The B-cell–depleting drug rituximab was associated with a twofold increased risk for infection in patients with relapsing-remitting multiple sclerosis (RRMS), regardless of treatment duration or whether patients had received other disease-modifying therapy (DMT) or had a short disease duration.
"We found an approximately doubled risk of serious infections with rituximab compared with other DMTs, regardless if used first line or as an escalation or switch agent, where the magnitude of risk increase appears to be stable over exposure time," wrote researchers led by Thomas Frisell, PhD, Karolinska Institutet, Stockholm, Sweden.
"These findings underscore an important safety concern with B-cell depletion in RRMS, being evident also in individuals with shorter disease duration and no previous DMT exposure, in turn, motivating the application of risk mitigation strategies," the investigators wrote.
The study was published online on May 14 in the Journal of Neurology, Neurosurgery & Psychiatry.
Rapid Treatment Advances
The treatment landscape of MS has "evolved drastically over the last decade," with the introduction of increasingly effective DMTs, the researchers noted.
However, although new treatment options offer stronger suppression of MS inflammatory disease activity than old DMTs, they may also be associated with treatment-related risks — particularly infection.
The same investigators previously conducted a nationwide cohort study that reported an increased risk for hospital-treated infection with rituximab, a cancer drug that is used off-label for MS, and compared it with older platform self-injected MS DMTs.
In the current study, which had longer follow-up time, the investigators wanted to "refine risk estimates — particularly to what extent treatment time and history impacted infection risk with B-cell depletion."
The Swedish MS registry study included 4694 individuals aged 18 years or older with RRMS (n = 5999) who initiated rituximab treatment from January 1, 2012, to June 30, 2021. Infection rates in this group were compared with those of 6049 patients treated with other DMTs and 20,308 age- and sex-matched MS-free control participants who were included to further benchmark infection rates.
Patients treated with DMTs other than rituximab experienced a dramatically higher rate of inpatient-treated infections than control participants (10.4; 95% CI, 8.1-12.9, per 1000 person years vs 6.6; 95% CI, 6.0-7.2, per 1000 person years). Infection rates with rituximab were even higher at 22.7 (95% CI, 18.5-27.5, per 1000 person years).
Results revealed similar patterns for outpatient infections and antibiotic prescriptions. Moreover, infection rates with rituximab did not vary with first- vs later-line treatment, the type of DMT used before switching to rituximab, or exposure time.
Most of the findings remained similar in a sensitivity analysis that censored follow-up on February 29, 2020, to exclude a potential bias introduced by the COVID-19 pandemic.
'Important Information'
Although the incidence rates for serious infections were somewhat reduced and rates of antibiotic prescriptions increased, the differences between rituximab and the other DMTs remained similar. No differences in the incidence rate of serious or outpatient-treated infections, by the duration of rituximab exposure, were deemed statistically significant.
A second sensitivity analysis restricted the study population of the rituximab switch cohort only to individuals with ≥ 1 year of exposure to the previous therapy, but the findings remained largely unchanged.
"Contrary to our expectations, we did not detect any meaningful differences between treatment-naive and previously treated PwMS [people with MS] neither at the group level nor with specific prior DMTs, although there was a trend for lower risk with a switch to rituximab from injectables than highly effective DMTs," the authors wrote.
The study's limitations included lack of data on tobacco-smoking status, although Sweden has a "very low rate" of daily smokers, so the impact is "likely to be small." The researchers also did not analyze cumulative dose or dosing intervals, although a "large majority" could be expected to have been exposed to biannual infusions with 500 mg of rituximab, at least until the outbreak of COVID-19.
Lastly, they did not have access to laboratory data so were unable to include immunoglobulin levels or lymphocyte counts to potentially identify relevant subgroups among rituximab-exposed people varying in infection risk.
Nevertheless, they believe the findings provide "important information for patients and treating neurologist in discussions of the benefit-risk balance with different treatment strategies," they stated. "In parallel, additional efforts should be made to further develop risk mitigation strategies to diminish treatment-related risks with anti-CD20 therapies."
The research was partially funded through a Patient-Centered Outcomes Research Institute Award. Further funding included grants from the Swedish Research Council, Stockholm County, the Swedish Brain Foundation, and Neuro Sweden. Frisell reported no relevant financial relationships. The other authors' disclosures are listed in the original paper.
Batya Swift Yasgur, MA, LSW, is a freelance writer with a counseling practice in Teaneck, New Jersey. She is a regular contributor to numerous medical publications, including Medscape Medical News and WebMD, and is the author of several consumer-oriented health books as well as Behind the Burqa: Our Lives in Afghanistan and How We Escaped to Freedom (the memoir of two brave Afghan sisters who told her their story).