Interleukin-6 as a Key Biomarker in Facioscapulohumeral Dystrophy: Evidence From Longitudinal Analyses.

Objective: Facioscapulohumeral muscular dystrophy type 1 (FSHD1) is a progressive neuromuscular disorder with no approved treatments. Identifying reliable biomarkers is critical to monitor disease severity, activity, and progression. Interleukin-6 (IL-6) has been proposed as a candidate biomarker, but longitudinal validation is limited.

Methods: We analyzed pooled data from two prospective longitudinal cohorts: CTRN-FSHD France (NCT04038138) and Cytokine FSHD (NCT04694456), each comprising 30 genetically confirmed ambulant FSHD1 patients. Serum IL-6 levels and clinical assessments were collected at baseline (M0), 12 months (M12), and 18 months (M18); whole-body muscle MRI (T1-weighted and STIR sequences) was obtained at M0 and M12. Associations between IL-6 levels and clinical severity scores, functional measures, and MRI-derived muscle composition were evaluated.

Results: Serum IL-6 levels correlated significantly with clinical severity metrics, including Clinical Severity Score, 6-Minute Walk Test, Manual Muscle Testing, and Motor Function Measure Domain 1 at all time points. Higher IL-6 levels were associated with increased muscle fat infiltration and free water content compatible with muscle edema on MRI. Longitudinal analyses showed that increases in IL-6 over 12 months were significantly correlated with changes in T1 (fat infiltration) and STIR (muscle edema) composite scores, reflecting structural and inflammatory disease progression.

Interpretation: These findings validate IL-6 as a biomarker of FSHD1 severity and underscore its potential as an activity and progression biomarker. The correlation between IL-6, clinical scores, and MRI-based muscle composition changes highlights its potential utility for monitoring disease evolution and evaluating therapeutic responses in FSHD1 patients.