Inclusion body myositis

Inclusion body myositis (IBM) is an inflammatory muscle disease, characterized by slowly progressive wasting and weakness of the arms and legs. Two features characterize the sporadic inclusion body myositis (sIBM) muscle: profound inflammation and protein abnormalities within the muscle cells. The inflammation aspect is similar to polymyositis however, polymyositis does not display many of the abnormal cellular changes seen in sIBM. Additionally, in contrast with polymyositis(PM), sIBM affects men more than women and is resistant to treatment (PM often responds well). Symptoms usually begin after 50 years of age. There is no effective treatment for the disease.

Sporadic inclusion body myositis ^* (sIBM) is a disease of the muscle cells. The muscle cells somehow become abnormal and the immune system kills them, weakening the muscles. Its name comes form the fact that the muscles in sIBM are characterized by "inclusion bodies" within the cells. 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. It is more common in men (2 to 3 males to 1 female). sIBM is an age-related disease - as we get older it gets more and more common. It usually appears after the age of 50 and 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 and progresses steadily and may lead to severe weakness and wasting of arm and leg muscles. Patients may become unable to perform daily living activities and be confined to wheelchairs. 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).

Symptoms

How sIBM affects individuals is quite variable as is the age of onset (which 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. Usually, the muscles initially afflicted by sIBM are those in the arms and legs, resulting in difficulty performing various everyday tasks, such as getting out of chairs. Another common and distinct characteristic of sIBM is an early and severe weakening of the finger flexor muscles, leading to difficulties in grasping and holding on to things..

During the course of the illness, the patient's mobility is progressively restricted as it becomes hard for them 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.

In up to 33 to 50 percent of cases, patients with sIBM develop weakness in the pharyngeal muscles, used in swallowing.

Patients with sIBM eventually need to resort to a cane or a walker. In most cases, a wheelchair eventually becomes a necessity, usually within 5 to 10 years from initial diagnosis.

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

Causes

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

It appears that in people with sIBM, the muscle cells display “flags” telling the immune system that they are infected or damaged and the immune system attacks the cells and kills them, which would label it as an autoimmune disorder. One confusing aspect is that medications that lower the immune response do not improve sIBM symptoms, as should happen in the case of an autoimmune disorder.

There are also many abnormal protein changes within the muscle cells. Some researchers believe it is these protein changes that are primary and that precced or trigger the abnormal immune response.

From a recent article: "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

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 another inflammatory muscle disorder called 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. An electromyography (EMG) is often done. 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 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 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).

Weakness and wasting (shrinkage) in the quadriceps along with the finger flexor muscles and a CK level of about ten times normal are findings suggestive of sIBM. These findings are then often confirmed with a muscle biopsy.

Treatment

There have been several attempts to use different medications to treat sIBM but in clinical trials, none has been shown to be effective. No medication has ever been developed specifically for sIBM.

Other Directly Related Disorders

There are several other rare genetic forms of muscle illness related to sIBM, called inclusion body myopathy (myopathies). In these forms, inflammation (myositis) is not a major feature of the muscle cells (myopathy just means diseased muscle). These illnesses are inherited, but different types are inherited in different ways. About one case of inclusion body myopathy is seen for every ten cases of sporadic inclusion body myositis. See hereditary inclusion body myopathy

Other Related Disorders

When sIBM was originally described, the major feature was muscle inflammation. Two other disorders were also known to display muscle inflammation, so 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 does not display the subsequent protein abnormalities seen in IBM. As well, polymyositis tends to respond well to treatments, IBM does not. IBM and polymyositis apparently involve different disease mechanisms than are seen in dermatomyositis.

External links and references

Latest review: January 2006 Twenty two articles resulted from a conference held on inclusion body myositis (s-IBM) - Inclusion-body myositis: Clinical and pathologic aspects, and basic research potentially relevant to treatment. January 26-28, 2005 in Santa Monica. The TMA funded the Conference and the Muscular Dystrophy Association assisted by funding the printing and distribution of the Conference report. The 22 articles were published in electronic format as an Expedited E-Pub at www.neurology.org on December 16, 2005. They appear in print in Neurology Volume 66(2) Supplement 1 January 24, 2006. ^*

Muscular disorders