By Jai S. Perumal, MD

Assistant Professor of Neurology, Weill Cornell Medical College

Dr. Perumal reports she receives grant/research support from Genzyme Corp., and is on the speakers bureau for Biogen Idec, Genzyme Corp., Acorda Therapeutics, and Teva Pharmaceuticals.

SYNOPSIS: Based on a meta-analysis and review of rituximab use in the treatment of neuromyelitis optica spectrum disorders, the authors reported that rituximab was efficacious in reducing relapse rate and disability, but cautioned about potential side effects and adverse events, especially when considering rituximab as first-line therapy.

SOURCE: Damato V, Evoli A, Iorio R. Efficacy and safety of rituximab therapy in neuromyelitis optica spectrum disorders. A systematic review and meta-analysis. JAMA Neurol 2016;73:1342-1348.

Neuromyelitis optica (NMO) is an inflammatory disease of the central nervous system that preferentially affects the optic nerves and spinal cord. Classic NMO or Devic's disease is characterized by concurrent episodes of optic neuritis (ON) and transverse myelitis (TM). NMO spectrum disorder (NMOSD) is diagnosed in patients with isolated ON or TM who have the NMO IgG (aquaporin-4) antibody, which is potentially pathogenic and has high specificity for this group of diseases. NMO was accepted as a distinct entity from multiple sclerosis (MS) after the discovery of the aquaporin-4 antibody in 2004. The aquaporin-4 test is > 80% sensitive and > 99% specific for NMOSD. This distinction of NMOSD from MS is important, as the disease course and treatment options for this disease are different from that of MS.

There are no FDA-approved treatments for NMOSD. Traditionally, relapses are treated with a course of intravenous steroids and steroid-refractory relapses are treated with intravenous immunoglobulin (IVIg) or plasmapheresis (PLEX). Long-term disease-modifying treatments that have been used in NMOSD include pulse corticosteroids, IVIg, azathioprine, mycophenolate mofetil, and rituximab. Rituximab, a monoclonal anti-CD 20 antibody, increasingly is being used in the treatment of NMOSD and often is considered a first-line therapy for this disease.

Given this scenario, the authors conducted a systematic review and meta-analysis of all published data on the use of rituximab in NMOSD to evaluate the safety and efficacy in this disease. To identify the studies, the authors conducted a search of MEDLINE, Cochrane Central Register of Controlled Trials, and databases using the terms, neuromyelitis optica and rituximab or Devic’s disease and rituximab. Out of 119 records that were identified, using their selection criteria, 46 studies were included in the analysis. The analysis was restricted to publications in English, studies with more than two patients, and patients who met the strict criteria for NMOSD.

The combined data set of all the studies included 438 patients. The mean age was 32 years (range 2-77 years), 83.7% were AQP4-IgG positive, the mean disease duration at time of first rituximab infusion was 50 months (range 1.5-276 months), and the mean follow-up after rituximab infusion was 27.5 months (range 3-272 months). In 57 patients (13%), rituximab was the first-line therapy, and the remainder of patients had tried one or more alternate options before rituximab treatment was initiated. Various regimen of rituximab were used, including 375 mg/m2 weekly for four weeks, 1 gram every two weeks for two courses, 500 mg/weekly for two weeks, and others regimens.

When efficacy was evaluated, the mean risk reduction on annualized relapse rate was 0.79 (95% confidence interval [CI], -1.09 to -0.50). The mean reduction in Expanded Disability Status Scale score (from studies where it was reported) was 0.64 (95% CI, -1.18 to -0.10). Among the variables that were analyzed, shorter disease duration alone had a positive effect on magnitude of efficacy. Adverse events were reported in 26% of patients. These included infusion-related reactions (10.3%), infections (9.1%), persistent leukopenia (4.6%), and development of posterior reversible leukoencephalopathy (two patients, 0.5%). The severity and nature of the infections was not specified in this analysis, but none of the patients were reported to have developed progressive multifocal leukoencephalopathy (PML). Seven (1.6%) deaths were reported, but the causes of death not specified and the authors noted that the cause of death could have been the severity of the patients’ disease itself and not necessarily related to rituximab therapy.


Based on this comprehensive review, it appears that rituximab is effective in reducing relapses and decreasing risk of disability in patients with NMOSD. There are side effects and adverse events associated with this treatment, including infusion-related reactions and infections. However, the nature and severity of the infections were not specified, and no case of PML was reported. Although a few fatalities were reported in the studies, the causes of death were not mentioned, and they could have been due to the consequences from severe disease and not necessarily due to therapy. It also appears that early treatment with rituximab was associated with better outcomes. Since NMOSD is often characterized by severe relapses, which can lead to permanent residual disability, early prevention of these relapses would have the greatest effect on morbidity and quality of life. Rituximab appears to be a good choice as a first-line treatment in NMOSD, but one would need to proceed with caution and monitor patients closely for any potential adverse event.