Steps in Inclusion Body Myositis

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Interferon-gamma mediates skeletal muscle lesions through JAK/STAT pathway activation in inclusion body myositis

Dysimmune and Inflammatory Myopathies (DIMs) are acquired idiopathic myopathy associated with immune response dysregulation. Inclusion Body Myositis (IBM), the most common DIMs, is characterized by endomysial infiltrates of cytotoxic T lymphocytes CD8, muscle type II-interferon (IFNγ) signature, and by the lack of response to immunomodulatory therapies. We showed that IBM was pathologically characterized by the presence of chronic degenerative myopathic features including myofiber atrophy, fibrosis, adipose involution, and the altered functions of skeletal muscle stem cells. Here, we demonstrated that protracted systemic exposure to IFNγ delayed muscle regeneration and led to IBM-like muscular degenerative changes in mice. In vitro, IFNγ treatment inhibited the activation, proliferation, migration, differentiation, and fusion of myogenic progenitor cells and promoted their senescence through JAK-STAT-dependent activation. Finally, JAK-STAT inhibitor, ruxolitinib abrogated the deleterious effects of IFNγ on muscle regeneration, suggesting that the JAK-STAT pathway could represent a new therapeutic target for IBM.

Overview on Diagnosis and Management of Polymyositis

Polymyositis (PM) is an autoimmune disorder; result from abnormal activation of cytotoxic T lymphocytes (CD8 cells) and macrophages against muscular antigens as well as the strong extrafusal muscular expression of major histocompatibility complex class 1 causing damage to the endomysium of the skeletal muscles. Polymyositis develops over the months as compared to inclusion body myositis (IBM), which is a slowly progressive chronic myopathy developing in older individuals over a period of months to years with more severe symptoms. Many patients require treatment for many years. Polymyositis affects the distal musculature of the esophagus in the late stage of disease in up to 70% of the patients leading to the inability to swallow, as well as regurgitation problems that can cause aspiration pneumonia. The principal goals of therapy are to improve strength and improve physical functioning. Many patients require treatment for several years. The 5-year survival rate for treated patients is in the order of 95%. Up to one-third of PM patients may be left with some degree of residual muscle weakness.

A Rare Case of Sporadic Inclusion Body Myositis with Atypical Presentation

Sporadic inclusion body myositis (IBM) is the most common acquired inflammatory myopathy that occurs after the age of 50 years. IBM typically involves wrist and finger flexors and quadriceps, but all sporadic IBM may not have the classic presentation of distal arm and proximal leg involvement. Treating physicians must be aware of this atypical presentation to avoid the misdiagnosis of IBM, leading to treatment with immunosuppressive agents. The aim of this study is to increase the awareness among physicians about the atypical presentation of IBM and to emphasize the importance of muscle biopsy in such cases. Here we report a case of 52 years old male diagnosed with sporadic IBM by muscle biopsy presented with atypical presentation.

Revisiting the Role of GSK3, A Modulator of Innate Immunity, in Idiopathic Inclusion Body Myositis

Idiopathic or sporadic inclusion body myositis (IBM) is the leading age-related (onset > 50 years of age) autoimmune muscular pathology, resulting in significant debilitation in affected individuals. Once viewed as primarily a degenerative disorder, it is now evident that much like several other neuro-muscular degenerative disorders, IBM has a major autoinflammatory component resulting in chronic inflammation-induced muscle destruction. Thus, IBM is now considered primarily an inflammatory pathology. To date, there is no effective treatment for sporadic inclusion body myositis, and little is understood about the pathology at the molecular level, which would offer the best hopes of at least slowing down the degenerative process. Among the previously examined potential molecular players in IBM is glycogen synthase kinase (GSK)-3, whose role in promoting TAU phosphorylation and inclusion bodies in Alzheimer’s disease is well known. This review looks to re-examine the role of GSK3 in IBM, not strictly as a promoter of TAU and Abeta inclusions, but as a novel player in the innate immune system, discussing some of the recent roles discovered for this well-studied kinase in inflammatory-mediated pathology.

Acquired Muscle Disorders

Muscle diseases consist of various disorders that primarily affect skeletal muscle, but they can also affect cardiac or smooth muscle. The disorders may be inherited or acquired. The pathophysiology, clinical manifestations, diagnostic pathways, and treatment options will vary for each disorder. This chapter reviews common acquired muscle disorders. Inflammatory myopathies are characterized by muscle weakness and inflammatory reaction in muscle, and often, but not always, are accompanied by elevated creatine kinase values. They can occur with infections, systemic inflammatory diseases, or they may be idiopathic. On the basis of clinical, histologic, and immunopathologic criteria, idiopathic inflammatory myopathies can be distinguished as dermatomyositis, polymyositis, or inclusion body myositis. When dermatomyositis or polymyositis occurs in association with a connective tissue disease, the disorder is called overlap syndrome.

Diagnosis and Clinical Development of Sporadic Inclusion Body Myositis and Polymyositis With Mitochondrial Pathology: A Single-Center Retrospective Analysis

To review our diagnostic and treatment approaches concerning sporadic inclusion body myositis (sIBM) and polymyositis with mitochondrial pathology (PM-Mito), we conducted a retrospective analysis of clinical and histological data of 32 patients diagnosed as sIBM and 7 patients diagnosed as PM-Mito by muscle biopsy. Of 32 patients identified histologically as sIBM, 19 fulfilled the 2011 European Neuromuscular Center (ENMC) diagnostic criteria for “clinico-pathologically defined sIBM” at the time of biopsy. Among these, 2 patients developed sIBM after years of immunosuppressive treatment for organ transplantation. Of 11 patients fulfilling the histological but not the clinical criteria, including 3 cases with duration <12 months, 8 later fulfilled the criteria for clinico-pathologically defined sIBM. Of 7 PM-Mito patients, 4 received immunosuppression with clinical improvement in 3. One of these later developed clinico-pathologically defined sIBM; 1 untreated patient progressed to clinically defined sIBM. Thus, muscle histology remains important for this differential diagnosis to identify sIBM patients not matching the ENMC criteria and the PM-Mito group. In the latter, we report at least 50% positive, if occasionally transient, response to immunosuppressive treatments and progression to sIBM in a minority. The mitochondrial abnormalities defining PM-Mito do not seem to define the threshold to immunosuppression unresponsiveness.

Inclusion body myositis: correlation of clinical outcomes with histopathology, electromyography and laboratory findings

Objective To determine whether histopathological, electromyographic and laboratory markers correlate with clinical measures in Inclusion Body Myositis (IBM) Methods We reviewed our electronic medical records to identify patients with IBM according to ENMC 2011 criteria, seen between 2015 and 2020. We only included patients who had a muscle biopsy and needle electromyography (EMG) performed on the same muscle (opposite or same side). We used a detailed grading system (0- normal to 4- severe) to score histopathological and EMG findings. Clinical severity was assessed by the modified Rankin scale (mRS), muscle strength sum score (SSS), quadriceps strength and severity of dysphagia on swallow evaluation. Serum markers of interest were creatine kinase level, and cN-1A antibodies. Results We included 50 IBM patients, with a median age of 69 years; 64% were males. Median disease duration at diagnosis was 51 months. On muscle biopsy, endomysial inflammation mainly correlated with dysphagia, and inversely correlated with mRS. Vacuoles and congophilic inclusions did not correlate with any of the clinical measures. On EMG, the shortness of motor unit potential (MUP) duration correlated with all clinical measures. Myotonic discharges, and not fibrillation potentials, correlated with the severity of inflammation. Serum markers did not have a statistically-significant correlation with any of the clinical measures. Conclusions Dysphagia was the main clinical feature of IBM correlating with endomysial inflammation. Otherwise, inclusion body myositis clinical measures had limited correlation with histopathological features in this study. The shortness of MUP duration correlated with all clinical measures.