Newer disease-modifying treatments for multiple sclerosis (MS) are effective but also known to carry a greater risk of infections in a patient group already more likely to be troubled by infections — and this higher risk is particularly evident in treatment with rituximab, a DMT often used off-label in Sweden, a nationwide study into its use reports.
The study “Infection Risks Among Patients With Multiple Sclerosis Treated With Fingolimod, Natalizumab, Rituximab, and Injectable Therapies” was published in the journal Jama Neurology.
Compared to the public at large, MS patients are thought to be at an increased risk of infections, because disease-modifying therapies used to lower relapse rates act by dampening the immune system. Although helpful, such therapies can raise a risk of subsequent infections.
Evidence suggests that treatment with first-generation DMTs, such as beta-interferon (sold as Avonex and Rebif, among others) or glatiramer acetate (Copaxone and its generic, Glatopa), do not raise this infection risk further. In contrast, newer, second-generation DMTs are linked to a greater infection risk. These DMTs include Tysabri (natalizumab) and Gilenya (fingolimod).
However, “the magnitude of potential risk increase is not well established in real-world populations,” the researchers wrote, as this evidence has largely been gathered in clinical trials.
Moreover, few data are available regarding the risk of infection with rituximab, an engineered antibody developed by Roche to specifically target the cell surface protein CD20 often found in immune B-cells. Rituximab is sold under the brand name Rituxan in the U.S. and MabThera in Europe, among others, approved largely to treat certain blood cancers. It is used off-label in MS, meaning it is not approved specifically for this disease.
Researchers in Sweden performed a nationwide observational study to better determine actual infection rates among Swedish MS patients being treated with rituximab, Tysabri, Gilenya, Copaxone, and interferon beta.
They analyzed data from relapsing-remitting MS (RRMS) patients registered in the Swedish MS register (SMSreg), treated between 2011 and 2017. SMSreg covers approximately 80% of all MS patients in Sweden. As controls, researchers evaluated five people without MS for each patient they studied, all matched for age, sex, and region.
In total, data from 6,421 RRMS patients (mean age of 39 at treatment start) were analyzed. During the period, they registered a total of 8,600 treatments — 2,217 initiations of interferon beta and Copaxone, 1,535 starts with Gilenya, 1,588 initiations of Tysabri, and 3,260 of rituximab. The control group consisted of 42 ,645 individuals.
Results showed that, compared to controls, RRMS patients were more often to require a sick leave (28.1% vs 11.0%), use antidepressants (26.8% vs 15.7%), and have more infections (4.1% vs 2.3%) in the five years before treatment start.
Researchers then assessed the impact of each DMT on the risk of serious infections, defined as those requiring hospitalization. They also looked at outpatient treatment with antibiotics or herpes antiviral medications.
The infection incident rate was found to be 5.2 per 1000 person-years (the sum of follow-up years of all included patients in a specific study) in the general population, with RRMS patients in general showing a higher risk of infection in all treatments analyzed. That is, an incidence rate of 8.9 in patients treated with interferon beta and Copaxone, 11.4 in those taking Tysabri, and an incidence rate of 14.3 with Gilenya that rose to 19.7 with use of rituximab.
After adjusting for patients characteristics, like age and disability level, the rate of infections remained significantly higher for rituximab (hazard ratio of 1.70, meaning a 1.7 times higher risk of infection), and higher — but not significantly so — for Gilenya (hazard ratio of 1.30) and Tysabri (hazard ratio 1.12) when compared to use of interferon beta and Copaxone (first-generation DMTs).
Antibiotic use was also found to be greater among patients treated with rituximab and Tysabri. In contrast, use of herpes antivirals was similar among patients given rituximab, interferon beta and Copaxone, but in general their use was lower than that seen with
“This nationwide cohort study found that patients with multiple sclerosis are at a generally increased risk of infections, and this risk is partly dependent on the choice of treatment,” the researchers wrote. “Among newer treatments, off-label use of rituximab was associated with the highest rate of serious infections.”
These findings call attention to the need for physicians and patients to be “aware of infection risks associated with newer multiple sclerosis treatments, and perhaps particularly anti-CD20 therapies” like rituximab, the team suggested.