Investigating the Role of Serum IL-6 in Predicting Outcomes of B- Cell Depleting Therapy in Multiple Sclerosis: A Retrospective Cohort Study

Background: Interleukin-6 (IL-6) plays a pivotal role in autoimmune inflammation through its effects on B-cell differentiation, Th17 expansion, and regulatory T-cell suppression. Given ocrelizumab’s (OCR) mechanism of selective CD20 ⁺ B-cell depletion, baseline IL-6 levels have been hypothesized to predict disease activity and long-term outcomes in multiple sclerosis (MS). However, the prognostic value of serum IL-6 in OCR-treated patients remains unclear. Methods: This retrospective study included 73 patients with relapsing–remitting MS (RRMS, n = 30) or primary progressive MS (PPMS, n = 43) who initiated OCR at University Hospital Düsseldorf between 2018 and 2023. Baseline serum IL-6 was compared with 87 healthy controls (HC) and correlated with clinical, radiological, and biomarker outcomes over 24 months. Clinical endpoints included confirmed progression independent of relapse activity (PIRA), and relapse-associated worsening (RAW), alongside MRI activity and Serum Neurofilament Light Chain (sNfL) and Serum Glial Fibrillary Acidic Protein (sGFAP) levels. Between-group comparisons used Welch’s t-test or Wilcoxon rank-sum test, paired longitudinal comparisons used paired t-tests or Wilcoxon signed-rank tests, and associations between baseline biomarkers and outcomes were evaluated using Cox regression, multivariable linear or logistic regression, and rank-based linear models for IL-6. Results: Baseline serum IL-6 levels showed no significant differences between the overall MS cohort and HC, nor between RRMS and PPMS subgroups. No baseline biomarker, including IL-6, sNfL, and sGFAP predicted disease activity. Longitudinal analysis under OCR revealed largely stable IL-6 concentrations but patients maintaining No Evidence of Disease Activity-3 (NEDA-3) showed 50% reduction in IL-6 at 12 months, whereas those with loss of NEDA-3 remained stable. Conclusion: Baseline serum IL-6 alone is insufficient to predict clinical or radiological outcomes in OCR-treated MS patients. However, the significant longitudinal decline specifically in stable patients suggests that IL-6 dynamics, rather than static baseline measures, may better reflect sustained therapeutic response. These findings underscore the limited utility of serum IL-6 alone as a biomarker and support further exploration of longitudinal, multiparametric approaches.