Disability, Anti-CD20 Therapy Drive Serious Infection Risk in MS

TORONTO — Disability, even when mild, was strongly associated with risk of serious infection in patients with multiple sclerosis (MS), and anti-CD20 therapy was linked to a doubling of this risk compared with interferon beta or glatiramer acetate, two established, lower-efficacy disease-modifying therapies (DMTs).Results of two large real-world studies showed such infections were not rare. One study showed about one in seven patients had an infection over an average of nearly 11 years, most often a urinary tract infection.In the first study, led by Chloé Pierret, PhD, the risk rose steadily with disability level, from about double for those with mild disability to roughly ten-fold at the most severe levels. The risk was further increased by anti-CD20 therapies, alemtuzumab or mitoxantrone, and comorbidities, including bladder dysfunction. Older age was not an independent risk factor once disability and comorbidities were considered.“We think that these factors should always be taken into account when assessing infection risk in MS,” said Pierret, who is an epidemiologist and biostatistician at the Multiple Sclerosis Centre of Catalonia (Cemcat), Vall d’Hebron University Hospital, Barcelona, Spain.In the second study, Jacob Granfors, a PhD candidate at the Karolinska Institutet, Stockholm, Sweden, found that patients with MS treated with rituximab, an anti-CD20 drug widely used off-label for MS, had about twice the rate of infection requiring hospitalization compared with interferon and glatiramer acetate (hazard ratio [HR], 1.99) and three times that of the general population. Both studies were presented at the 10th Joint Americas Committee for Treatment and Research in Multiple Sclerosis-European Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS-ECTRIMS) 2026.Disability a Major Risk FactorFor the first study, researchers linked data from the Multiple Sclerosis Centre of Catalonia with the region’s healthcare administrative database to identify patients with MS treated at the center from 2007 to 2024.The retrospective cohort included 2755 patients (67.6% female; mean age, 39.5 years) followed for an average of 10.7 years. The main outcome was time to infection serious enough to require hospitalization.Researchers examined sociodemographic factors, including age, sex, and socioeconomic status, and MS-related factors, including disease duration, DMT use, relapse activity, and disability, measured using the Expanded Disability Status Scale (EDSS).Other health-related factors included chronic conditions such as diabetes, autoimmune disease, respiratory disease, depression or anxiety, cardiovascular disease, body mass index, and prior nonserious infection.Overall, the crude rate of serious infection was 2.3 per 100 person-years, and 14.6% of patients had at least one such infection. Urinary tract infections were the most common, followed by non-COVID respiratory infections and COVID.After adjustment, anti-CD20 therapies were associated with double the risk of serious infection compared with interferon or glatiramer acetate, and about 2.5 times the risk compared with alemtuzumab or mitoxantrone. The risk was not elevated with sphingosine-1-phosphate (S1P) receptor modulators, cladribine, or natalizumab. Comorbidities also played a role. Risk of serious infection increased by 40% to 90% with respiratory disease, diabetes, chronic kidney disease, and bladder dysfunction, which Pierret noted is “quite prevalent in the MS population.”Age was linked to serious infection risk in the unadjusted analysis, but not after adjustment for disability, comorbidities, and other factors.Even mild disability was associated with increased infection risk. Compared with patients with an EDSS score of 0-2, those with a score of 2.5-3.0 had more than double the risk (HR, 2.22). Risk escalated with each level of disability, reaching nearly 10-fold for patients with a score of 7.5 or higher (HR, 9.91).Next steps include adding laboratory markers, vaccination status, and cumulative dose exposure to the risk analyses, Pierret said.“Clinically, the results argue for looking beyond age alone,” commented Thomas Frisell, PhD, senior lecturer, Department of Medicine, Division of Clinical Epidemiology, Karolinska Institutet, Stockholm, Sweden, who was a session co-chair.“Although more data would be valuable for a specific condition, MS specialists should assess disability, bladder, and respiratory problems, diabetes, kidney disease, and infection history when considering long-term anti-CD20 therapy, and revisit that assessment as the patient’s condition changes,” he said.Infection Risk With Rituximab in MS vs RAThe second study examined risk of serious infection among patients treated with the anti-CD20 monoclonal antibody rituximab for MS vs RA — two diseases for which the drug is widely used.Swedish guidelines emphasize the elevated risk of serious infection associated with rituximab in MS, but not in RA, Frisell noted. For the study, Frisell and colleagues used data from linked national registries in Sweden. The study population included all patients diagnosed with MS or RA, but excluded those with a recent infection to ensure recorded cases were incident infections.The MS cohort included 7512 patients who were taking rituximab and 82,024 matched-controls from the general population based on age, sex, and region. The RA cohort included 3225 patients who were taking rituximab and 258,005 matched-controls.Patients with RA who started rituximab were older than those with MS (average age, 58 vs 39 years). Rituximab was usually the first DMT used in MS but was used later in patients with RA. Patients with MS generally received lower doses of rituximab compared to patients with RA.The incidence rates of hospitalized infection in the MS cohort ranged from 7 to 22 per 1000 person-years. Infection rates were higher in the RA cohort, ranging from 14 to 66 per 1000 person-years.In both groups, the highest incidence rates occurred during rituximab treatment but were higher for patients with RA. The absolute risk of serious infection during rituximab treatment at 4 years was 15% in RA compared to 7% in MS.In MS, rituximab was associated with a threefold higher infection rate compared to the general population (HR, 3.09) and a twofold higher rate compared with other DMTs (HR, 2.03). In RA, infection rates were also higher for rituximab compared to the general population (HR, 3.83) and tumor necrosis factor inhibitors (HR, 1.78).The older age of patients with RA explained some, but not all, of the higher risk of serious infection, said Pierret. “The results might be a slight wake-up call for rheumatologists,” Frisell told Medscape Medical News.He suggested that Swedish treatment guidelines for RA place a greater emphasis on the increased risk of serious infection with rituximab, noting that this risk is addressed in current MS treatment guidelines. Patients with RA may receive other medications along with rituximab, including methotrexate. Combination therapy is less common in MS, although corticosteroids may be used to treat relapses, Frisell noted.“We’re talking about two different diseases, and you’re trying to achieve slightly different things, although in both diseases, the aim of treatment is to knock out the immune system in certain places,” he added. Consider Infection Risk When PrescribingElaine Kingwell, PhD, principal research fellow, primary care and population health, University College London, UK, and session co-chair, found the strength of the association between disability and serious infection risk “particularly striking.”“While clinicians have long recognized that some patients are at higher risk than others, this study reinforces the importance of considering patient characteristics, and not just treatment choice, when assessing infection risk in MS,” she said.Kingwell noted that, in the rituximab study, patients with RA were substantially older and had a higher baseline risk of serious infection.“For that reason, I would be cautious about concluding that rituximab is inherently more hazardous in rheumatoid arthritis than in multiple sclerosis,” said Kingwell. She noted the other studies suggest infection risk depends on individual patient characteristics, and not just what treatment they receive.“Taken together, the findings of both studies highlight the need to assess infection risk at the individual patient level when making treatment decisions,” she said.Pierret’s research was supported by the FranceSEP Foundation, which also provided her with fellowship funding. The Swedish Research Council funded Frisell’s study and also provides him with support. Kingwell has reported no relevant financial relationships.