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Inclusion body myositis

Sporadic inclusion body myositis (sIBM) is an inflammatory muscle disease, characterized by slowly progressive weakness and wasting of the distal and proximal muscles, most apparent in the muscles of the arms and legs. In sporadic inclusion body myositis [MY-oh-sigh-tis] muscle, 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 (vacuole)s, deposits of amyloid-related proteins within the cells and filamentous inclusions (hence the name inclusion body myositis) of abnormal proteins.

sIBM is a rare disease, diagnosed in only about 5 people per million, although not much research exists on the number of cases and some doctors feel the numbers are much higher. sIBM is an age-related disease - its incidence increases with age and symptoms usually begin after 50 years of age. Its prevalence rises to about 35 cases per million in people over 50 . It is the most common acquired muscle disorder seen in older people, although about 20% of cases display symptoms before the age of 50. Weakness comes on slowly (over months or years) and progresses steadily and may lead to severe weakness and wasting of arm and leg muscles. It is slightly more common in men than women. Patients may become unable to perform daily living activities and most require assistive devices within 5 to 10 years of symptom onset. sIBM is not considered a fatal disorder - all things being equal, sIBM will not kill you (but the risk of serious injury due to falls is increased). There is no effective treatment for the disease.

Classification

  • The common type is sIBM (sporadic Inclusion Body Myositis): 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. See hereditary inclusion body myopathy.

Signs and Symptoms

How 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 -- turning doorknobs, gripping keys, etc.

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 is not part of the "textbook" description, many patients report severe muscle pain, especially in the thighs.

In up to 60 percent of cases, patients with sIBM develop weakness in the pharyngeal muscles, used in swallowing, causing choking

Patients with sIBM usually eventually need to resort to a cane or a walker and in most cases, a wheelchair eventually becomes a necessity.

From a recent article: "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."

Causes

The causes, of sIBM are currently unknown, though it is likely that it results from the interaction of a number of factors, both genetic and environmental. The understanding of sIBM is slowly maturing and evolving.

Currently, there are two major theories about how sIBM is caused:

1) Some researchers (e.g., Dr. Dalakas) advocate the theory that the inflammation / immune reaction, caused by an unknown trigger - likely an undiscovered virus or an autoimmune disorder, is the primary, proximal cause of sIBM and that the degeneration of muscle fibres and protein abnormalities are secondary features.

Despite the arguments "in favor of an adaptive immune response in s-IBM, a purely autoimmune hypothesis for s-IBM is untenable because of the disease's resistance to most immunotherapy."

2) Some researchers (e.g., Dr. Engel and Dr. Askanas) advocate the theory that sIBM is a degenerative disorder related to aging of the muscle fibres and that abnormal, potentially pathogenic protein accumulations in myofibers play a key causative role in s-IBM (apparently before the immune system comes into play). This theory emphasizes the abnormal intracellular accumulation of many proteins, protein aggregation and misfolding, proteosome inhibition, and endoplasmic reticulum (ER) stress.

Dalakas (2006) said: "we can say that two processes, one autoimmune and the other degenerative, occur in the muscle cells in parallel."

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.

Recent research points to a protein called Ubiquitin ligase RNF5 (or RING Finger Protein 5). Scientists have found that RNF5 plays a key role in the progression of IBM. Following this discovery, the team developed three mouse models: one in which the RNF5 gene was missing, and two in which cells could be triggered to overproduce RNF5. Whether RNF5 is the primary cause for sIBM, or an important contributor in the development of this muscle disorder is yet to be determined. Dr. Ronai, lead author of the study, says the link established between ER stress, RNF5 and sIBM strengthen the theory stating that ER stress is causative for the disease and will now allow further study of the mechanisms underlying this disabling and all too common muscle disease. In addition “We now have a great mouse model that can be used to screen for drugs that might alleviate symptoms of sIBM,” says Dr. Ronai.

A self-sustaining T cell response would make sIBM a type of autoimmune disorder. One confusing aspect is that medications that lower the immune response do not improve sIBM symptoms, as would be expected in the case of an 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 -- about 15 or so -- that have shown clear evidence of a virus called HTLV-1. This is a complex virus that can cause leukemia but in most cases, lays dormant and people end up being lifelong carriers of the virus. It's too early to say that this is the particular virus directly involved in causing IBM. The Dalakas article 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.

As mentioned above, in the past, some researchers have suggested that it is the protein changes that are primary and that precede or trigger the abnormal immune response. From an article by Askanas and Engel: "Two hypotheses predominate regarding the key pathogenic mechanisms involved in s-IBM: an amyloid-beta-related degenerative process and an immune dysregulation. Ultimately, both may be considered important, and their possible interrelationship may be clarified. An intriguing feature is the accumulation within s-IBM muscle fibers of amyloid-beta (Ab), phosphorylated tau protein, and at least 20 other proteins that are also accumulated in the brain of Alzheimer's disease patients. In the s-IBM muscle fibers, there is evidence of misfolding of proteins, pathologic proteinaceous inclusions including aggresomes, abnormalities of the two protein-disposal systems involving the ubiquitin proteasome pathway and the lysosomes, mitochondrial dysfunctions, and oxidative stress. The pronounced T-cell inflammation can be striking, and it is characterized by activated, antigen-driven, cytotoxic CD8+ T-cells.

Genetic Aspects of sIBM

There are genetic features that do not directly cause IBM but that appear to predispose a person to getting IBM - having this particular combination of genes increases one's susceptibility to getting IBM. Some 67% of IBM patients have a particular combination of human leukocyte antigen genes in a section of the 8.1 ancestral haplotype in the center of the MHC class II region. sIBM is not passed on from generation to generation, although the susceptibility region of genes may be.

There are also several very rare forms of hereditary inclusion body myopathy (myopathies) that are linked to specific genetic defects and that are passed on from generation to generation. Because these forms do not show inflammation, they are classified as myopathies and not myositis types. Because they do not display inflammation as a primary symptom, they may in fact be similar, but different diseases than sporadic inclusion body myositis. There are several different types, each inherited in different ways. See hereditary inclusion body myopathy.

Genetic gene expression is different to genetic alterations polymorphism (biology). Gene expression indicates when a gene is switched on to perform its function. It now possible to determine which genes are switched on or off in certain disease processes and to indicate those that may be considered inappropriate.

A 2006 study reported in Proc Natl Acad Sci U S A found cells isolated from IBM, fail to differentiate into skeletal myotubes. These data correlate with lack in connective tissue of IBM muscle of alkaline phosphatase (ALP)-positive cells. A myogenic inhibitory basic helix-loop-helix factor B3 is highly expressed in IBM mesoangioblasts. Indeed, silencing this gene or overexpressing MyoD rescues the myogenic defect of IBM mesoangioblasts, opening novel cell-based therapeutic strategies for this crippling disorder. (see discussion)

The results of a 2008 study suggested that widespread, uncontrolled activation of genes is unlikely to be a component of the pathogenesis (cause) of IBM.

The detection of unexpected gene transcripts (expressions) using microarrays in inflammatory myopathy tissue has led to the discovery of new types and roles of immune system cells present in muscle in these diseases. Plasma cells and myeloid dendritic cells are abundant in polymyositis and inclusion body myositis muscle. The identification of new cells and pathways in inflammatory myopathies has led to deeper mechanistic understanding of these diseases and potential therapeutic approaches.

A 2007 review that summarized current understanding of the contribution of genetic susceptibility factors to the development of sIBM concluded there is no indication that the genes responsible for the familial or hereditary conditions are involved in sIBM.

Diagnosis

The term “inclusion body myositis” was originally introduced in 1971. Over the ensuing 35 years, s-IBM has been increasingly recognized and reported, mainly due to increased awareness by doctors and because of improved diagnostic tests. In spite of much progress, sIBM is still often difficult to diagnose and many patients are initially misdiagnosed, often with polymyositis.

A diagnosis is based on clinical signs and testing. The first common clinical signs are falling down and tripping and weakness in the finger flexors - the muscles involved in grip. Several different tests may be done to help diagnose sIBM including a blood test of the level of creatine kinase (CK) (also known as phosphocreatine kinase or creatine phosphokinase (CPK)). This is an enzyme in the blood produced when muscle cells are damaged, normally by the ordinary wear and tear of everyday life. Elevated levels indicate that abnormal muscle damage has occurred, or is occurring. Typically, in sIBM, CK values are about 10 times normal levels but may fall during the course of the disease . An electromyography (EMG) is often done and shows characteristic abnormalities. In this test, a small electric current is put into a muscle and a machine records how the muscle responds.

The best test to diagnose sIBM is a muscle biopsy (MBx). A small piece of muscle is surgically removed and then is studied in the laboratory. Several major changes in the muscle cells are usually visible that are characteristic of sIBM:

  • Inflammation is present and inflammatory cells are seen invading the muscle cells
  • Holes ("vacuoles") appear in the muscle fibers ("vacuolar degeneration")
  • Inclusions ("clumps" of material) are found inside the muscle fibers, these are associated with the build-up of several different abnormal proteins, including tau protein and beta amyloid.
  • There are twisted, abnormal filamentous protein strands called "paired-helical filaments" (PHFs). PHFs contain a protein called phosphorylated tau (p-tau) that shows up when the muscle is tested with a stain called SMI-31 monoclonal antibody – this test recognizes p-tau of the PHFs within s-IBM muscle fibers and also in the AD brain.
  • Another abnormal protein is called ubiquitin. Inclusions containing ubiquitin can usually be seen in the muscle biopsies of sIBM patients, but they do not appear in any other muscle illnesses (e.g., not in polymyositis).

Dalakas (2006) said: "If a patient has the typical clinical phenotype of sIBM, but the muscle biopsy shows only features of a chronic inflammatory myopathy (inflammation, large fibers, splitting, and increased connective tissue, but no vacuoles), the diagnosis is probable sIBM. If, however, there is also strong upregulation of major histocompatibility complex (MHC) class I antigens, and amyloid deposits and cytochrome-oxidase-negative fibers are present, the diagnosis of sIBM is rather more certain. . . . Shaking hands with a patient can provide the first indication of sIBM, because of the weak grip. If the patient complains of falls due to weakness at the knees and feet, has atrophic thighs, and does not report paresthesias or cramps, sIBM is very likely. Diagnostic dilemmas arise when the weakness and atrophy are slightly asymmetric or limited to the lower extremities, raising the possibility of a lower motor neuron disease. Motor neuron disorders, however, can be distinguished from IBM by the presence of hyperreflexia, cramps, fasciculations and large motor units on EMG."

Treatment

There have been several attempts to use different medications (immunotherapies) to treat sIBM but in clinical trials, although some have produced minor short term improvements, none has been shown to be effective in the long term. These include the common immunotherapeutic agents, such as corticosteroids, azathioprine, methotrexate, cyclosporine, cyclophosphamide and total lymphoid irradiation. Why this is so is a mystery because based on the theory presented here: these drugs should have a better effect in helping IBM. The response of dysphagia to intravenous immunoglobulin (IVIG) can be significant . The mild benefits in muscle strength experienced by HIBM patients after IVIG treatment may be related to the provision of sialic acid supplied by IVIG. Other sources of sialic acid are being explored as treatment options for HIBM.

Recent 2007 findings that the chemokine receptor profile of the idiopathic inflammatory myopathies (IM) indicates the predominance of Th1-mediated (inflammatory cytokine) cellular immune responses in all three IM. See T helper cell balance. Studies identified three ligand-receptor pairs, as potential targets for chemokine-based therapy in IM.

No medication has yet been developed specifically for sIBM.

New treatments called Biologic agents (Biologics) are being developed to treat immune disorders -- these are not drugs as we commonly understand them, made from chemicals, they are developed from proteins taken from the cell. One study by Dalakas is now under way is using an agent called Campath (alemtuzumab) to treat IBM .

A 2008 review of management strategies concluded that Inclusion body myositis is refractory to corticosteroids (cortisols) and to several immunomodulating therapies that have been used. Osteoporosis and opportunistic infections pose a significant risk during treatment of patients. This review discusses the clinical manifestations, pathology, and treatment approaches for the inflammatory myopathies.

Clinical Trials

Currently (October 2006) a study is being done to examine the safety and effectiveness of alemtuzumab (Campath (Registered Trademark)) for improving muscle strength in patients with sporadic inclusion body myositis (s-IBM). See:

Clinical trials are planned (2008) to investigate lithium as a treatment for IBM

Other Related Disorders

When sIBM was originally described, the major feature noted was muscle inflammation. Two other disorders were also known to display muscle inflammation, and sIBM was classified along with them. They are dermatomyositis (DM) and polymyositis (PM) and all three illnesses were called idiopathic inflammatory myositis or inflammatory myopathies (idiopathic means they don’t know what causes it).

It appears that sIBM and polymyositis share some common features, especially the initial sequence of immune system activation, however, polmyositis comes on over weeks or months, does not display the subsequent muscle degeneration and protein abnormalities as seen in IBM, and as well, polymyositis tends to respond well to treatments, IBM does not. IBM is often confused with (misdiagnosed as) polymyositis and polymyositis that does not respond to treatment is likely IBM.

Dermatomyositis appears to be a different disease altogether with different root causes unrelated to either PM or sIBM.

Recent Research Highlights

(April, 2008):

1). RING Finger Protein 5. Recent research has shown that a protein called RING Finger Protein 5 (RNF5) is important in muscle maintenance and regeneration. This protein is up-regulated (overproduced) in IBM. This protein is involved in the quality control process that scrutinizes protein production in the endoplasmic reticulum. This research team developed 3 mouse models to further research the role of this protein in muscle disorders. Research with these mice demonstrated that overexpression of RNF5 resulted in changes in the muscle consistent with those changes seen in IBM. Overproduction of RNF5 resulted in rapid and significant muscle deterioration, weakness and weight loss. This was followed by extensive muscle regeneration. These changes were also associated with markers of endoplasmic reticulum (ER) stress (ERS), a response to mis-folded protein buildup. Sensing this backup of abnormal protein, the ER recruits a mechanism of helpers through the Unfolded Protein Response mechanism (UPR). These helper chaperones then assist in the process of identifying and marking abnormal proteins for breakdown and recycling. It appears that at some point, the UPR response is overwhelmed and cannot handle the overload of mis-folded proteins, resulting in their buildup.

This research supports the theory that IBM is caused by ER stress and RNF5 may be an early causative link in this chain or possibly to trigger itself. This research opens up a new avenue of investigation for IBM. In addition, the mouse models developed provides an excellent means to test new drugs for their impact on IBM. Finally, the role played by the substrates of RNF5 in human muscle will have to be further investigated and articulated. Reference.

2). A recent study has found that the common drug lithium chloride (usually used to treat bipolar disorder) may be effective in slowing the development of IBM. The research demonstrated that an enzyme called GSK-3 beta is responsible for increasing the phosphorylation of tau protein, a hallmark of Alzheimer disease. High phospho-tau levels are also seen in IBM. This research demonstrated that lithium chloride blocks the GSK-3 beta enzyme. The impact in a mouse model was to the delay the rate of muscle decline. When this was observed, researchers performed tests on samples of human muscle tissue that confirmed the role of the enzyme again. Prolonged treatment with lithium chloride may also benefit motor function because it was found that mice maintained on the control diet showed a significant deterioration in performance over the 6-month test period. In contrast, all LiCl-treated mice showed a trend toward improved motor performance compared with the control animals, although this did not reach statistical significance. This research suggested in conclusion that clinical trials on IBM patients may be indicated.

3) Myostatin is a negative regulator of muscle growth. Research on muscle disorders has examined ways to inhibit Myostatin as a method to promote muscle growth and thus compensate for the muscle disease process. Problems such as immune reaction have previously prevented clinical use. Recent research has now demonstrated that Myostatin inhibition through a gene therapy technique increases muscle mass and strength in a mouse model. In this model, focused on duchenne muscular dystrophy, muscle mass and strength was increased. These results appear promising as a strategy to increase muscle mass in patients who have muscle related disorders, and this technique could be applied to IBM in the future. Reference.

References

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