Infection Risk Associated With MS Therapies Varies


This is the first study to compare infection risk with rituximab alongside other highly effective disease-modifying therapies.

Dr Thomas Frisell

Thomas Frisell, PhD, coordinator of the Clinical Epidemiology Unit, Karolinska Institutet

Thomas Frisell, PhD

New national study results show that patients with multiple sclerosis (MS) may face a general elevated risk for infections, which is partially dependent on their choice of disease-modifying therapy (DMTs). This is the first study to compare infection risk with rituximab treatment as well as other highly effective DMTs.

Ultimately, the use of injectable therapies such as interferon beta and glatiramer acetate was associated with the lowest rate of infections, while those taking rituximab experienced the highest rate of infections. In total, the cohort included 6421 patients with MS.

“Per the results of this study, physicians and patients should be aware of infection risks associated with newer multiple sclerosis treatments and perhaps particularly anti-CD20 therapies,” study author Thomas Frisell, PhD, coordinator of the Clinical Epidemiology Unit, Karolinska Institutet, and colleagues wrote.

The full cohort consisted of patients receiving rituximab (n = 3260), natalizumab (n = 1588), fingolimod (n = 1535), and interferon beta/glatiramer acetate (n = 2217), plus a comparator cohort of 42,645 individuals. Of the treated cohort, 8600 treatment episodes were recorded. The mean age at treatment initiation ranged from 35 years (standard deviation [SD], 10.1) to 40.4 years (SD, 10.6).

The rate of all infections was substantially higher in all MS cohorts than in the general population--a difference that endured post-adjustment (hazard ratio [HR], 0.65; 95% CI, 0.47—0.89). Notably, this was more pronounced with hospitalized infections. Compared to the general population, who had a rate of 5.2 (95% CI, 4.8–5.5) infections per 1000 person-years, the crude rate of infections was higher in those taking interferon beta/glatiramer acetate, with an incidence rate of 8.9 (95% CI, 6.4–12.1). The infection rate in patients taking fingolimod, natalizumab, and rituximab was even higher, at rates of 14.3 (95% CI, 10.8–18.5), 11.4 (95% CI, 8.3–15.3) and 19.7 (95% CI, 16.4–23.5) per 1000 person-years, respectively.

“This nationwide cohort study is, to our knowledge, the largest observational study investigating the risks for infection associated with different DMTs in patients with MS,” Frisell and colleagues noted. “These data provide further support for previous reports that patients with MS are at a generally increased risk of infections, as well as some support for an increased risk of infections in high-efficacy DMTs compared with injectable therapies.”

After adjusting for confounders, the rates of infection remained significantly elevated for patients on rituximab (HR, 1.70; 95% CI, 1.11—2.61). Rates for fingolimod (HR, 1.30; 95% CI, 0.84–2.03) and natalizumab (HR, 1.12; 95% CI, 0.71–1.77) were also elevated, but not to the point of statistical significance compared with interferon beta/glatiramer acetate.

In comparison to rituximab, the rate of serious infection was 34% lower for those receiving natalizumab (HR, 0.66; 95% CI, 0.45—0.97) and 23% lower for those receiving fingolimod (HR, 0.77; 95% CI, 0.54–1.09); only the natalizumab difference was statistically significant.

“This study also highlights the potentially different risk profiles of rituximab vs fingolimod and natalizumab, with rituximab being associated with a higher risk of serious infections but lower risk of herpetic infections,” the authors wrote. The use of herpes antiviral drugs during rituximab treatment was comparable to that of interferon beta/glatiramer acetate and lower than those seen in natalizumab treatment (HR, 1.82; 95% CI, 1.34—2.46) and fingolimod (HR, 1.71; 95% CI, 1.27–2.32).

Rituximab and natalizumab were associated with the highest rates of antibiotic use, with rates ranging from 15% to 18% lower with fingolimod and interferon beta/glatiramer acetate compared with rituximab. When adjusting for potential confounders, this rate remained “mostly unchanged” according to the authors (fingolimod: HR, 0.86; 95% CI, 0.76-0.97; interferon beta/glatiramer acetate: HR, 0.81; 95% CI, 0.71-0.92).

In total, 2 cases of progressive multifocal leukoencephalopathy (PML), 1 in the fingolimod subgroup and 1 the rituximab subgroup, were reported. Both cases featured patients who had switched from natalizumab within 6 months of PML diagnosis. No deaths were recorded with an infection as the underlying cause.

“These findings should be considered in the risk-benefit assessment of MS therapies, and further monitoring is important to better assess long-term risks,” Frisell and colleagues concluded.


Luna G, Alping P, Burman J. Infection Risks Among Patients With Multiple Sclerosis Treated With Fingolimod, Natalizumab, Rituximab, and Injectable Therapies. JAMA Neurol. Published online October 7, 2019. doi:10.1001/jamaneurol.2019.3365.

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