Dottorato in PLASTICITÀ NEUROSENSORIALE

Titolo della tesi: Refining the spectrum of inflammatory myopathies: Exploring Overlap Syndromes, Mitochondrial Pathology, and Immune Triggers

Preface Inflammatory myopathies constitute a heterogeneous spectrum of muscle diseases, characterized by a complex interplay of immunological, degenerative, and metabolic mechanisms. Advances in molecular genetics, immunopathology, and high-resolution imaging have progressively redefined their nosological boundaries, revealing possible significant overlap between entities once considered distinct [1,2]. These insights have fostered a more nuanced understanding of inflammatory myopathies as a dynamic continuum rather than discrete disorders, shaped by the convergence of immune-mediated injury and intrinsic muscle vulnerability. This work, aims to refine the current understanding of inflammatory myopathies through an integrated clinico-sero-pathological, and molecular approach. The research was carried out in collaboration with major European neuromuscular centers, leveraging multicentric data to explore how specific pathological signatures—such as granulomatous inflammation, dystrophic and autoimmune overlap, mitochondrial dysfunction and immune triggers—shape disease mechanisms, prognosis, and treatment response. The first section focuses on granulomatous myositis (GM), a rare and poorly defined condition that may occur as an isolated entity or in association with systemic diseases, including sarcoidosis [3]. By analyzing one of the largest cohorts reported to date [4], this study delineates its clinical spectrum and frequent evolution toward inclusion body myositis (IBM), supporting the concept of shared immunopathogenic pathways linking granulomatous inflammation to degenerative mechanisms. The second section explores the unexpected coexistence between facioscapulohumeral muscular dystrophy (FSHD) and autoimmune myositis. The findings showed a surprisingly high prevalence of this association [5], hypothesizing that DUX4-mediated immune dysregulation and chronic muscle damage may predispose to autoimmune activation, while inflammation itself may unmask latent dystrophic traits. This bidirectional interplay exemplifies the blurred boundaries between inherited and immune-mediated muscle disorders [6,7], highlighting how degenerative and autoimmune processes can converge within the same pathological continuum. The third section investigates mitochondrial pathology in non-IBM myositis, emphasizing its role as a marker of disease severity and treatment refractoriness. By quantifying cytochrome c oxidase (COX)-negative muscle fibers and correlating them with clinical outcomes, this multicentric study demonstrates that mitochondrial dysfunction represents a key determinant of poor prognosis and may anticipate in some cases the transition toward inclusion body myositis (IBM) [8,9]. These findings suggests that similar degenerative pathways could be progressively activated across the myositis spectrum. This convergence supports the view that IBM is not an isolated entity, but rather the end-stage of a chronic inflammatory–degenerative process driven by sustained immune-mediated stress and impaired mitochondrial homeostasis, as exemplified by polymyositis with mitochondrial pathology (PM-Mito) [10,11]. Finally, the fourth section continues to explore autoimmune overlap syndromes and immune- triggered myopathies, focusing on the coexistence of myasthenia gravis (MG) and inflammatory myopathy (IM), as well as neurological immune-related adverse events (irAEs) induced by immune checkpoint inhibitors (ICI) therapy [12]. In the multicentric cohort analyzed, MG–IM overlap emerged as a heterogeneous entity encompassing both idiopathic forms (i-MG-IM) and ICI-related cases (ir-MG-IM), each displaying distinct clinical and immunopathological signatures [13,14]. i-MG-IM typically represent a thymoma-associated entity characterized by variable muscle weakness distribution. In contrast, ir-MG-IM displays a more aggressive, monophasic course with simultaneous MG and IM onset, frequently associated with myocarditis, and respiratory failure [15,16]. Antibody- and complement- dependent injury predominates in i-MG-IM, whereas ir-MG-IM often lacks classical MG serology and complement activation, suggesting that immune checkpoint blockade triggers an alternative pathogenic cascade. The observation of anti-titin and anti-RyR antibodies in both i- and ir-MG-IM further suggests partial overlap between spontaneous and therapy-induced autoimmunity, possibly reflecting latent autoimmunity unmasked by checkpoint inhibition. Collectively, these studies refine the conceptual spectrum of inflammatory myopathies by integrating morphological, immunological, and molecular evidence into a unifying framework. They demonstrate that the interplay between inflammation, degeneration, and intrinsic muscle vulnerability defines the clinical diversity of myositis, bridging autoimmune, degenerative, and therapy-induced mechanisms. Ultimately, this thesis not only contributes novel multicentric data to the field but also proposes a mechanism-based, personalized classification of inflammatory myopathies, paving the way toward precision medicine approaches in the diagnosis and treatment of complex neuromuscular diseases.