Predictors of hypogammaglobulinemia during rituximab maintenance therapy in rheumatoid arthritis: A 12-year longitudinal multi-center study

Objective: Rituximab (RTX) is an anti-CD20 monoclonal antibody that selectively depletes B-cell population. Thus, it presents a potential risk for the development of hypogammaglobulinemia and related infectious events. Our aim was to identify predictors of hypogammaglobulinemia in RA patients long-term treated with RTX. Methods: Multicenter observational usual care study of patients with RA on RTX maintenance therapy (minimal exposition of 30 months). Serum protein electrophoresis was performed before each RTX infusion. Hypogammaglobulinemia and severe hypogammaglobulinemia were defined as total gamma globulin < 6 g/L and < 4 g/L, respectively. The primary outcome was the occurrence within the follow-up period of hypogammaglobulinemia. Results: 134 patients met inclusion criteria and were followed-up for 79.5 +/- 24.6 months. Hypogammaglobulinemia occurred during the follow-up period in 23 patients (2.7 events per 100 pt-yrs). The mean time to development of hypogammaglobulinemia was 64 +/- 23 months. Patients who developed hypogammaglobulinemia were more likely to experience severe infections (26.1% vs. 6.3%, P = 0.033). Multivariate Cox analysis identified gammaglobulin levels < 8 g/L at baseline as an independent predictor of hypogammaglobulinemia (HR 7.34 [95% CI: 2.00-26.90], P = 0.003). Concomitant methotrexate (MTX) intake was also predictive of a reduced risk of hypogammaglobulinemia occurrence (HR 0.26 [95% Cl: 0.08-0.87], P = 0.03). Conclusion: Our results show that gammaglobulin levels of less than 8 g/L at baseline is a strong independent risk factor for developing subsequent hypogammaglobulinemia, whereas concomitant MTX therapy seems to be a protective factor in RA patients treated long-term with RTX. (C) 2018 Elsevier Inc. All rights reserved.