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Largest Study of Infection Rates in MS Confirms Higher Risk of Newer Agents

Article In Brief

An analysis of data from a nationwide registry suggests that the newer multiple sclerosis drugs are associated with higher risks of infection. It also suggests that “vigilance and early treatment” could mitigate these increased risks.

For patients with multiple sclerosis (MS), risk of infection leading to hospitalization is higher for those taking the newer, most aggressive therapies, and rituximab is associated with the highest risk, according to a JAMA Neurology study of over 6000 Swedish MS patients.

Using data from a nationwide registry, the study provides physicians with a broader picture of treatment-related infection risk than has emerged from clinical trials.

“Patients who are elderly or who have comorbidities are usually excluded from clinical trials over concern for excess adverse events, but in the clinic, those patients also need treatment,” said lead study author Thomas Frisell, PhD, associate professor of epidemiology and a coordinator of clinical epidemiology at the Karolinska Institute in Stockholm, Sweden.

“The underlying disease in these patients may not be more severe, but they may be at higher risk of infection than those in clinical trials.”

Increased rates of infection in MS have long been recognized, Dr. Frisell said, including in clinical trials. “Since all MS drugs are immunomodulatory, they will in some way reduce the function of the subject's immune system and are likely to increase the susceptibility to infection.”

Study Details

To explore the relative risk of different agents in MS treatment, Dr. Frisell and colleagues linked data in the Swedish MS registry, which covers approximately 80 percent of Swedish MS patients, to national health care and census data. They included patients who began treatment with interferon beta, glatiramer acetate, fingolimod, natalizumab, or rituximab between 2011 and 2017. Because previous studies have shown that the relative risks of glatiramer acetate and interferon-beta are about equal, these two agents were grouped together for purposes of comparison with each of the others. Those receiving treatment with more than one drug were counted in each group.

Health records were used to identify patients who were hospitalized for infections, the main outcome measure of the study. Adjustments were made for age, sex, country of birth, previous hospitalizations, number of previous MS medications, and a variety of other factors.

The study included 6421 patients, who collectively commenced a new treatment during the study period 8600 times. The mean age at start of treatment was 39 years, and 72 percent of the patients were female. There were 2217 initiations of interferon beta and glatiramer acetate, 1535 of fingolimod, 1588 of natalizumab, and 3260 of rituximab, Dr. Frisell said. The total average time on each drug within the group ranged from 2.0 years for rituximab to 2.7 years for fingolimod.

The large number of patients treated with rituximab in Sweden is partly due to the interest in the Swedish neurologic community about the positive results of a phase 2 trial of the drug, Dr. Frisell noted. While the manufacturer, Genentech, declined to pursue further development, neurologists continued to use it off-label, and shared their enthusiasm about its benefits with colleagues.

“It just took off,” he said. But because it is not approved for MS in that country, there has been “a huge national debate about it in Sweden.” It is not used to the same extent in the United States, although it is on the formulary list of at least one major insurer, Kaiser Permanente.

Infections occurred in 4.1 percent of the group as a whole, compared with 2.3 percent of the general population. “We found that patients with MS are at increased risk of infection, and that in itself is an important reminder,” Dr. Frisell said.

The hospitalization incidence rate per 1000 person-years was 8.9 for glatiramer acetate/interferon beta (“the injectables”), 14.3 for fingolimod, 11.4 for natalizumab, and 19.7 for rituximab. After adjusting for age and sex, when compared to the injectables, the hazard ratio was 1.81 for fingolimod, 1.53 for natalizumab, and 2.34 for rituximab. After multiple other adjustments, the respective hazard ratio were 1.30, 1.12, and 1.70, but the 95% confidence intervals crossed 1 for both fingolimod and natalizumab, while remaining entirely above 1 for rituximab.

This elevation of risk for newer, more powerful immunomodulatory therapies “is in line with previous literature,” Dr. Frisell said, especially a recent Canadian study showing a greater infection risk (not just those leading to hospitalizations) among MS patients taking natalizumab and fingolimod versus the injectables.

Herpes infections were an exception to the pattern in Dr. Frisell's study, with higher risks for both fingolimod and natalizumab compared with rituximab. “This finding deserves more study, and should be taken into account in treatment,” he said.

Overall, he added, and taking other large studies into account, “the safety of the injectables may be better than the newer treatments. The risks are not enormous, and with some vigilance and early treatment, it is possible to mitigate these increased risks.”

Expert Commentary

“Observational studies like this are very important” for understanding the impact of treatment in the general MS community, commented Helen Tremlett, PhD, professor and Canada Research Chair in Neuroepidemiology and Multiple Sclerosis at the University of British Columbia in Vancouver.

Dr. Tremlett was the lead author of the study on Canadian MS patients. That study, of 6793 MS patients, of whom 1716 received a disease-modifying therapy, showed that infection-related physician or hospital claims were not increased by exposure to the injectables relative to no disease-modifying therapy, but were higher in those patients receiving natalizumab or an oral therapy, such as fingolimod.

“These studies are complementary,” Dr. Tremlett said, “and the bottom line is still the same: People with MS are generally at increased risk of infections, most of which are bacterial, and that risk seems to differ by treatment. It is a complicated picture because we have so many drugs, and these kinds of studies can help us practice better evidence-based treatment.”

Aimee Borazanci, MD, faculty physician at the Barrow Neurological Institute in Phoenix, commented that the results coincide with her clinical observations that the injectables appear to be more trouble-free. However, she noted they contradicted her own experience with rituximab, which in her practice has been less commonly associated with infection compared to fingolimod or natalizumab.

“But I think we all know that any MS patients on any of these medications will have a higher risk of infection, and in that respect the results are an important confirmation,” Dr. Borazanci said. “One value of this study is that it provides data from a very large cohort that we can use when we talk to patients about which medications to choose.”

Myla Goldman, MD, chair of the division of multiple sclerosis and general neurology at Virginia Commonwealth University, called the new work “a very interesting study that highlights the real-world impact of these therapies,” which may help physicians make decisions about risk. While rituximab is not widely used in the US, she noted, it has the same mechanism of action—blocking CD-20—as ocrelizumab, and that drug has begun to be used extensively as a first-line treatment.

“Ocrelizumab is the only medication approved for primary progressive MS, and these patients as a group tend to be older, and may have more comorbidities,” she noted. If the data on rituximab is relevant to ocrelizumab, “that potentially means that patients treated with ocrelizumab are also at a higher risk of infection, relative to some of these other agents.

“Safety, including the risk for infection, has to be part of the conversation,” she said. “That has never been more relevant than it is today in the shadow of a viral pandemic. When I talk to patients about medication selection, safety is on an equal footing with efficacy.”

Importantly, Dr. Tremlett noted that these studies mainly focused on bacterial infections (not viral) and were published between 2017 and 2019. She stressed that people with MS should not stop taking their disease-modifying drugs without consulting with their treating neurologist.

She cited some MS-specific resources related to the current COVID-19 situation from the US National MS Society——and from the Multiple Sclerosis International Federation,


Drs. Frisell and Tremlett had no competing interests. Dr. Borazanci has received fees for the speakers bureaus of Biogen, Genentech, and Genzyme, and consulting fees from EMD Serono.

Link Up for More Information

• Luna G, Alping P, Burman J, et al. Infection risks among patients with multiple sclerosis treated with fingolimod, natalizumab, rituximab, and injectable therapies JAMA Neurol 2020;77(2):184–191.
• Wijnands JMA, Zhu F, Kingwell E, et al. Disease-modifying drugs for multiple sclerosis and infection risk: a cohort study J Neurol Neurosurg Psychiatry 2018;89(10):1050–1056.