4.2.5 Current IBM Research.

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This is a highly selective sampling of articles related to inclusion body myositis.

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⚀ 2022

 Jensen, K. Y., Nielsen, J. L., Schroder, H. D., Jacobsen, M., Boyle, E., Jorgensen, A. N., Bech, R. D., Frandsen, U., Aagaard, P., & Diederichsen, L. P. (2022). Lack of muscle stem cell proliferation and myocellular hypertrophy in sIBM patients following blood-flow restricted resistance training. Neuromuscular Disorders, S0960896622001171. https://doi.org/10.1016/j.nmd.2022.04.006. OPEN ACCESS.

⧉ Satellite cell content, myonuclei number, mCSA and capillary density remained unaffected following 12-weeks low-load BFR resistance training, indicating limited myogenic capacity and satellite cell plasticity in long-term sIBM patients.

 D'Alton, C., Johnstone, R., Du Plessis, C., Pursad, A., & Kohn, T. A. (2022). The effect of systematic exercise training on skeletal muscle strength in a patient with advanced inclusion body myositis: A case study. South African Journal of Sports Medicine, 34(1). https://doi.org/10.17159/2078-516X/2022/v34i1a13145. OPEN ACCESS.

⧉ It was shown that the training had no adverse effects on the health of the patient. Muscle strength measured at eight weeks and on completion of the intervention, remained the same as at baseline. In conclusion, the exercise programme was found to be safe and seemed to maintain muscle strength in a patient with advanced stage IBM.

 Preusse, C., Marteau, T., Fischer, N., Hentschel, A., Sickmann, A., Lang, S., Schneider, U., Schara‐Schmidt, U., Meyer, N., Ruck, T., Dengler, N. F., Prudlo, J., Dudesek, A., Görl, N., Allenbach, Y., Benveniste, O., Goebel, H., Dittmayer, C., Stenzel, W., & Roos, A. (2022). Endoplasmic reticulum‐stress and unfolded protein response‐activation in immune‐mediated necrotizing myopathy. Brain Pathology. https://doi.org/10.1111/bpa.13084 OPEN ACCESS.

⧉ Perturbed protein clearance is a pathophysiological hallmark in sporadic inclusion body myositis [24], characterized by accumulation of protein aggregates within muscle fibers and characteristic vacuole formation. In addition, in a previous study we described activation of a highly specific autophagic pathway (CASA) in skeletal muscle tissue of IMNM patients [5]. Moreover, results of our proteomic profiling on IMNM-patients derived skeletal muscles confirmed activation of the protein clearance machinery by increased abundances of proteasomal and autophagic proteins along with cytosolic chaperones. These biochemical findings accord with the results of our ultrastructural studies on IMNM-patients derived muscle biopsies revealing the presence of autophagic vacuoles accompanied by enlarged ER-structures suggesting the presence of ER-stress. Along this line, the same proteomic signature revealed an increase of ER/SR-resident proteins suggesting altered ER/SR-homeostasis. Prompted by these combined morphological and proteomic findings and the facts that ER/SR-stress and UPR activation often precede activation of the autophagic system, we further investigated the presence of ER/SR-stress and UPR-activation in the pathophysiology of IMNM. Results of these combined studies seem indicative of a broad UPR-activation and novel pathognomic feature of IMNM.

⧉ . ER-stress and UPR activation are pathophysiological features observed in a variety of neuromuscular diseases [33] and our detailed findings add IMNM to the (growing) list of neurological diseases accompanied by ER-stress and altered protein homeostasis. Notably, the extent of activation is moderate and different in comparison to that in myofibers of IBM patients. Hence, we hypothesize that this is at least in part reflected by the fact that IMNM is a subacute disease and muscle biopsy is performed in the very beginning of its manifestation, while there is obvious persistence of its activation over many years in IBM patients' muscles.



 Senn, K. C., Gumbert, L., Thiele, S., Krause, S., Walter, M. C., & Nagels, K. H. (2022). The health-related quality of life, mental health and mental illnesses of patients with inclusion body myositis (IBM): Results of a mixed methods systematic review. Orphanet Journal of Rare Diseases, 17(1), 227. https://doi.org/10.1186/s13023-022-02382-x OPEN ACCESS.

⧉  In conclusion, six studies reported on determinants and dimensions of health-related quality of life (HRQoL) and mental illnesses in IBM in this systematic review, supporting decreased physical HRQoL in contrast to the normal population or other NMD patients. Unfortunately, rigour determinants and dimensions of HRQoL and mental illness could not be definitively clarified for IBM from the included studies. Importance is especially attributed to weakness, physical role perceptions and functioning as well as dysphagia. A research gap was identified for psychological and social HRQoL in IBM patients, although qualitative studies suggested relevant social and psychological factors for patients and caregivers. Interestingly, quantitative studies report differing values for patients’ mental health and point out a considerable role of depression as a possible mediator for HRQoL. However, qualitative in-depth studies of HRQoL and its determinants are missing until now. Our work suggests that a more holistic understanding of HRQoL in IBM is needed to identify disease specific determinants of HRQoL. Until the physical limitations in IBM cannot be cured or significantly improved, the focus should be pointed on psychosocial prevention of mental illness and support for the daily life of patients and families.

 Wadman, R. I., Rheenen, W. van, van der Pol, W. L., & van den Berg, L. H. (2022). Major advances in neuromuscular disorders in the past two decades. The Lancet Neurology, 21(7), 585–587. https://doi.org/10.1016/S1474-4422(22)00190-9. OPEN ACCESS.

⧉ In the past two decades, antibodies have also been discovered in relation to myopathies and chronic inflammatory demyelinating polyradiculoneuropathy. These findings led to the reclassification of myositis into new clinicoaetiological categories, enabling development of specific diagnostic work­ups and therapeutic approaches. 2 For example, the entity polymyositis is increasingly replaced by inclusion body myositis, antisynthetase syndrome, overlap myositis with connective tissue diseases, and immune­mediated necrotising myopathy. These diseases are diagnosed on the basis of the presence of myositis­specific antibodies and pathological characteristics.

 Abcuro, Inc., a clinical-stage biotechnology company developing therapies for the treatment of autoimmune diseases and cancer through precise modulation of cytotoxic T and NK cells, today announced the presentation of additional clinical results from its ongoing Phase 1 clinical trial of its lead product candidate ABC008 in patients with inclusion body myositis (IBM) at the 4th Global Conference on Myositis (GCOM) 2022 being held in Prague, Czech Republic on June 6-9, 2022. The additional data finds that ABC008 demonstrates proof-of-mechanism for depleting highly cytotoxic T cells, which attack and destroy muscle tissue in IBM.

⧉ 2022-06-08abcuro PDF.



 Katz, A., Thomson, K., & Morgan, D. (2022). An emerging role of platelet-rich plasma and hyperbaric oxygen in the management of inclusion body myositis: A case report. International Journal of Advances in Medicine, 9(6), 756. https://doi.org/10.18203/2349-3933.ijam20221361. OPEN ACCESS.

⧉ Hyperbaric oxygen therapy and platelet-rich plasma injections were provided as adjunctive therapy to a 70year-old female patient with inclusion body myositis. After treatment, she had improvement in her muscle function and improved ambulation. This case study highlights the impact of adjunctive therapy in a patient with inclusion body myositis.

⧉ Note: the author did not declare any conflict of interest yet works for a company providing hyperbaric medical services.

♦♦♦  Nelke, C., Kleefeld, F., Preusse, C., Ruck, T., & Stenzel, W. (2022). Inclusion body myositis and associated diseases: An argument for shared immune pathologies. Acta Neuropathologica Communications, 10(1), 84. https://doi.org/10.1186/s40478-022-01389-6. OPEN ACCESS.

⧉ The prototypical pathomorphology of IBM comprises four major categories:
1- Highly specific inflammatory features consisting of endomysial T cell infiltrates showing a predominance of CD8 +lymphocytes.
2- Rimmed vacuoles and a range of misfolded proteins either associated with the vacuoles or lying beneath the myofibrils.…Of note, amyloidogenic deposits (misfolded proteins with a β-pleated structure) must not be mistaken for amyloid-β, which is processed by secretases and shed to the extracellular (not intracellular) space.
3- Mitochondrial damage with ragged-red, -blue or -brown fibers as well as cytochrome c oxidase (COX)-negative (and SDH-positive) fibers.…The absence of mitochondrial damage renders the diagnosis of IBM highly unlikely.
4- The extent of tissue damage increases over time as characterized by increased fibrous and fatty tissue in the endomysium.

⧉ Some authors also argue for PM belonging to the clinicopathological spectrum of IBM. This notion is exemplified by the concept of PM with mitochondrial pathology (PM-Mito).…The available studies do not currently allow for a conclusive statement as to whether PM, PM-Mito and IBM are clearly distinct disease entities or whether they belong to a common spectrum of IIM.

⧉ HIV-positive patients may develop a distinct inflammatory myopathy reminiscent of IBM. In a retrospective trial, 11 out of 1562 patients with IIM were positive for HIV [47]. It is curious to note that initially, these patients presented with a PM phenotype featuring high CK level and both proximal and distal muscle weakness. Eventually, these patients progressed to an IBM-like phenotype with distinct weakness of the finger flexors, knee extensors and ankle dorsiflexors [47].…In addition to inflammatory features, detection of protein aggregates, such as p62, LC3 or TDP-43, is also more frequent in HIV-IBM. While the morphology of HIV-IBM closely mimics IBM without associated HIV infection, therapeutic responses diverge between the two disorders, as HIV-IBM patients have been observed to sometimes benefit from immunosuppressant treatment [47]. Interestingly, a similar pattern of disease is seen in patients infected with human T-lymphotropic virus-type I (HTLV-I) [54].…Taken together, HIV-associated myopathy displays an intricate association to IBM. A clinical progression to an IBM-like phenotype in HIV-associated myopathy argues for a shared immunopathology.

⧉ Taken together, the association of IBM and SjS is characterized by distinct immune features, including the HLA-DR3 haplotype, an association with T cell large granular lymphocytic leukaemia and the anti-cN-1A-antibody. The extent of these co-occurrences appears not to be shared by other rheumatological disorders and argues for a specific link between the immunopathology of IBM and SjS.


⧉ We speculate that IBM and associated pathologies develop in a permissive environment that promotes early T cell exhaustion and senescence, which cumulates in the accrual of terminally differentiated cells mediating autoimmunity against skeletal muscle. T cell senescence is unable to explain the full extent of IBM pathophysiology, but it might provide a framework for the treatment-refractory course of disease and the characteristic expansion of terminally differentiated, cytotoxic CD8 + T cells present in blood and muscle.
Future studies aimed at understanding how IBM and associated conditions co-occur might shed light on the intricate pathophysiology of IBM. To dissect this interplay, research might focus on studying autoimmunity across IBM, HIV-IBM, SjS and granulomatous myositis to identify similarities and differences between these disorders.

 Machado, P., Barohn, R., McDermott, M., Blaetter, T., Lloyd, T., Shaibani, A., Freimer, M., Amato, A., Ciafaloni, E., Jones, S., Mozaffar, T., Gibson, S., Wicklund, M., Levine, T., Sundgreen, C., Carstensen, T., Bonefeld, K., J⊘rgensen, A. N., Phonekeo, K., … Dimachkie, M. (2022). A Randomized, Double-Blind, Placebo-Controlled Study of Arimoclomol in Patients with Inclusion Body Myositis (S23.010). Neurology, 98(18 Supplement), 969. http://n.neurology.org/content/98/18_Supplement/969.abstract.

⧉ This trial did not demonstrate a benefit of arimoclomol in IBM with respect to its primary and secondary efficacy endpoints.

 Zeng, R., Glaubitz, S., & Schmidt, J. (2022). Antibody Therapies in Autoimmune Inflammatory Myopathies: Promising Treatment Options. Neurotherapeutics. https://doi.org/10.1007/s13311-022-01220-z OPEN ACCESS.

⧉ Especially in IBM, further understanding of the pathophysiology will hopefully lead to the identification of new targets for antibody therapy or other treatment modalities.



⧉  https://en.wikipedia.org/wiki/Alemtuzumab.

♦♦♦  Bhashyam, A., Lubinus, M., Filmore, E., Wilson, L., Williams, J., Gonzalez Ramos, O., & Bhai, S. (2022). Pain profile and opioid medication use in patients with idiopathic inflammatory myopathies. Rheumatology, keac271.https://doi.org/10.1093/rheumatology/keac271 OPEN ACCESS.

⧉ in a sample of 113 IBM patients, some 106 (81%) reported pain, and of this group, 88 took pain medication (83%). Of the 88, 55 (62.5%) took opioids, and 82 (93.2%) took non-opioid pain medication.

♦♦♦  Lindgren, U., Pullerits, R., Lindberg, C., & Oldfors, A. (2022). Epidemiology, survival and clinical characteristics of inclusion body myositis. Annals of Neurology, ana.26412. https://doi.org/10.1002/ana.26412. OPEN ACCESS.

⧉  128 patients with IBM – 1985 to 2017 from Sweden
The prevalence was 32 per million inhabitants, 19 per million women and 45 per million men December 31st 2017.
Mean age of onset 64.4.
age of onset 64.8 years for quadriceps weakness,
age of onset 62.2 for finger flexor,
age of onset 67.7 for swallowing difficulties

⧉ Dysphagia is more common in women as a presenting symptom – 23%, and men 10%: 14% overall.
during the course of the disease, 84% in women and 74% in men: 77% overall. 25% of all patients needed invasive treatment of their swallowing

⧉ Mean survival from presenting symptom for deceased patients 13.8 years.
Mean expected age of death; 82 for men and 85 for women in the general population.
From symptom onset, a persisting decreased cumulative relative survival was seen from year 12 for women and year 20 for men. Survival began to decrease from year three after diagnosis for women and year 13 after diagnosis for men.
From looking at table 2 we see that years of survival from symptom onset is: 13.8 years for all patients, 13.5 for men, and 14.3 for women.

⧉ 20 patients reported myalgia
8% of patients required ventilation assistance.
The presence of autoimmune disease was 21%.
56% had tried immuno treatment for the past 12 months, and 13 had tried at least two different treatments for more than 12 months each.

⧉ anti-cN1A Autoantibodies in 40% of 50 patients analyzed: five were women – 31%, 15 were men – 44% of the tested individuals. Symptom duration 12.3 years when positive 12.0 when negative. Symptom onset 63 years when positive 61.9 when negative. Most common presenting symptom in both groups is quadriceps weakness. Dysphagia is more common as a presenting symptom in positives, but Dysphagia in the course of the disease is 80% in both groups. Other autoimmune diseases 20% in positives and 27% in negatives.
Wheelchair use: 35% when positive 40% when negative.

⧉ 77% of patients reported dysphagia during the disease course invasive treatment was common. Women are affected by dysphagia earlier and more frequently. Quadriceps weakness more common in men.
Immunomodulating treatment was tried in a total of 82% of the patients and 50% had tried corticosteroid treatment.

 Šušnjar, U., Škrabar, N., Brown, A. L., Abbassi, Y., Phatnani, H., NYGC ALS Consortium, Phatnani, H., Fratta, P., Kwan, J., Sareen, D., Broach, J. R., Simmons, Z., Arcila-Londono, X., Lee, E. B., Van Deerlin, V. M., Shneider, N. A., Fraenkel, E., Ostrow, L. W., Baas, F., … Buratti, E. (2022). Cell environment shapes TDP-43 function with implications in neuronal and muscle disease. Communications Biology, 5(1), 314. https://doi.org/10.1038/s42003-022-03253-8 OPEN ACCESS.

⧉ we show that splicing changes represent a robust indication of pathological conditions both in the skeletal muscle of IBM patients and in the brain of individuals affected with FTLD.

 Hossain, M. M., Wilkerson, J., McGrath, J. A., Farhadi, P. N., Brokamp, C., Khan, M. T. F., Goldberg, B., Brunner, H. I., Macaluso, M., Miller, F. W., & Rider, L. G. (2022a). The geospatial distribution of myositis and its phenotypes in the United States and associations with roadways: Findings from a national myositis patient registry. Frontiers in Medicine, 9, 842586. https://doi.org/10.3389/fmed.2022.842586 OPEN ACCESS.

⧉ Using a large U.S. database to evaluate the spatial distribution of IIM and its phenotypes, this study suggests clustering in some regions of the U.S. and a possible association of proximity to roadways

 Harlaar, L., Ciet, P., van Tulder, G., Brusse, E., Timmermans, R. G. M., Janssen, W. G. M., de Bruijne, M., van der Ploeg, A. T., Tiddens, H. A. W. M., van Doorn, P. A., & van der Beek, N. A. M. E. (2022). Diaphragmatic dysfunction in neuromuscular disease, an MRI study. Neuromuscular Disorders, 32(1), 15–24. https://doi.org/10.1016/j.nmd.2021.11.001. OPEN ACCESS

⧉ We conclude that spirometry-controlled MRI enables us to investigate respiratory dysfunction across neuromuscular diseases, suggesting that the diaphragm is affected in a different way in myopathies and motor neuron diseases.

⧉ Lastly, both patients with inclusion body myositis had a limited motion of the thoracic wall, suggesting involvement of intercostal muscles. Their relatively normal function of the diaphragm may be the reason why respiratory failure in these patients is rarely described and often remains asymptomatic

 Gregory, W. J., & Saygin, D. (2022). Assessment of physical activity and muscle function in adult inflammatory myopathies. Current Rheumatology Reports, 24(3), 54–63. https://doi.org/10.1007/s11926-022-01059-5.

 Baldini, C., Arnaud, L., Avčin, T., Beretta, L., Bellocchi, C., Bouillot, C., Burmester, G.-R., Cavagna, L., Cutolo, M., de Vries-Bouwstra, J., Doria, A., Ferro, F., Fonseca, J. E., Fonzetti, S., Fulvio, G., Galetti, I., Gottenberg, J.-E., Hachulla, E., Krieg, T., … Mariette, X. (2022). Sjögren’s syndrome and other rare and complex connective tissue diseases: An intriguing liaison. Clinical and Experimental Rheumatology. 40 (Suppl. 134): S00S00.

 Dalakas, M. C. (2022). Complement in autoimmune inflammatory myopathies, the role of myositis-associated antibodies, COVID-19 associations, and muscle amyloid deposits. Expert Review of Clinical Immunology, 18(4), 413–423. https://doi.org/10.1080/1744666X.2022.2054803 OPEN ACCESS.

 Jørgensen, A., Jensen, K., Nielsen, J., Frandsen, U., Hvid, L., Bjørnshauge, M., Diederichsen, L., & Aagaard, P. (2022). Effects of blood‐flow restricted resistance training on mechanical muscle function and thigh lean mass in sIBM patients. Scandinavian Journal of Medicine & Science in Sports, 32(2), 359–371. https://doi.org/10.1111/sms.14079.

⧉ Sporadic inclusion body myositis (sIBM) is an idiopathic inflammatory muscle disease associated with skeletal muscle inflammation and a parallel progressive decline in muscle strength and physical function. Eventually, most sIBM patients require use of wheelchair after about 10 years of diagnosis and assistance to perform activities of daily living. This study presents data from a randomized controlled intervention trial (NCT02317094) that examined the effect of 12 weeks low-load blood-flow restricted (BFR) resistance training on maximal muscle strength, power, rate of force development (RFD), thigh lean mass (TLM), and voluntary muscle activation (VA) in sIBM patients. A time-by-group interaction in knee extensor strength was observed in the stronger leg (p ≤ 0.033) but not the weaker leg. Within-group changes were observed with BFR training (BFR) manifested by increased knee extensor strength in the strongest leg (+13.7%, p = 0.049), whereas non-exercising patients (CON) showed reduced knee extensor strength (−7.7%, p = 0.018). Maximal leg extensor power obtained for the stronger leg remained unchanged following BFR training (+9.5%, p = 0.37) while decreasing in CON (−11.1%, p = 0.05). No changes in TLM were observed. VA declined post-training (p = 0.037) in both BFR (−6.3% points) and CON (−7.5% points). The present data indicate that BFR resistance training can attenuate the rate of decline in mechanical muscle function typically experienced by sIBM patients. The preservation of muscle mass and mechanical muscle function with BFR resistance training may be considered of high clinical importance in sIBM patients to countermeasure the disease-related decline in physical function.

 Roy, B., Zubair, A., Petschke, K., O’Connor, K. C., Paltiel, A. D., & Nowak, R. J. (2022). Reliability of patient self-reports to clinician-assigned functional scores of inclusion body myositis. Journal of the Neurological Sciences, 120228. https://doi.org/10.1016/j.jns.2022.120228.

⧉ Yale IBM Registry (IBMR) was launched in November 2016 to address the knowledge gap in IBM natural history data. The registry interface provides an IBM personalized index calculator (IBM-PIC) based on the IBM-functional rating scale (IBM-FRS).

⧉ IBM-PIC is a reliable indicator of the IBM-FRS score obtained by the physician. It is anticipated that this online platform will be a valuable tool for assessing IBM severity and monitoring disease progression remotely both in clinical practice and research studies.

 Pawlitzki, M., Nelke, C., Korsen, M., Meuth, S. G., & Ruck, T. (2022). Sirolimus leads to rapid and sustained clinical improvement of motor deficits in a patient with inclusion body myositis. European Journal of Neurology, 29(4), 1284–1287. https://doi.org/10.1111/ene.15231OPEN ACCESS.

⧉ The substantial clinical improvement without immunological treatment effects recorded for cytotoxic CD8+ T cells as observed in our patient might argue for treatment strategies harnessing myoprotective effects. Interestingly, in contrast to recent therapeutic approaches in IBM, sirolimus exerts both immunosuppressive and myoprotective effects. As such, we speculate that the negative outcome of arimoclomol in IBM might be attributed to the lack of immunosuppression, arguing for a dual-treatment strategy.

 Snedden, A. M., Kellett, K. A. B., Lilleker, J. B., Hooper, N. M., & Chinoy, H. (2022). The role of protein aggregation in the pathogenesis of inclusion body myositis. Clinical and Experimental Rheumatology, 11.OPEN ACCESS.

⧉ In this review we have discussed possible mechanisms of protein aggregation in IBM following cytotoxic T-cell attack, and myocyte dysfunction. We have also discussed possible roles of aggregated proteins as antigens, disruptors of nuclear and mitochondrial function and prions propagating further protein aggregation in myocytes. However, a lot of the mechanisms of protein aggregation and dysfunction in IBM remain unknown. This review has focused on the roles of proteins which accumulate in RVs, but RVs are only found in a small proportion of myocytes in IBM muscle. Further work needs to be performed on cytoplasmic proteins with more sensitive proteomic techniques to identify less abundant proteins but to also characterise their post-translational modifications. This may lead to novel therapeutic targets, and may identify biomarkers for the diagnosis of IBM, disease activity and progression.


 ♦♦♦Johari, M., Vihola, A., Palmio, J., Jokela, M., Jonson, P. H., Sarparanta, J., Huovinen, S., Savarese, M., Hackman, P., & Udd, B. (2022). Comprehensive transcriptomic analysis shows disturbed calcium homeostasis and deregulation of T lymphocyte apoptosis in inclusion body myositis. Journal of Neurology. https://doi.org/10.1007/s00415-022-11029-7 OPEN ACCESS.

⧉ We observe dysregulation of genes involved in calcium homeostasis, particularly affecting the T-cell activity and regulation, causing disturbed Ca2+ -induced apoptotic pathways of T cells in IBM muscles. Additionally, LCK/p56, which is an essential gene in regulating the fate of T-cell apoptosis, shows increased expression and altered splicing usage in IBM muscles.

⧉ Interpretation Our analysis provides a novel understanding of the molecular mechanisms in IBM by showing a detailed dysregulation of genes involved in calcium homeostasis and its effect on T-cell functioning in IBM muscles. Loss of T-cell regulation is hypothesized to be involved in the consistent observation of no response to immune therapies in IBM patients. Our results show that loss of apoptotic control of cytotoxic T cells could indeed be one component of their abnormal cytolytic activity in IBM muscles.

⧉ We observed a significant association with genes involved in various calcium-related pathways and identified disturbed calcium regulation specific to T cells in IBM muscles, highlighting the relevance of calcium homeostasis for T-cell activity in IBM muscles. In particular, we identified calcium-induced T lymphocyte apoptosis to be disturbed in IBM muscles.

⧉ Antigen-driven T-cell cytotoxicity is the most reproducible and plausible part of the complex molecular pathomechanism in IBM. However, it remains unknown what antigen drives this IBM-specific immune cascade.

 Shaw, G. Y., Sechtem, P. R., Searl, J., Keller, K., Rawi, T. A., & Dowdy, E. (2007). Transcutaneous Neuromuscular Electrical Stimulation (VitalStim) Curative Therapy for Severe Dysphagia: Myth or Reality? Annals of Otology, Rhinology & Laryngology, 116(1), 36–44. https://doi.org/10.1177/000348940711600107.

 Shrivastava, M. K., Harris, C., Holmes, S., Brady, S., & Winter, S. C. (2022). Inclusion body myositis and dysphagia. Presentation, intervention and outcome at a swallowing clinic. The Journal of Laryngology & Otology, 1–22. https://doi.org/10.1017/s0022215121004758.

⧉ Twenty-four patients were included, with a mean age of 72. Baseline modified Sydney swallow questionnaires (m-SSQ) identified problems with hard/dry food, food sticking, and repeated swallowing. Twenty-two patients had an RSI score that could indicate significant reflux. Video swallow identified specific problems, including with tongue base retraction (96%) and residual pharyngeal pooling (92%). Seven patients (30%) had features of aspiration on imaging despite a median PAS score of 2. Four patients received balloon dilatation, and two patients underwent cricopharyngeal myotomy.

⧉ The severity of dysphagia in IBM can vary from mild to severe and is generally progressive over time. Even ‘mild’ problems can have an impact on quality of life due to the limitations associated with social interaction, particularly around meals. There are also potential physical, social, and psychological consequences. As the dysphagia becomes more severe, it can result in a failure to maintain adequate nutrition, contributing to cachexia, and can predispose to aspiration pneumonia. These factors are considered to contribute to the mortality in patients with IBM

 Witting, N., Daugaard, D., Prytz, S., Biernat, H., Diederichsen, L. P., & Vissing, J. (2022). Botulinum toxin treatment improves dysphagia in patients with oculopharyngeal muscular dystrophy and sporadic inclusion body myositis. Journal of Neurology. https://doi.org/10.1007/s00415-022-11028-8.

⧉ Botulinum toxin injection of the cricopharyngeal muscle in patients with OPMD and sIBM had a beneficial effect on dysphagia in most of the treated patients. Two of 13 patients experienced a temporary worsening not reflected in dysphagia score. Limitations are the un-blinded and un-randomized design and subjective assessments methods.

⧉ Taken together, our results suggest that the majority of patients with dysphagia due to sIBM or OPMD may benefit from cricopharyngeal botulinum toxin injection. Very limited side effects were observed. Unfortunately, no positive or negative prognostics markers for effect could be identified in this trial.

 Alfano, L. N., Salam, S., Machado, P. M., & Dimachkie, M. M. (2022). Measuring change in inclusion body myositis: Clinical assessments versus imaging. Clinical and Experimental Rheumatology, 10. OPEN ACCESS.

⧉ While there has been a great foundation of work to date focused on characterising sIBM disease, including enhanced understanding of general disease progression and underlying pathophysiology, there remains an urgent need to critically appraise, validate, and develop objective, valid and reliable measures in order to achieve clinical trial readiness in sIBM. Natural history studies in sIBM have provided insight and enabled informed clinical counselling and care management, although most work has focused primarily on the impact of disease progression on motor function and its impacts on activities of daily living. Further research is needed to truly understand the prevalence, symptom onset, and the underlying pathophysiology of bulbar dysfunction (dysphagia and dysarthria) in sIBM. These learnings would promote rational recommendations for proactive management and would facilitate the development and validation of COAs that accurately quantify abilities and change over time. Various imaging techniques are available to better characterise underlying pathophysiology in sIBM in both limb muscles and bulbar musculature and function. Careful evaluation with validated COAs reliably measuring disease progression and its impact on abilities will inform future treatment plans and the development of more targeted disease-modifying therapeutics.

 Salam, S., Dimachkie, M. M., Hanna, M. G., & Machado, P. M. (2022). Diagnostic and prognostic value of anti-cN1A antibodies in inclusion body myositis. Clinical and Experimental Rheumatology, 10.PMID: 35225226. OPEN ACCESS.

⧉ At this stage it is difficult to accurately conclude whether anti-cN1A antibodies have a concrete role in clinical practice. Whilst these antibodies are being evaluated, rather than a core diagnostic test they may be useful as supportive tool in aiding diagnosis; for example, in patients with classical features and nondiagnostic findings on repeat muscle biopsy or who cannot undergo biopsy. Diagnosis of IBM should not rely exclusively on isolated disease features. Expert diagnosis is based on the combination of clinical findings and results of investigations (e.g. muscle biopsy, imaging, laboratory, autoantibody and EMG evaluations).

 ♦♦♦Goyal, N. A., Coulis, G., Duarte, J., Farahat, P. K., Mannaa, A. H., Cauchii, J., Irani, T., Araujo, N., Wang, L., Wencel, M., Li, V., Zhang, L., Greenberg, S. A., Mozaffar, T., & Villalta, S. A. (2022). Immunophenotyping of inclusion body myositis blood T and NK cells. Neurology, 10.1212/WNL.0000000000200013. https://doi.org/10.1212/WNL.0000000000200013.

⧉ We found that a population of KLRG1+ Tem and TemRA cells were expanded in both the CD4+ and CD8+ T cell subpopulations in IBM patients. KLRG1 expression in CD8+ T cells increased with T cell differentiation with the lowest levels of expression in naïve T cells (Tn) and highest in highly differentiated TemRA and CD56+CD8+ T cells. The frequency of KLRG1+ total NK cells and subpopulations did not differ between IBM and healthy donors. IBM disease duration correlated with increased CD8+ T cell differentiation

⧉ Here we have further performed deep immunophenotyping of the IBM blood T cell compartment to resolve at higher resolution the nature of the T cell expansions, and found that CD4 + and CD8 + T cells were skewed towards the highly differentiated Tem2, Tem4, and TemRA phases. This skewing suggests that IBM T cells are chronically exposed to undefined antigens. CD8 +T cells in the Tem and TemRA phases, unlike naïve T cells, are resistant to corticosteroids and apoptosis. Indeed, in vivo administration of corticosteroids to healthy volunteers resulted in a decrease in blood CD8 + naïve T cells but a relative increase in CD8+ TemRA cells. 36 Our present findings that T cells shift to a highly differentiated state, together with the previously reported terminally differentiated phenotype of muscle T cells, could therefore explain the relative refractoriness of IBM to corticosteroids.

⧉ Furthermore, the identification of minimal KLRG1 expression on IBM patient blood Tregs (3%) suggests that a therapeutic strategy aimed at depleting highly differentiated T cells by targeting KLRG1 would not deplete Tregs. Because Tregs are critical in suppressing undesired autoimmunity, avoiding Treg depletion is an absolute requirement for an immunotherapeutic approach. Other T cell depleting strategies have not avoided Treg depletion, and some have provoked autoimmunity (e.g., alemtuzumab, daclizumab) which have limited their use or led to withdrawal from the market.

⧉ The expansion of a differentiated CD4 + population in IBM has not been previously noted. This expansion included the CD28 - Tem4 population, suggesting that these CD4 + T cells may function as cytotoxic T cells, not helper T cells, as the CD4+ CD28 - population has cytotoxic capacity and has been identified in other autoimmune diseases.

 Wu, Y., Zhao, Z., Zhang, J., Wang, Y., & Song, X. (2022). Identification of Hub Genes and Biological Pathways in Inclusion Body Myositis Using Bioinformatics Analysis. International Journal of General Medicine, Volume 15, 1281–1293. https://doi.org/10.2147/IJGM.S346965. OPEN ACCESS

⧉ Immune cell infiltrations also play a crucial part in IBM pathogenesis. Greenberg reported a group of KLRG1 + T cells that could aggressively intrude IBM myofiber. Therefore, targeting this cell type is a potential treatment for IBM patients. 21 Herein, CD8 T cells, Tregs, and macrophages were crucial in IBM. T cells and macrophages are the primary infiltrated immune cells in IBM, similar to this study. Tregs can inhibit effector response mediated by CD8+ T cells, thus protecting muscle cells. 22 Herein, the overall degree of Tregs was significantly down-regulated in the IBM group than in the healthy controls. Moreover, the results showed that the hub genes may be involved in the regulation of multiple immune cells in IBM. These findings suggest that targeting hub genes and immune cells might be an effective therapeutic strategy for IBM patients.

Special section. An autoimmune or myodegenerative disease?

 Britson: One Sentence Summary Depletion of T cells in a xenograft model of sporadic inclusion body myositis suppresses inflammation but not TDP-43 pathology or muscle degeneration.
Everyday language summary: It may sound strange to use mice, but researchers cannot do these studies on humans. So, what they've done is they take mice and take out their normal mouse immune system. They then introduce human immune cells – they "humanize" the mice, creating mice that have a human-like immune system. Britson took muscle cells from IBM patients and put them inside the legs of these mice. These cells died, but the mouse muscle then showed regeneration of new muscle cells that were human. These new human muscle cells in the mice continued to show the "usual features of IBM disease", including invading human KLRG1+ T cells, rimmed vacuoles, and the abnormal accumulation of proteins including TDP-43. The mice were then treated with a "drug" (OKT3) to kill the invading human T cells. Although this treatment reduced the number of invading KLRG1+ T cells by 96%, the newly generated human-like muscle cells still showed distinctive IBM features. This makes it look like the features of IBM may be caused by something else, other than the autoimmune invasion of these immune cells, and that killing off these immune cells in humans might not be a treatment that would stop IBM. So, the debate continues back and forth: is IBM caused by some sort of degenerative process, an autoimmune problem, a combination of both, or, some other cause they have not yet discovered.
Editorial comment: Figure 8D shows that untreated and treated fibers showing rimmed vacuoles were identical at 1%. Figure 8E shows that untreated and treated fibers showed identical p62 aggregates at .5%. It's hard for me to understand how the degenerative theory of IBM pathogenesis is supported when only .5% of cells show aggregates.
Footnote: the success of this model, using human cells in these mice to get IBM-looking problems, should be an important step forward to allow more IBM research to be done using this method.

 Mammen, A. L. (2022). Inclusion body myositis: An autoimmune or myodegenerative disease? Neurology, 10.1212/WNL.0000000000200188. https://doi.org/10.1212/WNL.0000000000200188.

⧉ In favor of a primary role for autoimmunity in IBM: In this issue of Neurology, Goyal et al. [see above] performed a detailed analysis of KLRG1+ T cells in the blood of patients with IBM and healthy controls to evaluate the potential of selectively targeting these cells with therapeutic monoclonal antibodies. They confirmed that KLRG1+ CD8+ T cells are highly differentiated cells that are over-represented in the blood of patients with IBM. As these cells are thought to arise with chronic antigen stimulation, this finding supports a role for autoimmunity in this disease. Interestingly, they also discovered a population of KLRG1+ CD4+ T cells circulating in IBM patients. … Importantly, they showed that while KLRG1 is expressed at high levels in a population of highly differentiated CD4+ cells that may function as cytotoxic T cells, this cell surface protein is only minimally expressed on regulatory T cells. Thus, a monoclonal antibody targeting KLRG1 would be expected to deplete the cytotoxic T cells that infiltrate IBM muscle without compromising the ability of regulatory T cells to suppress autoimmunity.
The countervailing view that IBM is a myodegenerative process:… [However,] a recent study by Britson et al. provides support for the countervailing view that IBM is a myodegenerative process and that depleting T cells may not be sufficient to reverse the course of the disease. … Although this treatment reduced the number of infiltrating T cells by 96%, the regenerated muscle fibers still had distinctive IBM features such as rimmed vacuoles and abnormally distributed TDP-43. These observations suggest that many of the abnormal features in IBM muscle occur independently of T cell infiltration, raising the possibility that depleting KLRG1+ T cells in IBM patients may not be sufficient to reverse the disease process. So, Mammen's interpretation: is weakness in IBM due to a myodegenerative process, autoimmunity, or some combination of both? The debate continues.

 Britson, K. A., Ling, J. P., Braunstein, K. E., Montagne, J. M., Kastenschmidt, J. M., Wilson, A., Ikenaga, C., Tsao, W., Pinal-Fernandez, I., Russell, K. A., Reed, N., Mozaffar, T., Wagner, K. R., Ostrow, L. W., Corse, A. M., Mammen, A. L., Villalta, S. A., Larman, H. B., Wong, P. C., & Lloyd, T. E. (2022). Loss of TDP-43 function and rimmed vacuoles persist after T cell depletion in a xenograft model of sporadic inclusion body myositis. Science Translational Medicine, 14(628), eabi9196. https://doi.org/10.1126/scitranslmed.abi9196

⧉ Abstract Sporadic inclusion body myositis (IBM) is the most common acquired muscle disease in adults over age 50, yet it remains unclear whether the disease is primarily driven by T cell–mediated autoimmunity. IBM muscle biopsies display nuclear clearance and cytoplasmic aggregation of TDP-43 in muscle cells, a pathologic finding observed initially in neurodegenerative diseases, where nuclear loss of TDP-43 in neurons causes aberrant RNA splicing. Here, we show that loss of TDP-43–mediated splicing repression, as determined by inclusion of cryptic exons, occurs in skeletal muscle of subjects with IBM. Of 119 muscle biopsies tested, RT-PCR–mediated detection of cryptic exon inclusion was able to diagnose IBM with 84% sensitivity and 99% specificity. To determine the role of T cells in pathogenesis, we generated a xenograft model by transplanting human IBM muscle into the hindlimb of immunodeficient mice. Xenografts from subjects with IBM displayed robust regeneration of human myofibers and recapitulated both inflammatory and degenerative features of the disease. Myofibers in IBM xenografts showed invasion by human, oligoclonal CD8 + T cells and exhibited MHC-I up-regulation, rimmed vacuoles, mitochondrial pathology, p62-positive inclusions, and nuclear clearance and cytoplasmic aggregation of TDP-43, associated with cryptic exon inclusion. Reduction of human T cells within IBM xenografts by treating mice intraperitoneally with anti-CD3 (OKT3) suppressed MHC-I up-regulation. However, rimmed vacuoles and loss of TDP-43 function persisted. These data suggest that T cell depletion does not alter muscle degenerative pathology in IBM.

⧉ Our demonstration of TDP43 cryptic exons in muscle from subjects with IBM is consistent with the notion that nuclear depletion of TDP-43 represents an early contributor to IBM pathogenesis. Although many different immunohistochemical assays and combinations of clinical and pathological features have been suggested to have high sensitivity and specificity for the diagnosis of IBM, the PCR-based cryptic exon detection assay that we report here demonstrates high sensitivity (84%) and specificity (99%) for IBM diagnosis in a large myositis cohort (119 subjects: IBM, n = 44; control, n = 75). Because the incorporation of cryptic exons that are spliced in-frame likely encode previously unidentified epitopes (neoantigens), we hypothesize that such neoantigens may contribute to the autoimmune response in IBM. If confirmed in additional cohorts, then the detection of these neoantigens in serum or muscle has potential as functional biomarkers for clinical applications.

⧉ These xenografts can recapitulate the complex genetic and epigenetic abnormalities that exist in human disease that may never be reproducible in other animal models, and xenografts form a complete in vivo system for modeling disease and developing new therapies.

⧉ Our data show that muscle from subjects with IBM robustly regenerates in immunodeficient mice to form skeletal muscle xenografts despite the presence of an inflammatory milieu, and the characteristic degenerative pathological features of IBM are recapitulated in this xenograft model.

⧉ In addition to these degenerative features, IBM xenografts also show elevation of MHC-I, intense endomysial inflammation, and oligoclonal expansion of CD8 + T cells that express markers of highly differentiated cytotoxic T cells including CD57 and KLRG1. toxic T cells including CD57 and KLRG1. Persistence of these T cells and evidence of invasion of non-necrotic myofibers in IBM xenografts strongly suggest ongoing antigen stimulation by newly forming myofibers.

⧉  Using a monoclonal CD3 antibody (OKT3) (52), we successfully depleted 96% of T cells from IBM xenografts.

⧉  Although OKT3 treatment substantially ameliorated inflammatory changes in IBM xenografts, degenerative pathological features including rimmed vacuoles and loss of TDP-43 function persist.

⧉ Nonetheless, this xenograft model of IBM has the advantage of exhibiting both degenerative and inflammatory features. Our data are most consistent with a model in which loss of TDP-43 function and rimmed vacuole formation in IBM occur independently or upstream of T cell infiltration. These findings support the view that IBM should be considered within the spectrum of TDP-43 proteinopathy, along with ALS, FTD, and other neurodegenerative diseases exhibiting TDP-43 pathology.

 Odeh, H. M., & Shorter, J. (2022). Aggregates of TDP-43 protein spiral into view. Nature, 601(7891), 29–30. https://doi.org/10.1038/d41586-021-03605-0 Paper.

 Arseni, D., Hasegawa, M., Murzin, A. G., Kametani, F., Arai, M., Yoshida, M., & Ryskeldi-Falcon, B. (2022). Structure of pathological TDP-43 filaments from ALS with FTLD. Nature, 601(7891), 139–143. https://doi.org/10.1038/s41586-021-04199-3 Paper.

 Jo, M., Lee, S., Jeon, Y.-M., Kim, S., Kwon, Y., & Kim, H.-J. (2020). The role of TDP-43 propagation in neurodegenerative diseases: Integrating insights from clinical and experimental studies. Experimental & Molecular Medicine, 52(10), 1652–1662. https://doi.org/10.1038/s12276-020-00513-7. Paper.

 Jeong, Y. H., Ling, J. P., Lin, S. Z., Donde, A. N., Braunstein, K. E., Majounie, E., Traynor, B. J., LaClair, K. D., Lloyd, T. E., & Wong, P. C. (2017). Tdp-43 cryptic exons are highly variable between cell types. Molecular Neurodegeneration, 12(1), 13. https://doi.org/10.1186/s13024-016-0144-x. Paper.

 Ling, J. P., Pletnikova, O., Troncoso, J. C., & Wong, P. C. (2015). TDP-43 repression of nonconserved cryptic exons is compromised in ALS-FTD. Science, 349(6248), 650–655. https://doi.org/10.1126/science.aab0983. Paper.

 McHugh, J. (2019). TDP-43 in the muscles: Friend or foe? Nature Reviews Rheumatology, 15(1), 1–1. Paper.

 Vogler, T. O., Wheeler, J. R., Nguyen, E. D., Hughes, M. P., Britson, K. A., Lester, E., Rao, B., Betta, N. D., Whitney, O. N., Ewachiw, T. E., Gomes, E., Shorter, J., Lloyd, T. E., Eisenberg, D. S., Taylor, J. P., Johnson, A. M., Olwin, B. B., & Parker, R. (2018). TDP-43 and RNA form amyloid-like myo-granules in regenerating muscle. Nature, 563(7732), 508–513. https://doi.org/10.1038/s41586-018-0665-2.Paper.

End of special section.

 De Paepe, B., Bracke, K. R., & De Bleecker, J. L. (2022). An exploratory study of circulating cytokines and chemokines in patients with muscle disorders proposes CD40L and CCL5 represent general disease markers while CXCL10 differentiates between patients with an autoimmune myositis. Cytokine: X, 4(1), 100063. https://doi.org/10.1016/j.cytox.2022.100063 OPEN ACCESS

⧉ In this exploratory study, we report CXCL10 serum levels to be significantly higher in IBM patients as compared to patients diagnosed with IMNM. The muscle fibers themselves are a potent source of circulating inflammatory factors in response to tissue damage and inflammation termed myokines, which allow active modulation of the pathogenesis of myositis. Muscle fibers can be induced to produce a broad spectrum of factors including cytokines (transforming growth factor-β (TGF-β), interleukin (IL)-6, IL-15, IL-18) and chemokines (CXCL10, CCL2, CCL4, CCL5, CCL20) [13,14]. The higher levels in IBM compared to the other patient groups could be explained by more prominent accumulation of muscle-infiltrating inflammatory cells in IBM, which display pronounced CXCL10 staining [15] less frequently observed in inflammatory cells in muscular dystrophy tissues [16]. Strongest CXCL10 expression could be shown in the CD68 + and CD3 + cells actively invading nonnecrotic muscle fibers [17], a diagnostic feature observed in IBM and polymyositis. Our observation of significantly higher CXCL10 levels in IBM compared to IMNM thus points to CXCL10 as a potential circulating marker for overt inflammation and active invasion of muscle fibers, which can only be determined by taking an invasive muscle biopsy. This observation needs to be confirmed in larger cohorts of patients that include other patient subgroups.

⧉ To conclude, we propose circulating cytokines and chemokines may be developed further as multi-biomarkers for muscle disorders, complementing the diagnostic arsenal of patient-friendly blood sampling already in place today for determining muscle enzymes and autoantibodies. Cytokine profiling may orient diagnosis toward or away from a genetic muscle disorder or autoimmune myositis. CXCL10 surfaces as a biomarker which could be developed further to diagnose autoimmune myositis, and the detailed description of cytokine and chemokine profiles may offer new insight into the complex immunopathogeneses of this heterogeneous group of inflammatory muscle disorders.

 Li, Y., Chen, W., Ogawa, K., Koide, M., Takahashi, T., Hagiwara, Y., Itoi, E., Aizawa, T., Tsuchiya, M., Izumi, R., Suzuki, N., Aoki, M., & Kanzaki, M. (2022). Feeder-supported in vitro exercise model using human satellite cells from patients with sporadic inclusion body myositis. Scientific Reports, 12(1), 1082. https://doi.org/10.1038/s41598-022-05029-w OPEN ACCESS

⧉ Our results demonstrated that sIBM myotubes possess essentially normal muscle functions, including contractility development, de novo sarcomere formation, and contraction‑dependent myokine upregulation, upon EPS treatment. However, we found that some of sIBM myotubes, but not healthy control myotubes, often exhibit abnormal cytoplasmic TDP‑43 accumulation upon EPS‑evoked contraction, suggesting potential pathogenic involvement of the contraction‑inducible TDP‑43 distribution peculiar to sIBM. Thus, our "feeder‑supported in vitro exercise model" enables us to obtain contractile human‑origin myotubes, potentially utilizable for evaluating exercise‑dependent intrinsic and pathogenic properties of patient muscle cells. Our approach, using feeder layers, further expands the usefulness of the "in vitro exercise model".

⧉ In summary, we established a "feeder-supported in vitro exercise model" applicable to sIBM myotubes derived from the primary satellite cells of sIBM patients. This newly established "feeder-supported in vitro exercise model" enables us to readily produce contractile human-origin myotubes that can be subjected to further experimental and diagnostic analyses to gain details regarding exercise-evoked biological responses in vitro. Thus, our approach, using feeder cells, further expands the usefulness of the "in vitro exercise model".

 Reina-Ruiz, Á. J., Galán-Mercant, A., Molina-Torres, G., Merchán-Baeza, J. A., Romero-Galisteo, R. P., & González-Sánchez, M. (2022). Effect of Blood Flow Restriction on Functional, Physiological and Structural Variables of Muscle in Patients with Chronic Pathologies: A Systematic Review. International Journal of Environmental Research and Public Health, 19(3), 1160. https://doi.org/10.3390/ijerph19031160

⧉ The application of the BFR technique can provide benefits in the short and medium term to increase strength, muscle thickness and cardiovascular endurance, even improving the physiological level of the cardiovascular system. In addition, BFR combined with low-load exercises also achieves benefits comparable to high-intensity exercises without the application of BFR, benefiting patients who are unable to lift high loads.

 Ikenaga, C., Date, H., Kanagawa, M., Mitsui, J., Ishiura, H., Yoshimura, J., Pinal‐Fernandez, I., Mammen, A. L., Lloyd, T. E., Tsuji, S., Shimizu, J., Toda, T., & Goto, J. (2022). Muscle transcriptomics shows overexpression of cadherin 1 in inclusion body myositis. Annals of Neurology, ana.26304. https://doi.org/10.1002/ana.26304 OPEN ACCESS

⧉ Skeletal muscle regeneration is an essential process of repairing muscles that have been injured by various causes including the inflammatory cell infiltrates. NCAM1, MYOG, MYH3, and MYH8 were upregulated in IBM as shown in a previous report. 11 The expression of CDH1 correlated with that of these genes moderately to very strongly in the two datasets. These results suggest that the expression of CDH1 could be related to the regeneration of muscle of IBM patients. The expression of CDH1 was confirmed in proliferating human myoblast cultures and regenerating skeletal muscles of cardiotoxin-injured mice.

⧉ the overexpression of cadherin 1 protein in skeletal muscles was characteristic of IBM, which suggests the potential usefulness of cadherin 1 as a diagnostic marker of IBM. Further analysis using samples of other muscle diseases including muscular dystrophies would be necessary to assess the specificity of cadherin 1 for the diagnosis of IBM.

⧉ In summary, we demonstrated for the first time that cadherin 1 is overexpressed in the cytoplasm of myofibers from patients with IBM. Its expression in the muscle of IBM patients was higher compared with that of control and other idiopathic inflammatory myopathies. Clarifying of the cause and consequences of cadherin 1 upregulation may further our understanding of the pathological mechanisms of IBM.



↩ Main.

⚀ 2021

 Dykes, L. (2021, November 4). Niti Goel, MD: Depletion of KLRG1+ T cells in clinical trial of ABC008 in inclusion body myositis. Rheumatology Network. link

⧉ Overall, we were excited to see that we're depleting the target cells with this dose. ABC008 is a monoclonal antibody designed to target KLRG1+, which is a marker of highly differentiated cytotoxic T cells. And these T cells have been shown to be instrumental in the pathogenesis of inclusion body myositis. So, in depleting these T cells, we demonstrated the proof of mechanism we were hoping to see with ABC008 at our lowest dose planned. Based on our preliminary modeling data, we expected that we might see depletion.
. . . this may be a drug that is beneficial for IBM because it's targeting the pathogenesis of the disease.
. . . The results are very exciting, especially in terms of what it means for individuals that have inclusion body myositis, since there are no effective therapies for the treatment of this disease. Obviously, further details from subsequent cohorts are going to give us more information about the recommended phase 2 doses for subsequent studies.

 Esteban, M. J., Kassar, D., Padilla, O., & McCallum, R. (2021). Dysphagia as the presenting symptom for inclusion body myositis. Journal of Investigative Medicine High Impact Case Reports, 9, 232470962110502. https://doi.org/10.1177/23247096211050211 OPEN ACCESS

⧉ We report a case of a 63-year-old Hispanic female who initially presented with dysphagia and progressive weakness who was eventually diagnosed with IBM.

 Lundberg, I. E., Fujimoto, M., Vencovsky, J., Aggarwal, R., Holmqvist, M., Christopher-Stine, L., Mammen, A. L., & Miller, F. W. (2021). Idiopathic inflammatory myopathies. Nature Reviews Disease Primers, 7(1), 86. https://doi.org/10.1038/s41572-021-00321-x

⧉ The newest IBM diagnostic criteria use evaluation of finger flexor or quadriceps weakness, endomysial inflammation, and either invasion of non-necrotic muscle fibres or presence of rimmed vacuoles.

⧉ Evidence that IBM is an autoimmune disease includes the presence of predisposing immunogenetic risk factors, a large number of antibody-secreting plasma cells within IBM muscle tissue, and the frequent occurrence of auto- antibodies recognizing the NT5C1A protein in the blood of patients with IBM. Furthermore, the observation that cytotoxic CD8 + T cells surround and invade muscle fibres in IBM muscle specimens provided early evidence that muscle damage could be mediated by T cells. Indeed, subsequent studies revealed that CD8 + T cells are clonally expanded in muscle tissue and that the same clones are found in both blood and multiple muscles from the same patient, where they persist. Although the T cell targets remain unknown, these findings suggest that T cell stimulation by the relevant auto-antigen persists for years in these patients. Interestingly, some of the T cell clone identities are shared between different patients with IBM, suggesting a common as yet undefined target auto-antigen among those with IBM. Importantly, studies showed that both CD4+ and CD8 + T cells in patients with IBM have unusual properties, including aberrant loss of CD28 or CD5 expression with the gain of CD16, CD94 and CD57 expression that is associated with terminally differentiated T cells92,93 . Phenotypically similar to the abnormal lymphocytes seen in patients with T cell large granulocytic leukaemia, the infiltrating T cells in IBM would also be expected to have increased cytotoxic potential and resistance to apoptosis. These features may help explain why IBM is refractory to glucocorticoids and other immunomodulatory therapies but this population of T cells could also be a promising target for therapeutic intervention.
In addition to the invasion of myofibres by CD8+ CD57+ T cells, IBM muscle specimens are notable for the presence of rimmed vacuoles and protein inclusions within muscle fibres. For example, in one study, aggregates of p62 and TDP43 proteins were found in 12 percent of IBM myofibres but only rarely in those of other IIM subtypes. Although other reports suggest that p62 accumulation may be a non-specific feature of IIM, TDP43 positivity is recognized as highly specific for IBM. Hence, IBM might have a considerable degenerative component but it has not been shown whether the accumulation of these proteins would lead to muscle cell degeneration. Furthermore, it remains unclear whether these changes occur in response to intensive immune-mediated damage or reflect some other underlying non-immune pathological process.

⧉ IBM is clinically characterized by asymmetrical weakness of both proximal and distal muscles that often includes the quadriceps and long finger flexors (Fig. 6). IBM occurs mainly in individuals greater than 50 years of age. Dysphagia occurs in greater than 50 percent of patients, whereas other extramuscular manifestations are rare. Hallmarks of muscle histopathological findings include endomysial T cell infiltrates and vacuoles rimmed by membranous cytoplasmic material. IBM can be associated with Sjögren syndrome and other connective tissue diseases. The co-occurrence of IBM with sarcoid myopathy has also been reported. IBM progresses slowly over decades and does not usually respond to immunosuppressive therapy.


⧉ [Fails to mention respiratory involvement in IBM, see: (Lelièvre et al., 2021).]

⧉ Unlike DM and PM, IBM is typically refractory to immunotherapy. Although glucocorticoids and other immunosuppressive therapies have not been tested in randomized controlled trials, the general consensus is that they are not efficacious, even though glucocorticoids may improve muscle enzyme levels in the short term and dysphagia in some patients. IVIg might slow disease progression but its long-term effectiveness remains unclear. Methotrexate, which is commonly used in other forms of myositis, failed to slow the progression of muscle weakness in a small, randomized, double-blind, placebo-controlled study in patients with IBM. Intravenous bimagrumab, an anti-activin type II receptor antibody, was evaluated in the largest phase III clinical trial in IBM to date and failed to meet its primary endpoint of 6-minute walk distance at 52 weeks. Pilot studies of arimoclomol, which co-induces the heat shock response by prolonging the activation of heat shock factor 1 and may promote normalization of protein handling within muscle, and rapamycin (sirolimus), which inhibits protein kinase that regulates several intracellular processes, including survival, protein synthesis and autophagy, have shown encouraging results but these have not been confirmed. Unfortunately, a phase II/III clinical trial of arimoclomol in IBM failed to meet its primary endpoint; however, a phase III clinical trial of rapamycin is ongoing. Exercise is currently the only treatment, which has consistently shown a varied degree of benefit in IBM, although the optimal type of exercise programme is yet to be determined.

 Piazzi, M., Bavelloni, A., Cenni, V., Faenza, I., & Blalock, W. L. (2021). Revisiting the Role of GSK3, A modulator of innate immunity, in idiopathic inclusion body myositis. Cells, 10(11), 3255. https://doi.org/10.3390/cells10113255 OPEN ACCESS

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

⧉ In the past, the role of GSK3 in IBM was assessed primarily for its role in the formation of Abeta–TAU inclusions. Recent findings now tightly link GSK3 with antiviral/innate immune signaling regulation, whereby GSK3 activity inhibits the type I IFN response but promotes pro-inflammatory signaling. This is interesting, as the role of GSK3 in pathology is often found associated with that of the innate immune/antiviral/stress response kinase PKR, which is both an inducer of type I IFNs as well as an IFN response gene known to be involved in neurodegenerative diseases (Alzheimer’s disease, Huntington’s chorea and Creutzfeldt–Jakob disease), muscular degenerative disease (myotonic dystrophy) and cachexia [94]. While the effects of CD8 + CTL and NK cell infiltration should be monitored, small molecule inhibitors (SMIs) to GSK3 may offer one of the best and most cost-efficient therapies/co-therapies currently available to regulate both inclusion body formation and apoptosis in muscle tissue as well as the chronic inflammatory signaling in IBM. Some of the more promising inhibitors might be 9-ING-41 and Tideglusib, which have FDA orphan-drug status.

 Bolko, L., Jiang, W., Tawara, N., Landon-Cardinal, O., Anquetil, C., Benveniste, O., & Allenbach, Y. (2021). The role of interferons type I, II and III in myositis: A review. Brain Pathology, 31(3), 1–13. https://doi.org/10.1111/bpa.12955 OPEN ACCESS



 Pinto, M. V., Laughlin, R. S., Klein, C. J., Mandrekar, J., & Naddaf, E. (2021). Inclusion body myositis: Correlation of clinical outcomes with histopathology, electromyography and laboratory findings. Rheumatology, keab754. https://doi.org/10.1093/rheumatology/keab754

⧉ Results: We included 50 IBM patients, with a median age of 69 years; 64% were males. Median disease duration at diagnosis was 51 months. On muscle biopsy, endomysial inflammation mainly correlated with dysphagia, and inversely correlated with mRS. Vacuoles and congophilic inclusions did not correlate with any of the clinical measures. On EMG, the shortness of motor unit potential (MUP) duration correlated with all clinical measures. Myotonic discharges, and not fibrillation potentials, correlated with the severity of inflammation. Serum markers did not have a statistically-significant correlation with any of the clinical measures.

⧉ Conclusions: Dysphagia was the main clinical feature of IBM correlating with endomysial inflammation. Otherwise, inclusion body myositis clinical measures had limited correlation with histopathological features in this study. The shortness of MUP duration correlated with all clinical measures.

 ♦♦♦Winkler, M., von Landenberg, C., Kappes-Horn, K., Neudecker, S., Kornblum, C., & Reimann, J. (2021). Diagnosis and Clinical Development of Sporadic Inclusion Body Myositis and Polymyositis With Mitochondrial Pathology: A Single-Center Retrospective Analysis. Journal of Neuropathology & Experimental Neurology, nlab101. https://doi.org/10.1093/jnen/nlab101

⧉ Due to the similar autoinflammatory process in PM and reports of the frequent occurrence of various autoimmune diseases in the sIBM population (up to 33%) (12), one line of thought is that sIBM might be a primary autoimmune inflammatory disorder then converting (at least in part) into a degenerative process (13). Recent data point toward changes in accord with secondary effects of chronic inflammatory (over)stimulation, in particular detection of peripheral regulatory T-cell deficiency (14), T-cell large granular lymphocyte expansion (15), and increased expression levels of markers for T-cell exhaustion and senescence (16). Some argue that a causative population of highly differentiated cytotoxic T cells (TEMRA) is unaffected, possibly selected, by all conventional immunosuppressive and immunomodulatory treatments (17).

⧉ Among the observations cited to support the view of a primary inflammatory trigger (13) are also PM cases that show limited sIBM-like histological changes and may respond to immunosuppression, but later develop typical sIBM, or that show a sIBM-like clinical presentation but only later fulfill the histological criteria. However, there are few reports concerning these and the patients’ outcome and response to treatment does not appear to be homogeneous.

⧉ In brief, 10 PM patients with more than 4% fibers negative in COX enzyme histochemistry and multiple mtDNA deletions were reported in 1997 (18). These "polymyositis with mitochondrial pathology (PM-Mito)" cases were found to be somewhat older than other PM patients, to have selective quadriceps weakness and poor response to immunosuppressive therapy, thus sharing features with sIBM, but missing rimmed vacuoles or congophilic material.

⧉  In a follow-up to the first report (18), 9 of the original PM-Mito patients had had a further muscle biopsy and 4 were reclassified as sIBM due to the presence of rimmed vacuoles (21).

⧉ Thus, muscle histology remains important for this differential diagnosis to identify sIBM patients not matching the ENMC criteria and the PM-Mito group. In the latter, we report at least 50 percent positive, if occasionally transient, response to immunosuppressive treatments and progression to sIBM in a minority. The mitochondrial abnormalities defining PM-Mito do not seem to define the threshold to immunosuppression unresponsiveness.

 Lu, K., Yong, K. X. X., Skorupinska, I., Deriziotis, S., Collins, J. D., Henley, S. M. D., Hanna, M. G., Rossor, M. N., Ridha, B. H., & Machado, P. M. (2021). A cross‐sectional study of memory and executive functions in patients with sporadic inclusion body myositis. Muscle & Nerve, mus.27426. https://doi.org/10.1002/mus.27426 OPEN ACCESS

⧉ Memory and executive function in patients with IBM did not differ from normative data, and we observed no evidence of associations between the cognitive composite and disease duration or level of disability. This addresses a question frequently asked by patients and will be of value for clinicians and patients alike.

 Dimachkie, M., Machado, P., Sundgreen, C., Blaettler, T., Statland, J., Heim, A., Greensmith, L., Hanna, M., & Barohn, R. (2021). The early history of arimoclomol for inclusion body myositis. RRNMF Neuromuscular Journal, 2(2). https://doi.org/10.17161/rrnmf.v2i2.15404 OPEN ACCESS

⧉ This strong partnership drove regulatory interactions and processes and allowed for the implementation of add-on studies to investigate pharmacokinetics, introduce clinician and patient global impression scales, a muscle MRI substudy, and most importantly, an open-label extension opportunity for the 4809 participants. All along the way, the ultimate goal has been to move forward the field of IBM with strong communication that promotes lasting and trusting partnership. If the IBM4809 study results are positive, this strong partnership is positioned to support filing for regulatory approval in the US and Europe, with the possibility to offer the first effective therapy for people with IBM.

 Saygin, D., Oddis, C. V., Dzanko, S., Koontz, D., Moghadam-Kia, S., Ardalan, K., Coles, T. M., & Aggarwal, R. (2021). Utility of patient-reported outcomes measurement information system (PROMIS) physical function form in inflammatory myopathy. Seminars in Arthritis and Rheumatism, 51(3), 539–546. https://doi.org/10.1016/j.semarthrit.2021.03.018

 ♦♦♦Naddaf, E., Shelly, S., Mandrekar, J., Chamberlain, A. M., Hoffman, E. M., Ernste, F. C., & Liewluck, T. (2021). Survival and associated comorbidities in inclusion body myositis.Rheumatology, keab716. https://doi.org/10.1093/rheumatology/keab716

⧉ Traditionally, IBM is not considered to affect longevity, and survival is reported to be similar to the life expectancy of the general population in France and the Netherlands.(21, 22) We demonstrate in our study that survival is reduced in IBM patients when compared to age and sex-matched controls. IBM patients died on average 3 years younger than population controls. These results are similar to those reported in Noway and Olmsted county.(16, 24) Our reported 10-year survival of 36% from match date (mean age at match date was 73.5 years) was relatively similar to the 42% 10-year survival from diagnosis (mean age at diagnosis was 69.9 years) reported by Dobloug et al.(43) The risk of death in our study was influened by age at match and probably by the presence of dysphagia. In previous reports, survival was mainly influened by age at diagnosis.(21, 43) Similar to previous reports, the death in IBM patient was most commonly related to respiratory complications including respiratory failure or pneumonia.(24, 43-47) In contrast, the most common cause of death in IIM group was cancer, similar to population controls. Lastly, there was a trend for lower survival in IBM patients treated with corticosteroids, which is intriguing and has not been previously reported. Benveniste et al. reported that IBM patients treated with glucocorticosteroids or other immunosuppressants needed a walking aid sooner than untreated patients, with no difference in the rate of progression to a wheelchair.(21) In our study, there was no clear difference baseline characteristics between the treated and untreated patients. It remains unclear whether the difference in survival is a direct effect of the use of corticosteroids, versus other confounding factors. Nevertheless, there is no evidence that treatment with corticosteroids has any benefit in IBM patients, and thus it should be avoided.

 Mavroudis, I., Knights, M., Petridis, F., Chatzikonstantinou, S., Karantali, E., & Kazis, D. (2021). Diagnostic accuracy of Anti-CN1A on the diagnosis of inclusion body myositis. A hierarchical bivariate and bayesian meta-analysis. Journal of Clinical Neuromuscular Disease, 23(1), 31–38. https://doi.org/10.1097/CND.0000000000000353

⧉ In this study, we investigated the diagnostic accuracy of anti-CN1A antibodies for sporadic IBM in comparison with other inflammatory myopathies, autoimmune disorders, motor neurone disease, using a hierarchical bivariate approach, and a Bayesian model taking into account the variable prevalence. The results of the present analysis show that antiCN1A antibodies have moderate sensitivity, and despite having high specificity, they are not useful biomarkers for the diagnosis of IBM, polymyositis or dermatomyositis, other autoimmune conditions, or neuromuscular disorders. Neither the hierarchical bivariate nor the Bayesian analysis showed any significant usefulness of anti-CN1A antibodies in the diagnosis of IBM.

⧉ AntiCN1A antibodies are present in 33%–76% of patients with IBM, and their presence can be related to disease severity, whereas patients positive for them have more pronounced bulbar weakness and higher mortality rate; 19,34 however, these are preliminary observations that require prospective validation. Although, it is worth noting that the same antibodies can be also present in healthy controls, other inflammatory myopathies, and other neurological conditions, but with lower prevalence.19

 He, C., Lee, J. S., Cool, C. D., Wicklund, M. P., & Fischer, A. (2019). Development of autoimmune interstitial lung disease in a patient with inclusion body myositis. The American Journal of Medicine, 132(12), e854–e855. https://doi.org/10.1016/j.amjmed.2019.06.023

 ♦♦♦Shelly, S., Mielke, M. M., Mandrekar, J., Milone, M., Ernste, F. C., Naddaf, E., & Liewluck, T. (2021). Epidemiology and Natural History of Inclusion Body Myositis: A 40-Year Population-Based Study.Neurology, 10.1212/WNL.0000000000012004. https://doi.org/10.1212/WNL.0000000000012004

⧉ Results: We identified 20 patients (10 clinicopathologically-defined, 9 clinically-defined and 1 probable) according to the ENMC criteria and 1 patient with all features of clinicopathologically-defined sIBM except for symptom onset less 45. The prevalence of sIBM in 2010 was 18.20 per 100,000 people ≥50 years old. Ten patients developed cancers. The incidence of cancers in sIBM did not differ from that observed in the general population [OR=1.89 (95% CI: 0.639-5.613; P=0.24)]. Two-thirds of patients developed dysphagia and half required feeding tube. Nine patients required wheelchair. The median time from symptom onset-to-wheelchair dependence was 10.5 (range: 129) years. Overall survival was shorter in sIBM compared to the general population [84.1(95%CI: 78-88.4) versus 87.5 (95%CI: 85.2-89.5) years, P=0.03]. Thirteen patients died, nine were sIBM-related (7 respiratory and 2 unspecified sIBM complications). Female gender (P=0.03) and dysphagia (P=0.05) were independent predictors of death.

⧉ Conclusion: Olmsted County has the highest prevalence of sIBM reported to date. sIBM patients have similar risk of cancers, but slightly shorter life expectancy compared to matched non sIBM patients.

 ♦♦♦Greenberg, S. A. (2021).Counting People with Inclusion Body Myositis. Neurology, 10.1212/WNL.0000000000011994. https://doi.org/10.1212/WNL.0000000000011994

⧉ A commentary on Shelley, above.

 ♦♦♦ Paul, P., Liewluck, T., Ernste, F. C., Mandrekar, J., & Milone, M. (2021). Anti‐cN1A antibodies do not correlate with specific clinical, electromyographic, or pathological findings in sporadic inclusion body myositis. Muscle & Nerve, 63(4), 490–496. https://doi.org/10.1002/mus.27157.

⧉ Results: Anti-cN1A antibodies were present in 47/92 (51%) patients with sIBM. Comparison of seropositive and seronegative cohorts yielded no significant difference in clinical features, including facial weakness, oropharyngeal and respiratory involvement, or disease severity. The antibody titer did not correlate with the clinical phenotype, CK value, or presence of myotonic discharges on EMG. Anti-cN1A antibody positive patients appeared to have more frequent auto-aggressive inflammation on muscle biopsy but not as an isolated myopathological feature.

⧉ Conclusions: Our study showed that anti-cN1A antibody positive and negative sIBM patients have similar clinical features and disease severity. Anti-cN1A antibodies in our sIBM cohort did not correlate with any studied clinical or laboratory parameter and, therefore, were of limited value in the patient's assessment.

 Lucchini, M., Maggi, L., Pegoraro, E., Filosto, M., Rodolico, C., Antonini, G., Garibaldi, M., Valentino, M. L., Siciliano, G., Tasca, G., De Arcangelis, V., De Fino, C., & Mirabella, M. (2021). Anti-cN1A Antibodies Are Associated with More Severe Dysphagia in Sporadic Inclusion Body Myositis. Cells, 10(5), 1146. https://doi.org/10.3390/cells10051146 OPEN ACCESS

⧉ We did not find significant difference regarding demographic variables, nor quadriceps or finger flexor weakness. Nevertheless, we found that anti-cN1A-positive patients presented significantly lower scores in IBMFRS item 1 (swallowing, p = 0.045) and more frequently reported more severe swallowing problems, expressed as an IBMFRS item 1 score ≤ 2 (p less than 0.001). We confirmed the low sensitivity and high specificity of anti-cN1A Ab in s-IBM patients with a high positive predictive value. The presence of anti-CN1A antibodies identified patients with a greater risk of more severe dysphagia.

 Hogrel, J. Y. (2021). Still seeking the holy grail of outcome measures in inclusion body myositis. Journal of Neurology, Neurosurgery & Psychiatry, jnnp-2021-326460. https://doi.org/10.1136/jnnp-2021-326460

 Sangha, G., Yao, B., Lunn, D., Skorupinska, I., Germain, L., Kozyra, D., Parton, M., Miller, J., Hanna, M. G., Hilton-Jones, D., Freebody, J., & Machado, P. M. (2021). Longitudinal observational study investigating outcome measures for clinical trials in inclusion body myositis. Journal of Neurology, Neurosurgery & Psychiatry, jnnp-2020-325141. https://doi.org/10.1136/jnnp-2020-325141

 Coskun Benlidayi, I., & Gupta, L. (2021). The pathophysiological effects of exercise in the management of idiopathic inflammatory myopathies: A scoping review. International Journal of Rheumatic Diseases, November 2020, 1756-185X.14104. https://doi.org/10.1111/1756-185X.14104

 Amato, A. A., Hanna, M. G., Machado, P. M., Badrising, U. A., Chinoy, H., Benveniste, O., Karanam, A. K., Wu, M., Tankó, L. B., Schubert-Tennigkeit, A. A., Papanicolaou, D. A., Lloyd, T. E., Needham, M., Liang, C., Reardon, K. A., de Visser, M., Ascherman, D. P., Barohn, R. J., Dimachkie, M. M., … RESILIENT Study Extension Group. (2021). Efficacy and Safety of Bimagrumab in Sporadic Inclusion Body Myositis: Long-Term Extension of RESILIENT. Neurology, 1–12. https://doi.org/10.1212/WNL.0000000000011626

 Oikawa, Y., Izumi, R., Koide, M., Hagiwara, Y., Kanzaki, M., Suzuki, N., Kikuchi, K., Matsuhashi, T., Akiyama, Y., Ichijo, M., Watanabe, S., Toyohara, T., Suzuki, T., Mishima, E., Akiyama, Y., Ogata, Y., Suzuki, C., Hayashi, H., Kodama, E. N., … Abe, T. (2020). Mitochondrial dysfunction underlying sporadic inclusion body myositis is ameliorated by the mitochondrial homing drug MA-5. PLOS ONE, 15(12), e0231064. https://doi.org/10.1371/journal.pone.0231064 OPEN ACCESS

 Greenberg, Steven A. (2020). 253 - Inflammatory Myopathies. In Goldman-Cecil Medicine (26th Edition, pp. 1745–1750.e2). Elsevier Inc.

 Suzuki, N., Mori-Yoshimura, M., Yamashita, S., Nakano, S., Murata, K., Mori, M., Inamori, Y., Matsui, N., Kimura, E., Kusaka, H., Kondo, T., Ito, H., Higuchi, I., Hashiguchi, A., Nodera, H., Kaji, R., Tateyama, M., Izumi, R., Ono, H., … Aoki, M. (2019). The updated retrospective questionnaire study of sporadic inclusion body myositis in Japan. Orphanet Journal of Rare Diseases, 14(1), 155. https://doi.org/10.1186/s13023-019-1122-5 OPEN ACCESS

 Roy, B., & Griggs, R. C. (2021). Challenges for Treatment Trials of Inclusion Body Myositis. Neurology, 1–8. https://doi.org/10.1212/WNL.0000000000011628

 McMillan, R. A., Bowen, A. J., Bayan, S. L., Kasperbauer, J. L., & Ekbom, D. C. (2021). Cricopharyngeal Myotomy in Inclusion Body Myositis: Comparison of Endoscopic and Transcervical Approaches. Laryngoscope, 1–6. https://doi.org/10.1002/lary.29444

 Taira, K., & Mori‐Yoshimura, M. (2021). Regarding Cricopharyngeal Myotomy in Inclusion Body Myositis: Comparison of Endoscopic and Transcervical Approaches. The Laryngoscope, lary.29539. https://doi.org/10.1002/lary.29539

 De Paepe, B., Merckx, C., Jarošová, J., Cannizzaro, M., & De Bleecker, J. L. (2020). Myo-Inositol Transporter SLC5A3 Associates with Degenerative Changes and Inflammation in Sporadic Inclusion Body Myositis. Biomolecules, 10(4), 521. https://doi.org/10.3390/biom10040521 OPEN ACCESS

 ♦♦♦Snedden, A. M., Lilleker, J. B., & Chinoy, H. (2021). In pursuit of an effective treatment: The past, present and future of clinical trials in inclusion body myositis. Current Treatment Options in Rheumatology. https://doi.org/10.1007/s40674-020-00169-4 OPEN ACCESS

⧉ 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.

 Živković, S. A., Gruener, G., & Narayanaswami, P. (2021). Doctor—Should I get the COVID‐19 vaccine? Infection and immunization in individuals with neuromuscular disorders. Muscle & Nerve, 50(6), mus.27179. OPEN ACCESS

⧉ All individuals with NMDs who are not taking IS agents should be encouraged to receive COVID-19 vaccines since the risk of COVID-19 infections likely outweighs the potential risks of the vaccine.
Individuals with NMDs who are taking IS/IM agents should be counseled that there is no data currently regarding the safety or efficacy of COVID-19 mRNA vaccines in this population, but the vaccine benefits of reducing COVID-19 infection likely outweigh the potential risks. Even reduced efficacy may confer benefits against COVID-19 infections.
Individuals with autoimmune NMDs should be counseled that no data are currently available on the safety and efficacy of mRNA COVID-19 vaccines in this population. An increased risk of developing autoimmune or inflammatory disorders was not observed in clinical trial participants who received an mRNA COVID-19 vaccine compared to placebo. There is no data regarding the risk of exacerbation of autoimmune NMDs by COVID-19 vaccine. Persons with autoimmune conditions who have no contraindications to vaccination may receive an mRNA COVID-19 vaccine.

 Savelieff, M. G., & Feldman, E. L. (2021). Inclusion body myositis: small steps towards future advances. The Lancet Rheumatology, 3(1), e5–e6. https://doi.org/10.1016/S2665-9913(20)30346-5

⧉ Unfortunately, despite the pronounced involvement of autoimmunity and inflammation in inclusion body myositis, global immunosuppression and immunomodulation are ineffective treatments, as are approaches aimed at impaired muscle regeneration or inclusions.1 These drug failures are due to the complexity that underlies inclusion body myositis pathogenesis and gaps in our understanding of the full natural disease course, challenging our ability to select appropriate clinical endpoints and biomarkers of drug efficacy. Additionally, the heterogeneity of clinical phenotypes, the slowly progressive nature of the disease, and its relative rarity lengthen trial durations and render patient recruitment difficult.

⧉ In The Lancet Rheumatology, Olivier Benveniste and colleagues 4 report findings from the RAPAMI phase 2b trial of sirolimus (also known as rapamycin) for treatment of patients with inclusion body myositis. The authors selected sirolimus, which possesses both immunomodulation and pro-autophagy properties, as a two-pronged approach aimed at two aspects of disease pathology.

⧉ the RAPAMI trial emphasised the importance of factoring in disease severity when selecting an optimal clinical trial endpoint in a slowly progressive chronic disease. In RAPAMI, patients with inclusion body myositis were severely impaired, which led the investigators to use the rate of change in quadriceps strength as the primary outcome. However, the trial results suggest that a functional test, such as 6-min walking distance, might be a more relevant marker of both disease progression and drug efficacy in a disabled patient population.

⧉ RAPAMI emphasised how crucial it is to determine the time course and type of immune dysregulation in inclusion body myositis, and whether it is causative or secondary to other dysregulated pathways. These findings would guide the optimal timing during the disease course for administering sirolimus, or other targeted immunotherapies, to produce maximum benefit.

 Benveniste, O., Hogrel, J.-Y., Belin, L., Annoussamy, M., Bachasson, D., Rigolet, A., Laforet, P., Dzangué-Tchoupou, G., Salem, J.-E., Nguyen, L. S., Stojkovic, T., Zahr, N., Hervier, B., Landon-Cardinal, O., Behin, A., Guilloux, E., Reyngoudt, H., Amelin, D., Uruha, A., … Allenbach, Y. (2021). Sirolimus for treatment of patients with inclusion body myositis: a randomised, double-blind, placebo-controlled, proof-of-concept, phase 2b trial. The Lancet Rheumatology, 3(1), e40–e48. https://doi.org/10.1016/S2665-9913(20)30280-0

⧉ In conclusion, this pilot, phase 2b study found no evidence for efficacy of sirolimus for treating inclusion body myositis based on maximal voluntary isometric knee extension strength and other muscle strength measures, and the side-effects of treatment were substantial for some patients. However, we believe there was enough evidence of benefit in certain secondary outcomes to justify a larger multicentre phase 3 trial, and we suggest that such a trial should be done with a different primary outcome measure (eg, 6-min walking distance or fat fraction measured by quantitative nuclear MRI).



 Romani, M., Sorrentino, V., Oh, C., Li, H., de Lima, T. I., Zhang, H., Shong, M., & Auwerx, J. (2021). NAD+ boosting reduces age-associated amyloidosis and restores mitochondrial homeostasis in muscle. Cell Reports, 34(3), 108660. https://doi.org/10.1016/j.celrep.2020.1086690 OPEN ACCESS

⧉ our findings in IBM cells and GMC101 worms, supported also by the compound-dependent effects observed in APPSwe expressing C2C12 (Figure 6C), strongly suggest a therapeutic potential for NAD + enhancing strategies in treating or delaying the progression of IBM and other amyloidogenic proteinopathies, such as AD (Sorrentino et al., 2017).
Collectively, our results in C. elegans, mice, and humans support the notion that natural aging is typified by muscle amyloidosis and, very importantly, that late-life treatments aimed at restoring metabolic and mitochondrial homeostasis also increase cellular and organismal proteostasis, therefore beneficially impacting on health- and lifespan in a more pleiotropic fashion than that reported so far.

 Lelièvre, M. H., Hudson, M., Botez, S. A., & Dubé, B. P. (2021). Determinants and functional impacts of diaphragmatic involvement in patients with inclusion body myositis. Muscle & Nerve, 63(4). https://doi.org/10.1002/mus.27170

⧉ Our main results can be summarized as follows: 1) in our patients with IBM, the spectrum of diaphragm activity was wide, and could easily and rapidly be assessed using ultrasonography and 2) lower diaphragm activity was significantly related to disease duration, dyspnea levels at rest and on exertion [Dyspnea is the medical term for shortness of breath], lung function abnormalities and exercise capacity. Together, these findings provide new insights on the possible effects of IBM on the diaphragm and on the contribution of respiratory muscle involvement to respiratory symptoms and exercise limitation in this population. This should alert clinicians involved in the care of patients with IBM to the possibility of diaphragm weakness when confronted with symptoms of unexplained dyspnea or exercise intolerance. In addition, our results support the usefulness of ultrasonography as a clinical tool in this population, allowing a rapid, simple and non-invasive estimation of diaphragm function that is related to relevant clinical outcomes.

 Umay, E., Sakin, Y. S., Ates, M. P., Alicura, S., Gundogdu, I., Ozturk, E. A., & Koc, G. (2021). Esophageal dysphagia in neuromuscular disorder patients with validity and reliability study of the brief esophageal dysphagia questionnaire. Acta Neurologica Belgica. https://doi.org/10.1007/s13760-020-01563-4

⧉ Evaluation of swallowing in patients with NMD should include not only the oropharyngeal phase of swallowing, but also esophageal phase. For this purpose, the BEDQ can be used as a rapid, valid, and reliable test for the evaluation of ED.




↩ Main.

⚀ 2020

 Basualto-Alarcón, C., Urra, F. A., Bozán, M. F., Jaña, F., Trangulao, A., Bevilacqua, J. A., & Cárdenas, J. C. (2020). Idiopathic inflammatory myopathy human derived cells retain their ability to increase mitochondrial function. PLOS ONE, 15(11), e0242443. https://doi.org/10.1371/journal.pone.0242443 OPEN ACCESS

⧉ "Non-immune mediated" hypotheses have arisen to consider inner skeletal muscle cell processes as trigger factors in the clinical manifestations of IIMs. Alterations in oxidative phosphorylation, ATP production, calcium handling, autophagy, endoplasmic reticulum stress, among others, have been proposed as alternative cellular pathophysiological mechanisms. In this study, we used skeletal muscle-derived cells, from healthy controls and IIM patients to determine mitochondrial function and mitochondrial ability to adapt to a metabolic stress when deprived of glucose. We hypothesized that mitochondria would be dysfunctional in IIM samples, which was partially true in normal glucose rich growing medium as determined by oxygen consumption rate. However, in the glucose-free and galactose supplemented condition, a medium that forced mitochondria to function, IIM cells increased their respiration, reaching values matching normal derived cells. Unexpectedly, cell death significantly increased in IIM cells under this condition. Our findings show that mitochondria in IIM is functional and the decrease respiration observed is part of an adaptative response to improve survival. The increased metabolic function obtained after forcing IIM cells to rely on mitochondrial synthesized ATP is detrimental to the cell’s viability. Thus, therapeutic interventions that activate mitochondria, could be detrimental in IIM cell physiology, and must be avoided in patients with IIM.

⧉ In summary, our evidence suggests that boosting mitochondrial function in IIM, as is done in other muscle-related diseases, could have a detrimental effect on skeletal muscle health. Future research should focus on unraveling the balance between ROS generation and ROS scavenging to develop new therapeutic strategies for this complex group of diseases.

⧉ Mitochondria of IIM-derived cells are functional and can adapt and respond to a metabolic challenge. However, a concomitant effect is that cells tend to become more susceptible to cellular insults that result in increased death.

 de Souza, F. C., Behrens Pinto, G., de Souza, J., Olivo Pallo, P., Hoff, L., & Shinjo, S. (2020). Sporadic inclusion body myositis in the rheumatology clinic. Indian Journal of Rheumatology, 15(6), 145. https://doi.org/10.4103/injr.injr_80_20 OPEN ACCESS

⧉ The main irreversible complications of sIBM are dysphagia and walking difficulties. The disease affects more men than women, and the symptom onset mainly occurs between 50 and 70 years of age. Due to its slow progression, sIBM diagnosis is frequently delayed and therefore misdiagnosed as other muscle diseases. sIBM remains refractory to treatment (e.g., glucocorticoid, and immunosuppressive/immunomodulatory/immunobiological drugs). Although there have been no robust clinical trials, training exercise/physiotherapy should be prescribed regularly in sIBM patients.

 Mavroudis, I., Petridis, F., & Kazis, D. (2020). Inclusion Body Myositis. Genetics, Biomarkers and Muscle Biopsy. International Journal of Neuroscience, 0(0), 1–10.https://doi.org/10.1080/00207454.2020.1763340.

 Vivekanandam, V., Bugiardini, E., Merve, A., Parton, M., Morrow, J. M., Hanna, M. G., & Machado, P. M. (2020). Differential Diagnoses of Inclusion Body Myositis. Neurologic Clinics, 38(3), 697–710. https://doi.org/10.1016/j.ncl.2020.03.014

 ♦♦♦Ikenaga, C., Findlay, A. R., Goyal, N. A., Robinson, S., Cauchi, J., Hussain, Y., Wang, L. H., Kershen, J. C., Beson, B. A., Wallendorf, M., Bucelli, R. C., Mozaffar, T., Pestronk, A., & Weihl, C. C. (2020). Myositis associated anti-NT5C1A autoantibody in clinical practice. MedRxiv, 2020.03.25.20043760. https://doi.org/10.1101/2020.03.25.20043760 OPEN ACCESS

⧉ Among patients with muscle diseases, the seropositivity of anti-NT5C1A was 63% sensitive and 85% specific for the diagnosis of IBM.

⧉ Anti-NT5C1A was found in 182/287 patients with IBM (63%)

⧉ Conclusions:
This is the largest description of patients tested by a clinical diagnostic lab for anti-NT5C1A. We confirm the sensitivity and specificity of anti-NT5C1A for IBM and identified clinicopathologic features in IBM which correlate with anti-NT5C1A status. Notably, anti-NT5C1A testing increased both the diagnostic sensitivity and specificity of IBM when combined with patient age, gender and creatine kinase (CK) level. We propose that future IBM diagnostic criteria include anti-NT5C1A testing.

 ♦♦♦Gupta, L., Lilleker, J. B., Agarwal, V., Chinoy, H., & Aggarwal, R. (2020). COVID-19 and myositis - unique challenges for patients. Rheumatology, 1–4. https://doi.org/10.1093/rheumatology/keaa610 OPEN ACCESS

⧉ -Our survey highlights that COVID-19 has incurred a detrimental effect on patients with myositis.

⧉ -Difficulties in procuring medicines, delayed biologic infusions, and disrupted physiotherapy sessions were common.

⧉ -Such delays and omissions in clinical care may translate to poorer outcomes in the future.

 Phillips, M. C. L., Murtagh, D. K. J., Ziad, F., Johnston, S. E., & Moon, B. G. (2020). Impact of a Ketogenic Diet on Sporadic Inclusion Body Myositis: A Case Study. Frontiers in Neurology, 11(November), 1–8. https://doi.org/10.3389/fneur.2020.582402 OPEN ACCESS

⧉ We report the case of a 52-year-old woman with worsening IBM who pursued a modified ketogenic diet for 1 year. Adverse effects were mild and resolved 3 weeks into the diet. Prior to starting her ketogenic diet, despite the use of a walking stick at all times, she was experiencing one to two falls per week as well as swallowing difficulties, musculoskeletal pain, and depression. Moreover, magnetic resonance imaging (MRI) of the bilateral thighs during the year prior to the diet indicated worsening muscle inflammation and a 14% decrease in thigh muscle volume, which corresponded to a 4% decrease in the ratio of thigh muscle to thigh total volume. After 1 year on her ketogenic diet, our patient regained independent walking, and her swallowing difficulties, pain, and depression resolved. She maintained her strength, improved in every test of function, enhanced her quality of life, and lowered her blood creatine kinase. MRI of the bilateral thighs during the year of the diet indicated stabilized muscle inflammation and a 2.9% decrease in thigh muscle volume, which in the context of diet-induced fat loss corresponded to a sustained 1% increase in the ratio of thigh muscle to thigh total volume. This case is unique in that a ketogenic diet was utilized as the primary treatment strategy for a patient with confirmed IBM, culminating in substantial clinical improvement, stabilized muscle inflammation, and a slowed rate of muscle atrophy. Our patient has remained on her ketogenic diet for over 2 years now and continues to enjoy a full and independent life.

 Cantó-Santos, J., Grau-Junyent, J. M., & Garrabou, G. (2020). The Impact of Mitochondrial Deficiencies in Neuromuscular Diseases. Antioxidants, 9(10), 964. https://doi.org/10.3390/antiox9100964 OPEN ACCESS

⧉ The aim of the review is to discuss the mechanisms underlying energy production, oxidative stress generation, cell signaling, autophagy, and inflammation triggered or conditioned by the mitochondria. Briefly, increased levels of inflammation have been linked to reactive oxygen species (ROS) accumulation, which is key in mitochondrial genomic instability and mitochondrial respiratory chain (MRC) dysfunction.

⧉ Other NMDs with mtDNA deletions are sporadic inclusion body myositis (sIBM) (reported in 67% of sIBM patients) [108,109]


Figure 2. Schematic view of the mechanistic model of mitochondrial-related pathways in a cell.

 Zhang, Y., Li, K., Pu, C., Dang, H., Liu, J., & Shi, Q. (2020). A novel application of tau PET in the diagnosis of sporadic inclusion body myositis. Medicine, 99(31), e21524. https://doi.org/10.1097/MD.0000000000021524 OPEN ACCESS

⧉ In conclusion, [18 F] THK5317-PET can reveal muscular tau deposition in vivo, which provides a new and noninvasive diagnostic method for sIBM and offers the opportunity to monitor the progression of tau pathology along with muscle impairment.

 Panebianco, M., Marchese-Ragona, R., Masiero, S., & Restivo, D. A. (2020). Dysphagia in neurological diseases: a literature review. Neurological Sciences, 41(11), 3067–3073. https://doi.org/10.1007/s10072-020-04495-2 OPEN ACCESS

 Leeuwenberg, K. E., Alfen, N., Christopher‐Stine, L., Paik, J. J., Tiniakou, E., Mecoli, C., Doorduin, J., Saris, C. G. J., & Albayda, J. (2020). Ultrasound can differentiate inclusion body myositis from disease mimics. Muscle & Nerve, 61(6), 783–788. https://doi.org/10.1002/mus.26875 OPEN ACCESS

⧉ Discussion: Ultrasound appears to be a good test to differentiate established IBM from PM/DM and neuromuscular controls, with value as a diagnostic tool for IBM.

 Lawless, C., Greaves, L., Reeve, A. K., Turnbull, D. M., & Vincent, A. E. (2020). The rise and rise of mitochondrial DNA mutations. Open Biology, 10(5), 200061. https://doi.org/10.1098/rsob.200061 OPEN ACCESS

⧉ Here we summarize our current understanding of the clonal expansion of mitochondrial DNA mutations in different tissues and highlight key unanswered questions. We then discuss the various existing biological models, along with their advantages and disadvantages. Finally, we explore what has been achieved with mathematical modelling so far and suggest future work to advance this important area of research.

 Rosenbohm, A., Buckert, D., Kassubek, J., Rottbauer, W., Ludolph, A. C., & Bernhardt, P. (2020). Sporadic inclusion body myositis: no specific cardiac involvement in cardiac magnetic resonance tomography. Journal of Neurology, 267(5), 1407–1413. https://doi.org/10.1007/s00415-020-09724-4 OPEN ACCESS

 Stevanovic, J., Vulovic, M., Pavicevic, D., Bezmarevic, M., Stojkovic, A., Radunovic, A., Aksic, M., Milosevic, B., Cvetkovic, A., Jovanovic, M., & Ivosevic, A. (2020). Physical therapy improves motion in a patient with inclusion body myositis - a case report. Vojnosanitetski Pregled, 77(11), 1216-1220. https://doi.org/10.2298/VSP171110165 OPEN ACCESS

⧉ Physical therapy plays a significant role in the treatment of IBM, since it leads to improvement of the functional capacity of patients in daily activities, thus reducing their disability

 Hedberg-Oldfors, C., Lindgren, U., Basu, S., Visuttijai, K., Lindberg, C., Falkenberg, M., Larsson Lekholm, E., & Oldfors, A. (2021). Mitochondrial DNA variants in inclusion body myositis characterized by deep sequencing. Brain Pathology, 31(3). https://doi.org/10.1111/bpa.12931 OPEN ACCESS

⧉ In conclusion, deep sequencing and quantification of mtDNA variants revealed that IBM muscles had markedly increased levels of large deletions and duplications, and there were also indications of increased somatic single nucleotide variants and reduced mtDNA copy numbers compared to age-matched controls. The distribution and type of variants were similar in IBM muscle and controls indicating an accelerated aging process in IBM muscle, possibly associated with chronic inflammation.

 ♦♦♦Oikawa, Y., Izumi, R., Koide, M., Hagiwara, Y., Kanzaki, M., Suzuki, N., Kikuchi, K., Matsuhashi, T., Akiyama, Y., Ichijo, M., Watanabe, S., Toyohara, T., Suzuki, T., Mishima, E., Akiyama, Y., Ogata, Y., Suzuki, C., Hayashi, H., Kodama, E. N., … Abe, T. (2020). Mitochondrial dysfunction underlying sporadic inclusion body myositis is ameliorated by the mitochondrial homing drug MA-5. PLOS ONE, 15(12), e0231064. https://doi.org/10.1371/journal.pone.0231064. OPEN ACCESS

⧉ Sporadic inclusion body myositis (sIBM) is the most common idiopathic inflammatory myopathy, and several reports have suggested that mitochondrial abnormalities are involved in its etiology. We recruited 9 sIBM patients and found significant histological changes and an elevation of growth differential factor 15 (GDF15), a marker of mitochondrial disease, strongly suggesting the involvement of mitochondrial dysfunction.

⧉ We recently reported a new mitochondria-homing drug, mitochonic acid-5 (MA-5) (4[2,4-difluorophenyl]-2-[1H-indole-3-yl]-4-oxobutanoic acid), which increases the cellular ATP level and reduces mitochondrial reactive oxygen species (mtROS) production, protecting patients with mitochondrial dysfunction from fibroblast death [10–12].

⧉ Mitochonic acid-5 (MA-5) increased the cellular ATP level, reduced mitochondrial ROS, and provided protection against sIBM myoblast death. MA-5 also improved the survival of sIBM skin fibroblasts as well as mitochondrial morphology and dynamics in these cells. The reduction in the gene expression levels of Opa1 and Drp1 was also reversed by MA-5, suggesting the modification of the fusion/fission process. These data suggest that MA-5 may provide an alternative therapeutic strategy for treating not only mitochondrial diseases but also sIBM.

⧉ Here, we demonstrated a significant elevation of a mitochondrial disease biomarker, growth differential factor 15 (GDF15) [13], in sIBM patient serum and found mitochondrial dysfunction in both patient myoblasts and skin fibroblasts. Under these conditions, MA-5 improved cell survival, increased ATP, and improved mitochondrial morphology and dynamics, suggesting the potential of MA-5 for sIBM therapy.

⧉ These data suggest that the GDF15 level is a useful marker that can predict mitochondrial damage in sIBM patients and evaluate the efficacy of MA-5 treatment.

⧉ skin fibroblasts can serve as a comparable tool [comparable to myoblasts from muscle byopsies] for diagnostic use in sIBM patients.

⧉ Here, we report the presence of mitochondrial dysfunction in sIBM and that a mitochondria-homing drug, MA-5, may be a potential candidate drug for sIBM.

⧉ We found that the circulating GDF15 level was significantly higher in sIBM patients than that in normal controls. We also found that the GDF15 level in myoblast culture medium was increased by BSO and decreased by MA-5. These data strongly suggest underlying mitochondrial dysfunction in sIBM patients and that GDF15 may serve as an alternative marker [alternative to the (cN-1A) antibody] for diagnosing sIBM and evaluating the efficacy of therapies.

⧉ MA-5 is a novel treatment not only for sIBM but also for sarcopenia, cachexia and muscle atrophy.

⧉ In conclusion, MA-5 is an alternative therapeutic strategy for treating mitochondrial diseases as well as sIBM. The use of GDF15 for diagnostics will also be useful in a forthcoming clinical trial of MA-5.

 ♦♦♦Hermanns, B., Molnar, M., & Schröder, J. M. (2000). Peripheral neuropathy associated with hereditary and sporadic inclusion body myositis: Confirmation by electron microscopy and morphometry. Journal of the Neurological Sciences, 179(1–2), 92–102. https://doi.org/10.1016/S0022-510X(00)00395-6

⧉ Peripheral neuropathy, although occasionally without apparent clinical manifestation, appears to be a common and aggravating feature in IBM; its pathogenesis, however, remains elusive.

 Dieudonné, Y., Allenbach, Y., Benveniste, O., Leonard-Louis, S., Hervier, B., Mariampillai, K., Nespola, B., Lannes, B., Echaniz-Laguna, A., Wendling, D., Von Frenckell, C., Poursac, N., Mortier, E., Lavigne, C., Hinschberger, O., Magnant, J., Gottenberg, J.-E., Geny, B., Sibilia, J., & Meyer, A. (2020). Granulomatosis-associated myositis: High prevalence of sporadic inclusion body myositis. Neurology, 94(9), e910–e920. https://doi.org/10.1212/WNL.0000000000008863

⧉ high prevalence of sporadic inclusion body myositis (SIBM) in patients with granulomatous myositis, and a significant proportion of these SIBM patients also had systemic features suggestive of sarcoidosis.

 Danielsson, O., Häggqvist, B., Gröntoft, L., Öllinger, K., & Ernerudh, J. (2020). Apoptosis in idiopathic inflammatory myopathies with partial invasion; a role for CD8+ cytotoxic T cells? PLOS ONE, 15(9), e0239176. https://doi.org/10.1371/journal.pone.0239176 OPEN ACCESS

⧉ Polymyositis and inclusion body myositis are idiopathic inflammatory myopathies, with a pathology characterized by partial invasion of non-necrotic muscle fibres by CD8 + cytotoxic T-cells, leading to fibre degeneration. Although the main effector pathway of CD8 + T-cells is to induce apoptosis of target cells, it has remained unclear if apoptosis occurs in these diseases, and if so, if it is mediated by CD8 + T-cells. In consecutive biopsy sections from 10 patients with partial invasion, muscle fibres and inflammatory cells were assessed by immunohistochemistry and apoptotic nuclei by the TUNEL assay. Analysis of muscle fibre morphology, staining pattern and quantification were performed on digital images, and they were compared with biopsies from 10 dermatomyositis patients and 10 controls without muscle disease. Apoptotic myonuclei were found in muscle with partial invasion, but not in the invaded fibres. Fibres with TUNEL positive nuclei were surrounded by CD8 + T-cells, granzyme B + cells and macrophages, but lacked FAS receptor expression. In contrast, apoptotic myonuclei were rare in dermatomyositis and absent in controls. The findings confirm that apoptosis occurs in idiopathic inflammatory myopathies and support that it is mediated by CD8 + cytotoxic T- cells, acting in parallel to the process of partial invasion.

⧉ Interestingly, our results showed that apoptotic nuclei were present almost exclusively in biopsies containing partial invasion, and that the presence of apoptosis was strongly associated with MHC I expressing muscle fibres that did not show the classical signs of partial invasion. However, these fibres did have adherent inflammatory cells expressing CD8+, granzyme B + as well as CD68 and CD163. . . . Taken together, our findings lend support to an immune-mediated mechanism leading to apoptosis. This process seems to occur in muscle affected by partial invasion, but apparently constituting a parallel process.

⧉ In conclusion: Apoptosis of muscle fibre nuclei is present in inflammatory myopathies with partial invasions, and these processes occur in the same area, but rarely in the same fibre. The affected fibres express MHC I and are surrounded by CD8 + T-cells, macrophages and granzyme B + cells. The findings collectively support that apoptosis, induced by cytotoxic CD8 + T-cells in IIM, may be a mechanism activated in parallel with the fibre disintegration seen in partial invasion. In addition to its apoptosis inducing potential, granzyme B may have other important roles in IIM with partial invasion. Inflammatory cells with macrophage/myeloic dendritic properties are also present in infiltrates invading muscle fibres and adhere to fibres with apoptotic myonuclei.

 Pinal-Fernandez, I., Casal-Dominguez, M., Derfoul, A., Pak, K., Miller, F. W., Milisenda, J. C., Grau-Junyent, J. M., Selva-O'Callaghan, A., Carrion-Ribas, C., Paik, J. J., Albayda, J., Christopher-Stine, L., Lloyd, T. E., Corse, A. M., & Mammen, A. L. (2020). Machine learning algorithms reveal unique gene expression profiles in muscle biopsies from patients with different types of myositis. Annals of the Rheumatic Diseases, 79(9), 1234–1242. https://doi.org/10.1136/annrheumdis-2019-216599 OPEN ACCESS

⧉ Conclusions Unique gene expression profiles in muscle biopsies from patients with Msa-defined subtypes of myositis and iBM suggest that different pathological mechanisms underly muscle damage in each of these diseases. In this study, we showed that machine learning algorithms trained on transcriptomics data could accurately classify myositis muscle biopsies from IBM and antibody-positive DM, AS and IMNM patients. This demonstrates that these IIM types have unique gene expression profiles.

 Nicolau, S., Liewluck, T., & Milone, M. (2020). Myopathies with finger flexor weakness: Not only inclusion-body myositis. Muscle & Nerve, 62(4), 445-454. https://doi.org/10.1002/mus.26914

⧉ In conclusion, prominent finger flexor weakness can occur in a number of myopathies, the most common being sIBM. However, finger flexor weakness is not restricted to sIBM, and frequently occurs in DM1 and DM2.

 ♦♦♦Lee, J. H., Boland-Freitas, R., Liang, C., Howells, J., & Ng, K. (2020). Neuropathy in sporadic inclusion body myositis: A multi-modality neurophysiological study. Clinical Neurophysiology, xxxx. https://doi.org/10.1016/j.clinph.2020.07.025

⧉ Conclusion: A concurrent neuropathy exists in a significant proportion of sIBM patients, with nerve excitability studies revealing changes possibly consistent with axolemmal depolarization or concurrent neuronal adaptation to myopathy. Neuropathy in sIBM does not correlate with muscle disease severity and may reflect a differing tissue response to a common pathogenic factor.

⧉ Significance: This study affirms the presence of a concurrent neuropathy in a large proportion of sIBM patients that appears independent of the severity of myopathy.

⧉ The mechanisms underlying this sIBM related neuropathy remain unclear. The absence of a clear correlation between the severity of muscle disease and markers of nerve dysfunction strongly suggest that neuropathy occurs independent of the inflammatory and degenerative changes seen in sIBM myocytes, perhaps reflecting a differing tissue response to a common, but as yet undefined pathogenic factor.

 Capkun, G., Schmidt, J., Ghosh, S., Sharma, H., Obadia, T., de Vera, A., Risson, V., & Amzal, B. (2019). Development and validation of a Bayesian survival model for inclusion body myositis. Theoretical Biology and Medical Modelling, 16(1), 17. https://doi.org/10.1186/s12976-019-0114-4 OPEN ACCESS

⧉ For IBM patients, results suggest an increased risk of premature death compared with the general population of the same age and gender.

 Vivekanandam, V., Bugiardini, E., Merve, A., Parton, M., Morrow, J. M., Hanna, M. G., & Machado, P. M. (2020). Differential Diagnoses of Inclusion Body Myositis. Neurologic Clinics, 38(3), 697-710. https://doi.org/10.1016/j.ncl.2020.03.014

 Walters, J., & Barborie, A. (2020). Muscle biopsy: What and why and when? Practical Neurology, practneurol-2019-002465. https://doi.org/10.1136/practneurol-2019-002465 OPEN ACCESS

 Suzuki, N., Soga, T., Izumi, R., Toyoshima, M., Shibasaki, M., Sato, I., Kudo, Y., Aoki, M., & Kato, M. (2020). Hybrid Assistive Limb® for sporadic inclusion body myositis: A case series. Journal of Clinical Neuroscience, 81, 92-94. https://doi.org/10.1016/j.jocn.2020.09.031

⧉ In the present study, we performed HAL therapy on three elderly patients with sIBM and found that it was both safe and effective in improving gait and maintaining the ability to ambulate. The first case was notable because the patient remained capable of walking 15 years after the onset of sIBM and 30 months since the initiation of HAL therapy.

⧉ The other limitation is that the long-term efficacy of HAL therapy for treating sIBM should be evaluated rigorously compared with the natural course of sIBM taking both placebo effect and appropriate allocation of medical resources into account. As is in the 1st case, disease progression makes it difficult to continue walking. The physicians should consider the risk of falling and recommend to quit HAL therapy at some point. Further evaluation of the longterm effect of HAL therapy on sIBM should be monitored in the future study.

 Catalán-García, M., García-García, F. J., Moreno-Lozano, P. J., Alcarraz-Vizán, G., Tort-Merino, A., Milisenda, J. C., Cantó-Santos, J., Barcos-Rodríguez, T., Cardellach, F., Lladó, A., Novials, A., Garrabou, G., & Grau-Junyent, J. M. (2020). Mitochondrial Dysfunction: A Common Hallmark Underlying Comorbidity between sIBM and Other Degenerative and Age-Related Diseases. Journal of Clinical Medicine, 9(5), 1446. https://doi.org/10.3390/jcm9051446 OPEN ACCESS

⧉ In summary, the conclusions of the present work stand for null comorbidity between sIBM and AD but partial comorbidity between sIBM and Type 2 Diabetes Mellitus (T2DM) through the impairment of glucose homeostasis, mitochondrial function, and probably lifestyle conditions. Although further investigation is needed to validate this pilot study, these findings provide better knowledge of sIBM complications.

⧉ On account that effective treatment for sIBM is not yet available, this should be a red flag and the monitorization of the prediabetic state in myositis patients to avoid potential complications in clinical practice associated with the management of both diseases should be considered, thus contributing to improving the quality of life of patients with inflammatory myopathies.

 ♦♦♦Ang, J. F. & Digala, L. P. (2020). Neuromuscular respiratory weakness. In N. Arora et al. (Eds.), Neuromuscular Urgencies and Emergencies, pp. 15-21. Springer. https://doi.org/10.1007/978-3-030-53145-4_2

⧉ The most common cause of death in neuromuscular diseases is chronic respiratory failure. The weakness of the diaphragm, intercostal muscles, and accessory respiratory muscles causes respiratory insufficiency and results in diminished ventilation. This type of insufficiency is known as type 2 respiratory failure or failure of the respiratory pump. It differs from type 1 hypoxic respiratory failure, which is caused by various lung disease.

⧉ Neuromuscular weakness causing respiratory failure is usually nonspecific, chronic, and insidious in presentation.

⧉ Reduced ventilation and ineffective cough from the weakness of respiratory, pharyngeal, and laryngeal muscles compromises the airway clearance and predisposes these patients to recurrent pneumonia and premature death.



⧉ Noninvasive ventilation with airway clearance therapy is considered standard practice for patients with neuromuscular respiratory failure. The major goal of noninvasive ventilation is to ensure adequate ventilation.

⧉ Some patients need full-time ventilation and mouthpiece ventilation when awake. An angled mouth-piece or straw-type mouthpiece is placed near the mouth so that patients can trigger a breath by creating a small negative pressure (sip ventilation). Mounting the ventilator on a wheelchair and suspending the mouthpiece on a gooseneck stand allows the patient to remain mobile and still have access to positive pressure as needed.

⧉ Although the patient's neuromuscular disease might not present with respiratory failure in the initial encounter, they are at high risk of developing one. Hence, prompt and timely screening is mandatory to identify patients that will benefit from NIV, as supportive respiratory therapies have proven to improve the quality of life when initiated promptly. Follow-up rate must be determined based on the established rate of progression of respiratory failure.

 ♦♦♦Greenberg, S. A. (2020). Pathogenesis of inclusion body myositis. Current Opinion in Rheumatology, Publish Ah. https://doi.org/10.1097/BOR.0000000000000752

⧉ Greenberg (2020) states "IBM is an autoimmune disease. Multiple arms of the immune system are activated, but a direct attack on muscle fibers by highly differentiated T cells drives muscle destruction."

⧉ Greenberg (2020) states that IBM is resistant to therapies because of this highly differentiated T-cell population, which is not effectively reduced by corticosteroids.

⧉ Greenberg (2020) states "T-cell cytotoxicity directed against myofibers is the only pathogenic mechanism we are certain of for IBM."

⧉ Greenberg (2020) states "Five studies over the last decade have shown an increased frequency of highly differentiated CD4 and CD8 T cells in IBM muscle or blood."

⧉ Greenberg (2020) states "IBM is unique among muscle diseases for its muscle genomic signature of T-cell cytotoxicity."

 Riddell, V., Bagby, S., & McHugh, N. (2020). Myositis autoantibodies. Current Opinion in Rheumatology, Publish Ah. https://doi.org/10.1097/BOR.0000000000000742

 Pipitone, N., & Salvarani, C. (2020). Up-to-date treatment and management of myositis. Current Opinion in Rheumatology, Publish Ah. https://doi.org/10.1097/BOR.0000000000000745

 Uchio, N., Unuma, A., Kakumoto, T., Osaki, M., Zenke, Y., Sakuta, K., Kubota, A., Uesaka, Y., Toda, T., & Shimizu, J. (2020). Pembrolizumab on pre-existing inclusion body myositis: A case report. BMC Rheumatology, 4(1), 48. https://doi.org/10.1186/s41927-020-00144-5 OPEN ACCESS

 Lin, A. Y., Siener, C. S., Faino, A. V., Seiffert, M., Weihl, C. C., & Wang, L. H. (2020). Optimizing hand-function patient outcome measures for inclusion body myositis. Neuromuscular Disorders, xxxx, 8-15. https://doi.org/10.1016/j.nmd.2020.08.358

⧉ We found that Patient-Reported Outcome measures hand-function have a higher correlation with pinch and grip strength than the Inclusion Body Myositis-Functional Rating Scale.

 Giannini, M., Fiorella, M. L., Tampoia, M., Girolamo, F., Fornaro, M., Amati, A., Lia, A., Abbracciavento, L., D'Abbicco, D., & Iannone, F. (2020). Long-term efficacy of adding intravenous immunoglobulins as treatment of refractory dysphagia related to myositis: A retrospective analysis. Rheumatology, 1-9. https://doi.org/10.1093/rheumatology/keaa443 OPEN ACCESS

 Vieira, A. C., & Vieira, A. (2020). Sporadic inclusion body myositis: A rare hazardous entity with important imaging findings. Acta Reumatologica Portuguesa, 45(2), 147-149. http://www.ncbi.nlm.nih.gov/pubmed/32895356 OPEN ACCESS

 Zeng, R., & Schmidt, J. (2020). Impact and management of dysphagia in inflammatory myopathies. Current Rheumatology Reports, 22(10). https://doi.org/10.1007/s11926-020-00950-3

 ♦♦♦Oldroyd, A. G. S., Lilleker, J. B., Williams, J., Chinoy, H., & Miller, J. A. L. (2020). Long-term strength and functional status in inclusion body myositis and identification of trajectory subgroups. Muscle and Nerve, July 2019, 76-82. https://doi.org/10.1002/mus.26859 OPEN ACCESS

⧉ This study has quantified annual dynamometry-derived muscle strength and functional status change in a large "real-world" IBM cohort with long follow-up duration and also identified distinct subgroups, according to change of grip and knee extension strength and functional status change over time.

⧉ Our study has identified that the pattern and annual rate of strength change differ markedly between male and females.

⧉ In clinical practice, it is evident that not all patients with IBM follow a similar trajectory of disease progression; our study attempted to define whether there is a continuous spectrum of severity or whether patients congregate into discrete subgroups. The variation of progression among trajectory subgroups was marked.

 Kushlaf, H. (2020). Diving into the heterogeneity of inclusion body myositis. Muscle and Nerve, 62(1), 7-9. https://doi.org/10.1002/mus.26897

⧉ This report (Oldroyd, above) illustrates several important points regarding the heterogeneity of IBM. The known heterogeneity of IBM involves the age at onset of weakness, the site of onset of weakness, the rate of progression of weakness, and ultimately the course of the disease.

⧉ In conclusion, IBM is a heterogeneous disease. We must harness our knowledge of IBM heterogeneity for use in designing IBM treatment trials. Failure to account for the known heterogeneity may result in drawing false negative conclusions from clinical trials. Moreover, investigating the basis of heterogeneity will prove useful in our understanding of IBM pathogenesis, a significant milestone adopted in Parkinson's disease.

 Oyama, M., Ohnuki, Y., Inoue, M., Uruha, A., Yamashita, S., Yutani, S., Tanboon, J., Nakahara, J., Suzuki, S., Shiina, T., Nishino, I., & Suzuki, S. (2020). HLA-DRB1 allele and autoantibody profiles in Japanese patients with inclusion body myositis. PloS One, 15(8), e0237890. https://doi.org/10.1371/journal.pone.0237890 OPEN ACCESS

⧉ Japanese IBM patients had the specific HLA-DRB1 alleles and autoantibody profiles.

 Lassche, S., Rietveld, A., Heerschap, A., van Hees, H. W., Hopman, M. TE, Voermans, N. C., Saris, C. G., van Engelen, B. G., & Ottenheijm, C. A. (2019). Muscle fiber dysfunction contributes to weakness in inclusion body myositis. Neuromuscular Disorders, 29(6), 468-476. https://doi.org/10.1016/j.nmd.2019.03.001 OPEN ACCESS

⧉ Muscle fiber dysfunction was accompanied by reduced active stiffness, which reflects a decrease in the number of attached actin-myosin cross-bridges during activation. Myosin concentration was reduced in IBM fibers. Because reduced specific force contributes to muscle weakness in patients with IBM, therapeutic strategies that augment muscle fiber strength may provide benefit to patients with IBM.

⧉ Specific force is reduced in IBM single muscle fibers and contributes to in vivo reduced specific force of the quadriceps. Muscle fiber weakness is caused by a decreased number of actin-myosin cross-bridges during activation, which is caused by myosin loss. Therapeutic strategies that augment muscle fiber strength may provide benefit to patients with IBM.

 Sivakumar, K., Cochrane, T. I., Sloth, B., Ashar, H., Laurent, D., Tanko, L. B., & Amato, A. A. (2020). Long-term safety and tolerability of bimagrumab (BYM338) in sporadic inclusion body myositis. Neurology, 10.1212/WNL.0000000000010417.

⧉ Long-term treatment up to 2 years with bimagrumab had good safety profile and was well-tolerated in individuals with sIBM. An increase in muscle mass was noted on a group level, however, there was no evidence of clinical improvement.

 Balakrishnan, A., Aggarwal, R., Agarwal, V., & Gupta, L. (2020). Inclusion body myositis in the rheumatology clinic. International Journal of Rheumatic Diseases, May, 1126-1135. https://doi.org/10.1111/1756-185X.13902



 Dieudonne, Y., Allenbach, Y., Benveniste, O., Leonard-Louis, S., Hervier, B., Mariampillai, K., Nespola, B., Lannes, B., Echaniz-Laguna, A., Wendling, D., Von Frenckell, C., Poursac, N., Mortier, E., Lavigne, C., Hinschberger, O., Magnant, J., Gottenberg, J. E., Geny, B., Sibilia, J., & Meyer, A. (2020). Granulomatosis-associated myositis: High prevalence of sporadic inclusion body myositis. Neurology, 94(9), e910-e920. https://doi.org/10.1212/WNL.0000000000008863

⧉ Patients with granuloma-myositis should be carefully screened for sIBM associated with sarcoidosis in order to best tailor their care.

 Labeit, B., Pawlitzki, M., Ruck, T., Muhle, P., Claus, I., Suntrup-Krueger, S., Warnecke, T., Meuth, S., Wiendl, H., & Dziewas, R. (2020). The impact of dysphagia in myositis: A systematic review and meta-analysis. Journal of Clinical Medicine, 9(7), 2150. https://doi.org/10.3390/jcm9072150 OPEN ACCESS

⧉ Dysphagia is a frequent complication in IIM with an estimated pooled prevalence of 36% and a peak prevalence of 56% in IBM.

 Kundu, D., Prerna, K., Chaurasia, R., Bharty, M. K., & Dubey, V. K. (2020). Advances in protein misfolding, amyloidosis and its correlation with human diseases. 3 Biotech, 10(5), 1-22. https://doi.org/10.1007/s13205-020-2166-x

 Mavroudis, I., Petridis, F., & Kazis, D. (2020). Inclusion body myositis. genetics, biomarkers and muscle biopsy. International Journal of Neuroscience, 86(6), 1-10. https://doi.org/10.1080/00207454.2020.1763340

 Limaye, V. S., Cash, K., Smith, C., Koszyca, B., Patel, S., Greenberg, S. A., & Hissaria, P. (2020). Inclusion-body myositis and primary Sjögren syndrome: Mechanisms for shared etiologies. Muscle & Nerve, January, mus.26830. https://doi.org/10.1002/mus.26830

 Lin, A. Y., Clapp, M., Karanja, E., Dooley, K., Weihl, C. C., & Wang, L. H. (2020). A cross-sectional study of hand function in inclusion body myositis: Implications for functional rating scale. Neuromuscular Disorders, 30(3), 200-206. https://doi.org/10.1016/j.nmd.2019.12.002

 Ansari, B., Salort-Campana, E., Ogier, A., Le Troter PhD, A., De Sainte Marie, B., Guye, M., Delmont, E., Grapperon, A., Verschueren, A., Bendahan, D., & Attarian, S. (2020). Quantitative muscle MRI study of patients with sporadic inclusion body myositis. Muscle & Nerve, 61(4), 496-503. https://doi.org/10.1002/mus.26813

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⧉ range of motion exercises for finger and thumb flexors are essential in IBM to avoid contractures due to severe muscle weakness (Fig. 33.3):



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