Effect of Reduced-Dose vs High-Dose Glucocorticoids Added to Rituximab on Remission Induction in ANCA-Associated Vasculitis: A Randomized Clinical Trial

Abstract

Importance: The 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/m2/wk, 4 doses) (n = 70) or high-dose prednisolone (1 mg/kg/d) plus rituximab (n = 70).

Main outcomes and measures: The 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 ∞) 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.

Trial registration: ClinicalTrials.gov Identifier: NCT02198248.

Figure 1.. Allocation, Randomization, and Flow of Patients Through the Low-Dose Glucocorticoid Vasculitis Induction Study

Eligible patients were randomized to reduced-dose or high-dose glucocorticoid groups at a ratio of 1:1 using a minimization method with probability assignment. The assignment probability was set to 0.9. The full analysis set was used for the primary analysis. Patients who did not receive rituximab were excluded from the analysis (1 cerebral hemorrhage before rituximab infusion after randomization in the reduced-dose group; 1 withdrawal of consent and 1 unexpected discovery of cancer before rituximab infusion after randomization in the high-dose group). We failed to collect the data of 3 patients in 1 hospital, thus they were excluded from the analysis. Therapies based on physician preference included 14 increasing doses of prednisolone, 2 azathioprine, 1 plasma exchange, 1 cyclophosphamide, 1 mycophenolate mofetil, and/or 1 rapid reduction of prednisolone dose. ANCA indicates antineutrophil cytoplasm antibody; eGFR, estimated glomerular filtration rate.

Figure 2.. Secondary and Exploratory Outcomes Over 6 Months

The median time of observation was 180 days (interquartile range, 180-180) for all panels. The boxes indicate the medians and interquartile ranges, the vertical lines indicate the 1.5 interquartile range, and the circles and triangles indicate outliers. A, Disease activity of vasculitis was assessed using the Birmingham Vasculitis Activity Score. The scores range from 0 to 63, and higher scores indicate more active disease. B and C, Visual analog scales based on self-assessment by patients to measure the intensity of overall disease activity and treatment toxicity. The scales range from 0 cm to 10 cm, and higher scores indicate more severe activity and toxicity. D, Normal limit of C-reactive protein level is 0.3 mg/dL or less. E, Serum IgG levels were measured by turbidimetric immunoassay, and the normal range is 870 to 1700 mg/dL.