Background/Purpose: 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 longitudinal observational usual care study including RA patients according to ACR 1987 and/or ACR/EULAR 2010 classification criteria followed and treated with RTX. A previous study assessing the safety profile of RTX in patients with RA reported a median follow-up of 30 months (1). Therefore, we decided to include RA patients on RTX maintenance therapy, after a minimal exposition of 30 months. Serum protein electrophoresis was performed one to three days before each RTX infusion. Hypogammaglobulinemia and severe hypogammaglobulinemia were defined as total gammaglobulin <6g/L and <4g/l, respectively. Safety monitoring included the collection of all adverse events (AE) in particular severe infections.

Results: 134 patients met inclusion criteria: 113 female subjects (84.3%); mean age 52.1 ± 11.4 years. Mean follow-up was 79.5 ± 24.6 months and analysis was based on 854.9 patient-years (pt-yrs) of observation. Mean RTX cumulative dose was 12.0 ± 4.9g. Baseline gammaglobulin levels were significantly lower in subjects aged >65 years as compared to subjects aged <65 years: 10.42 ± 3.05g/L vs 12.85 ± 3.89 g/L respectively (p=0.0002). Hypogammaglobulinemia (<6g/L) occurred during the follow-up period in 23 patients (2.7 events per 100 pt-yrs), leading to an incidence of 17.1%. The mean time to development of hypogammaglobulinemia was 64±23 months. A total of 9.7% of patients had severe infections (1.5 events per 100 pt-yrs). Patients who developed hypogammaglobulinemia were more likely to experience severe infections (26.1% vs. 6.3%, P=0.033). Univariate Cox analysis identified age over 65 years (HR 4.28 [95% CI 0.92-19.97], P<0.001), low gammaglobulin levels prior the first RTX infusion (<8g/L) (HR 7.35 [95% CI 1.82-29.68], P<0.001) as predictors of protective factor (HR 0.26 [95% CI 0.08-0.87], P=0.03).

Conclusion: Our results show that gammaglobulin levels of less than 8g/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. Identifying such predictors will raise clinicians’ awareness and allow more tailored monitoring of RA patients long-term treated with RTX.

References: (1) Isvy et al, Joint Bone Spine 2012

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/predictors-of-hypogammaglobulinemia-during-rituximab-maintenance-therapy-in-rheumatoid-arthritis-a-12-year-longitudinal-multi-center-study/