Treatment of inflammatory myopathies

The treatment of the immune-mediated inflammatory myopathies remains largely empirical. Corticosteroids are usually effective in polymyositis and dermatomyositis but may need to be combined with methotrexate or azathioprine in some patients. Intravenous immunoglobulin (IVIg) is effective as add-on therapy in some patients not adequately controlled with steroids or immunosuppressive agents, but further controlled trials of IVIg are necessary to define the indications and optimal dose regimens. Cyclophosphamide, cyclosporin, or chlorambucil may be effective in patients with refractory polymyositis or dermatomyositis. Low-dose whole body or lymphoid irradiation is a last option in severely disabled patients resistant to all other treatments. As a small proportion of patients with inclusion body myositis respond to corticosteroid or immunosuppressive therapy, a 3–6-month trial of such therapy is justified in this condition. More specific immunotherapy for these disorders awaits identification of the target antigens and further clarification of the immunopathogenetic mechanisms. © 1997 John Wiley & Sons, Inc. Muscle Nerve 20:651–664, 1997.     

Obstructive sleep apnea in patients with inflammatory myopathies

The purpose of this study was to determine the frequency of obstructive sleep apnea in patients with inflammatory myopathy. An observational and prospective study was performed on a cohort of adult patients with inflammatory myopathy followed at a specialized outpatient clinic. Sixteen consecutive adult patients were evaluated by the Epworth Sleepiness Scale (ESS) and by complete polysomnography study. Disease activity and severity were assessed using the Myositis Disease Activity Assessment Tool (MDAAT) and Myositis Damage Index (MDI), respectively. Associations between sleep parameters and other factors were calculated using the chi‐square test, Fisher's exact test, Mann–Whitney U‐test, and Wilcoxon's test. A serum autoantibody profile was determined for all patients. The mean apnea–hypopnea index was 28.7 (23.8), and 14 patients (87%) had an apnea–hypopnea index >5. The mean frequency of respiratory arousals was 20.1 (12.5). Eleven (68%) patients reported frequently–always snoring, and 3 (19%) had excessive daytime sleepiness (ESS >10). Seven patients were offered continuous positive airway pressure (CPAP) therapy; 4 tolerated the procedure well and reported a clear improvement in daytime sleepiness and/or sleep quality. No significant association was observed between the apnea–hypopnea index and clinical or immunological groups. Dysphagia, disease activity, and disease severity were not significantly associated with any sleep parameters. The frequency of obstructive sleep apnea in adult patients with inflammatory myopathy is high. The possibility that these alterations play a role in persistent fatigue in these patients cannot be ruled out. Muscle Nerve 39: 144–149, 2009     

Inflammatory myopathies: clinical,diagnostic and therapeutic aspects

The three major forms of immune-mediated inflammatory myopathy are dermatomyositis (DM), polymyositis (PM), and inclusion-body myositis (IBM). They each have distinctive clinical and histopathologic features that allow the clinician to reach a specific diagnosis in most cases. Magnetic resonance imaging is sometimes helpful, particularly if the diagnosis of IBM is suspected but has not been formally evaluated. Myositis-specific antibodies are not helpful diagnostically but may be of prognostic value; most antibodies have low sensitivity. Muscle biopsy is mandatory to confirm the diagnosis of an inflammatory myopathy and to allow unusual varieties such as eosinophilic, granulomatous, and parasitic myositis, and macrophagic myofasciitis, to be recognized. The treatment of the inflammatory myopathies remains largely empirical and relies upon the use of corticosteroids, immunosuppressive agents, and intravenous immunoglobulin, all of which have nonselective effects on the immune system. Further controlled clinical trials are required to evaluate the relative efficacy of the available therapeutic modalities particularly in combinations, and of newer immunosuppressive agents (mycophenolate mofetil and tacrolimus) and cytokine-based therapies for the treatment of resistant cases of DM, PM, and IBM. Improved understanding of the molecular mechanisms of muscle injury in the inflammatory myopathies should lead to the development of more specific forms of immunotherapy for these conditions.     

Review: An update on inflammatory and autoimmune myopathies

The review provides an update on the diagnosis of the main subtypes of inflammatory myopathies including dermatomyositis (DM), polymyositis (PM), necrotizing autoimmune myositis (NAM) and sporadic inclusion body myositis (sIBM). The fundamental aspects on muscle pathology and the unique pathomechanisms of each subset are outlined and the diagnostic dilemmas concerning the distinction of PM from sIBM and NAM are addressed. Dermatomyositis is a complement-mediated microangiopathy leading to destruction of capillaries, hypoperfusion and inflammatory cell stress on the perifascicular regions. NAM, is an increasingly recognized subacute myopathy triggered by statins, viral infections, cancer or autoimmuity with macrophages as the final effector cells causing fibre injury. In PM and sIBM cytotoxic CD8-positive T cells clonally expand in situ and invade major histocompatibility-I-expressing muscle fibres. The pathology of sporadic inclusion body myositis is complex because, in addition to the inflammatory mechanisms, there are degenerative features characterized by vacuolization and the accumulation of stressor and amyloid-related misfolded proteins. Inducible pro-inflammatory molecules, such as interleukin 1-β, may enhance the accumulation of stressor proteins. The principles for more effective treatment strategies are discussed.     

Cytokines, chemokines, and cell adhesion molecules in inflammatory myopathies

The inflammatory myopathies include dermatomyositis (DM), polymyositis (PM), and sporadic inclusion-body myositis (s-IBM). In DM, the main immune effector response appears to be humoral and directed against the microvasculature, whereas in both PM and s-IBM, cytotoxic CD8+ T cells and macrophages invade and eventually destroy nonnecrotic muscle fibers expressing major histocompatibility complex class I. The need for more specific and safer therapies in inflammatory myopathies has prompted researchers to better decipher the molecular events associated with inflammation and muscle fiber loss in these diseases. The complex specific migration of leukocyte subsets to target tissues requires a coordinated series of events, namely activation of leukocytes, adhesion to the vascular endothelium, and migration. Cell adhesion molecules (CAM) and chemokines play a major role in this multistep process. In addition, cytokines by stimulating CAM expression and orchestrating T-cell differentiation also influence the immune response. This review focuses on recent advances in defining the molecular events involved in leukocyte trafficking in inflammatory myopathies. Specific topics include a concise summary of clinical features, pathological findings and immunopathology observed in inflammatory myopathies, background information about cytokines, chemokines and cell adhesion molecules, and the expression of these molecules in inflammatory myopathies.     

Sarcoplasmic redistribution of nuclear TDP‐43 in inclusion body myositis

The nucleic acid binding protein TDP‐43 was recently identified in normal myonuclei and in the sarcoplasm of inclusion body myositis (IBM) muscle. Here we found TDP‐43 sarcoplasmic immunoreactivity in 23% of IBM myofibers, while other reported IBM biomarkers were less frequent, with rimmed vacuoles in 2.8%, fluorescent Congo red material in 0.57%, SMI‐31 immunoreactivity in 0.83%, and focal R1282 beta‐amyloid immunoreactivity in 0.00% of myofibers. The presence of as little as >1% of myofibers with nonnuclear sarcoplasmic TDP‐43 was highly sensitive (91%) and specific (100%) to IBM among 50 inflammatory myopathy patient samples, although some patients with hereditary inclusion body myopathies and myofibrillar myopathy also had sarcoplasmic TDP‐43. TDP‐43 mutations were sought, and none were identified. TDP‐43 could be one of many nucleic acid binding proteins that are abnormally present in IBM sarcoplasm. They could potentially interfere with the normal function of extranuclear RNAs that maintain myofiber protein production. Muscle Nerve 40: 19–31, 2009     

Tau aggregates are abnormally phosphorylated in inclusion body myositis and have an immunoelectrophoretic profile distinct from other tauopathies

Sporadic inclusion body myositis (s-IBM) is the most frequent progressive acquired inflammatory myopathy in people older than 50 years. Abnormal aggregates of 'Alzheimer's proteins', including tau proteins, have been previously demonstrated in s-IBM. In the present study, we have investigated by immunohistochemistry and immunoblotting analysis the presence of tau proteins in muscle biopsy samples from patients with s-IBM and other myopathies with rimmed vacuoles, using newly developed antibodies raised against tau protein epitopes found in Alzheimer's disease brain. Tau immunoreactivity was shown in rimmed vacuoles or inclusions, preferentially with antibodies directed against phosphorylated carboxy-terminal epitopes of tau proteins. Cytoplasmic reactivity was also demonstrated in atrophic, nonvacuolated fibres, as well as in non-necrotic fibres invaded by inflammatory cells. Abnormally phosphorylated tau aggregates were also found in other compartments of the muscle fibre in s-IBM and other myopathies. Tau immunoblotting showed an electrophorectic profile of a doublet within the range of 60–62 kDa isovariants, which was different from tauopathies of the central nervous system. Finally, the unique pattern of immunoreactivity of s-IBM samples towards anti-tau antibodies is a new clue to a possible distinct subclass of peripheral tauopathy, different from the tauopathies of the central nervous system.     

The role of interleukin-17 in immune-mediated inflammatory myopathies and possible therapeutic implications

The idiopathic inflammatory myopathies are a heterogeneous group of autoimmune muscle disorders with distinct clinical and pathological features and underlying immunopathogenic mechanisms. Traditionally, CD4⁺ Th1 cells or CD8⁺ cytotoxic effector T cells and type I/II interferons have been primarily implicated in the pathogenesis of the inflammatory myopathies. The presence of IL-17A producing cells in the inflamed muscle tissue of myositis patients and the results of in vitro studies suggest that IL-17A and the Th17 pathway may also have a key role in these diseases. The contribution of IL-17A to other chronic inflammatory and autoimmune diseases has been well established and clinical trials of IL-17A inhibitors are now at an advanced stage. However the precise role of IL-17A in the various forms of myositis and the potential for therapeutic targeting is currently unknown and warrants further investigation.     

Fetus-like dystrophin expression and other cytoskeletal protein abnormalities in centronuclear myopathies

We have investigated supposed maturational arrest of muscle in ceatronuclear myopathies (CNMs) by characterizing the expression of dystrophin, other cytoskeletal proteins, and fetal myosin in the muscle fibers of 9 CNM patients (4 sporadic, 3 familial, 2 adult sporadic). Dystrophin and β-spectrin localized intracytoplasmically in centrally nucleated fibers. Talin and vinculin were normally expressed. Desmin was radially organized in several fibers in all patients. Scattered vimentin positive fibers were found in 3 cases. Six myotonic dystrophy cases and 4 inflammatory myopathy cases with regenerating fibers were also studied: dystrophin and the membrane cytoskeletal proteins were normally expressed in the former; and dystrophin, spectrin, and vinculin were reduced in the latter. Intracytoplasmic dystrophin is further evidence of maturational arrest in CNMs. Spectrin and dystrophin codistnbute in these pathological conditions as in normal muscle. We conclude that the altered cytoskeletal network found in CNMs likely plays a pathogenetic role in these conditions. © 1994 John Wiley & Sons, Inc.     

Inclusion body myositis in French patients. A clinicopathological evaluation

In order to establish the frequency of inclusion body myositis (IBM) in a European neuropathological unit and to evaluate the specificity of IBM pathology, we reviewed the 850 muscle biopsies performed in our laboratory over the past 7 years. Clinical histopathological and ultrastructural evaluation of all cases showing rimmed vacuoles, a constant histopathological feature of IBM, was done and the diagnosis of IBM was assessed using the clinico-pathological criteria of Calabrese, Mitsumoto & Chou (1987). Among the nine cases showing rimmed vacuoles, five were classified as IBM (group 1), either definite (3/5) or probable (2/5), and four suffered from a chronic denervating process of muscle (group 2). The overall frequency of IBM (0.6% of all muscle biopsies) was similar to that reported by North American authors. IBM represented 16% of adult idiopathic inflammatory myopathies investigated in our laboratory. Clinical and histopathological findings in group 1 were homogeneous and distinctive. Muscle biopsy was consistent with an inflammatory myopathy in all patients in group 1 and with a non-inflammatory denervating process in 3/4 patients in group 2. Typical intrasarcoplasmic inclusions were detected by electron microscopy in 3/5 cases in group 1 and 1/4 in group 2, which raises questions about the specificity of the 16-18 nm tubulofilaments. Failure to demonstrate inclusions in two patients with otherwise typical IBM, was probably related to the paucity of rimmed vacuoles observed in these cases.     

Genetics of inclusion-body myositis

Sporadic inclusion-body myositis (sIBM) is the most common acquired muscle disease in Caucasians over the age of 50 years. Pathologically it is marked by inflammatory, degenerative, and mitochondrial changes that interact in a yet-unknown way to cause progressive muscle degeneration and weakness. The cause of the disease is unknown, but it is thought to involve a complex interplay between environmental factors, genetic susceptibility, and aging. The strongest evidence for genetic susceptibility comes from studies of the major histocompatibility complex (MHC), where different combinations of alleles have been associated with sIBM in different ethnic groups. The rare occurrence of familial cases of inclusion-body myositis (fIBM) adds additional evidence for genetic susceptibility. Other candidate genes such as those encoding some of the proteins accumulating in muscle fibers have been investigated, with negative results. The increased understanding of related disorders, the hereditary inclusion-body myopathies (hIBM), may also provide clues to the underlying pathogenesis of sIBM, but to date there is no indication that the genes responsible for these conditions are involved in sIBM. This review summarizes current understanding of the contribution of genetic susceptibility factors to the development of sIBM.     

Inclusion body myositis--sensory dysfunction revealed with quantitative determination of somatosensory thresholds

In order to evaluate sensory function in inclusion body myositis (IBM), nine patients were subjected to sensibility screening and quantitative determination of somatosensory thresholds. Data were compared with results from electrophysiological examination and muscle biopsy. On sensibility screening all but one of the IBM patients had abnormal findings in hands and/or feet mostly affecting thermal sensibility. Vibratory thresholds were abnormal in five and thermal thresholds in four of the patients. Mean vibratory thresholds were significantly (P < 0.05) higher in the IBM patients when compared with the controls. Significantly increased heat pain thresholds were found in hands and feet when compared with the controls while thermal thresholds were normal. Nerve conduction velocities were decreased in three patients, EMG showed both myopathic and neuropathic abnormalities in six patients. Eight patients had neuropathic abnormalities on muscle biopsy. The sensory dysfunction found suggests an affection of peripheral nerves in IBM mainly affecting large diameter myelinated nerve fibres corroborating earlier findings of a peripheral neuropathy in IBM.     

Immunohistochemical study of semicarbazide-sensitive amine oxidase/vascular adhesion protein-1 in the hippocampal vasculature: Pathological synergy of Alzheimer's disease and diabetes mellitus

Semicarbazide‐sensitive amine oxidase/vascular adhesion protein‐1 (SSAO/VAP‐1) is involved in vascular endothelial damage as well as in the vascular degeneration underlying diabetes mellitus and Alzheimer's disease (AD). Recent evidence suggests that classic pathological features of AD are more pronounced in diabetic mellitus patients. To investigate the expression and distribution of SSAO/VAP‐1 in the two pathologies, we have performed an immunohistochemical study in human hippocampal vessels of AD, AD with diabetic mellitus (ADD), diabetic mellitus (DM), and nondemented (ND) patients. The present results demonstrate major vessel accumulation of both SSAO/VAP‐1 and amyloid‐β immunolabeling intensity in ADD compared with AD patients. Interestingly, nearly damaged vessels with high levels of SSAO/VAP‐1 also showed increased oxidative damage markers (AGE, RAGE, and SOD‐1) and glial activation (GFAP and HLA). Overall, this work suggests that high vascular SSAO/VAP‐1 levels in human hippocampus may contribute to vascular degeneration, which can explain the severe progression in patients with both pathologies. © 2012 Wiley Periodicals, Inc.     

Increase of cytochrome c oxidase negative fibers in rimmed vacuole myopathy with inflammatory changes

The physiological significance of cytochrome c oxidase (CCO) deficiency in rimmed vacuole myopathy (RVM) is not fully understood. Frequencies of CCO negative muscle fibers (CCO(?)F) were compared with two cases of in-clusion body myositis (IBM) and another two cases with RVM without inflammatory changes (i.e. oculopharyngeal distal myopathy (OPDM) and distal myopathy with rimmed vacuole formation (DMRV)). The frequencies of CCO(?)F were 6.9% in the case of definite IBM with 10 years of disease duration, 0.3% in possible IBM of 1 year duration, 1.3% in OPDM of 11 years duration, and 0.1% in DMRV of 2 years duration. The frequencies of CCO(?)F were generally higher in RVM than in controls. However, the incidence of CCO(?)F increased with time in patients with IBM compared with patients with RVM without inflammation. The present findings may provide important information on the myopathological distinction of IBM and RVM without inflammation.     

Magnetic resonance imaging pattern recognition in sporadic inclusion‐body myositis

Introduction: In sporadic inclusion‐body myositis (IBM), additional tools are needed to confirm the diagnosis, particularly in clinically atypical or pathologically unproven patients. The aims of this study were to define the pattern of muscle MRI in IBM and to assess its accuracy in differentiating IBM from other myopathies that overlap with it clinically or pathologically. Methods: Blind assessment was done on the scans of 17 definite IBM, 2 possible IBM, and 118 patients with other myopathies. Results: The diagnostic accuracy to detect definite IBM was 95% for the typical pattern (with 100% specificity) and 97% for both typical and consistent patterns (with 97% specificity). Conclusions: Muscle MRI is an accurate tool for diagnostic work‐up of suspected IBM patients and may be particularly helpful in patients with early disease or who lack the classical IBM pathology. Muscle Nerve 52 : 956–962, 2015