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Safety of dimethyl fumarate for multiple sclerosis: A systematic review and meta-analysis
Geoffrey Liang1, Julia Chai2, Huah Shin Ng3
1Faculty 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.
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.
Insights
Dimethyl fumarate (DMF) increases risks for adverse events like flushing and lymphopenia in multiple sclerosis (MS) patients short-term. Longer-term safety and lymphopenia consequences require further investigation.
Area of Science:
- Neurology
- Pharmacology
- Clinical Research
Background:
- The safety of dimethyl fumarate (DMF) for treating multiple sclerosis (MS) requires comprehensive evaluation.
- Existing data on adverse events (AEs) associated with DMF in MS patients is limited.
Purpose of the Study:
- To systematically review and synthesize available literature on adverse events (AEs) linked to DMF use in MS.
- To quantify the risk of specific AEs and treatment discontinuations due to AEs associated with DMF.
Main Methods:
- A comprehensive literature search was conducted across multiple databases (MEDLINE, EMBASE, etc.) up to May 2019.
- Included observational studies and randomized controlled trials (RCTs) reporting AEs, serious AEs (SAEs), or discontinuations.
- Meta-analyses were performed on RCT data to calculate risk ratios (RR) and number needed to treat for harmful outcomes (NNTH).
Main Results:
- 12,380 MS patients on DMF were analyzed; compared to placebo, DMF increased risks of lymphopenia, pruritus, flushing, and gastrointestinal events.
- NNTH values indicated a higher risk for flushing (3.7), GI complaints (5.7), and grade III/IV lymphopenia (28.8).
- Discontinuations were primarily due to GI symptoms (8.9%), lymphopenia (4.1%), and flushing (3.6%); overall AE risk was higher with DMF (RR=1.37), but SAE risk was similar.
Conclusions:
- Short-term DMF use in MS is associated with an increased incidence of adverse events, particularly flushing, GI issues, and lymphopenia.
- The number needed to treat for harmful outcomes highlights specific risks, such as flushing and severe lymphopenia.
- Long-term safety data for DMF, especially concerning the effects of lymphopenia, remains undetermined.
