Gaps in Observational Data Challenge Understanding of Infection Risk in MS Treatments

Infections are a significant concern for people living with multiple sclerosis (MS) who receive disease-modifying treatments (DMTs).1 Although clinical trials have documented some infection risks, those studies have often excluded older individuals, people with comorbidities, and those with long disease histories.

A systematic review published in Neurological Sciences found that real-world evidence on this safety issue remains limited, with inconsistent findings compared with randomized trial data. | Image credit: sdecoret - stock.adobe.com

A recent systematic review published in Neurological Sciences found that real-world evidence on this safety issue remains limited, with inconsistent findings compared with randomized trial data.

The Multiple Sclerosis International Federation claims that about 2.9 million people globally live with MS, and the prevalence of the disease has gone up dramatically since 2013 (2.3 million), which has often been attributed to improved diagnostic techniques and longer lifespans of people with MS.2

Researchers from Utrecht University and Amsterdam University Medical Center analyzed observational studies published through April 2023 that compared at least 1 DMT with another or with no therapy, focusing specifically on infection outcomes.1 After screening more than 5300 records from PubMed and Embase, 22 studies met the inclusion criteria. Together, these studies examined 9 therapies, including interferon-β, glatiramer acetate, dimethyl fumarate, fingolimod, natalizumab, ocrelizumab, alemtuzumab, cladribine, and teriflunomide.

The review covered diverse populations. One large Canadian cohort included 6793 people with MS (mean age, 45.4 years; 73.6% women), with 25% exposed to at least 1 DMT. A Swedish registry-based analysis followed 6421 individuals across 8600 treatment episodes, with a mean age of 39 years and 72% women. Follow-up times varied widely, ranging from 1 year to more than a decade.

Despite the breadth of data, the researchers emphasized how limited the evidence base remains. Only 5 of the 22 studies reported relative risks of infection, with the others presenting incidence rates or raw counts of infectious events. Out of 45 possible treatment contrasts, 9 had never been studied and 19 had been assessed only once. “Observational study data on the risk of infection in people with MS on DMT are sparse,” the authors wrote.

Natalizumab was the most frequently studied therapy, with 27 contrasts across 12 studies. Fingolimod followed closely, with 26 contrasts across 15 studies. The most commonly assessed infection types included neurological infections—often progressive multifocal leukoencephalopathy—respiratory infections, and urinary tract infections. However, only 1 study reported a relative risk for respiratory infections, and no observational studies offered risk estimates for common conditions such as urinary tract infections, despite their known burden in the MS population.

Importantly, observational findings did not always align with trial evidence. For example, data from real-world studies suggested that natalizumab was associated with higher risk of respiratory and urinary tract infections compared with no treatment. By contrast, trial data showed the opposite, although the differences were not statistically significant. The authors suggested that the discrepancies may reflect broader inclusion criteria in observational studies, where older patients, individuals with comorbidities, and those switching therapies are more likely to be represented.

The review also found concerns about study quality. Of the 5 studies that reported relative risks, 3 were judged to have a moderate risk of bias and 2 a serious risk of bias, primarily due to confounding. This, combined with heterogeneous definitions of infection across studies, limited the strength of the overall conclusions.

Still, the authors argued that real-world research offers important opportunities. Observational studies can capture long-term safety outcomes and rare but severe infections that are difficult to study in trials. They can also provide insight into how treatment sequencing and patient characteristics affect infection risk.

“The growing availability of real-world data on MS and DMT use provides an opportunity to study specific infections on DMT, which is particularly valuable to populations underrepresented in trials,” the authors concluded.

References

1. Leung MWY, Van de Garde EMW, Uitdehaag BMJ, Klungel OH, Bazelier MT. The relative risk of infection in people with multiple sclerosis using disease-modifying treatment: a systematic review of observational studies. Neurol Sci. 2025;46(2):2555-2569. doi:10.1007/s10072-025-08018-9

2. Number of people with MS. MS International Federation’s Atlas of MS. Accessed August 21, 2025. https://atlasofms.org/map/global/epidemiology/number-of-people-with-ms