Multiple Sclerosis, Disease-Modifying Therapies, and Infections

BACKGROUND AND OBJECTIVES: The use of highly effective multiple sclerosis (MS) disease-modifying therapies (DMTs) is rapidly increasing. Yet, little is known about their real-world risks of infections. The goals of this study were to assess the comparative risk of outpatient and serious infections across DMTs in a large, diverse, U.S. cohort and determine whether such risks are attributable to DMTs, having MS, or other factors. METHODS: We conducted a retrospective cohort study of Kaiser Permanente Southern California members from 2008 through 2020 with MS and non-MS controls matched on age, sex, race, and ethnicity. MS treatments, serious (those requiring hospitalization) and outpatient infections, and covariates were collected from the electronic health record. Adjusted hazard ratios (aHR) and risk ratios (aRR) were estimated using the Cox and Poisson regression, respectively. RESULTS: Six thousand, six hundred and twenty-six patients with MS with 11,929 treatment episodes (2,487 rituximab, 546 natalizumab, 298 fingolimod, 4,629 interferon-beta/glatiramer acetate, IFN/GLAT, and 3,969 untreated) and 33,550 population controls were included in the analyses. The average age at treatment start ranged from 38.9 to 49.2 years, and 74% were women. Untreated (aRR = 1.39, [95% CI = 1.35–1.44]) and IFN/GLAT-treated patients with MS (aRR = 1.60, [95% CI = 1.56–1.65]) had a higher risk of outpatient infections and serious infections (aHR = 2.97, [95% CI = 2.65–3.32 and aHR = 2.31, [95% CI = 2.04–2.62], respectively) compared with controls. Rituximab (aRR = 1.19, [95% CI = 1.14–1.25]), fingolimod (aRR = 1.22, [95% CI = 1.09–1.37]), and to a lesser extent, natalizumab treatment (aRR = 1.08, [95% CI = 0.97–1.20]) were associated with an increased risk of outpatient infections compared with IFN/GLAT. Rituximab (aHR = 1.41, [95% CI = 1.09–1.84]) and natalizumab (aHR = 1.40, [95% CI = 0.96–2.04]) treatment were associated with a similar increased risk of serious infections compared with IFN/GLAT. The only treatment-specific association identified was fingolimod with outpatient herpetic infections. Higher comorbidity index, previous hospitalization for infections, and advanced disability significantly increased the risk of serious infections independent of DMTs. Hospitalization for UTI-related pseudorelapses accounted for 24%–48% of serious infections. DISCUSSION: Patients with MS have higher risks of outpatient and serious infections compared with patients without MS. The risk of outpatient infections was similarly increased by rituximab and fingolimod and serious infections by rituximab and natalizumab compared with IFN/GLAT. Steps to minimize risks include optimizing bladder care, comorbidity prevention, varicella vaccination, and considering discontinuing or avoiding DMT use in patients with advanced disability and/or previous hospitalizations for infections.