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Steven A Greenberg - One of the best experts on this subject based on the ideXlab platform.
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Highly differentiated cytotoxic T cells in Inclusion Body myositis
Brain, 2019Co-Authors: Steven A Greenberg, Sek Won Kong, Clare Baecher-allan, Jack L Pinkus, Anthony A Amato, David M DorfmanAbstract:Inclusion Body myositis is a late onset treatment-refractory autoimmune disease of skeletal muscle associated with a blood autoantiBody (anti-cN1A), an HLA autoimmune haplotype, and muscle pathology characterized by cytotoxic CD8+ T cell destruction of myofibres. Here, we report on translational studies of Inclusion Body myositis patient muscle compared with a diverse set of other muscle disease samples. Using available microarray data on 411 muscle samples from patients with Inclusion Body myositis (n = 40), other muscle diseases (n = 265), and without neuromuscular disease (normal, n = 106), we identified a signature of T-cell cytotoxicity in Inclusion Body myositis muscle coupled with a signature of highly differentiated CD8 T-cell effector memory and terminally differentiated effector cells. Further, we examined killer cell lectin-like receptor G1 (KLRG1) as a marker of this population of cells, demonstrated the correlation of KLRG1 gene expression with lymphocyte cytotoxicity across 28 870 human tissue samples, and identified the presence of KLRG1 on pathogenic Inclusion Body myositis muscle invading T cells and an increase in KLRG1 expressing T cells in Inclusion Body myositis blood. We examined Inclusion Body myositis muscle T-cell proliferation by Ki67 immunohistochemistry demonstrating that diseased muscle-invading T cells are minimally or non-proliferative, in accordance with known properties of highly differentiated or terminally differentiated T cells. We found low expression of KLRG1 on infection-protective human lymphoid tissue central memory T cells and autoimmune-protective human blood regulatory T cells. Targeting highly differentiated cytotoxic T cells could be a favourable approach to treatment of Inclusion Body myositis.
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Inclusion Body myositis: clinical features and pathogenesis
Nature Reviews Rheumatology, 2019Co-Authors: Steven A GreenbergAbstract:Inclusion Body myositis (IBM) progresses slowly and is commonly misdiagnosed initially as arthritis or polymyositis; IBM is associated with cardiovascular complications and other autoimmune diseases and has a high economic cost. IBM has unique physical examination features (such as finger flexor and knee extensor weakness) that distinguish it from most other muscle diseases. IBM has a greater range of autoimmune T cell abnormalities than any other muscle disease; treatment refractoriness has paradoxically given rise to the view that IBM is not an autoimmune disease. Degenerative abnormalities that can occur in IBM include numerous myofibre protein aggregates associated with endoplasmic reticulum stress. Degenerative abnormalities might occur following autoimmunity in cell culture and mouse models and following immune cell dysfunction in patients infected with HIV or human T cell lymphotropic virus type 1. Treatment refractoriness probably reflects the inability of current therapies to inhibit or deplete the highly differentiated population of effector memory and terminally differentiated effector T cells present in IBM. Inclusion Body myositis (IBM) is a slowly progressive disease characterized by unique clinical and pathological features. This Review discusses the historical and clinical aspects of IBM and the mounting evidence arguing for the important pathogenic function of the immune system. Inclusion Body myositis (IBM) is often viewed as an enigmatic disease with uncertain pathogenic mechanisms and confusion around diagnosis, classification and prospects for treatment. Its clinical features (finger flexor and quadriceps weakness) and pathological features (invasion of myofibres by cytotoxic T cells) are unique among muscle diseases. Although IBM T cell autoimmunity has long been recognized, enormous attention has been focused for decades on several biomarkers of myofibre protein aggregates, which are present in
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health care costs and comorbidities for patients with Inclusion Body myositis
Current Medical Research and Opinion, 2018Co-Authors: Allison Keshishian, Steven A Greenberg, Neetu Agashivala, O Baser, Kristen JohnsonAbstract:Objective: This study identifies the health care costs and utilization, as well as comorbidities, in a Medicare population of Inclusion Body myositis (IBM) patients.Methods: Medicare patients aged ...
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association of Inclusion Body myositis with t cell large granular lymphocytic leukaemia
Brain, 2016Co-Authors: Jack L Pinkus, Steven A Greenberg, Anthony A Amato, Thomas Kielsgaard Kristensen, David M DorfmanAbstract:SEE HOHLFELD AND SCHULZE-KOOPS DOI101093/BRAIN/AWW053 FOR A SCIENTIFIC COMMENTARY ON THIS ARTICLE: Inclusion Body myositis and T cell large granular lymphocytic leukaemia are rare diseases involving pathogenic cytotoxic CD8+ T cells. After encountering four patients with both disorders, we prospectively screened 38 patients with Inclusion Body myositis for the presence of expanded large granular lymphocyte populations by standard clinical laboratory methods (flow cytometry, examination of blood smears, and T cell receptor gene rearrangements), and performed muscle immunohistochemistry for CD8, CD57, and TIA1. Most (22/38; 58%) patients with Inclusion Body myositis had aberrant populations of large granular lymphocytes in their blood meeting standard diagnostic criteria for T cell large granular lymphocytic leukaemia. These T cell populations were clonal in 20/20 patients and stably present on follow-up testing in 15 patients a median of 350 days later. T cell aberrant loss of CD5 or gain of expression of CD16 and CD94 were common (19/42, 45%). In comparison, 2/15 (14%) age-matched patients with dermatomyositis, polymyositis, or necrotizing myopathy, and 0/20 (0%) age-matched healthy subjects had large granular lymphocyte expansions, with none of these patients having T cell aberrant expression of CD5, CD16 or CD94. Reduced blood CD4/CD8 ratio, increased blood CD8 count, and lymphocytosis were additional biomarkers highly correlated with flow cytometry-measured large granular lymphocyte expansions. Cross-sectional data suggested more aggressive disease in patients with such expansions than without. Muscle immunohistochemistry demonstrated invasion of large granular lymphocytes into muscle in 15/15 Inclusion Body myositis patients but in only 1/28 patients with dermatomyositis or polymyositis. The extent of CD8+ and CD57+ cells in Inclusion Body myositis muscle correlated with the size of blood large granular lymphocyte populations. Myofibre-invading cells expressed CD57, a marker of persistent T cell exposure to antigen and T cell aggressiveness. In many patients with Inclusion Body myositis, the autoimmune T cell expansion has evolved into a neoplastic-like or overtly neoplastic disorder, perhaps contributing to its relative refractoriness to immune-directed therapies previously reported.
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Inclusion Body myositis.
Current opinion in rheumatology, 2011Co-Authors: Steven A GreenbergAbstract:Purpose of reviewSporadic Inclusion Body myositis (sIBM) is a poorly understood immune and degenerative disease of skeletal muscle. Here, current opinion of the nature of this disease is summarized.Recent findingsRecent findings for sIBM include further characterization of muscle involvement through
Marinos C. Dalakas - One of the best experts on this subject based on the ideXlab platform.
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sporadic Inclusion Body myositis diagnosis pathogenesis and therapeutic strategies
Nature Reviews Neurology, 2006Co-Authors: Marinos C. DalakasAbstract:Sporadic Inclusion Body myositis is a slowly progressive inflammatory myopathy that is characterized histopathologically by a combination of degenerative and autoimmune inflammatory features in the muscle fibers. In this review, Marinos Dalakas describes the clinical features of sporadic Inclusion Body myositis, and considers potential disease mechanisms and therapeutic strategies.
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inflammatory disorders of muscle progress in polymyositis dermatomyositis and Inclusion Body myositis
Current Opinion in Neurology, 2004Co-Authors: Marinos C. DalakasAbstract:Purpose of review To provide an update on the major advances in inflammatory myopathies. Recent findings Polymyositis is an uncommon disorder that can be misdiagnosed when the old, and never validated, criteria of Bohan and Peter are used. New diagnostic criteria were recently introduced, in which the MHC/CD8 complex is considered a specific immunopathological marker because it distinguishes the antigen-driven inflammatory cells that characterize polymyositis and sporadic Inclusion-Body myositis from the non-specific, secondary inflammation seen in other disorders, such as dystrophies. In sporadic Inclusion-Body myositis the inflammatory cells invade non-vacuolated fibers, whereas the vacuolated fibers are not invaded by T cells, implying two independent processes, a primary immune process with antigen-driven T cells identical to polymyositis, and a degenerative process in which beta-amyloid and amyloid-related proteins participate in vacuolar degeneration. In polymyositis and sporadic Inclusion-Body myositis, antigen-specific and clonally expanded autoinvasive T cells persist for years, even in different muscles, as reconfirmed by proof-of-principle techniques involving CDR3 spectratyping combined with laser microdissected single-cell polymerase chain reaction of the T-cell receptor genes. The formation of immunological synapse between autoinvasive T cells and muscle fibers was recently strengthened by the upregulation of co-stimulatory molecules ICOS/ICOS-L and PD-L1. A new, distinct myopathy characterized by T-cell-triggered macrophage hyperactivation has now been recognized in patients with dermatomyositis-like disease. Summary Despite recent progress, the antigen(s) responsible for T-cell activation in polymyositis and sporadic Inclusion-Body myositis and the cause of vacuolar degeneration in sporadic Inclusion-Body myositis remain unclear. Newer, more aggressive immunotherapies may be encouraging, but control trials are needed to prove efficacy.
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Mitochondrial DNA variants in Inclusion Body myositis.
Neuromuscular disorders : NMD, 2000Co-Authors: Chee Choy Kok, Valerie Askanas, Adam Boyt, Silvana Gaudieri, Ralph N. Martins, Marinos C. Dalakas, Lyn Kiers, Frank L. Mastaglia, Michael J. GarleppAbstract:Mitochondrial DNA variants have been shown to be associated with many diseases. Mutations at mitochondrial DNA nucleotide positions 3192, 3196, 3397 and 4336 have been described in association with late-onset Alzheimer's disease. The pathological similarities between Inclusion Body myositis and Alzheimer's disease prompted an analysis of the relationship between the reported mutations and sporadic Inclusion Body myositis. The 4336G variant was not significantly increased in patients with Inclusion Body myositis or Alzheimer's disease when compared to controls. None of the patients with Inclusion Body myositis carried mutations at nucleotide positions 3192, 3196 and 3397. A transition at nucleotide position 4580 was detected in some patients with Inclusion Body myositis and Alzheimer's disease but was not significantly higher in frequency when compared to controls. Phylogenetic analysis showed that the 4336G and 4580A variants clustered together in their respective group. A group of patients with Inclusion Body myositis also clustered together on a separate branch of the phylogenetic tree. Closer investigation of this group revealed a common polymorphism at nucleotide position 16311. The frequency of the 16311C variant was higher in Inclusion Body myositis than in Alzheimer's disease and controls, although when only caucasian patients were considered the increased frequency was not statistically significant. Further studies will be required to determine whether this variant plays a role in the pathogenesis of Inclusion Body myositis.
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Inclusion Body myositis and myopathies.
Current opinion in neurology, 1997Co-Authors: Kumaraswamy Sivakumar, Marinos C. DalakasAbstract:Sporadic Inclusion Body myositis is a frequent, acquired, adult-onset vacuolar myopathy affecting proximal and distal muscles with a distinct, easily identifiable clinical pattern. Although its primary cause is still unknown, autoimmune, viral, and degenerative processes, alone or in combination, are being considered. A uniform and sustained therapeutic response using the currently available immunomodulatory agents has not yet been achieved. Hereditary, inherited noninflammatory rimmed vacuolar myopathies with similar histologic features, collectively called hereditary Inclusion Body myopathies, are being redefined with the use of molecular genetics. The implications of the recent advances in clinical and basic sciences are discussed in the present review.
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polymyositis dermatomyositis and Inclusion Body myositis
The New England Journal of Medicine, 1991Co-Authors: Marinos C. DalakasAbstract:THE polymyositis and dermatomyositis complex encompasses a heterogeneous group of acquired muscle diseases called inflammatory myopathies because muscle weakness and inflammatory infiltrates within the skeletal muscles are the principal clinical and histologic findings.1 2 3 4 5 6 7 8 9 10 11 12 Traditionally, polymyositis and dermatomyositis have been viewed as pathogenetically similar and part of the spectrum of "idiopathic" inflammatory myopathies,9 , 10 , 13 , 14 despite the variability in their clinical and laboratory characteristics, prognosis, and response to therapy. With the evolution over the past 10 years of rather well defined clinical, demographic, histologic, and immunopathological criteria and the identification of Inclusion-Body myositis as a distinct type of polymyositis,15 the inflammatory myopathies now . . .
Anthony A Amato - One of the best experts on this subject based on the ideXlab platform.
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Highly differentiated cytotoxic T cells in Inclusion Body myositis
Brain, 2019Co-Authors: Steven A Greenberg, Sek Won Kong, Clare Baecher-allan, Jack L Pinkus, Anthony A Amato, David M DorfmanAbstract:Inclusion Body myositis is a late onset treatment-refractory autoimmune disease of skeletal muscle associated with a blood autoantiBody (anti-cN1A), an HLA autoimmune haplotype, and muscle pathology characterized by cytotoxic CD8+ T cell destruction of myofibres. Here, we report on translational studies of Inclusion Body myositis patient muscle compared with a diverse set of other muscle disease samples. Using available microarray data on 411 muscle samples from patients with Inclusion Body myositis (n = 40), other muscle diseases (n = 265), and without neuromuscular disease (normal, n = 106), we identified a signature of T-cell cytotoxicity in Inclusion Body myositis muscle coupled with a signature of highly differentiated CD8 T-cell effector memory and terminally differentiated effector cells. Further, we examined killer cell lectin-like receptor G1 (KLRG1) as a marker of this population of cells, demonstrated the correlation of KLRG1 gene expression with lymphocyte cytotoxicity across 28 870 human tissue samples, and identified the presence of KLRG1 on pathogenic Inclusion Body myositis muscle invading T cells and an increase in KLRG1 expressing T cells in Inclusion Body myositis blood. We examined Inclusion Body myositis muscle T-cell proliferation by Ki67 immunohistochemistry demonstrating that diseased muscle-invading T cells are minimally or non-proliferative, in accordance with known properties of highly differentiated or terminally differentiated T cells. We found low expression of KLRG1 on infection-protective human lymphoid tissue central memory T cells and autoimmune-protective human blood regulatory T cells. Targeting highly differentiated cytotoxic T cells could be a favourable approach to treatment of Inclusion Body myositis.
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association of Inclusion Body myositis with t cell large granular lymphocytic leukaemia
Brain, 2016Co-Authors: Jack L Pinkus, Steven A Greenberg, Anthony A Amato, Thomas Kielsgaard Kristensen, David M DorfmanAbstract:SEE HOHLFELD AND SCHULZE-KOOPS DOI101093/BRAIN/AWW053 FOR A SCIENTIFIC COMMENTARY ON THIS ARTICLE: Inclusion Body myositis and T cell large granular lymphocytic leukaemia are rare diseases involving pathogenic cytotoxic CD8+ T cells. After encountering four patients with both disorders, we prospectively screened 38 patients with Inclusion Body myositis for the presence of expanded large granular lymphocyte populations by standard clinical laboratory methods (flow cytometry, examination of blood smears, and T cell receptor gene rearrangements), and performed muscle immunohistochemistry for CD8, CD57, and TIA1. Most (22/38; 58%) patients with Inclusion Body myositis had aberrant populations of large granular lymphocytes in their blood meeting standard diagnostic criteria for T cell large granular lymphocytic leukaemia. These T cell populations were clonal in 20/20 patients and stably present on follow-up testing in 15 patients a median of 350 days later. T cell aberrant loss of CD5 or gain of expression of CD16 and CD94 were common (19/42, 45%). In comparison, 2/15 (14%) age-matched patients with dermatomyositis, polymyositis, or necrotizing myopathy, and 0/20 (0%) age-matched healthy subjects had large granular lymphocyte expansions, with none of these patients having T cell aberrant expression of CD5, CD16 or CD94. Reduced blood CD4/CD8 ratio, increased blood CD8 count, and lymphocytosis were additional biomarkers highly correlated with flow cytometry-measured large granular lymphocyte expansions. Cross-sectional data suggested more aggressive disease in patients with such expansions than without. Muscle immunohistochemistry demonstrated invasion of large granular lymphocytes into muscle in 15/15 Inclusion Body myositis patients but in only 1/28 patients with dermatomyositis or polymyositis. The extent of CD8+ and CD57+ cells in Inclusion Body myositis muscle correlated with the size of blood large granular lymphocyte populations. Myofibre-invading cells expressed CD57, a marker of persistent T cell exposure to antigen and T cell aggressiveness. In many patients with Inclusion Body myositis, the autoimmune T cell expansion has evolved into a neoplastic-like or overtly neoplastic disorder, perhaps contributing to its relative refractoriness to immune-directed therapies previously reported.
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treatment of sporadic Inclusion Body myositis with bimagrumab
Neurology, 2014Co-Authors: Anthony A Amato, Kumaraswamy Sivakumar, Mohammad Salajegheh, Namita Goyal, William S David, Jens Praestgaard, Estelle Lachtrifilieff, Anneulrike Trendelenburg, Didier Laurent, David J GlassAbstract:Objective: To study activin signaling and its blockade in sporadic Inclusion Body myositis (sIBM) through translational studies and a randomized controlled trial. Methods: We measured transforming growth factor β signaling by SMAD2/3 phosphorylation in muscle biopsies of 50 patients with neuromuscular disease (17 with sIBM). We tested inhibition of activin receptors IIA and IIB (ActRII) in 14 patients with sIBM using one dose of bimagrumab (n = 11) or placebo (n = 3). The primary outcome was the change in right thigh muscle volume by MRI at 8 weeks. Lean Body mass, strength, and function were secondary outcomes. Twelve of the patients (10 bimagrumab, 2 placebo) participated in a subsequent 16-week observation phase. Results: Muscle SMAD2/3 phosphorylation was higher in sIBM than in other muscle diseases studied ( p = 0.003). Eight weeks after dosing, the bimagrumab-treated patients increased thigh muscle volume (right leg +6.5% compared with placebo, p = 0.024; left leg +7.6%, p = 0.009) and lean Body mass (+5.7% compared with placebo, p = 0.014). Subsequently, bimagrumab-treated patients had improved 6-minute walking distance, which peaked at 16 weeks (+14.6%, p = 0.008) compared with placebo. There were no serious adverse events; the main adverse events with bimagrumab were mild acne and transient involuntary muscle contractions. Conclusions: Transforming growth factor β superfamily signaling, at least through ActRII, is implicated in the pathophysiology of sIBM. Inhibition of ActRII increased muscle mass and function in this pilot trial, offering a potential novel treatment of sIBM. Classification of evidence: This study provides Class I evidence that for patients with Inclusion Body myositis, bimagrumab increases thigh muscle volume at 8 weeks.
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Inclusion Body myositis update
Current Opinion in Rheumatology, 2014Co-Authors: Arash H Lahouti, Anthony A Amato, Lisa ChristopherstineAbstract:PURPOSE OF REVIEW To examine new developments in sporadic Inclusion Body myositis (IBM), including updated clinical and prognostic factors, novel autoantiBody associations, unique histopathologic findings, proposed new clinical diagnostic criteria, and novel therapeutic agents. RECENT FINDINGS IBM is a slowly progressive disease, leading to wheelchair use, on average, 12-20 years after onset of symptoms; however, it does not appear to interfere with life expectancy. Older age at the onset of first symptoms as well as immunosuppressive therapy are likely associated with more rapid disease progression. Quantitative muscle strength of knee extensor and the IBM functional rating scale seem to be sensitive disease progression markers and may be useful clinical trial outcome measures. Newly proposed diagnostic criteria utilize data-driven approaches with very high sensitivity and specificity. A novel autoantiBody, as well as unique proteins seen histopathlogically, may help hone in on diagnosis as well as to deepen our understanding of IBM pathophysiology. Novel treatments, including follistatin and bimagrumab, are directed at potential therapeutic targets. SUMMARY We have observed an explosion of knowledge in IBM in the recent past, which challenges traditional dogma and ushers in a new era of understanding with potential clinical implications for those who suffer with IBM.
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sarcoplasmic redistribution of nuclear tdp 43 in Inclusion Body myositis
Muscle & Nerve, 2009Co-Authors: Jack L Pinkus, Anthony A Amato, Mohammad Salajegheh, Paul J Taylor, Remedios Nazareno, Robert H Baloh, Steven A GreenbergAbstract: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 non-nuclear sarcoplasmic TDP-43 was highly sensitive (91%) and specific (100%) to IBM among 50 inflammatory myopathy patient samples, though 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.
Valerie Askanas - One of the best experts on this subject based on the ideXlab platform.
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Inclusion Body myositis a multifactorial muscle disease associated with aging current concepts of pathogenesis
Current Opinion in Rheumatology, 2007Co-Authors: Valerie Askanas, King W EngelAbstract:PURPOSE OF REVIEW Sporadic Inclusion-Body myositis, the most common muscle disease of older persons, has no known cause or persistently beneficial treatment. The unfolding pathogenesis could lead to new treatment strategies and it is now of growing interest among clinicians and basic scientists. About 100 papers related to the subject were published in 2006 and the first part of 2007 (we cite only articles most relevant to this review). RECENT FINDINGS This review focuses on the current concepts of the pathogenesis of sporadic Inclusion-Body myositis. Both degeneration and mononuclear-cell inflammation are components of the pathology, but how each relates to the pathogenesis remains unclear. We suggest that an intramuscle fiber degenerative component is primary, leading to muscle-fiber destruction, while the lymphocytic inflammatory component may only slightly contribute to sporadic Inclusion-Body myositis muscle-fiber damage. Intracellular accumulation of amyloid-beta precursor protein, amyloid-beta, and amyloid-beta oligomers in an aging muscle-fiber cellular milieu, and other abnormalities, appear to be key pathogenic factors. We summarize intracellular molecular events and their consequences, and correlate findings in sporadic Inclusion-Body myositis muscle biopsies with Inclusion-Body myositis experimental models in tissue culture and in transgenic mice. SUMMARY Treatment of sporadic Inclusion-Body myositis remains a challenge. Antiinflammatory approaches used so far are without major or enduring benefit. Possible new treatment avenues are suggested.
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Inclusion Body myositis clinical diagnostic and pathologic aspects
Neurology, 2006Co-Authors: King W Engel, Valerie AskanasAbstract:The diagnostic aspects of sporadic Inclusion-Body myositis (s-IBM), and a few comments on our own approach to its treatment, are presented to foster the goals of this symposium, which was organized to provoke new ideas concerning the cause and treatment of this currently unsolvable disease. s-IBM is the most common, progressive, debilitating muscle disease beginning in persons over age 50 years, and it is more common in men. Diagnostic parameters reviewed are clinical, muscle-biopsy histochemistry, electrophysiologic and CSF evaluations. Overall, the degenerative phenomena in s-IBM muscle fibers seem to be the major cause of the progressive, unstoppable weakness, rather than the lymphocytic inflammation. Available treatments are of only slight, temporary benefit for only some s-IBM patients, indicating a desperate need for definitive therapies.
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Mitochondrial DNA variants in Inclusion Body myositis.
Neuromuscular disorders : NMD, 2000Co-Authors: Chee Choy Kok, Valerie Askanas, Adam Boyt, Silvana Gaudieri, Ralph N. Martins, Marinos C. Dalakas, Lyn Kiers, Frank L. Mastaglia, Michael J. GarleppAbstract:Mitochondrial DNA variants have been shown to be associated with many diseases. Mutations at mitochondrial DNA nucleotide positions 3192, 3196, 3397 and 4336 have been described in association with late-onset Alzheimer's disease. The pathological similarities between Inclusion Body myositis and Alzheimer's disease prompted an analysis of the relationship between the reported mutations and sporadic Inclusion Body myositis. The 4336G variant was not significantly increased in patients with Inclusion Body myositis or Alzheimer's disease when compared to controls. None of the patients with Inclusion Body myositis carried mutations at nucleotide positions 3192, 3196 and 3397. A transition at nucleotide position 4580 was detected in some patients with Inclusion Body myositis and Alzheimer's disease but was not significantly higher in frequency when compared to controls. Phylogenetic analysis showed that the 4336G and 4580A variants clustered together in their respective group. A group of patients with Inclusion Body myositis also clustered together on a separate branch of the phylogenetic tree. Closer investigation of this group revealed a common polymorphism at nucleotide position 16311. The frequency of the 16311C variant was higher in Inclusion Body myositis than in Alzheimer's disease and controls, although when only caucasian patients were considered the increased frequency was not statistically significant. Further studies will be required to determine whether this variant plays a role in the pathogenesis of Inclusion Body myositis.
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Sporadic Inclusion-Body Myositis and Hereditary Inclusion-Body Myopathies: Diseases of Oxidative Stress and Aging?
Archives of neurology, 1998Co-Authors: Valerie Askanas, W. K. EngelAbstract:Sporadic Inclusion-Body myositis and hereditary Inclusion-Body myopathies are progressive and highly debilitating muscle diseases. The most characteristic morphologic feature of sporadic Inclusion-Body myositis and hereditary Inclusion-Body myopathies is vacuolar degeneration of muscle fibers, accompanied by intrafiber clusters (“tangles”) of paired-helical filaments and by accumulation of several proteins that are characteristic of a brain of patients with Alzheimer disease. In neither the hereditary Inclusion-Body myopathies nor sporadic Inclusion-Body myositis are the sequential steps of the pathogenic cascade understood. The several forms of hereditary Inclusion-Body myopathies have different genetic transmissions and probably different genetic defects. Because the sporadic Inclusion-Body myositis and hereditary Inclusion-Body myopathies have several characteristic pathologic features in common, we postulate that their different causes trigger the same upstream aberration leading to a similar downstream cascade of pathologic events, which are ultimately responsible for the characteristic muscle-fiber degeneration. We propose that important contributory factors leading to the Inclusion-Body myositis‐specific muscle fiber destruction are muscle aging and oxidative stress, putatively induced by the upstream overexpression of b-amyloid precursor protein within abnormal muscle fibers.
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Inclusion Body myositis and myopathies.
Annals of neurology, 1995Co-Authors: Robert C. Griggs, Jerry R Mendell, Valerie Askanas, Salvatore Dimauro, Andrew G. Engel, George Karpati, Lewis P. RowlandAbstract:Preface Part I. Overview of Pathologic and Pathogenic Comparison Between Sporadic Inclusion-Body Myositis and Hereditary Inclusion-Body Myopathies: 1. Newest approaches to diagnosis and pathogenesis of sporadic Inclusion-Body myositis and hereditary Inclusion-Body myopathies, including molecular-pathologic similarities to Alzheimer disease Part II. Historical Perspective: 2: Evolving concepts of Inclusion-Body myositis Part III. Sporadic Inclusion-Body Myositis - Clinical and Diagnostic Considerations: 3: Sporadic Inclusion-Body myositis: Clinical and laboratory features and diagnostic criteria 4: Inclusion-Body myositis: natural history 5: Uncommon clinico-pathological forms of sporadic Inclusion-Body myositis: Report of four cases 6: Inclusion-Body myositis: pathological changes 7: Unusual pathological forms of Inclusion-Body myositis, and neuromuscular disorders with IBM-like changes 8: Electrophysiological findings in Inclusion-Body myositis 9: Genetic factors in sporadic Inclusion-Body myositis Part IV. Hereditary Inclusion-Body Myopathies - Clinical and Diagnostic Considerations: 10: Hereditary Inclusion-Body myopathy in Jews of Persian origin: Clinical and laboratory data 11. Hereditary Inclusion-Body myopathy (h-IBM) with quadriceps sparing: epidemiology and genetics 12: Familial autosomal-recessive Inclusion-Body myositis with asymptomatic leukoencephalopathy 13: Welander distal myopathy - clinical, pathophysiological, and molecular aspects 14. Tibial muscular dystrophy - clinical, genetic, and morphological characteristics 15. Distal myopathy with rimmed vacuoles, Inclusion-Body myositis and related disorders in Japan 16. Inclusion-Body myopathies 17. Is the muscle fiber in Inclusion Body-myositis an antigen-presenting cell of an innocent bystander? 18. Viruses, immunodeficiency and Inclusion-Body myositis 19. Myonuclear abnormalities may play a central role in the pathogenesis of muscle fiber damage in Inclusion-Body myositis 20. Nuclear degeneration and rimmed vacuole formation in neuromuscular disorders 21. Mitochondrial alterations in sporadic Inclusion-Body myositis 22. mtDNA analysis in muscle of patients with sporadic Inclusion-Body myopathy Part V. Treatment: 23. Evaluation of treatment for sporadic Inclusion-Body myositis 24. Personal experience in treating sporadic Inclusion-Body myositis Subject index.
Mohammad Salajegheh - One of the best experts on this subject based on the ideXlab platform.
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treatment of sporadic Inclusion Body myositis with bimagrumab
Neurology, 2014Co-Authors: Anthony A Amato, Kumaraswamy Sivakumar, Mohammad Salajegheh, Namita Goyal, William S David, Jens Praestgaard, Estelle Lachtrifilieff, Anneulrike Trendelenburg, Didier Laurent, David J GlassAbstract:Objective: To study activin signaling and its blockade in sporadic Inclusion Body myositis (sIBM) through translational studies and a randomized controlled trial. Methods: We measured transforming growth factor β signaling by SMAD2/3 phosphorylation in muscle biopsies of 50 patients with neuromuscular disease (17 with sIBM). We tested inhibition of activin receptors IIA and IIB (ActRII) in 14 patients with sIBM using one dose of bimagrumab (n = 11) or placebo (n = 3). The primary outcome was the change in right thigh muscle volume by MRI at 8 weeks. Lean Body mass, strength, and function were secondary outcomes. Twelve of the patients (10 bimagrumab, 2 placebo) participated in a subsequent 16-week observation phase. Results: Muscle SMAD2/3 phosphorylation was higher in sIBM than in other muscle diseases studied ( p = 0.003). Eight weeks after dosing, the bimagrumab-treated patients increased thigh muscle volume (right leg +6.5% compared with placebo, p = 0.024; left leg +7.6%, p = 0.009) and lean Body mass (+5.7% compared with placebo, p = 0.014). Subsequently, bimagrumab-treated patients had improved 6-minute walking distance, which peaked at 16 weeks (+14.6%, p = 0.008) compared with placebo. There were no serious adverse events; the main adverse events with bimagrumab were mild acne and transient involuntary muscle contractions. Conclusions: Transforming growth factor β superfamily signaling, at least through ActRII, is implicated in the pathophysiology of sIBM. Inhibition of ActRII increased muscle mass and function in this pilot trial, offering a potential novel treatment of sIBM. Classification of evidence: This study provides Class I evidence that for patients with Inclusion Body myositis, bimagrumab increases thigh muscle volume at 8 weeks.
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sarcoplasmic redistribution of nuclear tdp 43 in Inclusion Body myositis
Muscle & Nerve, 2009Co-Authors: Jack L Pinkus, Anthony A Amato, Mohammad Salajegheh, Paul J Taylor, Remedios Nazareno, Robert H Baloh, Steven A GreenbergAbstract: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 non-nuclear sarcoplasmic TDP-43 was highly sensitive (91%) and specific (100%) to IBM among 50 inflammatory myopathy patient samples, though 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.
