Rituximab Provides Long-Term Benefits in Neuromyelitis Optica

By Will Boggs MD

July 15, 2015

NEW YORK (Reuters Health) - Rituximab is effective as long-term treatment in patients with neuromyelitis optica spectrum disorder (NMOSD), researchers from Korea report.

"Overall, more than 90% of patients had a benefit from rituximab therapy: 94% of patients had a marked reduction in the annualized relapse rate (ARR) (<25% of the pre-rituximab ARR), 70% of patients were relapse-free, and disability improved or stabilized in 96% of patients," Dr. Ho Jin Kim, from Research Institute and Hospital of National Cancer Center, Goyang, South Korea, told Reuters Health by email. "Moreover, these results were derived from the largest cohort with longest follow-up so far."

Dr. Kim's team previously reported the therapeutic efficacy of rituximab in 30 patients with NMOSD with five years' follow-up. In that study, depletion of memory B cells in peripheral blood was associated with a clinical response to rituximab.

The current report includes 100 patients with NMOSD treated a median five years. It also explores the influence of fragment c gamma receptor 3A (FCGR3A) polymorphisms that are associated with a poorer response to rituximab therapy in hematologic disease.

As noted by Dr. Kim above and as included in the July 13 JAMA Neurology online report, 70% of patients were relapse-free through treatment ranging as long as 108 months.

Mean ARR declined from 2.4 relapses annually to 0.1 relapse annually with rituximab treatment. Median Expanded Disability Status Scale (EDSS) scores improved from 4 before treatment to 3 after treatment (p<0.001 for both).

Thirty patients experienced 49 relapses while receiving treatment. Most relapses were mild to moderate in severity, and only seven relapses in four patients required plasma exchange following steroid treatment.

The FCGR3A-158F allele was associated with a risk of insufficient memory B-cell depletion and a short retreatment interval during the first two years of rituximab treatment, as well as an increased risk of at least one relapse while receiving rituximab treatment. It was not, however, associated with EDSS worsening or with more than two relapses annually.

"This finding highlights the requirement of tailored strategy of rituximab treatment in each patient considering inter-individual difference of the drug response as well as disease activity," Dr. Kim said.

"Rituximab is a good second-line therapy in patients who have inadequate response to commonly used first-line treatment, such as azathioprine or mycophenolate mofetil," Dr. Kim said. "However, in patients who had an incomplete recovery from severe attack or who had attacks with short inter-attack interval, rituximab can be used as a first-line therapy. The rationale behind this is the fact that even a single attack may cause severe irreversible disability in NMOSD and a superiority of clinical efficacy of rituximab over oral immunosuppressive treatments."

Dr. Sean J. Pittock, from Mayo Clinic, Rochester, Minnesota, coauthored an accompanying editorial. He told Reuters Health by email, "This research group had made strides toward defining an optimal dosing schedule in treating to a target of CD27 positive B-cell suppression. Furthermore, it may be possible to individualize therapy on the basis of FCGR3A, either by recommending a more conservative monitoring strategy and a more frequent dosing regimen, or by recommending treatment with an alternative 'standard of care' immunosuppressant, such as azathioprine or mycophenolate mofetil, with or without prednisone. The personalized approach to rituximab therapy in NMOSD has wide-reaching implications for therapeutic management of autoimmune neurological disorders."

"Rituximab is considered one of the most successful examples of targeted immunotherapy, and has been increasingly applied off-label in a number of settings involving B-cell dysfunction, including many autoimmune disorders such as rheumatoid arthritis and multiple sclerosis," Dr. Pittock said. "Early studies and case reports have found promising results in antibody-mediated neurological autoimmune conditions such as myasthenia gravis, autoimmune encephalopathies, and multifocal motor neuropathy, and many physicians now consider rituximab a second- or third-line treatment in patients refractory to standard immunotherapy regimens."

Dr. Orhan Aktas, from Heinrich Heine University Dusseldorf, in Germany, considers rituximab first-line therapy for NMOSD. He told Reuters Health by email, "I think the suggested impact of the FCGR3A genotypes on biological and clinical response to rituximab therapy is intriguing and could guide clinicians to tailored/selective immunosuppressive therapy for NMOSD."

"B cell depletion is a promising therapeutic strategy for the majority -- but not all -- patients with NMOSD," Dr. Aktas said. "Therapeutic B cell depletion needs close follow-ups in order to identify nonresponders and to switch them to alternative strategies."

The National Research Center of Korea and the National Cancer Center of Korea supported this research. Dr. Kim reported several relevant relationships.

SOURCE: http://bit.ly/1HujEHH and http://bit.ly/1dYNaNj

JAMA Neurol 2015.

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