HLA-dependent association between EBNA1 antibody levels and disability progression in multiple sclerosis

BACKGROUND: Epstein-Barr virus (EBV) is strongly implicated in the development of multiple sclerosis (MS) but whether EBV-related immune responses are also relevant for disease progression after diagnosis remains unclear. We investigated whether Epstein-Barr nuclear antigen 1 (EBNA1) antibody levels are associated with disability progression in MS and whether this association is modified by human leucocyte antigen (HLA)-A*02:01 and HLA-DRB1*15:01. METHODS: We analysed 5706 patients with MS from two population-based Swedish studies with longitudinal follow-up in the Swedish MS registry. EBNA1 IgG levels were analysed as a continuous variable, expressed per one SD increase. The primary outcome was confirmed disability worsening (CDW). Cox proportional hazards models were used to estimate hazard ratios (HRs) with 95% confidence intervals (CIs). Effect modification by HLA-A*02:01 and DRB1*15:01 was assessed using interaction terms and stratified analyses. Secondary and sensitivity analyses included dichotomisation of EBNA1 levels, alternative progression outcomes, delayed-entry models and treatment-related analyses. RESULTS: Higher EBNA1 antibody levels were associated with a reduced risk of CDW among individuals carrying both A*02:01 and DRB1*15:01 (HR 0.87, 95% CI 0.81 to 0.93), whereas associations were weaker or absent in other HLA strata. Findings were similar in secondary and sensitivity analyses. CONCLUSION: Our findings suggest that EBV-related antibody responses may have prognostic relevance for MS progression in specific genetic contexts, highlighting the importance of host-virus interactions beyond disease onset.