Safety of dimethyl fumarate for multiple sclerosis: A systematic review and meta-analysis

Geoffrey Liang; Julia Chai; Huah Shin Ng; Helen Tremlett

doi:10.1016/j.msard.2020.102566

Safety of dimethyl fumarate for multiple sclerosis: A systematic review and meta-analysis

Mult Scler Relat Disord. 2020 Nov:46:102566. doi: 10.1016/j.msard.2020.102566. Epub 2020 Oct 5.

Authors

Geoffrey Liang¹, Julia Chai², Huah Shin Ng³, Helen Tremlett⁴

Affiliations

¹ Faculty of Medicine (Neurology), University of British Columbia and The Djavad Mowafaghian Centre for Brain Health, 2215 Wesbrook Mall, Vancouver, BC, V6T 1Z3, Canada; Faculty of Medicine, University of British Columbia, Vancouver, BC, Canada. Electronic address: geoffreyliang@alumni.ubc.ca.
² Faculty of Medicine (Neurology), University of British Columbia and The Djavad Mowafaghian Centre for Brain Health, 2215 Wesbrook Mall, Vancouver, BC, V6T 1Z3, Canada; Faculty of Science, University of British Columbia, Vancouver, BC, Canada. Electronic address: juliachai98@hotmail.com.
³ Faculty of Medicine (Neurology), University of British Columbia and The Djavad Mowafaghian Centre for Brain Health, 2215 Wesbrook Mall, Vancouver, BC, V6T 1Z3, Canada. Electronic address: huahshin.ng@ubc.ca.
⁴ Faculty of Medicine (Neurology), University of British Columbia and The Djavad Mowafaghian Centre for Brain Health, 2215 Wesbrook Mall, Vancouver, BC, V6T 1Z3, Canada. Electronic address: helen.tremlett@ubc.ca.

PMID: 33296968
DOI: 10.1016/j.msard.2020.102566

Abstract

Background: The safety profile of dimethyl fumarate (DMF) for multiple sclerosis (MS) is not fully understood.

Objective: To systematically review the literature for adverse events (AE) associated with DMF for MS.

Methods: We searched MEDLINE, EMBASE, CINAHL, Web of Science, CENTRAL, and clinicaltrials.gov for articles published from database inception to May/2019. Studies (observational and randomized controlled trials (RCTs)) reporting AEs, serious AEs (SAE), or discontinuation due to AEs were included. We summarized the proportion of DMF-exposed patients affected and calculated the risk ratios (RR) and number needed to treat for an additional harmful outcome (NNTH) and 95% confidence intervals (CI) for the DMF relative to placebo-exposed participants. RCT findings were pooled via meta-analyses.

Results: Twenty-one observational studies, 4 RCTs, 1 RCT extension study, and 2 open-label studies were included, totalling 12,380 MS patients on DMF followed for an average of 19.8 months. Compared to placebo, DMF-exposed patients had a higher risk of grade III/IV lymphopenia (NNTH = 28.8;95%CI:20.2-50.5), pruritus (NNTH = 22.1;95%CI:14.0-52.3), flushing (NNTH = 3.7;95%CI:3.3-4.1), gastrointestinal related events (NNTH = 5.7;95%CI:3.5-15.7), nausea (NNTH = 23.4;95%CI:14.9-54.7), diarrhea (NNTH = 21.2;95%CI:13.6-47.6), and abdominal pain (NNTH = 19.2;95%CI:12.9-37.9). Patients discontinued DMF because of GI symptoms (498/5619;8.9%), lymphopenia (163/4003;4.1%), and flushing (173/4779;3.6%). From pooled analyses of 4 RCTs, AE risks were higher in the DMF versus placebo groups (RR = 1.37;95%CI:1.27-1.48), but SAEs were similar (RR = 1.01;95%CI:0.77-1.33).

Conclusion: Over the short-term, DMF was associated with a higher risk of AEs. The NNTH included 4 for flushing, 6 for gastrointestinal complaints, and 29 for severe or life-threatening (grade III/IV) lymphopenia. The longer-term safety of DMF, including consequences of lymphopenia remain unknown.

Keywords: Adverse events; Dimethyl fumarate; Meta-analysis; Multiple sclerosis; Safety; Systematic review.

Publication types

Meta-Analysis
Systematic Review

MeSH terms

Dimethyl Fumarate* / adverse effects
Humans
Multiple Sclerosis* / drug therapy

Substances

Dimethyl Fumarate