Long-term Effectiveness and Safety of Rituximab in Neuromyelitis Optica Spectrum Disorder and MOG Antibody Disease

Abstract

Background and objectives: Rituximab is used widely for relapse prevention in neuromyelitis optica spectrum disorder (NMOSD) and myelin oligodendrocyte glycoprotein (MOG)-IgG-associated disease (MOGAD); however, data regarding the effectiveness and safety of long-term rituximab use in these conditions are limited. In this study, we sought to evaluate long-term clinical outcomes in patients with aquaporin-4 IgG-seropositive (AQP4-IgG+) NMOSD and MOGAD treated with rituximab.

Methods: We performed a retrospective chart review of patients with AQP4-IgG+ NMOSD or MOGAD followed at the Johns Hopkins Neuromyelitis Optica Clinic and included patients who had received at least 1 dose of rituximab.

Results: We identified 111 patients with NMOSD and 23 patients with MOGAD who fulfilled the inclusion criteria. The median duration of rituximab treatment for the patients with NMOSD was 3.7 years (range: 0.5-13.2 years) and for the patients with MOGAD was 2.1 years (range: 0.5-7.0 years). The annualized relapse rate (ARR) decreased after rituximab initiation in both NMOSD (median ARR: pretreatment 1.1, posttreatment 0; p < 0.001) and MOGAD (median ARR: pretreatment 1.9, posttreatment 0.3; p = 0.002). Relapses on rituximab occurred in 31 patients with NMOSD (28%) and 14 patients with MOGAD (61%). The majority of NMOSD treatment failures (37/48 relapses; 77%) occurred either within the initial 6 months after starting rituximab (n = 13 relapses) or in the setting of delayed/missed rituximab doses and/or peripheral B-cell reconstitution (n = 24 relapses), whereas in MOGAD, these circumstances were present in a smaller proportion of treatment failures (19/35 relapses; 54%). The risk of relapse on rituximab was greater for patients with MOGAD compared with patients with NMOSD (hazard ratio: 2.8, 95% CI: 1.5-5.2, p = 0.001). Infections requiring hospitalization occurred in 13% and immunoglobulin G (IgG) hypogammaglobulinemia in 17% of patients. The median rituximab treatment duration before IgG hypogammaglobulinemia onset was 5.4 years (interquartile range: 3.8-7.7 years).

Discussion: Rituximab treatment is associated with the reduced annualized relapse rate in AQP4-IgG-seropositive NMOSD, especially in the absence of gaps in treatment and/or B-cell reconstitution. In MOGAD, although a reduction in relapses was observed after initiation of rituximab, this association appeared to be less robust than in AQP4-IgG-seropositive NMOSD. Severe infections and hypogammaglobulinemia occurred in a significant proportion of patients, highlighting the need for close monitoring of infectious complications.

Classification of evidence: This study provides Class IV evidence that rituximab decreases the annualized relapse rate in AQP4-IgG-seropositive NMOSD and MOGAD.

Figure 1. Study Population

AQP4-IgG+ = aquaporin-4 IgG seropositive; MOGAD = myelin oligodendrocyte glycoprotein–IgG–associated disease; NMOSD = neuromyelitis optica spectrum disorder.

Figure 2. Clinical Attacks, Infections Requiring Hospitalization, and Hypogammaglobulinemia Over Time in Patients With AQP4-IgG+ NMOSD and MOGAD Before and After Initiation Rituximab Treatment

Attacks are shown up to 15 years before rituximab initiation. From the AQP4-IgG+ NMOSD 11 patients (patients 9, 10, 17, 20, 23, 25, 29, 30, 49, 101, and 111) and from the MOGAD group 2 patients (patients 8 and 10) had experienced relapses before 15 years pre-rituximab. AQP4-IgG+ = aquaporin-4 IgG seropositive; MOGAD = myelin oligodendrocyte glycoprotein–IgG–associated disease; NMOSD = neuromyelitis optica spectrum disorder.

Figure 3. Characterization of Clinical Relapses of Patients With AQP4-IgG+ NMOSD and MOGAD on Rituximab

(A) Flow diagram of type of relapses during treatment. (B) Kaplan-Meier curves showing the time to relapse after starting rituximab treatment (1 patient with NMOSD considered in 2 different epochs given prolonged treatment gap of 9 years). (C) Annualized relapse rate before and after rituximab treatment. ** p = 0.003; **** p < 0.001 AQP4-IgG+ = aquaporin-4 IgG seropositive; HR = hazard ratio MOGAD = myelin oligodendrocyte glycoprotein–IgG–associated disease; NMOSD = neuromyelitis optica spectrum disorder.

Figure 4. Disability Outcomes

Disability scores before rituximab treatment and at the last visit; data for pre- and post-treatment disability were available for 96 patients with AQP4-IgG+ NMOSD and 18 patients with MOGAD for gait, 84 patients with AQP4-IgG+ NMOSD and 16 patients with MOGAD for micturition, and 69 patients with AQP4-IgG+ NMOSD and 15 patients with MOGAD for vision. AQP4-IgG+ = aquaporin-4 IgG seropositive; MOGAD = myelin oligodendrocyte glycoprotein–IgG–associated disease; NMOSD = neuromyelitis optica spectrum disorder.

Figure 5. Adverse Events During Follow-up on Rituximab Treatment in Patients With AQP4-IgG+ NMOSD and MOGAD

Infections requiring hospitalization (A) and hypogammaglobulinemia (B and C). The green line in C corresponds to the average trend of IgG levels, derived from a linear mixed-effects model. One patient with AQP4-IgG+ NMOSD was considered 2 different treatment epochs given prolonged treatment gap (9 years). AQP4-IgG+ = aquaporin-4 IgG seropositive; MOGAD = myelin oligodendrocyte glycoprotein–IgG–associated disease; NMOSD = neuromyelitis optica spectrum disorder.