scholarly journals In Pursuit of an Effective Treatment: the Past, Present and Future of Clinical Trials in Inclusion Body Myositis

2021 ◽  
Author(s):  
A. M. Snedden ◽  
J. B. Lilleker ◽  
H. Chinoy
Keyword(s):  
Clinical Practice ◽  
Effective Treatment ◽  
Inclusion Body ◽  
Therapeutic Effect ◽  
Outcome Measures ◽  
Inclusion Body Myositis ◽  
Cytotoxic T Cells ◽  
Treatment Options ◽  
Trial Methodology ◽  
Short Treatment

Abstract Purpose of review No clinical trial in sporadic inclusion body myositis (IBM) thus far has shown a clear and sustained therapeutic effect. We review previous trial methodology, explore why results have not translated into clinical practice, and suggest improvements for future IBM trials. Recent findings Early trials primarily assessed immunosuppressive medications, with no significant clinical responses observed. Many of these studies had methodological issues, including small participant numbers, nonspecific diagnostic criteria, short treatment and/or assessment periods and insensitive outcome measures. Most recent IBM trials have instead focused on nonimmunosuppressive therapies, but there is mounting evidence supporting a primary autoimmune aetiology, including the discovery of immunosuppression-resistant clones of cytotoxic T cells and anti-CN-1A autoantibodies which could potentially be used to stratify patients into different cohorts. The latest trials have had mixed results. For example, bimagrumab, a myostatin blocker, did not affect the 6-min timed walk distance, whereas sirolimus, a promotor of autophagy, did. Larger studies are planned to evaluate the efficacy of sirolimus and arimoclomol. Summary Thus far, no treatment for IBM has demonstrated a definite therapeutic effect, and effective treatment options in clinical practice are lacking. Trial design and ineffective therapies are likely to have contributed to these failures. Identification of potential therapeutic targets should be followed by future studies using a stratified approach and sensitive and relevant outcome measures.

Highly differentiated cytotoxic T cells in inclusion body myositis

Brain ◽  
2019 ◽  
Vol 142 (9) ◽  
pp. 2590-2604 ◽  
Author(s):  
Steven A Greenberg ◽  
Jack L Pinkus ◽  
Sek Won Kong ◽  
Clare Baecher-Allan ◽  
Anthony A Amato ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Inclusion Body ◽  
Inclusion Body Myositis ◽  
Cytotoxic T Cells ◽  
Killer Cell ◽  
Cd8 T Cell ◽  
Muscle Disease ◽  
Effector Memory ◽  
Muscle Pathology

Abstract 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 — a case based clinicopathological update

Open Medicine ◽  
2014 ◽  
Vol 9 (1) ◽  
pp. 80-85
Author(s):  
Levente Bodoki ◽  
Melinda Vincze ◽  
Zoltán Griger ◽  
Tamás Csonka ◽  
Balázs Murnyák ◽  
...  
Keyword(s):  
Inclusion Body ◽  
Inclusion Body Myositis ◽  
Treatment Options ◽  
Inflammatory Myopathies ◽  
Proximal Muscle Weakness ◽  
Proximal Muscle ◽  
Older Patient ◽  
Close Collaboration ◽  
Systemic Autoimmune Diseases ◽  
Case Based

AbstractInclusion body myositis is a slowly progressive myopathy affecting predominantly the middle-aged and older patient population. It is a major form of the idiopathic inflammatory myopathies which are chronic systemic autoimmune diseases characterized by symmetrical proximal muscle weakness. Unfortunately, there is no effective therapy yet; however, the early diagnosis is essential to provide treatment options which may significantly slow the progression of the disease. In our case-based clinicopathological study the importance of the close collaboration between the clinician and the neuropathologist is emphasised.

Immunopathogenesis of Inflammatory Myopathies

2019 ◽  
pp. 177-192
Author(s):  
Marinos C. Dalakas
Keyword(s):  
Inclusion Body ◽  
Clinical Features ◽  
Muscle Tissue ◽  
Muscle Biopsy ◽  
Inclusion Body Myositis ◽  
Treatment Options ◽  
Inflammatory Myopathies ◽  
Antisynthetase Syndrome ◽  
Autoimmune Myositis ◽  
Overlap Myositis

This chapter looks at inflammatory myopathies (IM), which constitute a heterogeneous group of acquired myopathies that have in common the presence of inflammation in the muscle tissue. The chapter looks at specific clinical features such as dermatomyositis, polymyositis, necrotizing autoimmune myositis, antisynthetase syndrome-overlap myositis, and inclusion body myositis. It then considers diagnosis, which can be made through muscle biopsy and the detection of autoantibodies. Finally, it looks at treatment options.

scholarly journals Inclusion body myositis – pathomechanism and lessons from genetics

Open Medicine ◽  
2015 ◽  
Vol 10 (1) ◽  
Author(s):  
Balázs Murnyák ◽  
Levente Bodoki ◽  
Melinda Vincze ◽  
Zoltán Griger ◽  
Tamás Csonka ◽  
...  
Keyword(s):  
Inclusion Body ◽  
Inflammatory Disease ◽  
Inclusion Body Myositis ◽  
Genetic Basis ◽  
Late Onset ◽  
Treatment Options ◽  
Pathological Features ◽  
Familial Cases ◽  
Incurable Disease ◽  
Clinical And Pathological Features

AbstractInclusion body myositis is a rare, late-onset myopathy. Both inflammatory and myodegenerative features play an important role in their pathogenesis. Overlapping clinicopathological entities are the familial inclusion body myopathies with or without dementia. These myopathies share several clinical and pathological features with the sporadic inflammatory disease. Therefore, better understanding of the genetic basis and pathomechanism of these rare familial cases may advance our knowledge and enable more effective treatment options in sporadic IBM, which is currently considered a relentlessly progressive incurable disease.

scholarly journals Hereditary inclusion body myopathy: a clinical and genetic review

2020 ◽  
Vol 28 ◽  
pp. 1-23 ◽  
Author(s):  
Paulo Victor Sgobbi de Souza ◽  
Bruno de Mattos Lombardi Badia ◽  
Eduardo Augusto Gonçalves ◽  
Igor Braga Farias ◽  
Wladimir Bocca Vieira de Rezende Pinto ◽  
...  
Keyword(s):  
Clinical Practice ◽  
Inclusion Body ◽  
Inclusion Body Myositis ◽  
Case Reports ◽  
Case Series ◽  
Inflammatory Disorder ◽  
Clinical Imaging ◽  
Inclusion Body Myopathy ◽  
Hereditary Inclusion Body Myopathy ◽  
Degenerative Disorder

Introduction. Inclusion body myositis represents the most common acquired myopathy in clinical practice in patients over 50 years old. Despite classical approach to this myopathy as an inflammatory disorder, a muscle degenerative disorder is now considered the main mechanism linked to these vacuolar myopathies. Hereditary presentations, although quite rare, represent an expanding and underrecognized group in clinical practice. Objective. perform a structured review of the current literature regarding hereditary inclusion body myopathies. Method. review of U.S. NLM PubMed and MEDLINE database of original articles, case reports, case series and review articles including the terms “inclusion body myositis” OR “inclusion body myopathy” AND “genetics” OR “hereditary”. Results. We present in this article a wide review regarding the main clinical, imaging, pathophysiological, genetic and therapeutic aspects related to hereditary myopathies linked to seven different clinical and genetic presentations (GNE, MATR3, VCP, SQSTM1, MYH2, HNRNPA2B1 and HNRNPA1). Conclusion. Hereditary inclusion body myopathy is associated with at least 7 distinct clinic and genetic monogenic forms.

Optimizing hand-function patient outcome measures for inclusion body myositis

2020 ◽  
Vol 30 (10) ◽  
pp. 807-814
Author(s):  
Ava Yun Lin ◽  
Catherine Sly Siener ◽  
Anna V. Faino ◽  
Michelle Seiffert ◽  
Conrad C Weihl ◽  
...  
Keyword(s):  
Patient Outcome ◽  
Inclusion Body ◽  
Outcome Measures ◽  
Inclusion Body Myositis ◽  
Hand Function ◽  
Patient Outcome Measures
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