patients with a history of relapse. The RITAZAREM trial (ClinicalTrials.gov identifier: NCT01697267) 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 rituximab, of two relapse-prevention strategies: repeat dosing of rituximab or daily oral azathioprine. Method Patients with AAV were recruited at the time of relapse and received induction therapy with rituximab and glucocorticoids. If remission was achieved by month 4, patients were randomized in a 1:1 ratio to receive either rituximab (1000 mg every 4 months for 5 doses) or azathioprine (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. The formal hypothesis testing plan initially considers the hazard ratio for relapse across all time periods. If, and only if this global test is significant at a 5% level then the hazard ratios during the treatment period and the follow-up periods are considered separately. Results 190 patients were enrolled and 170 randomized at 4 months (85 to rituximab; 85 to azathioprine). 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. Rituximab was superior to azathioprine 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 rituximab group had experienced a relapse compared to 32/85 (38%) patients in the azathioprine group. In the rituximab group 2/11 (18%) relapses were classified as major, compared to 12/32 (38%) in the azathioprine group. 19/85 (22%) patients in the rituximab group and 31/85 (36%) patients in the azathioprine group experienced at least one severe adverse event (SAE). 25/85 (29%) and 42/85 (49%) patients in the rituximab group developed hypogammaglobulinaemia (IgG <5g/l) and non-severe infections respectively, compared to 21/85 (25%) and 41/85 (48%) in the azathioprine group. Conclusion In the RITAZAREM trial, following induction of remission with rituximab, rituximab was superior to azathioprine 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.

Urinary HMGB1 levels are associated with CD4+ T-cells in urine in patients with ANCA-associated vasculitis and active nephritis

Maintenance Immunosuppression in Antineutrophil Cytoplasmic Antibody–Associated Vasculitis

ANCA-associated renal vasculitis

FRI0341 Urinary hmgb1 levels are associated with cd4+ t-cells in urine in patients with anca-associated vasculitis and active nephritis.

AB0472 INFECTIOUS PROFILE IN PATIENTS WITH ANCA-ASSOCIATED VASCULITIS: RETROSPECTIVE ANALYSIS IN A REFERRAL CENTRE

Biannual rituximab infusions over 18 months effectively maintain remission after a "standard" remission induction regimen for patients with antineutrophil cytoplasmic antibody-associated vasculitis (AAV). To evaluate the efficacy of prolonged rituximab therapy in preventing AAV relapses in patients with granulomatosis with polyangiitis (GPA) or microscopic polyangiitis (MPA) who have achieved complete remission after completing an 18-month maintenance regimen. Randomized controlled trial. (ClinicalTrials.gov: NCT02433522). 39 clinical centers in France. 68 patients with GPA and 29 with MPA who achieved complete remission after the first phase of maintenance therapy. Rituximab or placebo infusion every 6 months for 18 months (4 infusions). The primary end point was relapse-free survival at month 28. Relapse was defined as new or reappearing symptoms or worsening disease, with a Birmingham Vasculitis Activity Score greater than 0. From March 2015 to April 2016, 97 patients (mean age, 63.9 years; 35% women) were randomly assigned, 50 to the rituximab and 47 to the placebo group. Relapse-free survival estimates at month 28 were 96% (95% CI, 91% to 100%) and 74% (CI, 63% to 88%) in the rituximab and placebo groups, respectively, an absolute difference of 22% (CI, 9% to 36%) with a hazard ratio of 7.5 (CI, 1.67 to 33.7) (P= 0.008). Major relapse-free survival estimates at month 28 were 100% (CI, 93% to 100%) versus 87% (CI, 78% to 97%) (P= 0.009), respectively. At least 1 serious adverse event developed in 12 patients (24%) in the rituximab group (with 9 infectious serious adverse events occurring among 6 patients [12%]) versus 14 patients (30%) in the placebo group (with 6 infectious serious adverse events developing among 4 patients [9%]). No deaths occurred in either group. Potential selection bias based on previous rituximab response and tolerance. Extended therapy with biannual rituximab infusions over 18 months was associated with a lower incidence of AAV relapse compared with standard maintenance therapy. French Ministry of Health and Hoffmann-La Roche.

Background:Patients with antineutrophil cytoplasmic antibody (ANCA) associated vasculitis (AAV), which includes Granulomatosis with Polyangiitis (GPA), Microscopic Polyangiitis (MPA), and Eosinophilic Granulomatosis with Polyangiitis (EGPA), can experience a substantial disease burden...

Long-term efficacy of remission-maintenance regimens for ANCA-associated vasculitides

OP0055 Using The Birmingham Vasculitis Activity Score as A Screening Tool in Patients with Suspected Vasculitis

BackgroundDespite the proven diagnostic significance, the prognostic role of ANCA, in particular for assessing disease activity, remains questionable. Numerous studies have attempted to estimate the role of ANCA monitoring with...

Eosinophilic granulomatosis with polyangiitis (EGPA) is an eosinophilic antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis. Rituximab has emerged as the standard of care in other types of ANCA-associated vasculitis, but controlled studies on its use in EGPA are yet lacking. To compare rituximab with conventional strategy for the induction of remission in patients with EGPA. Phase 3, multicenter, randomized, controlled, double-blind, superiority trial. (ClinicalTrials.gov: NCT02807103). France. Patients with a diagnosis of EGPA, newly diagnosed or relapsing disease at the time of screening, with active disease defined as a Birmingham Vasculitis Activity Score (BVAS) of 3 or greater. Glucocorticoids plus rituximab (1 g 2 weeks apart) compared with the conventional strategy (glucocorticoids alone or in combination with cyclophosphamide in severe forms) for induction of remission. The primary end point was remission defined as a BVAS, version 3, of 0 and a prednisone dose of 7.5 mg/d or less at day 180. Secondary end points included duration of remission during the study, average daily glucocorticoid dose, and safety. A total of 105 participants were randomly assigned. Thirty-three (63.5%) patients in the rituximab group achieved the primary end point compared with 32 (60.4%) in the control group (relative risk, 1.05 [95% CI, 0.78 to 1.42]; P = 0.75). Results were similar at day 360. The mean duration of remission was 48.5 ± 6.51 weeks in the rituximab group and 49.1 ± 7.42 weeks in the conventional strategy group (P = 0.41). All relapse and major relapse rates were similar between the 2 groups. There was no statistically significant difference in the average daily glucocorticoid dose and no statistically significant differences in the rates of adverse events between the treatment groups. Design not appropriate to answer the question of equivalence between rituximab and cyclophosphamide in patients with severe EGPA. Rituximab was not superior to a conventional remission induction strategy in EGPA. French Ministry of Health.

Cyclophosphamide induction regimens for antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis are effective in 70 to 90% of patients, but they are associated with high rates of death and adverse events. Treatment with rituximab has led to remission rates of 80 to 90% among patients with refractory ANCA-associated vasculitis and may be safer than cyclophosphamide regimens. We compared rituximab with cyclophosphamide as induction therapy in ANCA-associated vasculitis. We randomly assigned, in a 3:1 ratio, 44 patients with newly diagnosed ANCA-associated vasculitis and renal involvement to a standard glucocorticoid regimen plus either rituximab at a dose of 375 mg per square meter of body-surface area per week for 4 weeks, with two intravenous cyclophosphamide pulses (33 patients, the rituximab group), or intravenous cyclophosphamide for 3 to 6 months followed by azathioprine (11 patients, the control group). Primary end points were sustained remission rates at 12 months and severe adverse events. The median age was 68 years, and the glomerular filtration rate (GFR) was 18 ml per minute per 1.73 m(2) of body-surface area. A total of 25 patients in the rituximab group (76%) and 9 patients in the control group (82%) had a sustained remission (P=0.68). Severe adverse events occurred in 14 patients in the rituximab group (42%) and 4 patients in the control group (36%) (P=0.77). Six of the 33 patients in the rituximab group (18%) and 2 of the 11 patients in the control group (18%) died (P=1.00). The median increase in the GFR between 0 and 12 months was 19 ml per minute in the rituximab group and 15 ml per minute in the control group (P=0.14). A rituximab-based regimen was not superior to standard intravenous cyclophosphamide for severe ANCA-associated vasculitis. Sustained-remission rates were high in both groups, and the rituximab-based regimen was not associated with reductions in early severe adverse events. (Funded by Cambridge University Hospitals National Health Service Foundation Trust and F. Hoffmann-La Roche; Current Controlled Trials number, ISRCTN28528813.)

Background:Anti-neutrophil cytoplasmic antibodies (ANCA) associated vasculitis (AAV), affects small and medium-sized vessels. The exact mechanisms leading to an excess production of ANCA are not clear. In healthy individuals, ANCA specific...