Inclusion body myositis
Inclusion body myositis (IBM) is an inflammatory muscle disease characterized by slowly progressive weakness and wasting of both distal and proximal muscles, most apparent in the muscles of the arms and legs. There are two types: sporadic inclusion body myositis (sIBM), which is more common, and hereditary inclusion body myopathy (hIBM). IBMmyositis.com In sporadic inclusion body myositis MY-oh-sigh-tis, two processes, one autoimmune and the other degenerative, appear to occur in the muscle cells in parallel. The inflammation aspect is characterized by the cloning of T cells that appear to be driven by specific antigens to invade muscle fibers. The degeneration aspect is characterized by the appearance of holes in the muscle cell vacuoles, deposits of abnormal proteins within the cells and in filamentous inclusions (hence the name inclusion body myositis). Weakness comes on slowly (over months or years) and progresses steadily and usually leads to severe weakness and wasting of arm and leg muscles. It is more common in men than women.http://patient.info/doctor/inclusion-body-myositis Patients may become unable to perform activities of daily living and most require assistive devices within 5 to 10 years of symptom onset.http://www.ibmfoundation.org/index.php/understanding-ibm sIBM is not considered a disorder, but the risk of serious injury due to falls is increased. One common and potentially fatal complication is dysphagia. There is no effective treatment for the disease. sIBM is a rare yet increasingly prevalent disease and is the most common cause of inflammatory myopathy in people over age 50. Recent research from Australia indicates that the incidence of IBM varies in different populations and ethnic groups. The authors found that the current prevalence was 14.9 per million in the overall population, with a prevalence of 51.3 per million population in people over 50 years of age.http://rarediseases.org/rare-diseases/sporadic-inclusion-body-myositis/ As seen in these numbers, sIBM is an age-related disease – its incidence increases with age and symptoms usually begin after 50 years of age. It is the most common acquired muscle disorder seen in people over 50, although about 20% of cases display symptoms before the age of 50.
- The common type is sIBM; it strikes individuals apparently at random.
- There is a type that has been observed in multiple siblings in the same generation in several families, termed familial inflammatory sIBM, but it is not passed on from generation to generation.
- There are also several very rare forms of hereditary inclusion body myopathy (hIBM) that are linked to specific genetic defects and that are passed on from generation to generation, each inherited in different ways.
Signs and symptomsHow sIBM affects individuals is quite variable as is the age of onset (which generally varies from the forties upwards). Because sIBM affects different people in different ways and at different rates, there is no "textbook case." Eventually, sIBM results in general, progressive muscle weakness. The muscles in the thighs called the quadriceps and the muscles in the arms that control finger flexion—making a fist—are usually affected early on. Common early symptoms include frequent tripping and falling, weakness going up stairs and trouble manipulating the fingers (including difficulty with tasks such as turning doorknobs or gripping keys). Foot drop in one or both feet has been a symptom of IBM and advanced stages of polymyositis (PM). During the course of the illness, the patient's mobility is progressively restricted as it becomes hard for him or her to bend down, reach for things, walk quickly and so on. Many patients say they have balance problems and fall easily, as the muscles cannot compensate for an off-balanced posture. Because sIBM makes the leg muscles weak and unstable, patients are very vulnerable to serious injury from tripping or falling down. Although pain has not been traditionally part of the "textbook" description, many patients report severe muscle pain, especially in the thighs. When present, difficulty swallowing (dysphagia) is a progressive condition in those with inclusion body myositis and often leads to death from aspiration pneumonia. Dysphagia is present in 40 to 85% of IBM cases. IBM can also result in diminished capacity for aerobic exercise. This decline is most likely a consequence of the sedentary lifestyle that is often associated with the symptoms of IBM (i.e. progressive muscle weakness, decreased mobility, and increased level of fatigue). Therefore, one focus of treatment should be the improvement of aerobic capacity. Patients with sIBM usually eventually need to resort to a cane or a walker and in most cases, a wheelchair eventually becomes a necessity. "The progressive course of s-IBM leads slowly to severe disability. Finger functions can become very impaired, such as for manipulating pens, keys, buttons, and zippers, pulling handles, and firmly grasping handshakes. Arising from a chair becomes difficult. Walking becomes more precarious. Sudden falls, sometimes resulting in major injury to the skull or other bones, can occur, even from walking on minimally-irregular ground or from other minor imbalances outside or in the home, due to weakness of quadriceps and gluteus muscles depriving the patient of automatic posture maintenance. A foot-drop can increase the likelihood of tripping. Dysphagia can occur, usually caused by upper esophageal constriction that often can be symptomatically improved, for several months to years, by bougie dilation per a GI or ENT physician. Respiratory muscle weakness can sometimes eventuate."
CausesThe cause of IBM is unknown. IBM likely results from the interaction of a number of genetic and environmental factors. There are two major theories about how sIBM is caused. One hypothesis suggests that the inflammation-immune reaction, caused by an unknown trigger – likely an undiscovered virus or an autoimmune disorder– is the primary cause of sIBM and that the degeneration of muscle fibers and protein abnormalities are secondary features. Despite the arguments "in favor of an adaptive immune response in sIBM, a purely autoimmune hypothesis for sIBM is untenable because of the disease's resistance to most immunotherapy." The second school of thought advocates the theory that sIBM is a degenerative disorder related to aging of the muscle fibers and that abnormal, potentially pathogenic protein accumulations in myofibrils play a key causative role in sIBM (apparently before the immune system comes into play). This hypothesis emphasizes the abnormal intracellular accumulation of many proteins, protein aggregation and misfolding, proteosome inhibition, and endoplasmic reticulum (ER) stress. One review discusses the "limitations in the beta-amyloid-mediated theory of IBM myofiber injury." Dalakas (2006) suggested that a chain of events causes IBM—some sort of virus, likely a retrovirus, triggers the cloning of T cells. These T cells appear to be driven by specific antigens to invade muscle fibers. In people with sIBM, the muscle cells display “flags” telling the immune system that they are infected or damaged (the muscles ubiquitously express MHC class I antigens) and this immune process leads to the death of muscle cells. The chronic stimulation of these antigens also causes stress inside the muscle cell in the endoplasmic reticulum (ER) and this ER stress may be enough to cause a self-sustaining T cell response (even after a virus has dissipated). In addition, this ER stress may cause the misfolding of protein. The ER is in charge of processing and folding molecules carrying antigens. In IBM, muscle fibers are overloaded with these major histocompatibility complex (MHC) molecules that carry the antigen protein pieces, leading to more ER stress and more protein misfolding. A self-sustaining T cell response would make sIBM a type of autoimmune disorder. When studied carefully, it has not been impossible to detect an ongoing viral infection in the muscles. One theory is that a chronic viral infection might be the initial triggering factor setting IBM in motion. There have been a handful of IBM cases—approximately 15—that have shown clear evidence of a virus called HTLV-1. The HTLV-1 virus can cause leukemia, but in most cases lies dormant and most people end up being lifelong carriers of the virus. One review says that the best evidence points towards a connection with some type of retrovirus and that a retroviral infection combined with immune recognition of the retrovirus is enough to trigger the inflammation process.
- amyloid protein
- The hypothesis that beta amyloid protein is key to IBM has been supported in a mouse model using an Aβ vaccine that was found to be effective against inclusion body myositis in mouse models. Although this vaccine is likely not safe for human use, it still shows that attacking Aβ has efficacy in mice against IBM.
- Following up on earlier leads, the Greenberg group report finding that the protein TDP-43 is a very prominent and highly sensitive and specific feature of IBM. This protein is normally found within the nucleus but in IBM is found in the cytoplasm of the cell. This important advance should help develop a new screening technique for IBM and may provide clues in terms of a therapeutic approach