Abstract
BACKGROUND: Neuromyelitis optica spectrum disorder (NMOSD) is a demyelinating condition in the central nervous system whose relapses cause severe disability progression. Although conventional blood lipid markers are linked to disease course and outcomes, the predictive value of emerging lipid indicators, such as remnant cholesterol (RC) and lipid ratios, for NMOSD relapse remains unclear. METHODS: The single-centre retrospective study enrolled a total of 245 patients diagnosed with NMOSD, based on the availability of clinical and laboratory data. To evaluate RC and lipid ratios in predicting NMOSD relapse, multivariate Cox proportional hazards models and restricted cubic spline evaluations were applied. Predictive performance was assessed using the concordance index (C-index), continuous net reclassification improvement (NRI) and integrated discrimination improvement (IDI). Subgroup evaluations examined the stability of the observed RC-relapse connection across diverse patient strata. Cumulative hazard function curves illustrated the clinical relevance of the RC inflection point. Additionally, mediation analyses tested whether inflammatory markers mediated the RC effect on relapse. RESULTS: Among 245 NMOSD patients, 55.10% of the patients relapsed during follow-up. RC, non-high-density lipoprotein cholesterol to high-density lipoprotein cholesterol ratio, total cholesterol and low-density lipoprotein cholesterol levels emerged as independent determinants of relapse across both continuous and categorical Cox models, after adjusting for demographic, clinical and therapy-associated factors. An "S"-shaped nonlinear relationship was observed between RC values and relapse risk, with a turning point at 0.46 mmol/L: protective below, risk factor above. Performance metrics (C-index, NRI, IDI) indicated that RC significantly improved relapse prediction. The RC-relapse association persisted across subgroups, with the inflection point effectively distinguishing relapsing patients in the anti-aquaporin 4-immunoglobulin G seropositive and monoclonal antibody treatment group. Mediation analysis revealed increased neutrophil ratio and decreased lymphocyte ratio partially mediated RC's effect on relapse. CONCLUSIONS: RC was identified as the most robust lipid metabolism indicator for predicting NMOSD relapse, displaying an inflection at 0.46 mmol/L. Neutrophil ratio and lymphocyte ratio may partially mediate the relationship between elevated RC and relapse. These findings aid timely recognition of patients at elevated risk and provision of individualised therapeutic interventions to reduce disability and improve long-term outcomes in this debilitating disease.