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Research 2017

Site presented by Bill Tillier.

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2017

Yamashita, S., Tawara, N., & Ando, Y. (2017). Anti-NT5C1A autoantibodies for the diagnosis and study of the pathogenesis of sporadic inclusion body myositis. Clinical and Experimental Neuroimmunology, 1-10. https://doi.org/10.1111/cen3.12420

Schrey, A., Airas, L., Jokela, M., & Pulkkinen, J. (2017). Botulinum toxin alleviates dysphagia of patients with inclusion body myositis. Journal of the Neurological Sciences, 380, 142-147. https://doi.org/10.1016/j.jns.2017.07.031

Amici, D. R., Pinal-Fernandez, I., Mazala, D. A. G., Lloyd, T. E., Corse, A. M., Christopher-Stine, L., . . . Chin, E. R. (2017). Calcium dysregulation, functional calpainopathy, and endoplasmic reticulum stress in sporadic inclusion body myositis. Acta Neuropathologica Communications, 5(1), 24. https://doi.org/10.1186/s40478-017-0427-7 [free]
-we observed robust (4-fold) elevation in the autolytic activation of a Ca 2+ -activated protease, calpain-1, as well as increased signaling for translational attenuation (eIF2alpha phosphorylation) downstream of the unfolded protein response. Finally, in IBM samples we observed mRNA and protein under-expression of calpain-3, the skeletal muscle-specific calpain, which broadly supports proper Ca 2+ homeostasis. Together, these data provide novel insight into mechanisms by which intracellular Ca 2+ regulation is perturbed in IBM and offer evidence of pathological downstream effects.
-While Ca 2+ dysregulation is unlikely to be a primary pathogenic mechanism in IBM, it may contribute to muscle atrophy and weakness through its pleiotropic effects on protease dynamics, gene expression, myocellular proteostasis, and mitochondrial function. As such, future investigations may investigate if targeted treatment aimed to restore Ca 2+ homeostasis and/or limit the downstream effects of prolonged Ca 2+ dysregulation may be a viable therapeutic strategy in IBM.

See Fig. 5 below.

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Capkun, G., Callan, A., Tian, H., Wei, Z., Zhao, C., Agashivala, N., & Barghout, V. (2017). Burden of Illness and Healthcare Resource Use in US Patients with sporadic Inclusion Body Myositis. Muscle & Nerve, 1-29. https://doi.org/10.1002/mus.25686

Kobayashi, Z., Fukatsu, E., Itaya, S., Akaza, M., Ota, K., Numasawa, Y., . . . Shintani, S. (2017). Fist sign in inclusion body myositis. Neuromuscular Disorders, 27(4), 385-386. https://doi.org/10.1016/j.nmd.2017.01.016

Leclair, V., & Lundberg, I. E. (2017). Recent clinical trials in idiopathic inflammatory myopathies. Current Opinion in Rheumatology, 1. https://doi.org/10.1097/BOR.0000000000000430

Mendell, J. R. (2017). Reply to Letter to the Editor submitted by Steven Greenberg: "Unfounded Claims of Improved Functional Outcomes Attributed to Follistatin Gene Therapy in Inclusion Body Myositis." Molecular Therapy. https://doi.org/10.1016/j.ymthe.2017.09.003

Greenberg, S. A. (2017). Unfounded Claims of Improved Functional Outcomes Attributed to Follistatin Gene Therapy in Inclusion Body Myositis. Molecular Therapy. https://doi.org/10.1016/j.ymthe.2017.09.002

Rygiel, K. A., Tuppen, H. A., Grady, J. P., Vincent, A., Blakely, E. L., Reeve, A. K., . . . Turnbull, D. M. (2016). Complex mitochondrial DNA rearrangements in individual cells from patients with sporadic inclusion body myositis. Nucleic Acids Research, 44(11), 5313-5329. http://doi.org/10.1093/nar/gkw382

Guttsches, A. K., Brady, S., Krause, K., Maerkens, A., Uszkoreit, J., Eisenacher, M., . . . Kley, R. A. (2017). Proteomics of rimmed vacuoles define new risk allele in inclusion body myositis. Annals of Neurology, 81(2), 227-239. http://doi.org/10.1002/ana.24847

Rothwell, S., Lilleker, J. B., & Lamb, J. A. (2017). Genetics in inclusion body myositis. Current Opinion in Rheumatology. http://doi.org/10.1097/BOR.0000000000000431
See Fig. 2 below.

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Schmidt, K., & Schmidt, J. (2017). Inclusion body myositis. Current Opinion in Rheumatology, 32(3), 1. http://doi.org/10.1097/BOR.0000000000000436
See Fig. 1 below.

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Weihl, C. C., & Mammen, A. L. (2017). Sporadic inclusion body myositis - a myodegenerative disease or an inflammatory myopathy. Neuropathology and Applied Neurobiology, 43(1), 82-91. http://doi.org/10.1111/nan.12384

Noda, S., Koike, H., Maeshima, S., Nakanishi, H., Iijima, M., Matsuo, K., . . . Sobue, G. (2017). Transforming growth factor-beta signaling is upregulated in sporadic inclusion body myositis. Muscle & Nerve, 55(5), 741-747. http://doi.org/10.1002/mus.25405

Keller, C. W., Schmidt, J., & Lunemann, J. D. (2017). Immune and myodegenerative pathomechanisms in inclusion body myositis. Annals of Clinical and Translational Neurology, 4(6), 422-445. http://doi.org/10.1002/acn3.419
See Fig. 1 and 2 below.

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Amici, D. R., Pinal-Fernandez, I., Mázala, D. A. G., Lloyd, T. E., Corse, A. M., Christopher-Stine, L., et al. (2017). Calcium dysregulation, functional calpainopathy, and endoplasmic reticulum stress in sporadic inclusion body myositis. Acta Neuropathologica Communications, 5(1), 24. http://doi.org/10.1186/s40478-017-0427-7

Gallay L, Petiot P. Sporadic inclusion-body myositis: Recent advances and the state of the art in 2016. Revue neurologique (2016), http://dx.doi.org/10.1016/j.neurol.2016.07.016
abstract: Sporadic inclusion-body myositis (sIBM) is the most frequent myopathy after 50 years of age. As the clinical presentation may often be typical, pathological confirmation by muscle biopsy may be necessary, but sometimes difficult. Further delineation of the framework of this particular disease, especially during its early-onset stage, appears to be challenging. New classifications of diagnostic criteria as well as the identification of new diagnostic hallmarks appear to be the two main tools towards achieving this purpose. sIBM pathophysiology has long been discussed and yet remains controversial. Since its initial description, there have been two major pathogenic hypotheses: inflammatory and degenerative. To date, the debate is still ongoing, as recent works support both these pathophysiological mechanisms, although the inflammatory process seems to be slightly more preeminent in the recent literature. Treatment remains the most disappointing aspect of the disease as, despite various therapeutic attempts, no significant efficacy has been reported thus far. Nevertheless, advances in our pathophysiological understanding of the disease are paving the way for further therapeutic perspectives that might arise in the years to come. The objective of the present work was to summarize the most significant data published on sIBM during the past 2 years.
At present, our understanding and management of sIBM appears to be at a crossroads. Significant advances have been made, but more have yet to be achieved in this complex disease. New insights into its pathogenic processes could serve as rationales for future therapeutic perspectives for this unresponsive disease. A more permissive classification would also be useful for allowing the diagnosis to be made early in the onset of the disease, a stage at which treatment could potentially be more effective.

Meyer, A., Lannes, B., Goetz, J., Echaniz-Laguna, A., Lipsker, D., Arnaud, L., . . Sibilia, J. (2017). Inflammatory muscle disease: A new landscape. Joint Bone Spine. http://doi.org/10.1016/j.jbspin.2017.03.005
-In the past, IBM has been notoriously misdiagnosed usually first as polymyositis
-Again, in the past, polymyositis was perceived as a fairly common disorder
-This new study states the following: polymyositis is now emerging as a rare entity that is often mistaken for more recently described patterns of IMD [inflammatory muscle diseases].

Greenberg, S. A. (2017). Inclusion Body Myositis Pathogenesis: Steady Progress. Annals of Neurology. http://doi.org/10.1002/ana.24920

Tawara, N., Yamashita, S., Zhang, X., Korogi, M., Zhang, Z., Doki, T., . . . Ando, Y. (2017). Pathomechanisms of anti-cN1A autoantibodies in sporadic inclusion body myositis. Annals of Neurology. http://doi.org/10.1002/ana.24919

Cerino, M., Gorokhova, S., Laforet, P., Ben Yaou, R., Salort-Campana, E., Pouget, J., . . . Krahn, M. (2017). Genetic characterization of a French cohort of GNE-mutation negative inclusion body myopathy patients using exome sequencing. Muscle & Nerve, 4(2012), 2-14. http://doi.wiley.com/10.1002/mus.25638

Johari, M., Arumilli, M., Palmio, J., Savarese, M., Tasca, G., Mirabella, M., . . . Udd, B. (2017). Association study reveals novel risk loci for sporadic inclusion body myositis. European Journal of Neurology, 24(4), 572-577. http://doi.org/10.1111/ene.13244

Mendell, J. R., Sahenk, Z., Al-zaidy, S., Rodino-klapac, L. R., Lowes, P., Alfano, L., . . . Brian, K. (2017). Follistatin Gene Therapy for Sporadic Inclusion Body Myositis Improves Functional Outcomes. Molecular Therapy, 25(4), 1-10. http://doi.org/10.1016/j.ymthe.2017.02.015

Rothwell, S., Cooper, R. G., Lundberg, I. E., Gregersen, P. K., Hanna, M. G., Machado, P. M., . . . Chinoy, H. (2017). Immune-array Analysis in Sporadic Inclusion Body Myositis Reveals HLA-DRB1 Amino Acid Heterogeneity across the Myositis Spectrum. Arthritis & Rheumatology, 11(10), 300-308. http://doi.org/10.1002/art.40045

McHugh, J. (2017). Inflammatory myopathies: Genetic associations with IBM. Nature Reviews Rheumatology, 2017. http://doi.org/10.1038/nrrheum.2017.8
The HLA region is strongly associated with inclusion body myositis (IBM), according to new findings published in Arthritis & Rheumatology, confirming an immune-related genetic component in this subtype of myositis. "While a degenerative component is recognised [in IBM], this is the first study to focus solely on immune-related genes," comments corresponding author Simon Rothwell. "Since there is no proven treatment in IBM, the identification of new genetic risk factors may ultimately lead to new effective treatments."
- A report by McHugh on Rothwell, S., Cooper, R. G., Lundberg, I. E., Gregersen, P. K., Hanna, M. G., Machado, P. M., . . . Chinoy, H. (2017). Immune-array Analysis in Sporadic Inclusion Body Myositis Reveals HLA-DRB1 Amino Acid Heterogeneity across the Myositis Spectrum. Arthritis & Rheumatology, 11(10), 300-308. http://doi.org/10.1002/art.40045

Gang, Q., Bettencourt, C., Machado, P. M., Brady, S., Holton, J. L., Pittman, A. M., . . . Houlden, H. (2016). Rare variants in SQSTM1 and VCP genes and risk of sporadic inclusion body myositis. Neurobiology of Aging, 47, 218.e1-218.e9. http://doi.org/10.1016/j.neurobiolaging.2016.07.024

Guttsches, A., Brady, S., Krause, K., Maerkens, A., Uszkoreit, J., Eisenacher, M., . . . Kley, R. A. (2016). Proteomics of rimmed vacuoles define new risk allele in inclusion body myositis. Annals of Neurology. http://doi.org/10.1002/ana.24847

Lilleker, J. B., Rietveld, A., Pye, S. R., Mariampillai, K., Benveniste, O., Peeters, M. T. J., . . . van Engelen, B. G. M. (2017). Cytosolic 5'-nucleotidase 1A autoantibody profile and clinical characteristics in inclusion body myositis. Annals of the Rheumatic Diseases, annrheumdis-2016-210282. http://doi.org/10.1136/annrheumdis-2016-210282

Nakano, S., Oki, M., & Kusaka, H. (2016). The role of p62/SQSTM1 in sporadic inclusion body myositis. Neuromuscular Disorders. http://doi.org/10.1016/j.nmd.2016.12.009

Weihl, C. C., & Mammen, A. L. (2017). Sporadic Inclusion Body Myositis: A myodegenerative disease or an inflammatory myopathy. Neuropathology and Applied Neurobiology, 38(1), 42-49.
Conclusion For the past two decades, the field of sIBM research has been split with some researchers suggesting that sIBM pathogenesis begins with inflammation leading to myodegeneration and others favouring a primary degenerative myopathy stimulating autoimmunity. Now with emerging therapies aimed at targeting muscle degeneration and other therapies focused on immune modulation, it is essential to understand the connection between these two pathologies. A siloed approach that ignores one or the other will not advance future therapeutics. Instead, additive therapies or dual acting therapies that focus on both aspects of disease pathogenesis will likely need to be employed.
http://doi.org/10.1111/nan.12384

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