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Adverse Events Associated With Disease-Modifying Drugs for Multiple Sclerosis: A Multiregional Population-Based Study
Huah Shin Ng1, Feng Zhu1, Yinshan Zhao1
1From the Division of Neurology (H.S.N., F.Z., Y.Z., H.T.), Department of Medicine and the Djavad Mowafaghian Centre for Brain Health, University of British Columbia, Vancouver, Canada; Flinders Health and Medical Research Institute (H.S.N.), College of Medicine and Public Health, Flinders University, Adelaide, Australia; SA Pharmacy (H.S.N.), Northern and Southern Adelaide Local Health Networks, Australia; College of Pharmacy and Nutrition (S.Y., C.E.), University of Saskatchewan; Saskatchewan Health Quality Council (S.Y., X.L.), Saskatoon; Department of Community Health Sciences (O.E.), Rady Faculty of Health Sciences, University of Manitoba, Winnipeg; Nova Scotia Health and the Departments of Psychiatry, Psychology and Neuroscience, and Medicine (J.D.F.), Dalhousie University, Halifax; and Departments of Internal Medicine and Community Health Sciences (R.A.M.), Max Rady College of Medicine, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, Canada.
Background And Objectives:
It is not possible to fully establish the safety of a disease-modifying drug (DMD) for multiple sclerosis (MS) from randomized controlled trials as only very common adverse events occurring over the short-term can be captured, and the quality of reporting has been variable. We examined the relationship between the DMDs for MS and potential adverse events in a multiregion population-based study.
Methods:
We identified people with MS using linked administrative health data from 4 Canadian provinces. MS cases were followed from the most recent of first MS or related demyelinating disease event on January 1, 1996, until the earliest of emigration, death, or December 31, 2017. DMD exposure primarily comprised β-interferon, glatiramer acetate, natalizumab, fingolimod, dimethyl fumarate, teriflunomide, and alemtuzumab. We examined associations between DMD exposure and infection-related hospitalizations and physician visits using recurrent events proportional means models and between DMD exposure and 15 broad categories of incident adverse events using stratified multivariate Cox proportional hazard models.
Results:
We identified 35,894 people with MS. While virtually all DMDs were associated with a 42%-61% lower risk of infection-related hospitalizations, there was a modest increase in infection-related physician visits by 10%-33% for select DMDs. For incident adverse events, most elevated risks involved a second-generation DMD, with alemtuzumab's hazard of thyroid disorders being 19.42 (95% CI 9.29-36.51), hypertension 4.96 (95% CI 1.78-13.84), and cardiovascular disease 3.72 (95% CI 2.12-6.53). Natalizumab's highest risk was for cardiovascular disease (adjusted hazard ratio [aHR] 1.61; 95% CI 1.24-2.10). For the oral DMDs, fingolimod was associated with higher hazards of cerebrovascular (aHR 2.04; 95% CI 1.27-3.30) and ischemic heart diseases (aHR 1.64; 95% CI 1.10-2.44) and hypertension (aHR 1.73; 95% CI 1.30-2.31); teriflunomide with higher hazards of thyroid disorders (aHR 2.30; 95% CI 1.11-4.74), chronic liver disease (aHR 1.94; 95% CI 1.19-3.18), hypertension (aHR 1.76; 95% CI 1.32-2.37), and hyperlipidemia (aHR 1.61; 95% CI 1.07-2.44); and from complementary analyses (in 1 province), dimethyl fumarate with acute liver injury (aHR 6.55; 95% CI 1.96-21.87).
Discussion:
Our study provides an extensive safety profile of several different DMDs used to treat MS in the real-world setting. Our findings not only complement those observed in short-term clinical trials but also provide new insights that help inform the risk-benefit profile of the DMDs used to treat MS in clinical practice. The results of this study highlight the continued need for long-term, independent safety studies of the DMDs used to treat MS.
Classification Of Evidence:
This study provides Class III evidence that for patients with MS, while DMD exposure reduces the risk of infection-related hospitalizations, there are increased risks of infection-related physician visits and incident adverse events for select DMDs.
Insights
Disease-modifying drugs (DMDs) for multiple sclerosis (MS) reduce infection hospitalizations but may increase infection-related doctor visits and other adverse events. Real-world data offers crucial long-term safety insights beyond clinical trials.
Area of Science:
- Pharmacovigilance and Pharmacoepidemiology
- Neurology and Clinical Therapeutics
- Public Health and Health Services Research
Background:
- Randomized controlled trials (RCTs) have limitations in fully assessing the long-term safety of disease-modifying drugs (DMDs) for multiple sclerosis (MS).
- Short-term adverse events captured in RCTs may not reflect the full spectrum of risks associated with DMDs.
- Variability in reporting adverse events in clinical trials necessitates real-world safety evaluations.
Purpose of the Study:
- To examine the association between DMD exposure and potential adverse events in a large, multi-region, population-based cohort of individuals with MS.
- To establish a comprehensive real-world safety profile for various DMDs used in MS treatment.
- To inform clinical practice by providing insights into the risk-benefit profiles of different MS therapies.
Main Methods:
- Utilized linked administrative health data from four Canadian provinces to identify and follow 35,894 individuals with MS.
- Employed recurrent events proportional means models to assess associations between DMD exposure and infection-related hospitalizations/physician visits.
- Used stratified multivariate Cox proportional hazard models to evaluate associations between DMD exposure and 15 categories of incident adverse events.
Main Results:
- Most DMDs were associated with a significant reduction (42%-61%) in infection-related hospitalizations, but some showed a modest increase (10%-33%) in infection-related physician visits.
- Elevated risks for specific adverse events were observed with certain DMDs, including alemtuzumab (thyroid disorders, hypertension, cardiovascular disease), natalizumab (cardiovascular disease), fingolimod (cerebrovascular, ischemic heart diseases, hypertension), and teriflunomide (thyroid disorders, liver disease, hypertension, hyperlipidemia).
- Dimethyl fumarate showed an association with acute liver injury in complementary analyses.
Conclusions:
- This population-based study provides an extensive real-world safety profile for multiple DMDs used in MS treatment.
- Findings complement RCT data, offering new insights into the risk-benefit profiles of DMDs in clinical practice.
- Highlights the ongoing need for long-term, independent safety studies of DMDs for MS.
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