Impact of Rituximab on Immunoglobulin Concentrations and B Cell Numbers after Cyclophosphamide Treatment in Patients with ANCA-Associated Vasculitides

Abstract

ObjectiveTo assess the impact of immunosuppressive therapy with cyclophosphamide (CYC) and rituximab (RTX) on serum immunoglobulin (Ig) concentrations and B lymphocyte counts in patients with ANCA-associated vasculitides (AAVs).MethodsRetrospective analysis of Ig concentrations and peripheral B cell counts in 55 AAV patients.ResultsCYC treatment resulted in a decrease in Ig levels (median; interquartile range IQR) from IgG 12.8 g/L (8.15-15.45) to 9.17 g/L (8.04-9.90) (p = 0.002), IgM 1.05 g/L (0.70-1.41) to 0.83 g/L (0.60-1.17) (p = 0.046) and IgA 2.58 g/L (1.71-3.48) to 1.58 g/L (1-31-2.39) (p = 0.056) at a median follow-up time of 4 months. IgG remained significantly below the initial value at 14.5 months and 30 months analyses. Subsequent RTX treatment in patients that had previously received CYC resulted in a further decline in Ig levels from pre RTX IgG 9.84 g/L (8.71-11.60) to 7.11 g/L (5.75-8.77; p = 0.007), from pre RTX IgM 0.84 g/L (0.63-1.18) to 0.35 g/L (0.23-0.48; p<0.001) and from pre RTX IgA 2.03 g/L (1.37-2.50) to IgA 1.62 g/L (IQR 0.84-2.43; p = 0.365) 14 months after RTX. Treatment with RTX induced a complete depletion of B cells in all patients. After a median observation time of 20 months median B lymphocyte counts remained severely suppressed (4 B-cells/µl, 1.25-9.5, p<0.001). Seven patients (21%) that had been treated with CYC followed by RTX were started on Ig replacement because of severe bronchopulmonary infections and serum IgG concentrations below 5 g/L.ConclusionsIn patients with AAVs, treatment with CYC leads to a decline in immunoglobulin concentrations. A subsequent RTX therapy aggravates the decline in serum immunoglobulin concentrations and results in a profoundly delayed B cell repopulation. Surveying patients with AAVs post CYC and RTX treatment for serum immunoglobulin concentrations and persisting hypogammaglobulinemia is warranted.

Long-Term Maintenance Therapy Using Rituximab-Induced Continuous B-Cell Depletion in Patients with ANCA Vasculitis

“…Hypogammaglobulinemia was a late and modest complication without apparent major sequelae, which led to discontinuation of rituximab in several patients. These results differ from a previous report showing a marked decline in Ig levels, especially with rituximab administration after cyclophosphamide use (19). Explanations for this discrepancy may relate to small cohort size, cyclophosphamide dosing, and cumulative exposure to other immunosuppressants in the other cohort.…”

A Feeder-Free Differentiation System Identifies Autonomously Proliferating B Cell Precursors in Human Bone Marrow

“…Thus, it is difficult to extrapolate results from mouse models directly to B cell development in humans. However, BM transplantation (20) and immunosuppressive therapies in cancer or autoimmunity (21,22) affect proliferation and development of B cells, thus changing B cell homeostasis, immune responses, and the susceptibility to infections.…”

Erratum: Eular/ERA-EDTA recommendations for the management of ANCA-associated vasculitis

“…Patients may require interventions by specialists with expertise in AAV, such as immunological monitoring, use of rituximab in patients with refractory disease, specialised radiography, assessment of eye involvement, injection of subglottic stenosis and renal transplantation. [17][18][19][20][21][22][23][24] For patients with refractory disease, the best option may be consideration of referral to centres participating in clinical trials. AAV may relapse years after remission is achieved, even in previously unaffected organ systems.…”