By Jai S. Perumal, MD

Assistant Professor of Neurology, Weill Cornell Medical College; Assistant Attending Neurologist,
New York-Presbyterian Hospital

Dr. Perumal reports she is a consultant for Genzyme, EMD Serono, and Biogen.

SYNOPSIS: Based on an observational prospective study of 16 patients with anti-myelin oligodendrocyte protein (MOG) disease and 29 anti-aquaporin-4 disease, the authors report lesser efficacy of rituximab in anti-MOG patients, characterized by higher occurrence of relapses in the anti-MOG group, even while the biological effect of rituximab on memory B-cell suppression was sustained.

SOURCE: Durozard P, Rico A, Boutiere C, et al. Comparison of the response to rituximab between myelin oligodendrocyte glycoprotein and aquaporin-4 antibody diseases. Ann Neurol 2020;87:256-266.

Myelin oligodendrocyte protein (MOG) antibody disease increasingly is being recognized as an entity distinct from multiple sclerosis (MS) or aquaporin-4 (AQP4) antibody (Ab)-positive neuromyelitis optica spectrum disorder (NMOSD). Anti-MOG disease often has a presentation similar to NMOSD or acute disseminated encephalomyelitis. Patients who test positive for MOG antibodies do not appear to overlap with MS or AQP4 Ab-positive patients. Even as the clinical features, disease characteristics, and immune pathology of this disease are being studied, we know very little about optimal treatment of anti-MOG disease. Acute relapses are treated with the conventional regimen for relapses of acute central nervous system (CNS) inflammatory/demyelinating conditions (i.e., intravenous steroids, intravenous immunoglobulin, or plasma exchange). With regard to long-term therapies, immune-suppressive treatments, such as rituximab, mycophenolate mofetil, and intravenous immunoglobulin (IVIG), often are used, but there is little data on the efficacy of these treatments.

Rituximab is an anti-CD20 chimeric monoclonal antibody that frequently is used for treatment of NMOSD and other CNS inflammatory conditions. As previously mentioned, it has been used as well for the treatment of MOG antibody disease; however, there are reports that it may not be as effective in MOG-Ab disease as it is in AQP4-Ab disease. The authors undertook this study to compare the relative efficacy of rituximab in patients with MOG-Ab disease and AQP4-Ab disease, and to correlate the clinical efficacy with the biological effect on memory B-cell suppression with rituximab. Although there may be more than one mechanism of action, the efficacy of rituximab in AQP4 Ab disease mostly is due to memory B-cell depletion. The primary outcome of the study was the proportion of relapses occurring despite memory B-cell depletion in MOG and AQP4-Ab–positive patients.

Twenty-nine patients with AQP4-Ab and 16 with MOG-Ab were enrolled in this longitudinal study. For AQP4-Ab patients, the sex ratio was female/male: 26/3 vs. female/male: 8/8 for MOG-Ab–positive patients. Median age at disease onset was 29.5 years (range, 13-59 years) and 42 years (range, 20-72 years) for MOG-Ab and AQP4-Ab–positive patients, respectively. For 11 of 16 MOG-Ab–positive patients, rituximab was the first treatment. Previous treatment for other MOG-Ab–positive patients included mycophenolate mofetil for two patients and natalizumab, fingolimod, and teriflunomide for the remaining three. For AQP4-Ab–positive patients, rituximab was first-line therapy in 23 of 29; previous treatment for other patients included azathioprine for three and cyclophosphamide, mitoxantrone, and glatiramer acetate for the remaining three. Median follow-up duration after initiating rituximab was 1.59 years (range, 0.76-3.21 years) and 3.15 years (range, 1.12-6.58 years) for MOG-Ab and AQP4-Ab positive patients.

Rituximab treatment consisted of 1,000 mg infused twice at a two-week interval as induction, followed by maintenance treatment of a single infusion of 1,000 mg. Re-infusions of rituximab were based on an individualized dosing schedule according to the frequency of reemerging memory B-cells (CD27-positive B cells). Memory B-cells were measured monthly from the second month after the initial rituximab infusion. Physical and neurological exams were conducted at the time of the infusion and three months post-infusion, and at times of suspected relapses.

Overall, 23 relapses were reported after rituximab initiation in this study. Ten relapses occurred in six of 16 (37.5%) patients with MOG antibodies, and 13 occurred in seven of 29 (24%) with AQP4 antibodies. The median time of relapse after the most recent infusion was 2.6 (0.6-5.8) and seven (0.8-13) months, respectively (P < 0.001). Memory B-cells had reemerged in two of 10 (20%) relapses in patients with MOG antibodies and 12 of 13 (92.5%) with AQP4 antibodies (P < 0.001). These observations show that 80% (8/10) of relapses in MOG-Ab disease occurred while memory B-cell suppression from rituximab was still effective, while just 7.5% (1/13) of relapses in AQP4-Ab disease occurred at the time of sustained memory B-cell suppression. Median time to relapse after the most recent infusion was 2.6 (0.6-5.8) months in MOG-Ab patients, which would be at the time of effective memory B-cell depletion by rituximab. In AQP4-Ab patients, median time to relapse was 7 (0.8-13) months, which would be at the time of reemergence of memory B-cells post-infusion.

COMMENTARY

Based on the findings, it appears that in patients with MOG-Ab disease, or at least in a subset of patients with this disease, memory B-cell depletion from rituximab does not seem to be effective in reducing relapses. However, at the present time, there are little data on how other immunosuppressive treatments might fare in comparison to rituximab for MOG-Ab disorder. The efficacy of rituximab in AQP4-Ab disorders seems to be further fortified by the findings from this study. The fact that 12/13 relapses in this patient group occurred when memory B-cells were reemerging suggests that, rather than the standard regimen, an individualized re-dosing schedule based on memory B-cell recovery may be more rational in the treatment of this disease.