Investigating the role of serum IL-6 in predicting outcomes of b-cell depleting therapy in multiple sclerosis: a retrospective cohort study

BACKGROUND: 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. Therefore, the objective of this study was to evaluate whether baseline and longitudinal serum IL-6 levels can predict clinical and radiological outcomes in OCR-treated MS patients. METHODS: This exploratory, single-center retrospective cohort 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 2025. Baseline serum IL-6 was compared with 86 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 (p = 0.178), nor between RRMS and PPMS subgroups (p = 0.024; adjusted post-hoc p > 0.05). No baseline biomarker, including IL-6 (HR 1.83; 95% CI 0.73-4.61; p = 0.989), 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 (mean change - 1.30 pg/mL, p = 0.0318), whereas those with loss of NEDA-3 remained stable (mean change 0.09 pg/mL). 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.