Inclusion body myositis

IBM stands for "inclusion body myositis: not "inclusion body myopathy."[6] The 'inclusion body' refers to a histological finding of rimmed vacuoles in muscle tissue.[6] However, IBM does not refer to the collection of diseases that feature these inclusion bodies. It refers to a specific disease entity.[6]

Multiple genetic diseases that feature inclusion bodies have been grouped into "hereditary inclusion body myopathies (hIBM)."[6] Myopathy is used because inflammation is not a prominent finding. There is inconsistency in what individual disease entities fall under the category of hIBM.[6] The term "sporadic inclusion body myositis" (sIBM) was introduced as a way to refer to IBM to avoid confusion with hIBM.[6] However, one author discourages use of sIBM, as it implies that IBM and hIBM differ only in inheritance; they actually have unrelated mechanisms and manifestations of disease.[6]

Affected quadriceps (rectus femoris) in IBM

sIBM causes progressive muscle weakness.[1] How sIBM affects individuals is variable, including the age of onset (which generally varies from the forties upwards) and rate of progression. Because of this variability, there is no "textbook case".[13]

Common early symptoms include frequent tripping and falling and difficulty going up stairs. Foot drop in one or both feet can occur.[14] Part of the cause for this dysfunction is the early involvement of the quadriceps muscles.[1] Weakness of the tibialis anterior muscle is responsible for foot drop. Another common early symptom is trouble manipulating the fingers, such as difficulty with tasks such as turning doorknobs or gripping keys. Weakness of finger flexion and ankle dorsiflexion occurs early.[1] sIBM also preferentially affects the wrist flexors, biceps, and triceps.[1]

During the course of the illness, the patient's mobility is progressively restricted as it becomes difficult to bend down, reach for things, and walk quickly. 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.

Affected arms and fingers in IBM

Progressive difficulty swallowing (dysphagia) is present in 40 to 85% of IBM cases and often leads to death from aspiration pneumonia.[15]

IBM can also result in diminished capacity for aerobic exercise. This decline is most likely a consequence of the sedentary lifestyle leading to disuse muscle atrophy 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.[16]

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 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."[17]

The cause of IBM is unknown. IBM likely results from the interaction of a number of genetic and environmental factors.[18]

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.[19] 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."[20]

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.[17]

One review discusses the "limitations in the beta-amyloid-mediated theory of IBM myofiber injury."[21]

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.[19]

A self-sustaining T cell response would make sIBM a type of autoimmune disorder. When studied carefully, it has not been possible 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.[19]

• 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.[22]
• 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[23]

Inclusion body myositis histology

Elevated creatine kinase (CK) levels in the blood (at most ~10 times normal) are typical in sIBM but affected individuals can also present with normal CK levels. Electromyography (EMG) studies display variable abnormalities such as increased insertional activity,[26] increased spontaneous activity (fibrillation potentials and sharp waves),[1] and large/broad or short/narrow motor unit potentials.[1] On EMG, recruitment patterns can be reduced or increased. Findings can vary even within the same muscle of an affected individual.[1] Muscle biopsy may display several common findings including inflammatory cells invading muscle cells, vacuolar degeneration, and inclusion bodies of aggregations of multiple proteins.[27] sIBM is a challenge to the pathologist and even with a biopsy, diagnosis can be ambiguous.[28]

A diagnosis of inclusion body myositis was historically dependent on muscle biopsy results. Antibodies to cytoplasmic 5'-nucleotidase (cN1A; NT5C1A) have been strongly associated with the condition.[1] However, other inflammatory conditions, such as lupus, can have a positive anti-NT5C1A.[1] As of 2019, it remains to be established whether a positive anti-NT5C1A antibody test can make muscle biopsy unneeded.[1]

Inclusion body myositis MRI

Muscle imaging can help establish the pattern of muscle involvement and selection of a biopsy site.[1]

There is no standard course of treatment to slow or stop the progression of the disease as of 2019.[1] sIBM patients do not reliably respond to anti-inflammatory, immunosuppressant, or immunomodulatory medications.[31] Most of disease management is supportive care.[1] Prevention of falls is an important consideration.[1] There is no consensus on exercise guidelines; however, 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.[32] An exercise regimen preferentially minimizes a patient's risk of injury and corresponds to the patient's goals.[1][33]

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 (of unknown origin) myositis or inflammatory myopathies.[34]

It appears that sIBM and polymyositis share some features, especially the initial sequence of immune system activation, however, polymyositis 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. Polymyositis that does not respond to treatment is likely IBM.[35]

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.[36]

Mutations in valosin-containing protein (VCP) cause multisystem proteinopathy (MSP), which can present (among others) as a rare form of inclusion body myopathy.[37]

Prevalence of disease in a rigorous meta-analysis in 2017 was 46 patients per million.[6] The earliest published prevalence was in 2000 and put at 5 per million.[6] A 2017 study in Ireland reported 112 per million.[6] It is not believed that the disease prevalence is increasing with time, but rather diagnostics and reporting are improving.[6]

Estimates of the mean age of onset range from 61 to 68 years old.[6]

In the biographical drama film Father Stu, the protagonist, a boxer-turned-Catholic priest, has sIBM.[38][39]

• Inflammatory myopathies

• GeneReview/NIH/UW entry on Inclusion Body Myopathy 2