The Experts below are selected from a list of 2532 Experts worldwide ranked by ideXlab platform
Marinos C. Dalakas - One of the best experts on this subject based on the ideXlab platform.
-
treatment for Inclusion Body Myositis
Cochrane Database of Systematic Reviews, 2015Co-Authors: Michael R Rose, Marinos C. Dalakas, James Miller, Kate E Jones, Kevin M W Leong, Maggie C Walter, Ruth Brassington, Robert C. GriggsAbstract:Background Inclusion Body Myositis (IBM) is a late-onset inflammatory muscle disease (myopathy) associated with progressive proximal and distal limb muscle atrophy and weakness. Treatment options have attempted to target inflammatory and atrophic features of this condition (for example with immunosuppressive and immunomodulating drugs, anabolic steroids, and antioxidant treatments), although as yet there is no known effective treatment for reversing or minimising the progression of Inclusion Body Myositis. In this review we have considered the benefits, adverse effects, and costs of treatment in targeting cardinal effects of the condition, namely muscle atrophy, weakness, and functional impairment. Objectives To assess the effects of treatment for IBM. Search methods On 7 October 2014 we searched the Cochrane Neuromuscular Disease Group Specialized Register, the Cochrane Central Register for Controlled Trials (CENTRAL), MEDLINE, and EMBASE. Additionally in November 2014 we searched clinical trials registries for ongoing or completed but unpublished trials. Selection criteria We considered randomised or quasi-randomised trials, including cross-over trials, of treatment for IBM in adults compared to placebo or any other treatment for Inclusion in the review. We specifically excluded people with familial IBM and hereditary Inclusion Body myopathy, but we included people who had connective tissue and autoimmune diseases associated with IBM, which may or may not be identified in trials. We did not include studies of exercise therapy or dysphagia management, which are topics of other Cochrane systematic reviews. Data collection and analysis We used standard Cochrane methodological procedures. Main results The review included 10 trials (249 participants) using different treatment regimens. Seven of the 10 trials assessed single agents, and 3 assessed combined agents. Many of the studies did not present adequate data for the reporting of the primary outcome of the review, which was the percentage change in muscle strength score at six months. Pooled data from two trials of interferon beta-1a (n = 58) identified no important difference in normalised manual muscle strength sum scores from baseline to six months (mean difference (MD) -0.06, 95% CI -0.15 to 0.03) between IFN beta-1a and placebo (moderate-quality evidence). A single trial of methotrexate (MTX) (n = 44) provided moderate-quality evidence that MTX did not arrest or slow disease progression, based on reported percentage change in manual muscle strength sum scores at 12 months. None of the fully published trials were adequately powered to detect a treatment effect. We assessed six of the nine fully published trials as providing very low-quality evidence in relation to the primary outcome measure. Three trials (n = 78) compared intravenous immunoglobulin (combined in one trial with prednisone) to a placebo, but we were unable to perform meta-analysis because of variations in study analysis and presentation of trial data, with no access to the primary data for re-analysis. Other comparisons were also reported in single trials. An open trial of anti-T lymphocyte immunoglobulin (ATG) combined with MTX versus MTX provided very low-quality evidence in favour of the combined therapy, based on percentage change in quantitative muscle strength sum scores at 12 months (MD 12.50%, 95% CI 2.43 to 22.57). Data from trials of oxandrolone versus placebo, azathioprine (AZA) combined with MTX versus MTX, and arimoclomol versus placebo did not allow us to report either normalised or percentage change in muscle strength sum scores. A complete analysis of the effects of arimoclomol is pending data publication. Studies of simvastatin and bimagrumab (BYM338) are ongoing. All analysed trials reported adverse events. Only 1 of the 10 trials interpreted these for statistical significance. None of the trials included prespecified criteria for significant adverse events. Authors' conclusions Trials of interferon beta-1a and MTX provided moderate-quality evidence of having no effect on the progression of IBM. Overall trial design limitations including risk of bias, low numbers of participants, and short duration make it difficult to say whether or not any of the drug treatments included in this review were effective. An open trial of ATG combined with MTX versus MTX provided very low-quality evidence in favour of the combined therapy based on the percentage change data given. We were unable to draw conclusions from trials of IVIg, oxandrolone, and AZA plus MTX versus MTX. We need more randomised controlled trials that are larger, of longer duration, and that use fully validated, standardised, and responsive outcome measures.
-
t cell receptor profiling in muscle and blood lymphocytes in sporadic Inclusion Body Myositis
Neurology, 2007Co-Authors: Mohammad Salajegheh, Goran Rakocevic, Raghavan Raju, Aleksey Shatunov, Lev G Goldfarb, Marinos C. DalakasAbstract:Background: Sporadic IBM (sIBM) is characterized by invasion of non-necrotic MHC-I class-expressing muscle fibers by clonally expanded CD8+ cells. Whether the endomysial cells expand in situ or are recruited from the circulation is unclear. Methods: We used CDR3 spectratyping of the T cell receptor (TCR) Vβ chains to determine clonal expansion of T cells in simultaneously obtained muscle and peripheral blood lymphocytes (PBL) from 12 patients with sIBM, and compared the difference between the two compartments. To determine whether the identified clones belonged to autoinvasive T cells, we performed immunohistochemistry on the same muscle specimens. Spectratyping was repeated in four muscle biopsies 1 year after the first. Results: In control PBL, all 24 TCR Vβ subfamilies had a polyclonal or Gaussian distribution. In sIBM PBL, 5% of the Vβ subfamilies demonstrated a single and 16% up to three peaks. In contrast, in their corresponding muscles, 27% ( p = 0.0003) of the Vβ subfamilies demonstrated a single and 71% ( p Conclusion: In sporadic Inclusion Body Myositis, the endomysial T cells are specifically recruited to the muscle or expand in situ. The restriction of multiple Vβ subfamilies and their change over time suggests recognition of various local antigens and epitope spreading. GLOSSARY: CDR3 = complementarity-determining-region 3; CK = creatine kinase (normal range 52 to 386 U/L); DAPI = 6-diamidino-2-phenylindole; MRC = Medical Research Council; PBL = peripheral blood lymphocytes; RT-PCR = reverse transcription PCR; sIBM = sporadic Inclusion Body Myositis; TCR = T cell receptor.
-
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.
-
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. Sporadic Inclusion Body Myositis (sIBM) presents with a characteristic clinical phenotype of slow-onset weakness and atrophy, affecting proximal and distal limb muscles and facial and pharyngeal muscles. Histologically, sIBM is characterized by chronic myopathic features, lymphocytic infiltrates invading non-vacuolated fibers, vacuolar degeneration, and accumulation of amyloid-related proteins. The cause of sIBM is unclear, but two processes—one autoimmune and the other degenerative—appear to occur in parallel. In contrast to dystrophies, in sIBM the autoinvasive CD8+ T cells are cytotoxic and antigen-driven, invading muscle fibers expressing major histocompatibility complex class I antigen and costimulatory molecules. The concurrent degenerative features include vacuolization, filamentous Inclusions and intracellular accumulations of amyloid-β-related molecules. Although viruses have not been amplified from the muscle fibers, at least 12 cases of sIBM have been seen in association with retroviral infections, indicating that a chronic persistent viral infection might be a potential triggering factor. Emerging data imply that continuous upregulation of cytokines and major histocompatibility complex class I on the muscle fibers causes an endoplasmic reticulum stress response, resulting in intracellular accumulation of misfolded glycoproteins and activation of the transcription factor NFκB, leading to further cytokine activation. In spite of the brisk, antigen-driven T-cell infiltrates, sIBM does not respond to immunotherapies. New therapies using monoclonal antibodies against lymphocyte signaling pathways might prove helpful in arresting disease progression.
-
inflammatory immune and viral aspects of Inclusion Body Myositis
Neurology, 2006Co-Authors: Marinos C. DalakasAbstract:Muscle biopsies from patients with sporadic Inclusion-Body Myositis (sIBM) consistently demonstrate that the inflammatory T cells almost invariably invade intact (not vacuolated) fibers, whereas the vacuolated fibers are rarely invaded by T cells. This indicates two concurrently ongoing processes, an autoimmune mediated by cytotoxic T cells and a degenerative manifested by the vacuolated muscle fibers and deposits of amyloid-related proteins. The autoimmune features of IBM are highlighted by the strong association of the disease with: a) HLA I, II antigens, in frequency identical to classic autoimmune diseases; b) other autoimmune disorders in up to 32% of the patients, autoantibodies, paraproteinemias, or immunodeficiency; c) HIV and HTLV-I infection with increasingly recognized frequency (up to 13 known cases); and d) antigen-specific, cytotoxic, and clonally expanded CD8+ autoinvasive T cells with rearranged T-cell receptor genes that persist over time, even in different muscles, and invade muscle fibers expressing MHC-I antigen and costimulatory molecules. In contrast to IBM, in various dystrophies the inflammatory cells are clonally diverse and the muscle fibers do not express MHC-I or costimulatory molecules in the pattern seen in IBM. Like other chronic autoimmune conditions with coexisting inflammatory and degenerative features (i.e., primary progressive MS), IBM is resistant to conventional immunotherapies. Recent data suggest that strong anti-T cell therapies can be promising and they are the focus of ongoing research.
Valerie Askanas - One of the best experts on this subject based on the ideXlab platform.
-
sodium phenylbutyrate reverses lysosomal dysfunction and decreases amyloid β42 in an in vitro model of Inclusion Body Myositis
Neurobiology of Disease, 2014Co-Authors: Anna Nogalska, Carla Dagostino, King W Engel, Valerie AskanasAbstract:Sporadic Inclusion-Body Myositis (s-IBM) is a severe, progressive muscle disease for which there is no enduring treatment. Pathologically characteristic are vacuolated muscle fibers having: accumulations of multi-protein aggregates, including amyloid-β(Aβ) 42 and its toxic oligomers; increased γ-secretase activity; and impaired autophagy. Cultured human muscle fibers with experimentally-impaired autophagy recapitulate some of the s-IBM muscle abnormalities, including vacuolization and decreased activity of lysosomal enzymes, accompanied by increased Aβ42, Aβ42 oligomers, and increased γ-secretase activity. Sodium phenylbutyrate (NaPB) is an orally bioavailable small molecule approved by the FDA for treatment of urea-cycle disorders. Here we describe that NaPB treatment reverses lysosomal dysfunction in an in vitro model of Inclusion-Body Myositis, involving cultured human muscle fibers. NaPB treatment improved lysosomal activity, decreased Aβ42 and its oligomers, decreased γ-secretase activity, and virtually prevented muscle-fiber vacuolization. Accordingly, NaPB might be considered a potential treatment of s-IBM patients.
-
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.
-
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.
-
novel cytoplasmic immunolocalization of rna polymerase ii in Inclusion Body Myositis muscle
Neuroreport, 2001Co-Authors: Grzegorz M Wilczynski, King W Engel, Valerie AskanasAbstract:Sporadic Inclusion-Body Myositis (IBM) is a progressive degenerative muscle disease of older persons. Abnormalities of gene-expression and RNA metabolism have recently been proposed to contribute to the IBM pathogenic cascade. We now demonstrate, using well characterized, epitope-specific antibodies, that the largest subunit of RNA polymerase II is abnormally accumulated in the cytoplasm of IBM muscle fibers, where it is co-localized with phosphorylated tau on IBM paired helical filaments. Since RNA polymerase II is a crucial nuclear factor involved in both transcription and mRNA processing, our results support the hypothesis that abnormality of either or both of those processes might be caused, in part, by pathological trafficking of RNA polymerase II, and that abnormal trafficking might be an important factor in the IBM pathogenic cascade.
-
Inclusion Body Myositis newest concepts of pathogenesis and relation to aging and alzheimer disease
Journal of Neuropathology and Experimental Neurology, 2001Co-Authors: Valerie Askanas, King W EngelAbstract:We review the newest advances related to seeking the pathogenic mechanism(s) of sporadic Inclusion-Body Myositis (s-IBM) and present the pathologic diagnostic criteria of s-IBM. We discuss the possible pathogenic role of several themes, such as 1) increased amyloid-β precursor protein (AβPP) and of its fragment Aβ; 2) phosphorylation of tau protein; 3) oxidative stress; 4) abnormal a) signal-transduction, b) transcription, and c) RNA accumulation; 5) “junctionalization” and “myogenous” denervation; and 6) lymphocytic inflammation. Evidence is provided supporting our hypothesis that overexpression of AβPP within the aging muscle fibers is an early upstream event causing the subsequent pathogenic cascade. The remarkable pathologic similarities between s-IBM muscle and Alzheimer disease (AD) brain are discussed, and the possible cause and significance are addressed.
Steven A Greenberg - One of the best experts on this subject based on the ideXlab platform.
-
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.
-
Inclusion Body Myositis clinical features and pathogenesis
Nature Reviews Rheumatology, 2019Co-Authors: Steven A GreenbergAbstract: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 <1% of myofibres in patients with IBM. This focus has given rise, together with the relative treatment refractoriness of IBM, to a competing view that IBM is not an autoimmune disease. Findings from the past decade that implicate autoimmunity in IBM include the identification of a circulating autoantiBody (anti-cN1A); the absence of any statistically significant genetic risk factor other than the common autoimmune disease 8.1 MHC haplotype in whole-genome sequencing studies; the presence of a marked cytotoxic T cell signature in gene expression studies; and the identification in muscle and blood of large populations of clonal highly differentiated cytotoxic CD8+ T cells that are resistant to many immunotherapies. Mounting evidence that IBM is an autoimmune T cell-mediated disease provides hope that future therapies directed towards depleting these cells could be effective.
-
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 ...
-
Inclusion Body Myositis
Continuum: Lifelong Learning in Neurology, 2016Co-Authors: Steven A GreenbergAbstract:Purpose of review Inclusion Body Myositis (IBM) is an enigmatic progressive disease of skeletal muscle. This review provides a summary of the clinical and pathophysiologic aspects of IBM. Recent findings The development of diagnostic blood testing for IBM followed from the discovery of a B-cell pathway in IBM muscle and circulating autoantibodies against NT5C1A, further establishing IBM's status as an autoimmune disease. The key role of cytotoxic T cells in IBM is further supported by the identification of a link between IBM and T-cell large granular lymphocytic leukemia. The testing of research diagnostic criteria in patients is improving its accuracy. Increases in estimated prevalences may be due to a combination of true increases and improved recognition of disease. Summary IBM has high unmet medical need. Advances in the mechanistic understanding of IBM as an autoimmune disease will drive effective therapeutic approaches. The identification of a B-cell pathway has resulted in the first identification of an IBM autoantigen and emphasized its status as an autoimmune disease. The recognition that large granular lymphocyte CD8+ T-cell expansions are present in both blood and muscle provides additional biomarkers for IBM and suggests a mechanistic relationship to the neoplastic disease T-cell large granular lymphocytic leukemia.
-
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.
Anthony A Amato - One of the best experts on this subject based on the ideXlab platform.
-
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.
-
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.
-
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.
-
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.
-
Inclusion Body Myositis old and new concepts
Journal of Neurology Neurosurgery and Psychiatry, 2009Co-Authors: Anthony A Amato, Richard J. BarohnAbstract:Inclusion Body Myositis (IBM) is the most common idiopathic inflammatory myopathy occurring in patients over the age of 50 years and probably accounts for about 30% of all inflammatory myopathies. Muscle biopsy characteristically reveals endomysial inflammation, small groups of atrophic fibres, eosinophilic cytoplasmic Inclusions and muscle fibres with one or more rimmed vacuoles. However, any given biopsy may lack these histopathological abnormalities; the clinical examination is often the key to diagnosis. Early and often asymmetrical weakness and atrophy of the quadriceps and flexor forearm muscles (ie, wrist and finger flexors) are the clinical hallmarks of IBM. The pathogenesis of IBM is unknown. It may be autoimmune inflammatory myopathy or a primary degenerative myopathy with a secondary inflammatory. A prevailing theory is that there is an overproduction of β-amyloid precursor protein in muscle fibres that is somehow cleaved into abnormal β-amyloid, and the accumulation of the latter is somehow toxic to muscle fibres. However, there are many problems with this theory and more work needs to be done. Unfortunately, IBM is generally refractory to therapy. Further research into the pathogenesis, along with both preliminary small pilot trials and larger double blind, placebo controlled efficacy trials, are needed to make progress in our understanding and therapeutic approach for this disorder.
S Herson - One of the best experts on this subject based on the ideXlab platform.
-
four year longitudinal study of clinical and functional endpoints in sporadic Inclusion Body Myositis implications for therapeutic trials
Neuromuscular Disorders, 2014Co-Authors: Jeanyves Hogrel, S Herson, Yves Allenbach, Kuberaka Mariampillai, Valerie Decostre, Aurelie Canal, G Leroux, Gwenn Ollivier, Laurent Servais, Olivier BenvenisteAbstract:Natural history studies in sporadic Inclusion Body Myositis are of fundamental interest for future therapeutic trials. Previous works have demonstrated the particular relevance of knee extension strength in the follow-up of this disease. This work aimed to extend a preceding natural history over 9 months to a four year period. Thirteen patients were assessed using clinical and functional scales and dynamometry. Except wrist extension torque and manual muscle testing composite score, all the measurements presented a significant decline. The most important changes were observed for knee extension and ankle flexion and extension. The relative change in knee extension strength correlated with the level of strength at baseline. A non-linear correlation was found between 6-minute walk distance and knee extension strength. This study confirms that knee extension strength is particularly relevant to follow patients with sporadic Inclusion Body Myositis. It also shows that a strength loss does not have linear consequences on motor ability. Finally strength and motor ability are complementing each other in the understanding of disease progression.
-
quadriceps strength is a sensitive marker of disease progression in sporadic Inclusion Body Myositis
Neuromuscular Disorders, 2012Co-Authors: Yves Allenbach, S Herson, Olivier Benveniste, Valerie Decostre, Aurelie Canal, B Eymard, C Blochqueyrat, Jeanyves HogrelAbstract:Abstract There are currently no effective treatments to restore the muscle function in sporadic Inclusion Body Myositis. Natural history studies of this disease are scarce. The goal of this study consisted in defining the functional pattern of patients with sporadic Inclusion Body Myositis and to follow its change over a 9-month period to determine the most sensitive outcome measures for future clinical trials. Twenty-two patients with definite sporadic Inclusion Body Myositis were assessed using clinical and functional scales. Dynamometry was used to evaluate the strength for hand grip and wrist, elbow, ankle and knee flexion and extension. Among the patients, 16 were reassessed 9 months later. The mean whole composite index was at 43.3 ± 16.5% of the predicted normal values. The weakest muscle functions were hand grip, wrist flexion and elbow flexion at the upper limbs and knee extension and ankle flexion at the lower limbs. Muscle weakness was generally asymmetrical, especially for upper limbs where all tested functions were significantly stronger at the dominant side. The patient strength was correlated with the disease duration only for knee extension, which was also the only muscle function to change significantly over 9 months. Knee extension strength seems to be the most relevant marker of disease progression in sporadic Inclusion Body Myositis when measured with suitable dynamometry.
-
long term observational study of sporadic Inclusion Body Myositis
Brain, 2011Co-Authors: Olivier Benveniste, Marguerite Guiguet, Jane Freebody, O Dubourg, Waney Squier, T Maisonobe, T Stojkovic, Maria Isabel Leite, Yves Allenbach, S HersonAbstract:We describe a long-term observational study of a large cohort of patients with sporadic Inclusion Body Myositis and propose a sporadic Inclusion Body Myositis weakness composite index that is easy to perform during a clinic. Data collection from two groups of patients (Paris and Oxford) was completed either during a clinic visit (52%), or by extraction from previous medical records (48%). One hundred and thirty-six patients [57% males, 61 (interquartile range 55-69) years at onset] were included. At the last visit all patients had muscle weakness (proximal British Medical Research Council scale <3/5 in 48%, distal British Medical Research Council scale <3/5 in 40%, swallowing problems in 46%). During their follow-up, 75% of patients had significant walking difficulties and 37% used a wheelchair (after a median duration from onset of 14 years). The sporadic Inclusion Body Myositis weakness composite index, which correlated with grip strength (correlation coefficient: 0.47; P < 0.001) and Rivermead Mobility Index (correlation coefficient: 0.85; P < 0.001), decreased significantly with disease duration (correlation coefficient: -0.47; P < 0.001). The risk of death was only influenced by older age at onset of first symptoms. Seventy-one (52%) patients received immunosuppressive treatments [prednisone in 91.5%, associated (in 64.8%) with other immunomodulatory drugs (intravenous immunoglobulins, methotrexate or azathioprine) for a median duration of 40.8 months]. At the last assessment, patients who had been treated were more severely affected on disability scales (Walton P = 0.007, Rivermead Mobility Index P = 0.004) and on the sporadic Inclusion Body Myositis weakness composite index (P = 0.04). The first stage of disease progression towards handicap for walking was more rapid among patients receiving immunosuppressive treatments (hazard ratio = 2.0, P = 0.002). This study confirms that sporadic Inclusion Body Myositis is slowly progressive but not lethal and that immunosuppressive treatments do not ameliorate its natural course, thus confirming findings from smaller studies. Furthermore, our findings suggest that immunosuppressant drug therapy could have modestly exacerbated progression of disability. The sporadic Inclusion Body Myositis weakness composite index might be a valuable outcome measure for future clinical trials, but requires further assessment and validation.
-
macrophagic myofasciitis associated with Inclusion Body Myositis a report of three cases
Neuromuscular Disorders, 2001Co-Authors: Patrick Cherin, Le C Hello, S Herson, Francois Authier, Marie Coquet, Jean-françois Viallard, P. Le F.n. Mouton, D. Ménard, J P LeroiAbstract:Abstract We describe three patients with macrophagic myofasciitis and Inclusion Body Myositis. All patients fulfilled diagnostic criteria for Inclusion Body Myositis and myopathologic criteria for macrophagic myofasciitis. In the three cases macrophagic myofasciitis complicated the evolution of a known and painless Inclusion Body Myositis and was diagnosed in a repeated deltoid biopsy because of the appearance of myalgia during the course of Inclusion Body Myositis in all cases. The unexpected appearance of myalgia during the course of painless Inclusion Body Myositis must arouse the suspicion of an association of another inflammatory muscle disease, macrophagic myofasciitis.
-
case report macrophagic myofasciitis associated with Inclusion Body Myositis a report of three cases
2001Co-Authors: Patrick Cherin, Le C Hello, Marie Coquet, P. Le F.n. Mouton, D. Ménard, S HersonAbstract:We describe three patients with macrophagic myofasciitis and Inclusion Body Myositis. All patients fulfilled diagnostic criteria for Inclusion Body Myositis and myopathologic criteria for macrophagic myofasciitis. In the three cases macrophagic myofasciitis complicated the evolution of a known and painless Inclusion Body Myositis and was diagnosed in a repeated deltoid biopsy because of the appearance of myalgia during the course of Inclusion Body Myositis in all cases. The unexpected appearance of myalgia during the course of painless Inclusion Body Myositis must arouse the suspicion of an association of another inflammatory muscle disease, macrophagic myofasciitis. q 2001 Elsevier Science B.V. All rights reserved.
