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Of Particular Note
The Myositis Association (TMA) are pleased to inform you that the Follistatin gene transfer for inclusion-body myositis has cleared its last regulatory hurdle and recruitment of patients begins this December  . The trial to be conducted at Nationwide Children's Hospital, in Columbus, OH expects to select patients in December to be enrolled, with the first patient injection to begin in January, 2012. The group at Nationwide Children's have worked hard to begin what we hope will be helpful to patients with sIBM to improve muscle strength. TMA will keep in touch with the investigators regarding the progress of the trial.
Review ArticleUpdate on sporadic inclusion body myositis.
Of Particular Note
Of Particular Note
Clinical trials roundup in idiopathic inflammatory myopathies.
Mann HF, Vencovsky J.
PURPOSE OF REVIEW:
To review recent advances in the treatment of idiopathic inflammatory myopathies (IIMs) with emphasis on new biological agents and on some less commonly used immunosuppressive drugs.
Double-blinded comparison of oral high-dose pulse dexamethasone with standard high daily prednisolone doses showed similar efficacy in the composite score, significantly longer median time to relapse with prednisolone and fewer side effects with dexamethasone treatment. Use of intravenous immunoglobulins (IVIGs) in IIMs is associated with variable results; however, recent retrospective evaluation of IVIGs administration to steroid-resistant patients with esophageal involvement showed good effect. Whereas smaller open studies with rituximab reported a very good efficacy, even in notoriously difficult-to-treat anti-signal recognition particle-positive cases, the double-blind trial has not reached the primary endpoint. Studies with TNF neutralization are reporting results ranging from only a modest or no effect to a promising outcome in the most recent trial with etanercept. Pilot studies suggest efficacy of alemtuzumab in inclusion body myositis and allogeneic mesenchymal stem cell transplantation in polymyositis/dermatomyositis.
Unmet need for efficacious therapy in IIMs exists and therefore a coordinated effort is necessary to properly evaluate various new classical and biological agents.
Of Particular Note
Novel demonstration of conformationally modified tau in sporadic inclusion-body myositis muscle fibers.
Nogalska A, D'Agostino C, Engel WK, Askanas V.
s-IBM is the most common muscle disease of older persons. Its muscle fiber molecular phenotype has close similarities to Alzheimer disease (AD) brain, including intra-muscle-fiber accumulations of (a) Abeta42 and its oligomers, and (b) large, squiggly or linear, clusters of paired-helical filaments (PHFs) that are immunoreactive with various antibodies directed against several epitopes of phosphorylated tau (p-tau), and thereby strongly resembling neurofibrillary tangles of AD brain. In AD brain, conformational changes of tau, including its modifications detectable with specific antibodies TG3 (recognizing phosphorylated-Thr231), and Alz50 and MC1 (both recognizing amino acids 5-15 and 312-322) are considered early and important modifications leading to tau's abnormal folding and assembly into PHFs. We have now identified conformationally modified tau in 14 s-IBM muscle biopsies by (a) light-and electron-microscopic immunohistochemistry, (b) immunoblots, and (c) dot-immunoblots, using TG3, Alz50 and MC1 antibodies. Our double-immunolabeling on the light- and electron-microscopic levels, which combined an antibody against p62 that recognizes s-IBM clusters of PHFs, revealed that TG3 immunodecorated, abundantly and exclusively, all p62 immunopositive clusters, while Alz50 labeling was less abundant, and MC1 was mainly diffusely immunoreactive. Interestingly, in the very atrophic degenerating fibers, TG3 co-localized with PHF-1 antibody that recognizes tau phosphorylated at Ser396/404, which is considered a later change in the formation of PHFs; however, most of TG3-positive inclusions in non-atrophic fibers were immunonegative with PHF-1. None of the 12 normal- and disease-control muscle biopsies contained conformational or PHF-1 immunoreactive tau. This first demonstration of conformational tau in s-IBM, because of its abundance in non-atrophic muscle fibers, suggests that it might play an early role in s-IBM PHFs formation and thus be pathogenically important.
Review ArticleCurr Opin Rheumatol. 2011 Aug 31. [Epub ahead of print]
Inclusion body myositis.
Sporadic inclusion body myositis (sIBM) is a poorly understood immune and degenerative disease of skeletal muscle. Here, current opinion of the nature of this disease is summarized.
Recent findings for sIBM include further characterization of muscle involvement through magnetic resonance imaging, the role of muscle as a host for immune cells, progress in the role of extranuclear TDP-43 in causing cellular injury, and the discovery of a new sIBM autoantibody.
sIBM understanding continues to advance, with progress regarding the mechanism of this disease.
Mesoangioblasts of inclusion-body myositis: a twofold tool to study pathogenic mechanisms and enhance defective muscle regeneration.
Morosetti R, Gliubizzi C, Broccolini A, Sancricca C, Mirabella M.
Source Institute of Neurology, Department of Neurosciences, Catholic University School of Medicine, Rome, Italy.
Mesoangioblasts are a class of adult stem cells of mesoderm origin, potentially useful for the treatment of primitive myopathies of different etiology. Extensive in vitro and in vivo studies in animal models of muscular dystrophy have demonstrated the ability of mesoangioblast to repair skeletal muscle when injected intra-arterially. In a previous work we demonstrated that mesoangioblasts obtained from diagnostic muscle biopsies of IBM patients display a defective differentiation down skeletal muscle and this block can be corrected in vitro by transient MyoD transfection. We are currently investigating different pathways involved in mesoangioblasts skeletal muscle differentiation and exploring alternative stimulatory approaches not requiring extensive cell manipulation. This will allow to obtain safe, easy and efficient molecular or pharmacological modulation of pro-myogenic pathways in IBM mesoangioblasts. It is of crucial importance to identify factors (ie. cytokines, growth factors) produced by muscle or inflammatory cells and released in the surrounding milieu that are able to regulate the differentiation ability of IBM mesoangioblasts. To promote myogenic differentiation of endogenous mesoangioblasts in IBM muscle, the modulation of such target molecules selectively dysregulated would be a more handy approach to enhance muscle regeneration compared to transplantation techniques. Studies on the biological characteristics of IBM mesoangioblasts with their aberrant differentiation behavior, the signaling pathways possibly involved in their differentiation block and the possible strategies to overcome it in vivo, might provide new insights to better understand the etiopathogenesis of this crippling disorder and to identify molecular targets susceptible of therapeutic modulation. PMID: 21842589
Inclusion body myositis in Alzheimer's disease.
Roos PM, Vesterberg O, Nordberg M.
Inclusion body myositis in Alzheimer's disease.
Acta Neurol Scand: 2011: 124: 215-217.
Background: The prevalence of Alzheimer disease is increasing. Could findings of similar deposits in brain and muscle tissue explain this increase? The purpose of this report is to illustrate that Alzheimer disease and inclusion body myositis may share a common aetiology.Results: We present a case where Alzheimer disease and inclusion body myositis coexist in the same patient. Amyloid beta deposition and the presence of phosphorylated tau protein have been noted in brain tissue and in muscle biopsy from patients with these disorders.
Methods: Electrophysiological methods are needed for proper diagnosis of this brain and muscle disorder. Recent data on deposit structures in both conditions may indicate an environmental aetiology for Alzheimer's disease and inclusion body myositis.
Conclusion: By combining electrophysiological methods with muscle biopsy in cases of Alzheimer's disease, the possible aetiological connection between simultaneous affection of both muscle and brain in this condition can be established.
Inclusion body myositis: diagnosis, pathogenesis, and treatment options.
Solorzano GE, Phillips LH 2nd.
Inclusion body myositis (IBM) is the most common acquired myopathy in people older than 50 years. IBM typically presents with distal upper extremity weakness accompanied by proximal lower extremity muscle weakness. Associated clinical findings include asymmetric weakness, foot drop, and dysphagia. The pathogenesis of IBM is not clear. In this article the authors briefly discuss postulated pathogenic mechanisms. Although no proven pharmacotherapy exists, some promising candidates are discussed.
Of Particular Note
Autoantibodies against a 43 KDa Muscle Protein in Inclusion Body Myositis.
PloS one, 6(5), e20266. doi: 10.1371/journal.pone.0020266.
Methodology/Principal Findings: Plasma autoantibodies from 65 people, including 25 with IBM, were analyzed by immunoblots against normal human muscle. Thirteen of 25 (52%) IBM patient samples recognized an approximately 43 kDa muscle protein. No other disease (N = 25) or healthy volunteer (N = 15) samples recognized this protein.
Conclusions: Circulating antibodies against a 43-kDa muscle autoantigen may lead to the discovery of a novel biomarker for IBM. Its high specificity for IBM among patients with autoimmune myopathies furthermore suggests a relationship to disease pathogenesis.
In this study we report identification of a circulating autoantibody against a 43-kDa muscle autoantigen that is specific to IBM among other patients with autoimmune myopathies that we examined.
The demonstration of antigen-stimulated plasma cell antibody production  and now a circulating IBM autoantibody against a 43 kDa muscle protein provides compelling evidence for humoral autoimmunity in IBM.
J. Neuroimmunol. (2011), doi:10.1016/j.jneuroim.2011.02.011
Susceptibility to sporadic inclusion body myositis (sIBM) in Caucasians has been consistently associated with alleles of the major histocompatibility complex (MHC) 8.1 ancestral haplotype (AH) (defined by HLA-B*0801 and HLA-DRB1*0301). In this study recombination mapping was utilised to further refine the known 8.1AH susceptibility region near HLA-DRB1*0301. Caucasian sIBM patients carrying part of the 8.1AH were genotyped for a selection of 8.1AH-haplotypic polymorphisms. A common 8.1AH-specific susceptibility region was defined, spanning 172kb and encompassing three genes - HLA-DRB3, HLA-DRA and BTNL2. It is thus likely that 8.1AH-derived susceptibility to sIBM originates from at least one of these genes.
The source of the 8.1AH-derived susceptibility to sIBM as defined in this study most likely originates from a 172 kb stretch of the Class II MHC region that encompasses part of BTNL2, HLA-DRA and HLA-DRB3, the latter of which comprise the alpha and beta subunits of HLA-DR. The mechanisms by which BTNL2 or HLA-DR could contribute to sIBM susceptibility remain unclear and warrant further investigation.
The association of sporadic inclusion body myositis and Sjogren's syndrome in carriers of HLA-DR3 and the 8.1 MHC ancestral haplotype.
Rojana-Udomsart A, Needham M, Luo YB, Fabian V, Walters S, Zilko PJ, Mastaglia FL.
Sporadic inclusion body myositis (sIBM) usually occurs as an isolated condition, but it may occur in association with another autoimmune disorder such as Sjogren's syndrome. We reviewed sIBM cases with Sjogren's syndrome (sIBM/SS) from the Perth Inflammatory Myopathies Database to determine whether they are distinguishable from other sIBM cases. Six such cases were identified, representing 12% of all sIBM cases. Muscle biopsies confirmed the presence of an inflammatory myopathy with rimmed vacuoles and the characteristic muscle fibre inclusions of sIBM. Five of the six were females, contrasting with a 2:1 male preponderance in the rest of the sIBM cohort. The mean age-at-onset and the pattern of muscle weakness were similar in the two groups. Four out of five sIBM/SS patients treated with immune therapies had improvement in muscle strength lasting for 6-24 months, whereas only 27% of other sIBM patients improved. All 6 patients with sIBM/SS carried the HLA-DRB1*0301 allele, or its equivalent HLA-DR3 serological specificity, compared with 83% of other sIBM cases and all carried some or all of the major markers of the 8.1 MHC ancestral haplotype which is also associated with Sjogren's syndrome. Patients with sIBM/SS represent a subgroup of sIBM cases who are more likely to be female and carriers of HLA-DR3 and the 8.1 MHC ancestral haplotype, and are more likely to respond to treatment. The association of sIBM and Sjogren's syndrome is likely to be due to a common genetic predisposition linked to the MHC and supports the notion that sIBM has an autoimmune basis.
Immunotherapy of Inflammatory Myopathies: Practical Approach and Future Prospects.
Neuroimmunology Unit, Department of Pathophysiology, University of Athens Medical School, Athens, Greece, firstname.lastname@example.org.
OPINION STATEMENT: The inflammatory myopathies, a group of chronic myopathic conditions, are potentially treatable, so proper diagnosis and early initiation of therapy are necessary. The most common types are polymyositis (PM), dermatomyositis (DM), necrotizing autoimmune myopathy (NAM), and inclusion body myositis (IBM). This review provides practical advice on treatment and identifies emerging new therapies. Although IBM is difficult to treat, PM, DM, and NAM respond to appropriate immunotherapies, if diagnosed early and treated aggressively. In uncontrolled studies, PM and DM respond to prednisone to some degree and for a period of time. The commonly used immunosuppressive drugs (azathioprine, cyclosporine, mycophenolate, or methotrexate) may offer some non-evidence-based "steroid-sparing" effect but provide minimal benefit on their own. As a result, the second-line therapy is intravenous immunoglobulin (IVIg), which a controlled study has shown to be effective in DM and which appears to be effective in PM and NAM; it offers minimal and transient benefit to only a small number of IBM patients, however. Uncontrolled series have suggested that rituximab and tacrolimus may offer additional benefit to some patients not adequately controlled with the aforementioned therapies. IBM is usually resistant to most therapies, but early initiation of therapy may be helpful at times. Emerging agents against T cells, B cells, transmigration, or transduction molecules are discussed as potential new treatment options. PMID: 21365201
Pathophysiology of inflammatory and autoimmune myopathies.
MD, FAAN National University of Athens Medical School, Department of Pathophysiology,75 Mikras Asias street, 11527 Athens, Greece.
The main subtypes of inflammatory myopathies include dermatomyositis (DM), polymyositis (PM), necrotizing autoimmune myositis (NAM) and sporadic inclusion-body myositis (sIBM). The review provides an update on the main clinical characteristics unique to each subset, including fundamental aspects on muscle pathology helpful to assure accurate diagnosis, underlying immunopathomechanisms and therapeutic strategies. DM is a complement-mediated microangiopathy leading to destruction of capillaries, distal hypoperfusion and inflammatory cell stress on the perifascicular regions. NAM is an increasingly recognized subacute myopathy triggered by statins, viral infections, cancer or autoimmunity with macrophages as the final effector cells mediating fiber injury. PM and IBM are characterized by cytotoxic CD8-positive T cells which clonally expand in situ and invade MHC-I-expressing muscle fibers. In IBM, in addition to autoimmunity, there is vacuolization and intrafiber accumulation of degenerative and stressor molecules. Pro-inflammatory mediators, such as gamma interferon and interleukin IL1-beta, seem to enhance the accumulation of stressor and amyloid-related misfolded proteins. Current therapies using various immunosuppressive and immunomodulating drugs are discussed for PM, DM and NAM, and the principles for effective treatment strategies in IBM are outlined. PMID: 21411269
Sporadic inclusion-body myositis: Conformational multifactorial ageing-related degenerative muscle disease associated with proteasomal and lysosomal inhibition, endoplasmic reticulum stress, and accumulation of amyloid-beta42 oligomers and phosphorylated tau.
Askanas V, Engel WK.
University of Southern California Keck School of Medicine, Good Samaritan Hospital, USC Neuromuscular Centre, Department of Neurology, Los Angeles, CA 90017, USA.
The pathogenesis of sporadic inclusion-body myositis (s-IBM), the most common muscle disease of older persons, is complex and multifactorial. Both the muscle fiber degeneration and the mononuclear-cell inflammation are components of the s-IBM pathology, but how each relates to the pathogenesis remains unsettled. We consider that the intramuscle fiber degenerative component plays the primary and the major pathogenic role leading to muscle fiber destruction and clinical weakness. In this article we review the newest research advances that provide a better understanding of the s-IBM pathogenesis. Cellular abnormalities occurring in s-IBM muscle fibers are discussed, including: several proteins that are accumulated in the form of aggregates within muscle fibers, including amyloid-beta2 and its oligomers, and phosphorylated tau in the form of paired helical filaments, and we consider their putative detrimental influence; cellular mechanisms leading to protein misfolding and aggregation, including evidence of their inadequate disposal; pathogenic importance of endoplasmic reticulum stress and the unfolded protein response demonstrated in s-IBM muscle fibers; and decreased deacetylase activity of SIRT1. All these factors are combined with, and perhaps provoked by, an ageing intracellular milieu. Also discussed are the intriguing phenotypic similarities between s-IBM muscle fibers and the brains of Alzheimer and Parkinson's disease patients, the two most common neurodegenerative diseases associated with ageing. Muscle biopsy diagnostic criteria are also described and illustrated. PMID: 21392932
In our opinion, it is becoming more evident that in s-IBM a unique type of muscle fiber degeneration leads to muscle fiber atrophy, and resulting in muscle fiber degeneration and death, manifest clinically by relentlessly progressive muscle weakness.
In conclusion, s-IBM is a degenerative, conformational muscle disease of multifactorial pathogenesis. We reviewed molecular mechanisms responsible for multiprotein aggregation and accumulation within s-IBM muscle fibers. We also propose that the accumulation of post-translationally-modified proteins in the degenerated muscle fibers, can be perceived as "foreign" (not self) and be responsible for inducing T-cell inflammation in the s-IBM muscle. Accordingly, we propose that s-IBM is not a primary inflammatory disease-that would explain lack of benefit with anti-dysimmune treatment.
Although we do not yet know a unique-primary abnormality or mechanism, the multiplicity of abnormalities in s-IBM muscle fibers present various potential targets for therapeutic drugs.
Myonuclear breakdown in sporadic inclusion body myositis is accompanied by DNA double strand breaks.
Nishii M, Nakano S, Nakamura S, Wate R, Shinde A, Kaneko S, Kusaka H.
Department of Neurology and Brain Medical Research Center, Kansai Medical University, Japan.
Rimmed vacuoles in sporadic inclusion body myositis (s-IBM) contain nuclear remnants. We sought to determine if the nuclear degeneration seen in s-IBM is associated with DNA damage. In muscle biopsy specimens from ten patients with s-IBM and 50 controls, we immunolocalized 1) phosphorylated histone H2AX (y-H2AX), which is a sensitive immunocytochemical marker of DNA double-strand breaks and 2) DNA-PK, which is an enzyme involved in double-strand break repair. In s-IBM, vacuolar peripheries often showed strong immunoreactivity to y-H2AX and the three components of DNA-PK (DNA-PKcs, Ku70, and Ku80). A triple fluorescence study of Ku70, emerin, and DNA displayed nuclear breakdown and it suggested impaired nuclear incorporation of Ku70. The percentage of positive nuclei for y-H2AX was significantly higher in vacuolated fibers than non-vacuolated fibers in s-IBM, or fibers in polymyosits. We hypothesize that a dysfunction of nuclear envelope may cause nuclear fragility, double-strand breaks and impaired nuclear transport in s-IBM.
Deciphering the clinical presentations, pathogenesis, and treatment of the idiopathic inflammatory myopathies.
Rider LG, Miller FW.
JAMA. 2011 Jan 12;305(2):183-90.
Distad BJ, Amato AA, Weiss MD.
Curr Treat Options Neurol. 2011 Jan 8. [Epub ahead of print]
Unfortunately, though a number of immunomodulatory treatments have been investigated in IBM, none has convincingly demonstrated benefit.
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