Ocrelizumab Associated With Nearly Twofold Increase in Serious Infections Vs. Platform Injectables in Multiple Sclerosis

Treatment with the B-cell-depleting therapy ocrelizumab has been shown to result in good control of multiple sclerosis (MS) disease activity and prevent accrual of long-term disability. Patients with long-term exposure to ocrelizumab, however, have a nearly twofold increase in risk of serious infection, although the risk doesn’t rise significantly with advanced age. So finds an observational study from Cleveland Clinic presented at ECTRIMS 2025 in Barcelona, Spain.

“In a large cohort of patients with MS at our center, the risk for serious infection was higher in those treated with ocrelizumab than in those treated with platform injectable therapies,” says Alise Carlson, MD, MSc, a neurologist with Cleveland Clinic’s Mellen Center for Multiple Sclerosis Treatment and Research who presented the results. “Our results align with and build on findings in clinical trials, extension studies and other observational real-world cohorts.”

Backdrop to the research

B-cell-depleting therapy is associated with significantly improved outcomes in the clinical care of individuals with MS. In clinical trials, however, treatment with this drug class has been shown to increase the risk of serious infections. Evidence also suggests that prolonged exposure may be associated with reduced immunoglobulin levels.

The extent of the infection risk in a real-world population of MS patients treated with ocrelizumab has not been well studied. This retrospective Cleveland Clinic study was designed to address that gap by comparing rates of serious infections in patients treated with ocrelizumab versus platform injectable therapies (such as interferon beta and glatiramer acetate) in a real-world population larger and more clinically heterogeneous than the clinical trial populations.

“Getting a handle on the magnitude of the risk is important because ocrelizumab use is increasing as the field has shifted toward early utilization of highly effective disease-modifying therapies,” Dr. Carlson notes, “but exposures in clinical trials are relatively short and typically do not include patients older than age 65.”

Study essentials

Data for the new research came from nearly 3,900 patients treated at Cleveland Clinic’s Mellen Center between March 2017 and December 2023. The comparator groups were 2,551 individuals who received ocrelizumab and 1,307 who received platform injectable therapies. Mean (± SD) treatment duration was 3.38 ± 1.84 years in the overall cohort, 3.34 ± 2.08 years in the platform injectable cohort and 3.40 ± 1.71 years in the ocrelizumab cohort.

“We performed propensity score matching, based on multiple demographic and clinical factors and medical comorbidities, to ensure that the two groups were as similar as possible,” Dr. Carlson explains. “One of the strengths of our study is a large number of participants from various races and ethnicities.”

Subanalyses of the ocrelizumab group were performed to assess the incidence of serious infections among patients in three age groups: < 55 years, 55-60 years and > 60 years. Differences in time from treatment to first serious infection also were analyzed, as was the relationship between immunoglobulin level and the incidence of serious infections in patients who received ocrelizumab.

Findings in brief

Patients treated with ocrelizumab were at significantly greater risk of serious infection compared with those who received platform injectable therapies (odds ratio = 1.98; 95% CI, 1.52-2.59; P < .01). The rate of serious infections per 100 patient-years was 4.21 with ocrelizumab versus 2.64 with platform injectables. The most common serious infections overall were respiratory (51% incidence at the patient level), genitourinary (19%) and skin/soft tissue/bone (14%).

Key subanalysis findings were as follows:

• Ocrelizumab was associated with a shorter time to first serious infection relative to platform injectables (hazard ratio = 1.86; 95% CI, 1.45-2.39).
• Hypogammaglobulinemia was not associated with a significantly higher risk of serious infection in ocrelizumab recipients.
• Age did not significantly affect the risk of serious infection within the ocrelizumab cohort.

Limitations and clinical implications

“This study leverages the very large patient population at the Mellen Center, where research is embedded into clinical care,” says senior author Daniel Ontaneda, MD, PhD, a neurologist with the Mellen Center. “Its results will be useful for clinicians and people with MS who are considering the long-term risks of one of the most widely prescribed disease-modifying treatments for MS.”

The results may not be generalizable to all patients with MS, the researchers note, because of differences in environmental exposures, genetics, patient preferences and healthcare access. Also, although the propensity model included age at treatment initiation, it did not include age at symptom onset or at diagnosis, and although the number of prior disease-modifying therapies was included in the propensity model, the class and duration of any prior treatments were not accounted for.

“Overall, these findings corroborate those reported in the literature to date,” Dr. Carlson says, “and they show that infection risk in a larger, more heterogeneous, real-world population is consistent with what was reported in clinical trials of ocrelizumab and in extension studies. These results illustrate the magnitude of the risk relative to platform treatment and may help support shared decision-making by patients and providers to select disease-modifying therapy.”

Disclosure

The study was funded by Genentech. Dr. Carlson reports research support from Genentech and Biogen, has served on scientific advisory boards for Sanofi, Novartis and TG Therapeutics, and has served as a consultant to Vigil Neuro, Icometrix and Ionis. Dr. Ontaneda reports research support from the National Institutes of Health, the National Multiple Sclerosis Society, the Patient-Centered Outcomes Research Institute, the Race to Erase MS Foundation, Genentech, Genzyme, Bristol Myers Squibb and Novartis. He has received consulting fees from Bristol Myers Squibb, Genentech/Roche, Novartis, Sanofi and Contineum Therapeutics.