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Abstract
Objective: Rituximab is used as an off-label treatment for relapsing–remitting multiple sclerosis (RRMS); however, the comparative efficacy and safety of rituximab versus currently licensed disease-modifying drugs (DMDs) for RRMS is unknown. A systematic literature review was conducted to evaluate the available data pertaining to efficacy and safety of rituximab in adult patients with RRMS and highly active relapsing multiple sclerosis (HA-RMS); data quality was critically assessed via risk of bias (RoB) assessment.
Methods: Biomedical literature databases were searched until mid-2018 and key proceedings were searched from 2016 to 2018. Critical appraisal of non-randomized studies was conducted using the Cochrane RoB assessment tool; randomized controlled trials (RCTs) were appraised using comprehensive assessment criteria based on the NICE guidelines.
Results: Thirty-eight unique studies based on 49 publications were identified: 25 RRMS studies (one RCT) and 13 HA-RMS studies (no RCTs). The evidence among patients with RRMS generally favored rituximab in comparison to placebo (relapse rate) and interferons/glatiramer acetate (relapse rate and disability progression), although much of the non-randomized data were descriptive and/or not statistically significant. In comparison to placebo, rituximab was associated with a greater risk of adverse events. Two-thirds of the non-randomized RRMS studies were associated with critical/serious RoB; the single RCT was associated with low RoB. Furthermore, all of the non-randomized HA-RMS studies were associated with critical/serious RoB.
Conclusions: Available evidence of off-label rituximab use for the treatment of patients with RRMS suggests generally favorable efficacy versus placebo and interferons/glatiramer acetate; however, the poor quality of the included studies limits any robust conclusions.
Transparency
Declaration of funding
This study was funded by EMD Serono Inc. (a business of Merck KGaA, Darmstadt, Germany).
Declaration of financial/other relationships
S.L.W. and G.H. have disclosed that they are employees of EMD Serono Inc. (a business of Merck KGaA, Darmstadt, Germany). M.K.S., B.S. and S.A. have disclosed that they are employees of Parexel International. C.V. is an employee of Merck KGaA, Darmstadt, Germany. CMRO peer reviewers on this manuscript have received an honorarium from CMRO for their review work. One of the peer reviewers discloses involvement in academic research (funded by national and regional grants) related to rituximab for over 10 years; however, they have not received any type of reimbursement from the pharmaceutical industry in over 5 years. The peer reviewers have no other relevant financial relationships to disclose.
Author contributions
All authors were involved in the conception and design of the research, collection of the data, analysis and interpretation of the data, drafting of the article, and the provision of final approval of the article for submission/publication. All authors agree to be accountable for all aspects of this work.
Acknowledgements
Assistance with the drafting of the manuscript was provided by Jason Allaire PhD of Generativity Solutions Group, Durham, NC funded by EMD Serono Inc. (a business of Merck KGaA, Darmstadt, Germany).
