⚁ 6.3 Current IBM Research.

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

2024

⚂ Ogawa-Momohara, M., & Muro, Y. (2024). Myositis-specific and myositis-associated autoantibodies: Their clinical characteristics and potential pathogenic roles. Immunological Medicine, 1-13. https://doi.org/10.1080/25785826.2024.2413604

⚃ The anti-cytosolic 5’-nucleotidase 1 A (NT5C1A) antibody was detected in the sera of patients with IBM and was recognized as a potential diagnostic marker for IBM in 2013 [77]. However, subsequent studies revealed that anti-NT5C1A antibodies are not specific to IBM. While they are detected in approximately 60% of IBM patients, they also show positivity in other myositis diseases such as dermatomyositis (DM), immune-mediated necrotizing myopathy (IMNM), and ASS, at a rate of 10-25% [78]. Additionally, anti-NT5C1A antibodies can be found in patients with other autoimmune diseases such as Sjögren’s syndrome and systemic lupus erythematosus (SLE) [79,80]. Furthermore, several studies have failed to identify any significant clinical differences between anti-NT5C1A antibody-positive and -negative IBM patient cohorts [81]. These findings cast doubt on the role of this antibody in the pathogenesis of IBM and warrant further investigation.

⚂ Schlaffke, L., Rehmann, R., Froeling, M., Güttsches, A.-K., Vorgerd, M., Enax-Krumova, E., & Forsting, J. (2024). Quantitative muscle MRI in sporadic inclusion body myositis (sIBM): A prospective cohort study. Journal of Neuromuscular Diseases, 11(5), 997-1009. https://doi.org/10.3233/JND-240053

⚃ In this study, we extended the findings of previous studies underlying the feasibility and utility of qMRI in the assessment of sIBM. qMRI metrics capture the disease-specific patterns of muscle involvement in terms of fat replacement and correlate with clinical outcome measures and their change over time. These findings underscore the potential of qMRI metrics as a biomarker for assessing and monitoring muscle tissue functionality in sIBM.

⚂ Daniel, E., Smith, I. C., Sampaio, M. L., Melkus, G., Hamilton, L. E., Bourque, P. R., & Warman-Chardon, J. (2024). Current biomarkers in inclusion body myositis. Journal of Neuromuscular Diseases. DOWNLOAD PDF.

⚂ Mohammed, R. (2024). Mitochondrial “Parking Lot” Paracrystalline Inclusions in Sporadic Inclusion Body Myositis: An Ultrastructural Analysis (Poster No. 103) Arch Pathol Lab Med-Vol 148, September 2024 Abstracts e319.
≻ Mitochondrial paracrystalline inclusions (PCIs), also known as “parking lot” inclusions, are commonly seen in association with mitochondrial myopathies. Their association with other disease processes is not clearly outlined. Sporadic inclusion body myositis (sIBM) is a rare form of inflammatory myopathy commonly affecting the elderly. sIBM is morphologically characterized by inflammation, rimmed vacuoles, and evidence of mitochondrial pathology. Mitochondrial changes commonly observed in sIBM are cytochrome oxidase (COX)-negative myofibers, ragged red fibers highlighted by trichrome stain and ultrastructural mitochondrial abnormalities. The detection of PCIs in association with sIBM has not been adequately highlighted in the literature. The patient was a 76-year-old man with history of progressive muscle weakness involving bilateral lower extremities. Muscle biopsy revealed multifocal endomysial and perivascular inflammatory infiltrate, composed of lymphocytes, macrophages, and rare plasma cells in association with scattered subsarcolemmal vacuoles (Figure 3.103).
≻ Ultrastructural evaluation revealed mitochondrial PCIs in addition to structurally abnormal mitochondria of irregular shape and size, myelin-like whorls, and rare filamentous inclusions (Figure 3.103). This case highlights the ultrastructural findings observed in sIBM and documents the occurrence of PCIs in association with sIBM. In case of poor tissue preservation or inability to freeze fresh muscle tissue, electron microscopy evaluation is still a helpful tool in the diagnosis of sIBM.

⚂ Herrera, M., Wencel, M., Hernandez, I., Goyal, N., Dimachkie, M., Lloyd, T., Mohassel, P., Weihl, C., Freimer, M., Shaibani, A., Wicklund, M., Dixon, S., Chahin, N., Wang, L., Shieh, P., Amato, A., Quinn, C., Carbunar, O., & Mozaffar, T. (2024). 564P Investigating motor and bulbar severity in NT5c1A seropositive and seronegative IBM participants in the INSPIRE-IBM trial. Neuromuscular Disorders, 43, 104441.155. https://doi.org/10.1016/j.nmd.2024.07.164
≻ INSPIRE-IBM is a prospective NIH-funded observational study including patients ages 40 years or older with clinically defined IBM fulfilled by the ENMC 2011 criteria, and disease onset within the past 10 years of the Baseline visit. Serology for NT5c1A was collected at Baseline. Functional assessments to evaluate disease severity included Manual Muscle Testing (MMT), Timed get up-and-go (TUG), Sydney Swallow Questionnaire (SSQ), and EAT-10. Serological status was available for 140 out of 150 participants with IBM who were enrolled. Sixty-nine of the 140 IBM patients (49%) were seropositive for NT5c1A antibodies at Baseline. Patients were divided into two groups (Group A with disease duration between 0-5 years and Group B with disease duration between 6-10 years). Seropositive group A showed significantly greater difficulty swallowing (EAT-10 and SSQ) than seronegative group A. Seropositive group B showed a trend towards more difficulty swallowing (EAT-10 and SSQ) and motor function weakness (MMT) compared to the seronegative group but did not reach statistical significance. Seropositive IBM patients appear to have more swallowing difficulties than seronegative patients, and this difference appears early on in the disease course.

⚂ Brady, S., Poulton, J., & Muller, S. (2024). Inclusion body myositis: Correcting impaired mitochondrial and lysosomal autophagy as a potential therapeutic strategy. Autoimmunity Reviews, 23(11), 103644. https://doi.org/10.1016/j.autrev.2024.103644
≻ Muscle biopsy shows endomysial inflammatory infiltrate, mitochondrial changes, and protein aggregation. Proteostasis (protein turnover) appears to be impaired, linked to potentially dysregulated chaperone-mediated autophagy and mitophagy (mitochondrial quality control). In this review, we bring together the most recent clinical and biological data describing IBM. We then address the question of diagnosing this pathology and the relevance of the current biological markers that characterize IBM. In these descriptions, we put a particular emphasis on data related to the deregulation of autophagic processes and to the mitochondria-lysosome crosstalk. Finally, after a short description of current treatments, an overview is provided pointing towards novel therapeutic targets and upcoming regulating molecules tested for treating IBM. Special attention is paid to autophagy inhibitors that may offer innovative breakthrough therapies for patients with IBM.
≻ … recent research has particularly highlighted the central place of lysosome in this complex disease, although no specific lysosomal defect has been characterized. However, clinical research into new therapies for IBM should especially include components (small molecules, peptides or antibodies) that target key components of the lysosomal autophagic process. Any molecules that modulate specific subtypes of autophagy (macroautophagy, CMA, mitophagy), without any primary effect on other vital cellular pathways (e.g., apoptosis, cell adhesion, migration, proliferation, and differentiation), might represent breakthrough therapies for IBM patients whom treatment is supporting rather that specific. Although a major obstacle in addressing IBM lies in the limited understanding of its aetiology and pathogenesis, as well as in the lack of robust diagnostic tools, new lines of research on correcting mitochondrial and lysosomal autophagy impairment may revolutionize IBM management and improve patient outcomes.

⚂ Notarnicola, A., Hellstrom, C., Horuluoglu, B., Preger, C., Bonomi, F., De Paepe, B., De Bleecker, J., Van Der Kooi, A. J., De Visser, M., Sacconi, S., Machado, P., Badrising, U. A., Rietveld, A., Pruijn, G., Rothwell, S., Lilleker, J. B., Chinoy, H., Benveniste, O., Svenungsson, E., … Lundberg, I. E. (2023). POS0603 Autoantibodies against a subunit of mitochondrial respiratory chain complex I in inclusion body myositis. Scientific Abstracts, 574. 1-574. https://doi.org/10.1136/annrheumdis-2023-eular.5738

⚃ Our results reveal a new autoimmune target in the mitochondrial respiratory chain complex I that might be specifically associated with IBM. This is of particular interest as mitochondrial abnormalities are known histological findings in muscle biopsies of IBM patients.

⚃ Published as: Notarnicola, A., Hellstrom, C., Horuluoglu, B., Pin, E., Preger, C., Bonomi, F., De Paepe, B., De Bleecker, J. L., Van der Kooi, A. J., De Visser, M., Sacconi, S., Machado, P., Badrising, U. A., Rietveld, A., Pruijn, G., Rothwell, S., Lilleker, J. B., Chinoy, H., Benveniste, O., … Lundberg, I. E. (2024). Autoantibodies against a subunit of mitochondrial respiratory chain complex I in inclusion body myositis. Journal of Autoimmunity, 149, 103332. https://doi.org/10.1016/j.jaut.2024.103332

⚂ Ohmura, S. I., Sato, K., Nishimura, R., & Miyamoto, T. (2024). Long-Term Dysphagia Severity in Patients With Idiopathic Inflammatory Myopathy: A Single-Center Retrospective Study. Cureus. https://doi.org/10.7759/cureus.71821

⚃ The overall prevalence of dysphagia in patients with IIM is 36% globally, with IBM being the most prevalent subtype at 56% [3]. In sporadic IBM patients with dysphagia, immunosuppressive treatment does not recover their swallowing function, and dysphagia development is associated with a poor survival rate [4,7].
≻ On the other hand, patients with IBM did not respond to immunosuppressive treatments, and no treatment slowed the disease progression [21]. In the current study, disease progression occurred in all patients with IBM, and they did not receive any immunosuppressive treatment when they had dysphagia. In addition, previous reports have shown that the swallowing function outcomes of IBM patients with dysphagia were very poor compared with those without IBM, and IBM patients with dysphagia did not recover their swallowing function with immunosuppressive therapy, and their gastrostomy rate was 24%, which was consistent with our study [3-7].
≻  In addition, several investigators have reported the effectiveness of interventional procedures for IBM patients with dysphagia [4,5,22]. In the current study, two IBM patients received interventional procedures, specifically cricopharyngeal balloon dilation (n = 2), but the treatment was ineffective. Previous studies showed that cricopharyngeal balloon dilation can improve dysphagia symptoms [4,5,22]; however, the effect may not be permanent, and repeated procedures are required. On the other hand, one study showed that cricopharyngeal myotomy was effective in IBM patients with dysphagia [5]. In the current study, no patient with IBM received cricopharyngeal myotomy, and it is possible that physicians should have considered cricopharyngeal myotomy for IBM patients with dysphagia.

⚂ Naddaf, E., Shammas, I., Dasari, S., Petterson, X.-M. T., Trushina, E., & Lanza, I. R. (2024). Mitochondria-centered metabolomic map of inclusion body myositis: Sex-specific alterations in central carbon metabolism. https://doi.org/10.1101/2024.09.29.615665 DOWNLOAD PDF.

⚃ Objective To investigate the mitochondria-centered metabolomic map [Note 1] of IBM in muscle tissue, highlighting sex-specific differences, and to determine the correlation of the changes in metabolites and gene expression with clinical parameters.

⚃ Results Muscle samples from IBM patients had elevated TCA cycle [aka Krebs cycle] intermediates with concomitant increase in anaplerotic amino acids, suggesting increased anaplerosis into the cycle. [Note 2]
≻ There was a decrease in upper glycolysis intermediates and an increase in most of the pentose phosphate pathway (PPP) metabolites. [Note 3]
≻ The PPP is the main source of NAPDH, a main antioxidant, and ribose-5-P a precursor of nucleic acids.
≻ There were marked sex-specific differences in the acylcarnitine profile, [Note 4] with a decrease in short-chain acylcarnitines only in males.
≻ Lastly, there was an increase in nucleic acid bases and a decrease in nucleotides.
≻ Several metabolites from various pathways had significant correlations with various clinical parameters, with the most pronounced sex-specific differences observed in correlations with acylcarnitines.

⚃ Conclusion Taken together, our findings identified clinically significant alterations in central carbon metabolism [Note 5] in IBM, with major differences between males and females.
≻ Future studies are needed to determine the role of the detected metabolic alterations in IBM pathogenesis and track the changes longitudinally over the disease course.

 
   ≻≻ Note 1: Metabolomics is the large-scale study of small molecules, commonly known as metabolites, within cells, biofluids, tissues or organisms. Collectively, these small molecules and their interactions within a biological system are known as the metabolome.
   ≻≻ Note 2: anaplerosis = a metabolic process that replenishes the intermediates of a metabolic pathway: here the TCA cycle.
   ≻≻ Note 3: The pentose phosphate pathway (PPP) is an anabolic pathway, responsible for generating ribose 5-phosphate and nicotinamide adenine dinucleotide phosphate (NADPH).
   ≻≻≻ The pentose phosphate pathway takes place in the liquid cytoplasm of the cell and produces NADPH. NADPH is involved in protecting the cell against the toxicity of reactive oxygen species (ROS) among other important roles.
   ≻≻≻ Ribose 5-phosphate is a precursor in the synthesis of nucleotides.
   ≻≻ Note 4: Acylcarnitine refers to the compounds formed by conjugating acyl-CoA moieties to carnitine. They play a crucial role in the metabolism of long-chain fatty acids and are utilized to transport acyl-CoAs out of the mitochondria.
   ≻≻ Note 5: Central Carbon Metabolism involves a complex series of enzymatic steps to convert carbon-containing molecules, such as sugars and other organic compounds, into energy and precursor molecules necessary for cell growth, proliferation, and survival.
   ≻≻≻ It encompasses glycolysis, the pentose phosphate pathway (PPP), and the Krebs cycle (also known as the TCA cycle).
   ≻≻≻ Glycolysis is the first step in central carbon metabolism, breaking down glucose into pyruvate. This pyruvate is transported into the mitochondria, where it is converted into acetyl-CoA, the starting molecule for the Krebs cycle.
   ≻≻≻ The Krebs cycle is an integral part of central carbon metabolism, linking the breakdown of carbohydrates (via glycolysis) to energy production and providing intermediates for biosynthesis. While not directly connected to the PPP, the Krebs cycle works alongside these pathways to manage carbon flow, energy production, and biosynthetic needs. Central carbon metabolism ensures that cells can efficiently use carbon sources to meet their energy and growth requirements.

⚂ Yamashita, S., Tawara, N., Sugie, K., Suzuki, N., Nishino, I., & Aoki, M. (2024). Impact of sex, age at onset, and anti-cN1A antibodies on sporadic inclusion body myositis. Journal of the Neurological Sciences, 464, 123164. https://doi.org/10.1016/j.jns.2024.123164

⚃ This study aimed to determine the influence of autoantibodies, gender, and age of onset on the clinical features of IBM.
≻ This study included 570 consecutive patients clinically suspected of IBM from all the 47 Japanese prefectures between June 2015 and March 2022.
≻ Positive/negative: Of 353 patients, 196 (55.5%) were positive and 157 were negative for anti-cN1A autoantibodies.
   ≻≻ A comparison of the clinical characteristics between the patients with and without the autoantibodies revealed that the antibody-positive cases showed significant differences in the frequency of finger flexion strength [less than] shoulder abduction strength, the absolute difference between both grip strengths, and a lower frequency of onset of gait problems.
   ≻≻ No other indices, such as pulmonary function, disease severity, or histopathological findings, demonstrated significant differences between the two groups.
   ≻≻ The finding that the first symptom in cN1A-negative cases was often gait disturbance was statistically significant, even after adjustment for gender, disease duration, and age at onset using logistic regression.
≻ Age: Of the 353 patients, 33 (9.3%) developed the disease at age 50 or younger, 89 (25.2%) at age 51-60, 133 (37.7%) at age 61-70, and 98 (27.8%) at age 71 or older.
   ≻≻ There was a significant difference in disease duration in the 4 groups, with the group that developed the disease at an older age having a shorter duration of disease.
   ≻≻ There was a significant difference in BMI between the Group 51-60 and Group over 71, with a trend toward lower BMI in the group with older age of onset.
   ≻≻ Histopathological findings showed no difference between the groups.
   ≻≻ Multiple regression showed that age at onset remained an independent factor with a significant effect on disease duration, even after adjusting for anti-cN1A autoantibodies and gender.
   ≻≻ Moreover, age at onset was independently associated with BMI and serum CK levels, even after adjusting for anti-cN1A autoantibodies, disease duration, and gender by multiple regression.
≻ Gender: Of the 353 patients, 147 (41.6%) were female and 206 (58.4%) were male.
   ≻≻ Multiple regression showed that gender remained an independent factor with a significant effect on BMI, even after adjusting for anti-cN1A autoantibodies, disease duration, and age at onset.
   ≻≻ Female patients had a lower BMI, whereas male patients had a higher frequency of finger weakness as the initial symptom, a larger absolute difference between both grip strength, and higher CK levels.
   ≻≻ Histopathologic findings showed that the frequency of RVs was significantly higher in the male patient group, while the frequency of lymphocytes surrounding non-necrotic fibers was significantly higher in the female patient group.
   ≻≻ Considering the IBMFRS scores, female patients had lower values for item 1 (swallowing), whereas male patients had lower values for item 2 (handwriting).

⚃ In this study, we have shown that anti-cN1A autoantibodies, gender, age of onset, and duration of disease may influence the clinical presentation of IBM.
≻ The influence of anti-cN1A autoantibodies on the clinicopathologic features of IBM remains controversial.

⚃ In conclusion, anti-cN1A autoantibody-positive patients had a higher frequency of finger flexion muscle weakness, suggesting that this autoantibody may modify the clinicopathological features of IBM.
≻ Sex and age of onset may influence the clinicopathological features of IBM, and a precision medicine approach should be considered based on the patient’s sex and age of onset as well as the etiopathogenesis.

⚂ Kleefeld, F., Cross, E., Lagos, D., Schoser, B., Hentschel, A., Ruck, T., Nelke, C., Walli, S., Hahn, K., Hathazi, D., Mammen, A. L., Casal-Dominguez, M., Gut, M., Gut, I. G., Heath, S., Schänzer, A., Goebel, H. H., Pinal-Fernandez, I., Roos, A., … Horvath, R. (2024). Mitochondrial leakage and mtDNA damage trigger early immune response in Inclusion Body Myositis. https://doi.org/10.1101/2024.08.05.606624 DOWNLOAD PDF.

⚃ Polymyositis with mitochondrial pathology (PM-Mito) was first identified in 1997 as a subtype of idiopathic inflammatory myopathy.
≻ Recent findings demonstrated significant molecular similarities between PM-Mito and Inclusion Body Myositis (IBM), suggesting a trajectory from early to late IBM and prompting the inclusion of PM-Mito as an IBM precursor (early IBM) within the IBM spectrum.
≻ Both PM-Mito and IBM show mitochondrial abnormalities, suggesting mitochondrial disturbance is a critical element of IBM pathogenesis.

⚃ We found widespread mitochondrial abnormalities in both PM-Mito and IBM, illustrated by elevated numbers of COX-negative and SDH-positive fibers and prominent ultrastructural abnormalities with disorganized and concentric cristae within enlarged and dysmorphic mitochondria.
≻ MtDNA copy numbers were significantly reduced, and multiple large-scale mtDNA deletions were already evident in PM-Mito, compared to healthy age-matched controls, similar to the IBM group.
≻ The activation of the canonical cGAS/STING inflammatory pathway, possibly triggered by the intracellular leakage of mitochondrial DNA, was evident in PM-Mito and IBM.
≻ Elevated levels of circulating Cell-free mitochondrial DNA (cfmtDNA) also indicated leakage of mtDNA as a likely inflammatory trigger.
≻ In PM-Mito and IBM, these findings were accompanied by dysregulation of proteins and transcripts linked to the mitochondrial membranes.

⚃ In summary, we identified that mitochondrial dysfunction with multiple mtDNA deletions and depletion, disturbed mitochondrial ultrastructure, and defects of the inner mitochondrial membrane are features of PM-Mito and IBM, underlining the concept of an IBM-spectrum disease (IBM-SD). The activation of inflammatory pathways related to mtDNA release indicates a significant role of mitochondria-associated inflammation in the pathogenesis of IBM-SD. Thus, mitochondrial abnormalities precede tissue remodeling and infiltration by specific T-cell subpopulations (e.g., KLRG1+ ) characteristic of late IBM. This study highlights the critical role of early mitochondrial abnormalities in the pathomechanism of IBM, which may lead to new approaches to therapy.

⚂ Zhang, Y., Chen, S., Tang, X., Peng, Y., Jiang, T., Zhang, X., Li, J., Liu, Y., & Yang, Z. (2024). The role of KLRG1: A novel biomarker and new therapeutic target. Cell Communication and Signaling, 22(1), 337. https://doi.org/10.1186/s12964-024-01714-7 DOWNLOAD PDF.

⚃ … recent clinical studies of KLRG1 inhibitors have focused only on inclusion body myositis (IBM) and T-cell large granular lymphocytic leukemia diseases, and the feasibility of using KLRG1 as a potential therapeutic target for other diseases still needs to be studied.
≻ … we present a comprehensive review elucidating the distribution, structural attributes, and functional signaling pathways of KLRG1 across various cell types, delineating its multifaceted involvement in assessment of the progression of disease pathogenesis.
≻ These findings demonstrate its significance as a biomarker in autoimmune and infectious diseases, as well as its contribution to immune modulation within both solid and hematological tumors.
≻ Additionally, we offer an overview of the recent advancements in KLRG1 inhibitor development for tumor immunotherapy, underscored by the promising synergistic efficacy of KLRG1 inhibitors combined with other targeted inhibitors.

⚂ Pinal-Fernandez, I., Muñoz-Braceras, S., Casal-Dominguez, M., Pak, K., Torres-Ruiz, J., Musai, J., Dell’Orso, S., Naz, F., Islam, S., Gutierrez-Cruz, G., Cano, M. D., Matas-Garcia, A., Padrosa, J., Tobias-Baraja, E., Garrabou, G., Aldecoa, I., Espinosa, G., Simeon-Aznar, C. P., Guillen-Del-Castillo, A., … Mammen, A. L. (2024). Pathological autoantibody internalisation in myositis. Annals of the Rheumatic Diseases, ard-2024-225773. https://doi.org/10.1136/ard-2024-225773 DOWNLOAD PDF.

⚃ In patients with myositis autoantibodies, antibodies accumulate inside myofibres in the same subcellular compartment as the autoantigen.
≻ Muscle biopsies from patients with autoantibodies targeting transcriptional regulators exhibit transcriptomic patterns consistent with dysfunction of the autoantigen.
≻ Introducing patient antibodies into cultured muscle cells recapitulates the transcriptomic effects observed in human disease.
≻ Further supporting evidence suggests that myositis autoantibodies recognising other autoantigens may also disrupt the function of their targets.
≻ How this study might affect research, practice or policy
   ≻≻ In myositis, autoantibodies are internalised into living cells, causing biological effects consistent with the disrupted function of their autoantigen.
   ≻≻ Treatments to reset, decrease the half-life or reduce the production of endogenous antibodies can be effective in various forms of myositis.

⚃ This study demonstrates that, in myositis, autoantibodies are internalised into living cells, causing biological effects consistent with the disrupted function of their autoantigen.
≻ Taken together, these findings disprove the conventional assumption that myositis autoantibodies are incapable of reaching their intracellular target and exerting a functional effect.

⚂ Acosta, I., Hofer, M., Hilton-Jones, D., Squier, W., & Brady, S. (2024). Treatment resistance in inclusion body myositis: The role of mast cells. Neuromuscular Disorders, 41, 20-23. https://doi.org/10.1016/j.nmd.2024.05.001

⚃ Our results show there was a greater number of mast cells present in IBM and neurogenic myositis than in normal muscle and steroid-responsive inflammatory myopathy. … Our study supports mast cells playing a role in the pathogenesis of IBM and FMNI. NI could contribute to the lack of response to immunosuppressive treatment in IBM.

⚂ Salam, S., Symonds, T., Doll, H., Rousell, S., Randall, J., Lloyd-Price, L., Hudgens, S., Guldberg, C., Herbelin, L., Barohn, R. J., Hanna, M. G., Dimachkie, M. M., & Machado, P. M. (2024). Measurement properties of the Inclusion Body Myositis Functional Rating Scale. Journal of Neurology, Neurosurgery & Psychiatry, jnnp-2024-333617. https://doi.org/10.1136/jnnp-2024-333617

⚃ Results: Among the 150 patients, mean (SD) IBMFRS total score was 27.4 (4.6). Convergent validity was supported by medium to large correlations (rs modulus: 0.42-0.79) and discriminant validity by moderate to large group differences (SES=0.51-1.59). Internal consistency was adequate (overall Cronbach’s alpha: 0.79). Test-retest reliability (ICCs=0.84-0.87) and reliability of telephone versus face-to-face administration (ICCs=0.93-0.95) were excellent, with Bland-Altman plots showing good agreement. Responsiveness in the worsened group defined by various external constructs was large at both 12 (SRM=-0.76 to -1.49) and 20 months (SRM=-1.12 to -1.57). In ROC curve analysis, a drop in two IBMFRS total score points was shown to represent a meaningful decline.
≻ Conclusions: When administered by trained raters, the IBMFRS is a reliable, valid and responsive tool that can be used to evaluate the impact of IBM and its treatment on physical function, with a 2-point reduction representing meaningful decline.

⚂ Abad, C., Pinal-Fernandez, I., Guillou, C., Bourdenet, G., Drouot, L., Cosette, P., Giannini, M., Debrut, L., Jean, L., Bernard, S., Genty, D., Zoubairi, R., Remy-Jouet, I., Geny, B., Boitard, C., Mammen, A., Meyer, A., & Boyer, O. (2024). IFNλ causes mitochondrial dysfunction and oxidative stress in myositis. Nature Communications, 15(1), 5403. https://doi.org/10.1038/s41467-024-49460-1 DOWNLOAD PDF.

⚃ The scarcity of myositis animal models has been a challenge in understanding the pathophysiology of IIMs and for therapeutic drug discovery.
≻ Here, we examine the mechanisms involved in Icos -/- NOD myositis and report the existence of severe mitochondrial defects and the beneficial effects of reactive oxygen species (ROS)-buffer administration.
≻ By means of transcriptome data analysis of muscle biopsies from patients with DM, and in vitro studies of human myoblasts exposed to IFNλ, we confirmed the correlation between this cytokine and mitochondrial anomalies in human myositis.
≻ Mitochondrial pathology is closely linked to oxidative stress and has been reported in IIMs and other inflammatory diseases.
≻ Skeletal muscle contraction demands high energy levels and thus greatly relies on optimal mitochondrial function as a major source of ATP.
≻ Given their critical role as bioenergetic powerhouses, it is not surprising here that mitochondrial defects led to a profound metabolic imbalance contributing to myositis pathogenesis.
≻ Therefore, whereas the current view is that muscle inflammation causes myofiber necrosis and subsequent regeneration through cell- and cytokine-mediated cytotoxicity, the present results add mitochondrial defects and oxidative stress as a major pathogenic component to the mechanisms of myositis, being both potential triggers as well as a consequence of muscle dysregulated inflammation.
≻ In conclusion, our study using a murine model of myositis suggests the presence of a self-sustaining loop between inflammation and mitochondrial dysfunction/oxidative stress in the pathogenesis of myositis, and provide evidence supporting its relevance in human myositis, pointing at mitochondria as a possible new therapeutic target.

⚂ Naddaf, E., Nguyen, T. K. O., Watzlawik, J. O., Gao, H., Hou, X., Fiesel, F. C., Mandrekar, J., Kokesh, E., Harmsen, W. S., Lanza, I. R., Springer, W., & Trushina, E. (2024). NLRP3 inflammasome activation and altered mitophagy are key pathways in inclusion body myositis. https://doi.org/10.1101/2024.06.15.24308845 DOWNLOAD PDF.

⚃ The pathogenesis of IBM remains poorly defined. Inflammation and mitochondrial dysfunction are the most common histopathological findings. In this study, we aimed to explore the interplay between inflammation and mitochondrial dysfunction in IBM patients, highlighting sex differences.
≻ We demonstrated activation of the NLRP3 inflammasome in IBM muscle samples, with the NLRP3 inflammasome pathway being the most upregulated. On muscle histopathology, there is increased NRLP3 immunoreactivity in both inflammatory cells and muscle fibers. Mitophagy is critical for removing damaged mitochondria and preventing the formation of a vicious cycle of mitochondrial dysfunction—NLRP3 activation. In the IBM muscle samples, we showed altered mitophagy, most significantly in males, with elevated levels of p-S65-Ubiquitin, a mitophagy marker. Furthermore, p-S65-Ubiquitin aggregates accumulated in muscle fibers that were mostly type 2 and devoid of cytochrome-c-oxidase reactivity. Type 2 muscle fibers are known to be more prone to mitochondrial dysfunction. NLRP3 RNA levels correlated with p-S65Ubiquitin levels in both sexes but with loss of in muscle strength only in males. Finally, we identified sex-specific molecular pathways in IBM, with females having activation of pathways that could offset some of the pathomechanisms of IBM.
≻ Conclusions: NLRP3 inflammasome is activated in IBM, along with altered mitophagy particularly in males, which is of potential therapeutic significance. These findings suggest sex-specific mechanisms in IBM that warrant further investigation.

⚂ Aspi, Md, M. T. B., & Arancon, Md, Mba, A. K. C. V. (2024). Anesthesia spearheading perioperative safety efforts in a patient with inclusion body myositis: A case report. Acta Medica Philippina, 5 (9). https://doi.org/10.47895/amp.v58i9.8830 DOWNLOAD PDF.

⚃ As patients with IBM are at risk for exaggerated sensitivity to neuromuscular blockers and respiratory compromise, anesthesia was at the helm of a multidisciplinary team approach. The perioperative management centered on preoperative optimization, prevention of aspiration, avoidance of anesthetics that may trigger malignant hyperthermia, and prevention of postoperative pulmonary complication. The hospital course was uncomplicated and the patient was discharged well after one day. This report emphasizes how improvements in resources, technology, and healthcare delivery, especially in anesthesia, help prevent perioperative adverse events.
≻ IBM may involve respiratory muscles, leading to diaphragmatic dysfunction and diminished respiratory effort. This increases the risk for postoperative pulmonary complications such as aspiration pneumonia and respiratory failure, needing prolonged ventilatory support in some cases.
≻ Since this report mainly focused on prevention of adverse effects, further studies are needed to establish the safety of anesthetic agents such hypnotics, analgesics, and neuromuscular blockers in order to expand the options for anesthesia management in patients with inclusion body myositis.

⚂ Lodin, K., Espinosa-Ortega, F., Lundberg, I., & Alexanderson, H. (2024). The Role of exercise to improve physiological, physical and psychological health Outcome in Idiopathic Inflammatory Myopathies (IIM). Journal of Inflammation Research, Volume 17, 3563-3585. https://doi.org/10.2147/JIR.S377102 DOWNLOAD PDF.

⚃ Exercise in combination with medical treatment is becoming an important part of the treatment for patients with IIM as exercise has the potential to promote health aspects of various dimensions in patients with IIM.

⚂ Wischnewski, S., Thäwel, T., Ikenaga, C., Kocharyan, A., Lerma-Martin, C., Zulji, A., Rausch, H.-W., Brenner, D., Thomas, L., Kutza, M., Wick, B., Trobisch, T., Preusse, C., Haeussler, M., Leipe, J., Ludolph, A., Rosenbohm, A., Hoke, A., Platten, M., … Schirmer, L. (2024). Cell type mapping of inflammatory muscle diseases highlights selective myofiber vulnerability in inclusion body myositis. Nature Aging. https://doi.org/10.1038/s43587-024-00645-9 DOWNLOAD PDF.

⚃ In IBM muscles, we observed a selective loss of type 2 myonuclei paralleled by increased levels of cytotoxic T and conventional type 1 dendritic cells.
≻ IBM myofibers were characterized by either upregulation of cell stress markers featuring GADD45A and NORAD or protein degradation markers including RNF7 associated with p62 aggregates.
≻ GADD45A upregulation was preferentially seen in type 2A myofibers associated with severe tissue inflammation.
≻ We also noted IBM-specific upregulation of ACHE encoding acetylcholinesterase, which can be regulated by NORAD activity and result in functional denervation of myofibers. Our results provide promising insights into possible mechanisms of myofiber degeneration in IBM and suggest a selective type 2 fiber vulnerability linked to genomic stress and denervation pathways.
≻ In summary, the herein reported genomic stress pathway might represent a critical damage mechanism in IBM (in addition to degeneration through dysregulated protein degradation) and be a potential therapeutic target to improve NMJ transmission.
≻ Reversible AChE inhibitors have proved useful in treating various neurological conditions, with inhibitors crossing the blood-brain barrier (BBB, for example, rivastigmine) used in the therapy of dementia in Alzheimer’s and Parkinson’s diseases and ones not crossing the BBB (for example, pyridostigmine) used in the therapy of myasthenia gravis.
≻ Considering increased AChE expression in a subset of IBM myofibers, a non-BBB, crossing, reversible AChE inhibitor such as pyridostigmine might be a therapeutic consideration in IBM.

⚂ Guirguis-Blake, J. M., Perdue, L. A., Coppola, E. L., & Bean, S. I. (2024). Interventions to Prevent Falls in Older Adults:  Updated Evidence Report and Systematic Review for the US Preventive Services Task Force. JAMA. https://doi.org/10.1001/jama.2024.4166 DOWNLOAD PDF.

⚃ Multifactorial and exercise interventions were associated with reduced falls in multiple good-quality trials.
≻ Exercise demonstrated the most consistent statistically significant benefit across multiple fall-related outcomes.

⚂ Warman-Chardon, J., Breiner, A., & Bourque, P. R. (2024). Inclusion body myositis. Canadian Medical Association Journal, 196 (14), E486-E486. https://doi.org/10.1503/cmaj.231815 DOWNLOAD PDF.

⚃ 1 Inclusion body myositis is the most common type of late-onset inflammatory myopathy: Inclusion body myositis is an idiopathic inflammatory myopathy.
≻ Whether its cause is primarily autoimmune or degenerative is debated.
≻ Its prevalence is 18 per 100 000 people, higher than dermatomyositis or amyotrophic lateral sclerosis (ALS).
≻ Inclusion body myositis predominantly affects males (3:1 to females), usually becoming symptomatic after age 50 years.

⚃ 2 Typical features are insidious, painless, and progressive weakness and muscle atrophy that is asymmetric and multifocal: Inclusion body myositis affects proximal and distal muscles, causing striking weakness of the quadriceps and finger flexor muscles. This leads to falls and loss of grip strength. Over time, foot drop and dysphagia also become prominent.

⚃ 3 Electromyography (EMG) and muscle biopsy are the leading diagnostic tools. Serum levels of creatinine kinase are only moderately elevated at 3002000 U/L. Needle EMG may show equivocal findings that can suggest both myopathy and neuropathy. Current auto-antibody tests (antiNT5C1A) have high specificity (90%) but only moderate sensitivity (40%); results must be interpreted in the clinical context. A muscle biopsy should be performed, which may reveal inflammation, rimmed vacuoles, and congophilic inclusions; interpretation requires expertise in neuromuscular pathology.

⚃ 4 Differential diagnosis includes motor neuron disease, other inflammatory myopathies, and late-onset muscular dystrophies. Lack of fasciculations and myopathic findings on EMG distinguish inclusion body myositis from motor neuron disease such as ALS. Asymmetry, selective weakness of finger flexors and muscle biopsy findings distinguish inclusion body myositis from other inflammatory myopathies or muscular dystrophies. Most patients benefit from referral to a neuromuscular specialist.

⚃ 5 Treatment is supportive: No immunosuppressive therapy has been proven to be helpful for inclusion body myositis, in contrast to other forms of myositis. Progressive motor disability causes 60% of patients to require a wheelchair at 10 years. Life expectancy is, however, only minimally reduced. Patients do not usually require tube feeding or assisted ventilation. Management focuses on adaptive measures, home exercises, and optimized nutrition.

⚂ Mano, T., Iguchi, N., Iwasa, N., Yamada, N., & Sugie, K. (2024). Compound muscle action potential of whole-forearm flexors: A clinical biomarker for inclusion body myositis. Clinical Neurophysiology Practice, 9, 162-167. https://doi.org/10.1016/j.cnp.2024.03.003 DOWNLOAD PDF.

⚃ The compound muscle action potential (CMAP) consists of hundreds of motor unit action potentials that are summed in a complex manner.
≻ We investigated the use of the CMAP amplitude, which reflects the number of nerve fibers of the whole-forearm flexor muscle (WFFM), as a clinical biomarker for IBM.
≻ Results: The WFFM CMAP was strongly correlated with disease duration and the IBMFRS score. The WFFM CMAP on the more affected side was lower than that on the less affected side. Furthermore, grip power was strongly correlated with the WFFM CMAP, whereas lateral pinch strength was strongly correlated with the WFFM and first dorsal interosseous CMAPs. The 3-point pinch strength was also correlated with the WFFM CMAP.
≻ Conclusions: This study demonstrates that the WFFM CMAP may serve as a biomarker of severity in IBM.
≻ Significance: Identification of this biomarker can support drug development, diagnosis, prognosis, and treatment options for patients with IBM.

⚂ McLeish, E., Sooda, A., Slater, N., Beer, K., Cooper, I., Mastaglia, F. L., Needham, M., & Coudert, J. D. (2024). Identification of distinct immune signatures in inclusion body myositis by peripheral blood immunophenotyping using machine learning models. Clinical & Translational Immunology, 13 (4), e1504. https://doi.org/10.1002/cti2.1504 DOWNLOAD PDF.

⚃ In this study, we conducted comprehensive immunophenotyping of peripheral blood leucocytes using multi-parameter flow cytometry.
≻ Our analysis encompassed a comparative cross-sectional exploration of IBM patients and healthy controls.
≻ Given IBM prevalence in those aged 50 and above, we strategically compared IBM with similarly aged HC, distinctly isolating disease specific immune shifts from age-related influences.
≻ We also aimed to compare immunophenotypes between IBM patients via unsupervised clustering techniques and examine correlations with clinical and functional measures, deepening our comprehension of IBM heterogeneous nature.
≻CD8+ TEMRA subset variability in discriminating between IBM and healthy individuals, we employed a random forest model.
≻ These cells did not emerge as a top-ranking feature in the model, which suggested their limited contribution to the model’s discriminatory power between IBM and HC.
≻ This finding raised intriguing questions about the true impact of CD8+ TEMRA cells in the immunological landscape of IBM and prompted us to explore alternative factors that possibly contribute to the disease pathology.
≻…Findings demonstrate that both the CD8+ and CD4+ compartments were dysregulated, which likely contributes to the immunopathology associated with IBM.
≻ Our independent validation strengthens CD+ T-bet+ as a potential IBM biomarker.
≻ IBM patients formed three clusters:
   ≻≻ (i) activated and inflammatory CD8+ and CD4+ T-cell profile and the highest proportion of anti-cN1A-positive patients in cluster 1;
   ≻≻ (ii) limited inflammation in cluster 2;
   ≻≻ (iii) highly differentiated, proinflammatory T-cell profile in cluster 3.
≻ Recently, the presence of CD8+ large granular lymphocytes (LGLs) has been revealed in the blood and muscle of approximately 34-58% of IBM patients.
≻ In line with these findings, cluster 3 further substantiates the importance of these late-differentiated T cells in IBM.

⚃ Our findings not only reaffirm previous insights into aberrant T cell alterations, notably heightened CD8+ T-bet+, but also achieve refined stratification of IBM patients via distinct immunophenotypic profiles.
≻ However, the clinical and functional ramifications of these immune phenotypes remain elusive.
≻ This investigation forms a robust foundation for delving deeper into the functional significance of CD8+ T-bet+ and CD8+ CD57+, alongside discrete immune subsets such as cd T cells and regulatory T cells.
≻ These findings provide a strong rational for future studies using the same approach to compare IBM cohort to cohorts affected by other inflammatory myopathies and to identify specific IBM biomarkers that may distinguish the disease from other IIMs. Comprehending these implications holds potential for future clinical applications, spanning IBM diagnosis, prognosis and management.

⚃ Cluster 1 represents highly activated and pro-inflammatory CD4+ T cells in conjunction with a differentiated CD8 profile. …
≻ Cluster 1 displayed a distinctive CD8+ T-cell profile characterised by a high degree of differentiation. …
≻ The prevalence of anti-cN1A seropositivity was the highest in this cluster (accounting for 43%) and was significantly increased compared to cluster 2;

⚃ Cluster 2 represents a low inflammation profile …
≻ Cluster 2 included patients exhibiting a distinct immunological profile characterised by reduced inflammation markers, as evidenced by the substantial decrease in all markers listed in the feature importance plot compared to clusters 1 and 3.
≻ Notably, this cluster displayed higher counts of CD8+ and CD4+ native T cells.
≻ Additionally, we did not observe an altered gamma delta T cell subset distribution in this cluster.
≻ Lowest proportion of anti-cN1A seropositivity with 22%.

⚃ Cluster 3 Is characterised by the predominance of highly differentiated pro-inflammatory CD8 and skewed gamma delta T cells. …
≻ Recently, the presence of CD8+ large granular lymphocytes (LGLs) has been revealed in the blood and muscle of approximately 34-58% of IBM patients.
≻ In line with these findings, cluster 3 further substantiates the importance of these late-differentiated T cells in IBM.
≻ Notably, patients in this cluster also possess an abundance of CD4+ and gamma-delta (Vd1 and Vd2) T cells exhibiting high expression levels of CD57. …
≻ Cluster 3 exhibits the highest proportion of total FoxP3+ and native Tregs of all clusters, suggesting the presence of regulatory mechanisms aimed at counteracting the pathological impact stemming from highly differentiated and inflammatory T cells.
≻ However, the apparent absence of proliferating Tregs poses a challenge to this interpretation. …
≻ It cannot be excluded that the identified Treg population might potentially contribute to the notably dysregulated T-cell profile in cluster 3. …
≻ It is worth noting a trend of increased disease severity in cluster 3’s patients compared to the other two clusters.
≻ This trend is supported by lower scores on functional measures such as the mTUG and 2MWT that reflect a reduction of leg muscle strength, while in contrast stronger average hand grip values were measured.
≻ The patients in this cluster have reported a more reduced ability to perform daily tasks resulting in lower IBM-FRS values than the other clusters’ patients.
≻ A higher level of dysphagia was also suggested by the higher average EAT-10 score measured, including some patients with very high scores that translate as a much-impaired swallowing function.
≻ We also note that cluster 3 has a longer disease duration with a median value of 11 years.
≻ However, the data distribution of this variable is normal in this cluster, with a large part of the measures that overlap most of those in the other 2 clusters. …
≻ Although, our data suggest that the immunophenotype associated with cluster 3 is associated with increased disease severity, future studies involving larger patient cohorts will be required to confirm these preliminary findings.

⚃ Importantly, we observed a significant difference in serostatus between cluster 1 and cluster 2 (P-value = 0.002), but not between clusters 1 and 3 or clusters 2 and 3.
≻ Notably, we did not find evidence of significantly different functional measures between these clusters.
≻ Nevertheless, a trend could be identified for cluster 3, where patients exhibited lower scores than the two other clusters for 2MWT, and TUG yet showed the highest scores for average hand grip strength, reduced IBM-FRS scores and increased EAT-10 score.
≻ However, considering the clusters’ low sample size, additional studies will be needed to confirm these observations.

⚃ In the context of inflammatory myopathies, IBM has been associated with a marked increase in CD8+ TEMRA cells, which are known for their resistance to apoptosis, enhanced cytotoxicity and secretion of pro-inflammatory cytokines. Accordingly, we measured a notable abundance of CD8+ TEMRA cells in this IBM cohort. Importantly, our study also revealed that this lymphocyte population also predominated in healthy aged controls, suggesting that ageing-related changes may contribute, at least in part, to this phenomenon.

⚂ Varone, N., Hinojosa, J., Nandakumar, D., Modi, N., Bhashyam, A. R., & Bhai, S. F. (2024). Exercise recommendations for patients with myositis: A narrative review of safety and efficacy. Clinical and Experimental Rheumatology. https://doi.org/10.55563/clinexprheumatol/m8fbs1 DOWNLOAD PDF.

⚃ Maintaining or increasing muscular strength and endurance as well as cardiorespiratory fitness (CRF) improves quality of life (QoL) as well as functional status in IIM patients. This narrative review highlights exercise interventions in patients of different IIM subtypes with the intent to provide a summary table with exercise recommendations that will safely and effectively improve QoL in myositis patients.
≻ Patients with IBM have a fitness level below the threshold for independence during ADLs, with a Vo2 max of 14.3 ml/ kg/min and anaerobic threshold lower than normative predicted values (23, 55). The advanced age of onset in IBM patients exposes this subset to increased risk of age-related fat infiltration of skeletal muscle tissue (56), compounding the effects of disease-related muscle weakness. Interventions reporting outcomes on IBM participants are presented in Table IV.
≻ It is of particular importance to encourage IBM patients to engage in adapted regular physical activity to preserve independence and mitigate fall risk.

⚂ Meryem T, Karim M, Marouane S, Zineb EJ, Haboub M, et al. (2023) A Rare Case of Non-Ischemic dilated cardiomyopathy revealing inclusion body myositis. J Case Rep Med Hist 3 (6): doi https://doi.org/10.54289/JCRMH2300128 DOWNLOAD PDF.

⚃ We report the observation of a 57-year-old patient known to be type 2 diabetic under treatment, admitted with acute congestive heart failure. the paraclinical examinations carried out were in favor of inclusion body myositis complicated by heart failure and dilated cardiomyopathy, the patient was treated with boluses of corticosteroids and immunosuppressants as well as treatment of heart failure, this attitude has improved his symptoms as well as his quality of life.

⚂ Mano, T., Iguchi, N., Eura, N., Iwasa, N., Yamada, N., Horikawa, H., & Sugie, K. (2024). Electromyography varies by stage in inclusion body myositis. Frontiers in Neurology, 14, 1295396. https://doi.org/10.3389/fneur.2023.1295396 DOWNLOAD PDF.

⚃ Results: In total, 30 patients with biopsy-confirmed IBM and 254 muscles were included. The rate of abnormal discharge did not differ according to disease stage. [early versus late stage] There was a difference in the frequency of occurrence between myogenic suggestive MUP and neurogenic of biceps and flexor digitorum profundus in the late phase. Abnormal MUP was observed even in muscles without muscle weakness, and myogenic changes were predominant in biceps and gastrocnemius with muscle weakness. The biopsy findings on the contralateral side of the muscle where electromyography was performed revealed a tendency for muscles that exhibited myogenic origin to have more inflammatory cells and RV; however, the difference was not significant.
≻ Conclusion: The target muscles for EMG must be selected considering the disease stage as well. In the early stages of IBM, EMG results should be interpreted cautiously, as neurogenic suggestive pattern of MUP might also be exhibited. Contralateral electromyography findings may be helpful in selecting muscles for muscle biopsies, such as biceps and quadriceps.
≻ IBM diagnosis is often delayed by an average of 5 years after symptom onset. It is diagnosed using a combination of clinical, neuroelectrophysiological, and pathological evaluations (10). In clinical practice, EMG results are central to the diagnosis and selection of patients for muscle biopsy (1). However, EMG findings vary with the stage of the disease and the extent of muscle damage. Clinicians should understand their characteristics to interpret EMG findings by stage.
≻ In this study, EMG findings confirmed the difference in the frequency of occurrence between myogenic and neurogenic suggestive patterns of biceps and FDP in late stages. Conversely, no difference was observed in the initial stage of the two muscles. This result suggests that as the disease progresses, myogenic changes become the main causative factor.
≻ Neurogenic changes in EMG likely represent a signature of denervation in IBM and segmented muscle fiber reinnervation. We observed a tendency for myogenic formation to increase in the early and late stages. However, the rate of neurogenic changes did not change. Although neurogenic changes are considered as the effects of aging or other coexisting evidence, it is possible that advanced myogenic changes in the late stage were mistakenly interpreted as neurogenic changes.
≻ Our results showed that abnormal MUPs are observed even in muscles with normal strength. This suggests that the disease state appears before the awareness of muscle weakness and that by the time muscle weakness appears, the disease state has already progressed. IBM progresses slowly; thus, we observed long-lasting neurogenic suggestive pattern MUPs caused by reinnervation. The action potentials in neurogenic motor units of IBM are sufficiently dense to overshadow myogenic changes.

⚂ Iu, E. C. Y., So, H., & Chan, C. B. (2024). Mitochondrial defects in sporadic inclusion body myositis—Causes and consequences. Frontiers in Cell and Developmental Biology, 12, 1403463. DOWNLOAD PDF. https://doi.org/10.3389/fcell.2024.1403463

⚃ This article reviews the disease hallmarks of sIBM, the plausible contributors of mitochondrial damage in the sIBM muscle, and the immunological responses associated with mitochondrial perturbations. Additionally, the potential application of mitochondrial-targeted chemicals as a new treatment strategy to sIBM is explored and discussed.
≻ In this article, we review the recent findings of mitochondrial dysfunction in sIBM and discuss their possible linkage with various disease symptoms. We will also discuss some potential mitochondrial-based therapeutic strategies for the treatment of sIBM.
≻ sIBM muscle features large-scale, single segment deletions (i.e., major rearrangement mutation) in the major arc of mtDNA molecules.
≻ The occurrence of mtDNA deletion in the muscle of sIBM patients is not limited to a consensus locus within a mtDNA molecule but is present in multiple regions. This suggests that the cause of mtDNA deletion and rearrangement might be more complex than previously assumed. The underlying mechanism that leads to the high frequency of mtDNA deletion in sIBM is still unknown.
≻ it is imperative to recognize the etiological role of mitochondria and developing novel drugs that improve the mitochondrial health as a novel treatment strategy for sIBM.

⚂ Lubinus, M., Hu, Y. P., Wilson, L., Williams, J., Bhashyam, A., & Bhai, S. (2023). POS0070-PARE Caregiver burden among Idiopathic Inflammatory Myopathy (IIM) caregivers. People with Arthritis and Rheumatism in Europe Abstracts, 246 .1-246. DOWNLOAD PDF. https://doi.org/10.1136/annrheumdis-2023-eular.1786

⚃ Myositis Support and Understanding (MSU), a non-profit patient-led advocacy organization for IIMs, distributed a survey to its members to better understand caregiver burden. The aim of this study was to evaluate the association between caregiver burden by IIM subtype and factors that impact caregiver wellbeing.
≻ Conclusion: Caregivers face a high degree of burden, most evident in IBM. Burden positively correlated with disease duration with an inflection time of 6 years, thereafter caregivers reported increased burden. The domains that were most impacted include personal strain, social and family life, role strain, and loss of control over one’s life. Insights from this study can help create specific emotional coping strategies for myositis patients and their caregivers.

⚂ Văcăraş, V., Vulturar, R., Chiş, A., & Damian, L. (2024). Inclusion body myositis, viral infections, and TDP-43: A narrative review. Clinical and Experimental Medicine, 24 (1), 91. https://doi.org/10.1007/s10238-024-01353-9 DOWNLOAD PDF.

⚃ IBM belongs to a group of neurological disorders, the TDP43 proteinopathies, which pathogenically involve TDP-43 [TAR-DNA-binding protein 43 (transactive response DNAbinding protein of 43 kDa)]. TDP-43, encoded by the TARDBP gene, an RNA- and DNA-binding nuclear regulatory protein, member of the heterogeneous nuclear ribonucleoprotein (hnRNP) family. In skeletal muscles, TDP-43 is involved in transcription regulation, RNA splicing, mRNA stability, RNA transport, and quality control and undergoes post-translational modifications with functional consequences. TDP-43 functions in muscles are complex, including myoregeneration. In neurodegeneration, the mechanisms of TDP-43 involvement include cytotoxic aggregations, nuclear loss, alteration of cellular functions, and others.

⚃ IBM muscle biopsies reveal cytoplasmic aggregation of TDP-43 and TDP-43 nuclear loss. Even an 1% amount of myofibers staining for TDP-43 in a muscle biopsy was highly sensitive and specific for IBM.

⚃ Increased Malat1 in IBM and TDP-43 aggregation may likely depend on viral characteristics and is in line with a slow inflammatory response.

⚃ TDP-43 could have an important role in the viral-induced IFN response in TDP-43 proteinopathies, including IBM (Table 2).

 Fig. 1 Regulation of TDP-43 in viral infections: potential implications for cellular processes in IBM pathogenesis.

⚃ Conclusions: TDP-43 is important in preventing the dsRNA-induced IFN responses. Viral infections may disrupt TDP-43 solubility and function, leading to its accumulation and lack of splicing regulation. The phenotypic differences between several IBM subtypes may be conditioned, besides genetic predisposing factors and age, also by environmental triggers such as certain viruses, and by epigenetic regulators. Malat1 upregulation in certain viral infections may contribute to a protracted immune response.
≻ Finding early disease markers and untangling mechanisms after a viral injury could inform whether there is a window of opportunity for the anti-inflammatory therapy, hopefully stopping or slowing the plethora of accompanying proteostasis, mitochondrial, and metabolic defects. Certain viruses, high viremia, coinfections, reactivation of latent viruses, and post-acute expansion of cytotoxic T cells may all contribute to IBM, mainly in an age-shaped immune landscape, with CD8+ T cells with IFN-ƴ production. In most such cases, the virally induced senescent, IFN-ƴ producing cytotoxic CD8+ T cells are the ones involved in IBM, in a genetically predisposed host. Immunophenotyping IBM patients to identify elevated CD8+ CD57+ populations may help stratify patients with prognostic and possibly therapeutic implications. Identifying pathogenic mechanisms may lead to the identification of potential new treatments or to drug repurposing to improve the outcome in this debilitating disease.

⚂ Nunn, G., Glenister, G., Hird, K., Beer, K., Cooper, I., Needham, M., & Brusch, A. (2024). Depression is a more significant predictor for wellbeing in Inclusion Body Myositis than physical disability [Preprint]. Rheumatology. https://doi.org/10.1101/2024.01.22.24301628 DOWNLOAD PDF.

⚃ Depression is a more significant predictor of wellbeing than disability in participants diagnosed with IBM. There was a high prevalence of depression and reduced wellbeing in participants, highlighting the importance of assessing these factors to optimise treatment in IBM.
≻Depression (PHQ-9) was negatively correlated with disability, where more severe depression was seen in participants with greater disability. This is a stronger correlation with disability than wellbeing. The results of this study revealed symptoms of moderate to severe depression in 78.2% of participants.
≻This study shows that self-reported scores on a depression scale is a more significant predictor of wellbeing than disability in participants diagnosed with IBM. There was a high prevalence of depression in the participants, even accounting for a comorbid physical condition. Given the interplay between wellbeing, depression, and disability, incorporating a focus on wellbeing into treatment may be a path towards improving health-related quality of life in IBM patients.

⚂ Salam, S., Allen, J., Dimachkie, M. M., Hanna, M. G., & Machado, P. M. (2023). Imaging swallowing function and the mechanisms driving dysphagia in inclusion body myositis. Clinical and Experimental Rheumatology. https://doi.org/10.55563/clinexprheumatol/t1x3qa DOWNLOAD PDF.

⚃ Up to 80% of patients develop some degree of swallowing impairment during the disease course. Dysphagia is a source of marked morbidity in IBM and predisposes patients to life-threatening complications such as aspiration pneumonia. The pathophysiology behind dysphagia in IBM is not fully understood. Evidence from imaging demonstrates that impaired swallowing is predominantly underpinned by oropharyngeal deficits. Changes in cricopharyngeal physiology is thought to be an important factor influencing dysphagia in IBM. However, it is unclear whether this is secondary to structural changes within the cricopharyngeus itself or driven by impairment of the muscles promoting pharyngeal clearance. The approach to dysphagia in IBM patients is limited by a lack of validated instruments to reliably assess swallowing function and an absence of effective therapeutic interventions derived from controlled trials targeting dysphagia. Imaging modalities such as the video fluoroscopic swallowing study (VFSS) are commonly used to evaluate dysphagia in IBM. Whilst VFSS is a commonly used technique in clinical practice; cumulative radiation exposure with repeated testing can be a limitation. Alternative imaging techniques could be developed further as outcome measures for assessing swallowing. In this review, we provide an overview of imaging techniques used to assess swallowing and the insight provided from such investigations into the mechanisms behind dysphagia in IBM. We suggest future directions for evaluation and outcome measurement of dysphagia in this population.

⚂ Nelke, C., Schmid, S., Kleefeld, F., Schroeter, C. B., Goebel, H. H., Hoffmann, S., Preuße, C., Kölbel, H., Meuth, S. G., Ruck, T., & Stenzel, W. (2024). Complement and MHC patterns can provide the diagnostic framework for inflammatory neuromuscular diseases. Acta Neuropathologica, 147 (1), 15. https://doi.org/10.1007/s00401-023-02669-8 DOWNLOAD PDF.

⚃ The focus of this review is to emphasize the diagnostic value of major histocompatibility complex (MHC) and complement patterns in the immunohistochemical analysis of these diseases. We explore the immunological background of MHC and complement signatures that characterize inflammatory features, with a specific focus on idiopathic inflammatory myopathies. With this approach, we aim to provide a diagnostic algorithm that may improve and simplify the diagnostic workup based on a limited panel of stainings. Our approach acknowledges the current limitations in the field of inflammatory neuromuscular diseases, particularly the scarcity of large-scale, prospective studies that validate the diagnostic potential of these markers. Further efforts are needed to establish a consensus on the diagnostic protocol to effectively distinguish these diseases.

⚂ Fontanelli, L., Vadi, G., Schirinzi, E., Di Rauso, G., Bellini, G., Ricci, G., & Siciliano, G. (2024). Intravenous immunoglobulin in the treatment of sporadic inclusion body myositis: Time for new evidence? Clinical and Experimental Rheumatology. https://doi.org/10.55563/clinexprheumatol/7x5o3q DOWNLOAD PDF.

⚃ … future studies with a higher number of patients, designed to objectively measure various outcome, and also aimed at evaluating the existence of distinctive characteristics related to IVIG response, are advisable in order to gather new evidence, and increase the appropriateness of the use of IVIG in s-IBM. Meanwhile, we believe that the use of IVIG in clinical practice should be approached with caution considering the potential adverse events and the economic burden of such medicines.

⚂ Afsar, A. P., Ghosh, S., Titus, R. S., Cheng, K., Kanawala, A. A., Kerkhof, P., Day, J., & Gupta, L. (2024). Content analysis of patient support groups related to myositis on Facebook. Clinical Rheumatology, 43 (2), 725-732. https://doi.org/10.1007/s10067-023-06854-8 DOWNLOAD PDF.

⚃ Our observations indicate that patients with myositis seek information on the condition online, and the multimedia nature of content presentation significantly influences engagement. These digital forums serve as valuable platforms for fostering connections among diverse individuals, providing a perceived safe space for sharing their personal experiences and varied perspectives, and potentially mitigating social isolation.

⚂ Reyngoudt, H., Baudin, P., Caldas De Almeida Araújo, E., Bachasson, D., Boisserie, J., Mariampillai, K., Annoussamy, M., Allenbach, Y., Hogrel, J., Carlier, P. G., Marty, B., & Benveniste, O. (2024). Effect of sirolimus on muscle in inclusion body myositis observed with magnetic resonance imaging and spectroscopy. Journal of Cachexia, Sarcopenia and Muscle, jcsm.13451. https://doi.org/10.1002/jcsm.13451 DOWNLOAD PDF.

⚃ Our study examines the complete quantitative MRI and phosphorus MRS (31 P MRS) data from the clinical phase-2b trial of sirolimus as described by Benveniste et al., 21 and their relationship with muscle function and strength.
≻ This study successfully utilized MRI-based quantitative biomarkers to demonstrate the efficacy of sirolimus in IBM patients, particularly those related to muscle atrophy and trophicity, namely, FF and cCSA.
≻ The comprehensive approach combining quantitative MRI and 31 P MRS with functional and strength evaluations holds promise for evaluating disease progression and treatment effectiveness in IBM.

⚂ Lilleker, J. B., Naddaf, E., Saris, C. G. J., Schmidt, J., De Visser, M., Weihl, C. C., Alexandersson, H., Alfano, L., Allenbach, Y., Badrising, U., Benveniste, O., Bhai, S., De Bleecker, J., Breeveld, M. C., Chinoy, H., Diederichsen, L., Dimachkie, M., Greenberg, S., Johari, M., … Weihl, C. (2024). 272nd ENMC international workshop: 10 Years of progress – revision of the ENMC 2013 diagnostic criteria for inclusion body myositis  and clinical trial readiness. 16–18 June 2023, Hoofddorp, The Netherlands. Neuromuscular Disorders, 37, 36–51. https://doi.org/10.1016/j.nmd.2024.03.001 DOWNLOAD PDF.

⚃ An outstanding overview of the new criteria by Dr Dooley. Webpage.
≻ DOWNLOAD PDF.

⚃ Workshop Synopsis: by Manuel Lubinus, additional editing by William Tillier
≻ The 272nd ENMC (European Neuro Muscular Centre) international workshop: 10 Years of progress – revision of the ENMC 2013 diagnostic criteria for inclusion body myositis and clinical trial readiness. 16–18 June 2023, Hoofddorp, The Netherlands.

⚃ The new consensus reflects significant advancements since the previous criteria were established in 2013. Recent developments in diagnostic technologies, improved understanding of IBM's pathogenesis, and the need for more effective clinical trial measures drove the new consensus.

⚃ Key Changes and Findings from the Workshop:
≻ This comprehensive revision reflects a significant step forward in standardizing the diagnostic approach to IBM, integrating modern diagnostic tools, and refining the understanding of its clinical management and research directions.

⚃ 1. New Diagnostic Criteria:
≻ The new criteria aim to simplify diagnosis by eliminating categories like "probable" and "possible" IBM, favouring a more dichotomous approach (either IBM or not).
≻ A new focus on muscle imaging, such as MRI and ultrasound, and serological testing for specific antibodies (anti-cytosolic 5'-nucleotidase-1A) was emphasized.

⚃ 2. Terminology Updates:
≻ The terminology around IBM has been updated to avoid confusion with similar conditions. Terms like "Sporadic IBM" are no longer recommended, and more precise genetic identifiers should be used for hereditary conditions (see below).

⚃ 3. Clinical Features and Pathology:
≻ Detailed descriptions of the typical IBM muscle weakness patterns, such as deep finger flexor weakness and knee extensor weakness, remain central to the diagnosis.
≻ The pathological features now include clear descriptions of mitochondrial abnormalities, rimmed vacuoles, and protein aggregates. [The clinical importance of the mitochondrial alterations is still not known.]
≻ The canonical set of myopathological features of IBM are:
     ≻≻ 1. Inflammation consisting of endomysial lymphocytes surrounding non-necrotic muscle fibers (with or without invasion), and an IBM-compatible MHC class I (and – if available MHC class II) pattern
     ≻≻ 2. Rimmed vacuoles and/or cytoplasmic protein aggregates
     ≻≻ 3. Mitochondrial abnormalities with COX negative and SDH positive fibers (more than one would expect in relation to age)
≻ Dysphagia is prevalent in IBM and can be a clue to the diagnosis, as it can be the first or most obvious feature in patients.
≻ Individuals with dysphagia in IBM may follow a distinct natural course compared to those without, emphasizing the need for prospective longterm studies including those on selection of optimal treatment techniques, timing and approach to optimize patient safety.
≻ Sleep disordered breathing is a common finding in IBM according to 2 studies. The frequency of respiratory insufficiency in IBM is unknown. … more extensive studies are required to prospectively assess diaphragmatic function and lung function measures. This research is also necessary to determine whether one or more of these measures could serve as potential outcome measure in clinical trials.
≻ There are significant deficits in our knowledge of the natural history of disease progression in IBM and none of the studies to date have evaluated these observations in a standardized fashion or with long enough duration, as the longest study was only 12 months.

⚃ 4. Outcome Measures for Clinical Trials:
≻ The workshop highlighted the limitations of current clinical outcome measures and proposed more specific measures tailored to IBM’s distinct clinical and pathological features.

⚃ 5. Epidemiological Updates:
≻ New epidemiological data provide insights into the prevalence and incidence of IBM, noting an increase in cases, which may reflect both improved diagnosis and a true rise in occurrence.

⚃ 6. Serological and Imaging Tools:
≻ Enhanced focus on serological markers (e.g., anti-cytosolic 5'-nucleotidase-1A antibodies [anti-NT5C1A or cN1a]) and advanced imaging techniques to improve diagnostic accuracy and monitor disease progression.

⚃ 7. Treatment and Management:
≻ Although no therapies are currently available to modify the disease course, the updated criteria and new understanding of IBM could help streamline therapeutic research and clinical trials.

⚃ Naming Criteria Changes for genetic conditions
≻ The 2024 ENMC workshop outlined specific terminology changes and criteria for distinguishing genetic conditions related to Inclusion Body Myositis (IBM), aiming to clarify the classification and improve the accuracy of diagnosis. Here are the key points from the workshop regarding genetic conditions:

⚃ 1. Avoiding Misleading Terms:
≻ The new guidelines suggest that all cases that were previously referred to as "sporadic" should now be termed "Inclusion Body Myositis" (IBM)

⚃ 2. Use of Precise Genetic Identifiers:
≻ For conditions historically grouped under the umbrella of IBM but are genetically distinct, the new criteria emphasize using specific genetic identifiers rather than broad classifications. For each hereditary condition, the exact gene involved should be named. This approach ensures that each condition is correctly identified and treated based on its unique genetic profile.

⚃ 3. Clinical Application:
≻ When diagnosing IBM or related conditions, it's crucial to identify the specific genetic variants involved to guide clinical management and the potential inclusion in clinical trials. Accurate genetic diagnosis helps understand the prognosis, potential therapeutic approaches, and family counseling.

⚃ Issues with IBM-FRS
≻ The document mentions several issues with using the IBMFRS (Inclusion Body Myositis Functional Rating Scale) as an outcome measure in clinical trials for IBM (Inclusion Body Myositis).

⚃ These issues include:
≻ Lack of content validity: the content validity of the IBMFRS for IBM has not been established. It is unclear whether the scale accurately measures the relevant aspects of the disease and its impact on patients.
≻ Limitations in addressing certain symptoms: The IBMFRS does not address fatigue or the degree of adaptation or difficulty it takes to (successfully) complete certain tasks. This means that the scale may not fully capture the range of symptoms and functional limitations experienced by IBM patients.
≻ Need for longitudinal validation studies: the IBMFRS, along with other outcome measures such as the IBM-HI (IBM Health Index) and PROMIS UE (Patient-Reported Outcomes Measurement Information System Upper Extremity), have yet to undergo longitudinal validation studies to determine the minimal clinically important difference (MCID) for change. This means the scale's ability to detect meaningful changes in IBM patients over time has not been fully established.
≻ Lack of evidence of clinical benefit: The workshop document acknowledges that the ultimate validation of an outcome measure is its ability to demonstrate a clinically meaningful benefit in the context of a positive clinical trial. However, there is currently a lack of evidence showing that the IBMFRS can successfully detect such benefits in IBM patients.
≻ While the IBMFRS has shown some positive psychometric properties, such as construct validity, test-retest reliability, and sensitivity to change, there are still limitations and uncertainties regarding its use as a primary outcome measure in IBM clinical trials.

⚃ Treatments
≻ The 2024 ENMC workshop document indicates that no specific therapies are currently available to modify the course of Inclusion Body Myositis (IBM). The workshop focused primarily on revising diagnostic criteria, understanding the pathogenesis, and improving clinical trial readiness rather than discussing new treatment options.
≻ However, the document does mention the importance of supportive treatments in managing the symptoms of IBM. This includes physical therapy to help maintain mobility and muscle function as long as possible, as well as interventions to manage complications such as swallowing difficulties (dysphagia), which is common in IBM and can be severe.
≻ While specific new therapeutic agents or approaches were not detailed in the workshop findings, establishing more precise diagnostic criteria and a better understanding of the disease's natural history and path mechanisms are essential steps toward developing effective treatments in the future. These advances also help design and implement clinical trials better tailored to IBM's unique characteristics.

⚂ Jensen, K. Y., Nielsen, J. L., Aagaard, P., Jacobsen, M., Jørgensen, A. N., Bech, R. D., Frandsen, U., Diederichsen, L. P., & Schrøder, H. D. (2024). Effects of sporadic inclusion body myositis on skeletal muscle fibre type specific morphology and markers of regeneration and inflammation. Rheumatology International . https://doi.org/10.1007/s00296-024-05567-8 DOWNLOAD PDF.

⚃ As evaluated for the first time in myositis patients, we observed that mCSA, peripheral myonuclei, myonuclear domain was higher in association to type 1 (slow-twitch) as compared to type 2 (fast-twitch) myofibres. Conversely, quiescent SCs and central myonuclei, were higher in association to type 2 fibres compared to type 1 fibres. For both M1 and M2, the density was observed to be higher in type 2 fibres, however no differences were observed on the “per fibre profile" analyses. No fibre type-specific differences were observed for proliferating SCs. These observations suggest distinct and exclusive pathological changes related to the respective fibre types.

⚃ As reported for the first time, sIBM appears to exert differential effects on the morphology as well as density and content of quiescent satellite cells, myonuclei, M1 and M2 macrophages and capillarisation of type 1 and type 2 myofibres. In contrast, no fibre type differences in number of associated proliferating satellite cell could be observed. Somewhat paradoxically, type 2 muscle fibres were characterized by focally elevated levels of quiescent satellite cells and central myonuclei, yet these fibres remained markedly atrophied. Likewise, type 1 fibre morphology was pathologically comprised with the presence of megafibres accompanied by large myonuclear domains. All suggest an impact of the sIBM disease on fibre morphology, presumably due to a preferential imbalance between myofibrillar regeneration and degeneration.

⚂ Roy, B., Dimachkie, M. M., & Naddaf, E. (2024). Phenotypic spectrum of inclusion body myositis. Clinical and Experimental Rheumatology. DOWNLOAD PDF. https://doi.org/10.55563/clinexprheumatol/fhrx3q

⚃ Recognition of the atypical presentations of IBM has increasingly been reported in the last decade. The pleomorphic [occurring in various distinct forms] presentation of IBM is important to identify for many reasons, and most important is the ongoing hunt for effective therapy. While these therapies are currently being evaluated in typical IBM phenotypes, the hope of future discovery is that successful therapies will benefit all IBM patients, regardless of their uniqueness and phenotype.

⚂ Wijnbergen, D., Johari, M., Ozisik, O., Hoen, P. A. C. ’T, Ehrhart, F., Baudot, A., Evelo, C. T., Udd, B., Roos, M., & Mina, E. (2024). Multi-omics analysis in inclusion body myositis identifies mir-16 responsible for HLA overexpression . DOWNLOAD PDF. https://doi.org/10.21203/rs.3.rs-3921651/v1

⚃ Our multi-omics analysis resulted in five subnetworks that exhibit changes in multiple omics layers. These subnetworks are related with antigen processing and presentation, chemokine-mediated signaling, immune response-signal transduction, rRNA processing, and mRNA splicing. An interesting finding is that the antigen processing and presentation subnetwork links the underexpressed miR-16-5p to overexpressed HLA genes by negative expression correlation. In addition, the rRNA processing subnetwork contains the RPS18 gene, which is not differentially expressed, but has significant variant association. The RPS18 gene could potentially play a role in the underexpression of the genes involved in 18S ribosomal RNA processing, which it is highly connected to.

⚃ We speculate that miR-16 could play a role in regulating MHC class I gene transcription in IBM, which in turn regulates immune system activation. Recently, Lucchini et al. identified dysregulation of hsa-miR-192-5p and hsa-miR-372-3p in serum of IBM patients [48]. These findings highlight the importance of studying the role of miRNAs in the context of molecular pathomechanisms of IBM.

⚂ Williams, E., Cooper, I., Beer, K., Hird, K., Cavalheri, V., Watson, K., & Needham, M. (2024). Does inspiratory muscle training improve lung function and quality of life in people with inclusion body myositis? A pilot study. Neuromuscular Disorders, 37 , 6-12. DOWNLOAD PDF. https://doi.org/10.1016/j.nmd.2024.02.002

⚃ Internationally, respiratory function is not routinely measured in patients with IBM as patients rarely report shortness of breath. The onset of lung function reduction appears to be silent, unrelated to the degree of limb muscle weakness and underappreciated due to limited exercise tolerance secondary to muscle weakness. Diaphragmatic involvement in IBM is becoming increasingly recognised and the degree of diaphragmatic dysfunction is correlated with reduced lung function, increased sleep-disordered breathing, dyspnoea and reduction in exercise capacity.

⚃ Inspiratory muscle training (IMT) is a form of resistance training that has been shown to improve respiratory function in populations ranging from elite footballers to geriatric patients with chronic obstructive pulmonary disease (COPD). It involves using a device, often handheld, which restricts the flow of air during inspiration, requiring the diaphragm and associated muscles to work harder during inspiration. IMT has significantly improved inspiratory muscle strength in patients with neuromuscular diseases including multiple sclerosis, myasthenia gravis and Duchenne muscular dystrophy but is less effective in rapidly progressive diseases such as amyotrophic lateral sclerosis.

⚃ Overall, this pilot study has demonstrated the potential safety and efficacy of an eight-week IMT program in training the inspiratory muscle function in a small group of IBM patients. This provides support for studies in larger populations to confirm the safety and effectiveness of this training method on respiratory function and related functional measures. It suggests that for IBM patients with marked respiratory weakness, IMT may be appropriate to strengthen these muscles. The impact this has on long-term quality of life, pulmonary infection risk, risk of ventilation and overall mortality is uncertain and is a key area of interest for future research.

⚂ Guglielmi, V., Cheli, M., Tonin, P., & Vattemi, G. (2024). Sporadic Inclusion Body Myositis at the Crossroads between Muscle Degeneration, Inflammation, and Aging. International Journal of Molecular Sciences, 25 (5), 2742. DOWNLOAD PDF. https://doi.org/10.3390/ijms25052742

⚃ Abstract: Sporadic inclusion body myositis (sIBM) is the most common muscle disease of older people and is clinically characterized by slowly progressive asymmetrical muscle weakness, predominantly affecting the quadriceps, deep finger flexors, and foot extensors. At present, there are no enduring treatments for this relentless disease that eventually leads to severe disability and wheelchair dependency. Although sIBM is considered a rare muscle disorder, its prevalence is certainly higher as the disease is often undiagnosed or misdiagnosed. The histopathological phenotype of sIBM muscle biopsy includes muscle fiber degeneration and endomysial lymphocytic infiltrates that mainly consist of cytotoxic CD8+ T cells surrounding nonnecrotic muscle fibers expressing MHCI. Muscle fiber degeneration is characterized by vacuolization and the accumulation of congophilic misfolded multi-protein aggregates, mainly in their non-vacuolated cytoplasm. Many players have been identified in sIBM pathogenesis, including environmental factors, autoimmunity, abnormalities of protein transcription and processing, the accumulation of several toxic proteins, the impairment of autophagy and the ubiquitin-proteasome system, oxidative and nitrative stress, endoplasmic reticulum stress, myonuclear degeneration, and mitochondrial dysfunction. Aging has also been proposed as a contributor to the disease. However, the interplay between these processes and the primary event that leads to the coexistence of autoimmune and degenerative changes is still under debate. Here, we outline our current understanding of disease pathogenesis, focusing on degenerative mechanisms, and discuss the possible involvement of aging.

⚃ Even though several studies have uncovered the processes participating in the degenerative and immune responses occurring in the disease, the relationship between these two aspects still remains unknown. Improving our knowledge of the pathogenic mechanisms is necessary to better understand this disorder, identify therapeutic targets, and design effective therapies for patients. Here, we provide an overview of the clinic, histopathology, and disease mechanisms of sIBM and discuss the contribution of skeletal muscle and immune system aging to the disease.

⚃ Figure 2. Schematic representation of the main molecular mechanisms contributing to the pathogenesis of sporadic inclusion body myositis (sIBM).

⚃ Conclusions: sIBM is a multifactorial disorder characterized by the coexistence of inflammation and degeneration. The pathological features of the disease have been extensively characterized, and alterations in specific cellular pathways have been proposed as contributors to disease pathogenesis. Notably, many of the cellular and molecular processes that are altered in sIBM are also affected by aging, which likely has an influence on disease onset and progression.
≻ Despite the fact that some cellular and molecular mechanisms have been uncovered, the etiology of the disease is still unknown, and the causal relationship between autoimmune and degenerative responses has not yet been established. Further studies are needed to illuminate these aspects with the long-term goal of designing effective therapies for this progressive and debilitating disease.

⚂ Conticini, E., Dourado, E., Bottazzi, F., Cardelli, C., Bruno, L., Schmidt, J., Carli, L., Cavagna, L., & Barsotti, S. (2024). Review Idiopathic inflammatory myopathies: One year in review 2023. Clinical and Experimental Rheumatology. DOWNLOAD PDF.

⚃ IBM is the most common form of IIM over 50 years of age (63) and represents an important risk factor for aspiration pneumonia, PEG tube placement, falls, and sepsis (64).
≻ Initial misdiagnosis is frequent, since although a biopsy is performed, less than half of the patients had all three pathologic hallmarks (endomysial inflammation, mononuclear cell invasion, and rimmed vacuoles) (65). Black patients had significantly greater weakness in several muscle groups, while female had stronger finger flexors and knee extensors than their male counterparts (65); although the overall response to therapy remains poor in IBM, this heterogeneity might influence the response to treatment.
≻ The typical clinical symptoms of IBM including weakness of hand grip and knee extension are well known. Atypical presentations are less common and often lead to a delayed or wrong diagnosis. Recent evidence supports previous notions that impairment of ventilator muscles (69) as well as camptocormia and dropped head can occur in IBM (70). The frequency of CD8+ CD57 + T-cell large granular lymphocytes (T-LGLs) was high in 40% of an Australian cohort of IBM patients, although most of these patients showed only a slight expansion of these cells and in rare cases a diagnosis of T-LGL leukaemia was made (66). These changes in the CD8+ T-lymphocyte milieu appear to exacerbate the immune dysregulation and to increase the disease burden in this subgroup of IBM patients, who in the Australian cohort were more likely to require mobility aids, implying greater disease severity.

⚂ Slater, N., Sooda, A., McLeish, E., Beer, K., Brusch, A., Shakya, R., Bundell, C., James, I., Chopra, A., Mastaglia, F. L., Needham, M., & Coudert, J. D. (2024). High-resolution HLA genotyping in inclusion body myositis refines 8.1 ancestral haplotype association to DRB1*03:01:01 and highlights pathogenic role of arginine-74 of DRβ1 chain. Journal of Autoimmunity, 142, 103150. https://doi.org/10.1016/j.jaut.2023.103150 DOWNLOAD PDF.

⚃ There are three genes that are critical in IBM, one that predisposes or increases the likelihood of having IBM, called HLA-DRB1*03:01:01, and two that protect against it occurring (DRB4*01:01:01 and DQA1*01:02:01). People who have the predisposing gene without the protective genes show a fourteenfold increased risk of developing IBM over the general Caucasian population and also developed IBM five years earlier. Interesting, no genes appeared to be associated with having the autoantibody.

⚃ “Individuals carrying the DRB1*03:01:01 but lacking the DRB4*01:01:01 and DQA1*01:02:01 alleles have a fourteen-fold higher risk of developing IBM compared to the general population. Furthermore, in this patient cohort IBM patients carrying the above mentioned genotype developed disease symptoms on average five years earlier than non-carriers. In contrast, the presence of a single gene copy of either DRB4*01:01:01 or DQA1*01:02:01 alleles entirely negated the risk driven by DRB1*03:01:01.”

2023

⚂ A short synopsis of 2023 research. DOWNLOAD PDF.

⚂ Picca, A., Faitg, J., Auwerx, J., Ferrucci, L., & D’Amico, D. (2023). Mitophagy in human health, ageing and disease. Nature Metabolism, 5(12), 2047-2061. https://doi.org/10.1038/s42255-023-00930-8 DOWNLOAD PDF.

⚂ Kummer, K., Bertram, I., Zechel, S., Hoffmann, D. B., & Schmidt, J. (2023). Inflammasome in Skeletal Muscle: NLRP3 Is an Inflammatory Cell Stress Component in Inclusion Body Myositis. International Journal of Molecular Sciences, 24(13), 10675. https://doi.org/10.3390/ijms241310675 DOWNLOAD PDF.>

⚃ In the cell culture model of IBM, the NLRP3 inflammasome was significantly overexpressed. … Because intracellular protein accumulation and endogenous cell stress have been shown to be activators of pro-inflammatory protein complexes it is reasonable to conclude that inflammasomes are a further link between inflammation and degeneration.

⚃ Here, we identify a strong overexpression of NLRP3 inflammasome as a cell stress marker in the skeletal muscle of IBM patients and a well-established muscle cell culture model of the disease.

⚃ Links between these two pathways indicate a mutual interplay of mechanisms. Among these, IL-1 β and NO-stress, as well as dysfunctional autophagic processing, have been demonstrated [1,10]. The NLRP3 inflammasome is an important catalyst for the release of IL-1 β in the innate immune response. Many overlaps between the previously known activators of this inflammasome and components of IBM protein aggregations suggest that the NLRP3 inflammasome is a central component of the interplay between inflammation and degeneration in IBM muscle and its model systems.

⚂ Argyriou, A., Horuluoglu, B., Galindo-Feria, A. S., Diaz-Boada, J. S., Sijbranda, M., Notarnicola, A., Dani, L., Van Vollenhoven, A., Ramsköld, D., Nennesmo, I., Dastmalchi, M., Lundberg, I. E., Diaz-Gallo, L., & Chemin, K. (2023). Single-cell profiling of muscle-infiltrating T cells in idiopathic inflammatory myopathies . EMBO Molecular Medicine, 15 (10), e17240. https://doi.org/10.15252/emmm.202217240 DOWNLOAD PDF.

⚃ By performing single-cell sequencing of infiltrating T cells in muscle from patients with IIM, we identified effector, tissue resident, Tregs and proliferating T cells. Our study unraveled the presence of four T-cell clusters expressing genes associated with tissue resident memory. Most of the clonally expanded muscle T cells were identified within the GZMB + effector and T RM cells. Identical clones were detected in PB and muscle T cells in repeated biopsies from two patients after 9 months of treatment suggesting resistance to immunosuppressive treatment. Our study provides a unique unbiased transcriptomic and TCR landscape of muscle T cells in IIM which might be used to design new treatment strategies and possible prognostic markers.

⚃ This study shows that T cells in skeletal muscle of patients with IIM display tissue resident memory features suggesting their maintenance within the tissue and their probable contribution to relapses. The immunoprofiling map of muscle-infiltrating T cells can be used to understand the mechanisms leading to tissue damage and to identify novel therapeutic targets.

⚂ Lacomis, D. (2023). What is in the Myopathy Literature? Journal of Clinical Neuromuscular Disease, 24 (3), 30-139. DOWNLOAD PDF.

⚃ Inclusion body myositis (IBM) remains a disease for which we have no substantially effective disease-modifying treatment. Perhaps the degenerative component makes the disorder refractory to immunotherapy, but Kleefield et al recently provided more evidence that there are dysfunctional T cells in IBM, a possible clue to the treatment resistant state.2
≻ These authors studied morphologic and molecular patterns in muscle biopsy specimens associated with diagnoses of IBM and the somewhat controversial subtype of polymyositis (PM) with mitochondrial pathology (PM-Mito), with the latter being considered a probable forme fruste of IBM by some. Biopsy specimens labeled PM-Mito lack rimmed vacuoles but have other features seen in IBM. The authors sought to determine if PM-Mito and IBM are part of the same disease spectrum.
≻ Histopathology and immunohistochemistry were performed on all 25 IBM and 25 PM-Mito specimens, and quantitative polymerase chain reaction on 41 gene transcripts was performed on 22 IBM and 17 PM-Mito specimens and on 5 healthy controls. Assays focused on interferon (IFN)-mediated inflammation, including IFN-induced guanylate binding protein (GBP) 6 expression, 3 T-cell dysfunction, and transactive response element DNA binding protein-43 (TDP 43)-associated cryptic exons. Known molecular markers of IBM, including killer cell lectin-like receptor G1 (KLRG1), which is present in terminally differentiated T-cells, were included. 4 Of interest to clinicians, molecules expressed by a highly pathogenic T-cell population have been postulated to be potential favorable targets for an IBM therapy.4
≻ Many of the PM-Mito patients lacked significant quadriceps and finger flexor weakness as is typical of IBM. Twenty-eight percent had dysphagia. Two of 6 tested had anti-cN1a antibodies. Most (13 of 14), who were followed, progressed to IBM.
≻ The authors found that histopathologic features overlapped in PM-Mito and IBM. Mononuclear cell expression of IFN-induced GBP6 and T-cell function KLRG1 was higher in IBM than PM-Mito, and both disease states had higher levels than in healthy controls. Other measures of T-cell dysfunction were present in both IBM and PM-Mito with quantitative differences—higher measures in IBM. TDP43-associated cryptic exons (splicing variants that may lead to frameshifts or stop codons or other changes in the resulting mRNA) were present in IBM and PM-Mito with higher values in IBM. As an aside, Britson et al 5 previously showed that the loss of TDP-43-mediated splicing repression occurred in an IBM xenograft model.
≻ The investigators feel that PM-Mito is an early form of IBM. They concluded that “specific IFN-mediated inflammation plays a key role in both IBM and PM-Mito. GBP6 was identified as a new molecule marker of type II IFN-induced inflammation distinguishing IBM from PM-Mito. Skeletal muscles from both groups harbor dysfunctional T cells of similar type, albeit in different quantity. T-cell senescence exemplified by KLRG1 positivity does not play a significant role in PM-Mito."2
≻ Greenberg 6 provided an accompanying editorial that outlines the history of IBM with respect to differentiating it from PM, and he nicely addresses controversies. He also agrees that highly differentiated cytotoxic T cells are resistant to death by apoptosis, and he notes that such T cells are not depleted in vivo by corticosteroids (CS). The notion that treatment-refractory IBM is associated with this highly differentiated cytotoxic T-cell state has merit. A drug that depletes KLRG1+ T cells is under study.7,8
≻ Although granulomatous inflammation is occasionally encountered in IBM, the most common cause of non-necrotizing granulomas in skeletal muscle is sarcoidosis. 9 Granulomas in muscle are often asymptomatic in patients with sarcoidosis, but symptomatic muscle involvement occurs in only 0.5% - 2.0%.

⚂ McLeish, E., Sooda, A., Slater, N., Kachigunda, B., Beer, K., Paramalingam, S., Lamont, P. J., Chopra, A., Mastaglia, F. L., Needham, M., & Coudert, J. D. (2023). Uncovering the significance of expanded CD8+ large granular lymphocytes in inclusion body myositis: Insights into T cell phenotype and functional alterations, and disease severity. Frontiers in Immunology, 14, 1153789. https://doi.org/10.3389/fimmu.2023.1153789 DOWNLOAD PDF.

⚃ Altogether, these results suggest that T-LGL expansion occurring in IBM patients is correlated with exacerbated immune dysregulation and increased disease burden.

⚃ Greenberg and coworkers reported that T-LGL expansions resulted in a more severe clinical phenotype indicated by a greater decline in muscle strength (13). In this study, we used patients' reliance on mobility aids as a surrogate measure of disease severity. Our findings that T-LGL HIGH patients experienced a more severely reduced mobility compared to T-LGL LOW patients confirmed the conclusions of this previous research. Considering that the proportion of T-LGLs was not correlated to ageing or disease duration, we can exclude that the increased reliance on mobility aids was not due to the normal ageing or progression of the disease, and rather propose that it may be causally linked to the expansion of this late differentiated T-LGL cell population.
≻ Even though it remains difficult to conclude whether the T-LGL expansion that we observed in this cohort of IBM patients is representative of T-LGL leukemia, given the relatively low T-LGL numbers and the absence of associated cytopenias, we propose that in the majority of patients these T cell expansions fall into the category of “reactive" T-LGL lymphoproliferative disease (17) and are more likely to be secondary, rather than a driver of IBM. We report a group of IBM patients who display an elevated proportion of CD8+ CD57 + cells with a senescent-like profile associated with upregulation of inhibitory NK cell receptors. These aberrant changes across the CD8+ , CD4+ and gd T cell landscape suggest altered TCR-dependent responsiveness, increased inflammatory and cytotoxic features, and reduced proliferative capabilities. These changes likely culminate in exacerbated immune dysregulation and increased disease burden occurring within this subgroup of IBM patients. This immunophenotype may represent an effective way to stratify IBM patients and may assist in providing a prognostic tool and in identifying suitable candidates for future targeted therapies.

⚂ Tanboon, J., Needham, M., Mozaffar, T., Stenzel, W., & Nishino, I. (2023). Editorial: Inflammatory muscle diseases: An update. Frontiers in Neurology, 14, 1259275. https://doi.org/10.3389/fneur.2023.1259275 DOWNLOAD PDF.

⚃ Interestingly, PM with mitochondrial pathology (PM-Mito), which contains features resembling IBM except for rimmed vacuoles (i.e., endomysial inflammation, mitochondrial pathology, highly differentiated cytotoxic T cells, and type 2 interferon (IFN2, IFN-Y) pathway upregulation) has been re-recognized and proposed as early IBM (eIBM) in IBM-spectrum disease (4, 5).

⚂ Behringer, M., Franz, A., & Hughes, L. (2023). Editorial: Clinical application and impact of blood-flow-restriction training. Frontiers in Physiology, 14, 1155080. https://doi.org/10.3389/fphys.2023.1155080 DOWNLOAD PDF.

⚃ For a long time, it was firmly believed that a high load in strength training was necessary to achieve muscle mass and strength gains. However, blood flow restriction training has fundamentally challenged this assumption. Numerous studies over the past decades have shown that these biopositive effects can be achieved even with low loads when blood flow to the working muscles is restricted and venous return from the working extremity to the heart is interrupted … A total of 35 experts participated in this Research Topic and presented the results from their current investigations. A total of nine studies were accepted to be published in the Research Topic. … The studies in this Research Topic have demonstrated that BFR training can be used successfully in a variety of clinical settings.

⚂ Di Leo, V., Bernardino Gomes, T. M., & Vincent, A. E. (2023). Interactions of mitochondrial and skeletal muscle biology in mitochondrial myopathy. Biochemical Journal, 480 (21), 1767-1789. https://doi.org/10.1042/BCJ20220233 DOWNLOAD PDF.

⚃ Mitochondrial dysfunction in skeletal muscle fibres occurs with both healthy aging and a range of neuromuscular diseases. The impact of mitochondrial dysfunction in skeletal muscle and the way muscle fibres adapt to this dysfunction is important to understand disease mechanisms and to develop therapeutic interventions. Furthermore, interactions between mitochondrial dysfunction and skeletal muscle biology, in mitochondrial myopathy, likely have important implications for normal muscle function and physiology. In this review, we will try to give an overview of what is known to date about these interactions including metabolic remodelling, mitochondrial morphology, mitochondrial turnover, cellular processes and muscle cell structure and function. Each of these topics is at a different stage of understanding, with some being well researched and understood, and others in their infancy. Furthermore, some of what we know comes from disease models. Whilst some findings are confirmed in humans, where this is not yet the case, we must be cautious in interpreting findings in the context of human muscle and disease. Here, our goal is to discuss what is known, highlight what is unknown and give a perspective on the future direction of research in this area.

⚂ Winkler, M., Seel, W., Kornblum, C., Simon, M., & Reimann, J. (2023). P340 The MikroIBioM study—Comparison of gut microbiome of sporadic Inclusion Body Myositis (sIBM) patients and unaffected spouses. Neuromuscular Disorders, 33, S100. https://doi.org/10.1016/j.nmd.2023.07.138 DOWNLOAD PDF.

⚃ Our high-level microbiome analysis did reveal significant differences of the gut microbiome in patients only for older: Pects, indicating that a more refined analysis may be needed. Cause effect relationships are notoriously difficult to determine for microbiome changes in diseases, and our sIBM findings are no exception to this.

⚂ Chen, S., Zhang, P., Duan, H., Wang, J., Qiu, Y., Cui, Z., Yin, Y., Wan, D., & Xie, L. (2023). Gut microbiota in muscular atrophy development, progression, and treatment: New therapeutic targets and opportunities. The Innovation, 4 (5), 100479. https://doi.org/10.1016/j.xinn.2023.100479 DOWNLOAD PDF.

⚃ This review aims to provide a comprehensive overview of the role of the gut microbiota in muscle atrophy-related diseases. We summarize clinical and pre-clinical studies that investigate the potential for gut microbiota modulation to enhance muscle performance and promote disease recovery. Furthermore, we delve into the intricate interplay between the gut microbiota and muscle atrophy-related diseases, drawing from an array of studies. Emerging evidence suggests significant differences in gut microbiota composition in individuals with muscle atrophy-related diseases compared with healthy individuals. It is conceivable that these alterations in the microbiota contribute to the pathogenesis of these disorders through bacterium-related metabolites or inflammatory signals. Additionally, interventions targeting the gut microbiota have demonstrated promising results for mitigating disease progression in animal models, underscoring the therapeutic potential of modulating the gut microbiota in these conditions. By analyzing the available literature, this review sheds light on the involvement of the gut microbiota in muscle atrophy-related diseases. The findings contribute to our understanding of the underlying mechanisms and open avenues for development of novel therapeutic strategies targeting the gut-muscle axis.

⚂ Suzuki, N., Kanzaki, M., Koide, M., Izumi, R., Fujita, R., Takahashi, T., Ogawa, K., Yabe, Y., Tsuchiya, M., Suzuki, M., Harada, R., Ohno, A., Ono, H., Nakamura, N., Ikeda, K., Warita, H., Osana, S., Oikawa, Y., Toyohara, T., … Aoki, M. (2023). Sporadic inclusion body myositis-derived myotube culture revealed muscle cell-autonomous expression profiles [Preprint]. In Review. https://doi.org/10.21203/rs.3.rs-3423305/v1 PDF

⚃ Myoblasts from three sIBM cases and six controls were differentiated into myotubes.
≻ In the RNA-sequencing analysis of these “myotube" samples, 104 differentially expressed genes (DEGs) were found to be significantly upregulated by more than twofold in sIBM, and 13 DEGs were downregulated by less than twofold.
≻ For muscle biopsy samples, a comparative analysis was conducted to determine the extent to which “biopsy" and “myotube" samples differed.
≻ Fiftythree DEGs were extracted of which 32 (60%) had opposite directions of expression change (e.g., increased in biopsy vs decreased in myotube).
≻ Apolipoprotein E (apoE) and transmembrane protein 8C (TMEM8C) were commonly upregulated in muscle biopsies and myotubes from sIBM.
≻ ApoE and myogenin protein levels were upregulated in sIBM.
≻ Given that enrichment analysis also captured changes in muscle contraction and development, the triggering of muscle atrophy signaling and abnormal muscle differentiation via TMEM8C or myogenin may be involved in the pathogenesis of sIBM.

⚃ The presence of DEGs in sIBM suggests that the myotubes formed from sIBM-derived myoblasts revealed the existence of muscle cell-autonomous degeneration in sIBM.
≻ The catalog of DEGs will be an important resource for future studies on the pathogenesis of sIBM focusing on primary muscle degeneration.

⚂ Nelke, C., Schroeter, C. B., Theissen, L., Preusse, C., Pawlitzki, M., Räuber, S., Dobelmann, V., Cengiz, D., Kleefeld, F., Roos, A., Schoser, B., Brunn, A., Neuen-Jacob, E., Zschüntzsch, J., Meuth, S. G., Stenzel, W., & Ruck, T. (2023). Senescent fibro-adipogenic progenitors are potential drivers of pathology in inclusion body myositis. Acta Neuropathologica, 146 (5), 725-745. https://doi.org/10.1007/s00401-023-02637-2 DOWNLOAD PDF.

⚃ Fibro-adipogenic progenitors (FAPs) are a mesenchymal cell population with high phenotypical plasticity that is crucially involved in skeletal muscle homeostasis and regeneration [5, 23]. Here, we report that tissue-resident FAPs, not myofibers, are the main cell type assuming a senescent phenotype in IBM. Depending on environmental cues, FAPs may differentiate into fibroblasts or adipocytes. In response to muscle damage, FAPs proliferate, expand and accumulate, constituting the main source of extracellular matrix proteins [23, 41]. Depletion of FAPs hinders muscle repair underscoring their functional importance [23, 41]. Conversely, in conditions of chronic muscle damage, FAPs may prove detrimental to muscle health. Their persistent activity cumulates in progressive tissue fibrosis and loss of normal tissue architecture [22, 23]. In line, we describe a novel population of senescent FAPs that reside in IBM muscle. These FAPs exhibit key hallmarks of cellular senescence including a pro-inflammatory secretome, engagement of the Jun/JunB-pathway and expression of senescence biomarkers (p21 and SA-β-Gal).

⚃ Senescent FAPs may represent a cell-autonomous mechanism that sustains inflammation and fibrotic remodelling in IBM despite therapeutically addressing immune cell pathology warranting further research.

⚂ Lindgren, U., Hedberg-Oldfors, C., Pullerits, R., Lindberg, C., & Oldfors, A. (2023). P322 Inclusion body myositis with early onset – a population-based study . Neuromuscular Disorders, 33, S95. https://doi.org/10.1016/j.nmd.2023.07.120

⚃ In a population-based study during a 33-year period, 142 patients with IBM were identified in western Sweden. Six patients fell outside the inclusion criteria due to young age at symptom onset and had a first muscle biopsy less than 50 years of age. These were designated as early-onset IBM and included in this study. … The mean age at symptom onset was 38 years and mean age at diagnosis was 45 years in patients with early-onset IBM, while mean age at symptom onset was 64 years and mean age at diagnosis was 70 years in the corresponding IBM cohort. Four patients with early-onset IBM were deceased at a mean age of 61 years, compared with a mean age of 80 years at death in the corresponding 73 deceased patients with IBM. The mean survival from diagnosis was 14 years. Five patients had swallowing difficulties. The mean decline in quadriceps strength per month was 1.21±0.2 Newton, corresponding to 0.91±0.2%. The remaining strength correlated to time from diagnosis (p less than 0.001). Mitochondrial changes including cytochrome c oxidase deficiency were a consistent finding in the muscle biopsies. Despite their young age, patients had a high mitochondrial DNA mutation load in muscle tissue compared to age-matched controls. Early-onset IBM is a severe inflammatory myopathy, causing progressive muscle weakness, high mitochondrial DNA mutation load in muscle fibers and a reduced cumulative survival in young and middle-aged individuals.

⚂ Vogt, S., Kleefeld, F., Preusse, C., Arendt, G., Bieneck, S., Brunn, A., Deckert, M., Englert, B., Goebel, H. H., Masuhr, A., Neuen-Jacob, E., Kornblum, C., Reimann, J., Montagnese, F., Schoser, B., Stenzel, W., & Hahn, K. (2023). Morphological and molecular comparison of HIV-associated and sporadic inclusion body myositis . Journal of Neurology. https://doi.org/10.1007/s00415-023-11779-y PDF

⚃ Conclusion Despite HIV-IBM and sIBM sharing important clinical, histopathological, and transcriptomic signatures, the presence of KLRG1 cells discriminated sIBM from HIV-IBM. This may be explained by longer disease duration and subsequent T-cell stimulation in sIBM. Thus, the presence of TEMRA cells is characteristic for sIBM, but not a prerequisite for the development of IBM in HIV+ patients.

⚃ Based on molecular data, the concept of an IBM spectrum disease (IBM-SD) has recently been introduced [6]. IBM-SD describes the clinical and histomorphological spectrum ranging from mild inflammation and mitochondrial abnormalities to full-blown IBM.

⚂ Choi, M. Y., Satoh, M., & Fritzler, M. J. (2023). Update on autoantibodies and related biomarkers in autoimmune inflammatory myopathies. Current Opinion in Rheumatology. https://doi.org/10.1097/BOR.0000000000000957 DOWNLOAD PDF.

⚃ The spectrum of autoantibodies and related biomarkers in AIM continues to expand. Many of these have clear clinical implications in regard to subsets and overlap conditions of AIM, associated malignancy and pathological findings.

⚂ Machado, P. M. (2023). Safety and efficacy of arimoclomol for inclusion body myositis : A multicentre, randomised, double-blind, placebo-controlled trial. Lancet Neurol 2023; 22: 900-11 10.1016/S1474-4422(23)00275-2 DOWNLOAD PDF.

⚃ Arimoclomol did not improve efficacy outcomes, relative to placebo, but had an acceptable safety profile in individuals with inclusion body myositis. This is one of the largest trials done in people with inclusion body myositis, providing data on disease progression that might be used for subsequent clinical trial design.

⚂ Garand, K. L. (Focht), Malandraki, G. A., & Dimachkie, M. M. (2023). Update on the evaluation and management of dysphagia in sporadic inclusion body myositis. Current Opinion in Otolaryngology & Head & Neck Surgery . https://doi.org/10.1097/MOO.0000000000000922 DOWNLOAD PDF.

⚃ Recent investigations confirm that dysphagia in IBM is a debilitating and complex symptom that warrants timely evaluation and management. Further, they highlight the lack of validation of standardized swallowing-related metrics specifically for IBM and the limited evidence supporting a consensus of management approaches. Small scale research and clinical anecdotal data support a multidisciplinary and multipronged patient-centered approach, including rehabilitative exercise protocols, for dysphagia management in IBM.

⚃ A paucity exists in the literature to effectively guide clinical decision-making for patients with IBM and dysphagia. Given this, it is our belief that a careful multidisciplinary and multipronged patient-centered approach is critical for dysphagia management in IBM. Prospective, longitudinal research on the underlying mechanisms of swallowing dysfunction using advanced and validated swallowing-related outcome measures is urgently needed.

⚂ Skolka, M. P., & Naddaf, E. (2023). Exploring challenges in the management and treatment of inclusion body myositis. “Current Opinion in Rheumatology.” https://doi.org/10.1097/BOR.0000000000000958 Website.

⚃ Patients with IBM and the medical community face numerous challenges in terms of clinical manifestations, diagnosis, and treatment. Overcoming these challenges necessitates the adoption of innovative research strategies. By understanding and addressing these hurdles, researchers and medical professionals can strive towards improving the management and treatment of IBM enhancing the quality of life for affected individuals.

⚃ Current management approach for IBM consists of close monitoring of swallowing and respiratory function, adapting an exercise routine, and addressing mobility issues.

⚃ There is a critical need to develop disease-modifying targeted therapies for IBM able to provide clinically meaningful improvements.

⚂ Taira, K., Mori-Yoshimura, M., Yamamoto, T., Oya, Y., Nishino, I., & Takahashi, Y. (2023). Clinical Subsets of Inclusion Body Myositis (P9-8.004). Tuesday, April 25, 0145. https://doi.org/10.1212/WNL.0000000000201783 DOWNLOAD PDF.

⚃ Conclusions: This study indicates the clinical subsets of IBM to expand the knowledge of the heterogeneity of the patients.

⚂ Cantó-Santos, J., Valls-Roca, L., Tobías, E., Oliva, C., García-García, F. J., Guitart-Mampel, M., Andújar-Sánchez, F., Esteve-Codina, A., Martín-Mur, B., Padrosa, J., Aránega, R., Moreno-Lozano, P. J., Milisenda, J. C., Artuch, R., Grau-Junyent, J. M., & Garrabou, G. (2023). Integrated multi-omics analysis for inferring molecular players in inclusion body myositis. Antioxidants, 12 (8), 1639. https://doi.org/10.3390/antiox12081639 DOWNLOAD PDF.

⚃ Preamble background information:

⚃ Many areas of research can be classified as omics. Examples include proteomics, transcriptomics, genomics, metabolomics, lipidomics, and epigenomics, which correspond to global analyses of proteins, RNA, genes, metabolites, lipids, and methylated DNA or modified histone proteins in chromosomes, respectively.
≻ – genomics (the study of a person’s genome);
≻ – proteomics (the study of proteomes, a set of proteins in an organism);
≻ – metabolomics (the study of metabolites, small molecules within cells produced during metabolism);
≻ – metagenomics (the study of genetic materials recovered from natural environments);
≻ – phenomics (the study of total phenotypic characteristics of an organism);
≻ – transcriptomics (the study of RNA transcripts produced by a genome).

⚃ High-throughput in sequencing refers to the amount of DNA molecules read at the same time. Technologies are now capable of sequencing many fragments of DNA in parallel. This enables scientists to read hundreds of millions of DNA fragments and generate more data, with less time and costs than ever before.

⚃ Inflammation is triggered by the infiltration of CD8+ cytotoxic T-cells in myofibers and the upregulation of major histocompatibility complex I (MHC-I). Degeneration is presented in the form of rimmed vacuoles and the inclusion of TDP43, p62, and amyloid protein deposits. In mitochondria, ragged-red fibers, complex IV (COX-negative) fibers from the mitochondrial respiratory chain (MRC), and complex II (SDH positive) fibers are displayed, which are also present in primary mitochondrial diseases and mitochondrial myopathies.

⚃ Ongoing clinical trials pertaining to IBM involve, for example, the ability of a monoclonal antibody against the KLRG1 receptor to deplete highly differentiated and cytotoxic CD8+ T cells (clinical trial code: NCT04659031), a rapamycin (previously approved to prevent rejection in organ transplantation and to treat certain types of cancer) that blocks effector T cells while preserving regulatory T cells and inducing autophagy (NCT04789070), and even stem cell muscle injections (NCT04975841)

⚃ Considering mitochondrial damage in IBM, it has been speculated that it could be the result of pro-inflammatory cytokine release (IL-1β, TNF-α, etc.) that could increase oxidative, nitrosative, and endoplasmic-reticulum-related stress. Such lesions may endanger mitochondrial membrane permeability and transport, leading to a dysfunctional MRC that would accumulate mtDNA mutations.

⚃ A mouse xenograft containing IBM muscle biopsies [15] served as a breakthrough in the field, facilitating the in vivo evaluation of disease pathophysiology. The major contribution of this model was the finding that rimmed vacuoles resisted after the murine xenografts were treated with anti-CD3+, which reduced CD8+ T cell levels and impaired MHC-I upregulation, thus supporting the idea that new treatments should target degeneration to treat muscle weakness. Another relevant model of IBM was developed and validated by our group [13] using patient-derived fibroblasts. This model recapitulated the main hallmarks of the target tissue of the disease (inflammatory, degenerative, and metabolic muscle imbalances). Impaired mitochondrial function in the IBM fibroblasts was similar to that of primary mitochondrial diseases [7,16] and was present in a peripheral tissue outside of muscle, thereby confirming molecular disturbances at the systemic level. A relevant finding of the study was an abnormal organic acid profile in fibroblasts associated with MRC dysfunction and oxidative stress.

⚃ Indeed, the identification of genetic variants, proteins, or metabolites associated with the onset and progression of several diseases has been achieved on account of the development of unbiased, high-throughput omics technologies.

⚃ Thus, in the present article, we aimed to identify novel target molecules and pathways in IBM that may prove to be non-invasive biomarkers, focusing on the mitochondrial and metabolic profile of the disease, by performing an omics analysis (targeted metabolome and RNA seq analyses) of different biological samples isolated from IBM patients (saliva, urine, plasma, fibroblasts, and muscle).

⚃ In the urine of the IBM patients, roughly half of the organic acids were upregulated, while the other half presented a reduction, as shown in Figure 3a

⚃ L-pyroglutamic acid and orotic acids:
≻ The sensitivity and specificity values are 50.0% and 83.3% for L-pyroglutamic acid and 100.0% and 83.3% for orotic acid, but these values changed to 100% sensitivity and specificity when both acids were tested together. The presence of altered organic acids in urine corroborated the imbalanced organic acid profile in fibroblasts and highlights L-pyroglutamic and orotic acid as potential fluid biomarkers.

⚃ [These] data support the notion of functional metabolic deregulation at the genetic level and confirm the relevance of metabolic deregulation in relation to this disease.

⚃ Differentially expressed genes (DEGs):
≻ All these multi-omics and interactome connections between metabolites and genes confirm the impact of metabolic dysregulation in IBM.

⚃ This study aimed to perform multi-omics profiling through the high-throughput analysis of numerous biological samples from IBM patients to infer novel target molecules with a differential profile in patients with this disease.

⚃ When the organic acid profile was examined in the subjects' urine and more metabolites were detected, L-pyroglutamic acid and orotic acid emerged as a surrogate biomarker of this disease.

⚃ the results display the emergent value of the reported metabolites along with their high sensitivity and specificity scores, their potential to support the diagnosis and follow-up of patient management, the systemic impact of this disease (previously thought to be restricted to muscle), and the relevance of metabolism in IBM (which was thought to be only minor and secondary). It is still unclear whether these findings could guide future treatment strategies, but the implication of metabolism and oxidative stress in IBM is now undeniable.

⚃ Conclusions:

⚃  Metabolic dysregulation in IBM is present outside the target tissue (muscle), as seen in the altered organic acids in fibroblasts and urine;

⚃  The multi-omics profiling of patients' samples allows for the evaluation of disease-associated phenotypes, constituting an untargeted approach enabling the potential detection of novel molecular players;

⚃  The detection of L-pyroglutamic and orotic acids in urine displayed an outstanding biomarker signature, with 100% sensitivity and specificity;

⚃  The validation of potential biomarkers in non-invasive samples like urine may eventually aid in the screening of patients' disease progression and treatment efficacy.

⚂ Ambrocio KR, Garand KLF, Roy B, Bhutada AM, Malandraki GA. Diagnosing and managing dysphagia in inclusion body myositis: A systematic review. Rheumatology (Oxford). 2023 Oct 3;62(10):3227-3244. doi: 10.1093/rheumatology/kead194. PMID: 37115631. Website.

⚃ Dysphagia is a common debilitating clinical feature of IBM. However, the impact of dysphagia in IBM has been historically overlooked. This study aimed to identify, evaluate and summarize the evidence regarding the assessment and management of dysphagia in persons with IBM undergoing treatment.

⚃ Conclusion: Various interventions have been reported to temporarily improve dysphagia in persons with IBM. However, these findings are based on limited and overall low-quality evidence. This study cautions against the generalization of these findings and emphasizes the need for further systematic research to improve the diagnosis and management of dysphagia in IBM.

⚂ Shaik, M. R., Shaik, N. A., & Mikdashi, J. (2023). Autoimmune Dysphagia Related to Rheumatologic Disorders : A Focused Review on Diagnosis and Treatment. Cureus . https://doi.org/10.7759/cureus.41883 DOWNLOAD PDF.

⚃ IBM is the leading cause of debilitating dysphagia related to inflammatory myopathies and is most common in those over the age of 50 [4]. The prevalence of dysphagia is estimated to be 50% per the Euro myositis registry, 56% per meta-analysis, and 40% per retrospective study [6,12,19]. Up to 80% of participants reported symptoms when a targeted questionnaire seeking symptoms of dysphagia was performed in a cohort with IBM [20]. About 10% may present with dysphagia as an isolated clinical feature [4]. For instance, Shibata et al. describe a case report in which a patient with IBM had dysphagia for five years prior to the onset of limb muscle weakness [21]. Dysphagia usually presents at an advanced disease stage, resulting in unsatisfactory treatment outcomes [22].

⚂ Connor, S. G., Fairchild, T. J., Learmonth, Y. C., Beer, K., Cooper, I., Boardman, G., Teo, S. Y. M., Shatahmasseb, B., Zhang, R., Hiscock, K., Coudert, J. D., Yeap, B. B., & Needham, M. (2023). Testosterone treatment combined with exercise to improve muscle strength, physical function and quality of life in men affected by inclusion body myositis: A randomised, double-blind, placebo-controlled, crossover trial. PLOS ONE, 18 (4), e0283394. Website.

⚃ Adding testosterone supplementation to exercise training did not significantly improve muscle strength or physical function over a 12-week intervention period, compared to exercise alone. However, the combination improved emotional well-being over this period, and relative stabilisation of disease was found during the 12-month OLE. A longer duration trial involving a larger group of participants is warranted.

⚂ Lee, S. A., Lee, H. J., Suh, B. C., Shin, H. Y., Kim, S. W., Yoon, B. A., Choi, Y. C., & Park, H. J. (2023). Clinical significance of anti-NT5c1A autoantibody in Korean patients with inflammatory myopathies. PLOS ONE, 18 (4), e0284409. Website.

⚃ Clinically significant differences were not found between anti-NT5c1A antibody-seropositive and seronegative IBM groups with respect to gender, age at symptom onset, age at diagnosis, disease duration, serum CK values, presence of other autoantibodies, dysphagia, and the pattern of muscle impairment.

⚂ Ma, A. K., Dai, F., & Roy, B. (2022). In-patient comorbidities in inclusion body myositis: A United States national in-patient sample-based study. Clinical and Experimental Rheumatology. Website.

⚃ IBM increases a patient's risk for dysphagia, falls, and infection as compared to other IIM patients.

⚂ Tani, T., Imai, S., & Fushimi, K. (2023). Increasing daily duration of rehabilitation for inpatients with sporadic inclusion body myositis may contribute to improvement in activities of daily living: A nationwide database cohort study. Journal of Rehabilitation Medicine, 55 , jrm00386. Tani2023.pdf

⚃ The results show that a longer daily duration of rehabilitation results in improved activities of daily living for inpatients with sporadic inclusion body myositis.

⚂ Lindgren, U. (2023). Inclusion body myositis Genetic, clinical, and epidemiological aspects. Retrieved May 23, 2023, from Website.

⚃ The inflammatory myopathy inclusion body myositis (IBM) is characterized by progressive muscle weakness and dysphagia in individuals over 45 years of age. Muscle biopsy shows inflammatory infiltrates, vacuoles with protein accumulation and cytochrome c oxidase (COX)-deficient muscle fibers. Multiple rearrangements are seen in mitochondrial DNA (mtDNA) in muscle. Inclusion body myositis is rare and larger population-based studies few. The aim of this thesis was to describe aspects of IBM in a population-based cohort in Region Västra Götaland (VGR), Sweden, from 1985 to 2017. Methods included analysis of muscle biopsies, DNA analysis, and review of medical records.

⚂ Mitra, A., Qaisar, R., Bose, B., & Sudheer, S. P. (2023). The elusive role of myostatin signaling for muscle regeneration and maintenance of muscle and bone homeostasis. Osteoporosis and Sarcopenia, S2405525523000092. https://doi.org/10.1016/j.afos.2023.03.008 OPEN ACCESS

⚃ Skeletal muscle is one of the leading frameworks of the musculo-skeletal system, which works in synergy with the bones. Long skeletal muscles provide stability and mobility to the human body and are primarily composed of proteins. Conversely, improper functioning of various skeletal muscles leads to diseases and disorders, namely, age-related muscle disorders called sarcopenia, a group of genetic muscle disorders such as muscular dystrophies, and severe muscle wasting in cancer known as cachexia. However, skeletal muscle has an excellent ability to undergo hypertrophy and enhanced functioning during sustained exercise over time. Indeed, these processes of skeletal muscle regeneration/hypertrophy, as well as degeneration and atrophy, involve an interplay of various signaling pathways. Myostatin is one such chemokine/myokine with a significant contribution to muscle regeneration or atrophy in multiple conditions. In this review, we try to put together the role and regulation of myostatin as a function of muscle regeneration extrapolated to multiple aspects of its molecular functions.

⚃ The role of myostatin is crucial in determining muscle homeostasis, as talked about throughout the article. It is an essential signalling molecule/myokine that dictates the fine balance between protein degradation and synthesis in skeletal muscles. Furthermore, the role of myostatin is not only restricted to muscles but can also be extrapolated to the bones as well. Hence, developing therapeutic interventions to target myostatin can be useful for tackling both muscle wastage disorders as well as inflammatory diseases of the bones. This would reduce the incidence of falls and fractures globally, especially in old age, and pave the way to improve the health of patients suffering from autoimmune diseases such as RA or sarcopenia.

⚂ Cantó-Santos, J., Valls-Roca, L., Tobías, E., García-García, F. J., Guitart-Mampel, M., Esteve-Codina, A., Martín-Mur, B., Casado, M., Artuch, R., Solsona-Vilarrasa, E., Fernandez-Checa, J. C., García-Ruiz, C., Rentero, C., Enrich, C., Moreno Lozano, P. J., Milisenda, J. C., Cardellach, F., Grau-Junyent, J. M., & Garrabou, G. (2023). Unravelling inclusion body myositis using a patient-derived fibroblast model . Journal of Cachexia, Sarcopenia and Muscle, jcsm.13178. https://doi.org/10.1002/jcsm.13178  OPEN ACCESS

⚃ These findings confirm the presence of molecular disturbances in peripheral tissues from IBM patients and prompt patients' derived fibroblasts as a promising disease model, which may eventually be exported to other neuromuscular disorders. We additionally identify new molecular players in IBM associated with disease progression, setting the path to deepen in disease aetiology, in the identification of novel biomarkers or in the standardization of biomimetic platforms to assay new therapeutic strategies for preclinical studies.

⚃ …in the present study we validated fibroblasts as a disease model for IBM, showing IBM alterations are present beyond the target tissue of the disease. This model could be exported to other myositis or neuromuscular diseases. Additionally, we unveil numerous pathways and specific molecules that emerge as relevant key players in disease aetiology or evolution, for further evaluation as candidate biomarkers or therapeutic targets.

⚂ Gaspar, B. L. (2023). Immune-mediated Myopathies and Neuropathies: Current trends and future prospects. Springer

⚃ Table of contents.

⚂ Leclair, V., Tsui, H., & Hudson, M. (2023). Pain in autoimmune inflammatory myopathies : A scoping review. RMD Open, 9 (1), e002591. https://doi.org/10.1136/rmdopen-2022-002591. OPEN ACCESS

⚃ This scoping review of 33 studies reporting on pain measures in AIM indicates that the burden of pain in subjects with AIM is greater than that of the general population and comparable to other chronic rheumatic diseases such as rheumatoid arthritis. However, it is important to note that pain was rarely the primary focus of the studies included. In addition, the studies were mostly small, single-centre studies with ill-defined populations and methodology that were at high risk of bias. This review highlights areas where research could help better characterise the pain experience in AIM. None of the studies included in this review formally explored the relationship between disease activity and pain in AIM using comprehensive disease activity measures. Potential non-inflammatory pain contributors such as comorbidities (eg, fibromyalgia) or disease damage (eg, muscle dysfunction/atrophy are often overlooked and can complicate disease activity assessment. … The burden of pain in AIM is considerable. However, due to the heterogeneity and low quality of the evidence available, significant knowledge gaps persist. Studies are needed to longitudinally characterise the pain experience in AIM, including predictors of severity and clinical correlates to identify possible pain mechanisms and offer targeted management to patients.

⚂ Roy, B., Lucchini, M., Lilleker, J. B., Goyal, N. A., Naddaf, E., Adler, B., Alfano, L. N., Malandraki, G. A., (Focht) Garand, K. L., Mochel, D., Badrising, U., Machado, P. M., Pagkatipunan, R., Wang, L., Funaro, M. C., Schmidt, J., Kushlaf, H., Schiopu, E., Stipancic, K., … Lloyd, T. E. (2022). Current status of clinical outcome measures in inclusion body myositis: A systematised review. Clinical and Experimental Rheumatology. https://doi.org/10.55563/clinexprheumatol/ifacv3.

⚃ Conclusion. There are inconsistencies in using outcome measures in clinical studies in IBM. The core set measures developed by the IMACS group for other IIMs are not directly applicable to IBM. As a result, there is an unmet need for an IBM-specific core set of measures to facilitate the evaluation of new potential therapeutics for IBM.

⚂ Michelle, E. H., Pinal-Fernandez, I., Casal-Dominguez, M., Albayda, J., Paik, J. J., Tiniakou, E., Adler, B., Mecoli, C. A., Danoff, S. K., Christopher-Stine, L., Mammen, A. L., & Lloyd, T. E. (2023). Clinical heterogeneity based on race and sex within a large cohort of inclusion body myositis patients [Preprint]. Neurology. [Preprint DOI:] https://doi.org/10.1101/2022.05.24.22275537

⚃ Results: Among the 335 patients meeting inclusion criteria for IBM, 64% were male with an average age of disease onset of 58.7 years and delay to diagnosis of 5.2 years. Initial misdiagnosis (52%) and immunosuppressant treatment (42%) were common. Less than half (43%) of muscle biopsies demonstrated all three pathologic hallmarks: endomysial inflammation, mononuclear cell invasion, and rimmed vacuoles. Black patients had significantly weaker arm abductors, hip flexors, and knee flexors compared to non-Black patients. Female patients had stronger finger flexors and knee extensors compared to their male counterparts. Younger age (less than 50 years) at onset was not associated with increased weakness.

⚃ The combination of endomysial inflammation, invasion of non-necrotic fibers, and rimmed vacuoles was seen in 43% of biopsies. An additional 41% contained at least two of these cardinal features, and 34% did not show rimmed vacuoles (Figure 3). The quadriceps muscle was the most common muscle selected for biopsy. The location of the muscle biopsy did not influence the number of pathologic features present, except for the more common presence of COX-negative fibers in the biceps (82%) or deltoid (83%) muscles compared to the quadriceps (47%).

⚃ This study demonstrates that Black and female patients with IBM differ from their White, male counterparts with respect to both pattern and progression of weakness. Although both Black and female patients demonstrated an overall pattern of weakness consistent with that typically seen in IBM, Black patients had significantly weaker proximal muscles, and female patients had less prominent knee extension and finger flexion weakness. Black patients exhibited more rapid development of weakness in arm abductors and knee extensors. In contrast, female patients demonstrated a slower decline in finger flexor and knee extensor strength compared to male patients, and females were more likely to develop dysphagia. These characteristics may explain why both Black and female patient populations were more likely to be initially misdiagnosed with polymyositis and treated with corticosteroids.

⚃ These findings suggest that Black and female patients represent clinically distinct subgroups within IBM with unique disease trajectories and, potentially, different responses to therapeutic interventions. The origin of these differences in clinical phenotype and disease progression are unclear.

2022

⚂ Kleefeld, F., Uruha, A., Schänzer, A., Nishimura, A., Roos, A., Schneider, U., Goebel, H. H., Schuelke, M., Hahn, K., Preusse, C., & Stenzel, W. (2022). Morphologic and Molecular Patterns of Polymyositis With Mitochondrial Pathology and Inclusion Body Myositis . Neurology, 99 (20). LINK.

⚃ PM-Mito and IBM qualitatively harbored a strikingly similar molecular signature and shared important histopathologic features. Expression of IFN-induced guanylate-binding protein (GBP)6 and T-cell function-related KLRG1 distinguished IBM from PM-Mito biopsies with IBM patients showing significantly higher expression of GBP6 and KLRG1. Cryptic exon expression was detected in both patient groups with IBM patients showing higher expression levels. Skeletal muscle biopsies from IBM patients showed significantly more GBP6 + cells and KLRG1 + lymphocytes in comparison with biopsies from patients with PM-Mito. CD45+, CD68+, CD57+, PD1+, and CD8+ cytotoxic T cells were also significantly more abundant in patients with IBM. Clinically, patients with PMMito presented with a spectrum of muscle-related symptoms including myalgia, proximal paraparesis, proximal tetraparesis, and incomplete IBM-like patterns. Thirteen of 14 (93%) patients with PM-Mito for whom clinical follow-up was available later developed clinically defined IBM. Notably, 2 follow-up biopsies obtained 5 and 7 years after the first ones were available in this cohort, both showing histopathologic progress to net IBM including GBP6 and KLRG1 upregulation.

⚃ Our combined data suggest that specific IFN-mediated inflammation plays a key role in both IBM and PM-Mito. GBP6 was identified as a new molecule of type II IFN-induced inflammation distinguishing IBM from PM-Mito. Skeletal muscles from both groups harbor dysfunctional T cells of similar type, albeit in different quantity. T-cell senescence exemplified by KLRG1 positivity does not play a significant role in PM-Mito. Based on these findings, we propose to include PM-Mito in the spectrum of IBM (IBM-spectrum disease [IBM-SD]) as a possible early form of this disease. The establishment of IBM-SD as a larger entity could potentially have a significant effect on the design of trials and therapeutic interventions.

⚃ Thirteen of 14 (93%) patients with PM-Mito for whom clinical follow-up was available later developed clinically defined IBM. Notably, 2 follow-up biopsies obtained 5 and 7 years after the first ones were available in this cohort, both showing histopathologic progress to net IBM including GBP6 and KLRG1 upregulation.

⚃ Based on these findings, we propose to include PM-Mito in the spectrum of IBM (IBM-spectrum disease [IBM-SD]) as a possible early form of this disease. The establishment of IBM-SD as a larger entity could potentially have a significant effect on the design of trials and therapeutic interventions.

⚃ In this study, we hypothesized that PM-Mito and IBM are part of a disease spectrum, rather than distinct disease entities. Therefore, the primary research question of this study was to analyze and compare molecular mechanisms in PMMito and IBM with a focus on interferon (IFN)-mediated inflammation and T-cell dysfunction and to study longitudinal changes in inflammation and gene expression in the assumed gradual transition from PM-Mito to IBM. … Nevertheless, in this study, we provide evidence that PM-Mito and IBM belong to a clinical continuum/disease spectrum that we suggest to term IBM spectrum disease (IBMSD). Accordingly, we recommend replacing the descriptive term “polymyositis with mitochondrial pathology” by “early IBM” (eIBM). Because IBM is considered a therapy refractory disease, the identification of an early and perhaps treatable form of the disease is of relevance to patients, clinicians, and myopathologists. Past therapeutic trials in the context of IBM might have yielded negative results because only the end stages of IBM spectrum disease have been included.

⚂ Deprez, A., Orfi, Z., Rieger, L., & Dumont, N. A. (2022). Impaired muscle stem cell function and abnormal myogenesis in acquired myopathies. Bioscience Reports, BSR20220284. https://doi.org/10.1042/BSR20220284

⚃ In sporadic inclusion-body myositis (sIBM), paracrine signals from lymphocytes contribute to the reduction in MuSC proliferation and MyoD expression, alongside with MuSC senescence.

⚂ Goyal, N. A. (2022). Inclusion body myositis. CONTINUUM: Lifelong Learning in Neurology, 28 (6), 1663-1677. https://journals.lww.com/continuum/abstract/2022/12000/inclusion_body_myositis.8.aspx

⚃ RECENT FINDINGS IBM is an often-misdiagnosed myopathy subtype. Due to the insidious onset and slow progression of muscle weakness, it can often be dismissed as a sign of aging as it commonly presents in older adults. While challenging to recognize upon initial clinical evaluation, the recent recognition of specialized stains highlighting features seen on muscle pathology, the use of diagnostic tools such as the anti-cytosolic 5'-nucleotidase 1A antibody biomarker, and the ability of muscle imaging to detect patterns of preferential muscle involvement seen in IBM has allowed for earlier diagnosis of the disease than was previously possible. While the pathogenesis of IBM has historically been poorly understood, several ongoing studies point toward mechanisms of autophagy and highly differentiated cytotoxic T cells that are postulated to be pathogenic in IBM.

⚂ Greenberg, S. A. (2022). Inclusion body myositis: Boundaries that may define transition to treatment refractoriness. Neurology, https://pubmed.ncbi.nlm.nih.gov/36195454/

⚃ Starting in 1996, PM patients similar to IBM but failing to meet IBM expert consensus criteria mostly because they lacked muscle rimmed vacuoles were reported and suspected to best be categorized within the existing entity of IBM

⚃ Two issues have challenged this field of PM/IBM overlap. First, for patients that look like they have IBM but lack a “canonical feature” of rimmed vacuoles, maybe the problem is that rimmed vacuoles are not “canonical” and are largely irrelevant as an IBM diagnostic criteria?

⚃ The second issue is why PM-Mito was ever considered a subtype of PM to begin with, an issue that exposes an even broader crack in some views of PM. PM-Mito requires the pathological finding of immune cell invasion of non-necrotic myofibers.
≻ Of 107 patients with myofiber invasion, 84% had IBM or IBM clinical features without rimmed vacuoles. Although some PM patients with myofiber invasion may respond to immunotherapies, they have 1/4th the myofiber invasion per unit area of IBM

⚃ These observations agree with previous similar data for muscle CD57+ and KLRG1+ cytotoxic T cells distinguishing IBM from PM, and further support a pathophysiological model in which treatment-refractory IBM is associated with a T cell transition to a highly differentiated cytotoxic state.

⚂ Aguilar-Vazquez, A., Chavarria-Avila, E., Salazar-Paramo, M., Armendariz-Borunda, J., Toriz-González, G., Rodríguez-Baeza, M., Sandoval-Rodriguez, A., Villanueva-Pérez, A., Godínez-Rubí, M., Medina-Preciado, J.-D., Lundberg, I., Lozano-Torres, Y., Gomez-Rios, C.-A., Pizano-Martinez, O., Martinez-Garcia, E.-A., Martin-Marquez, B.-T., Duran-Barragan, S., Palacios-Zárate, B.-L., Llamas-Garcia, A., … Vazquez-Del Mercado, M. (2022). - "ultrastructure damage" in myositis. Scientific Reports, 12 (1), 17671. https://www.nature.com/articles/s41598-022-22754-4 OPEN ACCESS

⚃ The muscle fiber ultrastructure in Idiopathic Inflammatory Myopathies (IIM) has been scarcely explored, especially in Inclusion Body Myositis. The aim of this study was to implement the Scanning Electron Microscopy (SEM) in a small cohort of IIM patients, together with the characterization of immunological profile for a better understanding of the pathophysiology.

⚃ We were able to find and describe muscle fiber ultrastructure with marked irregularities, porosities, disruption in the linearity and integrity of the fascicle, more evident in patients with increased serum levels of muscle enzymes and diminished muscle strength.

⚃ The use of SEM will allow us, with the highest resolution, to appropriately characterize the muscle fiber ultrastructure, and along with cytokines, chemokines and the presence of autoantibodies, might provide us a better understanding of the pathological features of IIM. Therefore, our study aim was to characterize the muscle fiber ultrastructure and to identify the possible association with the immunological profile and clinical features of the IIM clinical phenotypes.

⚂ Amlani, A., Choi, M. Y., Buhler, K. A., Hudson, M., Tarnopolsky, M., Brady, L., Schmeling, H., Swain, M. G., Stingl, C., Reed, A., & Fritzler, M. J. (2022). Anti-Valosin-Containing Protein (VCP/p97) Autoantibodies in Inclusion Body Myositis and Other Inflammatory Myopathies. ACR Open Rheumatology, acr2.11510. https://doi.org/10.1002/acr2.11510. OPEN ACCESS

⚃ The aim of this study was to determine the frequency and clinical significance of anti-VCP antibodies in sIBM and other IIMs.
≻ Anti-VCP has low sensitivity and moderate specificity for sIBM but may help fill the seronegative gap in sIBM. Further studies are needed to determine whether anti-VCP is a biomarker for a clinical phenotype that may have clinical value.

⚂ Chen, J., Wang, X.-Y., Li, S.-Y., Zhang, M.-Y., Guan, T., & Xu, Q. (2022). A 14-year-old girl with early-onset inclusion body myositis, systemic lupus erythematosus, Sjögren's syndrome, and autoimmune thyroiditis: A case report and literature review [Preprint]. In Review. https://doi.org/10.21203/rs.3.rs-2022255/v1.

⚃ We report a case of a 14-year-old girl diagnosed with sporadic inclusion body myositis, Sjögren's syndrome, systemic lupus erythematosus, and autoimmune thyroiditis. She was treated with steroids, intravenous immunoglobulin, and rituximab, which failed to relieve the progressive muscle weakness. Considering previous published cases, this case may be classified as a rare early onset form.
≻ Conclusions: Our patient had a family history of autoimmune thyroiditis combined with various connective tissue diseases. The persistence of thyroid autoantibodies may have predicted the onset and diagnosis of sIBM. In this case report, overlapping immune diagnoses and unusually young age may be factors in misdiagnosis of sporadic inclusion body myositis. Early and more positive treatment should be a discussion of future research. We suggest that failed treatment may be related to the patient's muscle enzyme levels.

⚂ Goel, N., Soler-Ferran, D., Coutreau, M., Escobar, J., Courtemanche, K., & Greenberg, S. (n.d.). Depletion of KLRG1+ T Cells in a First-in-human Clinical Trial of ABC008 in Inclusion Body Myositis (IBM). 3. https://doi.org/10.1136/annrheumdis-2022-eular.2141.

⚃ In study participants with IBM, a single SC dose of 0.1 mg/kg of ABC008 resulted in the depletion of CD8+ KLRG1+ cells with no apparent safety concerns. Higher dose cohorts are planned. Based on these results, a study evaluating ABC008 for the treatment of T-LGLL is also intended.

⚂ Namsrai, T., Parkinson, A., Chalmers, A., Lowe, C., Cook, M., Phillips, C., & Desborough, J. (2022). Diagnostic delay of myositis: An integrated systematic review. Orphanet Journal of Rare Diseases, 17 (1), 420. https://doi.org/10.1186/s13023-022-02570-9. OPEN ACCESS

⚃ Diagnostic delay of IIM has extensive impacts on the quality of life of people living with this disease. Understanding the experiences of people with IIM, from symptom onset to diagnosis, and factors that influence diagnostic delay is critical to inform clinical practice and training activities aimed at increasing awareness of this rare disease and expediting diagnosis.
≻ There was a significant difference in mean diagnostic delay between IBM and non-IBM types. Compared to non-IBM (12.52 months, 95% CI = 3.89-21.15), IBM type had significantly longer mean diagnostic delay (61.32 months, 95% CI = 44.99-77.65).

⚃ Mean diagnostic delay varied greatly between IBM and non-IBM groups (61.32 months or 5 years [16, 29], 95% CI = 44.99-77.65, versus 12.52 months or 1 year, 95% CI = 3.89-21.15). The unique clinical characterisations of IBM could be one reason for the significantly longer diagnostic delay in IBM as it is the only IIM type that starts with slowly progressing asymmetric distal muscle weakness

⚂ Thoma, A., Earl, K. E., Goljanek-Whysall, K., & Lightfoot, A. P. (2022). Major histocompatibility complex I-induced endoplasmic reticulum stress mediates the secretion of pro-inflammatory muscle-derived cytokines. Journal of Cellular and Molecular Medicine, jcmm.17621. https://doi.org/10.1111/jcmm.17621.

⚃ MHC I overexpression can induce pro-inflammatory cytokine/chemokine release from C2C12 myoblasts, a process which appears to be mediated in-part by the ER stress pathway.

⚂ Espay, A. J., & Okun, M. S. (2022). Abandoning the proteinopathy paradigm in Parkinson Disease . JAMA Neurology. https://doi.org/10.1001/jamaneurol.2022.4193.

⚂ Ma, A. K., Dai, F., & Roy, B. (2022). In-patient comorbidities in inclusion body myositis: A United States national in-patient sample-based study. Clinical and Experimental Rheumatology. https://doi.org/10.55563/clinexprheumatol/791fq8.

⚃ IBM increases a patient's risk for dysphagia, falls, and infection as compared to other IIM patients. Further population based studies are warranted to better elucidate the impact of these comorbidities in patients with IBM.

⚂ Nagy, S., Khan, A., Machado, P. M., & Houlden, H. (2022). Inclusion body myositis: From genetics to clinical trials. Journal of Neurology. https://link.springer.com/article/10.1007/s00415-022-11459-3 OPEN ACCESS

⚃ Inclusion body myositis (IBM) belongs to the group of idiopathic inflammatory myopathies and is characterized by a slowly progressive disease course with asymmetric muscle weakness of predominantly the finger flexors and knee extensors. The disease leads to severe disability and most patients lose ambulation due to lack of curative or disease-modifying treatment options. Despite some genes reported to be associated with hereditary IBM (a distinct group of conditions), data on the genetic susceptibility of sporadic IBM are very limited. This review gives an overview of the disease and focuses on the current genetic knowledge and potential therapeutic implications.

⚃ The overlaps with hIBM might help to develop a better understanding of the degenerative cascades of sIBM and to define target molecules. Insights into the underlying pathomechanism of IBM could further be applied in other degenerative diseases of the nervous system, either central or peripheral.

⚃ IBM increases a patient's risk for dysphagia, falls, and infection as compared to other IIM patients. Further population based studies are warranted to better elucidate the impact of these comorbidities in patients with IBM.

⚂ Dey, M., Naveen, R., Nikiphorou, E., Sen, P., Saha, S., Lilleker, J. B., Agarwal, V., Kardes, S., Day, J., Milchert, M., Joshi, M., Gheita, T., Salim, B., Velikova, T., Edgar Gracia-Ramos, A., Parodis, I., O'Callaghan, A. S., Kim, M., Chatterjee, T., … COVAD Study Group. (2022). Higher risk of short term COVID-19 vaccine adverse events in myositis patients with autoimmune comorbidities: Results from the COVAD study. Rheumatology (Oxford, England), keac603. https://doi.org/10.1093/rheumatology/keac603.

⚃ Patients with IIMs and coexisting systemic autoimmune diseases (SAIDs) experience more frequent adverse events (AEs) 391 following vaccination against COVID-19 compared to those with IIMs alone and healthy controls (HCs). Our study adds 392 to the growing body of evidence on the safety of COVID-19 vaccination in people with SAIDs, 393 specifically contributing more granular detail on patients with IIMs including the vulnerable and 394 relatively understudied proportion of these patients with autoimmune multimorbidity, compared to 395 other global studies on COVID-19 vaccination related adverse events.

⚂ Brokamp, G., Hurst, L., Hartog, L., Vilson, F., Reynolds, J., Elsheikh, B. H., & Arnold, W. D. (2022). Characterizing ventilatory muscle dysfunction in inclusion body myositis. American Journal of Physical Medicine & Rehabilitation, Publish Ahead of Print. https://doi.org/10.1097/PHM.0000000000002114.

⚃ Design: A retrospective review of pulmonary function tests, respiratory symptoms, and muscle strength testing. Results: Of the 54 patients reviewed (mean age: 65 ‡ 9 years and disease duration: 7 + 7 years), the majority (n = 32, 59%) had restrictive forced vital capacity (FVC) deficits at initial visit. Patients with reduced FVC showed higher prevalence of respiratory symptoms; but age, body mass index, and limb strength were similar when compared to patients without restrictive FVC. Mean rate of FVC decline of 0.108 L/year in IBM patients. Lower baseline limb strength correlated with longer disease duration and future FVC decline (e.g., weaker patients experienced faster decline). Conclusion: Based on FC, there is a high frequency of ventilatory pump muscle weakness in IBM, which is associated with a higher burden of respiratory symptoms. Baseline strength may indicate risk of respiratory decline and need for vigilant screening. Importantly, ventilatory and limb muscle decline may not progress in a corresponding manner, highlighting the importance of pulmonary function surveillance.

⚂ Che, W. I., Lundberg, I. E., & Holmqvist, M. (2022). Environmental risks for inflammatory myopathies. Rheumatic Disease Clinics of North America, 48 (4), 861-874. Che2022.pdf

⚃ It has been suggested that the onset of idiopathic inflammatory myopathies (IIMs) requires environmental triggers besides underlying genetic susceptibility. Ultraviolet radiation, smoking, infectious agents, certain pollutants, medications, and vitamin D deficiency are potential environmental triggers for IIM.
≻ Many of the suggested environmental factors for IIM enter human body via lungs and are related to features of lung involvement in IIM, supporting lung as the initial onset site of autoimmunity for some subgroups of IIM.

⚂ Elmansy, M., Morrow, J. M., Shah, S., Fischmann, A., Wastling, S., Reilly, M. M., Hanna, M. G., Helmy, E. M., El-Essawy, S. S., Thornton, J. S., & Yousry, T. A. (2022). Evidence of nerve hypertrophy in patients with inclusion body myositis on lower limb MRI. Muscle & Nerve, mus.27728. https://doi.org/10.1002/mus.27728.

⚃ Magnetic resonance neurography (MRN) reveals significant hypertrophy of the sciatic and tibial nerves in patients with IBM and CMT1A compared to controls. Further studies are needed to correlate with neurophysiological measures and assess whether this finding is useful diagnostically.

⚂ Girija, M. S., Tiwari, R., Vengalil, S., Nashi, S., Preethish-Kumar, V., Polavarapu, K., Kulanthaivelu, K., Arbind, A., Bardhan, M., Huddar, A., Unnikrishnan, G., Kiran, V. R., Chawla, T., Nandeesh, B., Nagaraj, C., & Nalini, A. (2022). PET-MRI in idiopathic inflammatory myositis: A comparative study of clinical and immunological markers with imaging findings. Neurological Research and Practice, 4 (1), 49. https://doi.org/10.1186/s42466-022-00213-9.

⚂ Hiniker, A., Daniels, B. H., Lee, H. S., & Margeta, M. (2013). Comparative utility of LC3, p62 and TDP-43 immunohistochemistry in differentiation of inclusion body myositis from polymyositis and related inflammatory myopathies. Acta Neuropathologica Communications, 1 (1), 29. https://doi.org/10.1186/2051-5960-1-29.

⚂ Cong, Y., Shintani, M., Imanari, F., Osada, N., & Endo, T. (2022). A new approach to drug repurposing with two-stage prediction, machine learning, and unsupervised clustering of gene expression. OMICS A Journal of Integrative Biology, 26 (6), 9. https://doi.org/10.1089/omi.2022.0026. OPEN ACCESS

⚂ Coudert, J. D., Slater, N., Sooda, A., Beer, K., Lim, E. M., Boyder, C., Zhang, R., Mastaglia, F. L., Learmonth, Y. C., Fairchild, T. J., Yeap, B. B., & Needham, M. (2022). Immunoregulatory effects of testosterone supplementation combined with exercise training in men with Inclusion Body Myositis: A double-blind, placebo-controlled, cross-over trial. Clinical & Translational Immunology, 11 (9). https://doi.org/10.1002/cti2.1416. OPEN ACCESS

⚂ Galindo-Feria, A. S., Wang, G., & Lundberg, I. E. (2022). Autoantibodies: Pathogenic or epiphenomenon. Best Practice & Research Clinical Rheumatology, 101767. https://doi.org/10.1016/j.berh.2022.101767. OPEN ACCESS

⚂ Murakami, A., Noda, S., Kazuta, T., Hirano, S., Kimura, S., Nakanishi, H., Matsuo, K., Tsujikawa, K., Iida, M., Koike, H., Sakamoto, K., Hara, Y., Kuru, S., Kadomatsu, K., Shimamura, T., Ogi, T., & Katsuno, M. (2022). Metabolome and transcriptome analysis on muscle of sporadic inclusion body myositis. Annals of Clinical and Translational Neurology, acn3.51657. https://doi.org/10.1002/acn3.51657. OPEN ACCESS

⚂ Nagai, A., Nagai, T., Yaguchi, H., Fujii, S., Uwatoko, H., Shirai, S., Horiuchi, K., Iwata, I., Matsushima, M., Ura, S., Anzai, T., & Yabe, I. (2022). Clinical features of anti-mitochondrial M2 antibody-positive myositis : Case series of 17 patients. Journal of the Neurological Sciences, 442, 120391. https://doi.org/10.1016/j.jns.2022.120391. OPEN ACCESS

⚂ Naddaf, E. (2022). Inclusion body myositis: Update on the diagnostic and therapeutic landscape. Frontiers in Neurology, 13, 1020113. https://doi.org/10.3389/fneur.2022.1020113. OPEN ACCESS

⚂ Parchani, A., Sudan, A., Singh, S., Singh, A., & Pathania, M. (2022). Novel insights into the use of biologicals in idiopathic inflammatory myopathies. In Physiology (Vol. 0) . IntechOpen. https://doi.org/10.5772/intechopen.106277. OPEN ACCESS

⚂ Aniceto, R. R., & da Silva Leandro, L. (2022). Practical blood flow restriction training : New methodological directions for practice and research. Sports Medicine - Open, 8 (1), 87. https://doi.org/10.1186/s40798-022-00475-2. OPEN ACCESS

⚃ this Current Opinion article aims to critically and chronologically examine the techniques used to prescribe the pressure exerted by the elastic wrap during pBFR training. In summary, several techniques were found to apply the elastic wrap during pBFR training, using the following as criteria: application by a single researcher; stretching of the elastic (absolute and relative overlap of the elastic); the perceived tightness scale; and relative overlap of the elastic based on the circumference of the limbs. Several studies have shown that limb circumference seems to be the greatest predictor of AOP. Therefore, we reinforce that applying the pressure exerted by the elastic for pBFR training based on the circumference of the limbs is an excellent, valid and safe technique.

⚂ Goyal, N. A., Greenberg, S. A., Cauchi, J., Araujo, N., Li, V., Wencel, M., Irani, T., Wang, L. H., Palma, A. M., Villalta, S. A., & Mozaffar, T. (2022). Correlations of Disease Severity Outcome Measures in Inclusion Body Myositis. Neuromuscular Disorders, S0960896622006344. https://doi.org/10.1016/j.nmd.2022.08.005.

⚃ the optimal measure of disease severity and disease progression for a clinical trial endpoint is not known for IBM. There is only limited data on the rates of progression of outcome measures within placebo arms of clinical trials, and the influence of factors such as age-related morbidities, the presence of anti-NT5c1A antibodies, and influence of immunological perturbations seen in IBM on disease severity and disease progression is not clear. The IBM functional rating scale (IBMFRS) is an increasingly commonly used outcome measure in IBM placebo-controlled clinical trials [5] and appears to correlate well with measures of muscle strength.[6-10] While several additional outcome measures are used in IBM clinical trials to evaluate disease progression, there is limited data on how well other measures such as timed get up, forced vital capacity, pinch dynamometry, and swallow function correlate. Thus, in this study we aimed to further understand how the currently used outcome measures in IBM clinical trials correlate with one another.

⚃ Our study showed that significant correlations were seen with several of the commonly used IBM outcome measures with one another. Furthermore, there appears to be good concordance with severity of the disease based on the IBMFRS score. Specifically, the patients in this study who had less severe disease (noted by a higher IBMFRS score), also showed strong correlations to measurements of FVC, strength scores and functional assessments, demonstrated by correlations to higher FVC (less respiratory insufficiency), higher strength scores (noted on MMT 12, grip and Jamar pinch), less time to get up from a chair, less disability (modified Rankin score), and less oral, bulbar, facial weakness (mOBFRS). Additionally, strong correlations were seen with handgrip and pinch strength, an important finding given that finger flexion weakness is often a significant disabling feature of IBM. While standard dynamometers for handgrip and pinch strength are not sensitive enough to detect changes in strength in severely weak patients resulting in a floor effect, we tested a new device called the Piezo pinch meter designed with a thin, more sensitive plate and sensor, and an ability to measure tip pinch strength of even severely weak patients that were unrecordable with the standard pinch dynamometer, addressing the floor effect in some patients with severe finger flexor weakness. The findings in this study indicate that several of these clinical measures correlate very well with another and are well able to evaluate disease progression.

⚃ Given the clinical heterogeneity of the disease within IBM patients, with some patients having more severe leg involvement and in others predominant grip or even bulbar involvement, all the different outcome measures tested in this study such as timed get up, pinch, FVC, and mOBFRS may reveal distinct facets of the disease.…. Through this NIAMS study and similar prospective studies we should finally be able to learn the rate of changes in these outcome measures (and thus disease progression) in IBM which will be helpful to design appropriate pharmacological intervention studies.

⚂ Ramdharry, G. M., & Anderson, M. (2022). Exercise in myositis: What is important, the prescription or the person? Best Practice & Research Clinical Rheumatology , 101772. https://doi.org/10.1016/j.berh.2022.101772.

⚃ What is striking from this review is that a large variety of exercise types, durations and prescriptions have been investigated with no increases in serum CK (refs) or inflammatory markers [32], with antiinflammatory effects [18] and increased recycling of damaged proteins [20] suggested. Another important finding from comparisons with no-exercise control groups is that a decline in muscle strength in IBM continues with no intervention [30] and exercise interventions improve muscle function parameters. These two conclusions support the premise that most activity is good for disease management, and these studies provide a wider “menu” of exercise types that people may wish to engage with.

⚃ The research community in this field needs to build on this change of focus to further a paradigm shift that includes people living with IIM in the design of programmes [35], outcome measurement [17] and support of the person rather than just focus on the muscle [26,31].

⚂ McLeish, E., Slater, N., Sooda, A., Wilson, A., Coudert, J. D., Lloyd, T. E., & Needham, M. (2022). Inclusion body myositis: The interplay between ageing, muscle degeneration and autoimmunity. Best Practice & Research Clinical Rheumatology , 101761. https://doi.org/10.1016/j.berh.2022.101761.  OPEN ACCESS .

⚃ Synopsis:  IBM presents with a distinctive pattern of weakness involving the quadriceps and finger flexor muscles, although other muscles including throat muscles become affected over time. … Overall, the progressive muscle wasting and loss of function observed in IBM likely result from a combination of autoimmune mechanisms, chronic inflammation and degenerative processes. … The cause of IBM is unknown but is likely related to several factors, including aging, predisposing genetic factors, inflammation, and accumulation of abnormal proteins, leading to muscle breakdown and poor muscle regeneration, causing progressive muscle loss, weakness, and disability. … It is not understood which comes first: inflammation or degeneration. … Disruptions occur in the processes that regulate proteins within the muscle cells resulting in clumps of different kinds of proteins forming in the cells. This creates problems for the cells that lead to dysfunction or the cell dying. … Changes associated with aging involve the normal loss of muscle and strength as well as changes within the immune system. Aging also affects the ability of cells to regulate proteins and is associated with abnormalities in mitochondria. The interaction of these aging issues with genetic predispositions likely contributes to IBM developing. … It appears that some unknown trigger initiates an immune system response. This sets off a complicated chain reaction, eventually damaging the muscles. … Inflammation and degeneration interact with each other. Both are also impacted by factors described above: the impacts of aging and genetic predispositions. Both inflammation and degeneration activate a crucial link in the chain reaction that is seen in IBM. Finally, loops in these chain reactions can develop, keeping the reactions going. … Researchers need a better understanding of how inflammatory and degenerative aspects interact and what stimulates them in the cell. This will be required to develop effective treatments. The initial trigger of the immune system needs to be discovered. Finally, more research needs to be done on what factors play critical roles in damaging muscle in IBM.

⚃ From article:

⚃ IBM presents with a distinctive pattern of weakness involving the quadriceps and finger flexor muscles, although other muscles including pharyngeal muscles become affected over time. Pathological hallmarks of IBM include autoimmune features, including endomysial infiltration by highly differentiated T cells, as well as degenerative features marked by intramyofibre protein aggregates organised into inclusion bodies.

⚃ The aetiopathogenesis of IBM is still largely unknown, but it is likely that in the ageing environment and with genetic susceptibility factors, both inflammation and misfolded protein accumulation due to impaired autophagy and proteasome systems contribute to myofibre breakdown and poor regeneration, causing progressive muscle loss, weakness and disability. However, whether the inflammation is initially responsible for the degenerative changes, or that the degenerative changes precede and trigger autoimmunity, has not been fully elucidated. This review recapitulates our understanding of the relevant degenerative and inflammatory changes observed in IBM and discusses the interrelationship between autoimmunity and degeneration, as well as the contribution of ageing in the aetiopathology of IBM.

⚃ …loss of TDP-43 function is specific to IBM compared to other inflammatory myopathies and appears independent of the inflammation (Fig. 1). This may be important in understanding one of the mechanisms of myodegeneration.

⚃ …findings suggest the possibility that variants in the autophagic machinery may predispose certain individuals to disrupted proteostasis and progressive supersaturation and aggregation of multiple proteins, as seen in IBM.

⚃ the accumulation of ubiquitinated, misfolded, protein aggregates may cause proteasome inhibition and ultimately the myodegeneration that is seen in IBM.

⚃ IBM muscle features mitochondrial abnormalities including a higher proportion of COX negative fibres, ragged red fibres and mitochondrial DNA (mtDNA) deletions compared to healthy aged-matched samples … continuous UPR stimulation leads to the activation of ER transmembrane sensors, including activation transcription factor-6 (ATF6), inositol-requiring protein (IRE) 1a and protein kinase R (PKR)-like endoplasmic reticulum kinase (PERK) and ultimately leads to UPR-associated degeneration

⚃ Collectively, ageing-related changes affect the skeletal muscle and immune system, in both a direct and interdependent manner. The combined negative impact of ageing on mitochondrial function and proteostasis in muscle creates additive and self-amplifying pathological conditions when occurring in genetically predisposed individuals. These factors may combine to accelerate muscle atrophy, due to the inadequacy of older muscle to cope with the continuous cell stress caused by chronic inflammation and/or other degenerative mechanisms (Fig. 2). Therefore, the contribution of ageing is an important consideration in the pathogenesis of IBM.

⚃ Increasing evidence suggests that IBM may be primarily an autoimmune disease, mediated by terminally differentiated effector (TEMRA) T cells, with secondary degenerative changes that once established, can progress even in the absence of ongoing inflammation. Detailed characterisation of the underlying immune-mediated mechanisms of IBM is crucial, as this will provide a critical step towards the identification of cellular and molecular targets for future therapies.

⚃ …both through their antigen presentation capacity to T cells and their pro-inflammatory role, macrophages may play a critical for the initiation of muscle damage and autoimmune processes in IBM.

⚃ One of the distinctive characteristics of IBM pathology is the intense endomysial infiltration of CD8+ T cells surrounding and invading non-necrotic muscle fibres demonstrating diffuse overexpression of MHC class I molecules expressed on sarcolemma … An unresolved question is what antigen triggers the CD8+ and CD4+ T cell autoreactivity. … These results highlight a continuous, antigen-driven T-cell response that is prominent in the muscle of patients with IBM, but further studies using modern techniques are required to further elucidate T cell specificity.

⚃ The presence of antibodies that target cytosolic 5' -nucleotidase 1A (cN1A) e an intracellular enzyme highly expressed in skeletal muscles — has been reported in 33—72% of patients in various IBM cohorts … The molecular mechanisms by which anti-cN1A antibodies arise and subsequently contribute to IBM pathogenesis remain under investigation. … autoantibodies against cN1A are important in the pathogenesis of IBM, specifically in relation to muscle atrophy.  … In summary, it is evident that responses of both innate and adaptive arms of immunity are actively involved in IBM. Understanding how they interact and integrate into skeletal muscle biology may uncover previously unexplored mechanisms that can direct future studies towards novel therapeutic targets. Additionally, the complexity of these inter-related systems could provide a reasonable explanation as to why therapeutic interventions targeting the adaptive immune system may be insufficient at stopping further muscle breakdown.

⚃ Due to the presence of both inflammatory and degenerative pathological features in IBM, there has been a long-standing question as to whether one aspect of this disease drives the other, or if they are acting independently in an additive manner. There are multiple potential links between inflammation and cellular stress (see Fig. 4), and both likely contribute ultimately to muscle atrophy but understanding how these two processes interact and what drives them is critical to developing specific therapies.

Global conference on myositis 2022: 6th 9th June 2022 Prague, Czech Republic

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⚂ 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.

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⚂ 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 immune-­mediated necrotising myopathy. These diseases are diagnosed on the basis of the presence of myositis ­specific 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.

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Global conference on myositis 2022: 6th 9th June 2022 Prague, Czech Republic

⚂ 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://link.springer.com/article/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.

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⚃ 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
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⚃ 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.
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⚃ 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://www.nature.com/articles/s42003-022-03253-8 OPEN ACCESS .

⚃ As TDP-43 inclusions have recently been described in the muscle of inclusion body myositis patients, this highlights the need to understand the role of TDP-43 beyond the central nervous system. Using RNA-seq, we directly compare TDP-43-mediated RNA processing in muscle (C2C12) and neuronal (NSC34) mouse cells. TDP-43 displays a cell-type-characteristic behaviour targeting unique transcripts in each cell-type, which is due to characteristic expression of RNA-binding proteins, that influence TDP-43's performance and define cell-type specific splicing. Among splicing events commonly dysregulated in both cell lines, we identify some that are TDP-43-dependent also in human cells. Inclusion levels of these alternative exons are altered in tissues of patients suffering from FTLD and IBM. We therefore propose that TDP-43 dysfunction contributes to disease development either in a common or a tissue-specific manner.

⚃ 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://link.springer.com/article/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.

⚃ Sjögren's syndrome (SS) is a systemic autoimmune disease that frequently occurs concomitantly with other systemic connective tissue disorders, including rare and complex diseases such as systemic lupus erythematosus (SLE) and systemic sclerosis (SSc). The presence of SS influences the clinical expression of the other autoimmune diseases, thus offering the unique opportunity to explore the similarities in genetic signatures, as well as common environmental and biologic factors modulating the expression of disease phenotypes. In this review, we will specifically discuss the possibility of defining "SS/SLE" and "SS/SSc" as distinct subsets within the context of connective tissue diseases with different clinical expression and outcomes, thus deserving an individualised assessment and personalised medical interventions.

⚂ 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 .

⚃ Inclusion-body myositis is a complex disorder because autoimmunity co-exists with myodegeneration. CD8+cytotoxic T-cells not only surround but also invade healthy, non-necrotic muscle fibers, which aberrantly express MHC-I, probably induced by T-cell-activated cytokines; the CD8/MHC-I complex is characteristic of IBM aiding in the histological diagnosis. Plasma cells and myeloid dendritic cells are also seen among the endomysial infiltrates, while nonspecific anti-cytosolic 5'-nucleotidase- 1A (cN1A), detected in 33-51% of IBM patients, highlight the immune dysregulation and B-cell activation. The evidence of degeneration is highlighted by the presence of autophagic vacuoles with bluish-red material, proteinacious aggregates positive for ubiquitin, tau and TDP43 and congophilic amyloid deposits within the muscle fibers next to the vacuoles, visualized best with crystal violet or fluorescent optics as shown in Figure 4(a); chronic myopathic changes with atrophy and increased connective tissue as well as ‘ragged-red’ or cytochrome oxidase-negative fibers due to abnormal mitochondria, are also frequent. The co-existence of degeneration and autoimmunity has been the impetus to study their interrelationship. MHC-1 or nitric oxide-induced cell stress along with long-standing proinflammatory cytokines, like interferon-Y and IL1-β, can cumulatively enhance degeneration with further accumulation of stressor molecules, misfolded proteins, and amyloid deposits leading to further disease progression with muscle atrophy and myofiber loss.

⚂ 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.15231 OPEN 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.

⚃ 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, 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.

⚂ 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://pubmed.ncbi.nlm.nih.gov/35131907/

⚃ 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.

⚂ Odeh, H. M., & Shorter, J. (2022). Aggregates of TDP-43 protein spiral into view. Nature, 601 (7891), 29-30. https://www.nature.com/articles/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://www.nature.com/articles/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://www.nature.com/articles/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://www.nature.com/articles/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://www.nature.com/articles/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.

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://www.nature.com/articles/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). Dimachkie2021.pdf 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.

⚃ The depiction in figure 1B is wrong. The color in the lines is reversed—the blue curve with lower survival is for patients treated with corticosteroids. The authors stand by what they said in the text: “Patients treated with corticosteroids had a median survival of 31 months compared with 76 months in the untreated group. However, this did not reach statistical significance (P >0.2), which could be due to the small sample size and low event rate as shown in Fig. 1. There was no difference in survival based on treatment with corticosteroids in the IIM group, or based on treatment with other immunosuppressant drugs in either group (data not shown)."

⚂ 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://pubmed.ncbi.nlm.nih.gov/33597289/

⚂ 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://n.neurology.org/content/96/12/555

⚂ 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. Zivkovic2021.pdf 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://link.springer.com/article/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.

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://journals.lww.com/ijru/fulltext/2020/15002/sporadic_inclusion_body_myositis_in_the.10.aspx 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://journals.lww.com/md-journal/fulltext/2020/07310/a_novel_application_of_tau_pet_in_the_diagnosis_of.125.aspx 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://link.springer.com/article/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://link.springer.com/article/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://link.springer.com/chapter/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://journals.lww.com/co-rheumatology/abstract/2020/11000/pathogenesis_of_inclusion_body_myositis.12.aspx

⚃ 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: recent perspectives . Current Opinion in Rheumatology , Publish Ah. https://journals.lww.com/co-rheumatology/abstract/2020/11000/myositis_autoantibodies__recent_perspectives.13.aspx

⚂ Pipitone, N., & Salvarani, C. (2020). Up-to-date treatment and management of myositis. Current Opinion in Rheumatology , Publish Ah. https://journals.lww.com/co-rheumatology/abstract/2020/11000/up_to_date_treatment_and_management_of_myositis.9.aspx

⚂ 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://link.springer.com/article/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://link.springer.com/article/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

⚂ Zhang, J., Khasanova, E., & Zhang, L. (2020). Bioinformatics analysis of gene expression profiles of Inclusion body myositis. Scandinavian Journal of Immunology . https://doi.org/10.1111/sji.12887

⚂ Leeuwenberg, K. E., van 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 , 637915. https://doi.org/10.1002/mus.26875 OPEN ACCESS

⚂ Guttsches, A., Jacobsen, F., Schreiner, A., Mertens-Rill, J., Tegenthoff, M., Marcus, K., Vorgerd, M., & Kley, R. A. (2020). Chaperones in sporadic inclusion body myositis—Validation of proteomic data. Muscle & Nerve, 61 (1), 116-121. https://doi.org/10.1002/mus.26742 OPEN ACCESS

⚂ Alexanderson, H., & Regardt, M. (2020). Role of Exercise in the Management of Myositis. In Managing Myositis (pp. 323-334). Cham: Springer International Publishing. https://link.springer.com/chapter/10.1007/978-3-030-15820-0_33

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

 .

⚂ Bernstein, S. (2019, April 15). New tools for myositis diagnosis, classification & management: Anti-NT5C1a in IBM. The Rheumatologist [newsmagazine] https://www.the-rheumatologist.org/article/new-tools-for-myositis-diagnosis-classification-management/7/

⚂ Brand-Saberi, B. (Ed.). (2020). Essential current concepts in stem cell biology . Cham: Springer. https://link.springer.com/book/10.1007/978-3-030-33923-4

⚂ Haczkiewicz, K., Sebastian, A., Piotrowska, A., Misterska-Skóra, M., Hałoń, A., Skoczyńska, M., … Podhorska-Okołów, M. (2019). Immunohistochemical and ultrastructural analysis of sporadic inclusion body myositis: A case series. Rheumatology International, 39 (7), 1291–1301. https://link.springer.com/article/10.1007/s00296-018-4221-z OPEN ACCESS

⚂ Lilleker, J. B., Hodgson, R., Roberts, M., Herholz, K., Howard, J., Hinz, R., & Chinoy, H. (2019). Florbetapir positron emission tomography: Identification of muscle amyloid in inclusion body myositis and differentiation from polymyositis. Annals of the Rheumatic Diseases, 78 (5), 657–662. https://doi.org/10.1136/annrheumdis-2018-214644 OPEN ACCESS

⚂ Opinc, A. H., Brzezińska, O. E., & Makowska, J. S. (2019). Disability in idiopathic inflammatory myopathies: Questionnaire-based study. Rheumatology International, 39 (7), 1213–1220. https://link.springer.com/article/10.1007/s00296-019-04302-y OPEN ACCESS

⚂ Ratajczak, M. Z. (Ed.). (2019). Stem cells: Therapeutic applications. Cham: Springer. https://link.springer.com/book/10.1007/978-3-030-31206-0

⚂ Roy, B., Rutkove, S. B., & Nowak, R. J. (2020). Electrical impedance myography as a biomarker of inclusion body myositis: A cross-sectional study. Clinical Neurophysiology, 131 (2), 368–371. https://doi.org/10.1016/j.clinph.2019.10.030

⚂ Sá J, Costelha J, Marinho A. (2019). Inclusion body myositis treated with alemtuzumab. EJCRIM [European Journal of Case Reports in Internal Medicine] 6 : https://doi:10.12890/2019_001368 OPEN ACCESS

⚂ Turner, R. M., & Pirmohamed, M. (2019). Statin-Related Myotoxicity: A Comprehensive Review of Pharmacokinetic, Pharmacogenomic and Muscle Components. Journal of Clinical Medicine, 9 (1), 22. https://doi.org/10.3390/jcm9010022 OPEN ACCESS

⚂ Appendix.  Common abbreviations in IBM research.

≻ 2MWT = 2-min walk test
≻ 6MWD = The 6-min walk distance test
≻ AChE = Acetylcholinesterase: a cholinergic enzyme
≻ ADCC = Antibody-dependent cell-mediated cytotoxicity
≻ ALPS = Autoimmune lymphoproliferative syndrome
≻ ALS = Amyotrophic lateral sclerosis
≻ AML = Acute myeloid leukemia
≻ AMPK = AMP-responsive protein kinase
≻ APCS = Antigen-presenting cells
≻ apoE = Apolipoprotein E
≻ APP β = amyloid precursor protein
≻ ATP = adenosine triphosphate
≻ B-amyloid = beta amyloid protein
≻ BBB = blood-brain barrier
≻ BFR = Blood Flow Restriction training
≻ BiPAP = Bi meaning two, PAP meaning Positive Airway Pressure
≻ CBD = Cannabidiol [marijuana]
≻ CD8+ TEMRA = Terminally Differentiated Effector Memory CD8 + T Cells
≻ CDK = Cyclin-dependent kinase
≻ CfmtDNA = Cell-free mitochondrial DNA
≻ CI = Confidence interval
≻ CK = serum total creatine kinase
≻ CLL = Chronic lymphocytic leukemia
≻ CMAP = compound muscle action potential
≻ cN1A = Cytosolic 5′-nucleotidase 1 A
≻ CO2 = carbon dioxide
≻ COX = cytochrome oxidase
≻ CP = cricopharyngeal: muscle in the throat.
≻ CPAP = Continuous Positive Airway Pressure
≻ CRF = cardiorespiratory fitness
≻ CS = corticosteroids
≻ CTLA-4 = Cytotoxic T lymphocyte-associated protein 4
≻ DAMPs = damage-associated molecular patterns
≻ DC = dendritic cells
≻ DEGs = differentially expressed genes
≻ DM = dermatomyositis
≻ dsRNA = double-strand RNA
≻ EAT-10 = Eating Assessment Tool
≻ eIBM = early IBM
≻ ELISA = Enzyme linked immunosorbent assay
≻ EMG = electromyogram (Electromyography)
≻ EMST = Expiratory Muscle Strength Trainer
≻ ENMC = European Neuromuscular Centre
≻ ER = stress endoplasmic reticulum stress
≻ FAPs = Fibro-adipogenic progenitors
≻ FDA = The Food and Drug Administration
≻ FDP = flexor digitorum profundus muscle
≻ FEFMax = The maximum Forced Expiratory Flow rate
≻ FF = deep finger flexor
≻ fIBM = Familial IBM (old term)
≻ FVC = Forced vital capacity
≻ GADD45A = Growth arrest and DNA-damage-inducible protein
≻ GBP = guanylate binding protein
≻ GC = Glucocorticoids
≻ GSK3 = glycogen synthase kinase 3
≻ H. Pylori = Helicobacter pylori
≻ HAM = HTLV-I associated myelopathy
≻ HC = Healthy control
≻ HCQ = Hydroxychloroquine
≻ HCV = Hepatitis C virus
≻ hIBM = hereditary inclusion body myopathy (old term)
≻ HIV = Human immunodeficiency virus
≻ hKLRG1 = Human KLRG1
≻ HLA genes = Human leukocyte antigen genes
≻ HM = Hematological malignancies
≻ HTLV-I = human T cell leukaemia virus type I
≻ IBM = Inclusion body myositis (Sporadic inclusion body myositis)
≻ IBM-SD = IBM-spectrum disease
≻ IBMFRS = Inclusion body myositis functional rating scale
≻ IFN = interferon
≻ IFN-Y = Interferon-y (type 2)
≻ IFN2 = type 2 interferon
≻ IFNs = Type 1 interferons
≻ IIM = Idiopathic Inflammatory Myopathies
≻ IL-2 = Interleukin-2
≻ ILC-25 = Type 2 innate lymphoid cells
≻ ILD = Interstitial lung disease
≻ IMNM = immune-mediated necrotizing myopathy
≻ IMT = Inspiratory muscle training
≻ IN = interferon
≻ IncRNA = long non-coding RNAs
≻ ITIM = Immunoreceptor tyrosine-based inhibitory motif
≻ IVIG = Intravenous immunoglobulin
≻ KE = knee extensor
≻ KLRG1 = killer cell lectin-like receptor G1
≻ LCMV = Lymphocytic choriomeningitis virus
≻ LGLs = large granular lymphocytes
≻ LVR = Lung Volume Recruitment
≻ MA-5 = Mitochonic acid-5
≻ MAAs = myositis-associated auto-antibodies
≻ mAb = Monoclonal antibody
≻ MHC = major histocompatibility complex
≻ MIC = Maximum Insufflation Capacity
≻ mKLRG1 = Mouse KLRG1
≻ ML = Machine learning
≻ MM = Multiple myeloma
≻ MRI = magnetic resonance imaging
≻ mRNA = Messenger RNA
≻ MSAs = Myositis-specific auto-antibodies
≻ Mtdamps = Mitochondrial DAMPs
≻ Mtdna = Mitochondrial DNA
≻ mTOR = Mammalian target of rapamycin
≻ Mtug = modified Timed up and go score
≻ MUAP = motor unit action potential
≻ MUP = motor unit potential
≻ N-cad = N-cadherin
≻ NDs = Neurodegenerative diseases
≻ NK = Natural killer (cells)
≻ NLRP3 = NLR Family Pyrin Domain Containing 3: a protein coding gene.
≻ NORAD = Noncoding RNA activated by DNA damage
≻ NSAIDs = nonsteroidal anti-inflammatory drugs
≻ OM = overlap myositis
≻ OR = Odds ratio
≻ OSA = Obstructive sleep apnea
≻ PaCO2 = arterial carbon dioxide concentration
≻ PB = Peripheral blood
≻ PCF: = Peak Cough Flow
≻ PCO2 = partial pressure of carbon dioxide (in arterial or venous blood)
≻ PD-1 = Programmed cell death protein 1
≻ PEG tube = Percutaneous Endoscopic Gastrostomy tube
≻ PM-Mito = Polymyositis with mitochondrial pathology
≻ PM = polymyositis
≻ PPV = pneumococcal polysaccharide vaccine
≻ PRO = patient-reported outcome
≻ QMT = quantitative muscle testing
≻ QoL = quality of life
≻ RBP = ribonucleoproteins
≻ RBPs = RNA-binding proteins
≻ RCT = randomized control trial
≻ rKLRG1 = Rat KLRG1
≻ ROS = Reactive oxygen species
≻ Rrna = ribosomal RNA
≻ RV = rimmed vacuoles
≻ SLE = Systemic lupus erythematosus
≻ T-LGLs = T-cell large granular lymphocytes
≻ TCR = T cell receptor
≻ TDP-43 = TAR DNA-binding protein 43 kDa
≻ THC = delta-9-tetrahydrocannabinol [marijuana]
≻ TNF-α = Tumor necrosis factor α
≻ Tregs = Regulatory T cells
≻ TUG = timed up & go test
≻ ULN = upper limit of normal.
≻ VC = Vital capacity.
≻ VFSS = video fluoroscopic swallowing study
≻ VO 2 = peak peak oxygen uptake
≻ VSMCs = vascular smooth muscle cells
≻ WFFM = whole-forearm flexor muscle