Longitudinal changes of serum immunoglobulins under ocrelizumab: factors associated with hypogammaglobulinemia and infection risk in a real-world multiple sclerosis cohort

BACKGROUND AND OBJECTIVES: Ocrelizumab (OCR) is an effective anti-CD20 therapy for relapsing-remitting and primary progressive multiple sclerosis (MS), but long-term effects on humoral immunity in real-world settings remain incompletely characterized. We investigated longitudinal changes in serum immunoglobulins, explored factors associated with hypogammaglobulinemia, and assessed associations with infection risk. METHODS: In this retrospective, single-center observational study, adult patients with MS treated with OCR between 2018 and 2023 were included after ≥ 2 treatment cycles. Patients underwent standardized clinical, radiological, and laboratory follow-up, including serial measurements of serum immunoglobulins and varicella-zoster virus (VZV) serology. Infections were graded according to CTCAE criteria. RESULTS: Of 116 patients (81% relapsing-remitting MS; median follow-up 2.3 years), approximately one-third developed lower limit of normal (LLN) IgM and one-sixth LLN IgG. Declines in immunoglobulins were class-specific and treatment-duration-dependent, most pronounced for IgM. Low baseline immunoglobulin levels were the strongest factors associated with LLN values, whereas demographic and disease-related factors were not. Prior immunotherapy, particularly fingolimod or interferon, was associated with hypogammaglobulinemia. Severe infections were rare (1.1 per 100 patient-years) and not consistently associated with LLN immunoglobulins. DISCUSSION: OCR induced predictable, class-specific declines in immunoglobulins. Despite frequent hypogammaglobulinemia - particularly affecting IgM - no association with an increased short- to mid-term risk of clinically relevant infections was observed, although limited event numbers restrict conclusions. These findings support individualized immunoglobulin monitoring focused on patients with low baseline levels or prior immunotherapy exposure and underscore the need for prospective studies to define clinically meaningful thresholds for intervention during long-term anti-CD20 therapy.