Inclusion Body Myositis
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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. [1] 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. [2, 3]
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 subsequent years, 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.
s-IBM has been traditionally classified as one of the idiopathic inflammatory myopathies along with dermatomyositis (DM) and polymyositis (PM). However, the pathologic findings of sporadic inclusion body myositis (s-IBM) involve both inflammatory and degenerative characteristics, and the true primary pathogenesis of the disease remains a subject of significant debate. Theoretically, the possibilities include (1) a primary T-cell mediated autoimmune response causing muscle damage, (2) a primary degenerative process involving abnormal protein processing leading to a secondary inflammatory response, and (3) separate and independent immune and degenerative processes caused by an external trigger. [4]
s-IBM is characterized by the presence of non-necrotic myofibers invaded by mononuclear inflammatory cells, which, as a pathologic phenomenon, is significantly more common than vacuolated, congophilic, and necrotic fibers. [5, 6] It is found at all stages of the disease in both treated and untreated patients.
The endomysial infiltrates in patients with s-IBM are composed primarily of CD8+ T cells and macrophages in a 2:1 ratio. [7] Myeloid dendritic (antigen-presenting) and CD138+ plasma cells are also present in substantial numbers, [8, 9] while B cells and natural killer (NK) cells are rare. T cells, macrophages, and myeloid dendritic cells all have the potential to invade non-necrotic muscle fibers. [10] The autoinvasive CD8+ T cells surround major histocompatibility complex (MHC) class I-immunoreactive myofibers and express perforin and other markers of activation. [11, 12, 13]
Identical autoinvasive T-cell clones can persist over time, even in different muscles, [14, 15] but the amplified subfamilies sometimes change, which suggests of epitope spreading. [16] Collectively, these observations implicate an antigen-driven, MHC class I-restricted, cytotoxic T-cell–mediated process directed against myofibers. The specific antigens responsible for this reaction are unknown.
Various chemokines, cytokines, and chemokine receptors are upregulated in the inflammatory cell infiltrates, blood vessels, and myofibers in s-IBM. [17] In microarray experiments, cytokine and chemokine genes are differentially upregulated to a significantly greater degree in s-IBM and polymyositis than in dermatomyositis. [18, 19]
Humoral immunity may also play a role 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 polymyositis than in dermatomyositis. [18, 19] Although B cells are rarely encountered in s-IBM muscle, plasma cells occur in the endomysium of patients with s-IBM in numbers 4 times higher than B cells. [8] Moreover, an analysis of antigen receptor H chain gene transcripts of B and plasma cells isolated from s-IBM muscle showed evidence of clonal expansion and variation, isotype switching, and somatic hypermutation, indicative of a local antigen-driven humoral response. [20]
Additional evidence for a primary immune etiology includes the fact that as many as 20-33% of patients with s-IBM have a concomitant systemic or neurologic autoimmune disease. [21, 22] Monoclonal gammopathies are identified with increased frequency in patients with s-IBM compared to age-related controls. [23] In addition, s-IBM is known to occur in association with chronic viral infections known to produce immune dysregulation (eg, HIV, human T-cell lymphotrophic virus I [HTLV-I], and hepatitis C). [24, 25, 26, 27]
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.
Myofibers in s-IBM exhibit vacuolization, atrophy, abnormal myonuclei, [28, 29] and deposits of degeneration-associated proteins. Similar to actions in Alzheimer disease, myofibers in s-IBM accumulate amyloid-β (Aβ), phosphorylated tau (p-tau), apolipoprotein E, presenilin-1, the normal cellular isoform of prion protein (PrPc), and many other characteristic proteins. [30, 31, 32] Two major types of protein aggregates are found in s-IBM myofibers: (1) rounded, plaquelike, Aβ inclusion bodies; and (2) linear, squiggly, p-tau inclusions (paired helical filaments). [30, 31] Both are amyloidogenic.
In general, protein aggregation ensues from the binding of unfolded and misfolded polypeptides. [33] 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. A specifically 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. [33, 34]
Of these various alien molecules, Aβ is putatively toxic. [35] Soluble Aβ oligomers are believed to be more cytotoxic than the insoluble β-pleated sheets. [36] Aβ accumulation results from increased synthesis and abnormal processing of amyloid precursor protein (APP) in s-IBM muscle. [37] Askanas and Engel have proposed that overexpression of APP and accumulation of toxic Aβ oligomers are early upstream events in the pathogenesis of s-IBM, predisposing to tau phosphorylation, oxidative stress, proteosomal inhibition, endoplasmic reticulum (ER) stress, mitochondrial dysfunction, and, hence, abnormal signal transduction and transcription. [38, 39] That said, the accumulation of Aβ in s-IBM myofibers has been challenged. [40]
Accumulation of unfolded or misfolded proteins in the ER triggers the unfolded protein response (UPR), which is a survival mechanism. [41, 42] 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 Aβ and APP, suggesting that the UPR is activated in s-IBM and promotes proper APP folding. [43] Another protective agent is heat shock protein (HSP) 70, which promotes refolding of Aβ and other misfolded or unfolded proteins. [31]
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-3β (GSK-3β). Both Cdk5 and GSK-3β are strongly expressed in vacuolated myofibers, where they colocalize with p-tau and the paired helical filaments. [44, 30] Lithium inhibits GSK-3β and was shown to decrease tau phosphorylation in a transgenic mouse model of s-IBM. [45] Its clinical efficacy in s-IBM is now being investigated in a pilot study.
Most of the rimmed vacuoles in s-IBM are autophagic and composed of lysosomes. [25, 46, 47] Accumulated Aβ and APP are specific targets of macroautophagy in this disease. [47] However, some of the vacuoles lack lysosomal features and instead contain nuclear proteins, suggesting that they result from the breakdown of myonuclei. [48, 49] Nuclear membrane remnants (lamin A/C and emerin), nuclear histones, and the nuclear transcription factor pElk-1 have been found in rimmed vacuoles. [48, 50] Thus, the formation of rimmed vacuoles in s-IBM is probably mediated by more than one mechanism.
As a likely secondary phenomenon, various mitochondrial abnormalities have been identified in s-IBM muscle, including ragged red fibers, cytochrome c oxidase-deficient fibers, and multiple mitochondrial DNA (mtDNA) mutations. [51, 52, 53] These changes might be mediated by aberrant mtDNA replication and maintenance due to oxidative stress, abnormal APP overexpression, [54] or proinflammatory cytokines. [55]
The downstream pathologic effects of the degenerative process were investigated in a recent proteomic, histochemical, and immunohistochemical study, which demonstrated preferential type 2 (fast twitch) myofiber involvement in most s-IBM muscles. [56] In particular, many fast twitch-specific structural proteins were differentially reduced. Expression of the corresponding gene transcripts was relatively preserved, suggesting that the protein loss was not caused by transcriptional failure. Four glycolytic enzymes were also decreased, especially glycogen-debranching enzyme.
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/II-expressing myofibers. For example, immunoproteosome subunits are upregulated in s-IBM myofibers at sites of pathologic protein accumulation, sometimes colocalized with MHC I. [57] The immunoproteosome is specialized to produce antigenic peptides that can be presented by MHC class I molecules to CD8+ T cells. [58] Similarly, autophagosomes process intracellular antigens for MHC II presentation and CD4+ T cell recognition. [59] Thus, Aβ might be presented to CD4+ and CD8+ cells by degenerating myofibers in s-IBM, with an ensuing autoreactive T-cell response.
In addition, ER stress and the UPR can initiate inflammation via multiple intracellular signaling pathways. [60] However, 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 Aβ or any other abnormally accumulated protein in s-IBM. [5]
Alternatively, the inflammatory milieu within s-IBM muscle fibers might lead to the accumulation of misfolded MHC-related glycoproteins and trigger the overproduction of APP, Aβ, p-tau, and other such proteins, creating ER stress. [61, 4] In s-IBM, proinflammatory cytokines and chemokines correlate with the intramuscular accumulation of APP. [13] Exposure to IL-1β in particular might produce upregulation of APP with subsequent AB-associated degeneration. In a transgenic mouse model of IBM, lipopolysaccharide-induced inflammation increased steady state levels of APP and enhanced tau-phosphorylation in skeletal muscle, possibly secondary to proinflammatory cytokine (IL-1β, IL-6, and TNF-α)-mediated upregulation of the glycogen synthase kinase-3B (GSK-3B) signaling pathway. [45]
Of course, neither APP/Aβ-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 alpha-B-crystallin-immunoreactive myofibers in the absence of any significant structural abnormality. [62] These “X fibers” are several-fold 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.
Alpha-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 alpha-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. [62, 30] Muth et al demonstrated an association between alpha-B-crystallin and APP/Aβ in X-fibers, supporting an early inflammatory response, with subsequent degenerative Aβ accumulation and vacuolar changes. [63]
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. [64, 65] A western Australian survey in 2006 revealed a prevalence of 39.5 per million for individuals older than 50 years (unpublished).
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. Patients are often significantly disabled because of finger flexor weakness.
In a study of gait in 42 persons with s-IBM, muscle force values were found to be significantly lower than predicted values (P< .001). During habitual walking, gait speed and cadence were ≤83% of normal values. During fast walking, total gait cycle time was 133% of normal, while gait speed and cadence were 58% and 78%, respectively, of normal. [66]
Dysphagia due to weakness of the cricopharyngeal musculature 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 s-IBM 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. [64] In a 12-year follow-up study in the Netherlands, life expectancy was normal (81 years), although activities of daily living were restricted. [67] The most common cause of death was respiratory system disorders.
No race predilection for s-IBM is known, but the condition has been noted to be uncommon among African Americans, Koreans, and Mesoamerican Mestizos. [68]
Reported male-to-female ratio ranges from 1.4:1 to 3:1. [69, 65, 64]
Age of onset ranges from the late second to ninth decades. Mean age of onset is 56-60 years. [69, 64, 65]
While a large majority of individuals develop symptoms when older than 50 years, 17-20% present before the age of 50. [69, 70, 64]
The diagnosis of inclusion body myositis is often delayed by a mean of 5-8 years from time of symptom onset. [69, 64, 71, 70, 72]
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Disease
Points of Differentiation
h-IBM
Clinically and genetically heterogeneous group of diseases; positive family history; muscle biopsy features similar to s-IBM, but no inflammation
Polymyositis (PM)*
Weakness usually symmetric and proximally predominant; occasional cardiac and pulmonary involvement; similar to s-IBM, biopsy shows endomysial inflammation with invasion of non-necrotic fibers by CD8+ cells, but unlike s-IBM, rimmed vacuoles and ragged red fibers are infrequent and amyloid deposits and tubulofilaments not seen (see Histologic Findings)
Dermatomyositis (DM)
Weakness usually symmetric and proximally predominant; occasional cardiac and pulmonary involvement; characteristic skin lesions; characteristic biopsy findings (eg, perifascular atrophy, muscle infarcts, microvascular MAC deposits in the endomysium, focal capillary depletion, and conspicuous alterations in endothelial cells of endomysial microvasculature)
Oculopharyngeal muscular dystrophy (OPMD)
Predominant involvement of oculopharyngeal musculature (no extraocular muscle involvement in s-IBM); biopsy shows vacuoles, myopathic changes, and infrequent tubulofilaments (similar to s-IBM) but no inflammation; biopsy also shows pathognomonic intranuclear filamentous inclusions having smaller diameters than s-IBM tubulofilaments in 2-9% of nuclei; genetic testing is available for OPMD (PABPN1 gene); rare, genetically distinct oculopharyngodistal variant in Japan
Late-onset distal myopathies
Clinically and genetically heterogeneous group of diseases; positive family history unless sporadic case; biopsy may show rimmed vacuoles and tubulofilamentous inclusions in Welander, distal myopathy, Nonaka distal myopathy, and tibial muscular dystrophy, all of which can be classified as h-IBM. Gene testing is available for Nonaka distal myopathy (GNE) and tibial muscular dystrophy (titin).
Overlap myositis
PM- or DM-like clinical and myopathological presentation but with additional systemic and serologic features diagnostic of an underlying connective tissue disease (eg, systemic lupus erythematosus, Sjögren syndrome, rheumatoid arthritis, scleroderma, or mixed connective tissue disease)
Unlike s-IBM, extraocular muscles are routinely involved; weakness is usually symmetric and tends to fluctuate, increasing with repeated or sustained exertion; spontaneous remissions can occur; motor unit action potentials (MUAPs) are unstable (increased jitter), whereas jitter is typically normal in s-IBM; repetitive nerve stimulation often shows abnormal decrement (rare in s-IBM); antibodies to acetylcholine receptors or muscle-specific kinase (MuSK) absent in s-IBM
Motor neuron disease
Upper motor neuron signs such as hyperreflexia and extensor plantar responses are not present in s-IBM; EMG in s-IBM may show neurogenic changes (ie, enlarged MUAPs), but these changes are relatively minor compared with predominance of smaller MUAPs, suggesting myopathy; fasciculation potentials are characteristic of motor neuron disease but rarely reported in s-IBM; recruitment is decreased in motor neuron disease and “early” in s-IBM; muscle biopsy in motor neuron disease shows denervation atrophy.
Weakness is typically proximal-predominant (torso included); respiratory failure seen in about one third of adults; EMG is myopathic, similar to that of s-IBM, but in acid maltase deficiency, insertional activity is prominently increased, with profuse complex repetitive and myotonic discharges, whereas myotonic discharges are not seen in s-IBM and complex repetitive discharges are uncommon; muscle biopsy shows lysosomal (acid phosphatase-positive), glycogen-laden (PAS-positive) vacuoles, foci of acid phosphatase reactivity in nonvacuolated fibers, and glycogen accumulation by electron microscopy.
Chronic inflammatory demyelinating polyradiculoneuropathy
Weakness is usually both proximal and distal and mildly asymmetric, similar to s-IBM, but more often distally accentuated and lacking in the characteristic quadriceps/deep finger flexor emphasis of s-IBM; almost all patients have sensory signs and symptoms; examination shows diffuse hypo/areflexia; nerve conductions are abnormal, consistent with demyelination; EMG shows chronic reinnervational and no myopathic changes; serum creatine kinase (CK) is typically normal.
*Patients whose polymyositis does not respond to treatment and who have a clinical picture suggestive of s-IBM should be reevaluated. A repeat biopsy should be considered, as they may have s-IBM. Failure to confirm the diagnosis on initial biopsy may have been due to sampling error or insufficient processing.
Condition
Changes in MUAP Features
Nonspecific abnormality
Increased complexity (ie, phases, turns, late components)
Only amplitude reduced
Specific for myopathy
Shortened duration (simple or nonpolyphasic MUAPs)
Area reduced
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, Peripheral Nerve Society, World Muscle Society
Disclosure: Nothing to disclose.
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, American Association of Neuromuscular and Electrodiagnostic Medicine
Disclosure: Nothing to disclose.
Paul E Barkhaus, MD, FAAN, FAANEM Professor of Neurology and Physical Medicine and Rehabilitation, Chief, Neuromuscular and Autonomic Disorders Program, Director, ALS Program, Department of Neurology, Medical College of Wisconsin
Paul E Barkhaus, MD, FAAN, FAANEM is a member of the following medical societies: American Academy of Neurology, American Association of Neuromuscular and Electrodiagnostic Medicine, American Clinical Neurophysiology Society, American Neurological Association
Disclosure: Nothing to disclose.
Helen C Lin, MD Assistant Professor of Neurology, Medical College of Wisconsin
Helen C Lin, MD is a member of the following medical societies: American Academy of Neurology, American Association of Neuromuscular and Electrodiagnostic Medicine
Disclosure: Nothing to disclose.
Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference
Disclosure: Received salary from Medscape for employment. for: Medscape.
Glenn Lopate, MD Associate Professor, Department of Neurology, Division of Neuromuscular Diseases, Washington University in St Louis School of Medicine; Consulting Staff, Department of Neurology, 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, Phi Beta Kappa
Disclosure: Serve(d) as a director, officer, partner, employee, advisor, consultant or trustee for: Alnylam Pharmaceuticals<br/>Received income in an amount equal to or greater than $250 from: Alnylam Pharmaceuticals; GLG.
Nicholas Lorenzo, MD, MHA, CPE Co-Founder and Former Chief Publishing Officer, eMedicine and eMedicine Health, Founding Editor-in-Chief, eMedicine Neurology; Founder and Former Chairman and CEO, Pearlsreview; Founder and CEO/CMO, PHLT Consultants; Chief Medical Officer, MeMD Inc
Nicholas Lorenzo, MD, MHA, CPE is a member of the following medical societies: Alpha Omega Alpha, American Academy of Neurology, American Association for Physician Leadership
Disclosure: Nothing to disclose.
Dianna Quan, MD Professor of Neurology, Director of Electromyography Laboratory, University of Colorado School of Medicine
Dianna Quan, MD is a member of the following medical societies: American Academy of Neurology, American Association of Neuromuscular and Electrodiagnostic Medicine, American Neurological Association
Disclosure: Nothing to disclose.
Dr. Barkhaus acknowledges support in part from the Department of Veterans Affairs. Disclaimer: This article does not necessarily reflect the views of the Department of Veterans Affairs or the United States Government.
The authors and editors of Medscape Reference gratefully acknowledge the contributions of previous author, Helen C Lin, MD, to the original writing and development of this topic.
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