A Personalized Rituximab Retreatment Approach Based on Clinical and B-Cell Biomarkers in ANCA-Associated Vasculitis

Abstract

Background: Time to relapse after rituximab for the treatment of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is variable, and optimal retreatment strategy has remained unclear. In AAV following rituximab induction, the study objective was to evaluate clinical and B-cell predictors of relapse in order to develop a retreatment algorithm.

Methods: A retrospective observational study was conducted in 70 rituximab-treated ANCA-associated vasculitis patients followed up for over 10 years. Complete response (CR) was defined as Birmingham Vasculitis Activity Score v3.0 = 0. Retreatment was given on clinical relapse, defined as new features or worsening of persistent disease (not by biomarker status). Peripheral B-cell subsets were measured using highly sensitive flow cytometry. Predictors were tested using multivariable Cox regression.

Results: Median time to retreatment for cycles 1-5 were 84, 73, 67, 60, and 73 weeks. Over 467 patient-years follow-up, 158 relapses occurred in 60 patients; 16 (in 15 patients) were major (renal = 7, neurological = 4, ENT = 3, and respiratory = 2). The major-relapse rate was 3.4/100 patient-years. In multivariable analysis, concomitant immunosuppressant [HR, 0.48 (95% CI, 0.24-0.94)], achieving CR [0.24 (0.12-0.50)], and naïve B-cell repopulation at 6 months [0.43 (0.22-0.84)] were associated with longer time to relapse. Personalized retreatment using these three predictors in this cohort would have avoided an unnecessary fixed retreatment in 24% of patients. Area under the receiver operating characteristic for prediction of time to relapse was greater if guided by naïve B-cell repopulation than if previously evaluated ANCA and/or CD19⁺ cells return at 6 months had been used, 0.82 and 0.53, respectively.

Conclusion: Our findings suggest that all patients should be coprescribed oral immunosuppressant. Those with incomplete response or with absent naïve B cells should be retreated at 6 months. Patients with complete response and naïve repopulation should not receive fixed retreatment. This algorithm could reduce unnecessary retreatment and warrant investigation in clinical trials.

Keywords: B cell; cyclophosphamide; immunoglobulin; rituximab; vasculitis.

Figure 1

Flow chart of participant into the study.

Figure 2

Comparison of peripheral B-cell subsets across three diseases and validation of B-cell biomarkers of relape. B-cell subsets including naïve (A), memory (B), and plasmablast (C) were compared between patients with rheumatoid arthritis, systemic lupus erythematosus, and AAV at rituximab initiation. The latter was divided into those with and without severe systemic inflammation; raised CRP (i.e., >10 mg/L). The box plots denote median, and the error bars represent Tukeys. Analyses were performed using Kruskal-Wallis followed by Mann-Whitney U test. Naïve B-cell repopulation at 6 months as a biomarker of later relapse was analyzed using Kaplan-Meier survival analysis in both the published discovery cohort (D) and the validation cohort (E).

Figure 3

Comparison of relapse prediction based on naïve B cells and ANCA and/or CD19+ cell return. Time to relapse was compared between patients with and without naïve repopulation in (A) at 6 months and (D) at 12 months and between patients with and without ANCA and/or CD19+ cells return in (B) at 6 months and (E) at 12 months respectively using Kaplan-Meier survival analyses. Areas under the receiver operating characteristic (AUROC) were compared between the two biomarker-led retreatment strategies (C) at 6 months and (F) at 12 months postrituximab.

Figure 4

Flow diagram. A proposal for personalized rituximab retreatment algorithm based on clinical predictors and early naïve B-cell return in ANCA-associated vasculitis.