Rituximab-induced hypogammaglobulinemia in patients with neuromyelitis optica spectrum disorders

Abstract

Objective: To evaluate the long-term effects of rituximab (RTX) on total and specific immunoglobulins (Igs) in patients with neuromyelitis optica spectrum disorders (NMOSDs).

Methods: Total IgG, IgA, and IgM levels were evaluated in 15 patients with NMOSDs treated with RTX (median follow-up 70 months). Anti-aquaporin 4 (AQP4)-IgG titration was performed on samples from 9 positive patients. Anti-tetanus (TET), anti-varicella-zoster virus (VZV), and anti-Epstein-Barr virus nuclear antigen (EBNA) IgGs were also tested in patients with NMOSDs and in 6 healthy controls (HCs).

Results: RTX reduced total IgG by 0.42 g/L per year, IgA by 0.08 g/L per year, and IgM by 0.07 g/L per year. Hypogammaglobulinemia (hypo-IgG) (IgG < 7 g/L) developed in 11/15 patients. Severe hypo-IgG (IgG < 4 g/L) was found in 3/15 patients, of whom 2 patients developed serious infectious complications. In group analysis, anti-AQP4 IgG titers were reduced by RTX over time, and a significant correlation between anti-AQP4 IgG titers and total IgG levels was found. The effects of RTX were observed on pathogen-specific IgGs as well. In particular, the levels of anti-TET IgG in patients were significantly lower than those in HCs. The half-life of anti-TET IgG was reduced by about 50% in patients compared with the general population.

Conclusions: Long-term RTX treatment is associated with the risk of hypo-Ig and reduction of anti-TET protection in patients with NMOSDs. Results obtained in this study suggest the importance of monitoring total and specific Ig levels before and during treatment with anti-CD20 drugs to prevent hypo-Ig-related complications and to optimize clinical management.

Figure 1. Total IgG, IgA, and IgM levels and hypo-Ig prevalence during RTX treatment

IgG, IgA, and IgM levels were measured in 188 samples from 15 patients with NMOSDs treated with RTX. Median follow-up period was 70 (range 17–124) months. Levels of total IgG, IgA, and IgM in all serum samples are represented in panels A, C, and E, respectively. Black lines represent the thresholds defining hypo-IgG (<7.0 g/L), –IgA (<0.7 g/L), and –IgM (<0.4 g/L). In addition, based on augmented infectious risk, severe hypo-IgG was defined as total IgG levels <4.0 g/L and severe hypo-IgM as total IgM levels <0.2 g/L. Long-term RTX treatment reduced the levels of all Ig classes. Statistical analysis was performed using univariate linear mixed models. Panels B, D, and F show the prevalence of hypo-Ig over time according to each specific cutoff. The percentage of patients developing hypo-IgG, hypo-IgA, and hypo-IgM has been calculated in patients with a prolonged follow-up period (≥5 years, n = 7 patients), which showed an increased prevalence over time. In particular, prevalence of patients developing hypo-IgG is represented in panel B: patients developing severe hypo-IgG (IgG < 4g/L) are represented in purple, as patients showing mild hypo-IgG (5 g/L ≤ IgG < 7 g/L) are represented in gray. Prevalence of patients developing hypo-IgA (IgA < 0.7 g/L) is shown in panel D (gray). Prevalence of patients developing hypo-IgM is shown in panel F: patients developing severe hypo-IgM (IgM <0.2 g/L) are represented in purple, as patients showing mild hypo-IgM (0.2 g/L ≤ IgG < 0.4 g/L) are represented in gray.

Figure 2. Correlation between total IgG levels and anti-AQP4 IgG titer

Anti-AQP4 IgG levels were measured in 121 samples from 9 patients positive to AQP4 antibodies. Anti-AQP4 IgG titer decreases during the RTX follow-up period (panel A, Kruskal–Wallis test, p = 0.0001). One of 9 patients (#2) seroreverted during the follow-up period. A strong correlation between total IgG and anti-AQP4 IgG levels was shown in 7 of 9 patients (panel B; linear regression model, p < 0.0001).

Figure 3. Effects of RTX on specific anti-pathogen IgGs

Anti-TET, anti-VZV, and anti-EBNA IgGs were tested in 48 samples from 15 patients with NMOSDs and in 12 samples from 6 HCs. Panels A, C, and D show the over-time variation in the levels of anti-TET IgG, anti-VZV, and anti-EBNA IgG index in patients with NMOSDs (circle, black line) and in HCs (triangle, purple line). The first measurement (open circle or triangle) and the last available measurement (closed circle or triangle) among the entire follow-up period were considered for each subject. Anti-TET IgG showed a reduction in 10/15 patients and in HCs (A). The yellow line shows the threshold of ineffective protection from tetanus (light-gray zone, anti-TET IgG <0.1 U/mL). The levels of anti-TET IgG resulted significantly lower in patients during RTX treatment as compared to HCs (B). Anti-VZV IgG was reduced in 8/15 patients and 0/6 controls (C). The yellow line shows the threshold of negativity status for anti-VZV (light-gray zone, index ≤1.0). Seven patients with NMOSDs and 3 HCs showed levels of anti-VZV IgG index upper the limit of detection (index >6.4, dark-gray zone).