eMedicine Specialties > Neurology > Neuromuscular Diseases

Inclusion Body Myositis

Author: M Isabel Periquet Collins, MD, Assistant Professor, Department of Neurology, Medical College of Wisconsin
Coauthor(s): Michael P Collins, MD, Associate Professor, Department of Neurology, Medical College of Wisconsin; Paul E Barkhaus, MD, Professor, Department of Neurology, Medical College of Wisconsin; Director of Neuromuscular Diseases, Milwaukee Veterans Administration Medical Center
Contributor Information and Disclosures

Updated: May 15, 2006

Introduction

Background

Sporadic inclusion body myositis (s-IBM) and hereditary inclusion body myopathies (h-IBM) encompass a group of disorders sharing the common pathological finding of vacuoles and filamentous inclusions. They collectively demonstrate a wide variation in clinical expression, age of onset, associated diseases, and prognosis. This article focuses on s-IBM. For discussion of h-IBM, the reader is referred to other sources (Askanas, 1998; Argov, 2004).

The term inclusion body myositis was originally used by Yunis and Samaha in 1971 for a case of myopathy that phenotypically suggested chronic polymyositis but showed cytoplasmic vacuoles and inclusions on muscle biopsy. In the ensuing three decades, s-IBM has been increasingly recognized and reported, primarily because of increased awareness of the condition and improved histologic techniques. A relatively common myopathic process, s-IBM is an important diagnostic consideration in the evaluation of progressive weakness in older Caucasian males.

Expression of s-IBM is variable, but all cases eventually evolve into a syndrome of diffuse, progressive, asymmetric, proximal and distal weakness that is generally refractory to immunosuppressive treatment.

Pathophysiology

s-IBM is still classified as one of the idiopathic inflammatory myopathies along with dermatomyositis (DM) and polymyositis (PM), but the primacy of the inflammatory response in this condition remains a subject of debate. The true pathogenicity of the inflammatory reaction is supported by a number of clinical, morphologic, and immunologic observations.

First, as many as 20-33% of patients have a concomitant systemic or neurologic autoimmune disease (Koffman, 1998; Badrising, 2004). Second, monoclonal gammopathies are identified with increased frequency in patients with s-IBM compared with age-related controls (Dalakas, 1997). Third, s-IBM is known to occur in association with chronic viral infections known to produce immune dysregulation (eg, HIV, HTLV-I, hepatitis C) (Cupler, 1996; Saperstein, 1999; Tsuruta, 2001; Dalakas, 2006).

Fourth, although s-IBM is poorly responsive to many immunosuppressive agents, one small randomized controlled trial revealed a positive response to antithymocyte globulin (see Treatment). Fifth, s-IBM has a strong association with a susceptibility gene in the central major histocompatibility (MHC) region, possibly butyrophilinlike MHC class II associated gene (Price, 2004). Sixth, s-IBM is characterized by the presence of non-necrotic myofibers being invaded by mononuclear inflammatory cells, which as a pathologic phenomenon, is significantly more common than vacuolated, congophilic, and necrotic fibers (Pruitt, 1996). It is found at all stages of the disease in both treated and untreated patients. Most invaded fibers are nonvacuolated and lack amyloid deposits. Seventh, in contrast to normal muscle, MHC class I molecules are expressed on myofibers in patients with s-IBM, primarily in regions infiltrated by inflammatory cells (Karpati, 1988).

The endomysial infiltrates in patients with s-IBM are composed of primarily CD8+ T cells and macrophages in a 2:1 ratio (Engel and Arahata, 1984). B cells and natural killer cells are sparse. The autoinvasive CD8+ T cells surround MHC class I-immunoreactive myofibers and express perforin and other markers of activation (Arahata and Engel, 1988; Orimo, 1994; Schmidt, 2004). They have clonally restricted expression of the complementarity determining region 3 of the T-cell receptor (TCR) gene. Identical T-cell clones persistent over time, even in different muscles (Amemiya, 2000; Muntzing, 2003). Collectively, these observations implicate an antigen-driven, MHC class I-restricted, cytotoxic T-cell–mediated process directed against myofibers. The specific antigen responsible for this reaction has remained elusive.

In recent years, additional mechanisms underlying the T-cell–mediated destruction of myofibers have been adduced. Activation of naive CD8+ cells requires not only an interaction between the TCR and the antigen presented by the MHC I molecule but also a concomitant interaction between costimulatory molecules. An important costimulatory pair is CD28 expressed on T cells and B7 expressed on antigen presenting cells (APCs). Two B7 family members—BB1 and inducible co-stimulator ligand (ICOS-L)—are upregulated on MHC-expressing myofibers in s-IBM, whereas others (eg, B7.1 and B7.2) are not (Behrens, 1998; Schmidt, 2004) The counter receptor for ICOS-L—ICOS—is expressed by 5-10% of the autoinvasive CD8+ cells, the majority of which also express perforin. The B7-related molecule, B7-H1, is also upregulated on myofibers in s-IBM but serves an inhibitory role (Wiendl, 2003) Thus, myofibers may act as both stimulatory and regulatory APCs in s-IBM.

Abundant proinflammatory and regulatory cytokines, chemokines, and chemokine receptors are upregulated in s-IBM. Various studies have shown increased expression of such cytokines as interleukin 1 (IL-1), interleukin 2 (IL-2), interleukin 6 (IL-6), interleukin 10 (IL-10), tumor necrosis factor-a, (TNF-a), interferon-g (INF-g), and transforming growth factor-b (TGF-b) (Figarella-Branger, 2003; Dalakas, 2006). Upregulated chemokines include CCL2, CCL3, CCL4, CCL5, CCL8, CCL13, CCL18, CCL19, CCL21, CXCL1, CXCL2, CXCL3, CXCL9, CXCL10 CXCL11, CXCL13, and CXCL14 (Greenberg, 2002; Figarella-Branger, 2003; Raju, 2003; Civatte, 2005; De Paepe, 2005; De Paepe and De Bleecker, 2005; Raju and Dalakas, 2005).
 
The corresponding cytokine receptors CCR1, CCR2, CCR3, CCR4, CCR5, CXCR2, CXCR3, and CXCR4 are upregulated on autoinvasive inflammatory cellsand/or endothelial cells. The predominantly upregulated chemokines vary between studies. In microarray experiments, cytokine and chemokine genes are differentially upregulated to a significantly greater degree in s-IBM and PM than in DM (Greenberg, 2002; Raju and Dalakas, 2005).

An additional role for humoral immunity may be present in the pathogenesis of s-IBM. Microarray studies have shown that many of the highest differentially expressed genes in s-IBM are immunoglobulin (Ig) genes. Indeed, Ig gene transcripts are expressed to a much greater degree in s-IBM and PM than in DM I (Greenberg, 2002; Raju and Dalakas, 2005). Although B cells are rarely encountered in s-IBM muscle specimens, a recent immunohistochemical study revealed Ig-transcribing plasma cells in the endomysium of patients with s-IBM in numbers 4 times higher than B cells (1/12 as numerous as T cells) (Greenberg, 2005). That said, no evidence exists to date that plasma cell-produced antibodies mediate tissue destruction in s-IBM muscle.

Despite the preceding arguments in favor of an adaptive immune response in s-IBM, a purely autoimmune hypothesis for s-IBM is untenable because of the disease's resistance to most immunotherapy. Therefore, the alternate theory has arisen that s-IBM is a primarily degenerative disorder related to aging of the muscle, supported by the finding of abnormal, potentially pathogenic protein accumulations in myofibers. Askanas and Engel, in particular, have advanced the hypothesis that s-IBM is a myodegenerative disease featuring the intracellular accumulation of many proteins, protein aggregation and misfolding, proteosome inhibition, and endoplasmic reticulum (ER) stress (Askanas and Engel, 2006).

Similar to the brain in patients with Alzheimer disease, myofibers in s-IBM accumulate amyloid-b (A b), phosphorylated tau (p-tau), apolipoprotein E, presenilin-1, the normal cellular isoform of prion protein (PrPc), and many other characteristic proteins (Mikol and Engel, 2004; Askanas and Engel, 2006). A b is a 40- to 42-amino acid peptide that is a putatively toxic, proteolytic product of amyloid-b precursor protein (A b PP). It has the tendency to self associate into oligomers or polymeric b -pleated sheet amyloid in s-IBM myofibers. Soluble A b oligomers are believed to more cytotoxic than the insoluble b -pleated sheets (Glabe and Kayed, 2006).

In s-IBM, deposits containing A b 42 are much more common than ones containing A b 40.

A b accumulation results from increased synthesis and abnormal processing of A b PP in s-IBM muscle (Vattemi, 2003). Free cholesterol is abnormally accumulated in s-IBM, colocalized with A b, p-tau, and caveolin-1, and may increase A b production (Jaworska-Wilczynska, 2002). Askanas and Engel have proposed that overexpression of A b PP and accumulation of toxic A b oligomers are early upstream events in the pathogenesis of s-IBM, predisposing to tau phosphorylation, oxidative stress, proteosomal inhibition, ER stress, mitochondrial dysfunction, and hence abnormal signal transduction and transcription (Askanas and Engel, 2006).

Two major types of protein aggregates are found in s-IBM myofibers: (1) rounded, plaquelike, A b inclusion bodies and (2) linear, squiggly, p-tau inclusions (paired helical filaments) (Mikol and Engel, 2004; Askanas and Engel, 2006). Both are amyloidogenic. In general, protein aggregation ensues from the binding of unfolded and misfolded polypeptides (Lee and Yu, 2005). Unfolded and misfolded proteins, in turn, result from increased transcription, impaired disposal, abnormal crowding, or abnormal posttranslational modification of proteins, as might be induced by oxidative stress, various toxins, and aging.
 
The inclusions of s-IBM contain markers of oxidative stress, g -tubulin, clusterin, a -synuclein, PrPc, ubiquitin, mutated ubiquitin (UBB+1), heat shock protein (HSP) 70, 26S proteosome subunits, and ER chaperones indicative of the unfolded protein response (UPR) (Fratta, 2004; Fratta, 2005; Ferrer, 2005; Mikol and Engel, 2004; Askanas and Engel, 2006).

A proposed mechanism involved in the formation of protein aggregates in s-IBM is inhibition of the ubiquitin-26S proteosome system, which is the primary degradation pathway for misfolded, unfolded, and other damaged proteins (Lee and Yu, 2005; Ciechanover, 2006).

Factors that might contribute to proteosome dysfunction in s-IBM include increased production of A b PP/A b, the aging myofiber milieu, oxidative stress, ubiqitinated UBB+1, p-tau, and protein overcrowding (Fratta, 2005). HSP70, on the other hand, plays a protective role, promoting refolding of A b and other misfolded/unfolded proteins (Askanas and Engel, 2006). The UPR is another protective mechanism (Mori, 2000; Zhang and Kaufman, 2006). The ER is an intracellular organelle involved in the processing, folding, and assembly of proteins destined for the extracellular space, plasma membrane, or secretory apparatus.

Accumulation of unfolded or misfolded proteins in the ER triggers the UPR, which is a survival mechanism. The UPR comprises (1) the transcriptional induction of ER chaperone proteins to facilitate the folding, processing, and export of secretory proteins; (2) translational attenuation to reduce protein overload; and (3) increased retrotranslocation of misfolded proteins into the cytoplasm for ubiquitination and subsequent proteosomal degradation. In s-IBM muscle, expression of ER chaperone proteins is increased, colocalized with A b and A b PP, suggesting that the UPR is activated in s-IBM and promotes proper A b PP folding (Vattemi, 2004).

Several protein kinases are also involved in the s-IBM pathogenic cascade. Kinases that promote tau phosphorylation include cyclin-dependent kinase 5 (Cdk5) and glycogen synthase kinase 3 b (GSK3 b). Phosphorylation of tau by GSK3 b is enhanced by A b. Both Cdk5 and GSK b 3 are strongly expressed in vacuolated myofibers, where they colocalize with p-tau and the paired helical filaments (Nakano, 1999; Mikol and Engel, 2004). Mitogen-activated protein kinases (MAPKs) are also upregulated in s-IBM, especially extracellular signal-regulated kinase (ERK), which associates with the paired helical filaments (Li and Dalakas, 2000; Nakano, 2001).

Theoretically, the abnormal protein accumulations in s-IBM could be linked to the T-cell–mediated immune response by way of self-antigen presentation in MHC I-expressing myofibers. For example, immunoproteosome subunits LMP2, LMP7, and MECL1 are upregulated in s-IBM myofibers at sites of pathologic protein accumulation, sometimes colocalized with MHC I (Ferrer, 2004). The immunoproteosome is specialized to produce antigenic peptides that can be presented by MHC class I molecules (Dahlmann, 2005). Thus, A b might be presented to CD8+ T cells by degenerating myofibers in s-IBM, with an ensuing immune response amplified by increased T-cell reactivity to A b in elderly persons (Monsonego, 2003).
 
However, as previously noted, the myofibers invaded by T cells in s-IBM are almost never vacuolated, and the vacuolated fibers are almost never surrounded by mononuclear inflammatory cells, arguing against a cytotoxic T-cell response to A β or any other abnormally accumulated protein in s-IBM.

Of course, neither A b PP/A b -induced toxicity nor CD8+ T-cell–mediated cytotoxicity may be the primary event in s-IBM. In this regard, muscle biopsy specimens in patients with s-IBM harbor numerous a B-crystallin-immunoreactive myofibers in the absence of any significant structural abnormality (Banwell and Engel, 2000). These "X fibers" are severalfold more frequent than necrotic, regenerating, vacuolated, and non-necrotic/invaded fibers and are many times more frequent than fibers with Congo red-, phosphorylated tau-, or ubiquitin-positive inclusions. a B-crystallin is a small HSP, but the expression of other HSPs and markers of oxidative stress are not increased in X fibers, arguing against the presence of a nonspecific stress response or oxidative stress in these fibers.

The implication of this finding is that increased expression of a B-crystallin is an early event in the pathogenesis of s-IBM, triggered by an unidentified stressor acting upstream to the development of vacuolated, necrotic, invaded, and congophilic fibers. Engel has speculated that this stressor might be a viral infection or mutated gene (Banwell and Engel, 2000; Mikol and Engel, 2004).

Frequency

United States

s-IBM is considered the most common acquired myopathy in patients older than 50 years and accounts for 16-28% of inflammatory myopathies in the United States and Canada.

International

In 2 population-based studies, a prevalence of 4.9 per million was reported in the Netherlands (which was felt to be an underestimate) and 9.3 per million in western Australia. The corresponding figures for individuals older than 50 years were 16 and 35.3 per million, respectively (Badrising, 2000; Phillips, 2000).

Mortality/Morbidity

  • The slow, relentless progression of muscle weakness in s-IBM leads to difficulty with ambulation, frequent falls, and eventual need for assistive-gait devices. Bone fractures and other complications may occur as a result of falls.
  • Dysphagia due to weakness of the cricopharyngeal musculature commonly occurs and may predispose individuals to aspiration pneumonia.
  • Mortality rate is difficult to assess based on current data. Affected individuals tend to be older, the disease is insidious and chronic, and patients often die of other medical problems. In a population-based study, the mean age of death of patients with sIBM was not significantly different from that of the general population. Cause of death was disease-related (aspiration pneumonia and respiratory insufficiency) in 2 of 22 reported deaths (Badrising, 2000).

Race

  • No race predilection for s-IBM is known, but it is uncommon among African Americans.

Sex

  • Reported male-to-female ratio ranges from 1.4:1 to 3:1 (Lotz, 1989; Phillips, 2000;, Badrising, 2000).

Age

  • Age of onset ranges from the late second to ninth decades. Mean age of onset is 56-60 years (Lotz, 1989; Badrising, 2000; Phillips, 2000).
  • While a large majority of individuals develop symptoms when older than 50 years, 17-20% present before the age of 50 (Lotz, 1989; Lindberg, 1994; Badrising, 2005).

Clinical

History

Since s-IBM is an acquired myopathic process, weakness or impairment of muscle function in the area(s) affected is the presenting symptom.

  • The distribution of weakness in s-IBM is variable, but both proximal and distal muscles are usually affected and, unlike polymyositis and dermatomyositis, asymmetry is common.
  • Early involvement of the knee extensors, ankle dorsiflexors, and wrist/finger flexors is characteristic of s-IBM.
  • Weakness of the wrist and finger flexors is often disproportionate to that of their extensor counterparts. Hence, loss of finger dexterity and grip strength may be a presenting or prominent symptom.
  • Dysphagia is common, occurring in 40-66% of patients with well-established disease and in 9% of patients at presentation (Lotz, 1989; Badrising, 2005). Dysphagia may manifest as a feeling of stasis, a need to swallow repeatedly, regurgitation, or choking.
  • Isolated erector spinae weakness or "droopy neck" syndrome has been reported with s-IBM (Hund, 1995).
  • Myalgias and cramping are relatively uncommon.
  • Sensory and autonomic dysfunction is not present except in patients with a concurrent polyneuropathy.
  • Cardiac disease is common; it is most likely due to the older age of most patients. Direct cardiac muscle involvement by the disease has not been demonstrated.

Physical

  • Clinical suspicion for s-IBM should be very high when the pattern of weakness affects (1) the finger/wrist flexors out of proportion to the finger/wrist extensors and shoulder abductors or (2) knee extensors disproportionate to the hip flexors.
  • Patients have variable degrees of limb weakness and atrophy, which is usually both proximal and distal, and often, but not always, asymmetric.
  • Facial muscle weakness may occur, but extraocular muscles are not affected and ptosis is not seen.
  • Tendon reflexes may be normal or decreased.
  • Decreased sensation in the distal lower extremities and reduced ankle jerks are not uncommon, as some patients have a concurrent polyneuropathy, which may be disease-related.
  • Other neurological subsystem involvement (eg, cognitive function, coordination, upper motor neuron dysfunction) is not seen in s-IBM. The presence of such findings should raise suspicion for other processes.
  • Examination for skin lesions, joint swelling/tenderness, and other systemic signs suggesting a concomitant autoimmune disorder should be routinely performed.
  • Cardiovascular examination should evaluate for hypertension, cardiac dysrhythmia/conduction abnormalities, and cardiac failure.

Causes

The cause of s-IBM remains unknown. See Pathophysiology.

More on Inclusion Body Myositis

Overview: Inclusion Body Myositis
Differential Diagnoses & Workup: Inclusion Body Myositis
Treatment & Medication: Inclusion Body Myositis
Follow-up: Inclusion Body Myositis
Multimedia: Inclusion Body Myositis
References
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Further Reading

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Keywords

sporadic inclusion body myositis, s-IBM, hereditary inclusion body myopathies, h-IBM, idiopathic inflammatory myopathies

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Contributor Information and Disclosures

Author

M Isabel Periquet Collins, MD, Assistant Professor, Department of Neurology, Medical College of Wisconsin
M Isabel Periquet Collins, MD is a member of the following medical societies: American Academy of Neurology and American Association of Neuromuscular and Electrodiagnostic Medicine
Disclosure: Nothing to disclose.

Coauthor(s)

Michael P Collins, MD, Associate Professor, Department of Neurology, Medical College of Wisconsin
Michael P Collins, MD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Neurology, American Association of Neuromuscular and Electrodiagnostic Medicine, American Medical Association, and Peripheral Nerve Society
Disclosure: Nothing to disclose.

Paul E Barkhaus, MD, Professor, Department of Neurology, Medical College of Wisconsin; Director of Neuromuscular Diseases, Milwaukee Veterans Administration Medical Center
Paul E Barkhaus, MD is a member of the following medical societies: American Academy of Neurology, American Association of Neuromuscular and Electrodiagnostic Medicine, and American Neurological Association
Disclosure: Nothing to disclose.

Medical Editor

Dianna Quan, MD, Director, Electromyography Laboratory, Department of Neurology, Assistant Professor, University of Colorado Health Sciences Center
Dianna Quan, MD is a member of the following medical societies: American Academy of Neurology, American Association of Neuromuscular and Electrodiagnostic Medicine, and Phi Beta Kappa
Disclosure: Nothing to disclose.

Pharmacy Editor

Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine
Disclosure: Nothing to disclose.

Managing Editor

Glenn Lopate, MD, Associate Professor, Department of Neurology, Division of Neuromuscular Diseases, Washington University School of Medicine; Chief of Neurology, St Louis ConnectCare, Consulting Staff, Barnes Jewish Hospital
Glenn Lopate, MD is a member of the following medical societies: American Academy of Neurology, American Association of Neuromuscular and Electrodiagnostic Medicine, and Phi Beta Kappa
Disclosure: Nothing to disclose.

CME Editor

Selim R Benbadis, MD, Professor, Director of Comprehensive Epilepsy Program, Departments of Neurology and Neurosurgery, University of South Florida School of Medicine, Tampa General Hospital
Selim R Benbadis, MD is a member of the following medical societies: American Academy of Neurology, American Academy of Sleep Medicine, American Clinical Neurophysiology Society, American Epilepsy Society, and American Medical Association
Disclosure: Nothing to disclose.

Chief Editor

Nicholas Y Lorenzo, MD, Chief Editor, eMedicine Neurology; Consulting Staff, Neurology Specialists and Consultants
Nicholas Y Lorenzo, MD is a member of the following medical societies: Alpha Omega Alpha and American Academy of Neurology
Disclosure: Nothing to disclose.

 
 
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