Inclusion body myositis


Inclusion body myositis is the most common inflammatory muscle disease in older adults. The disease is characterized by slowly progressive weakness and wasting of both proximal muscles and distal muscles, most apparent in the finger flexors and knee extensors. IBM is often confused with an entirely different class of diseases, called hereditary inclusion body myopathies. The "M" in hIBM is an abbreviation for "myopathy" while the "M" in IBM is an abbreviation for "myositis". These diseases should not be confused with each other. In IBM, two processes appear to occur in the muscles in parallel, one autoimmune and the other degenerative. Inflammation is evident from the invasion of muscle fibers by immune cells. Degeneration is characterized by the appearance of holes, deposits of abnormal proteins, and filamentous inclusions in the muscle fibers. sIBM is a rare disease, with a prevalence ranging from 1 to 71 individuals per million.
Weakness comes on slowly in an asymmetric manner and progresses steadily, leading to severe weakness and wasting of arm and leg muscles. IBM is more common in men than women. Patients may become unable to perform activities of daily living and most require assistive devices within 5 to 10 years of symptom onset. sIBM is not considered a disorder, but the risk of serious injury due to falls is increased. Death in IBM is sometimes related to malnutrition and respiratory failure. There is no effective treatment for the disease.

Signs and symptoms

How sIBM affects individuals is quite variable as is the age of onset. 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 quadriceps and forearm muscles are usually affected early on. Common early symptoms include frequent tripping and falling, weakness going up stairs and trouble manipulating the fingers. Foot drop in one or both feet has been a symptom of IBM and advanced stages of polymyositis.
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 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. 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."

Causes

The 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. This hypothesis emphasizes the abnormal intracellular accumulation of many proteins, protein aggregation and misfolding, proteosome inhibition, and endoplasmic reticulum stress.
One review discusses the "limitations in the beta-amyloid-mediated theory of IBM myofiber injury."
Dalakas 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 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 and this ER stress may be enough to cause a self-sustaining T cell response. 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 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.
sIBM is not inherited and is not passed on to the children of IBM patients. 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 rare forms of hereditary inclusion body myopathy that are linked to specific genetic defects and that are passed on from generation to generation. Since these forms do not show features of muscle inflammation, they are classified as myopathies rather than forms of myositis. Because they do not display inflammation as a primary symptom, they may in fact be similar, but different diseases to sporadic inclusion body myositis. There are several different types, each inherited in different ways. See hereditary inclusion body myopathy.
A 2007 review concluded there is no indication that the genes responsible for the familial or hereditary conditions are involved in sIBM.

Diagnosis

Elevated creatine kinase levels in the blood are typical in sIBM but affected individuals can also present with normal CK levels. Electromyography studies usually display abnormalities such as increased insertional activity and short duration motor unit potentials. Muscle biopsy may display several common findings including; inflammatory cells invading muscle cells, vacuolar degeneration, inclusions or plaques of abnormal proteins. sIBM is a challenge to the pathologist and even with a biopsy, diagnosis can be ambiguous.
A diagnosis of inclusion body myositis was historically dependent on muscle biopsy results. Antibodies to cytoplasmic 5'-nucleotidase have been strongly associated with the condition. In the clinical context of a classic history and positive antibodies, a muscle biopsy might be unnecessary.

Differential diagnosis

IBM is often initially misdiagnosed as polymyositis. A course of prednisone is typically completed with no improvement and eventually sIBM is confirmed. sIBM weakness comes on over months or years and progresses steadily, whereas polymyositis has an onset of weeks or months. Other forms of muscular dystrophy must be considered as well.

Classification

There is no standard course of treatment to slow or stop the progression of the disease. sIBM patients do not reliably respond to the anti-inflammatory, immunosuppressant, or immunomodulatory medications. Management is symptomatic. Prevention of falls is an important consideration. Specialized exercise therapy may supplement treatment to enhance quality of life. Physical therapy is recommended to teach the patient a home exercise program, to teach how to compensate during mobility-gait training with an assistive device, transfers and bed mobility.

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 and polymyositis and all three illnesses were called idiopathic myositis or inflammatory myopathies.
It appears that sIBM and polymyositis share some 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 polymyositis. Polymyositis that does not respond to treatment is likely IBM.
Dermatomyositis shares a number of similar physical symptoms and histopathological traits as polymyositis, but exhibits a skin rash not seen in polymyositis or sIBM. It may have different root causes unrelated to either polymyositis or sIBM.
Mutations in valosin-containing protein cause multisystem proteinopathy, which can present as a rare form of inclusion body myopathy.