Elsevier

The Lancet Neurology

Volume 6, Issue 7, July 2007, Pages 620-631
The Lancet Neurology

Review
Inclusion body myositis: current pathogenetic concepts and diagnostic and therapeutic approaches

https://doi.org/10.1016/S1474-4422(07)70171-0Get rights and content

Summary

Inclusion body myositis is the most common acquired muscle disease in older individuals, and its prevalence varies among countries and ethnic groups. The aetiology and pathogenesis of sporadic inclusion body myositis are still poorly understood; however genetic factors, ageing, and environmental triggers might all have a role. Unlike other inflammatory myopathies, sporadic inclusion body myositis causes slowly progressing muscular weakness and atrophy, it has a distinctive pattern of muscle involvement, and is unresponsive to conventional forms of immunotherapy. This review covers the clinical presentation, diagnosis, treatment, and the latest information on genetic susceptibility and pathogenesis of sporadic inclusion body myositis.

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

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.

References (153)

  • MC Dalakas

    Muscle biopsy findings in inflammatory myopathies

    Rheum Dis Clin North Am

    (2002)
  • MC Dalakas

    The molecular and cellular pathology of inflammatory muscle diseases

    Curr Opin Pharmacol

    (2001)
  • A Bender et al.

    T cell heterogeneity in muscle lesions of inclusion body myositis

    J Neuroimmunol

    (1998)
  • I Lundberg et al.

    Analysis of cytokine expression in muscle in inflammatory myopathies, Duchenne dystrophy, and non-weak controls

    J Neuroimmunol

    (1995)
  • FL Mastaglia et al.

    Idiopathic inflammatory myopathies: epidemiology, classification, and diagnostic criteria

    Rheum Dis Clin North Am

    (2002)
  • P Cherin et al.

    Macrophagic myofasciitis associated with inclusion body myositis: a report of three cases

    Neuromuscul Disord

    (2001)
  • K Murata et al.

    Expression of the co-stimulatory molecule BB-1, the ligands CTLA-4 and CD28, and their mRNA in inflammatory myopathies

    Am J Pathol

    (1999)
  • G Vattemi et al.

    Endoplasmic reticulum stress and unfolded protein response in inclusion body myositis muscle

    Am J Pathol

    (2004)
  • CC Yang et al.

    Immunolocalization of transcription factor NF-kB in inclusion body myositis muscle and at normal human neuromuscular junctions

    Neurosci Lett

    (1998)
  • SM Chou

    Myxovirus-like structures in a case of human chronic polymyositis

    Science

    (1967)
  • EJ Yunis et al.

    Inclusion body myositis

    Lab Invest

    (1971)
  • JR Mendell et al.

    Amyloid filaments in inclusion body myositis: novel findings provide insight into nature of filaments

    Arch Neurol

    (1991)
  • AA Amato et al.

    Inclusion body myositis: clinical and pathological boundaries

    Ann Neurol

    (1996)
  • UA Badrising et al.

    Epidemiology of inclusion body myositis in the Netherlands: a nationwide study

    Neurology

    (2000)
  • BA Phillips et al.

    Prevalence of sporadic inclusion body myositis in Western Australia

    Muscle Nerve

    (2000)
  • R Dabby et al.

    Inclusion body myositis mimicking motor neuron disease

    Arch Neurol

    (2001)
  • V Askanas et al.

    Inclusion body myositis: a myodegenerative conformational disorder associated with Aβ, protein misfolding, and proteasome inhibition

    Neurology

    (2006)
  • MC Dalakas

    Sporadic inclusion body myositis—diagnosis, pathogenesis, and therapeutic strategies

    Nat Clin Pract

    (2006)
  • EA Shamim et al.

    Differences in idiopathic inflammatory myopathy phenotypes and genotypes between Mesoamerican Mestizos and North American caucasians: ethnogeographic influences in the genetics and clinical expression of myositis

    Arthritis Rheum

    (2002)
  • KJ Felice et al.

    Inclusion body myositis in Connecticut: observations in 35 patients during an 8-year period

    Medicine

    (2001)
  • MJ Garlepp et al.

    HLA associations with inclusion body myositis

    Clin Exp Immunol

    (1994)
  • UA Badrising et al.

    Associations with autoimmune disorders and HLA class I and II antigens in inclusion body myositis

    Neurology

    (2004)
  • JB Lampe et al.

    Analysis of HLA class I and II alleles in sporadic inclusion-body myositis

    J Neurol

    (2003)
  • LA Love et al.

    A new approach to the classification of idiopathic inflammatory myopathy: myositis-specific autoantibodies define useful homogeneous patient groups

    Medicine

    (1991)
  • P Price et al.

    Two major histocompatibility complex haplotypes influence susceptibility to sporadic inclusion body myositis: critical evaluation of an association with HLA-DR3

    Tissue Antigens

    (2004)
  • TP O'Hanlon et al.

    Immunogenetic risk and protective factors for the idiopathic inflammatory myopathies: distinct HLA-A, -B, -Cw, -CRB1 and -DQA1 allelic

    Medicine

    (2005)
  • AA Amato et al.

    Inclusion body myositis in twins

    Neurology

    (1998)
  • GJ Hengstman et al.

    Familial inclusion body myositis with histologically confirmed sensorimotor axonal neuropathy

    J Neurol

    (2000)
  • K Sivakumar et al.

    An inflammatory, familial, inclusion body myositis with autoimmune features and a phenotype identical to sporadic inclusion body myositis: studies in three families

    Brain

    (1997)
  • V Askanas et al.

    New advances in inclusion body myositis

    Curr Opin Rheumatol

    (1993)
  • I Nishino et al.

    Distal myopathy with rimmed vacuoles is allelic to hereditary inclusion body myopathy

    Neurology

    (2002)
  • OM Vasconcelos et al.

    GNE mutations in an American family with quadriceps-sparing IBM and lack of mutations in sIBM

    Neurology

    (2002)
  • M Orth et al.

    Sporadic inclusion body myositis not linked to prion protein codon 129 methionine homozygosity

    Neurology

    (2000)
  • K Sivakumar et al.

    Exons 16 and 17 of the amyloid precursor protein gene in familial inclusion body myopathy

    Ann Neurol

    (1995)
  • MJ Garlepp et al.

    Apolipoprotein E and inclusion body myositis

    Ann Neurol

    (1996)
  • V Askanas et al.

    Apolipoprotein E alleles in sporadic inclusion body myositis and hereditary inclusion body myopathy

    Ann Neurol

    (1996)
  • G Gossrau et al.

    Apolipoprotein E and α-1-antichymotrypsin polymorphisms in sporadic inclusion body myositis

    Eur Neurol

    (2004)
  • CR Harrington et al.

    Apolipoprotein E type epsilon 4 allele frequency is not increased in patients with sporadic inclusion body myositis

    Neurosci Lett

    (1995)
  • S Love et al.

    Apolipoprotein E allele frequencies in sporadic inclusion body myositis

    Muscle Nerve

    (1996)
  • P Price et al.

    The genetic basis for the association of the 8.1 ancestral haplotype (A1, B8, DR3) with multiple immunopathological diseases

    Immunol Rev

    (1999)
  • Cited by (0)

    View full text