Autoimmune Diseases May Quietly Worsen a Common Muscular Dystrophy

Facioscapulohumeral muscular dystrophy, or FSHD, has long been a puzzle for the clinicians who treat it. The disease, which affects roughly one in 8,000 to one in 20,000 people worldwide, progressively weakens the muscles of the face, shoulder blades, and upper arms, yet patients carrying the same genetic defect can experience wildly different outcomes. Some carriers never develop a single symptom, while others lose the ability to walk, with up to 20 percent eventually requiring full-time wheelchair use. A new study published in Annals of Clinical and Translational Neurology by researchers at the Nice University Hospital’s National Neuromuscular Diseases Reference Center now points to a surprising contributor to this variability: autoimmune disease. In a cohort of 299 genetically confirmed FSHD1 patients, more than a quarter carried at least one autoimmune condition, and those patients were significantly more severely affected than their counterparts without immune disorders.

The genetic roots of FSHD lie in a region of chromosome 4 called D4Z4, a stretch of repeated DNA sequences that normally keeps a gene called DUX4 silenced. In FSHD1, which accounts for about 95 percent of cases, these repeats contract to between one and ten units instead of the usual eleven or more, allowing DUX4 to be aberrantly expressed in muscle tissue. DUX4 is a transcription factor that wreaks havoc once activated, driving oxidative stress, impaired muscle regeneration, and the activation of innate immune and antiviral pathways. The shorter the residual repeat array, the more DUX4 is released and, generally, the earlier and more severe the disease. But this relationship is far from complete. Even relatives carrying identical D4Z4 contractions can differ dramatically in severity, a gap that has long suggested the involvement of additional modifiers, whether genetic, epigenetic, environmental, or immunological.

That immunology might matter in FSHD is not an entirely new idea. Muscle biopsies from patients frequently show inflammatory infiltrates dominated by CD8-positive T lymphocytes and macrophages, and magnetic resonance imaging reveals muscle edema during active phases of the disease. Transcriptomic studies have documented upregulation of interferon signaling and cytokine-related genes in FSHD tissues, and DUX4 itself can induce the expression of inflammatory mediators. Isolated case reports have also described patients with both FSHD and autoimmune conditions such as myasthenia gravis or inflammatory myopathies. What remained unknown was whether these co-occurrences were coincidental or whether autoimmune disease systematically shapes the course of the muscular dystrophy.

To answer that question, the Nice team analyzed 299 adults with genetically confirmed FSHD1, all evaluated between 2017 and 2025, for whom complete demographic, clinical, and genetic data were available. Each patient was classified using the Comprehensive Clinical Evaluation Form, a standardized tool that sorts patients into four categories: category A for the typical facial and scapular phenotype, category B for incomplete weakness limited to the scapular or facial muscles, category C for pauci-symptomatic or asymptomatic carriers, and category D for atypical presentations. Autoimmune diagnoses were only accepted when confirmed by the relevant specialist, with strict criteria applied for conditions such as Sjögren’s syndrome, which required fulfillment of the 2016 ACR/EULAR classification criteria with positive anti-SSA or anti-SSB antibodies.

The results were striking. Eighty-two patients, or 27.4 percent of the cohort, had at least one autoimmune disease, and fourteen of them carried two. In total, 96 autoimmune conditions spanning fourteen distinct diagnoses were recorded. Hashimoto’s thyroiditis was the most common, affecting 32 patients, followed by autoimmune diabetes in 16, atopic dermatitis in 12, myasthenia gravis in 10, and primary biliary cholangitis and psoriasis in 7 each. When the researchers compared these counts with published prevalence estimates from the general population, several conditions stood out as dramatically overrepresented. Myasthenia gravis appeared roughly 167 times more often than expected, primary biliary cholangitis about 106 times, autoimmune diabetes nearly 43 times, idiopathic inflammatory myositis about 72 times, and Sjögren’s syndrome more than 16 times. By contrast, common inflammatory skin disorders such as atopic dermatitis and psoriasis were not enriched, suggesting that the association involves specific autoimmune mechanisms rather than a generalized tendency toward inflammation.

The clinical implications were equally compelling. Patients with autoimmune comorbidities were older at examination, with a mean age of 56.3 years compared with 51.2 years, and had a later disease onset, at 38.4 years versus 33.7 years. More intriguingly, despite carrying significantly larger D4Z4 repeat arrays, 7.18 repeat units on average versus 6.53, which should ordinarily predict a milder disease, these patients scored significantly worse on the FSHD severity scale, 7.98 versus 6.56. The distribution of phenotypes also shifted: autoimmune patients were far more likely to fall into category D, the atypical group, at 30.5 percent versus 8.3 percent of non-autoimmune patients, and less likely to show the classical category A presentation. Within categories A and B, autoimmune patients again had significantly higher severity scores.

To test whether autoimmunity was an independent driver of severity rather than a byproduct of age or genetic background, the researchers built a multivariable linear regression model incorporating age, sex, disease duration, D4Z4 repeat number, and autoimmune status. The genetic effect held firm: each additional repeat unit was associated with a decrease in severity score of nearly one point, with a beta coefficient of minus 0.96, while each additional year of disease duration added 0.11 points. But the autoimmune signal was even more pronounced. After adjusting for every other variable, the presence of an autoimmune disease added an average of 2.12 points to the severity score, an effect that was highly statistically significant. Notably, there was no interaction between autoimmune status and repeat number, meaning the autoimmune penalty appeared to operate in parallel with, rather than through, the primary genetic defect.

Perhaps the most provocative finding concerns the subgroup of patients carrying seven to ten D4Z4 repeat units, the larger residual arrays conventionally associated with milder disease. Autoimmune disease was substantially more frequent in this group, affecting 36.1 percent of patients with seven to ten repeats compared with just 16.2 percent of those with shorter alleles, and 73 of the 96 recorded autoimmune conditions occurred in the larger-repeat subgroup. The authors propose a conceptual model in which the relative contribution of disease modifiers depends on repeat size. In patients with short alleles, below seven repeats, the primary genetic contraction dominates the clinical picture. In those with larger alleles, however, secondary factors, including autoimmune disease, unrelated genetic disorders, hormones, telomere shortening, aging, and immunosenescence, may play a proportionally greater role in shaping phenotype and severity. This could explain why patients with seemingly mild genetics sometimes develop serious disease, and why the seven-to-ten repeat range appears repeatedly as a hotspot for modifier effects in this and previous studies from the same group.

The biological mechanisms linking autoimmunity and FSHD severity remain speculative but plausible. Chronic muscle injury in FSHD may release intracellular antigens and pro-inflammatory mediators that fuel immune activation, while systemic autoimmune inflammation could in turn exacerbate muscle dysfunction, impair regeneration, or interact with the epigenetic regulation of the D4Z4 locus itself. The later disease onset observed in autoimmune patients hints that an age-related pro-inflammatory state, compounded by immunosenescence, may gradually tip the balance in genetically susceptible individuals. The authors are careful to note that their study is retrospective and single-center, that referral bias may have inflated the detection of autoimmune comorbidities in a national neuromuscular center, and that several rare conditions were represented by too few cases for firm conclusions. Still, the message for clinical practice is clear: systematically screening FSHD patients for autoimmune disease could refine prognosis and, if future longitudinal studies confirm causality, open the door to immune-targeted therapies for a subgroup of patients whose disease severity is being quietly amplified by their own immune systems.

Subject of Research: The association between autoimmune comorbidities and clinical severity in facioscapulohumeral muscular dystrophy type 1

Article Title: Autoimmune Comorbidities as Modifiers of Phenotypic Heterogeneity in Facioscapulohumeral Dystrophy

Article References: Pini, J., Tammam, G., Ezaru, A., Gambella, M., Sanson, B., Villa, L., Cavalli, M., Ioncea, M.-B., Puma, A., & Sacconi, S. (2026). Autoimmune Comorbidities as Modifiers of Phenotypic Heterogeneity in Facioscapulohumeral Dystrophy. Annals of Clinical and Translational Neurology, Article acn3.70529. https://doi.org/10.1002/acn3.70529

Image Credits: AI Generated

DOI: 10.1002/acn3.70529

Keywords: FSHD, muscular dystrophy, autoimmune disease, DUX4, D4Z4, myasthenia gravis, Hashimoto's thyroiditis, disease modifiers, genetics, inflammation, clinical severity, neuromuscular disorders