Circulating microRNA as biomarkers for predicting cladribine response in multiple sclerosis

Reliable biomarkers capturing early biological responses to treatment in multiple sclerosis (MS) remain limited. Circulating microRNAs (miRNAs) may provide complementary information on treatment-related biological changes and subsequent clinical response. We prospectively evaluated circulating miRNAs in 20 patients with relapsing-remitting MS initiating cladribine tablets. Twenty-one miRNAs were measured at baseline and approximately six months after treatment initiation, with clinical outcomes assessed over 24 months. Seven miRNAs showed significant treatment-associated changes after Benjamini-Hochberg correction. A fixed three-miRNA model discriminated baseline from post-treatment samples with an apparent AUC of 0.79 (95% CI, 0.67–0.91) and a leave-one-pair-out cross-validated AUC of 0.78 (95% CI, 0.64–0.90). Separately, on-treatment miR-320 family levels, which did not show significant treatment-associated changes, were associated with subsequent NEDA-3, with AUCs up to 0.84 (95% CI, 0.64–1.00), suggesting a potential role in early response assessment. In patients with available neurofilament light chain measurements, there was no significant difference in predictive performance between hsa-miR-320b and neurofilament light chain. These findings suggest that circulating miRNAs may capture distinct aspects of biological treatment effects and subsequent clinical response to cladribine and warrant further investigation as complementary biomarkers for treatment monitoring and response assessment in larger independent cohorts.