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 (vacuoles), 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 (Dalakas 2006). 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.

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 flexation -- 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 (Dalakas, 2006).

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." W. King Engel, and Valerie Askanas NEUROLOGY 2006;66 (Suppl 1): S20–S29

Types
-The common type is sIBM - it strikes individuals apparently at random.

-There is a type that has been observed in the siblings in several families: termed familial inflammatory sIBM, but 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.

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. Our 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." (Collins, Inclusion Body Myositis, eMedicine article from WebMD, Last Updated: May 15, 2006, Retrieved March 28, 2007 from http://www.emedicine.com/neuro/topic422.htm#section~introduction)

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, says "we can say that two processes, one autoimmune and the other degenerative, occur in the muscle cells in parallel."

Dalakas 2006 suggests 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. One confusing aspect is that medications that lower the immune response do not improve sIBM symptoms, as we would expect in the case of an autoimmune disorder.

When studied carefully, it has not been impossible to detect an ongoing viral infection in the muscles. The new 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 (Dalakas, 2006).

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 a recent article by Askanas and Engel: "Two hypotheses predominate regarding the key pathogenic mechanisms involved in s-IBM: an amyloid-b-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 Alzheimer brain. 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." Askanas V, Dalakas MC, Engel WK. NEUROLOGY 2006;66 (Suppl 1): Si.

amyloid protein

beta amyloid protein

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 (Dalakas 2006). 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 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) says: "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 (see below), 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 can be significant (Dalakas, 2006). 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 (see below).

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:

Genetics 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 our 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 (Dalakas 2006). 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.

Recent (November 2006) Research Advance.
Published online before print October 31, 2006 Proc. Natl. Acad. Sci. USA, 10.1073/pnas.0603386103

MyoD expression restores defective myogenic differentiation of human mesoangioblasts from inclusion-body myositis muscle.

Roberta Morosetti *, Massimiliano Mirabella *, Carla Gliubizzi *, Aldobrando Broccolini *, Luciana De Angelis ¶, Enrico Tagliafico ||, Maurilio Sampaolesi **, Teresa Gidaro *, Manuela Papacci *, Enrica Roncaglia ||, Sergio Rutella, Stefano Ferrari ||, Pietro Attilio Tonali *, Enzo Ricci *, and Giulio Cossu **

,*Department of Neurosciences and Interdisciplinary Laboratory for Stem Cell Research and Cellular Therapy, Catholic University, Largo A. Gemelli 8, 00168 Rome, Italy; Fondazione Don Carlo Gnocchi, 00194 Rome, Italy; Institute of Cell Biology and Tissue Engineering, San Raffaele Biomedical Science Park, 00128 Rome, Italy; ¶Department of Histology and Embriology, University "La Sapienza," 00161 Rome, Italy; ||Department of Biomedical Sciences, University of Modena and Reggio Emilia, 41100 Modena, Italy; **Stem Cell Research Institute, San Raffaele Hospital, 20132 Milan, Italy; Institute of Hematology, Catholic University, 00168 Rome, Italy; and Department of Biology, University of Milan, 20133 Milan, Italy Edited by Tullio Pozzan, University of Padua, Padua, Italy, and approved September 19, 2006 (received for review April 28, 2006)

This is a highly selective layman's translation and synopsis. Please refer to the original article for confirmation of the information presented here.

Synopsis: This research reports the isolation and characterization of mesoangioblasts, [ME - so - angie - OH - blasts] vessel-associated stem cells, obtained from the diagnostic muscle biopsies of patients with inflammatory myopathies (IM). Mesoangioblasts represent a distinct type of mesoderm progenitor cells that eventually develop (differentiate) into a variety of mesoderm tissues including skeletal, cardiac and smooth muscle. The number of mesoangioblast cells isolated, their rate of growth and lifespan, their marker expression, and their ability to differentiate into smooth muscle do not differ between mesoangioblasts from normal patients and IM mesoangioblasts. IBM mesoangioblasts show the same ability to divide that is observed in normal muscle suggesting that the disease has not reduced their proliferation potency. Nevertheless, although IBM mesoangioblasts can normally differentiate into smooth muscle cells (SMCs), their differentiation into skeletal muscle seems markedly impaired, because no skeletal myotubes are seen arising from IBM mesoangioblasts after laboratory stimulation. Thus, mesoangioblasts isolated from IBM, fail to differentiate into skeletal myotubes (developing skeletal muscle fibers characterized by their tubular appearance).

IBM mesoangioblasts were found to express high levels of genes known to inhibit the generation of new muscle (myogenesis) such as TGFbeta-1, SFRP-2 (secreted frizzled-related protein 2), and BHLHB3 (basic helix-loop-helix domain containing class B3 transcription factor).

In IBM mesoangioblasts, BHLHB3, is highly over active and this in turn inhibits MyoD function, thus preventing the creation of new muscle (myogenesis). IBM mesoangioblasts did not give rise to differentiated myotubes and did not display any MyoD genetic activity (no MyoD mRNA), and MyoD could not be induced by the researcher's laboratory techniques.

The problem of reduced MyoD function in IBM can be addressed in two ways. First, through cell transplantation. Using a mouse model, the researchers treated [human] IBM mesoangioblasts in the laboratory with a virus (an adenoviral vector) carrying with it the full-length mouse MyoD. So, the researchers took the genetic code for MyoD from mice and used the virsus to put it into these IBM mesoangioblast cells. These treated cells were then transplanted into the muscle of special research mice, significantly restoring normal muscle function. This introduction of MyoD overcomes the BHLHB3 inhibition. It also activates the MyoD that is already present in the cells, irreversibly making the cells generate new muscle.

Second, the researchers examined the effect of using a genetic method to block out the function of the BHLHB3 gene. The IBM mesoangioblasts display increased levels of BHLHB3 messenger RNA (mRNA), the inhibitor of MyoD. Therefore, the researchers used small interfering RNA (siRNA) created specifically to block the action of BHLHB3 in mesoangioblasts from three IBM patients. The siRNA treated cells were able to differentiate into muscle, giving rise to muscle myotubes after 7 days.

Therefore, either by silencing the overactive BHLHB3 gene or by transplanting modified cells in order to over express MyoD, we should be able to restore muscle genesis in the IBM mesoangioblasts, opening the way for new cell-based therapeutic strategies to treat 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.