Real-World Data Reveals Higher Infection Risk with MS Treatments, Particularly Ocrelizumab
Key Insights
A systematic review of 22 observational studies found sparse and inconsistent real-world evidence on infection risks associated with multiple sclerosis (search) disease-modifying treatments compared to clinical trial data.
Real-world study of 2,564 MS (search) patients showed ocrelizumab treatment carried nearly double the risk of serious infections compared to platform injectable therapies (OR = 1.98).
Observational findings often contradicted clinical trial results, with natalizumab showing higher respiratory and urinary tract infection risks in real-world settings versus trials.
Multiple sclerosis (search) patients receiving disease-modifying treatments face significantly higher infection risks in real-world clinical practice than previously documented in clinical trials, according to two new studies that highlight critical gaps in safety data for this vulnerable population.
A comprehensive systematic review published in Neurological Sciences analyzed observational studies covering nine different MS (search) therapies and found that real-world evidence on infection risks remains severely limited, with findings that often contradict randomized trial data. The research comes as the global MS population has grown to approximately 2.9 million people, representing a dramatic increase from 2.3 million in 2013.
Sparse Evidence Base Challenges Clinical Decision-Making
Researchers from Utrecht University and Amsterdam University Medical Center (search) screened over 5,300 records to identify 22 observational studies that met their inclusion criteria. The analysis revealed significant data gaps across the treatment landscape, with only five studies reporting relative risks of infection and 28 out of 45 possible treatment contrasts either never studied or assessed only once.
"Observational study data on the risk of infection in people with MS (search) on DMT are sparse," the authors wrote, emphasizing how limited the evidence base remains despite the critical importance of infection risk assessment.
The studies examined diverse populations, including a large Canadian cohort of 6,793 people with MS (search) (mean age 45.4 years, 73.6% women) and a Swedish registry-based analysis following 6,421 individuals across 8,600 treatment episodes. However, the heterogeneous nature of these studies, with follow-up times ranging from one year to more than a decade, complicated efforts to draw consistent conclusions.
Ocrelizumab Shows Elevated Real-World Infection Risk
A separate real-world analysis presented at ECTRIMS 2025 provided more definitive evidence of elevated infection risks with specific therapies. The retrospective cohort study from the Cleveland Clinic's Mellen Center (search) analyzed 2,564 individuals treated with ocrelizumab compared to 1,336 patients receiving platform injectable therapies.
Dr. Alise K. Carlson, the study's lead investigator, noted that "B-cell (search) depleting therapies are associated with improved control of disease activity and disability prevention in multiple sclerosis (search), but that these treatments may be associated with an increased risk of serious infections over time."
The ocrelizumab cohort experienced 367 serious infections compared to 118 in the matched control group. Patients treated with ocrelizumab faced nearly double the risk of serious infection (OR = 1.98; 95% CI: 1.52-2.59) and had significantly shorter time to first serious infection (HR = 1.86; 95% CI: 1.45-2.39).
Real-World Findings Contradict Trial Data
The systematic review revealed troubling discrepancies between observational studies and clinical trial results. Real-world data suggested natalizumab was associated with higher risks of respiratory and urinary tract infections (search) compared to no treatment, while trial data showed the opposite pattern, though differences were not statistically significant.
These contradictions may reflect the broader inclusion criteria in observational studies, where older patients, individuals with comorbidities, and those switching therapies are more likely to be represented compared to the carefully selected populations in clinical trials.
Study Quality Concerns Limit Conclusions
The systematic review identified significant methodological concerns that undermined the strength of available evidence. Of the five studies reporting relative risks, three were judged to have moderate risk of bias and two had serious risk of bias, primarily due to confounding factors. Additionally, heterogeneous definitions of infection across studies further limited the ability to draw robust conclusions.
Despite these limitations, the authors argued that observational studies offer unique opportunities to capture long-term safety outcomes and rare but severe infections that are difficult to study in controlled trials.
Age and Immunoglobulin Levels Show Limited Impact
The Cleveland Clinic study found no significant differences in serious infection risk among different age groups within the ocrelizumab cohort, including patients aged 55-60 years (OR = 1.11; 95% CI: 0.74-1.65) and those 60 years and older (OR = 1.38; 95% CI: 0.91-2.09).
Surprisingly, hypogammaglobulinemia (search) was not associated with increased risk for serious infections in ocrelizumab-treated patients, with odds ratios of 1.36 for immunoglobulin G and 1.21 for immunoglobulin M, neither reaching statistical significance.
Clinical Implications and Future Research Needs
The infection rate data revealed concerning real-world patterns, with ocrelizumab patients experiencing 4.21 serious infections per 100 person-years compared to 2.64 for those on platform injectable therapies. Dr. Carlson emphasized that "infection risk in real-world patients is higher than those which were reported in the clinical trials of ocrelizumab and in extension studies, with this difference only becoming statistically evident after 1.5 to 2 years."
The findings underscore the critical need for longer-term observational studies to better characterize infection risks across the MS (search) treatment landscape. As the authors of the systematic review concluded, "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."