Fc receptor-like 5 and anti-CD20 treatment response in granulomatosis with polyangiitis and microscopic polyangiitis

Abstract

BACKGROUNDBaseline expression of FCRL5, a marker of naive and memory B cells, was shown to predict response to rituximab (RTX) in rheumatoid arthritis. This study investigated baseline expression of FCRL5 as a potential biomarker of clinical response to RTX in granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA).METHODSA previously validated quantitative PCR-based (qPCR-based) platform was used to assess FCRL5 expression in patients with GPA/MPA (RAVE trial, NCT00104299).RESULTSBaseline FCRL5 expression was significantly higher in patients achieving complete remission (CR) at 6, 12, and 18 months, independent of other clinical and serological variables, among those randomized to RTX but not cyclophosphamide-azathioprine (CYC/AZA). Patients with baseline FCRL5 expression ≥ 0.01 expression units (termed FCRL5hi) exhibited significantly higher CR rates at 6, 12, and 18 months as compared with FCRL5lo subjects (84% versus 57% [P = 0.016], 68% versus 40% [P = 0.02], and 68% versus 29% [P = 0.0009], respectively).CONCLUSIONOur data taken together suggest that FCRL5 is a biomarker of B cell lineage associated with increased achievement and maintenance of complete remission among patients treated with RTX and warrant further investigation in a prospective manner.FUNDINGThe analysis for this study was funded by Genentech Inc.

Keywords: Autoimmunity; Clinical Trials; Vasculitis.

Figure 1. Sample processing flowchart.

Figure 2. Validation of FCRL5 mRNA gene expression biomarker in patients in the RAVE trial.

(A) Baseline FCRL5 mRNA levels assayed by qPCR in whole blood were compared in patients who achieved and failed to achieve complete remission at 6 months in both the RTX (n = 62 and n = 35, respectively) and the CYC arm (n = 49 and n = 42, respectively). Median and interquartile range shown as box plot; whiskers represent IQR. (B–D) Identified biomarker threshold (FCRL5 ≥ 0.01 versus FCRL5 < 0.01) was tested in baseline mRNA samples from patients in the RAVE trial as a predictor of complete remission at 6 months (B), 12 months (C), and 18 months (D), in subjects treated with RTX (blue bars) versus CYC (red bars). The number on the top of the bars in B–D denotes percentage remission rate in each subgroup, the number in brackets refers to the total number of subjects in each respective subgroup, and the number above it refers to the number of remitters. Wilcoxon rank-sum P value and Fisher’s exact P values shown in A and B–D, respectively. *P < 0.05.

Figure 3. Longitudinal flow cytometry data.

(A–E) patients have been stratified based on baseline FCRL5 expression. (F) Subjects have been stratified based on complete remission at month 6. The numbers of patients with available data at each visit are shown in the tables. Wilcoxon rank-sum P values are as follows: *P < 0.05; **P < 0.01. CR, complete remission.