A 5-Year Follow-up of Rituximab Treatment in Patients With Neuromyelitis Optica Spectrum Disorder

Abstract

IMPORTANCE A previous 2-year analysis of repeated rituximab treatment in patients with neuromyelitis optica (NMO) revealed significant improvements in relapse rates and disability. We report the findings from the longest follow-up of rituximab treatment in NMO, which provide reassurance regarding the long-term efficacy and safety of rituximab in NMO. OBJECTIVE To report the results of rituximab treatment in patients with relapsing NMO or NMO spectrum disorder (NMOSD) for a median of 60 months. DESIGN, SETTING, AND PARTICIPANTS Retrospective case series in an institutional referral center for multiple sclerosis, including 30 patients with relapsing NMO or NMOSD. INTERVENTIONS After induction therapy, a single infusion of rituximab (375 mg/m 2) as maintenance therapy was administered whenever the frequency of reemerging CD27 + memory B cells in peripheral blood mononuclear cells, as measured with flow cytometry, exceeded 0.05% in the first 2 years and 0.1% thereafter. MAIN OUTCOMES AND MEASURES Annualized relapse rate (ARR), disability (Expanded Disability Status Scale score), change in anti-aquaporin 4 antibody, and safety of rituximab treatment. RESULTS Of 30 patients, 26 (87%) exhibited a marked reduction in ARR over 5 years (mean [SD] pretreatment vs posttreatment ARR, 2.4 [1.5] vs 0.3 [1.0]). Eighteen patients (60%) became relapse free after rituximab treatment. In 28 patients (93%), the disability was either improved or stabilized after rituximab treatment. No serious adverse events leading to discontinuation were observed during follow-up. CONCLUSIONS AND RELEVANCE Repeated treatment with rituximab in patients with NMOSD over a 5-period, using an individualized dosing schedule according to the frequency of reemerging CD27 + memory B cells, leads to a sustained clinical response with no new adverse events.

Features of Human CD3+CD20+ T Cells

“…The reappearance of CD20-expressing B cells was previously linked to new relapses in NMO patients (29). B cell subsets reconstitute different after rituximab, initially only naive B cells with a delayed appearance of memory B cells; the reappearance of memory B cells may suggest that a maintenance therapy with rituximab should be performed (30). We ascertained that the replenishment of CD20-expressing T cells occurs much earlier than that of CD20-expressing B cells.…”

Present and Future Therapies in Neuromyelitis Optica Spectrum Disorders

“…The pivotal open-label study from Cree et al [21] established B-cell depletion as a therapeutic principle for NMOSD; 6/8 patients were relapse-free after 1 year of treatment. Several clinical case series and retrospective analyses (including 10-55 patients each, treatment up to 8 years) have confirmed these findings and reported a reduction of ARR in 87-96 %, freedom from relapses in 44-72 %, and an improvement of disability in 80-100 % of patients [79,81,97,[99][100][101][102]. Most patients in these studies were AQP4-IgG-positive, but response rates in patients with AQP4-IgG-negative NMOSD seem to be similar [97,102].…”

“…In line with these findings AQP4-IgG transiently increase after initiation of rituximab, with a subsequent decrease [107]. Lower titers of AQP4-IgG are probably associated with less disease activity but have not yet been established as a reliable biomarker of treatment response in rituximab-treated patients [74,100,101]. It is unknown whether the clinical effects of B-cell depletion are mediated by a reduction of AQP4-IgG or by inhibition of other proinflammatory B-cell functions.…”

“…A genetic polymorphism in the fragment c gamma receptor 3A (FCGR3A) allele has been shown to be associated with insufficient memory B-cell depletion and an elevated risk of attacks during rituximab treatment [104]. It is controversial whether a reduction in the dose during long-term treatment or even lower initial doses of rituximab are sufficient to suppress disease activity [100,103,105,106]. Generally, optimal dosing of rituximab is important to lower the failure rate [79,103].…”

Anti-B-Cell Therapies in Autoimmune Neurological Diseases: Rationale and Efficacy Trials

“…B-cell repopulation after B-cell depletion with rituximab in patients with NMO was characterized by the predominance of Bregs and restored the pretreatment disturbed balance between regulatory and memory B cells back to an advantageous state [51]. Of relevance, repeated treatment with rituximab on an individualized dosing schedule by monitoring of CD19+CD27+ memory B cells has been proposed for NMO and could have the potential to serve as a clinical tool for personalized therapy, if evaluated prospectively in a large number of patients [141].…”