A recently published study in Neurology comprising more than 25 years of data revealed key insights to the safety profile of several disease-modifying drugs (DMDs) used to treat multiple sclerosis (MS) in a real-world setting. The findings not only complimented those observed in short-term clinical trials but also provided new insights that help inform the risk-benefit profiles of the DMDs used in clinical practice.1
Senior author Helen Tremlett, PhD, professor of neurology at the University of British Columbia, and colleagues assessed potential adverse events (AEs) of 7 DMDs: ß-interferon, glatiramer acetate, natalizumab, fingolimod, dimethyl fumarate, teriflunomide, and alemtuzumab. Derived from 4 Canadian provinces, the real-world data included MS cases that were followed from the first recent MS or related demyelinating event on January 1, 1996, until the earliest emigration, death, or December 31, 2017.
The analysis included 35,894 patients with MS who were followed up for a mean of 12.0 (SD, 7.2) years. Current exposure to DMDs was associated with a lower hazard of infection-related hospitalizations, ranging from 42% (aHR, 0.58; 95% CI, 0.50-0.67) to 61% (aHR, 0.39; 95% CI, 0.16-0.94). By contrast, there was a modest increase in infection-related physician visits for any second-generation DMD (by 11%; 95% CI, 4%-17%), and for some individual DMDs, ranging from a 33% (95% CI, 13%-58%) higher hazard for alemtuzumab to 10%-13% for dimethyl fumarate (95% CI, 4%-18%) and fingolimod (95% CI, 3%-25%). Beta-interferon was the only DMD associated with a lower hazard in both health care settings, albeit only modestly for infection-related physician visits (aHR, 0.94; 95% CI, 0.90-0.99).
In terms of incident AEs, fingolimod was the only DMD associated with an increased hazard of ischemic heart disease (aHR, 1.64; 95% CI, 1.10-2.44; crude rate per 1000 person-years [CR], 15.60) and cerebrovascular disease (aHR, 2.04; 95% CI, 1.27-3.30; CR, 10.01). Only alemtuzumab was associated with a significantly higher hazard of chronic kidney disease (aHR, 6.43; 95% CI, 2.60-15.95; <6 cases), while teriflunomide was associated with a significantly higher hazard of chronic liver disease (aHR, 1.94; 95% CI, 1.19-3.18; CR, 11.51) and hyperlipidemia (aHR, 1.61; 95% CiI, 1.07-2.44; CR, 23.92).
Clinical Takeaways
Study Duration:
- The research spanned over 25 years, providing a comprehensive understanding of disease-modifying drugs (DMDs) used to treat multiple sclerosis (MS).
DMDs Examined:
- The study assessed seven DMDs: ß-interferon, glatiramer acetate, natalizumab, fingolimod, dimethyl fumarate, teriflunomide, and alemtuzumab.
Infection-Related Hospitalizations:
- Current exposure to DMDs was associated with a lower hazard of infection-related hospitalizations, ranging from 42% to 61%, emphasizing a positive impact on immune-related outcomes.
Cardiovascular and Other Risks:
- Fingolimod was linked to an increased hazard of ischemic heart disease and cerebrovascular disease. Alemtuzumab showed a higher risk of chronic kidney disease, while teriflunomide was associated with chronic liver disease and hyperlipidemia.
Hypertension and Mental Health:
- Several DMDs, including alemtuzumab, teriflunomide, fingolimod, and beta-interferon, were associated with an increased hazard of hypertension. Glatiramer acetate and natalizumab increased the hazard of mental health conditions.
Two DMDs were associated with increased risk for thyroid disorders; however, the risk was significantly higher hazard for alemtuzumab (19.42; 95% CI, 9.29-36.51; CR, 36.72) than teriflunomide (2.30; 95% CI, 1.11-4.74; CR, 5.21). The study authors wrote, "Although routine thyroid function testing (before initiation of alemtuzumab and every 3 months thereafter) is recommended, clinicians may wish to consider assessing risk factors for heart diseases, particularly given our observed high crude rate of cardiovascular disorders associated with alemtuzumab (58.92/1,000 person-years) relative to no DMD (25.55)."
A higher hazard for hypertension was observed in alemtuzumab (4.96; 95% CI, 1.78-13.84; <7 cases), teriflunomide (1.76; 95% CI, 1.32-2.37; CR, 42.50), fingolimod (1.73; 95% CI, 1.30-2.31; CR, 31.92), and beta-interferon (1.11; 95% CI, 1.04-1.17; CR, 30.39). Both glatiramer acetate and natalizumab increased the hazard of a mental health condition by 1.16 (95% CI, 1.07-1.26; CR, 85.81) and 1.36 (95% CI, 1.06-1.76; CR, 100.59), respectively.
Glatiramer acetate alone was associated with a lower hazard of hypertension (aHR, 0.87; 95% CI, 0.80-0.95; CR, 25.36) while both glatiramer acetate (aHR, 0.78; 95% CI, 0.65-0.94; CR, 4.61) and dimethyl fumarate (aHR, 0.43; 95% CI, 0.22-0.84; CR, 2.51) were associated with lower hazard of cerebrovascular diseases. No significant differences were observed between individual DMDs and the hazard of autoimmune diseases, cancer, diabetes, or migraine.
REFERENCE
1. Hg HS, Zhu F, Zhao Y, et al. Adverse events associated with disease-modifying drugs for multiple sclerosis: a multiregional population-based study. Neurology. 2024;102(3). doi:10.1212/WNL.000000000000208006
