Effect of Reduced-Dose vs High-Dose Glucocorticoids Added to Rituximab on Remission Induction in ANCA-Associated Vasculitis

Abstract

IMPORTANCEThe current standard induction therapy for antineutrophil cytoplasm antibody (ANCA)-associated vasculitis is the combination of high-dose glucocorticoids and cyclophosphamide or rituximab. Although these regimens have high remission rates, they are associated with considerable adverse events presumably due to high-dose glucocorticoids.OBJECTIVE To compare efficacy and adverse events between a reduced-dose glucocorticoid plus rituximab regimen and the standard high-dose glucocorticoid plus rituximab regimen in remission induction of ANCA-associated vasculitis. DESIGN, SETTING, AND PARTICIPANTS This was a phase 4, multicenter, open-label, randomized, noninferiority trial. A total of 140 patients with newly diagnosed ANCA-associated vasculitis without severe glomerulonephritis or alveolar hemorrhage were enrolled between November 2014 and June 2019 at 21 hospitals in Japan. Follow-up ended in December 2019. INTERVENTIONS Patients were randomized to receive reduced-dose prednisolone (0.5 mg/kg/d) plus rituximab (375 mg/m 2 /wk, 4 doses) (n = 70) or high-dose prednisolone (1 mg/kg/d) plus rituximab (n = 70). MAIN OUTCOMES AND MEASURESThe primary end point was the remission rate at 6 months, and the prespecified noninferiority margin was −20 percentage points. There were 8 secondary efficacy outcomes and 6 secondary safety outcomes, including serious adverse events and infections. RESULTS Among 140 patients who were randomized (median age, 73 years; 81 women [57.8%]), 134 (95.7%) completed the trial. At 6 months, 49 of 69 patients (71.0%) in the reduced-dose group and 45 of 65 patients (69.2%) in the high-dose group achieved remission with the protocolized treatments. The treatment difference of 1.8 percentage points (1-sided 97.5% CI, −13.7 to ϱ) between the groups met the noninferiority criterion (P = .003 for noninferiority). Twenty-one serious adverse events occurred in 13 patients in the reduced-dose group (18.8%), while 41 occurred in 24 patients in the high-dose group (36.9%) (difference, −18.1% [95% CI, −33.0% to −3.2%]; P = .02). Seven serious infections occurred in 5 patients in the reduced-dose group (7.2%), while 20 occurred in 13 patients in the high-dose group (20.0%) (difference, −12.8% [95% CI, −24.2% to −1.3%]; P = .04).CONCLUSIONS AND RELEVANCE Among patients with newly diagnosed ANCA-associated vasculitis without severe glomerulonephritis or alveolar hemorrhage, a reduced-dose glucocorticoid plus rituximab regimen was noninferior to a high-dose glucocorticoid plus rituximab regimen with regard to induction of disease remission at 6 months.

The Risk of Severe Infections Following Rituximab Administration in Patients With Autoimmune Kidney Diseases: Austrian ABCDE Registry Analysis

“…All SI were recorded on background glucocorticoid use. Reduced glucocorticoid regimens showed comparable efficacy estimates in AAV (6,7). In the PEXIVAS trial, the reduced-dose glucocorticoid regimen reached the primary end point, a combination of end-stage kidney disease and death from any cause, less frequently at one year of follow-up, although the differences were not significant.…”

“…A similar proportion of patients achieved remission, while serious adverse events were reduced in the reduced-dose arm. Notably, only 7 SI in 5 patients were recorded in the reduced-dose arm in comparison to 20 events in 13 patients in the high-dose glucocorticoid arm (7). In the ABCDE Registry, fourteen of the 19 recorded SI in the nephritic group occurred beyond 3 months of follow-up, and 8 after 12 months.…”

“…In the ABCDE Registry, fourteen of the 19 recorded SI in the nephritic group occurred beyond 3 months of follow-up, and 8 after 12 months. Studies such as LOVAS or the RAVE trial with a prescribed glucocorticoid withdrawal before month 6 after induction therapy highlighted both the safety and efficacy of such an approach (7,8). A retrospective study from Germany subdivided patients by the use of a glucocorticoid dose of either below 7.5 mg or greater/equal to 7.5 mg by month 6.…”

Rituximab Induction and Maintenance in ANCA-Associated Vasculitis: State of the Art and Future Perspectives

“…In this trial, there was no difference in the primary endpoint, which was the remission rate at 6 months. Importantly, serious adverse events and, in particular, serious infections occurred at a significantly lower rate in the reduced-dose prednisolone arm [74]. Overall, positive results, if confirmed, will be of major value to improving the safety of the induction regimen with RTX.…”

Recent Advancements in the Management of Anti-neutrophil Cytoplasmic Antibody-Associated Vasculitis: A Systematic Review

“…However, recent advancements in the treatment and management of AAV have dramatically increased patient prognosis in recent years [3], including the use of rituximab, avacopan, plasma exchange, immunological targeting, and intravenous pulse methylprednisolone, with all demonstrating success in achieving remission [2,[4][5][6][7][8][9]. Additionally, effective contemporary treatment involves combining plasma exchange with GCs, rituximab with CYC, and rituximab with GCs [9][10][11][12][13][14][15][16]. The purpose of this review is to provide relevant background data regarding the prevalence, significance, pathophysiology of AAV, and traditional treatment modalities while also describing the contemporary advancements in this disorder's treatment and management capabilities.…”