Rituximab-Induced Hypogammaglobulinemia and Risk of Infection in Neuromyelitis Optica Spectrum Disorders: A 14-Year Real-Life Experience

Background and objectives: To investigate the frequency and predictors of hypogammaglobulinemia during long-term rituximab (RTX) treatment in patients with neuromyelitis optica spectrum disorder (NMOSD) and its association with infections.

Methods: We retrospectively reviewed the data of patients with NMOSD who received RTX through the maintenance regimen based on memory B-cell detection for at least 1 year from 2006 to 2021 at an institutional referral center for NMOSD.

Results: A total of 169 patients received a median of 10 courses (range 1-27) of RTX reinfusion after induction over a median of 8 (range, 1-15) years. Their mean serum immunoglobulin (Ig)G level began to decline significantly after 2 years of treatment, steadily declined at a rate of 2%-8% per year for the following 8 years, and then plateaued after 10 years. The proportion of patients with hypo-IgG (<6 g/L) increased from 1.2% after 1 year of treatment to 41% after 14 years of treatment. While being treated with RTX, 58 (34%) patients had 114 infections, of whom 14 (8%) patients had 15 severe infections. Multivariable logistic regression analyses identified duration of RTX treatment in years (odds ratio [OR] 1.234, 95% confidence interval [CI] 1.015-1.502), mean annual RTX dose (OR 0.063, 95% CI 0.009-0.434), history of mitoxantrone (OR 3.318, 95% CI 1.109-9.93), hypo-IgG at baseline (OR 40.552, 95% CI 3.024-543.786), and body mass index >25 kg/m² (OR 4.798, 95% CI 1.468-15.678) as independent predictors of hypo-IgG. The risk of infection during RTX treatment was independently associated with high Expanded Disability Status Scale scores (OR 1.427, 95% CI 1.2-1.697) and relapses during RTX treatment (OR 1.665, 95% CI 1.112-2.492), but not with hypogammaglobulinemia.

Discussion: Over 14 years of long-term RTX treatment, IgG levels gradually decreased, and the frequency of hypo-IgG increased to 41% of the patients. Patients with prolonged memory B-cell depletion after RTX, previous mitoxantrone history, hypo-IgG at baseline, or obesity were at risk of developing RTX-induced hypogammaglobulinemia. Nevertheless, infection rates remained low during treatment, and reduced immunoglobulin levels were not associated with an increased incidence of infections.