Mitochondrial pathology in inflammatory myopathies: a marker of worse clinical outcome

Abstract Objectives Mitochondrial dysfunction is well documented in inclusion body myositis (IBM), but its role in non-IBM myosi- tis remains unclear. This study aimed to investigate the prevalence and clinical significance of mitochondrial pathology in non-IBM myositis and to assess its potential role as a marker for disease progression towards IBM, treatment response, and clinical outcomes. Methods Muscle biopsies from 850 patients with inflammatory myopathy (IM) across 6 neuromuscular centers in Italy, France, and Germany were retrospectively analyzed. Inclusion required meeting diagnostic criteria for definite adult IM, mitochondrial pathology (age-exceeding numbers of COX-negative fibers), and exclusion of definite IBM according to Hilton-Jones 2013 criteria. The percentage of COX-negative fibers was quantified, correlated with clinical outcomes, and compared with myositis control cases without relevant signs of mitochondrial alterations. Results Twenty-five patients with non-IBM myositis and mitochondrial abnormalities were identified. These patients, pre- dominantly women (68%), had a mean onset age of 58.8 years. Polymyositis with mitochondrial pathology (PM-Mito) and nonspecific myositis (NSM) were the most prevalent subtypes (72%). The mean percentage of COX-negative fibers was 3% (0.25–8.5%) in these patients. The presence of mitochondrial pathology was associated with treatment refractoriness and worse clinical outcome evaluated based on residual muscle weakness and the level of independence (p < 0.005). A higher percentage of COX-negative fibers also correlated with poorer clinical outcomes (p = 0.031). Four patients, initially diagnosed with PM-Mito and NSM, progressed to definite IBM. Conclusions Mitochondrial dysfunction represents a key element informing about disease severity and poor clinical outcomes in non-IBM myositis. It may predict progression to IBM, especially in PM-Mito and NSM, and guide treatment strategies.