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Highlighted summaries aimed at the average patient.

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Paraphrased and selected excerpts aimed at informing the average IBM patient.

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General overview.

■ Inclusion body myositis (IBM) is often seen as a mysterious disease, due to uncertainties about its cause, diagnosis, classification and treatment.

■ IBM is a slowly progressive skeletal muscle disease. Patients typically experience weakness in the muscles that bend the fingers (finger flexors) and extend the knee (the quadriceps). These clinical findings distinguish IBM from most other muscle diseases.

■  Examination of muscle tissues under the microscope reveals that the muscle cells have been invaded by T cells, a type of white blood cell involved in the immune response against viruses and other pathogens.

■ The involvement of T cells suggests that IBM may be an autoimmune disorder. However, immunosuppressive drugs used to treat other autoimmune disorders are ineffective against IBM.

■ In patients with IBM, the onset of symptoms of muscle weakness typically occurs between 45 and 70 years of age. Early symptoms may go unnoticed, and the disease may proceed slowly, in a gradual, subtle way, with harmful, accumulating effects. IBM is commonly misdiagnosed, often as arthritis or polymyositis, an autoimmune condition that causes muscle weakness in the hips, thighs, arms, back, and neck.

■ IBM is often associated with other diseases (called “co-morbidities”), including high blood pressure, diabetes, cardiovascular issues, and autoimmune diseases. Research suggests that IBM co-morbidities are not caused by IBM treatments, such as immunosuppressant therapy, but rather may result from the systemic inflammation observed in patients with autoimmune conditions.

History of IBM

[IBM was first viewed as a form of polymyositis caused by chronic viral infection of the muscles. Over the years, a series of clinical reports, published between 1978 and 2001, more fully described the clinical presentation of IBM patients, whose symptoms typically began with muscle weakness in the fingers and knees. The name "Inclusion Body Myositis" came from the observation that the muscle clls of IBM patients often contain clumps of aggregated proteins ("inclusion bodies")—a phenomenon that had previously been observed in other virus-infected cells.]

■ A crucial discovery came in the mid-1980s when scientists found that a specific type of immune cell—cell-killing T cells (cytotoxic CD8+ T cells) invade the muscle cells of patients with IBM, causing the muscle damage that leads to weakness. These observations launched a new, ongoing line of research into IBM, looking at autoimmune abnormalities and on therapies that target T cells.

■ Circulating autoantibodies have been known to be present in polymyositis and dermatomyositis for over 40 years. However, an autoantibody in IBM was only recognized in 2011.

■ In 2013, the target antigen of these [auto]antibodies was discovered in the muscle cells of IBM patients; cytosolic 5'-nucleotidase 1A (cNIA; encoded by NT5C1 A).

■ The identification of myofibre (muscle cell) protein aggregates and mitochondrial abnormalities in muscle biopsy samples of patients with IBM, both of which seem to occur as a result of autoimmunity;

■ Recognition of the genetic linkage of IBM to the HLA region (like other autoimmune diseases), has been confirmed by many studies;

Classification

■ IBM lies within the category of muscle diseases called the inflammatory myopathies. This category started with polymyositis in 1887, and has since undergone repeated subdivision. The generally accepted model currently has five major diseases (polymyositis, dermatomyositis, IBM, IMNM and non-specific myositis).

■ Several similar abbreviations of other diseases have created confusion regarding IBM.

▣ IBM is an abbreviation for 'inclusion body myositis' not 'inclusion body myopathy.'

▣ The abbreviation IBM refers clearly and only to the single disease inclusion body myositis, not to the hereditary inclusion body myopathies (hIBMs). The hIBM diseases lack the two main characteristic features of IBM: its distinctive pattern of muscle weakness and the presence of muscle microscopic immune cell invasion. Many publications have used the abbreviation IBM to refer to both IBM and hIBM; this has led to confusion and mistakes in the research.

▣ The term sporadic IBM (sIBM) was introduced to try and avoid confusion with hIBM by emphasizing its sporadic, or non-inherited, occurrence. But this can also be confusing because you could think that it is the same disease, in one case occurring sporadically, and in another case, occurring genetically. It should be emphasized that sIBM and hIBM are not the same—they are different diseases.

▣ Familial IBM (flBM) refers to the occurrence of typical IBM within families, almost always within a single generation of brothers and sisters. This pattern is similar to the familial occurrence of many other autoimmune diseases, such as myasthenia gravis and multiple sclerosis.

Clinical features of IBM

■ The main features seen by the doctor include finger flexor and quadriceps weakness: Finger flexor weakness makes it harder to close the fingers into a fist or to pick up objects. Quadriceps weakness makes it difficult to arise from a squatting position or, for example, to step up onto a chair. Quadriceps muscles are in the upper front part of the leg between the knee and hip. Weakness here destabilizes the knee leading to falling, tripping and poor balance.

fingerflex

From: https://cureibm.org/diagnosis/examination/

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■ Numbers reflecting the prevalence of IBM are probably underestimates because of the high rate of misdiagnosis. In a good study published in 2017, the overall prevalence of IBM was 46 patients per million people.

■ Typical estimates say, on average, IBM patients notice symptoms coming on between the ages of from 61 to 68 years.

■ IBM is often viewed as affecting people over 50 years old; however, 20 percent of patients develop symptoms in their forties.

■ Men get IBM slightly more often than females, about on average 1.6 times (so for every 16 men there should be 10 women with IBM).

■ IBM is first misdiagnosed as another condition in 40 to 53 percent of patients, and the average from symptom onset to correct diagnosis is 4.6 to 5.8 years.

■ IBM is a progressive disease, on average, IBM patients require the use of a cane after about 7 to 10 years from the time they notice symptoms and need to use a wheelchair from 13 to 15 years after they notice symptoms.

■ IBM typically presents in middle or late age with slowly progressive, painless difficulty walking or using the hands.

■ Walking difficulties typically result from knee buckling, owing to knee extensor weakness, or tripping owing to ankle weakness.

■ Grip impairment results from finger flexor weakness.

■ Symptoms are often initially blamed on age or arthritis; when a neuromuscular disease is suspected, a diagnosis of polymyositis or, less often, motor neuron disease (ALS) is more typical than an immediate recognition of IBM.

■ Muscle pain is very uncommon in IBM.

■ Dysphagia (difficult swallowing) is an underestimated part of IBM and is under-reported as a presenting symptom but is commonly present if looked for by asking questions or x-ray studies. Dysphagia becomes more evident as the disease progresses and might result in nutritional deficiency, weight loss and aspiration pneumonia—this is where you choke and food goes into your lungs—which is a major cause of death in IBM.

■ Breathing problems during the day, and breathing problems during sleep, are common but often go unnoticed—these problems can go unnoticed because their symptoms are not obvious.

■ IBM has unique physical features seen on examination. The high misdiagnosis rate is partly because many doctors do not recognize these unique features. These features are so clear and unique to IBM, that if the doctor recognizes them, a muscle biopsy may not be necessary to make a diagnosis.

■ A surprising number of patients with IBM (58 percent in one series) meet the diagnostic criteria for LGLL (large granular lymphocytic leukaemia), and a small number have overt leukaemia.

Degenerative and autoimmune aspects

■ Today, IBM is often viewed as both a degenerative and an autoimmune disease.

Autoimmune biomarkers and mechanisms

■ T cells, myeloid dendritic cells, macrophages and plasma cells all invade IBM muscle, but it is the invasion of muscle cells by T cells that is the most obvious microscopic feature of IBM muscle.

■ Although the immune system feature has been known for a long time, past research has focused on abnormal proteins within the muscle cell. However, less than 1 percent of muscle cells in patients with IBM show these abnormalities.

■ Past treatments aimed at reducing the attack by the immune system have not been very successful making some people think that the disease is not an autoimmune disorder.

■ However, research over the past 10 years has supported the idea that IBM is an autoimmune disorder.

▣ For example, a chemical flag from the immune system—an autoantibody (anti-cNIA)—was found circulating within the muscles and blood of IBM patients: this is a chemical signal that the immune system is involved.

▣ Large numbers of killer cells (CD8+ T cells), made by the immune system, have been discovered in the muscle and blood of IBM patients. It is these cells that attack the muscle cells, damaging and killing them. This supports the idea that it is an autoimmune disorder.

▣ There is no specific genetic risk factor associated with IBM. General genetic risk factors that are associated with other autoimmune disorders have also been associated with IBM. These risk factors are linked to a group of genes in a section of our DNA—called the 8.1 MHC haplotype—linked to controlling the functions of the immune system.

▣ IBM has more autoimmune (T cell) abnormalities than any other muscle disease; the failure of treatments aimed at the immune system made researchers think that IBM was not an autoimmune disorder, but as we will see below, there are other reasons for the failure of these treatments.

▣ Treatment failures probably reflect the inability of current medicines to stop or reduce the army of killer immune cells present in IBM.

▣ Understanding IBM as an autoimmune disorder opens doors to finding new and specific treatments.

Degenerative abnormalities

■ Enormous attention has been focused for decades on several chemical signals of protein clumps found inside muscle cells, but these abnormalities are present in less than 1 percent of muscle cells in patients with IBM.

■ In technical language, the degenerative features of IBM include rimmed vacuoles and the related myonuclear degeneration, mitochondrial pathology and myofibre (muscle cells) cytoplasmic protein aggregates.

■ In hindsight, a published belief in the degenerative theory now seems to be out of proportion to the data supporting it.

■ Currently, the evidence suggests that causality flows from autoimmunity to degeneration, not the reverse. In other words, the degenerative abnormalities are the result of the effects of the autoimmune process and widespread inflammation and its impacts.

■ Why then has the field of IBM attracted so much more interest in protein aggregates than other autoimmune diseases? Perhaps it is simply easier to see these clumps under the microscope in skeletal muscle than in other tissues.

Treatment

■ The best care for most patients with IBM involves strictly nonpharmacological management, including emotional support, physical therapy, education on fall precautions and exercise, respiratory evaluation and dysphagia evaluation.

■ Prednisone and IVIG simply don't work.

▣ Patients with IBM receiving long-term treatment (an average of 35 mg daily of prednisone for an average of 5.7 years) had the same number of invaded muscle cells as patients with IBM not receiving treatment.

▣ Patients with IBM receiving corticosteroids or IVIG did not experience a major reduction in the total number of muscle killing cells.

■ Alemtuzumab will likely make things worse.

▣ ATG (Anti-thymocyte globulin) and alemtuzumab rapidly get rid of nearly 100 percent of the immune killer cells, but once the immune system recovers after treatment, killer cells expand in even more numbers than there were before treatment.

From: Greenberg, S. A. (2019). Inclusion body myositis: Clinical features and pathogenesis. Nature Reviews Rheumatology 2019, 1. https://doi.org/10.1038/s41584-019-0186-x

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■ This article expands and digs deeper than the Greenberg (2019) article discussed above. I would describe it as an extremely complicated article for the average person.

■ Inclusion body myositis is a late onset treatment-resistant autoimmune disease of skeletal muscle associated with a blood autoimmune flag—autoantibody (anti-cN1A), a section of DNA linked to immune disorders—an HLA autoimmune haplotype, and muscle disease characterized by killer cells of the immune system attacking muscle cells—cytotoxic CD8+ T cell destruction of muscle cells.

■ Here, we report on studies of IBM patient muscle and blood samples compared with large numbers of muscle samples from other muscle diseases. The study identified a unique cytotoxic lymphocyte signature and a highly differentiated T-cell signature in IBM muscle, highlighting the relevance of highly differentiated cytotoxic T cells to the cause of IBM.

■ In particular, killer cell lectin-like receptor G1 (KLRG1), an inhibitory T- and NK-cell receptor that is known to mark highly differentiated cytotoxic T cells, is identified on IBM blood and muscle-invading T cells.

■ the autoimmunity shown in IBM muscle is distinct from other forms of inflammatory muscle diseases. . . . IBM may be the only muscle disease characterized by extensive killer cell muscle attack.

■ These studies highlight possible reasons for IBM treatment-resistance and the potential value of making a medicine targeting the killer cells of the immune system.

From: Greenberg, S. A., Pinkus, J. L., Kong, S. W., Baecher-allan, C., Amato, A. A., & Dorfman, D. M. (2019). Highly differentiated cytotoxic T cells in inclusion body myositis. Brain, 1-15. https://doi.org/10.1093/brain/awz214

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■ Inclusion body myositis is the most common acquired myopathy after the age of 50. It is characterized by progressive asymmetric weakness predominantly affecting the quadriceps and/or finger flexors. Loss of ambulation and dysphagia are major complications of the disease. Inclusion body myositis can be associated with cytosolic 5'-nucleotidase 1A antibodies. Muscle biopsy usually shows inflammatory cells surrounding and invading non-necrotic muscle fibers, rimmed vacuoles, congophilic inclusions, and protein aggregates. Disease pathogenesis remains poorly understood and consists of an interplay between inflammatory and degenerative pathways. Antigen-driven, clonally restricted, cytotoxic T cells represent a main feature of the inflammatory component, whereas abnormal protein homeostasis with protein misfolding, aggregation, and dysfunctional protein disposal is the hallmark of the degenerative component. Inclusion body myositis remains refractory to treatment. Better understanding of the disease pathogenesis led to the identification of novel therapeutic targets, addressing both the inflammatory and degenerative pathways.

■ It remains unclear whether the primary process is immunemediated or degenerative in nature. There is strong evidence for the inflammatory component, as detailed above, including clonally restricted, antigen-driven, infiltrating CD8-positive T cells; the strong genetic association with HLA genes; and the association with cN-1A antibodies and other autoimmune conditions such as systemic lupus erythematous and Sjogren's syndrome. Unlike in inclusion body myositis, these findings are not encountered in other neurodegenerative disorders. Regarding the degenerative component, there is growing evidence that inflammation can cause secondary degenerative features.

■ There remain many unanswered questions regarding IBM pathogenesis and, most importantly, the refractoriness to treatment. Perhaps, IBM is primarily an immune-mediated disorder, which unlike any other immune disorder, triggers downstream degenerative changes early on in the process. On the other hand, a primarily degenerative disorder with secondary inflammation is also a possibility. Regardless of the nature of the primary process, a successful treatment may necessitate addressing both the immune and degenerative components simultaneously. Alternatively, it may be that the therapeutic window of opportunity is confined, and requires intervention early on, prior to the development of the degenerative changes.

From: Naddaf, E., Barohn, R. J., & Dimachkie, M. M. (2018). Inclusion Body Myositis: Update on Pathogenesis and Treatment. Neurotherapeutics. https://doi.org/10.1007/s13311-018-0658-8

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