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PubMed2004

Randomized pilot trial of high-dose betaINF-1a in patients with inclusion body myositis.

Beta-interferon-1a (betaINF-1a) is well tolerated at low dose (30 microg IM/week) in inclusion body myositis (IBM). The authors investigated the safety and tolerability of high-dose (60 microg IM/week) betaINF-1a in a randomized, placebo-controlled trial in IBM. Twenty-seven of the 30 subjects enrolled completed the study. The adverse event profile was similar for the placebo and betaINF-1a groups. betaINF-1a, at a dose of 60 microg IM/week, is well tolerated in IBM, but no differences in muscle strength or mass were observed between the placebo and betaINF-1a groups at 6 months in this pilot study.

Aged↗

PubMed2004

Mutant ubiquitin UBB+1 is accumulated in sporadic inclusion-body myositis muscle fibers.

Mutant ubiquitin (UBB+1), a product of "molecular misreading," is toxic to cells because its ubiquitinated form inhibits the proteasome, contributing to accumulation of misfolded proteins and their ensuing toxicity. The authors demonstrate in 10 sporadic inclusion body myositis (s-IBM) muscle biopsies that UBB+1 is accumulated in aggregates containing amyloid-beta and phosphorylated-tau. In s-IBM, UBB+1 may be pathogenic by inhibiting proteasome, thereby promoting accumulation of cytotoxic misfolded amyloid-beta and phosphorylated-tau.

Amino Acid Sequence↗

PubMed2004

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

Whether autoimmune mechanisms play a role in the pathogenesis of inclusion body myositis (IBM) is unknown. Human leukocyte antigen (HLA) analysis in 52 patients, including 17 with autoimmune disorders (AIDs), showed that patients were more likely to have antigens from the autoimmune-prone HLA-B8-DR3 ancestral haplotype than healthy control subjects, irrespective of the presence of AIDs. Patients lacked the apparently protective HLA-DR53 antigen. The results provide further support for an autoimmune basis in IBM.

Age of Onset↗

PubMed2006

Mitochondrial abnormalities in inclusion-body myositis.

Mitochondrial changes are frequently encountered in sporadic inclusion-body myositis (s-IBM). Cytochrome c oxidase (COX)-deficient muscle fibers and large-scale mitochondrial DNA (mtDNA) deletions are more frequent in s-IBM than in age-matched controls. COX deficient muscle fibers are due to clonal expansion of mtDNA deletions and point mutations in segments of muscle fibers. Such segments range from 75 microm to more than 1,000 microm in length. Clonal expansion of the 4977 bp "common deletion" is a frequent cause of COX deficient muscle fiber segments, but many other deletions also occur. The deletion breakpoints cluster in a few regions that are similar to what is found in human mtDNA deletions in general. Analysis in s-IBM patients of three nuclear genes associated with multiple mtDNA deletions, POLG1, ANT1 and C10orf2, failed to demonstrate any mutations. In s-IBM patients with high number of COX-deficient fibers, the impaired mitochondrial function probably contribute to muscle weakness and wasting. Treatment that has positive effects in mitochondrial myopathies may be tried also in s-IBM.

Aging↗

PubMed2006

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

Sporadic inclusion-body myositis (s-IBM), the most common muscle disease of older persons, is of unknown cause and there is no successful treatment. We summarize our most recent findings, which provide a better understanding of the steps in the pathogenetic cascade. We suggest that s-IBM is primarily a myodegenerative disease. Intriguing are the phenotypic similarities between s-IBM muscle fibers and the brains of Alzheimer disease, the most common neurodegenerative disease of older persons. In s-IBM, abnormal accumulation of the amyloid-beta (Abeta) precursor protein and its proteolytic fragment, Abeta, associated with the aging intracellular milieu of the muscle fiber, appear to be key upstream pathogenic events. We propose that the identified abnormal accumulation, misfolding, and aggregation of proteins, perhaps provoked by the aging milieu and aggravated by the oxidative stress, lead to the s-IBM-specific vacuolar degeneration and atrophy of muscle fibers.

Aged↗

PubMed2006

Inflammatory, immune, and viral aspects of inclusion-body myositis.

Muscle biopsies from patients with sporadic inclusion-body myositis (sIBM) consistently demonstrate that the inflammatory T cells almost invariably invade intact (not vacuolated) fibers, whereas the vacuolated fibers are rarely invaded by T cells. This indicates two concurrently ongoing processes, an autoimmune mediated by cytotoxic T cells and a degenerative manifested by the vacuolated muscle fibers and deposits of amyloid-related proteins. The autoimmune features of IBM are highlighted by the strong association of the disease with: a) HLA I, II antigens, in frequency identical to classic autoimmune diseases; b) other autoimmune disorders in up to 32% of the patients, autoantibodies, paraproteinemias, or immunodeficiency; c) HIV and HTLV-I infection with increasingly recognized frequency (up to 13 known cases); and d) antigen-specific, cytotoxic, and clonally expanded CD8+ autoinvasive T cells with rearranged T-cell receptor genes that persist over time, even in different muscles, and invade muscle fibers expressing MHC-I antigen and costimulatory molecules. In contrast to IBM, in various dystrophies the inflammatory cells are clonally diverse and the muscle fibers do not express MHC-I or costimulatory molecules in the pattern seen in IBM. Like other chronic autoimmune conditions with coexisting inflammatory and degenerative features (i.e., primary progressive MS), IBM is resistant to conventional immunotherapies. Recent data suggest that strong anti-T cell therapies can be promising and they are the focus of ongoing research.

Aged↗

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↗

PubMed2006

A perspective on sporadic inclusion-body myositis: the role of aging and inflammatory processes.

Sporadic inclusion-body myositis (sIBM) is an age-related condition manifested after midlife. This review points out salient features of sIBM that are shared with normal aging in muscle and with inflammatory changes in vascular atheromas and senile plaques of Alzheimer disease (AD). The amyloid precursor protein (APP) and derived Abeta peptides are found in both AD and sIBM. Because transgenic expression of human APP induces sIBM like changes, it is of potential interest that an inducer of APP, IL-1, increases during aging in mouse muscle. Because various subsets of the usual aging changes in aging brain, muscle, and vessels can be attenuated in rodents by caloric intake and possibly in humans by drugs with anti-inflammatory and anticoagulant activities, this study suggests that diet and inflammation may be useful experimental variations in exploring the pathogenesis of sIBM.

Aged↗

PubMed2006

Inclusion-body myositis: clinical, diagnostic, and pathologic aspects.

The diagnostic aspects of sporadic inclusion-body myositis (s-IBM), and a few comments on our own approach to its treatment, are presented to foster the goals of this symposium, which was organized to provoke new ideas concerning the cause and treatment of this currently unsolvable disease. s-IBM is the most common, progressive, debilitating muscle disease beginning in persons over age 50 years, and it is more common in men. Diagnostic parameters reviewed are clinical, muscle-biopsy histochemistry, electrophysiologic and CSF evaluations. Overall, the degenerative phenomena in s-IBM muscle fibers seem to be the major cause of the progressive, unstoppable weakness, rather than the lymphocytic inflammation. Available treatments are of only slight, temporary benefit for only some s-IBM patients, indicating a desperate need for definitive therapies.

Adrenal Cortex Hormones↗

PubMed2006

The current status of treatment for inclusion-body myositis.

There is no established treatment that improves, arrests, or slows the progression of inclusion-body myositis (IBM). Many anti-inflammatory, immunosuppressant, or immunomodulating agents have been administered to patients with IBM but the design of clinical trials was such that it can only be concluded that none produced rapid improvement. The natural history of the disease is for stabilization or improvement in a third of patients for 6 months or more. Thus some agents that did not produce dramatic benefit may have been prematurely abandoned. However, because high-dose prednisone worsens strength while decreasing inflammation but increases amyloid accumulation, alternative targets for intervention and novel treatment strategies are needed.

Anti-Inflammatory Agents↗

PubMed2006

RNA interference as potential therapy for neurodegenerative disease: applications to inclusion-body myositis?

The discovery of RNA interference (RNAi) has led to powerful new approaches to silence targeted genes in a sequence-specific manner. The potential therapeutic application of RNAi to neurologic disease is highlighted by the recent success of several laboratories in suppressing the expression of neurodegenerative disease genes in transgenic mouse models. Here I discuss potential applications of RNAi to inclusion-body myositis (IBM) after first reviewing its application more generally to neurologic disease. The clearest application of RNAi to IBM is as a research tool to identify critical target genes that contribute to pathogenesis. Provided that proximal pathogenic targets are identified, RNAi could surface as a potential therapeutic strategy to modulate their expression.

Animals↗

PubMed2006

Treatment and prevention of the amyloidoses: can the lessons learned be applied to sporadic inclusion-body myositis?

The amyloid fibril represents a final common pathologic pathway for a variety of human proteins, all of which have a propensity to misfold. Each seems to require a predisposing event to realize its fibrillogenic potential. It may be mutation, inappropriate or incomplete cleavage, overproduction, or the availability of a template for misfolding. Therapies have been based on decreasing the stimulus (inflammation in the case of AA) reducing the number of producing cells (AL) and a variety of approaches to removing the extracellular aggregates. Sporadic inclusion-body myositis (sIBM), while physically resembling the extracellular amyloidoses, is an intracellular disease, hence imposes the additional requirement of developing a therapy that can access and function inside the affected or potentially affected, cell. Current approaches to the treatment of other forms of amyloidosis are discussed in the context of their applicability, or lack thereof, to sIBM.

Amyloid↗

PubMed1978

Inclusion body myositis: a distinct variety of idiopathic inflammatory myopathy.

We report six cases of inclusion body myositis (IBM), a distinct but infrequently recognized inflammatory disease of skeletal muscle. Clinically, IBM differs from dermatomyositis and polymyositis. It lacks features of collagen-vascular disease, has a relatively benign and protracted course, frequently involves distal muscles, is found mainly in males, and does not improve with corticosteroid treatment. Electronmicroscopic demonstration of abnormal filaments in muscle cells is necessary for definite diagnosis, but IBM may be suspected by the finding on cryostat sections of numerous hematoxylinophilic granules in "lined" vacuoles in muscle cells. These correspond to whorls of cytomembranes. Although in dermatomyositis the capillary network is partly destroyed, in IBM it is usually augmented. A viral etiology of IBM has been suggested but remains unproven.

Adolescent↗

PubMed1979

Benign acute childhood myositis.

Four school children, aged 6 to 9 years, had acute postinfectious myositis. The prodromal illness usually involved the upper respiratory tract, but gastrointestinal symptoms were also seen. Fever and nonspecific malaise were characteristic. After cessation of the illness, myalgia involved the calves and thighs. Arm and neck muscles were less frequently affected. Weakness was less marked than muscle pain. Serum creatine phosphokinase (CPK) was markedly increased in all cases. Myalgia and CPK levels subsided in less than a week, although one child was not back to normal for 4 weeks. Two children had electromyography, and patchy myopathic changes were found. Viral studies were not helpful in any of the cases.

Acute Disease↗

PubMed1980

Influenzal acute myositis in the elderly.

We report an 84-year-old man with completely regressive acute myositis. The presumed etiology was an Influenza A virus infection, based on the serologic results.

Acute Disease↗

PubMed1983

Inclusion body myositis (IBM): myopathy or neuropathy?

Inclusion body myositis (IBM) is described in six elderly patients (three women) and in a young familial patient. They all showed the morphologically characteristic vacuoles containing osmiophilic membranous whorls and intracytoplasmic or intranuclear inclusions. There is a well-delineated bimodal age spectrum of IBM, with onset in the second and sixth decades, but otherwise the disorder seems to be a specific entity. Clinical, electrophysiologic, and morphologic features suggest a neurogenic origin in some cases.

Aged↗

PubMed1983

Myositis of chronic graft versus host disease.

A 13-year-old girl with chronic graft versus host disease (GVHD) developed severe proximal weakness. Muscle biopsy showed necrotic fibers with anti-IgG deposits and interstitial inflammation. Steroid treatment helped, but her weakness recurred. Repeat biopsy showed persistent inflammation and possible steroid myotoxicity. Numerical ratio of capillaries to myofibers and capillary numerical density were higher than childhood dermatomyositis (CD), and capillaries had no tubuloreticular inclusions. Absence of quantitative histologic, ultrastructural, or immunocytochemical abnormalities of capillaries differentiated our patient from CD. We conclude that myositis of chronic GVHD can present as a severe myopathy that responds to steroids and differs from CD.

Adolescent↗

PubMed1992

Familial inclusion body myositis: evidence for autosomal dominant inheritance.

We report a kindred manifesting clinical features and muscle biopsy findings of inclusion body myositis (IBM). In this family, multiple members were affected in two generations with direct male-to-male and female-to-male transmission. This is the first reported instance of autosomal dominant inheritance in IBM, which usually occurs sporadically or, rarely, may be transmitted as an autosomal recessive disorder.

Adult↗