References for this review were identified by searches of Medline and PubMed for articles from 1966 until February 2007 with the terms “inclusion body myositis” and “inclusion body myopathies”. Articles were also identified through searches of the authors' own files. Only papers published in English were reviewed.
ReviewInclusion body myositis: current pathogenetic concepts and diagnostic and therapeutic approaches
Introduction
Chou first described sporadic inclusion body myositis in 1967 in a 66-year-old man with chronic polymyositis. A muscle biopsy showed that the patient had distinctive intranuclear and cytoplasmic filamentous inclusions and vacuoles.1 The term inclusion body myositis was not introduced until 1971, by Yunis and Samaha,2 and it was not until 1991 when Mendell and colleagues,3 using Congo red staining, first identified the presence of amyloid in muscle fibres. Sporadic inclusion body myositis is now recognised as the most common inflammatory myopathy in individuals over the age of 50 years and the most important myopathy associated with ageing. Unlike other inflammatory myopathies, this disorder is usually unresponsive to treatment and has a slowly progressing clinical course; it most severely affects the forearm flexor and quadriceps femoris muscles,4 leading to loss of manual control, impaired mobility, and a propensity to fall, which is one of the most disabling features of the disease. Because of the insidious nature of the disease and the limited awareness among medical practitioners of its existence, the diagnosis of sporadic inclusion body myositis is commonly delayed.5, 6 Early symptoms are attributed to arthritis in some cases, or the disorder can be misdiagnosed as motor neuron disease.7
The aetiopathogenesis of sporadic inclusion body myositis is enigmatic but almost certainly involves the complex interaction of ageing and genetic and environmental factors. The pathological characteristics of sporadic inclusion body myositis are a unique triad: inflammatory changes, with invasion by CD8+ lymphocytes of muscle fibres expressing MHC-I; cytoplasmic and intranuclear inclusions containing amyloid β and several other Alzheimer-type proteins; and segmental loss of cytochrome c oxidase (COX) activity in muscle fibres, which is associated with the presence of clonally expanded somatic mitochondrial DNA (mtDNA) mutations. The interaction among these various pathological changes remain unknown, and there is continuing debate as to whether sporadic inclusion body myositis is primarily a T-cell-mediated inflammatory myopathy or a myodegenerative disorder8, 9 characterised by abnormal protein aggregation and inclusion body formation, with a secondary inflammatory response.
In this Review we address the latest ideas in the pathogenesis of sporadic inclusion body myositis, the present understanding of the molecular derangements, the role of genetic factors that might underlie individual susceptibility to the disease, and the geographic and ethnic differences in its prevalence. We also discuss the importance of clinical and pathological markers in the diagnosis of sporadic inclusion body myositis and the current and emerging approaches to the treatment of this disorder.
Section snippets
Epidemiology
Although there have been few population studies, the incidence of sporadic inclusion body myositis varies between different countries and ethnic groups: the incidence is low in Korean, African-American and Mesoamerican Mestizo,10 middle eastern, and southern Mediterranean populations (P Serdaroglu, Istanbul University, personal communication) compared with northern European, North American white, and white Australian populations. Reported prevalence figures range from 4·9 per million in the
Genetics
The evidence for genetic susceptibility has come mainly from studies of the HLA and MHC. The strong association of sporadic inclusion body myositis with HLA-DR3 and the 8·1 MHC ancestral haplotype (defined by the alleles HLA-A1, B8, DRB3*0101, DRB1*0301, DQB1*0201) was first reported in patients from Western Australia,12 and confirmed in Dutch, German, and North American patients, respectively.13, 14, 15 The association of sporadic inclusion body myositis with DR3 is one of the most robust
Clinical features
Although sporadic inclusion body myositis usually presents after the age of 50 years, symptoms can start up to 20 years earlier.37 The most common reasons for presentation are related to weakness of the quadriceps muscles, such as difficulty rising from low chairs or from the squatting or kneeling positions (eg, when gardening), walking up or down stairs, and climbing ladders. Some patients with sporadic inclusion body myositis only present when they have severe weakness and atrophy of the
Diagnosis
Serum creatine kinase concentration is moderately raised in some cases (usually less than ten-times the upper limit of the normal range) but can also be normal or only mildly raised and is not a useful diagnostic finding. Electromyography can help to confirm the myopathic nature of the muscle weakness and atrophy, but the added findings of spontaneous activity (fibrillation potentials and positive waves) and high-amplitude, long-duration motor unit potentials in affected muscles can be
Pathogenesis
The cause and pathogenesis of sporadic inclusion body myositis remain unknown, despite evidence emphasising the importance of both the inflammatory and myodegenerative features of the disease. Both of these processes have a role in the disease process but which one occurs first and which has the dominant role is still debated.
There is much evidence that sporadic inclusion body myositis is primarily an immune-mediated muscle disease (Panel 2, Panel 3). The activation of CD8+ T cells and the
Treatment
Sporadic inclusion body myositis is a relentlessly progressive disorder: most patients require a walking aid after about 5 years and the use of a wheelchair by about 10 years.126, 127 This protracted course has made the results of drug trials difficult to interpret because few trials have been of adequate duration or have had sufficient power to detect even slight treatment effects. Therefore, there are insufficient data to enable an evidence-based approach to treatment.
Experience shows that
Conclusions and future challenges
The main challenges are to clarify further the pathogenesis of the disease and to develop more effective forms of treatment that will stop the pathological changes, if introduced early in the course of the disease. Of particular importance is the need to identify the changes in muscle fibres that precede the formation of rimmed vacuoles and amyloid inclusions and to clarify the role of oxidative stress, the factors involved in inducing cell stress and the upregulation of MHC-I expression, and
Search strategy and selection criteria
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HLA allele distribution distinguishes sporadic inclusion body myositis from hereditary inclusion body myopathies
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Sporadic inclusion body myositis in Japanese is associated with the MHC ancestral haplotype 52.1
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Immunolocalization of ubiquitin in muscle biopsies of patients with inclusion body myositis and oculopharyngeal muscular dystrophy
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Rimmed vacuoles and the added value of SMI-31 staining in diagnosing sporadic inclusion body myositis
Neuromuscul Disord
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Inclusion body myositis: morphological clues to correct diagnosis
Neuromuscul Disord
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