Inflammatory disorders of the skeletal muscle include polymyositis (PM), dermatomyositis (DM), (immune mediated) necrotizing myopathy (NM), overlap syndrome with myositis (overlap myositis, OM) including anti-synthetase syndrome (ASS), and inclusion body myositis (IBM). Whereas DM occurs in children and adults, all other forms of myositis mostly develop in middle aged individuals. Apart from a slowly progressive, chronic disease course in IBM, patients with myositis typically present with a subacute onset of weakness of arms and legs, often associated with pain and clearly elevated creatine kinase in the serum. PM, DM and most patients with NM and OM usually respond to immunosuppressive therapy, whereas IBM is largely refractory to treatment. The diagnosis of myositis requires careful and combinatorial assessment of (1) clinical symptoms including pattern of weakness and paraclinical tests such as MRI of the muscle and electromyography (EMG), (2) broad analysis of auto-antibodies associated with myositis, and (3) detailed histopathological work-up of a skeletal muscle biopsy. This review provides a comprehensive overview of the current classification, diagnostic pathway, treatment regimen and pathomechanistic understanding of myositis.

Distinct interrelationships between inflammation and β-amyloid-associated degeneration, the two major hallmarks of the skeletal muscle pathology in sporadic inclusion body myositis (sIBM), have remained elusive. Expression of markers relevant for these pathomechanisms were analysed in biopsies of sIBM, polymyositis (PM), dermatomyositis (DM), dystrophic and non-myopathic muscle as controls, and cultured human myotubes. By quantitative PCR, a higher upregulation was noted for the mRNA-expression of CXCL-9, CCL-3, CCL-4, IFN-γ, TNF-α and IL-1β in sIBM muscle compared to PM, DM and controls. All inflammatory myopathies displayed overexpression of degeneration-associated markers, yet only in sIBM, expression of the mRNA of amyloid precursor protein (APP) significantly and consistently correlated with inflammation in the muscle and mRNA-levels of chemokines and IFN-γ. Only in sIBM, immunohistochemical analysis revealed that inflammatory mediators including IL-1β co-localized to β-amyloid depositions within myofibres. In human myotubes, exposure to IL-1β caused upregulation of APP with subsequent intracellular aggregation of β-amyloid. Our data suggest that, in sIBM muscle, production of high amounts of pro-inflammatory mediators specifically induces β-amyloid-associated degeneration. The observations may help to design targeted treatment strategies for chronic inflammatory disorders of the skeletal muscle.

Interactions between inducible co‐stimulatory molecule (ICOS) and ICOS‐ligand (ICOS‐L) are crucial for T‐cell co‐stimulation, effector cell differentiation and memory CD8⁺ T‐cell activation. Because in the muscle of patients with sporadic inclusion body myositis (sIBM) clonally expanded CD8⁺ T cells invade major histocompatibility complex (MHC) class I‐expressing muscle fibres, we investigated ICOS·ICOS‐L interactions and correlated their expression with perforin, a marker for cytotoxic effector function by autoinvasive CD8⁺ T cells. The mRNA from 20 muscle biopsies of sIBM, 20 non‐inflammatory or dystrophic controls, two dermatomyositis (DM) and two polymyositis (PM) patients was reverse transcribed and reamplified by semi‐quantitative and quantitative reverse transcription–polymerase chain reaction (RT–PCR), using primers for ICOS, ICOS‐L and perforin. The glyceraldehyde 3‐phosphate dehydrogenase (GAPDH)‐normalized ratio of ICOS, ICOS‐L and perforin expression was compared with the degree of endomysial inflammation. Protein expression of ICOS, ICOS‐L and perforin was confirmed by immunohistochemistry. We demonstrate that ICOS‐L mRNA was upregulated in sIBM (arbitrary units, median ± SEM: 48.6 ± 14.9) compared with controls (6.2 ± 17.8, P < 0.05) and significantly correlated with the expression of ICOS (53.9 ± 16.6 versus 6.7 ± 8.9 in controls, P < 0.001). By triple labelling immunohistochemistry, the CD8⁺ T cells in sIBM and PM were found to invade ICOS‐L‐ and MHC class I‐co‐expressing muscle fibres. Among the autoinvasive CD8⁺ T cells, however, only a subset of ∼5–10% were ICOS positive, and thereby perceptive for ICOS·ICOS‐L signalling at the immunological synapse. In contrast, in Duchenne muscular dystrophy and DM, although ICOS and ICOS‐L mRNA expression was also increased, the majority of ICOS‐L‐ and ICOS‐positive cells were in the perimysial regions and connective tissue. The mRNA for perforin was increased in sIBM (28.1 ± 8.7) compared with controls (4.3 ± 11.2, P = 0.18), and significantly correlated with mRNA of ICOS, ICOS‐L and the degree of endomysial inflammation as assessed in coded haematoxylin/eosin tissue sections. By triple immunohistochemical staining and cell counting, perforin granules were found in 71% of the autoinvasive CD8⁺ T cells that were also ICOS positive. Our data indicate that in sIBM there is upregulation of ICOS·ICOS‐L co‐stimulatory signalling in association with enhanced perforin expression by the autoinvasive CD8⁺ T cells. The findings support previous suggestions that in IBM, the muscle fibres have the capacity for antigen presentation, thereby activating a specific subset among the autoinvasive CD8⁺ T cells to exert a cytotoxic effect. The observations strengthen the immunopathogenesis of sIBM, and offer the basis for future therapeutic interventions targeting ICOS·ICOS‐L co‐stimulatory interactions.

Objective: To assess safety and feasibility of real-time (RT) MRI for evaluation of dysphagia and to compare this technique to standard assessment by flexible endoscopic evaluation of swallowing (FEES) and videofluoroscopy (VF) in a cohort of patients with inclusion body myositis (IBM). Methods: Using RT-MRI, FEES, and VF, an unselected cohort of 20 patients with IBM was studied as index disease with a uniform dysphagia. Symptoms of IBM and dysphagia were explored by standardized tools including Swallowing-Related Quality of Life Questionnaire (SWAL-QoL), IBM Functional Rating Scale, Patient-Reported Functional Assessment, and Medical Research Council Scale. Results: Dysphagia was noted in 80% of the patients and SWAL-QoL was impaired in patients with IBM compared to published reference values of healthy elderly. Swallowing in a supine position during RT-MRI was well-tolerated by all patients. RT-MRI equally revealed dysphagia compared to VF and FEES and correlated well with the SWAL-QoL. Only RT-MRI allowed precise time measurements and identification of the respective tissue morphology. The pharyngeal transit times were 2-fold longer compared to published reference values and significantly correlated with morphologic abnormalities. Conclusions: RT-MRI is safe and equally capable as VF to identify the cause of dysphagia in IBM. Advantages of RT-MRI include visualization of soft tissue, more reliable timing analysis, and lack of X-ray exposure. RT-MRI may become a routine diagnostic tool for detailed assessment of the esophagus and other moving parts of the body, facilitating longitudinal evaluations in daily practice and clinical trials.

Sporadic inclusion body myositis is a severely disabling myopathy. The design of effective treatment strategies is hampered by insufficient understanding of the complex disease pathology. Particularly, the nature of interrelationships between inflammatory and degenerative pathomechanisms in sporadic inclusion body myositis has remained elusive. In Alzheimer’s dementia, accumulation of β-amyloid has been shown to be associated with upregulation of nitric oxide. Using quantitative polymerase chain reaction, an overexpression of inducible nitric oxide synthase was observed in five out of ten patients with sporadic inclusion body myositis, two of eleven with dermatomyositis, three of eight with polymyositis, two of nine with muscular dystrophy and two of ten non-myopathic controls. Immunohistochemistry confirmed protein expression of inducible nitric oxide synthase and demonstrated intracellular nitration of tyrosine, an indicator for intra-fibre production of nitric oxide, in sporadic inclusion body myositis muscle samples, but much less in dermatomyositis or polymyositis, hardly in dystrophic muscle and not in non-myopathic controls. Using fluorescent double-labelling immunohistochemistry, a significant co-localization was observed in sporadic inclusion body myositis muscle between β-amyloid, thioflavine-S and nitrotyrosine. In primary cultures of human myotubes and in myoblasts, exposure to interleukin-1β in combination with interferon-γ induced a robust upregulation of inducible nitric oxide synthase messenger RNA. Using fluorescent detectors of reactive oxygen species and nitric oxide, dichlorofluorescein and diaminofluorescein, respectively, flow cytometry revealed that interleukin-1β combined with interferon-γ induced intracellular production of nitric oxide, which was associated with necrotic cell death in muscle cells. Intracellular nitration of tyrosine was noted, which partly co-localized with amyloid precursor protein, but not with desmin. Pharmacological inhibition of inducible nitric oxide synthase by 1400W reduced intracellular production of nitric oxide and prevented accumulation of β-amyloid, nitration of tyrosine as well as cell death inflicted by interleukin-1β combined with interferon-γ. Collectively, these data suggest that, in skeletal muscle, inducible nitric oxide synthase is a central component of interactions between interleukin-1β and β-amyloid, two of the most relevant molecules in sporadic inclusion body myositis. The data further our understanding of the pathology of sporadic inclusion body myositis and may point to novel treatment strategies.