Cardiometabolic disease is associated with distinct proteomic signatures of acute disease activity in multiple sclerosis.

Multiple sclerosis (MS) disease activity and treatment response may be influenced by systemic health factors, including cardiometabolic disease (CMD). This study evaluated how CMD influences inflammatory protein profiles and whether CMD modifies the effect of disease-modifying therapy (DMT). A retrospective study was conducted within a single academic MS center. All participants underwent commercial multi-analyte proteomic testing (Octave® Bioscience). CMD was defined as hypertension, type 2 diabetes mellitus, and/or dyslipidemia. Four groups were analyzed: untreated without CMD, untreated with CMD, DMT-treated without CMD, and DMT-treated with CMD. A multivariable variability index (MVI) was calculated across 18 age- and sex-adjusted proteins, and CMD burden (one, two, or three conditions) was assessed. A total of 287 MS individuals were included (84% White, 78% female). Among untreated individuals, those with CMD demonstrated significantly higher concentrations of proteins associated with acute MS disease activity, including MIP 3-alpha (CCL20) (p = 0.0078), CUB domain-containing protein 1 (CDCP1) (p = 0.0176), and TRAIL-R1 (TNFRSF10A) (p = 0.0002). In treated individuals, CMD was associated with higher levels of monokine induced by gamma interferon (CXCL9) (p = 0.0025), NfL (p = 0.0201), serpin family A member 9 (p = 0.0291), and TRAIL-R1 (p = 0.0002), as well as lower levels of protogenin (p = 0.0376). MVI values were elevated in both CMD groups. CMD was associated with higher odds of prior relapse and/or MRI activity within two years before proteomic testing (OR 5.48, 95% CI: [1.18-25.40], p = 0.0227). Protein concentrations increased with greater CMD burden. Clinically measurable proteins associated with acute MS disease activity are elevated in individuals with CMD and increase with comorbidity burden, in both DMT-treated and untreated groups.