B cell repopulation kinetics after rituximab treatment in ANCA-associated vasculitides compared to rheumatoid arthritis, and connective tissue diseases: a longitudinal observational study on 120 patients

Abstract

Background: B cell depletion with rituximab (RTX) is approved for treatment of rheumatoid arthritis (RA) and ANCA-associated vasculitides (AAV). Recently, RTX has been shown to be effective in AAV maintenance therapy, but an optimal RTX treatment schedule is unknown and the time to B cell repopulation after RTX has not been studied.

Methods: Retrospective single-center analysis of B cell repopulation in patients with AAV, RA or connective tissue disease (CTD) treated with RTX.

Results: Beginning B cell repopulation within the first year after RTX treatment was observed in 93% of RA and 88% of CTD patients. Only 10% of patients with granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA) and no patient with eosinophilic granulomatosis with polyangiitis (EGPA) showed B cell repopulation within this time. Median time of B cell depletion was 26 months in GPA/MPA, and 21 months in EGPA compared to 9 months in RA, and 8 months in CTD (p < 0.0001). In 25 AAV-patients B cell depletion lasted for at least 44 months. There was a significant decline in serum immunoglobulin concentrations in GPA/MPA patients, but not in patients with RA or CTD. Significantly more GPA/MPA patients developed hygogammaglobulinemia (IgG <7 g/L) compared to patients with RA or CTD.

Conclusions: In contrast to RA and CTD, in AAV RTX induces long-lasting depletion of B cells that is associated with decreased antibody production. This observation points toward potential defects in the B cell compartment in AAV that are unmasked by immunosuppressive treatment and has important implications for the design of maintenance treatment schedules using RTX.

Keywords: ANCA; B lymphocyte; Hypogammaglobulinemia; Repopulation; Rituximab.

Fig. 1

B cell repopulation and time of B cell depletion after rituximab. B cell repopulation within the time period of 12 months was detectable in approximately 90% of the patients with RA or CTD but in less than 10% of the AAV patients (a). Median time of B cell depletion after RTX was significantly prolonged in patients with GPA and MPA or EGPA compared to patients with RA or CTD (b). After a second RTX course B cell depletion time and repopulation kinetics were similar compared to the first RTX treatment course in AAV patients (c). Abbreviations: AAV ANCA-associated vasculitides, CTD connective tissue disease, EGPA eosinophilic granulomatosis with polyangiitis, GPA granulomatosis with polyangiitis, MPA microscopic polyangiitis, n.s. not significant, RA rheumatoid arthritis, RTX rituximab

Fig. 2

Serum immunoglobulin concentrations before and after RTX treatment and frequency of newly developed hypogammaglobulinemia. Serum IgG and IgM concentrations significantly dropped after RTX treatment compared to baseline in patients with GPA and MPA, but not in RA and CTD (a, c). Compared to patients with RA or CTD significantly more patients with GPA and MPA or EGPA developed new hypogammaglobulinemia of the isotypes IgG (b) and IgM (d). Abbreviations: CTD connective tissue disease, EGPA eosinophilic granulomatosis with polyangiitis, GPA granulomatosis with polyangiitis, IgG immunoglobulin G, IgM immunoglobulin M, n.s. not significant, MPA microscopic polyangiitis, RA rheumatoid arthritis