⚀ 5. Causes and Research.

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⚁ 5.1      Current Research on IBM.

⚂ 5.1.2      Historical research.

⚁ 5.2      General Muscle Research.

⚁ 5.3      Causes of IBM.

⚁ 5.4      IBM Research: Focus and Reviews.

⚂ 5.4.1       Focus of IBM research.

⚂ 5.4.2       Major reviews.

⚂ 5.4.3       Major themes.

⚂ 5.4.4       The role of TDP-43 in IBM.

⚂ 5.4.5       Mitochondrial pathology in IBM.

⚂ 5.4.6       2025 Graphical Overview.

⚂ 5.4.7       Snapshot: An autoimmune or myodegenerative disease? 2022

⚁ 5.5      Functional assessment of IBM.

⚁ 5.6      Common abbreviations in IBM research.

⚁ 5.2  General Muscle Research.

⚂ Muscles are very complex systems and research into their basic structures and functions continues.

⚂ The causes of some muscle diseases (like IBM) are unknown and in turn, few specific treatments are available.
≻ Until more specific treatments are developed, researchers are looking into trying to develop general approaches to enhance muscle function.

⚂ If researchers could boost muscle function it might be possible to offset the effects of the different muscle diseases.
≻ The underlying muscle disease will not be treated, but with more muscle being produced, the overall impact of the disease may be reduced.
≻ Even a small increase in function could be significant to the patient having one of these illnesses.
≻ An example of this approach is a drug called Bimagrumab.
≻ This drug has been used to try to produce more muscle in various conditions.
≻ A report says it' s safe to use but did not appear to work in IBM: See: (Hanna et al., 2019).

⚁ 5.3  What goes wrong?

⚁ The science behind the possible causes of IBM is extremely complex and very challenging to put into understandable, everyday language.
≻ It’s very important to me to be careful not to create any confusion or misunderstandings.
≻ We can say that there are several major abnormalities seen in IBM:
– there are autoimmune issues,
– problems seen in mitochondria,
– and degenerative aspects involving proteins.

⚁ 5.4  IBM Research: Focus and Reviews.

⚂ 5.4.1 Focus of IBM research:
≻ Research specifically focused on IBM attempts to understand what causes the disease and how it unfolds.
≻ Currently, IBM research concentrates on three primary areas:
   ≻≻ The role of abnormal proteins seen in IBM,
   ≻≻ The role of autoimmunity in IBM,
   ≻≻ The role of Mitochondrial abnormalities in IBM.
≻ IBM is a very complex and challenging disease to research.
≻ New techniques (Multiomic and transcriptomic approaches) are being used to shed light on IBM and have the potential to create new biomarkers (to help in diagnosis) and help understand what causes IBM.
≻ Genetic predisposition is a significant factor.
≻ Research on Treatment:
   ≻≻ Most research on the treatment of IBM has looked at using existing medications and examining their impact on IBM.
   ≻≻ Specific new drugs are also being developed and tested (for example, the anti-KLRG1 antibody – Ulviprubart – is now in clinical trials for IBM).

⚂ 5.4.2 Major reviews:

⚂       2025 Review Article (Naddaf).

⚂       2025 Review Article (Krause, Ruck, & Kleefeld).

⚂      A 2024 review article: Anderson and Lloyd.

⚂      A 2022 review article: Naddaf, 2022. [pdf]

⚂      A 2022 review article from the Muscular Dystrophy Association (MDA).

⚄      As a pdf download.

⚂      A 2021 review article: Snedden, 2021. [pdf]

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⚂ 5.4.4 The role of TDP-43 in Inclusion Body Myositis Pathogenesis.

Recent research reported by Chizari, 2025, indicates that issues with a protein called TDP-43 might be an early, inherent step in the development of IBM. These TDP-43 abnormalities appear closely linked to chronic inflammation, mitochondrial dysfunction, and protein aggregation, and may help drive these downstream changes, although the exact sequence of events is still being clarified.

⚃  5.4.4.1      Overview in layperson's terms.

⚃  5.4.4.2      A more technical explanation.

⚃ 5.4.4.3      Key References on TDP-43.

⚃ 5.4.4.4      Extensive References on TDP-43 (pdf).

⚃ 5.4.4.1 Overview in layperson's terms.

⚄ Summary

⚅ Inclusion body myositis is thought to arise from several interacting factors, including a person’s genetic makeup, age-related changes in the immune system, and the gradual breakdown of normal cellular processes.
≻ Research from both muscle and brain studies suggests that defects in a protein called TDP-43 may be an early and important step in the development of IBM.
≻ Problems with TDP-43 are closely linked to long-lasting inflammation, mitochondrial energy-production problems, and clumps of abnormal protein seen in IBM.
≻ TDP-43 may help set these changes in motion, but the exact order in which they occur is still unknown, and it is not yet clear how or why this protein begins to malfunction.
≻ Even so, focusing on TDP-43 is helping researchers move a step closer toward understanding how IBM develops.

⚅ TDP-43 is a protein that normally spends most of its time in the cell’s nucleus, where it helps manage how many different RNA messages are processed and used to make proteins, acting as a kind of quality-control factor.
≻ In IBM, TDP-43 becomes abnormal and is lost from the nucleus, which allows faulty RNA processing and the production of unusual protein fragments, sometimes called “cryptic” products.

⚅ These abnormal proteins can accumulate in the nucleus and spread into the surrounding cytoplasm, where they clump and interfere with normal cell function, contributing to muscle-fibre damage.
≻ At the same time, abnormal TDP-43 can enter mitochondria and damage them, disrupting their normal function and reducing energy production, adding another layer of stress on already vulnerable muscle cells.

⚄ Some background:

⚅ TDP-43 is found in the cell’s central nucleus, where much of the process of reading genes and preparing instructions for protein creation occurs.
≻ You can think of TDP-43 as a quality-control supervisor for genetic messages (RNA).
≻ Its main role is to review these messages to ensure they are correctly edited, keeping the useful parts and removing unnecessary ‘nonsense’ segments (called cryptic exons).
≻ It also assists in transporting these messages to the appropriate locations within the cell and maintains their stability until they are utilized.
≻ In other words, TDP-43 verifies the blueprints for protein production to ensure their accuracy before the cell begins building.

⚄ What goes wrong in IBM:

⚅ In IBM, something goes wrong with TDP-43 in the muscle cell.
≻ Instead of staying in the nucleus and checking the genetic ‘blueprints,’ it leaks out into the fluid part of the cell (the cytoplasm) and starts to stick together in clumps.
≻ These clumps interfere with normal cell activity and are among the early signs that the muscle fibre is in trouble.
≻ As TDP-43 is lost from the nucleus, the cell also loses its ‘quality-control manager’: the genetic messages are not edited properly, nonsense sections (called ‘cryptic exons’) are accidentally left in, and these faulty blueprints lead to the production of abnormal proteins.

⚅ These abnormal proteins can be mistaken by the immune system for ‘foreign’ material and are sometimes called neoantigens, meaning new or altered targets the body has not seen before.
≻ When this happens, immune cells attack the affected muscle cells, triggering inflammation, ongoing damage, and, eventually, their death.

⚄ Malfunction Part A and Part B:

⚅ This sets up a two-part malfunction.
≻ In Part A, the faulty, abnormally manufactured proteins act as neoantigens, which trigger the immune system and also promote the build-up of abnormal protein clumps inside the muscle cell.
≻ In a separate but related problem, Part B, misdirected TDP-43 moves into the mitochondria and interferes with their work, impairing the cell’s ability to produce energy.

⚄ The Antigens:

⚅ The many: When TDP-43 fails, it disrupts the splicing of many different genes, sometimes dozens or even hundreds.
≻ Each error can, in theory, create a small ‘alien’ protein fragment that the body has never seen before.
≻ These strange-looking proteins are called neoantigens (new antigens).
≻ Together, they form a whole group of potential neoantigens that the immune system can mistake for foreign material and attack.

⚅ The one: A 2025 study by Chizari and colleagues found that, among all these possible neoantigens, the immune system responds most strongly and consistently to a single one derived from the HDGFL2 gene.
≻ In IBM muscle, the T cells that recognize this HDGFL2-derived neoantigen are the same highly activated cells that carry the KLRG1 ‘badge,’ suggesting that this particular abnormal protein fragment may be a key driver of the ongoing immune attack.

⚅ So, in simple terms, when TDP-43 is not working properly in the center of the cell and is no longer supervising protein construction, the HDGFL2 gene can produce a damaged, ‘mutilated’ version of its usual protein.
≻ The muscle cell then displays a piece of this ‘alien’ HDGFL2 protein on its surface, like waving a red flag.
≻ This process is called antigen presentation through MHC-I.
≻ Current research suggests that this HDGFL2-derived fragment is a particularly important neoantigen in IBM that helps signal the immune system that something is wrong.

⚄ The Attack:

⚅ Because these abnormal proteins appear foreign, the immune system treats the muscle cell as if it were infected and initiates a targeted, sniper-like attack using CD8⁺ T cells to eliminate it.
≻ In IBM, many of the CD8⁺ T cells attacking the muscle are not typical; they are highly specialized, battle-hardened ‘old veteran’ cells called T-LGLs (T-cell Large Granular Lymphocytes), which carry a distinctive surface marker, or ‘badge,’ known as KLRG1, indicating they are powerful, long-lived killer cells.
≻ Normal, healthy T cells (the young rookies) usually do not have this badge.

⚄ Muscle weakness and fatigue.

⚅ There are two forces that weaken the muscle.
≻ One, the progressive loss of muscle cells reduces the available volume of fibre to produce strong contractions.
   ≻≻ This is permanent structural loss; once those muscle cells are destroyed, they are replaced by fat and they are gone for good.
≻ And second, blockage in real-time of the mitochondrial energy cycles reduces available energy. In other words, in the remaining muscle cells that are still alive, the mitochondria are being sabotaged by TDP-43 blocking the normal production of energy.

⚅ Different types of fatigue.
≻ We have to be clear when we use the word fatigue because it means different things to different people.
≻ We often say that we have fatigue when we’re tired or that fatigue happens when we rest and sleep but we don’t feel better or rested afterwards. But there’s also a different kind of meaning to fatigue when applied to muscles.

⚅ 1. The “Brownout” Effect:
≻ Fatigue is different from simple weakness. Weakness is “I cannot lift this weight.” Fatigue is “I can lift it once, but I feel completely drained immediately after.”
≻ Mitochondria are responsible for generating ATP, the chemical “fuel” for every muscle contraction.
≻ In IBM, the TDP-43 invasion (Path B) specifically blocks Complex I of the electron transport chain. This creates a bottleneck in energy production.
   ≻≻ When a patient tries to move, their muscles are operating in a state of “energy brownout.” The demand for ATP outstrips the supply, leading to that heavy, exhausted sensation known as peripheral fatigue.

⚅ 2. Why it’s not just “laziness” or “aging”:
≻ Patients (and Doctors) often blame being out of shape (I had a Doctor tell me that I “was fat and 40 and should find the gymnasium”).
≻ Understanding that our cellular power plants have been sabotaged validates that our fatigue is physiological, not psychological. It is a direct result of the “Energy War” inside our cells.

⚅ While this explains muscle fatigue perfectly (legs feeling like lead), “general” fatigue (brain fog, sleepiness) can also be compounded by respiratory muscle weakness or the systemic burden of chronic inflammation (Path A cytokines circulating in the blood). But the specific sensation of muscular exhaustibility is classic mitochondrial failure.

⚄ Implications for treatment:

⚅ This discovery indicates that truly effective treatment will probably require a two-pronged approach:
≻ (1) decreasing the specific immune attack with more precisely targeted drugs, and
≻ (2) tackling the root cause by restoring normal TDP-43 function in the nucleus.
≻ Ulviprubart is an antibody designed to target cells carrying the KLRG1 ‘badge.’
≻ The idea is that if these attackers are removed, muscle cells may remain stressed and dysfunctional, but they will not be destroyed as rapidly.
≻ However, this strategy targets only one aspect of the problem.
≻ It does not fix the underlying TDP-43 dysfunction or the related mitochondrial defects.
≻ As researchers develop a clearer understanding of the key antigen targets and the role of TDP-43, it could become possible to develop more precise treatments that restore nuclear TDP-43 function and cellular health, rather than merely suppressing the immune response.

⚄ Why this new work by Chizari is significant:

⚅ This discovery helps unify the ‘degenerative’ and ‘inflammatory’ views of IBM by showing that the immune response is a focused, adaptive attack on muscle fibres carrying TDP-43-related abnormalities, rather than a random or nonspecific inflammation.
≻ It also offers a coherent explanation for mitochondrial dysfunction in IBM, as misdirected TDP-43 can directly damage mitochondria and disrupt energy production.
≻ Taken together, these findings support the idea that TDP-43 pathology is a central initiating step in IBM, even though the original reason TDP-43 becomes defective remains unknown.

⚄ Other TDP-43 protein diseases:

⚅ Amyotrophic lateral sclerosis (ALS): TDP-43 pathology is seen in the vast majority of ALS cases and is a key factor driving the loss of motor neurons, the nerve cells that control movement.
≻ Alzheimer’s (AD): In typical AD, inflammation is often viewed as a more general clean-up response to amyloid plaques and tau tangles. About half of people with Alzheimer’s-type dementia, however, also show TDP-43 pathology, and in these cases, cryptic peptides from genes such as HDGFL2 can be detected and may help flag affected brain cells for a more targeted immune response. This raises the possibility that, in some AD patients, a more ‘sniper-like’ immune process similar to that seen in IBM and ALS could contribute to faster loss of vulnerable brain cells, although this idea is still being actively investigated.

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⚃ 5.4.4.2 A more technical explanation.

⚄ Overview. Current work on TDP-43 focuses on how its misfolding, nuclear depletion, and cytoplasmic aggregation drive neurodegenerative and neuromuscular disease, including ALS, frontotemporal dementia, and IBM.
≻ Researchers are dissecting early toxic mechanisms (loss of RNA-processing functions, cryptic exon inclusion, stress-granule-related aggregation, mitochondrial and chromatin effects) and how these propagate between cells.
≻ Parallel efforts are developing disease-modifying therapies that prevent or reverse TDP-43 aggregation, restore nuclear localization, or correct downstream RNA mis-splicing, along with biomarker strategies to track TDP-43 pathology in vivo.

⚅ Aggregation and nuclear depletion of the RNA binding protein TDP-43 are the crucial pathological features of amyotrophic lateral sclerosis (ALS) and inclusion body myositis (IBM), two degenerative diseases of the CNS and muscle.
≻ The loss of TDP-43 nuclear function results in the aberrant inclusion of cryptic exons in mRNA transcripts, leading to the expression of de novo proteins.
≻ Clonally expanded and highly differentiated CD8 + T cells have been observed in individuals with TDP-43 proteinopathies and therapeutics modulating the T cell response have recently been found to extend survival. …
≻ This work identifies for the first time specific T cell antigens in ALS and IBM, directly linking adaptive immune response to TDP-43 pathology. …
≻ Overall, our result confirms that TDP-43 cryptic peptides could be processed, loaded to MHC class I molecules, and presented on the surface of neural cells, which is in turn recognized by crypticepitope specific TCRs.
≻ It also signifies that neural cells are susceptible to CD8 + T cell mediated killing, and further implicates CD8 + T cells in the pathogenesis of TDP-43 proteinopathies. …
≻ The consistent and widespread detection of HDGFL2 cryptic peptide in CSF, plasma, brain, and muscle supports its role as a potentially strong target for an adaptive immune response.
≻ Our findings show that it can induce T-cell mediated cell death and support a potential active role in the degenerative process.…
≻ Altogether, our data demonstrate a previously unknown pathological arm in TDP-43 proteinopathies where the adaptive immune system can be activated through MHC class I antigen presentation pathway, initiating from TDP-43 loss and support the rationale for immune-targeted therapies for TDP-43 proteinopathies. (Chizari et al., 2025).

⚅ The understanding of TAR DNA-binding protein 43 (TDP-43) in Inclusion Body Myositis (IBM) has evolved considerably between 2020 and 2025.
≻ The consensus has shifted from viewing TDP-43 as a passive aggregate within the cell’s fluid (the cytoplasm) to recognising it as a primary driver of IBM disease pathology.
≻ Specifically, the loss of TDP-43 from the cell’s centre (the nucleus) results in the loss of its essential role in the cell – to act as a quality control supervisor during protein production.
   ≻≻ It accomplishes this by detecting specific defects in the manufacturing process known as “cryptic exons.”
≻ When TDP-43 is not functioning properly, these cryptic exons remain in the genetic message, leading to the production of defective proteins.
≻ In a significant 2025 breakthrough (Chizari et al., 2025), these cryptic exons have been identified as the source of neoantigens (new antigens) that trigger the characteristic CD8+ T-cell attack observed in IBM muscles.
≻ This finding also bridges the gap between the older degenerative and inflammatory theories of IBM, demonstrating that the immune response is a specific, adaptive attack on muscle fibres exhibiting TDP-43-associated abnormalities.
≻ This means we can describe IBM as a disease rooted in a protein malfunction (TDP-43), with immune and mitochondrial factors as consequences.

A proteinopathy (or proteopathy) is a disease caused by abnormal or misfolded proteins that disrupt normal cell, tissue, or organ function.

⚅ The current literature places TDP-43 upstream in the IBM pathogenic cascade, initiating a “dual-hit” mechanism of intrinsic muscle degeneration and secondary inflammation.

⚄ Major Defects.

⚅ Nuclear Loss of Function (Primary Degenerative Event)
≻ Under normal (homeostatic) conditions, TDP-43 resides in the nucleus and suppresses the splicing of non-conserved “cryptic exons,” short “junk” sequences hidden within the genetic code that are normally ignored, but are mistakenly included in the final instruction manual (RNA) when TDP-43 is missing.
≻ In IBM, TDP-43 is lost from the nuclei of muscle cells and finds its way to the sarcoplasm (the muscle cell’s fluid), where it forms clumps.
≻ This nuclear clearance is now regarded as the key pathogenic step in IBM, occurring even in muscle fibres that lack visible rimmed vacuoles.

⚅ Splicing Defects and Cryptic Neoantigens (The Molecular Bridge)
≻ The depletion of nuclear TDP-43 causes a failure in genetic editing (the blueprints are wrong), leading to the inclusion of these cryptic exons in mRNA transcripts.
≻ Biomarker Revolution: Recent studies establish cryptic exon inclusion (e.g., in the UNC13A gene) as a highly sensitive (84%) and specific (99%) biomarker for IBM, distinguishing it from other myopathies like polymyositis or dermatomyositis.
≻ Creation of Neoantigens: The groundbreaking findings of Chizari et al., 2025 confirm that these incorrect transcripts are translated into proteins that the immune system sees as “non-self” (cryptic peptides), most notably, protein from the HDGFL2 gene.

⚅ Targeted Autoimmunity (The Inflammatory Response)
≻ Previously debated as a secondary or “scavenger” response, the T-cell infiltration is now understood as a targeted attack on these abnormal proteins.
   ≻≻ The cryptic peptides generated by TDP-43 dysfunction are processed and presented on the muscle fiber surface via MHC Class I molecules.
   ≻≻ This presentation transforms the muscle fiber into a target for cytotoxic CD8+ T cells, which recognize these peptides as neoantigens (Chizari et al., 2025).
≻ This finding explains why immunosuppression alone fails: it targets the downstream symptom (inflammation) without addressing the upstream generator of antigens (TDP-43 dysfunction).

⚅ Cytoplasmic Aggregation
≻ At the same time, mislocalized TDP-43 forms phosphorylated, ubiquitinated protein aggregates in the sarcoplasm.

⚅ Mitochondrial Dysfunction
≻ Cytoplasmic TDP-43 invades and accumulates within mitochondria, disrupting oxidative phosphorylation complexes (particularly I and III) and driving mitochondrial DNA damage.
≻ Wang et al. (2016) showed that TDP-43 contains “internal mitochondrial localization motifs” (specific codes in its protein structure) that act like a VIP pass, allowing it to pass through the mitochondrial membranes.
   ≻≻ Once inside, it resides in the inner mitochondrial membrane (facing into the matrix of the mitochondrion).
   ≻≻ From here, it is in an ideal position to bind to mitochondrial RNA (specifically ND3 and ND6 transcripts), blocking the assembly of Complex I, which directly causes energy failures.
   ≻≻ This same mitochondrial invasion has also been shown to occur in ALS, occurring within motor neuron cells.
≻ This directly links TDP-43 to the mitochondrial abnormalities (COX-negative fibers) classically seen in IBM (Huntley et al., 2019).
≻ Yu et al., 2020 showed that when TDP-43 enters the mitochondria, it causes the “permeability transition pore” (mPTP) to open. This allows mitochondrial DNA to leak out into the cytoplasm, which triggers inflammation (the cGAS/STING pathway).
≻ Prion-like Seeding: Sarcoplasmic TDP-43 in IBM possesses “seeding” capacity, capable of inducing further aggregation in a prion-like manner, a feature distinct to IBM among muscle diseases (Lynch & Weihl, 2024).

⚄ Areas of Debate and Controversy.

⚅ Therapeutic Targets While the “neoantigen” theory suggests that halting TDP-43 nuclear loss could stop the inflammation, earlier xenograft studies (2022) showed that depleting T cells did not halt TDP-43 pathology (Lynch & Weihl, 2024). This supports the view that while inflammation exacerbates the disease, the core degenerative machinery is self-perpetuating. The 2025 consensus suggests that effective therapy must likely restore nuclear TDP-43 function rather than simply suppress the immune system.

⚅ Triggering Event The initial trigger for TDP-43 nuclear export remains unknown. Hypotheses range from aging-related nuclear pore defects to viral triggers (e.g., retroviral activation), but no consensus exists on the “Patient Zero” event that starts the cascade (Krause et al., 2025).

⚄ Background on TDP-43.

⚅ TDP-43 (Transactive Response DNA Binding Protein 43)
≻  What it is: TDP-43 is a protein that is absolutely essential for life and is found in almost every cell in your body, primarily inside the nucleus. It is highly “conserved,” meaning its structure has remained largely unchanged throughout evolution, highlighting its critical biological importance.
≻ What it does: Think of TDP-43 as a quality control manager for genetic messages. Its main job is to bind to RNA (the messenger molecule that carries genetic instructions) and ensure it is processed correctly.
   ≻≻ Splicing: It helps “edit” genetic messages by ensuring the right parts are kept and the wrong parts (cryptic exons) are removed.
   ≻≻ Transport: TDP-43 helps move these messages to the right place in the cell.
   ≻≻ Stability: TDP-43 ensures the messages don’t fall apart before they can be used.

⚅ When TDP-43 stops working correctly, it leaves the nucleus (where it belongs) and clumps up in the main part of the cell (cytoplasm). This causes a double problem:
≻ 1. Loss of Function: The nucleus loses its quality control manager, leading to “bad” edits (like cryptic exons) in genetic messages.
≻ 2. Toxic Clumping: The clumps in the cytoplasm gum up cellular machinery and become toxic to the cell.

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⚃ 5.4.4.4. Key References

⚄ Britson, K. A., Mohassel, P., & Mammen, A. L. (2025). Loss of TDP-43 splicing repression occurs in myonuclei of inclusion body myositis skeletal muscle. Annals of Neurology, 97(3), 629-641. https://doi.org/10.1002/ana.27167

⚄ Chizari, S., Zanovello, M., Saigal, V., & Lloyd, T. E. (2025). TDP-43 pathology induces CD8+ T cell activation through cryptic epitope recognition. The Journal of Immunology, 215(Supp. 1), 283.99. https://doi.org/10.1093/jimmun/vkaf283.992

DOWNLOAD CHIZARI PDF.

⚄ De Boer, E. M. J., Orie, V. K., Williams, T., Baker, M. R., De Oliveira, H. M., Polvikoski, T., Silsby, M., Menon, P., Van Den Bos, M., Halliday, G. M., Van Den Berg, L. H., Van Den Bosch, L., Van Damme, P., Kiernan, M. C., Van Es, M. A., & Vucic, S. (2021). TDP-43 proteinopathies: A new wave of neurodegenerative diseases. Journal of Neurology, Neurosurgery & Psychiatry, 92(1), 86-95. https://doi.org/10.1136/jnnp-2020-322983

⚄ Huntley, M. L., Mendoza, C. S., & Weihl, C. C. (2019). Association between TDP-43 and mitochondria in inclusion body myositis. Acta Neuropathologica Communications, 7, 114. https://doi.org/10.1186/s40478-019-0766-6

⚄ Krause, K., Ruck, T., & Kleefeld, F. (2025). Inclusion body myositis – what are new lines of pathogenesis and therapy? Current Opinion in Neurology. https://doi.org/10.1097/WCO.0000000000001393

⚄ Lynch, E. M., & Weihl, C. C. (2024). Seeding-competent TDP-43 persists in human patient and mouse muscle after clearance of macro-aggregates. Science Translational Medicine, 16(775). https://doi.org/10.1126/scitranslmed.adp5730

⚄ Needham, M. (2025). Inclusion body myositis – what are new lines of pathogenesis? Current Opinion in Neurology, 38(5), 1-9. https://doi.org/10.1097/wco.0000000000001393

⚄ Wang, W., Wang, L., Lu, J., Siedlak, S. L., Fujioka, H., Liang, J., Jiang, S., Ma, X., Jiang, Z., Da Rocha, E. L., Sheng, M., Choi, H., Lerou, P. H., Li, H., & Wang, X. (2016). The inhibition of TDP-43 mitochondrial localization blocks its neuronal toxicity. Nature Medicine, 22(8), 869-878. https://doi.org/10.1038/nm.4130

⚄ Yu, C. H., Davidson, S., Harapas, C. R., Hilton, J. B., Mlodzianoski, M. J., Laohamonthonkul, P., Louis, C., Low, R. R. J., Moecking, J., De Nardo, D., Balka, K. R., Calleja, D. J., Moghaddas, F., Ni, E., McLean, C. A., Samson, A. L., Tyebji, S., Tonkin, C. J., Bye, C. R., … Masters, S. L. (2020). TDP-43 Triggers Mitochondrial DNA Release via mPTP to Activate cGAS/STING in ALS. Cell, 183(3), 636-649.e18. https://doi.org/10.1016/j.cell.2020.09.020

⚃ Extensive References.      Extensive References on TDP-43 (pdf).

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⚂ 5.4.5       Mitochondrial pathology in IBM.

⚁ 5.1 Current Research News on IBM.

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

(Because of the way articles come out, there is some overlap between years.)

2026

2025

⚂  Tillier: Synopsis of 2025 research.

⚂ Mayer, T., Scholle, L., Foerster, L., Schneider, I., Stoltenburg-Didinger, G., Delank, K., Kendzierski, T., Koelsch, A., Kleeberg, K., Kraya, T., Barba, L., Naegel, S., Schänzer, A., Otto, M., & Mensch, A. (2025). Alpha-Synuclein as a Potential Biomarker for Inclusion Body Myositis in Blood and Muscle. Neuropathology and Applied Neurobiology, 51(3), e70019. https://doi.org/10.1111/nan.70019

⚃ The proportion of fibres with αSN immunoreactivity was significantly higher in IBM compared to all groups (p less than 0.001) and discriminated IBM against all other neuromuscular disorders with a sensitivity of 79% and a specificity of 85%, which further improved when only non-regenerating fibres were examined. In serum, SN concentrations in IBM were generally not different from healthy controls. However, serum concentrations were inversely correlated with disease duration (r=-0.62, p=0.04) and positively correlated with the IBM functional rating scale (r=0.74, p=0.01). Consequently, stratification according to these clinical parameters showed significantly lower serum αSN concentrations in late-stage, more severely affected patients.
≻ Conclusions: αSN reactivity may serve as an additional immunohistochemical marker for IBM diagnosis. Furthermore, this study indicates that αSN serum concentrations decrease with disease duration and clinical deterioration. Therefore, serum αSN may be provisionally considered a monitoring biomarker in IBM, pending further studies.

⚃ There is a need for valid biomarkers to support the diagnosis of IBM, especially in the early stages of the disease. In this respect, our study is the first to investigate the diagnostic ability of αSN to differentiate IBM from other neuromuscular disorders, particularly other forms of IIM and (hereditary) myopathies that show inflammation and rimmed vacuolar pathology and thus may mimic IBM.
≻ In conclusion, this study provides evidence for the use of αSN immunostaining in the diagnosis of IBM. αSN immunoreactivity may complement the established set of histological markers already used in clinical practice for the diagnosis of IBM. Furthermore, this study suggests reduced serum αSN concentrations as a candidate monitoring biomarker for IBM and encourages future (longitudinal) studies to elucidate the potential pathological role of αSN in muscle diseases and its applicability as a biomarker.

⚂ Murphy, A., Mak, G., Gordon, K., Grafham, G. K., Provias, J., Tarnopolsky, M. A., & Lu, J.-Q. (2025). Muscle mitochondrial changes in antisynthetase syndrome and other idiopathic inflammatory myopathies. Journal of Neuropathology & Experimental Neurology, nlaf136. https://doi.org/10.1093/jnen/nlaf136

⚃ The ASyS group had higher serum creatine kinase levels and showed prominent mitochondrial abnormalities similar to IBM and greater than the DM group. While all IIM groups displayed conventional mitochondrial changes, including ultrastructural abnormalities with cristae alterations, paracrystalline inclusions were exclusive to IBM and ASyS. There were significantly more rod-like filamentous inclusions adjacent to mitochondria in the IBM and ASyS groups, compared to the DM group. Intra-mitochondrial filament aggregates with focal formation of inclusions were also identified in individual ASyS and IBM patients, suggesting a link between the mitochondrial filamentous inclusions and nuclear and/or cytoplasmic filamentous inclusions. These findings suggest that mitochondrial abnormalities, particularly in ASyS and IBM, may contribute to the pathogenic process and clinical manifestations of the disease.
≻  First, this is the first study to characterize muscle mitochondrial abnormalities in ASyS patients. The abnormalities in ASyS are similar to those in IBM and more prominent than those in DM patients.
≻ Second, in addition to AMS and AMC, which are observed across all 3 IIM groups, PCI [paracrystalline inclusions] were found exclusively in IBM and ASyS groups.

⚂ Dobbertin, T., & Schirmer, L. (2025). Spatially Resolved Profiling of Compartmentalized Muscle and Brain Inflammation. European Journal of Immunology, 55(12), e70119. https://doi.org/10.1002/eji.70119

⚃ We present and discuss recent studies that leveraged spatial profiling to gain systems-level insights into organized tissue compartments in the context of chronic inflammation. These examples underscore the power of spatial approaches in elucidating niche-specific mechanisms of immune crosstalk and tissue remodeling in both health and disease.

⚃ Skeletal muscle is a highly specialized and structurally organized tissue composed of diverse cell types, including innervated myofibers, fibroblasts (Fb), endothelial cells (EC), pericytes, resident and infiltrating immune cells, and muscle stem/progenitor cells (Figure 2). The myofibers, consisting of multinucleated, contractile cells expressing myosin heavy chain (MYH), serve as the primary functional units of muscle tissue. These fibers exhibit functional heterogeneity, with distinct MYH isoforms defining different fiber types: “slow” oxidative Type 1 fibers express MYH7, while the “fast” but more fatigue-prone Type 2 fibers express isoforms such as MYH2, MYH4, and MYH1. Myofibers also differ in metabolic properties, with Types 1 and 2A being oxidative and Types 2B and 2X primarily glycolytic. The spatial organization of skeletal muscle is equally critical to its function. Myofibers are ensheathed by the endomysium, grouped into fascicles surrounded by the perimysium, and embedded within a hierarchical extracellular matrix. … Taken together, the integration of spatial data revealed emerging myocyte and FAP cell states during muscle regeneration and inflammatory signals radiating from injury zones to healthy tissue, promoting pervasive fibrosis.
≻ In skeletal muscle, spatially resolved profiling has already advanced our understanding of fiber-type heterogeneity, regenerative dynamics, and immune-stromal-vascular crosstalk in both health and disease.

⚂ Da Silva Guimarães, B. L., De Souza, L. C., & Fujihara, M. T. F. (2025). Inspiratory Muscle Training for Weaning. In A. R. Baptistella, D. L. Borges, & L. F. D. F. Reis (Eds.), Weaning from Mechanical Ventilation (pp. 245-252). Springer Nature Switzerland. https://doi.org/10.1007/978-3-032-01145-9_17

⚃ Inspiratory muscle weakness has been associated with difficulty weaning from the ventilator, and the degree of weakness correlates with the duration of MV. MV is known to increase proteolysis and promote diaphragmatic atrophy. Thus, diaphragm weakness is considered one of the major causes of difficulty and prolongation of mechanical ventilation. … However, these studies collectively suggest that IMT for weaning is safe and feasible in critically ill patients, may improve inspiratory muscle strength and quality of life, and may lead to better clinical outcomes such as successful weaning and increased survival rates.

⚂ Herring, S. K., & Rodgers, B. D. (2025). Murine toxicology assessment of avgn7.2, a novel gene therapeutic for inclusion body myositis and other muscle wasting diseases. Gene Therapy. https://doi.org/10.1038/s41434-025-00578-x

⚃ AVGN7.2 is a novel gene therapeutic that attenuates activin receptors through muscle-specific human (h) SMAD7 expression and as part of its preclinical development, we performed a 91-day single-dose toxicology assessment of systemic safety, biodistribution and immunogenicity in accordance with Good Laboratory Practices.

⚂ Kaiser, M., Parikh, M. A., Turitto, G., Frishman, W. H., & Peterson, S. J. (2025). Bimagrumab: Novel medical therapy for inclusion body myositis, sarcopenia, and medication-induced lean body mass loss. Cardiology in Review. https://doi.org/10.1097/CRD.0000000000001113

⚃ Bimagrumab is a monoclonal antibody that targets activin type II receptors, blocks myostatin and related proteins: it promotes muscle growth and prevents muscle loss, while causing weight loss.
≻ It has been effective in sporadic inclusion body myositis with promising results, a disease that had no previous effective therapy.

⚃ It has recently been used in combination with semaglutide, a glucagon-like peptide-1 receptor agonist administered weekly as a subcutaneous injection for weight loss.
≻ Semaglutide reduces appetite, slows gastric emptying, and improves glucose regulation.
≻ As much as 40% of weight loss may come from lean body mass, primarily skeletal muscle, raising concerns about sarcopenia.
≻ Bimagrumab is a promising solution to counter the muscle-wasting effects of semaglutide.
≻ We review the development of bimagrumab, its mechanism of action, clinical trial results, and the safety profile.

⚃ Bimagrumab is a monoclonal antibody that targets the activin type II receptor, facilitating muscle gain and fat loss.
≻ It increases lean mass by 4-7% and decreases fat mass by 10-25% in clinical studies of sIBM, sarcopenia, or obesity with type 2 diabetes.
≻ The potential to combine with other modalities makes bimagrumab an interesting addition for individuals with a high risk of developing musclewasting.

⚂ Chizari, S., Zanovello, M., Kong, S., Saigal, V., Brown, A. L., Turchetti, V., Zampedri, L., Skorupinska, I., Minicuci, G. M., Paron, F., Tonin, P., Marchetto, G., Li, Z., Colón-Mercado, J. M., Dattilo, D., Barattucci, S., Gatt, A., Qi, A., Hanna, M., … Jiang, N. (2025). TDP-43 pathology induces CD8+ T cell activation through cryptic epitope recognition. Immunology. https://doi.org/10.1101/2025.06.22.660773

Chizari, S., Zanovello, M., Kong, S., Saigal, V., Brown, A. L., Turchetti, V., Zampedri, L., Skorupinska, I., Minicuci, G. M., Paron, F., Tonin, P., Marchetto, G., Li, Z., Colón-Mercado, J. M., Dattilo, D., Barattucci, S., Gatt, A., Qi, A., Hanna, M., … Jiang, N. (2025). TDP-43 pathology induces CD8+ T cell activation through cryptic epitope recognition. bioRxiv, 2025.06.22.660773. DOWNLOAD PDF.

⚃ Abstract Aggregation and nuclear depletion of the RNA binding protein TDP-43 are the crucial pathological features of amyotrophic lateral sclerosis (ALS) and inclusion body myositis (IBM), two degenerative diseases of the CNS and muscle. The loss of TDP-43 nuclear function results in the aberrant inclusion of cryptic exons in mRNA transcripts, leading to the expression of de novo proteins. Clonally expanded and highly differentiated CD8 + T cells have been observed in individuals with TDP-43 proteinopathies and therapeutics modulating the T cell response have recently been found to extend survival. However, the target antigens mediating T cell activation have remained elusive. Here, we investigate whether the de novo proteins induced by aberrant cryptic splicing due to TDP-43 nuclear loss can act as neo-antigens. We detect the HDGFL2 cryptic peptide and multiple other TDP-43 cryptic exons in IBM skeletal muscle, where their presence correlates with enrichment of T cells and class I antigen presentation pathways. Furthermore, we identify epitopes deriving from HDGFL2 and IGLON5 cryptic peptides which are recognized by clonally expanded and functionally differentiated populations of CD8 + T cells in ALS and IBM Patients. Finally, we demonstrate that T cells engineered to express the identified TCRs can bind and activate in response to the cryptic peptide derived epitopes (cryptic epitopes) and are able to kill TDP-43 deficient astrocytes. This work identifies for the first time specific T cell antigens in ALS and IBM, directly linking adaptive immune response to TDP-43 pathology.

⚃ Discussion ALS and IBM are both disorders where TDP-43 proteinopathy represents the predominant pathology. Recently, highly differentiated and clonal CD8 + T cells have been observed in ALS and IBM. However, their antigen targets and their potential role in ALS and IBM have remained elusive. TDP-43 loss of function leads to the generation of cryptic peptides, which are foreign to the human immune system as the encoding cryptic exons do not exist in the human thymus, raising the possibility that T cells recognizing these peptides are retained. In this study, we highlight significant disease specific expression of HDGFL2 cryptic peptide in IBM skeletal muscle tissue co-localized with TDP-43 nuclear loss using IHC in addition to an increase of T cell infiltrates and MHC class I antigen presentation pathways through RNA sequencing and proteomics. We further identify clonally expanded and highly differentiated CD8 + T cell clones which recognize epitopes derived from these cryptic peptides using a high-throughput and multi-dimensional integrated single T cell profiling platform we previously developed. Finally, we show that activated CD8+ T cells have the capacity to kill astrocytes with TDP-43 loss through cryptic-specific TCR recognition.
≻ Modulating adaptive immunity may have the potential to improve clinical outcomes in TDP-43 proteinopathies. … A phase II/III clinical trial is evaluating the use of an anti-KLRG1 antibody (Ulviprubart) to deplete cytotoxic T cells in IBM (NCT05721573). … These approaches, which hope to broadly control the hyperinflammation that is associated with ALS and IBM, could be further refined with an antigen-specific approach in the future. … Our work highlights cryptic epitopes as critical T cell antigens and demonstrates the feasibility of engineering T cells to recognize and respond to these antigens.

⚃ Altogether, our data demonstrate a previously unknown pathological arm in TDP-43 proteinopathies where the adaptive immune system can be activated through MHC class I antigen presentation pathway, initiating from TDP-43 loss and support the rationale for immune-targeted therapies for TDP-43 proteinopathies.

⚂ Beecher, G., Muhammad, S., Shammas, I., Chamberlain, A. M., Larson, K., Mandrekar, J., Harmsen, W. S., & Naddaf, E. (2025). Increased risk of a myocardial infarction in inclusion body myositis: A non-concurrent cohort study. European Journal of Neurology, 32(5), e70177. https://doi.org/10.1111/ene.70177

⚃ IBM is associated with increased risk of MI compared to population referents. Heightened cardiovascular monitoring and prevention strategies are needed in IBM.
≻ Patients with IBM had about 4 to 6 times higher hazard of developing an MI than referents, and this increased risk remained relatively unchanged after adjusting for age, sex, statin and aspirin use, diabetes mellitus, and gait impairment. Corticosteroid and other immunosuppressant use were neither risk factors nor protective for the development of MI in IBM.
≻ Decline in cardiorespiratory fitness and reduced peak oxygen uptake, which is an independent and critical risk factor for the development of coronary heart disease and overall survival, could theoretically play a role in MI risk in IBM.
≻ Taken together, several risk factors related to aging, chronic inflammation, altered autophagy, and mitochondrial dysfunction may contribute to increased risk of MI in patients with IBM.
≻ In clinical practice, proactive cardiovascular risk assessment and management, including the use of statins, which may be well-tolerated in patients with IIMs including IBM [30, 31], and other cardioprotective therapies, are warranted in this population to mitigate the risk of myocardial infarction.

⚂ Naddaf, E., & Roy, B. (2025). Updates on Diagnostic Criteria of Inclusion Body Myositis. Rheumatic Disease Clinics of North America, S0889857X25000523. https://doi.org/10.1016/j.rdc.2025.07.005

⚃ The updated 2024 European Neuromuscular Center IBM diagnostic criteria acknowledge the wide phenotypic spectrum of IBM and integrate new serologic and imaging-based diagnostic tools.
≻ IBM typically has an insidious onset with subtle difficulties in walking, getting up from a low seated position, climbing the stairs, knee buckling, or falls when the lower extremities are affected. On the other hand, weakness of finger flexors leads to a weakened grip, difficulty with using hand-held tools, gripping a golf club, opening round doorknobs, or picking up small objects.
≻ In the long term, the weakness continues to progress with patients eventually becoming wheelchair dependent, with complete loss of the hand use and often with significant dysphagia. IBM modestly affects longevity with mean age at death about 4 years younger than population controls in one study. Most common causes of death in IBM are related to complications of dysphagia and respiratory insufficiency.
≻ While diagnostic criteria are primarily developed for research purposes, they provide a framework for the diagnostic workup in clinical practice, to be tailored to individual patients on a case-by-case basis.

⚂ Imetkul, I., Kallow, Z. S., Edrees, A. E., Akram, S. A., Sabah, A., & Zhumagaliuly, A. (2025). Understanding the immunopathogenesis of autoimmune disorders: A comprehensive review. Trends in Immunotherapy, 47-60. https://doi.org/10.54963/ti.v9i3.1007

⚃ DOWNLOAD PDF.

⚂ Song, Y., Li, J., & Wu, Y. (2024). Evolving understanding of autoimmune mechanisms and new therapeutic strategies of autoimmune disorders. Signal Transduction and Targeted Therapy, 9(1), 263. https://doi.org/10.1038/s41392-024-01952-8

⚃ DOWNLOAD PDF.

⚂ Ambrocio, K. R., Ragusa, B. R., Aggarwal, R., Lacomis, D., Kouame, G., & Garand, K. L. (2025). A scoping review of respiratory dysfunction in inclusion body myositis. International Journal of Rheumatic Diseases, 28(9). https://doi.org/10.1111/1756-185x.70409

⚃ Inclusion body myositis (IBM) can result in deadly respiratory consequences. Yet, the mechanism driving this issue remains equivocal. We mapped the literature to identify physiological respiratory characteristics in IBM and the types of respiratory assessments used.
≻ Conclusion: Low-level evidence guides our understanding of IBM-induced respiratory dysfunction. Future studies should ensure detailed and transparent reporting and follow current best practices for respiratory assessment to define IBM-induced respiratory dysfunction.
≻ While respiratory involvement appears to be a pervasive symptom of IBM, the physiological characteristics underlying respiratory dysfunction and how it has been assessed are unclear.
≻ Despite respiratory dysfunction being extensively documented as a primary source of mortality in IBM, the mechanism underlying this issue has yet to be well defined. Our scoping review intended to clarify this issue. However, in the limited and mainly low-level evidence available, we found that accurate and nuanced interpretations of the physiological respiratory characteristics reported are primarily based on insufficiently described study demographics and assessment protocols, and outdated assessment interpretation standards. Nonetheless, reflecting on the available evidence provides valuable insight and gives us the opportunity to recalibrate future work to maximize the reliability, validity, and generalizability of conclusions drawn about respiratory dysfunction in IBM. We recommend that future work focus on systematic, rigorous, and prospective efforts in exploring respiratory biomechanics and function in IBM, including standardized cough, lung, and respiratory muscle metrics. Future work should strive to comply with the current best practices for performing, interpreting, and reporting respiratory assessments as outlined by the American Thoracic Society and the European Respiratory Society.

⚂ Kirou, R. A., Pinal-Fernandez, I., Casal-Dominguez, M., Pak, K., Ikenaga, C., Nelke, C., Wischnewski, S., Del Orso, S., Naz, F., Islam, S., Gutierrez-Cruz, G., Lloyd, T. E., Schirmer, L., Ruck, T., Stenzel, W., Selva-O’Callaghan, A., Milisenda, J. C., & Mammen, A. L. (2025). Activated dendritic cell subsets characterize muscle of inclusion body myositis patients and correlate with KLRG1+ and TBX21+ CD8+ T cells. medRxiv (Cold Spring Harbor Laboratory). https://doi.org/10.1101/2025.06.04.25328910

⚃ Our findings reveal that all three MDC (Myeloid dendritic cells) subsets are relatively increased and activated in muscle of IBM patients and correlate with IBM-specific inflammatory markers. Our data specifically implicates cDC1 cells in CD8+ T cell activation via specific expression of both KLRG1 ligands, CDH1 and CDH2, as well as IL12B in IBM muscle.
≻ A likely source of CD8+ T cell activation are myeloid dendritic cells (mDCs), a group of professional antigen-presenting cells. In recent years, there has been an explosion of high-throughput sequencing studies describing subsets of mDCs.
≻ While prior reports have described individual mDC subsets in IBM muscle, our results expand on these by providing a comprehensive analysis of three different types of mDCs in IBM patients compared to the other main types of myositis. Specifically, we have shown that cDC1 cells, cDC2 cells, and mregDC cells are present at higher proportions in IBM samples compared to other myositis and CTRL samples.
≻ Furthermore, we propose cDC1 cells to be principal activators of KLRG1+ and TBX21+ CD8+ T cells in IBM via upregulation of IL12B and the KLRG1 ligands CDH1 and CDH2. We also propose cDC2 cells to be principal responders to IFN-γ via upregulation of IFN-II-inducible genes and principal activators of CD4+ T cells via specific expression of multiple MHC-II-encoding genes.

⚂ Campanilho-Marques, R., Fonseca, J. E., & Machado, P. M. (2025). Treatment of idiopathic inflammatory myopathies. Joint Bone Spine, 92(6), 105932. https://doi.org/10.1016/j.jbspin.2025.105932

⚃ In this paper we aim to provide a review of the current therapeutic options based on IIM subtypes.

⚂ Naddaf, E., Skolka, M. P., Prokop, L., Dimachkie, M. M., Hogrel, J., Benveniste, O., Wang, Z., Mandrekar, J., West, C. P., & Murad, M. H. (2025). A systematic review and meta-analysis of the response to placebo in clinical trials of inclusion body myositis. Rheumatology, 64(7), 4125-4132, https://doi.org/10.1093/rheumatology/keaf146

⚃ Conclusion Participants with IBM displayed a measurable decline in their muscle strength and IBMFRS during clinical trials, in keeping with the disease’s slowly progressive nature. These estimates can inform sample size calculations in future studies.

⚂ Mari, A., Calabrese, F., Pasta, A., Lorenzon, G., Weusten, B., Keller, J., Visaggi, P., Roman, S., Marabotto, E., Dickman, R., Serra, J., De Bortoli, N., Iovino, P., Pohl, D., Dumitrascu, D., Ribolsi, M., Barber, C., Bor, S., Fox, M.,... Savarino, E. V. (2025). Esophageal and oropharyngeal dysphagia: Clinical recommendations from the United European Gastroenterology and European Society for Neurogastroenterology and Motility. United European Gastroenterology Journal. https://doi.org/10.1002/ueg2.70062

⚃ The Consensus Group voted on various statements that may guide clinicians in the management of dysphagia in clinical practice. Future research should focus on refining diagnostic and therapeutic strategies through high-quality randomized controlled trials, particularly in areas where current evidence is limited. Advances in diagnostic tools and novel endoscopic techniques are expected to significantly enhance the accuracy and efficiency of disease detection and management. Additionally, further studies are needed to evaluate long-term outcomes of emerging therapeutic options and their integration into routine clinical practice.

⚂ Allameen, N. A., Salam, S., Reddy, V., & Machado, P. M. (2025). Inclusion body myositis and immunosenescence: current evidence and future perspectives. Rheumatology, 64, 952-961. https://doi.org/10.1093/rheumatology/keae614

⚃ The pathogenesis of IBM is likely due to the complex interplay between dysregulated immunity and degenerative processes, in an ageing environment of genetically predisposed individuals. Due to a lack of response to conventional immunosuppression, other therapeutic avenues have been explored such as the modulation of protein homeostasis. However, more recent investigations into the association of IBM with T-LGLL and the presence of highly differentiated cytotoxic T cells, have reignited an interest in the role of immunosenescence in IBM. Evidence has demonstrated a predilection for the expression of markers, such a CD57 and KLRG1 on highly differentiated cytotoxic T cells. It remains to be established as to whether the presence of such cell populations in blood and muscle of IBM patients is an epiphenomenon or a driver for pathogenesis. Further research is required into these T cell populations to help determine whether they have a causative role. The monoclonal antibody ABC008/ Ulviprubart has been developed to target KLRG1 expressing T cells and is currently being evaluated in a large pivotal trial.

⚂ Selva-O’Callaghan, A., Matas-Garcia, A., & Milisenda, J. (2024). Sporadic Inclusion Body Myositis. In Y. Shoenfeld, R. Cervera, G. Espinosa, & M. E. Gershwin (Eds.), Autoimmune Disease Diagnosis (pp. 241-245). Springer Nature Switzerland. https://doi.org/10.1007/978-3-031-69895-8_32

⚃ No effective drug treatments are available for sIBM, and it is considered a refractory disease to conventional immunosuppressive therapy. Other strategies targeting muscle atrophy pathways, such as monoclonal antibodies against myostatin, a physiologic inhibitor of the skeletal muscle mass, have failed. Nevertheless, manifestations such as dysphagia, respiratory failure, or muscle mobility must be addressed by the treating physicians.
≻  Dysphagia screening is recommended on an annual basis due to relevance of associated aspiration pneumonia as the main cause of death in these patients. Cricopharyngeal bar due to scaring of cricopharyngeal muscle may be addressed in specific cases by cricopharyngeal myotomy, endoscopic dilatation, or botulinum toxin injection. Intravenous immunoglobulin may be useful in some cases with severe dysphagia, and it is worth to use it. Respiratory failure due to ventilatory insufficiency due to muscle weakness may occur at advanced stages. Pulmonary function test and nocturnal oximetry may assist the clinicians to take the proper decisions. Rehabilitation periodic evaluation is endorsed to know if the patients may benefit from assisted devices such as walkers or wheelchairs to maintain mobility. There is no place for general prevention strategies in patients with sIBM given the scarce knowledge about the etiopathogenesis of the disease.

⚂ Mayer, T., Scholle, L., Foerster, L., Schneider, I., Stoltenburg-Didinger, G., Delank, K., Kendzierski, T., Koelsch, A., Kleeberg, K., Kraya, T., Barba, L., Naegel, S., Schänzer, A., Otto, M., & Mensch, A. (2025). Alpha-Synuclein as a potential biomarker for inclusion body myositis in blood and muscle. Neuropathology and Applied Neurobiology, 51(3), e70019. https://doi.org/10.1111/nan.70019

⚃ Results: The proportion of fibres with αSN immunoreactivity was significantly higher in IBM compared to all groups (p < 0.001) and discriminated IBM against all other neuromuscular disorders with a sensitivity of 79% and a specificity of 85%, which further improved when only non-regenerating fibres were examined. In serum, αSN concentrations in IBM were generally not different from healthy controls. However, serum concentrations were inversely correlated with disease duration (r = -0.62, p = 0.04) and positively correlated with the IBM functional rating scale (r = 0.74, p = 0.01). Consequently, stratification according to these clinical parameters showed significantly lower serum αSN concentrations in late-stage, more severely affected patients. Conclusions: αSN reactivity may serve as an additional immunohistochemical marker for IBM diagnosis. Furthermore, this study indicates that αSN serum concentrations decrease with disease duration and clinical deterioration. Therefore, serum αSN may be provisionally considered a monitoring biomarker in IBM, pending further studies.

⚃ Summary
– Muscle fibres with alpha-synuclein-immunoreactive inclusions are more frequent in inclusion body myositis (IBM) than in non-IBM inflammatory myopathies, other myopathies and healthy controls.
– Alpha-synuclein immunohistochemical staining of muscle biopsies has sufficient sensitivity (79%) and specificity (81%) to differentiate IBM from other inflammatory myopathies.
– Regenerating muscle fibres account for a proportion of alpha-synuclein-reactive muscle fibres, the exclusion of which results in higher sensitivity (84%) and specificity (86%) for distinguishing IBM from other inflammatory myopathies.
– Serum alpha-synuclein concentrations are generally not altered in IBM but correlate with disease duration and clinical severity.
– Serum alpha-synuclein may qualify as a monitoring biomarker in IBM.

⚂ Gross, M. J. (2025). Stronger: The untold story of muscle in our lives. Penguin Group.

⚃ Stronger tells a story of breathtaking scope, from the battlefields of the Trojan War in Homer’s Iliad, where muscles enter the scene of world literature; to the all-but-forgotten Victorian-era gyms on both sides of the Atlantic, where women build strength and muscle by lifting heavy weights; to a retirement home in Boston, where a young doctor makes the astonishing discovery that frail ninety-year-olds can experience the same relative gains of strength and muscle as thirty-year-olds if they lift weights. These surprising tales play out against a background of clashing worldviews, an age-old competition between athletic trainers and medical doctors to define our understanding and experience of muscle. In this conflict, muscle got typecast: Simplistic binaries of brain versus brawn created a persistent prejudice against muscle, and against weight training, the type of exercise that best builds muscular strength and power. Stronger shows muscle and weight training in a whole new light. With warmth and humor, Michael Joseph Gross blends history and firsthand reporting in an inspiring narrative packed with practical information based on rigorous scientific studies from around the world. The research proves that weight training can help prevent or treat many chronic diseases and disabilities throughout the lifespan, including cardiovascular disease, cancer, type 2 diabetes, osteoarthritis, and depression. Stronger reveals how all of us, from elite powerlifters to people who have never played sports at all, can learn to lift weights in ways that yield life’s ultimate prize: the ability to act upon the world in the ways that we wish.

⚂ De Vries, G. M., Asselbergh, B., Monticelli, A., De Jonghe, P., Maudsley, S., Van Den Bergh, P. Y. K., Bigot, A., De Bleecker, J. L., Ermanoska, B., De Ridder, W., & Baets, J. (2025). Ageing signatures and disturbed muscle regeneration in muscle proteome of inclusion body myositis. Journal of Cachexia, Sarcopenia and Muscle, 16(3), e13845. https://doi.org/10.1002/jcsm.13845

⚃ Results: A total of 627 significantly differentially expressed proteins were found in IBM patients compared to control individuals. The proteomics dataset strongly reflected inflammatory signatures, dysregulations in cellular energy metabolism and altered myogenesis in IBM muscle. Identification of upstream regulators of IBM pathology yielded KDM5A as the top activated and RB1 as the top inhibited upstream regulator. KDM5A, a histone demethylase involved in transcription regulation and (myogenic) differentiation, interacts with RB1 and interconnects core IBM disease signatures in patient muscle tissue. IHC stainings on muscle tissue showed increased presence of myogenin-positive myonuclei (p less than 0.0001). KDM5A levels were increased in these myogenin-positive myonuclei in IBM patient muscle tissue compared to healthy controls (p less than 0.0001). In vitro differentiation of myoblasts showed gradual KDM5A downregulation throughout myogenic differentiation, confirming presence in immature myoblasts and low levels in more mature myotubes. Proof-of-concept pharmacological inhibition of KDM5A with ryuvidine showed a significant effect on amyloid precursor protein (APP) abundance (p = 0.0003) and aggregation (p = 0.0132) in a conditional IBM-mimicking inflammatory model. Conclusions: This unbiased proteomics study reflects known core features of IBM pathomechanisms while simultaneously providing novel insights into the proteomic landscape of IBM, most notably dysregulation of metabolic pathways and failure of myogenesis. The identification and exploration of KDM5A as a potential upstream driver of disease pathology could interconnect failure of myogenic differentiation with (known) disease processes in IBM and provides a target for future study and therapy.

⚃ In summary, this unbiased proteomic study provides unique insights into the proteomic landscape of IBM, capturing known core features of IBM pathomechanisms and highlighting strong signatures pointing towards the selective failure of myogenesis. In addition, we propose that KDM5A overactivity is upstream of important epigenetic changes in mature muscle and immature myoblasts, leading to ageing-associated skeletal muscle dysfunction and primary failure of muscle regeneration in IBM, in turn resulting in highly interconnected degenerative and inflammatory changes in skeletal muscle. These results position KDM5A overactivity and its downstream effects in IBM pathology as clear subjects of future studies.

⚂ Lauletta, A., Bosco, L., Merlonghi, G., Falzone, Y. M., Cheli, M., Bencivenga, R. P., Zoppi, D., Ceccanti, M., Kleefeld, F., Léonard-Louis, S., Stenzel, W., Benveniste, O., Maggi, L., Previtali, S. C., & Garibaldi, M. (2025). Mitochondrial pathology in inflammatory myopathies: A marker of worse clinical outcome. Journal of Neurology, 272(7), 480. https://doi.org/10.1007/s00415-025-13192-z

⚃ Conclusions Mitochondrial dysfunction represents a key element informing about disease severity and poor clinical outcomes in non-IBM myositis. It may predict progression to IBM, especially in PM-Mito and NSM, and guide treatment strategies.
≻ Recent studies suggest that PM-Mito may be an early form of IBM, raising the possibility that these conditions represent different stages of the same disease process rather than distinct entities that share immune-related pathways.
≻  The prevalence and significance of muscular mitochondrial pathology in non-IBM myositis have not been thoroughly investigated, particularly its potential role as a marker of progression to IBM or as a predictor of treatment unresponsiveness and poorer clinical outcomes.

⚃ Mild mitochondrial alterations are commonly observed in muscle specimens from healthy elderly individuals, progressively increasing with age [25]. Nevertheless, COX-negative muscle fibers usually do not exceed 1% of the total muscle fibers [2]. This study highlights the presence of mitochondrial pathology in non-IBM myositis patients, particularly the presence of COX-negative muscle fibers, with an overall prevalence in our cohort of 2.94% of patients showing mitochondrial alterations with non-IBM myositis. PM-Mito and nonspecific myositis (NSM) were the most prevalent subtypes (72%). The mean percentage of COX-negative fibers was 3% (0.25-8.5%). The presence of mitochondrial pathology was associated with a worse clinical outcome and treatment refractoriness compared to those patients without mitochondrial pathology (p = 0.003). Moreover, in the group with mitochondrial pathology, higher percentages of COXnegative fibers correlated with a poorer clinical outcome (p = 0.031), with a potential threshold of 2.5% COX-negative fibers predominantly associated with a clinical outcome score ≥ 2. This suggests that mitochondrial dysfunction could represent a marker of disease severity and treatment unresponsiveness in non-IBM myositis.

⚃ Conclusions The presence of mitochondrial pathology in myositis is associated with worse clinical outcomes and treatment refractoriness. A higher number of COX-negative muscle fibers also correlates with poorer clinical outcomes. The presence of COX-negative muscle fibers could predict progression to IBM over time, and more strict clinical monitoring is advisable. Mitochondrial pathology in muscle biopsy represents a potential biomarker of disease severity and treatment unresponsiveness in non-IBM myositis. Larger patient cohorts are required to confirm these findings.

⚂ Jayaraman, S., Wilson, A., Zheng, X. A., Montagne, J. M., Pinal-Fernandez, I., Mammen, A. L., Lloyd, T. E., & Larman, H. B. (2025). Characterizing local antibody responses in the muscle of inclusion body myositis patients. Journal of Autoimmunity, 154, 103437. https://doi.org/10.1016/j.jaut.2025.103437

⚃ Results: With the MSD assay we found human IgG, IgA, and IgM in a larger percentage of IBM xenografted mice versus controls. Using PhIP-Seq, we found anti-microbial reactivities secreted from IBM muscle are prevalent amongst a healthy control population but autoantigen reactivities in IBM are more unique at the peptide and protein level. Additionally, NT5C1A (IgG/IgA and IgM) and TIF1γ (IgG/A) autoantibodies are secreted from muscle tissues of 4/18 and 10/18 IBM xenograft donors, respectively.
≻ Conclusion: Our characterization of antibody responses within the muscle of IBM patients reveals that muscle infiltrating B cells produce both disease-associated autoantibodies and a broad spectrum of antibodies targeting non-self antigens.

⚃ … these results suggest that IgG/IgA and IgM NT5C1A autoantibodies are produced in IBM muscle. Furthermore, classswitched NT5C1A autoantibodies mostly target the same peptides as IgM antibodies, and autoantibodies found in both the muscle and the blood target the same NT5C1A immunodominant peptides. However, additional isotype reactivities to additional NT5C1A peptides may be found in the muscle versus the blood, potentially indicative of a more robust and diverse response inside the muscle tissue that is not always detectable in the serum.
≻ We demonstrated that B cells infiltrating IBM muscle secrete IgG, IgA, and IgM antibodies, which is consistent with the expression of those antibodies at the messenger RNA level. In the muscle of IBM patients, IgG/IgA antibody reactivities targeting pathogen peptides, identified via ToxScan and VirScan, are also prevalent in the blood of healthy controls. This finding suggests that many B cells found in inflamed muscle are likely associated with bystander B cell recruitment.
≻ … muscle-infiltrated B cells in IBM produce antibodies frequently observed in the blood, as well as autoantibodies that are distinct from those easily detected in the blood.

⚂ Grochowski, D., Bradley, D., Mankoski, R., & Tubridy, K. (2025). Epidemiology and Patient Journey in Inclusion Body Myositis (IBM): A Machine Learning (ML) Methodology Applied to Claims Data in the United States (US) (P10-2.004). Neurology, 104(7_Supplement_1), 3970. https://doi.org/10.1212/WNL.0000000000211362 [Poster] Presented at the 150th Annual Meeting of the American Academy of Neurology April 5-9, 2025 San Diego, CA. DOWNLOAD PDF.
≻ PLAIN LANGUAGE SUMMARY DOWNLOAD PDF.

⚃ Results:
≻  Patient journey: 2435 patients were qualified. 61% were male; 71% were aged ≥65 years at diagnosis. Pain and weakness were predominant pre-diagnosis symptoms, followed by (vs controls): mobility conditions (23% vs 4%), falling (16% vs 4%), and difficulty swallowing (15% vs 2%). Median time between first IBMrelated symptom and first IBM ICD-10 diagnosis claim was 4.4 years (3.3 years when pain was excluded as a symptom). In the year before diagnosis, 30% presented to the emergency department (controls, 17%); 20% who were admitted stayed an average of 1 week. Epidemiology: The IPP comprised 1633 patients; over 80% had a mobility condition, and 65% suffered a fall. The US diagnosed prevalence estimate was 26.45/million. Prevalence of symptomatic but undiagnosed patients ranged from 18.72 (highly specific algorithm) to 123.93/million (highly sensitive algorithm).
Conclusions:
≻  There are at least as many symptomatic undiagnosed patients with IBM as there are diagnosed patients. Earlier recognition of IBM is needed to provide appropriate care.

⚃ Conclusions
≻ Claims analyses indicated higher levels of pain and weakness and a higher level of healthcare resource utilization in patients with IBM relative to a matched control cohort
≻ Machine-learning analyses of claims data suggested there were at least as many symptomatic undiagnosed patients with IBM in the US as there were diagnosed patients with IBM
≻ Earlier recognition of patients with IBM is urgently needed if patients are to receive timely and appropriate care

⚂ Needham, M., Henderson, R. D., , C., Soler-Ferran, D., Wilkins, H. J., & Greenberg, S. A. (2025). Pharmacokinetics, Pharmacodynamics (PK/PD), and Safety Profile of Ulviprubart: Results from a 48-week, Open-label, Phase 1 Study in Patients with Inclusion Body Myositis (IBM) (P3-11.012). Neurology, 104(7_Supplement_1), 4610. https://doi.org/10.1212/WNL.0000000000211798 [Poster] Presented at the 150th Annual Meeting of the American Academy of Neurology April 5-9, 2025 San Diego, CA. DOWNLOAD PDF.

⚃ Results:
≻  Nineteen patients (mean age, 66 years; 79% male; mean disease duration, 10 years) were enrolled (0.1 mg/kg: n=3; 0.5 mg/kg: n=3; 2.0 mg/kg: n=13). Ulviprubart displayed a long absorption phase, slow clearance, and a half-life of 14-21 days. Depletion of peripheral CD8+ KLRG1+ and CD4+ KLRG1+ T cells was evident on day 1 postdose, with mean CD8+ KLRG1+ T cell maximum depletions of 69%, 97%, and 98% achieved by weeks 2-3 after a single dose of 0.1, 0.5, and 2.0 mg/kg, respectively. Depletion was sustained through the study. Protective regulatory T cells and B cells were preserved. No serious adverse events (AEs) or discontinuations due to AEs were reported.
Conclusions:
≻  Ulviprubart led to deep and selective depletion of peripheral blood KLRG1+ T cells in patients with IBM. Together with the favorable safety profile, these data support the continued development of ulviprubart.

⚃ Depletion of peripheral CD8+ KLRG1+ and CD4+ KLRG1+ T cells was evident on day 1 postdose, with mean CD8+ KLRG1+ T-cell maximum depletions of 69%, 97%, and 98% achieved by weeks 23 after a single dose of 0.1, 0.5, and 2.0 mg/kg ulviprubart, respectively, in Part 1 (SAD) (Figure 4A).

⚃ Conclusions
≻ Ulviprubart displayed PK [pharmacokinetic] properties consistent with other therapeutic monoclonal antibodies
≻ Ulviprubart led to deep and selective depletion of peripheral blood KLRG1+ T cells in patients with IBM in this first-in-human study without impacting regulatory T or B cells
≻ Together with the favorable safety profile, these data support the continued development of ulviprubart

⚂ Kamalanathan, A. S., Agarwal, V., Talamini, L., & Muller, S. (2025). Autophagy in myositis, a dysregulated pathway, and a target for therapy. Autoimmunity Reviews, 103817. https://doi.org/10.1016/j.autrev.2025.103817

⚃ Autophagy is a fundamental cellular process responsible for eliminating damaged organelles and misfolded, aggregated proteins and other cellular constituents. It is an evolutionarily conserved lysosomal degradation pathway, which plays multiple housekeeping roles in metabolism, cardiovascular health, immunity, iron homeostasis, infection, and cancer. It has vital functions in the development of the embryo by maintaining a critical balance of energy levels and sources.
≻ Dysregulated autophagy (especially CMA) may effectively importantly contribute to muscle degeneration and inflammation, leading several authors to propose that this route of intervention could be of great therapeutic interest.
≻ Autophagy plays an additional role in muscle fiber regeneration, influencing the fate of muscle stem cells. By maintaining quiescence, facilitating activation, and supporting differentiation, autophagy enables mitochondrial remodeling and balances apoptosis during myogenesis. Furthermore, autophagy modulates the immune microenvironment, influencing macrophage polarization and endothelial cell function to support regeneration through angiogenic or nonangiogenic pathways
≻ Altered mitophagy was especially demonstrated by the elevated expression levels of p-S65-ubiquitin, a mitophagy marker, in muscle lysates from IBM patients compared to controls.

⚂ Salam, S., Morrow, J. M., McDermott, M. P., Zafeiropoulos, N., Thornton, J. S., Shah, S., Wastling, S., Yousry, T. Y., Barohn, R. J., Hanna, M. G., Dimachkie, M. M., & Machado, P. M. (2025). Quantitative muscle magnetic resonance imaging as a biomarker for inclusion body myositis in clinical trials: Exploring the in vivo effects of arimoclomol. Clinical and Experimental Rheumatology. https://doi.org/10.55563/clinexprheumatol/5b9lme

⚃ Arimoclomol had no significant effects on the qMRI measurements evaluated, consistent with clinical outcomes from the main trial.
≻ The qMRI measurements demonstrated both validity and responsiveness, further supporting their potential utility as biomarkers in IBM.

⚂ Needham, M., Badrising, U. A., Beer, K., Heim, A. J., Doverty, A., Panicker, A., Benveniste, O., & Dimachkie, M. M. (2025). Challenges in international investigator-led rare disease clinical trials and the case for optimism in inclusion body myositis. Clinical and Experimental Rheumatology. https://doi.org/10.55563/clinexprheumatol/dyjcsn

⚃ This large, collaborative study has presented a mosaic of challenges and opportunities, many ubiquitous with investigator-led trials. Key challenges have included securing adequate funding, coordinating manufacture of placebo, negotiating international contracts, managing limited study budgets and delays linked to the COVID-19 pandemic. Alongside these challenges, the study team have found opportunities for creative and effective solutions, including the flexibility of building study databases, optimising digital data capture and harnessing patient involvement.
≻ In IBM, there have been only 4 international multicentre clinical trials in the last decade, (bimagrumab, arimoclomol, ABC008, and sirolimus) (6, 7), with only one (sirolimus) an investigator-initiated academic study. The phase 2/3 study of arimoclomol in Inclusion Body Myositis NCT02753530 was an international investigator-initiated academic study initially funded by the FDA Office of Orphan Products Development.
≻ Summary from ChatGPT: Reasons for Optimism: Despite [these] challenges, the study highlights positive developments:
   ≻≻ Strong collaboration among international research teams.
   ≻≻ Active involvement and partnership with patients. Adaptability in trial design and execution, such as flexible data management and digital data capture.

⚂ Dhaouadi, T., Riahi, A., Ben Abdallah, T., Gorgi, Y., & Sfar, I. (2025). Association of HLA-DR, HLA-DQ, and HLA-B alleles with inclusion body myositis risk: A systematic review, a meta-analysis, a meta-regression and a trial sequential analysis. International Journal of Immunopathology and Pharmacology, 39. https://doi.org/10.1177/03946320251321747.

⚃ The simultaneous presence of inflammatory and degenerative features in IBM is still a matter of debate as to which is the cause of the disease.
≻ Indeed, IBM muscle undergoes three major histological changes including degenerative processes, mitochondrial abnormalities and inflammatory features.

⚃ This meta-analysis demonstrated that the following alleles, DRB1*03, DRB1*03:01, DRB1*01, DRB1*01:01, DRB1*15:02, B*08, and DQB1*02 were significantly associated with increased IBM risk.
≻ Conversely, the DRB1*15:01 allele seems to be protective against IBM.
   ≻≻ The present study revealed that the HLADRB1*03 allele was associated with approximately a 9.2-fold increase in IBM risk, though with a moderate level of between-studies heterogeneity. Therefore, the effect size could vary from 4.5- to 18.8-fold increased disease risk in 95% of comparable populations.
   ≻≻ In this meta-analysis, the DRB1*03:01 allele conferred a roughly 8.4-fold increase in IBM risk. Heterogeneity between studies was low and the effect size could fall between 5.8- and 12.3-fold increase in IBM risk in 95% of comparable populations.
   ≻≻ This study showed that the DRB1*01 and DRB1*01:01 alleles were associated with roughly 2.3-2.6-fold increased IBM risk. Therefore, the association of the DRB1*01 allele with the susceptibility IBM is predominantly carried by the DRB1*01:01 allele.
   ≻≻ The present meta-analysis showed that while the DRB1*15:01 allele was associated with a halving of the IBM risk, the DRB1*15:02 allele conferred a roughly 3.5-fold increased IBM risk. Remarkably, if the DRB1*15:01 allele was more prevalent in Caucasians than in East-Asians, the DRB1*15:02 allele was more frequent in East-Asians comparatively to Caucasians. Hence, as the DRB1*1501 and *1502 alleles had opposite effects on IBM risk, and their respective frequencies considerably varied between Caucasians and East-Asians, it could explain the observed inter-ethnic disparity in the effect conferred by the DRB1*15 allele.
   ≻≻ This study showed that the HLA-B*08 allele was associated with about a 4-fold increase in IBM risk. As there was a moderate amount of between-studies heterogeneity, the effect size could fall between 1.04 and 15.86 in 95% of comparable populations. … However, meta-regression showed a significant positive correlation of the effect size with gender-ratio (M/F). This peculiar finding suggests that the HLA-B*08-associated IBM risk might be greater in men than in women.
   ≻≻ Only three studies reported the DQB1*02 allele frequency in IBM patients. This allele conferred an approximately 6.6-fold increased IBM risk with no heterogeneity between included studies.
   ≻≻ These findings indicate that: (1) as IBM occurs mostly in elderly subjects the patients age did not seem to influence HLA impact on IBM susceptibility, and (2) Unlike other autoimmune diseases, hormonal factors did not seem to modify genetic susceptibility to IBM.

⚂ Needham, M., Henderson, R. D., Liang, C., Soler-Ferran, D., Wilkins, H. J., & Greenberg, S. A. (2025). Pharmacokinetics, Pharmacodynamics (PK/PD), and Safety Profile of Ulviprubart: Results from a 48-week, Open-label, Phase 1 Study in Patients with Inclusion Body Myositis (IBM) (P3-11.012). Neurology, 104(7_Supplement_1), 4610. https://doi.org/10.1212/WNL.0000000000211798

⚃ [1 page narrative] Ulviprubart (ABC008) is a monoclonal antibody that selectively depletes cytotoxic CD8+ KLRG1+ T cells by targeting the cell-surface marker KLRG1 expressed on the vast majority of IBM-muscle-infiltrating T cells.
≻ Ulviprubart may have clinical activity in patients with IBM.
≻ Ulviprubart led to deep and selective depletion of peripheral blood KLRG1+ T cells in patients with IBM. Together with the favorable safety profile, these data support the continued development of ulviprubart.

⚂ Pongrácová, E., Buratti, E., & Romano, M. (2024). Prion-like spreading of disease in TDP-43 proteinopathies. Brain Sciences, 14(11), 1132. https://doi.org/10.3390/brainsci14111132

⚃ … little is still known about the spreading of this [TDP-43] pathology from cell to cell. Recent research has unveiled the possibility that TDP-43 may possess prion-like properties. Specifically, misfolded TDP-43 aggregates can act as templates inducing conformational changes in native TDP-43 molecules and propagating the misfolded state across neural networks. This review summarizes the mounting and most recent evidence from in vitro and in vivo studies supporting the prion-like hypothesis and its underlying mechanisms. The prion-like behavior of TDP-43 has significant implications for diagnostics and therapeutics.
≻ … Inclusion Body Myositis (IBM), an uncommon inflammatory muscle disease, exhibits TDP-43 abnormalities in the affected muscle tissue

⚃ TDP-43 pathology across diseases suggests common mechanisms, thus opening opportunities for unified therapeutic strategies. Investigating the prion-like behavior of TDP-43 could provide valuable insights into how these diseases spread and evolve.

⚂ Jabari, D., Heim, A., Ciersdorff, A., Wilkins, H., Agbas, A., Kosa, E., Hunt, S., Pasnoor, M., Dimachkie, M., & Barohn, R. (2024). Safety and tolerability of phenylbutyrate in inclusion body myositis. RRNMF Neuromuscular Journal, 5(1). https://doi.org/10.17161/rrnmf.v5i1.21356

⚃ Phenylbutyrate (PBA) showed a positive effect on the muscle cell model of Inclusion Body Myositis (IBM) by improving lysosomal activity, ameliorating consequences of impaired autophagy, and decreasing vacuolization. This provides a rationale to study this medication in patients with IBM.
≻ Phenylbutyrate was safe and well tolerated in patients with IBM in this pilot study. The change in the MitoTracker suggests target engagement, but a Phase II study is needed to confirm and study the efficacy of PBA in IBM.
≻ MitoTracker showed a significant drop with treatment. Reduced MitoTracker with treatment could be due to reduced mitochondrial number/mass. We propose that PBA induces autophagy/mitophagy as it is known to reduce protein aggregation and one way to process aggregates is to ship them to mitochondria and then induce mitophagy. A phase 2 study is needed to verify the MitoTracker change and to further evaluate for any clinical or biological outcome measures changes that might have been missed due to the small sample size and short duration of our pilot study.

⚂ López-Carbonero, J. I., García-Toledo, I., Fernández-Hernández, L., Bascuñana, P., Gil-Moreno, M. J., Matías-Guiu, J. A., & Corrochano, S. (2024). In vivo diagnosis of TDP-43 proteinopathies: In search of biomarkers of clinical use. Translational Neurodegeneration, 13(1), 29. https://doi.org/10.1186/s40035-024-00419-8

⚃ A crucial issue in neurodegenerative diseases, especially in TDP-43 proteinopathies, is the fact that the same clinical phenotype can be related to different proteinopathies, and at the same time TDP-43 proteinopathy can be found in other different clinical disorders.
≻ DP-43 encephalopathy [25] and Perry syndrome [26]. TDP-43 proteinopathy in skeletal muscle cells is a common finding in sporadic inclusion body myositis (IBM).
≻ Current evidence indicates the presence of measurable extra-neural TDP-43 pathology, which seems one of the most promising approaches for evaluating altered TDP-43 in TDP-43 proteinopathies.

⚂ Astouati, Q., Machet, T., Houssais, C., Noury, J. B., Allenbach, Y., Gallay, L., Quere, B., Assan, F., Benveniste, O., Broner, J., Duffau, P., Espitia, A., Grasland, A., Hayem, G., Le Guern, V., Martis, N., Mariampillai, K., Nocturne, G., Mariette, X., … Sanges, S. (2025). Inclusion-body myositis associated with Sjögren’s disease: Clinical characteristics and comparison with other Sjögren-associated myositis. Rheumatology, 64(3), 1431-1436. https://doi.org/10.1093/rheumatology/keae129.

⚃ IBM can occur in SjD patients, with muscle features reminiscent of classic sporadic IBM characteristics, but mostly affecting women. In SjD patients with muscle involvement, extra-glandular manifestations, high ESSDAI score, elevated CPK values and shorter delay after SjD diagnosis plead against IBM.
≻ Although IBM is classified among idiopathic IM, it is notoriously resistant to conventional anti-inflammatory and immunosuppressive drugs. Because SjD is associated with various muscle manifestations, it is crucial to accurately distinguish IBM from other myositis subtypes due to the therapeutic implications.
≻ Muscular presentation of both our SjD-IBM cohort and published cases resembles sporadic IBM (sIBM), with a progressive mode of onset, frequent asymmetrical, distal, quadriceps and finger flexor involvements, frequent dysphagia and low CPK and CRP levels. Interestingly, conversely to SjDIBM patients, sIBM more frequently affects men: as such, screening female IBM patients for SjD could be discussed. Further studies that directly compare SjD-IBM and sIBM are warranted to better identify clinical and pathophysiological similarities and differences between diseases.
≻ To our knowledge, this is the first publication that focused on identifying discriminating features between IBM and other IM in SjD patients. We found that non-IBM cases seem to have more frequent extra-glandular involvement and more elevated ESSDAI scores, which could indicate that these patients have a more active SjD disease. Alternatively, this could also reflect the existence of extra-muscular manifestations due to the associated myositis, which rarely occur during IBM. Further studies with a prospective design are warranted to settle this issue.

⚂ 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. (2025). Mitochondrial leakage and mtDNA damage trigger early immune response in Inclusion Body Myositis. Brain, https://doi.org/10.1093/brain/awaf118 DOWNLOAD PDF. PMID: 40193586. See here.

⚂ Deenen, J. C., Verbeek, A. L., Verschuuren, J. J., Van Engelen, B. G., & Voermans, N. C. (2025). Prevalence and incidence rates of 17 neuromuscular disorders: An updated review of the literature. Journal of Neuromuscular Diseases, 22143602241313118. https://doi.org/10.1177/22143602241313118

⚂ Badrising, U. A., Henderson, R., Reddel, S., Corbett, A., Liang, C., Reardon, K., Ghaoui, R., Bulsara, M., Brady, S., Brusch, A., Chan, D., Coudert, J. D., Fairchild, T., Jain, G., Kiernan, M. C., Leonard, D., Lloyd, T., Schmidt, J., McDermott, M. P., … Needham, M. (2025). Optimism in inclusion body myositis: A double-blind randomised controlled phase III trial investigating the effect of sirolimus on disease progression in patients with IBM as measured by the IBM Functional Rating Scale. Clinical and Experimental Rheumatology. https://doi.org/10.55563/clinexprheumatol/zvffa0

⚃ Sirolimus (rapamycin) may help maintain function by inhibiting T effector cells, preserving T regulatory cells, inducing autophagy, and improving mitochondrial function. This international trial follows a phase II pilot study.
≻ This phase IIb/III trial builds on prior findings to assess sirolimus’s potential in slowing or halting IBM progression, preserving patient function and independence, and advancing IBM therapeutic strategies and trial design.
≻ This multicentre global phase IIb/III randomised controlled trial is to validate the findings of a 1 prior singlecentre phase II study suggesting that sirolimus might slow progression of disease.
≻ If shown to be efficacious, sirolimus will be the first disease-modifying treatment for patients living with IBM.

⚂ Allameen, N. A., Salam, S., Reddy, V., & Machado, P. M. (2025). Inclusion body myositis and immunosenescence: Current evidence and future perspectives. Rheumatology, 64(3), 952-961.https://doi.org/10.1093/rheumatology/keae614

⚃ This review discusses the potential role of cellular immunosenescence in sustaining inflammation and/or fibrotic remodelling observed in IBM and appraises the rationale for some potential therapeutic approaches to mitigate disease progression.
≻ The pathogenesis of IBM is likely due to the complex interplay between dysregulated immunity and degenerative processes, in an ageing environment of genetically predisposed individuals.
≻ Further advancement in the understanding of the role that immunosenescence plays in IBM may improve prospects for developing targeted therapies against this complex disease.

⚂ Ikenaga, C., Wilson, A. B., Irwin, K. E., Peethambaran Mallika, A., Kilgore, C., Sinha, I. R., Michelle, E. H., Ling, J. P., Wong, P. C., & Lloyd, T. E. (2025). Loss of TDP-43 splicing repression occurs in myonuclei of inclusion body myositis patients. Annals of Neurology, 97(4), 629-641. https://doi.org/10.1002/ana.27167

⚃ We aimed to determine whether loss of TDP-43 splicing repression led to the production of ‘cryptic peptides’ that could be detected in muscle biopsies as a useful biomarker for IBM.
≻ Together, our findings establish that loss of TDP-43 splicing repression occurs in myonuclei of IBM skeletal muscle and suggest that detection of cryptic peptides in muscle biopsies may be a useful biomarker. We suggest that a therapeutic strategy designed to restore TDP-43 function should be considered to attenuate the degeneration of skeletal muscle in this devastating disease.
≻ Although IBM is an inflammatory muscle disease with cytotoxic T-cell invasion, the muscle of patients with IBM also shows pathological features commonly observed in neurodegenerative diseases, including ubiquitinated protein aggregates and TDP-43 pathology. In this study, we demonstrate that in addition to cytoplasmic aggregation and nuclear clearance of TDP-43, there is also a striking expression of a cryptic peptide-containing protein (HDGFL2), as is also observed in ALS. Considering the presence of loss of TDP-43 from myonuclei causes robust proteomic changes in the muscle of IBM, we would predict that many of the abnormally spliced transcripts are transcribed into abnormal proteins that could potentially be immunogenic, and act as neoepitopes, eliciting a T-cell mediated immune response.
≻ In summary, our study showed that the loss of TDP-43 repression, as indicated by our novel cryptic HDGFL2 antibody, occurs in myonuclei which is a specific biomarker for patients with IBM. Given that loss of TDP-43 function is an early event in the pathogenesis of ALS-frontotemporal dementia (FTD), we propose that loss of TDP-43 function is also playing a critical role in the pathophysiology of IBM. Given recent strategies to correct missplicing defects in other TDP-43 proteinopathies, including ALS and FTD, we suggest that similar approaches designed to complement loss of TDP43 function should be considered as a novel therapeutic strategy for this myodegenerative and inflammatory disease associated with aging.

⚂ Santos, E. J. F., Farisogullari, B., Yapp, N., Townsley, H., Sousa, P., & Machado, P. M. (2025). Efficacy and safety of pharmacological treatments in inclusion body myositis: A systematic review. RMD Open, 11(1), e005176. https://doi.org/10.1136/rmdopen-2024-005176

⚃ Drug interventions for IBM were not effective for most of the outcomes of interest. We observed inconsistency of outcome measures across trials. More RCTs are needed, of adequate size and duration, and using a standardised set of outcome measures.
≻ In conclusion, this review summarises existing evidence on the efficacy and safety of pharmacological interventions for IBM. While most interventions were not effective, they had favourable safety profiles. To advance treatment options, optimising outcome measures, agreeing on a core outcome set and follow-up duration, and accounting for disease-specific and individual factors are crucial. The development of new treatments, alongside advances in understanding IBM pathogenesis, is vital. Further studies are necessary to identify effective treatments for IBM.

⚂ Ervilha Pereira, P., De Bleecker, J. L., Bogaert, E., & Dermaut, B. (2025). Myopathic aggregation-prone variants in the TDP-43 prion-like domain: Genetics paving the way. Brain, awaf076. https://doi.org/10.1093/brain/awaf076

⚃  … multiple studies have described the presence of TDP-43 inclusions in muscular disorders, including inclusion body myositis but also other related rimmed vacuole myopathies.
≻ In addition, TAR DNA-binding protein-43 (TDP-43) has been reported to be essential in normal muscle physiology as it is implicated in the formation of so-called amyloid-like myogranules during normal muscle regeneration after injury.
≻ However, genetic evidence supporting a primary role for TDP-43 proteinopathy in muscle disease has been missing.
≻  Recent evidence might point towards loss of nuclear TDP-43 being the primary source of cellular distress and the main driver of TDP-43 pathology.
≻ On the muscular side, Britson et al. have shown that TDP-43-related cryptic exon inclusion serves as a good marker for the diagnostics of inclusion body myositis (IBM), with a sensitivity and specificity of 84% and 99%, respectively.
≻ The role of TDP-43 in muscle tissue is still a nascent line of investigation but rooted in prominent pathological observations and compelling evidence that TDP-43 may play a crucial role in the maintenance of skeletal and cardiac muscle.

⚂ Austin, K. L., Hawkins, B., Beer, K. A., Doverty, A. B., & Needham, M. (2024). Determining patient and carer priorities in inclusion body myositis: A patient-led research study. Clinical and Experimental Rheumatology. https://doi.org/10.55563/clinexprheumatol/5xqelc

⚃ The study identified 10 inter-related themes, and their relative importance was then determined.
≻ Ninety-five percent of total importance came from 7 themes:
   ≻≻ (1) Uncertain future;
   ≻≻ (2) Coping with daily frustrations;
   ≻≻ (3) Lack of cure, treatment and understanding;
   ≻≻ (4) Impact on carer’s capabilities and own needs;
   ≻≻ (5) Change of roles and relationships;
   ≻≻ (6) Getting information, education and support; and
   ≻≻ (7) Significant impact on mental health.
   ≻≻ Other themes identified were:
   ≻≻≻ (8) Financial impact;
   ≻≻≻ (9) Issues with government-provided care provision; and
   ≻≻≻ (10) Concerns around access to voluntary euthanasia.
≻ Participants reported low mean ‘coping scores’ across all themes.
≻ Conclusion This study identified gaps in care, education and support. The highest priority themes focussed on practical challenges of living with IBM in addition to significant impact on mental health. Understanding the priorities of IBM patients and carers is critical in directing resources and providing person-centered care and support.

⚃ The purpose of this Australian study was to discover the priorities of IBM patients and carers as seen through their own eyes; to assess the relative importance of these priorities; and to measure patient and carer perception of their ability to cope with these challenges.

⚃ Consistent with understanding of the phenotype of IBM (5), pain was not identified within either study phase, including within free text comments. The differences identified may also reflect the advantages of the action research approach in enabling a deeper understanding of disease impact and identifying themes beyond physical symptoms.
≻ We hope that highlighting the priorities of IBM patients and carers will help everyone involved in IBM care to be cognisant of the impact of disease, allow clinicians to screen for difficulties in these domains, and advocate for improved access to care, support and improved allocation of limited resources for each patient.

⚂ Cantó-Santos, J., Valls-Roca, L., Tobías, E., García-García, F. J., Guitart-Mampel, M., Andújar-Sánchez, F., Vilaseca-Capel, A., Esteve-Codina, A., Martín-Mur, B., Padrosa, J., Peruga, E., Madrigal, I., Segalés, P., García-Ruiz, C., Fernández-Checa, J. C., Moreno-Lozano, P. J., O’Callaghan, A. S., Sevilla, A., Milisenda, J. C., & Garrabou, G. (2025). Human induced pluripotent stem cell-derived myotubes to model inclusion body myositis. Acta Neuropathologica Communications, 13(1), 38. https://doi.org/10.1186/s40478-025-01933-0

⚃ IBM lacks effective treatment despite ongoing trials [10, 32]. IBM’s cause is unknown, lacking validated models and biomarkers. The invasive nature of the target tissue presents challenges in acquiring the ample amount of muscle tissue required for comprehensive molecular profiling of the disease, for establishing disease models and for potential biomarker or treatment discoveries.
≻ [Previous disease models have included various Mouse models and cell models derived from IBM patients using primary myoblasts, dermal fibroblasts and lymphocytes. Each of these models has its own limitations.]
≻  To overcome these limitations, patient-derived induced pluripotent stem cells (iPSC) have been proposed for drug discovery, disease modeling and regenerative medicine, since they can be differentiated into muscle stripes conserving patients’ characteristics and have unlimited cell passages.
≻  Due to the limitations of currently developed models of disease in IBM, and iPSCs’ potential for accurate muscle cell differentiation, we hypothesized that iPSC-derived myotubes could aid in revealing IBM etiology, biomarker or therapeutic discovery. Thus, in this proof-of-concept study, IBM patients vs. CTLs iPSCs were developed, characterized, differentiated into myotubes and phenotyped (by RNAseq, protein and functional means) to check if they displayed the IBM muscle hallmarks, including inflammation, degeneration and mitochondrial changes, thus becoming a potential cell model for IBM.

⚃ All these findings support patient-derived iPSC-myotubes as a relevant model for IBM, reflecting the main muscle hallmarks, including inflammation, autophagy dysfunction and mitochondrial alterations at transcriptomic, protein and functional levels. In further approaches, iPSC-myotubes may benefit from contact with lymphocytes or other immune cells that may boost the inflammatory profile. Also, since aging is associated to IBM development and has been suggested to play a role in IBM etiology, cell models may also take advantage of promoting aging features by exposure to specific toxins or expressing genes as progerin, a truncated version of the lamin A protein involved in the Hutchinson–Gilford progeria syndrome, which previously recapitulated cellular aging in Parkinson’s disease iPSC-derived neurons, potentially promoting premature aging hallmarks in IBM iPSC-myotubes. Additional phenotyping of iPSC-myotubes at morphological level, characterizing cell regenerative or differentiation capacity, as well as the mislocalization or malfunction of proteins and subcellular structures in these cells may strength the validity of this cell model for extended uses.
≻ … this was the first attempt to model IBM using iPSC-derived myotubes, which reflect some myopathic, inflammatory, autophagic and mitochondrial alterations from this disease. iPSC have unlimited proliferative potential and they could permanently be in a biobank ready to be differentiated into myotubes, to perform large-scale muscle cell platforms for high-throughput screening of therapeutic compounds in IBM.
≻ Overall, this proof-of-concept study of IBM iPSC-myotubes revealed that they recapitulated myopathic, inflammatory, autophagic and mitochondrial alterations. Thus, they could be valuable to increase the understanding of IBM pathophysiology, for the identification of biomarkers, and for testing potential treatments.
≻ In summary, IBM is a complex disease with multi-factorial contributors and limited disease models. IBM iPSC-derived myotubes effectively replicated key histopathological features of IBM, including aberrant expression of HLA, TDP-43, and COX markers. mRNA sequencing identified differentially expressed genes (DEGs) associated with myopathy, muscle structure, and developmental changes. Functionally, baseline inflammation was comparable between the IBM and control groups, but it significantly increased in IBM iPSC-myotubes upon lipopolysaccharide treatment. Autophagy was disrupted, with reduced levels of autophagy mediators. Mitochondrial dysfunction was also prominent, characterized by a preserved respiratory profile and antioxidant capacity, but with a decreased cytochrome c oxidase/citrate synthase ratio and elevated lactate secretion. Collectively, these findings highlight patient-derived iPSC-myotubes as a relevant model for IBM, replicating the main muscle hallmarks, including inflammation, autophagy dysfunction, and mitochondrial abnormalities at transcriptomic, protein, and functional levels. As such, this model holds promise for advancing the understanding of IBM pathophysiology, identifying biomarkers, and evaluating potential treatments.

⚂ Kirou, R. A., Pinal-Fernandez, I., Casal-Dominguez, M., Pak, K., Preusse, C., Dari, D., Del Orso, S., Naz, F., Islam, S., Gutierrez-Cruz, G., Naddaf, E., Liewluck, T., Stenzel, W., Selva-O’Callaghan, A., Milisenda, J. C., & Mammen, A. L. (2025). Distinct Cytokine and Cytokine Receptor Expression Patterns Characterize Different Forms of Myositis. https://doi.org/10.1101/2025.02.17.25321047

⚃ IBM patients had the most differentially overexpressed genes (71) among all clinical groups, including 37 that were IBM-specific. Among the top genes were several involved in type 1 inflammation, including CCL5, CXCR3, CCR5, CXCL9, and IFNG. Anti-Jo1 and anti-PM/Scl patients exhibited differential overexpression of a similar set of genes, while dermatomyositis patients exhibited differential overexpression of a different set of genes involved in type 1 inflammation. IMNM patients had the least number of differentially overexpressed genes with no predominant inflammatory pattern.

⚃ Inclusion Body Myositis (IBM) muscle biopsies exhibit differential overexpression of a set of genes involved in type 1 inflammation.
≻ The CCL5-CCR5 and XCL1-XCL2-XCR1 axes are specifically differentially overexpressed in IBM muscle and may contribute to TC 1-mediated inflammation.

⚃ Our findings add support to previous work implicating mediators of type 1 inflammation in the pathogenesis of IBM. For example, it has been demonstrated that highly differentiated CD8+ T cells are elevated in muscle and peripheral blood of IBM patients, including TBX21+ CD8+ T cells (TC 1 cells) in particular[8, 11, 32, 33]. Previous studies have also shown elevated muscle levels of numerous cytokines associated with type 1 inflammation, including CCL5, CXCL9, CXCL10, CXCL11, IFNG, and TNF in IBM patients compared to various myositis and non-myositis controls[6, 8-11]. Similar elevations of cytokines associated with type 1 inflammation, including CXCL9, CXCL10, IFN-γ, IL-12, and TNF have been demonstrated at the protein level in serum of IBM patients versus non-myositis controls[11, 34]. In our study, we confirmed the elevation of these cytokines in IBM, while also finding a strong correlation between the most differentially overexpressed inflammatory mediators in IBM and CD8A and TBX21. Furthermore, we found that the TH 1/TC 1 markers CXCR3 and CCR5 were differentially overexpressed in IBM, with higher median expression than in any other myositis group. The CCL5-CCR5 ligand-receptor pair was particularly specific for IBM, representing the top two IBM-specific differentially overexpressed genes. Interestingly, an allelic variant of CCR5 resulting in a non-functional receptor (CCR5Δ32) is thought to be protective against IBM according to a large genetic association study[35]. Furthermore, CCR5 is a macrophage entry receptor for R5-tropic strains of the human immunodeficiency virus (HIV), which has been associated with IBM[36]. Taken together, the CCL5-CCR5 axis seems to be particularly important to the type 1 inflammation in IBM and could represent a therapeutic target. CCR5 inhibitors are indicated for HIV infection and have been in clinical trials for a variety of other autoimmune diseases, including rheumatoid arthritis, graft-versus-host disease, and primary sclerosing cholangitis[37]. Furthermore, antigenpresenting dendritic cells have also been implicated in IBM inflammation[38]. Here, we found the type 1 conventional dendritic cell marker XCR1 and its ligands, XCL1 and XCL2, to be overexpressed in IBM patients and IBM-specific. The XCL1-XCR1 interaction activates TC 1 cells and has been implicated in other autoimmune disorders with type 1 inflammation, including sarcoidosis, Crohn’s disease, and rheumatoid arthritis [39, 40]. Although IBM has proved to be refractory to corticosteroids and some other immunosuppressants, this may be due to the durable nature of highly differentiated CD8+ T cells in evading cell death mechanisms, and they may be more susceptible to more targeted therapeutics[5].

⚂ Liarski, V. M. (2025). Retrospective analysis of US veterans with inclusion body myositis: Initial findings from the Veterans Affairs Corporate Data Warehouse. Military Medical Research, 12(1), 6. DOWNLOAD PDF.

⚃ Letter to the Editor: it is a brief summary not a full peer reviewed article.

⚃ Demographics:
≻ Data were extracted from the Veterans Affairs (VA) Corporate Data Warehouse (CDW) January 1, 2011 to December 31, 2021
≻ A total of 732 IBM patients and 1215 matched patient controls met study criteria
≻ The majority – 67.9% (497) – serving during the Vietnam-Era. There was no difference in service periods between IBM and patient controls.
≻ IBM veterans were predominantly male (96.7%), White (70.2%), and of nonHispanic or -Latino ethnicity (89.2%).
≻ The mean age of patients was (54.4 ± 8.5) years and mean age at IBM diagnosis was (48.4 ± 8.7) years.
≻ Black patients made up 22.1% of IBM veterans and 7.7% identified as other or did not provide race.

⚃ Diabetes mellitus and cancer:
≻ IBM patients were more likely to have a diagnosis of diabetes mellitus (49.5% vs. 6.6%, P less than 0.001) and cancer (38.4% vs. 2.8%, P less than 0.001), and be current or prior smokers (23.2% vs. 15.8%, P less than 0.001).
≻ The most common malignancies seen in IBM patients were prostate, skin, renal, bladder, and colon cancers, and lymphoma. There were no cases of T cell leukemia as previously reported.

⚃ Bronchiectasis and Interstitial lung disease:
≻ While IBM patients were more likely to display bronchiectasis (57.5% vs. 15.4%, P less than 0.001) and ILD [Interstitial lung disease] (61.9% vs. 48.4%, P less than 0.001). This difference could not be explained solely by smoking status (23.2% vs. 15.8%, P less than 0.001)
   ≻≻ Tillier: many patients in our IBM Facebook group report having mucus plugs and excess mucus. This is the first mention of bronchiectasis [bronc-key ECK ta-sis] that I have seen in the literature linking excess mucus with IBM.

⚃ Mortality:
≻ Strikingly worse mean survival among the [IBM Group] [mean 10% mortality for IBM 2.2 years (95%CI 1.8-2.6) vs. 15.0 years (95%CI 14.0-16.0) for matched controls, P less than 0.001; Fig. 1].

     ≻ Black patients with IBM were overrepresented and all IBM patients exhibited drastically decreased survival (mean 8.5 years) compared with controls.
≻ Two prior civilian cohorts reported a similar observation: a Dutch analysis reported 15 of 64 (24%) patients alive after 12 years, whereas a study from the Mayo clinic found a 10-year survival rate of 36%.
   ≻≻ It will be important in future work to determine if this mortality is linked to causes or processes unique to IBM and to explore links between IBM and lung disease.

⚂ Schopp, M., Beer, K., Cooper, I., Hird, K., Doverty, A., Panicker, A., Schütze, K., Brusch, A., & Needham, M. (2025). The relationship between patient-reported and clinician-assessed outcome measures in Inclusion body myositis—Insights from a retrospective cohort study. Neuromuscular Disorders, 46, 105272. Link.

⚃ Currently, IBM clinical trials use a combination of patient-reported and clinician-assessed outcome measures, including those examined in this study, to evaluate the efficacy of interventions.
≻ [IBM] Patients often feel their disease is progressing differently than strength-based outcome measures demonstrate. The disability paradox describes this phenomenon as a contradiction between patients’ perceptions of personal health and their objective health status.
≻ We found the IBMFRS to be the most reliable indicator of patient-perceived functionality, strongly correlating with clinician-assessed strength and functional outcome measures.
≻ This study aimed to determine the most suitable combination of outcome measures to use in IBM clinical trials through establishing the relationship between PROMS and clinician-assessed outcome measures in IBM. The IBMFRS, NSS, 2MWT and mTUG models were the best predictors of patient-perceived physical function.

⚂ Wijnbergen, D., Johari, M., Ozisik, O., ’T Hoen, P. A. C., Ehrhart, F., Baudot, A., Evelo, C. T., Udd, B., Roos, M., & Mina, E. (2025). Multi-omics analysis in inclusion body myositis identifies mir-16 responsible for HLA overexpression. Orphanet Journal of Rare Diseases, 20(1), 27. Link.

⚃ In this work, we performed an integrative multi-omics data analysis with prior knowledge to investigate mechanisms that are disrupted in IBM. We created a largescale network combining different types of interactions involving genes/proteins and miRNAs. Using an active subnetwork identification algorithm, we identified several subnetworks that were highly relevant for IBM and reflected processes that are already known to be affected in IBM, but also some novel ones.
≻ we applied active subnetwork identification on our IBM network. This resulted in five distinct subnetworks which we labeled according to their top GO terms:
   ≻≻ “Antigen processing and presentation” Contains 20 nodes, of which 19 are genes, and one is a miRNA. These 20 nodes are all significantly differentially expressed. Six nodes are overexpressed HLA genes (HLA-A, HLA-B, HLA-C, HLA-E, HLA-F, and HLA-G). In previous studies, their overexpression was consistent in IBM and other inflammatory myopathies. This subnetwork also contains several overexpressed CD genes, namely CD2, CD5, CD48, CD79A, CD8A, and CD8B, which are markers of Leukocytes. LCK was another overexpressed gene in this subnetwork, previously proposed as an apoptosis regulator involved in IBM. Besides protein-coding genes, this subnetwork contains the miRNA miR-16-5p, linked to the HLA-A, HLA-B, and HLA-C genes, with negative correlation coefficients ranging from - 0.51 to -0.58. Finally, this subnetwork is strongly correlated to the proportion estimation of CD8 T cells, CD4 memory activated T cells, regulatory T cells.
   ≻≻ “Chemokine-mediated signaling” Contains 29 genes and three miRNAs. Most of the genes involved in this subnetwork are overexpressed. These genes mainly include various cytokines, specifically chemokine ligands and receptors such as CCL5, CCR4, CXCL10, and XCL1. Many of these chemokines are involved in calcium signaling, which has been hypothesized by Johari et al. to play a role in IBM.
   ≻≻ “Immune response – signal transduction” Shares several genes with the previous two subnetworks, though the overlap is below the merging threshold. It shares LCK, CD2, CD8A, UBC, and PTPRC with the “antigen processing and presentation” subnetwork and CD4, UBC, and SYK with the “chemokinemediated signaling” subnetwork, connecting to these two subnetworks. Only the CD247, ZAP70, PIK3R1, VAV1, STAT1, CD28, FYN, LCP2 and RACK1 genes are unique to this subnetwork. Genes such as LCK, FYN, ZAP70 and VAV1 are part of T cell receptor signaling, which is triggered by binding of the T cell receptor to antigen presenting MHC complexes.
   ≻≻ “rRNA processing” Contains 15 genes. In this subnetwork, the RPS18 (ribosomal protein S18) gene has a significant variant burden but, interestingly, is not significantly differentially expressed. The rest of the genes in this subnetwork are downregulated with no significant variant burden. These include genes like WDR43, IMP4, NOP14, RRP9, PDCD11, UTP18, and UTP15, which have a role in the processing of the 18 S ribosomal RNA.
   ≻≻ and “mRNA splicing” Although five of the 38 genes in this subnetwork (ASPN, LRRC17, PPIC, DOCK4, and TLR3) are overexpressed, the rest of the genes are underexpressed. Many of these genes, such as DDX21, RBM8A, CWC25 and EFTUD2 are involved in mRNA splicing. This subnetwork also contains genes with a significant variant burden, namely SNAPC4 and DOCK4.

⚃ This work presents the identification of multi-omics signatures in IBM that provide insights into potential disease mechanisms that are at play. We identified five subnetworks that represent these signatures. Within these subnetworks, we find several interesting interactions which can be the basis for forming hypotheses in IBM.

⚃ There are also novel findings, such as the miR-16-5p. This miRNA was connected with many HLA genes in the “Antigen processing and presentation” subnetwork. Here, the downregulation of miR-16-5p was negatively correlated with the upregulation of the HLA genes, which is coherent with the canonical mechanism of miRNAs suppressing gene expression.
≻ 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.
≻ Specifically, the underexpressed miR-16-5p was connected to multiple overexpressed HLA genes by negative expression correlation. This connection could potentially play a role in the regulation of the HLA genes.
≻ Similarly, we found the RPS18 gene having both a variant burden and being connected to many underexpressed genes involved in 18 S ribosomal RNA processing. Mutations in this gene could thus affect the expression of the connected genes and play a role in IBM.

⚂ 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. Link.

⚃ cohort of 287 patients with IBM followed at nine European rheumatological or neurological centers
≻ anti-NDUFA11 was found in 10 out of 287 patients with inclusion myositis, but in none of the 59 patients with polymyositis or dermatomyositis.
≻ [NADH dehydrogenase [ubiquinone] 1 alpha subcomplex subunit 11 is an enzyme that in humans is encoded by the NDUFA11 gene]
≻ Our results indicate that a subunit of the mitochondrial respiratory chain complex I, the NADH dehydrogenase 1 alpha subcomplex 11 (NDUFA11), might act as an autoantigen in inclusion body myositis.
≻ The origin of mitochondrial changes in IBM is still not known but recent advances in understanding IBM pathogenesis are pointing to an autoimmune nature of the disease. Therefore, our finding of autoimmune reactivity towards the subunit NDUFA11 of mitochondrial complex I is intriguing.
≻ In conclusion, to our knowledge, this is the largest screening of IBM samples for autoantibody reactivities reported so far. 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 and their origin is still a matter of debate.

⚂ 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. (2025). NLRP3 inflammasome activation and altered mitophagy are key pathways in inclusion body myositis. Journal of Cachexia, Sarcopenia and Muscle, 16(1), e13672. https://doi.org/10.1002/jcsm.13672 DOWNLOAD PDF.

⚃ We demonstrated activation of the NLRP3 inflammasome in IBM muscle samples, with the NLRP3 inflammasome being the most upregulated pathway on RNA sequencing, along with increased expression of NLRP3 and ASC proteins in IBM group.
≻ NLRP3 RNA levels most strongly correlated with TLR7 (correlation coefficient p = 0.91) and complement activation-related genes, and inversely correlated with several mitochondria-related genes among others.
≻ On muscle histopathology, there was increased NRLP3 immunoreactivity in both inflammatory cells and muscle fibres.
≻ Mitophagy is critical for removing damaged mitochondria and preventing the formation of a vicious cycle of mitochondrial dysfunction—NLRP3 inflammasome activation.
≻ Herein, we showed altered mitophagy, as witnessed by the elevated levels of p-S65-Ubiquitin, a mitophagy marker, in muscle lysates from IBM patients compared to controls (median of 114.3 vs. 81.25 ECL units, p = 0.005).
≻ The p-S65-Ubiquitin levels were most significantly elevated in IBM males compared to male controls (136 vs. 83.5 ECL units; p = 0.013), whereas IBM females had milder nonsignificant elevation compared to female controls (97.25 vs. 69 ECL units, p = 0.31).
≻ On muscle histopathology, p-S65-Ubiquitin aggregates accumulated in muscle fibres that were mostly Type 2 and devoid of cytochrome-c-oxidase reactivity.
≻ NLRP3 RNA levels correlated with p-S65-Ubiquitin levels in both sexes (males: p = 0.48, females: p = 0.54) but with loss of muscle strength, as reflected by the manual motor test score, only in males (males: p = 0.62, females: p = -0.14).
≻ Lastly, we identified sex-specific molecular pathways in IBM.
   ≻≻ Females had upregulation of pathways related to response to stress, which could conceivably offset some of the pathomechanisms of IBM, while males had upregulation of pathways related to cell adhesion and migration.
≻ Conclusions: There is activation of the NLRP3 inflammasome 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.

⚃ Altered Mitophagy in Muscle Tissue From IBM Patients
≻ In the combined male and female analysis, mitophagy was among the top 10 downregulated pathways in the IBM cohort, and mitophagy plays an important role in regulating inflammation in general and NLRP3 inflammasome activation in particular.
≻ In this study, we demonstrated the activation of the NLRP3 inflammasome and altered mitophagy in muscles samples from patients with IBM. Despite their intended protective role, aberrant activation of inflammasomes has been linked to the development of various chronic conditions, especially neurodegenerative and other ageing-related diseases.
≻ Herein, we demonstrated via unbiased analysis of transcriptomic data that the NLPR3 inflammasome pathway was indeed the most upregulated pathway in muscle tissue from both males and females with IBM with increased NLRP3 and ASC protein expression.
≻ [However,] we demonstrated a strong correlation between the NLRP3 RNA level and the severity of muscle weakness, reflected by the MMT score, in males but not in females, supporting the clinical relevance of the activation of the NLRP3 inflammasome in IBM.
≻ Herein, we show robust alterations in mitophagy in IBM.
≻ The release of mitochondrial damage-associated molecular patterns (DAMPs), such as mtDNA, cytochrome c, mitochondrial reactive oxygen species (ROS) and mitochondria-specific cardiolipin molecules, are known activators of the NLRP3 inflammasome. Under normal conditions, damaged mitochondria and the NRLP3 inflammasome are both removed by mitophagy and autophagy, subsequently reestablishing cellular homeostasis.
≻ When mitophagy and autophagy are altered, as in IBM, a feedforward loop is established.
≻ Therefore, the inflammatory milieu results in additional oxidative stress and mitochondrial dysfunction with further release of mitochondrial DAMPs and subsequent aberrant NLRP3 inflammasome activation.
≻ This vicious, self-sustaining cycle may be a major contributor to the chronic deterioration of muscle strength in individuals with IBM.
≻ The original trigger for this self-sustained detrimental loop remains unclear.
   ≻≻ An ageing skeletal milieu, with ageing mitochondria and an autophagic system, is likely required for these events to occur given the age of the population at risk.
   ≻≻ Furthermore, antigen-driven inflammation at a preclinical stage preceding the activation of self-sustained inflammatory pathways that become nontargeted by conventional immunotherapies is possible.

⚃ Based on these results, a vicious cycle of mitochondrial dysfunction/altered mitophagy and NLRP3 inflammasome activation is likely to occur in IBM (Figure 5).

⚃ Another major finding of this study is the demonstration of sex differences in IBM pathomechanisms.
   ≻≻ In this study, we identified sex-spec genes and pathways that were differentially expressed only in one sex. … Taken together, we speculate that more preserved mitophagy in females enable them to better turn down the activation of the NLRP3 inflammasome and limit subsequent tissue damage.

⚃ Deciphering the intertwined nature of neurodegenerative diseases resulting in self-sustaining vicious cycles, such as those involving inflammasome activation and stalled mitophagy, has become of utmost importance, regardless of which is the cause versus the consequence. How to simultaneously target the various interwoven pathways involved in neurodegenerative diseases remains unknown and should be investigated in future studies.

2024

⚂ A synopsis of 2024 research (pdf). DOWNLOAD PDF.

⚂ Bhardwaj, Mudit & Khamankar, Shubhankit & Sinwal, Aashutosh & Ishu, & Poonia, Rahul & sharma, Vishv & Sinwal, Vaibhav. (2024). A review of recent advances in the classification, pathogenesis, diagnosis, and treatment of idiopathic inflammatory myopathies: Review article. Journal of Pharma Insights and Research. 2. 205-214. https://doi.org/10.69613/yd1kff94

⚂ Allameen, N. A., Salam, S., Reddy, V., & Machado, P. M. (2024). Inclusion body myositis and immunosenescence: Current evidence and future perspectives. Rheumatology, keae614. https://doi.org/10.1093/rheumatology/keae614 DOWNLOAD PDF.

⚃ The pathogenesis of IBM is likely due to the complex interplay between dysregulated immunity and degenerative processes, in an ageing environment of genetically predisposed individuals.

⚂ Merrison, A., & Brady, S. (Eds.). (2024). Muscle diseases: A guide to differential diagnosis, investigation and management. CRC Press.

⚂ 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.

⚂ 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.

⚂ 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.

⚃ 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.”

⚁ 5.5 Functional assessment of IBM.

⚁ 5.6 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
≻ SMI-31 = an antibody against phosphorylated tau epitopes
≻ 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