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PubMed1998

Upregulation of Fas/Fas ligand in inclusion body myositis.

In inclusion body myositis, T cells invade and destroy nonnecrotic muscle fibers. The mechanism by which T cells damage muscle fibers in inflammatory myopathies is not known. In this study we have investigated the expression of Fas and Fas ligand in muscle in five patients with inclusion body myositis. Reverse transcription polymerase chain reaction showed upregulation of both Fas and Fas ligand in all inclusion body myositis patients. Immunohistochemical investigation showed expression of Fas ligand in many of the muscle infiltrating mononuclear cells. Fas was expressed both in mononuclear cells and on the surface of muscle fibers in inclusion body myositis patients and in patients with polymyositis but not in patients with Duchenne muscular dystrophy or denervation. The results indicate that the Fas/Fas ligand system may be of importance for the inflammatory reaction and T-cell-mediated muscle cell injury.

Fas Ligand Protein↗

PubMed1997

Ubiquitin immunostaining and inclusion body myositis: study of 30 patients with inclusion body myositis.

Distinction of inclusion body myositis (IBM) from other forms of inflammatory myopathy is significant from prognostic and therapeutic standpoints. This study retrospectively examines ubiquitin expression by paraffin immunohistochemistry in muscle biopsy material from 30 patients with IBM. Patients included 19 men and 11 women (ages 29 to 80 years; mean, 64 years). All biopsies were characterized by endomysial chronic inflammation, muscle fiber degeneration and regeneration, rimmed vacuoles, and angular atrophic esterase-positive muscle fibers. Ragged red fibers were identified in biopsies of five patients and a partial cytochrome C-oxidase deficiency by enzyme histochemistry in biopsies of 10 patients. Evidence of intranuclear or cytoplasmic tubulofilamentous structures confirming a diagnosis of IBM was observed in all 30 cases. Paracrystalline mitochondrial inclusions were noted in five patients. Discrete myocyte intranuclear ubiquitin-positive inclusions were noted in 14 patients (47%). Discrete intracytoplasmic ubiquitin-positive inclusions were noted in 24 (80%) patients. Positive staining of rimmed vacuoles by ubiquitin was observed in 25 (83%) patients. Diffuse staining of scattered muscle fibers was observed in 21 (70%) patients. In a control group including patients with polymyositis (n = 3), dermatomyositis (n = 3), necrotizing vasculitis (n = 1), and granulomatous myositis (n = 1), discrete intranuclear or cytoplasmic ubiquitin-positive inclusions were not observed. Rimmed vacuoles were not seen either by light microscopy or ubiquitin immunostaining in any of the eight cases. Occasional myofibers from all eight cases showed diffuse, positive muscle fiber staining. Although not present in all cases, evidence of ubiquitin-positive myocytic intranuclear or cytoplasmic inclusions or positive-staining rimmed vacuoles in the setting of an inflammatory myopathy may be suggestive of a diagnosis of inclusion body myositis. Use of ubiquitin immunohistochemistry may be useful in cases in which frozen tissue or tissue processed for electron microscopy is not available, and IBM is suspected. Light or electron microscopic evidence of mitochondrial abnormalities were noted in a significant subset of patients (13 of 30; 43%) of patients with IBM.

Adult↗

PubMed1993

beta-Amyloid precursor epitopes in muscle fibers of inclusion body myositis.

Sporadic inclusion body myositis (IBM) and hereditary inclusion body myopathy (hIBM) are severe and progressive muscle diseases, characterized pathologically by vacuolated muscle fibers that contain 15- to 21-nm cytoplasmic tubulofilaments (CTFs). Those vacuolated muscle fibers also contain abnormally accumulated ubiquitin and beta-amyloid protein (A beta), and they contain amyloid in beta-pleated sheets as indicated by Congo red and crystal violet positivity. Using several well-characterized antibodies, we have now demonstrated that, in addition to A beta, two other epitopes, N-terminal and C-terminal, of the beta-amyloid precursor protein (beta PP) are abnormally accumulated in IBM vacuolated muscle fibers and similarly in hIBM. At the light microscopy level, immunoreactivities of N- and C-epitopes of beta PP closely colocalized with A beta and ubiquitin immunoreactivities. However, by immunogold electronmicroscopy, even though N-, C-, and A beta epitopes of beta PP and ubiquitin colocalized at the amorphous and dense floccular structures, only A beta was localized to the 6- to 10-nm amyloid-like fibrils and only ubiquitin was localized to CTFs. beta PP immunoreactive structures were often in proximity to CTFs, but CTFs themselves never contained beta PP immunoreactivities. The fact that A beta but not C- or N-terminal epitopes of beta PP localized to the 6- to 10-nm amyloid-like fibrils suggests that free A beta might be generated during beta PP processing and, after aggregation, may be responsible for the amyloid present within IBM muscle fibers. Our study demonstrates that three epitopes of beta PP accumulate abnormally in diseased human muscle, and therefore this phenomenon is not unique to Alzheimer's disease, Down's syndrome brain, and Dutch-type cerebrovascular amyloidosis.

Adolescent↗

PubMed1999

Inclusion body myositis.

Sporadic inclusion body myositis is a severely disabling muscle disease that mainly affects elderly individuals. The typical distribution of muscle weakness, poor response to immunosuppressive treatment, pathological accumulation of various proteins in vacuolated muscle fibres, inflammatory reaction and mitochondrial changes have all been subjects of recent research that has led to better understanding of the pathogenic events that leads to muscle degeneration and weakness.

Humans↗

PubMed1999

Treatment of inclusion body myositis.

Sporadic inclusion body myositis (s-IBM) is considered the most common muscle disease in patients older than 50 years, with a male predominance. Features of s-IBM include insidious onset, slowly and relentlessly progressive muscle weakness, a characteristic distribution and atrophy of both the proximal and distal muscle groups, and resistance to immunosuppressive drugs. The most characteristic pathologic feature is vacuolar degeneration of muscle fibers accompanied by intrafiber congophilia and clusters ("tangles") of paired-helical filaments, containing phosphorylated tau. The response of s-IBM to immunotherapy remains controversial. Some reports emphasized partial improvement in early stages of the disease. However, the lack of clear response to corticosteroids and immunosuppressive therapies, the deterioration of clinical strength despite suppression of inflammation but increasing number of fibers with vacuoles and amyloid deposits under therapy, and the accumulation of "Alzheimer-characteristic" proteins in vacuolated muscle fibers suggest that s-IBM may be a degenerative rather than an auto-immune inflammatory myopathy, and a secondary inflammation response.

Humans↗

PubMed1998

Dysphagia in patients with inclusion body myositis.

OBJECTIVES: Inclusion body myositis (IBM) is an inflammatory myopathy with a 40% reported incidence of dysphagia. A protracted course, refractory to medical therapy, frequently leads to consultation with an otolaryngologist for dysphagia management. We studied the incidence, symptoms, and mechanisms of dysphagia in patients with IBM. STUDY DESIGN: Retrospective study of medical records and self-reported follow-up survey; dysphagia is defined as difficulty in swallowing. MATERIALS: Twenty-two patients with biopsy-proven IBM. RESULTS: The rate of dysphagia was more than 80% (16 of 19), twice as high as previously reported. Progressive dysphagia was associated with a significantly worse functional class. Relevant management guidelines are established, including the timing for appropriate surgical intervention. CONCLUSION: Progressive dysphagia may signify more aggressive IBM or an episodic worsening in status. Recognition of the disease manifestations will afford proper patient management. Informed otolaryngologists can have a favorable impact on the dysphagia associated with IBM.

Activities of Daily Living↗

PubMed1999

Quantitative electrophysiologic studies in sporadic inclusion body myositis.

Sporadic inclusion body myositis (S-IBM) is a progressive, acquired disease of unknown etiology. Prior studies have suggested neurogenic involvement based on electrophysiologic data, although the biopsy is compatible with a myopathic process. Quantitative electrophysiologic studies were performed in the biceps brachii of 17 subjects with biopsy-proven S-IBM. Quantitative motor unit action potential (MUAP) analysis was compatible with myopathy in 16 subjects, with the remaining subject being within normal limits. Quantitative interference pattern was myopathic in all 13 subjects studied. Macro-EMG MUAP amplitude was reduced in 3 of 17 studies; the remainder were within normal range, and none was increased as would be expected in neurogenic disease. Fiber density was normal to borderline increased in all subjects. Possible reasons for encountering neurogenic-appearing MUAPs may include choice of muscle studies, because some patients have co-existing polyneuropathy and large-amplitude MUAPs from hypertrophied muscle fibers. The data from this study indicate that S-IBM is a myopathic process.

Action Potentials↗

PubMed2006

Pilot trial of etanercept in the treatment of inclusion-body myositis.

Inclusion-body myositis (IBM) is an inflammatory muscle disease that has proven resistant to treatment. Tumor necrosis factor molecules have been detected in muscle biopsies from patients with IBM. Etanercept is a TNFalpha receptor fusion protein that binds and inactivates tumor necrosis factor. Nine patients were treated with etanercept at a dose of 25 mg, two times a week for an average of 17 +/- 6.1 months. Each patient was evaluated using quantitative strength testing. Their data were compared to two different control groups. The first control group consisted of patients who participated in trials of beta-interferon-1A and had received placebo. There was no significant difference. The second control group was a natural history cohort of IBM patients. There was no statistically significant difference between the treated group and the natural history group at 6 and 12 months when looking at elbow flexors, or 6 months when looking at hand grip. In the treated patients there was a small but significant improvement (p = 0.002) in handgrip at 12 months.

Cohort Studies↗

PubMed2004

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

Sporadic inclusion body myositis (s-IBM) is a progressive muscle disease of unknown aetiology. Characteristically, intracellular amyloid deposits are detectable, including beta-amyloid precursor protein, phosphorylated tau, alpha1-antichymotrypsin (alpha1-ACT) and apolipoprotein E (ApoE). Polymorphisms and mutations of the encoding genes have been identified in a variety of neurodegenerative diseases including Alzheimer's disease (AD). Beside other factors, polymorphisms may lead to protein accumulation in both diseases. In particular, polymorphisms within the ApoE and alpha1-ACT gene have been implicated in the aetiology of AD and s-IBM. We analysed ApoE and alpha1-ACT gene polymorphisms in 35 s-IBM patients. We could not identify any statistical significant correlation between distinct ApoE and alpha1-ACT genotypes and the risk of developing s-IBM. Additionally, ApoE and alpha1-ACT genotypes seem not to influence the onset age of s-IBM. A combination of different alpha1-ACT and ApoE genotypes appears not to enhance the risk of developing s-IBM. Therefore, allelic variations of alpha1-ACT and ApoE are unlikely to be genetic key factors in the aetiology of s-IBM.

Adolescent↗

PubMed2003

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

Sporadic inclusion body myositis (s-IBM) is characterised by progressive weakness of proximal and distal limb muscles. Most patients are aged over 50 years at disease onset. Muscle biopsy reveals an inflammatory myopathy and cytoplasmic amyloid deposits. The mononuclear infiltrate is dominated by CD8+ T-cells. Several investigators have described associations between s-IBM and certain HLA antigens and alleles. However, to date neither HLA class I nor II alleles have been analysed in a large series of patients. We typed various HLA class I and II alleles in 47 patients suffering from s-IBM using sequence specific-primer pairs (SSPPCR). The results were compared with published German controls. Additional Bonferroni adjustment was performed over all allele groups corresponding to serologically defined antigens within one HLA class I or II locus. After Bonferroni adjustment, we found a significant increase in frequency of the following HLA alleles for s-IBM patients when compared with normal controls: A*03 (p = 0.0002), B*08 (p = 0.002), DRB1*03 (p = 0.0000002), and DQB1*05 (p = 0.02). HLA typing may be helpful to distinguish between subgroups of s-IBM patients. Moreover, HLA analysis may aid in identifying patients who might profit from future therapeutic strategies.

Alleles↗

PubMed2006

Proteomic analysis of inclusion body myositis.

Sporadic inclusion body myositis (IBM) is the most frequently acquired inflammatory myopathy of late adult life, yet its diagnostic criteria and pathogenesis remain poorly defined. Because effective treatment is lacking, research efforts have intensified to identify specific markers for this debilitating disorder. In this study, proteomic analysis of 4 cases of sporadic IBM was compared with 5 cases of inflammatory myopathy without clinicopathologic features of IBM to distinguish the IBM-specific proteome. Proteins were separated by 2-dimensional polyacrylamide gel electrophoresis and profiled by mass spectrometric sequencing. Expression of most proteins remained unchanged; however, 16 proteins were upregulated and 6 proteins were downregulated in IBM compared with cases of non-IBM inflammatory myopathy. These IBM-specific proteins included apolipoprotein A-I, amyloid beta precursor protein, and transthyretin, which have been associated with amyloidosis; superoxide dismutase, enolase, and various molecular chaperones indicate perturbations in detoxification, energy metabolism, and protein folding, respectively. The IBM-downregulated proteins mainly serve as carriers for muscle contraction and other normal muscle functions. We further applied Western blot and immunohistochemistry to verify the proteomic findings. This study validates proteomics as a powerful tool in the study of muscle disease and indicates a unique pattern of protein expression in IBM.

Aged↗

PubMed2001

Randomized pilot trial of betaINF1a (Avonex) in patients with inclusion body myositis.

BACKGROUND: Inclusion body myositis (IBM) is the most common acquired disease of muscle in adults over the age of 50 years. Although there is compelling evidence for the importance of immunologic abnormalities in its pathogenesis, the cause of the disease is not known, and it is considered to be resistant to treatment with corticosteroids and other conventional immunosuppressive agents. beta-Interferon (betaIFN), an immunomodulatory cytokine, is a candidate therapeutic agent for IBM. METHOD: A 24-week, multicenter, randomized, placebo-controlled, parallel-group clinical trial of 30 microg of beta-interferon-1a (betaINF1a) administered IM once a week in 30 patients with IBM was conducted. The primary goal was to establish the safety and tolerability of betaINF1a in IBM. A secondary goal was to obtain preliminary data on the efficacy of betaINF1a by measuring changes from baseline in muscle strength and muscle mass. RESULTS: Twenty-nine of the 30 subjects enrolled completed the study. Two subjects (one in the placebo group, one in the betaINF1a group) experienced severe adverse events. One subject, randomized to receive betaINF1a, died from an ischemic bowel after resection of a colonic mass. No subjects required dosage reductions, and the adverse event profile was similar for the placebo and betaINF1a groups. There were no significant differences in the changes in muscle strength and muscle mass between the placebo and betaINF1a groups at 6 months. CONCLUSIONS: betaINF1a at a dose of 30 microg/week IM is well tolerated in IBM. Further studies are needed to establish its therapeutic usefulness in this inflammatory myopathy.

Adjuvants, Immunologic↗

PubMed2002

A pilot randomized trial of oxandrolone in inclusion body myositis.

BACKGROUND: Inclusion body myositis (IBM) remains without effective therapy. As anabolic steroids have myotrophic properties, the authors studied whether a synthetic androgen, oxandrolone, would have efficacy in IBM. METHODS: A double-blind, placebo-controlled, crossover design was used. Patients received oxandrolone or placebo for 12 weeks followed by a minimum 2-month washout period, followed by 12 weeks of the alternative treatment. Maximal voluntary isometric contraction testing (MVICT), manual muscle testing (MMT), and functional performance testing were obtained before and after each treatment period, with the whole-body MVICT score as the primary outcome measure. RESULTS: Of 19 patients enrolled, 16 (14 men, 2 women; median age 68.5 years) had complete data for at least the first treatment period, with 13 completing the entire study. Whole-body MVICT improved by a median of 15.5 kg with drug and 4.1 kg with placebo (p = 0.06), whereas MMT demonstrated a median increase of 2.0 Medical Research Council points with drug and 0.9 point with placebo (p = 0.33). Upper-extremity MVICT demonstrated a significant treatment effect, with strength increasing a median 6.3 kg with drug vs 2.5 kg with placebo (p = 0.006). Stair climbing also increased a median of 1 step on average with drug versus no change with placebo (p < 0.001). Minimal adverse effects occurred. CONCLUSIONS: Oxandrolone had a borderline significant effect in improving whole-body strength and a significant effect in improving upper-extremity strength as measured by MVICT. Given these findings, further study of this drug, possibly in combination with an immunomodulating agent, is warranted.

Aged↗

PubMed1995

New advances in the understanding of sporadic inclusion-body myositis and hereditary inclusion-body myopathies.

This review emphasizes new advances in seeking the pathogenic mechanisms of sporadic inclusion-body myositis and hereditary inclusion-body myopathy syndromes. Clinical and pathologic similarities and differences between sporadic and hereditary forms are described. Hypotheses are presented regarding the possible causes and consequences of abnormally accumulated intramyofiber beta-amyloid precursor protein (beta APP) (including beta-amyloid protein and C- and N-terminal epitopes), hyperphosphorylated tau, alpha 1-antichymotrypsin, apolipoprotein E, prion protein, ubiquitin, nicotinic acetylcholine receptor and its 43-kD associated protein, fibroblast growth factor, and transforming growth factor-beta. Also increased are beta APP mRNA and prion protein mRNA. Striking similarities between the pathology of muscle specimens from sporadic inclusion-body myositis and samples from the brains of patients with Alzheimer's disease in regard to Congo red positivity and accumulations of several proteins are discussed. Because most of the proteins that pathologically accumulate throughout the abnormal muscle fibers also accumulate focally at normal human neuromuscular junctions, the possible "junctionalization" of nonjunctional nuclei as a pathogenic mechanism in the muscle fiber is discussed.

Diagnosis, Differential↗

PubMed1996

Difference in expression of phosphorylated tau epitopes between sporadic inclusion-body myositis and hereditary inclusion-body myopathies.

Sporadic inclusion-body myositis (s-IBM) and the hereditary inclusion-body myopathies (h-IBMs) are severe and progressive muscle diseases, characterized pathologically by vacuolated muscle fibers containing paired-helical filaments (PHFs). An interesting feature of the s- and h-IBM muscle phenotype is its striking similarity to Alzheimer-disease (AD) brain. We immunostained muscle biopsies of 9 s-IBM patients, 9 autosomal-recessive h-IBM patients, 1 autosomal-dominant h-IBM patients, and 18 normal and disease-controls with several antibodies known to react with the hyperphosphorylated tau of AD-PHFs. Those included SMI-31, SMI-310, PHF-1, and AT8. In both s- and h-IBM, virtually all vacuolated muscle fibers had strongly immunoreactive inclusions with SMI-31, and by immuno-electronmicroscopy SMI-31 was exclusively localized to PHFs. Approximately 40 to 50% of both s- and h-IBM vacuolated muscle fibers were also immunoreactive with AT8 antibody. To the contrary, in h-IBM, there was no immunoreactivity with SMI-310 and PHF-1 antibodies, whereas in s-IBM the vacuolated muscle fibers had strong immunoreactivity with those two antibodies. By immunoelectronmicorscopy, SMI-310 and PHF-1 also were localized to PHFs. Within s-IBM muscle fibers, the structures immunoreactive with SMI-310 were congophilic, whereas h-IBM muscle fibers did not have congophilia. Our studies: (a) demonstrate a distinct difference between s-IBM and the h-IBMs in regard to expression of immunoreactive phosphorylated tau and congophilia; (b) demonstrate a new "diagnostic duo" combination of SMI-31 and SMI-310 antibodies for identifying and distinguishing s-IBM and the h-IBMs; and (c) provide another close similarity of pathologic phenotypes between s-IBM muscle and AD brain, suggesting that similar cellular pathogenic mechanisms may be active in both diseases.

Adult↗

PubMed1998

Sporadic inclusion-body myositis and hereditary inclusion-body myopathies: current concepts of diagnosis and pathogenesis.

We discuss the pathologic diagnostic criteria and review the major new advances related to seeking the pathogenic mechanism of sporadic inclusion-body myositis (s-IBM) and hereditary inclusion-body myopathy (h-IBM). A classification of the various h-IBM syndromes is also presented. The several forms of the h-IBMs have different genetic transmissions and probably different genetic defects. In neither s-IBM nor the h-IBMs are the sequential steps of the pathogenic cascade understood. Because s-IBM and the h-IBMs have a number of characteristic pathologic features in common, we postulate that their different causes trigger the same upstream aberration leading to a similar downstream cascade of pathologic events, which are ultimately responsible for the characteristic muscle-fiber degeneration. Muscle-biopsy and experimental evidence is given supporting our hypothesis that overexpression of beta-amyloid precursor protein within abnormal muscle fibers is an early upstream event causing the pathogenic cascade. We also present evidence supporting our concept that muscle aging and oxidative stress are important factors contributing to the s-IBM-specific muscle fiber destruction. Additionally, the intriguing parallels between the pathologic phenotype of IBM muscle fibers and Alzheimer's disease brain are summarized.

Aging↗

PubMed1996

Apolipoprotein E and apolipoprotein E messenger RNA in muscle of inclusion body myositis and myopathies.

Sporadic inclusion body myositis and the hereditary inclusion body myopathies are severe, progressive muscle diseases, characterized pathologically by vacuolated muscle fibers containing paired helical filaments. We immunostained muscle biopsy specimens from sporadic inclusion body myositis, hereditary inclusion body myopathy, disease control, and normal patients with several antibodies against apolipoprotein E (ApoE). Approximately 80 to 90% of the vacuolated muscle fibers of sporadic inclusion body myositis contained well-defined, strongly immunoreactive ApoE inclusions. In hereditary inclusion body myopathy, only rare vacuolated fibers had immunoreactive inclusions, whereas most had diffuse cytoplasmic ApoE immunoreactivity. Ultrastructurally, ApoE immunoreactivity in sporadic myositis was localized mainly to the paired helical filaments. By contrast, in the hereditary form, ApoE immunoreactivity occurred on material in close proximity to the paired helical filaments, but never was on the paired helical filaments. In both muscle diseases, ApoE was also on the 6- to 10-nm filaments and amorphous material. In the sporadic form, ApoE-immunoreactive deposits colocalized with Congo red-positive deposits; however, in muscle fibers from patients with hereditary disease there was no congophilia. ApoE messenger RNA was not detectable in muscle fibers from patients with hereditary or sporadic disease but was expressed abundantly in muscle macrophages. In all control and inclusion body myositis or myopathy biopsy specimens, ApoE immunoreactivity was strong at the postsynaptic domain of neuromuscular junctions; nonjunctional regions of normal fibers were negative for ApoE. ApoE immunoreactivity occurred diffusely in regenerating muscle fibers, a subset of which had detectable ApoE messenger RNA.

Amyotrophic Lateral Sclerosis↗

PubMed2000

Association of active extracellular signal-regulated protein kinase with paired helical filaments of inclusion-body myositis muscle suggests its role in inclusion-body myositis tau phosphorylation.

The possible role of extracellular signal-regulated kinase (ERK) in the pathogenesis of inclusion-body myositis (IBM) was investigated by immunostaining the active phosphorylated form of ERK in muscle biopsies of six IBM and 14 control patients. Between 80% and 90% of IBM vacuolated muscle fibers contained well-defined ERK-immunoreactive inclusions, which were co-localized by light microscopy, with phosphorylated tau in 70 to 80% of those fibers. Immunoelectronmicroscopy colocalized ERK to small amorphous tufts adjacent to the muscle fiber paired-helical filaments. Strong ERK immunoreactivity was also present at the postsynaptic domain of all human neuromuscular junctions. Our study suggests 1) that ERK, a signal transducer, might play a role in IBM pathogenesis, including participation in the pathological phosphorylation of IBM tau; and 2) that signal transduction abnormalities may be a component of the IBM pathogenic cascade. Our novel immunolocalization of ERK at the postsynaptic domain of human neuromuscular junctions supports a role in transcription of junctional-protein genes. The ERK localized in nonjunctional regions of IBM fibers may underlie the known pathological up-regulation of junctional proteins there.

Humans↗