Autoimmune Comorbidities as Modifiers of Phenotypic Heterogeneity in Facioscapulohumeral Dystrophy

Facioscapulohumeral dystrophy type 1 (FSHD1) shows clinical heterogeneity that is only partly explained by D4Z4 repeat unit (RU) size. Although immune and inflammatory mechanisms may contribute to disease variability, the prevalence and clinical impact of autoimmune diseases in FSHD remain unclear. We investigated the spectrum of autoimmune comorbidities in FSHD1 and their relationship with D4Z4 repeat size, clinical phenotype, and disease severity.

We retrospectively analyzed 299 genetically confirmed FSHD1 patients followed at a national neuromuscular reference center. Clinical severity was assessed using the FSHD score and Comprehensive Clinical Evaluation Form classification. Demographic, genetic, and clinical features were compared according to autoimmune disease status. Multivariable linear regression assessed the independent association between autoimmune disease and FSHD severity, adjusting for age, sex, disease duration, D4Z4 RU number, and clinical phenotype.

Eighty-two patients (27.4%) had at least one autoimmune disease, totaling 96 autoimmune conditions. Several autoimmune diseases were markedly overrepresented compared with published population estimates. Patients with autoimmune disease had larger D4Z4 repeat arrays (7.18 ± 1.82 vs. 6.53 ± 1.81 RU, p = 0.002) but higher FSHD severity scores (7.98 ± 3.65 vs. 6.56 ± 3.51, p = 0.003). Autoimmune comorbidities were enriched in patients carrying 7-10 D4Z4 RU. In multivariable analysis, autoimmune disease remained independently associated with greater FSHD severity (β = 2.12, 95% CI 1.47-2.76, p < 0.0001).

Autoimmune diseases are frequent in FSHD1 and independently associated with greater severity despite larger D4Z4 repeat arrays, supporting immune-related mechanisms as potential modifiers of FSHD1 expression.