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Myositis
Kinds of Myositis Selected AbstractsInflammatory myositis in systemic sclerosis: a South Australian perspectiveINTERNATIONAL JOURNAL OF RHEUMATIC DISEASES, Issue 3 2005T. Y.-T. Abstract Background:, Muscle atrophy and weakness occurs commonly in patients with systemic sclerosis, especially late in the course of the disease. However, profound proximal muscle weakness secondary to myositis is an infrequent finding. Aim:, To determine the frequency and disease characteristics of patients with myositis in our cohort of systemic sclerosis patients. Methods:, A retrospective case note review of the clinical course of all patients enrolled on the South Australian scleroderma register, a population-based register of 374 living and 234 deceased patients with systemic sclerosis, last updated to the end of December 2002. Results:, Twenty patients with myositis were identified, the majority with diffuse cutaneous systemic sclerosis and overlap syndromes. The calculated frequency of this complication was 3.3% in our population-based cohort. All patients suffered profound proximal muscle weakness complicated by functional impairment. Other clinical features included weakness of cervical musculature (15%), dyspnoea (10%) and dysphagia (10%). Creatine kinase level was elevated in 80% of the patients, with the mean peak creatine kinase level of 1129 U/L. When further investigations were undertaken, 80% of patients demonstrated myopathic changes on electromyography and 92% of patients were found to have histological findings characteristic of an inflammatory process. Positive antinuclear antibodies were identified in all patients, including two with anti-PM-Scl autoantibodies. Conclusion:, Myositis is an infrequent clinical feature in patients with systemic sclerosis. Profound proximal weakness in association with elevated creatine kinase levels and myopathic changes on electromyography should alert the clinician to this complication. The presence of anti-PM-Scl autoantibodies in association with overlap syndromes may have a more favourable prognostic significance. [source] Review article: the gastrointestinal complications of myositisALIMENTARY PHARMACOLOGY & THERAPEUTICS, Issue 3 2010E. C. EBERT Aliment Pharmacol Ther,31, 359,365 Summary Background, The inflammatory myopathies are a group of acquired diseases characterized by a proximal myopathy caused by an inflammatory infiltrate of the skeletal muscle. The three major diseases are dermatomyositis, polymyositis and inclusion body myositis. Aims, To review the gastrointestinal manifestations of myositis. Methods, Over 110 articles in the English literature were reviewed. Results, Dysphagia to solids and liquids occurs in patients with myositis. The pharyngo-oesophageal muscle tone is lost and therefore patients develop nasal speech, hoarseness, nasal regurgitation and aspiration pneumonia. There is tongue weakness, flaccid vocal cords, poor palatal motion and pooling of secretions in the distended hypopharynx. Proximal oesophageal skeletal muscle dysfunction is demonstrated by manometry with low amplitude/absent pharyngeal contractions and decreased upper oesophageal sphincter pressures. Patients exhibit markedly elevated creatine kinase and lactate dehydrogenase levels consistent with muscle injury. Myositis can be associated with inflammatory bowel disease, coeliac disease and interferon treatment of hepatitis C. Corticosteroids and other immunosuppressive drugs comprise the mainstay of treatment. Inclusion body myositis responds poorly to these agents and therefore a myotomy is usually indicated. Conclusion, Myositis mainly involves the skeletal muscles in the upper oesophagus with dysphagia, along with proximal muscle weakness. [source] Involvement of Clusterin and the Aggresome in Abnormal Protein Deposits in Myofibrillar Myopathies and Inclusion Body MyositisBRAIN PATHOLOGY, Issue 2 2005I. Ferrer Myofibrillar myopathies (MM) are characterized morphologically by the presence of non-hyaline structures corresponding to foci of dissolution of myofibrils, and hyaline lesions composed of aggregates of compacted and degraded myofibrillar elements. Inclusion body myositis (IBM) is characterized by the presence of rimmed vacuoles, eosinophilic inclusions in the cytoplasm, rare intranuclear inclusions, and by the accumulation of several abnormal proteins. Recent studies have demonstrated impaired proteasomal expression and activity in MM and IBM, thus accounting, in part, for the abnormal protein accumulation in these diseases. The present study examines other factors involved in protein aggregation in MM and IBM. Clusterin is a multiple-function protein which participates in A,-amyloid, PrPres and ,-synuclein aggregation in Alzheimer disease, prionopathies and ,-synucleinopathies, respectively. ,-Tubulin is present in the centrosome and is an intracellular marker of the aggresome. Moderate or strong clusterin immunoreactivity has been found in association with abnormal protein deposits, as revealed by immunohistochemistry, single and double-labeling immunofluorescence and confocal microscopy, in MM and IBM, and in target structures in denervation atrophy. ,-Tubulin has also been observed in association with abnormal protein deposits in MM, IBM, and in target fibers in denervation atrophy. These morphological findings are accompanied by increased expression of clusterin and ,-tubulin in muscle homogenates of MM and IBM cases, as revealed by gel electrophoresis and Western blots. Together, these observations demonstrate involvement of clusterin in protein aggregates, and increased expression of aggresome markers in association with abnormal protein inclusions in MM and IBM and in targets, as crucial events related with the pathogenesis of abnormal protein accumulation and degradation in these muscular diseases. [source] Cytological features of nodular myositisCYTOPATHOLOGY, Issue 3 2003S. K. Mohanty No abstract is available for this article. [source] A new endoscopic technique for suspension of esophageal prosthesis for refractory caustic esophageal stricturesDISEASES OF THE ESOPHAGUS, Issue 3 2008E. Ancona SUMMARY., There is no clear consensus concerning the best endoscopic treatment of benign refractory esophageal strictures due to caustic ingestion. Different procedures are currently used: frequent multiple dilations, retrievable self-expanding stent, nasogastric intubation and surgery. We describe a new technique to fix a suspended esophageal silicone prosthesis to the neck in benign esophageal strictures; this permits us to avoid the frequent risk of migration of the expandable metallic or plastic stents. Under general anesthesia a rigid esophagoscope was placed in the patient's hypopharynx. Using transillumination from the optical device, the patient's neck was pierced with a needle. A n.0 monofilament surgical wire was pushed into the needle, grasped by a standard foreign body forceps through the esophagoscope and pulled out of the mouth (as in percutaneous endoscopic gastrostomy procedure). After tying the proximal end of the silicone prosthesis with the wire, it was placed through the strictures under endoscopic view. This procedure was successfully utilized in four patients suffering from benign refractory esophageal strictures due to caustic ingestion. The prosthesis and its suspension from the neck were well-tolerated until removal (mean duration 4 months). A postoperative transitory myositis was diagnosed in only one patient. One of the most frequent complications of esophageal prostheses in refractory esophageal strictures due to caustic ingestion is distal migration. Different solutions were proposed. For example the suspension of a wire coming from the nose and then fixed behind the ear. This solution is not considered optimal because of patient complaints and moreover the aesthetic aspect is compromised. The procedure we utilized in four patients utilized the setting of a silicone tube hanging from the neck in a way similar to that of endoscopic pharyngostomy. This solution is a valid alternative both for quality of life and for functional results. [source] Accumulation of amyloid-, protein in exocrine glands of transgenic mice overexpressing a carboxyl terminal portion of amyloid protein precursorINTERNATIONAL JOURNAL OF EXPERIMENTAL PATHOLOGY, Issue 4 2000Ken-Ichiro Fukuchi Amyloid-, protein (A,) and its precursor (,PP) play important roles in the pathogenesis of Alzheimer disease and inclusion-body myositis. In humans, A, deposits are found in brain, skeletal muscle, and skin. Therefore, we have investigated possible A, deposits in multiple tissues of two transgenic mouse lines overexpressing the signal plus A,-bearing 99-amino acid carboxyl terminal sequences of ,PP under the control of a cytomegalovirus enhancer/,-actin promoter. One of the lines developed A,-immunoreactive intracellular deposits consistently in the pancreas and lacrimal gland, and occasionally in gastric, DeSteno's, and lingual glands. Although the A, deposits increased during ageing and degenerative changes of the tissues were observed, little or no extracellular A, deposits were observed up to the age of 25 months. These lines of transgenic mice are useful for studying the molecular mechanisms of development and clearance of intracellular A, deposits. [source] Successful treatment of extensive muscle calcification in a patient with primary idiopathic polymyositis with diltiazemINTERNATIONAL JOURNAL OF RHEUMATIC DISEASES, Issue 3 2006Yasser EMAD Abstract A 25-year-old female patient with documented diagnosis of polymyositis developed extensive muscle calcification in the left thigh muscles with overlying skin induration one year after her disease onset, despite well controlled myositis. Plain X-ray of the left femur and hip revealed extensive calcification involving the periarticular soft tissue shadows around the left hip and left upper thigh. The patient received diltiazem 90 mg/day in divided doses and follow-up plain X-ray study after 6 months of treatment revealed almost complete resolution of the muscle calcifications. [source] Inflammatory myositis in systemic sclerosis: a South Australian perspectiveINTERNATIONAL JOURNAL OF RHEUMATIC DISEASES, Issue 3 2005T. Y.-T. Abstract Background:, Muscle atrophy and weakness occurs commonly in patients with systemic sclerosis, especially late in the course of the disease. However, profound proximal muscle weakness secondary to myositis is an infrequent finding. Aim:, To determine the frequency and disease characteristics of patients with myositis in our cohort of systemic sclerosis patients. Methods:, A retrospective case note review of the clinical course of all patients enrolled on the South Australian scleroderma register, a population-based register of 374 living and 234 deceased patients with systemic sclerosis, last updated to the end of December 2002. Results:, Twenty patients with myositis were identified, the majority with diffuse cutaneous systemic sclerosis and overlap syndromes. The calculated frequency of this complication was 3.3% in our population-based cohort. All patients suffered profound proximal muscle weakness complicated by functional impairment. Other clinical features included weakness of cervical musculature (15%), dyspnoea (10%) and dysphagia (10%). Creatine kinase level was elevated in 80% of the patients, with the mean peak creatine kinase level of 1129 U/L. When further investigations were undertaken, 80% of patients demonstrated myopathic changes on electromyography and 92% of patients were found to have histological findings characteristic of an inflammatory process. Positive antinuclear antibodies were identified in all patients, including two with anti-PM-Scl autoantibodies. Conclusion:, Myositis is an infrequent clinical feature in patients with systemic sclerosis. Profound proximal weakness in association with elevated creatine kinase levels and myopathic changes on electromyography should alert the clinician to this complication. The presence of anti-PM-Scl autoantibodies in association with overlap syndromes may have a more favourable prognostic significance. [source] Evaluation of diquat against an acute experimental infection of Flavobacterium columnare in channel catfish, Ictalurus punctatus (Rafinesque)JOURNAL OF FISH DISEASES, Issue 5 2009A M Darwish Abstract A trial was performed to evaluate the efficacy of diquat (6,7-dihydrodipyrido[1,2-a:2,,1,-c]pyrazinediium dibromide) against an acute experimental infection of Flavobacterium columnare in channel catfish, Ictalurus punctatus. Diquat is an Environmental Protection Agency-approved herbicide and has the potential to be legally and practically used against columnaris. Channel catfish were challenged, by cutaneous abrasion, and waterborne exposure to F. columnare and treated once at 22-h post-challenge with 2.5, 5.0, 10.0 and 15 mg L,1 of diquat active ingredient for 6 h. At the conclusion of the trial, 21-day post-challenge, diquat at 5.0, 10.0 and 15 mg L,1 significantly (P < 0.05) reduced the mortality of infected fish from 95% in the challenged non-treated fish to 68%, 59% and 49%, respectively. In vitro, the minimum inhibitory concentration (MIC) of 23 isolates of F. columnare was assayed. The majority of the isolates had an MIC value of 5 ,g mL,1 (15 of the 23 isolates). Infected fish exhibited acute clinical signs similar to a natural infection. The skin had severe ulcerative necrotizing dermatitis and the muscles had severe necrotizing myositis. The gills had severe multifocal necrotizing branchitis. The results demonstrate that diquat would reduce mortalities caused by an acute columnaris infection. [source] Cervical necrotizing fasciitis and myositis in a western lowland gorilla (Gorilla gorilla gorilla)JOURNAL OF MEDICAL PRIMATOLOGY, Issue 3 2009M.C. Allender Abstract A 39-yr-old wild-caught, female western lowland gorilla (Gorilla gorilla gorilla) died during an immobilization to assess swelling and apparent pain of the cervical region. Necropsy revealed a fistulous tract containing plant material in the oropharynx, above the soft palate, communicating with a left-sided cervical necrotizing fasciitis and myositis. Alpha-hemolytic Streptococcus and Prevotella sp. were isolated from the cervical lesion. This is a report of cervical necrotizing fasciitis in a western lowland gorilla. [source] Cystatin C colocalizes with amyloid-, and coimmunoprecipitates with amyloid-, precursor protein in sporadic inclusion-body myositis musclesJOURNAL OF NEUROCHEMISTRY, Issue 6 2003Gaetano Vattemi Abstract Cystatin C (CC), an endogenous cysteine protease inhibitor, is accumulated within amyloid-, (A,) amyloid deposits in Alzheimer's disease (AD) brain and was proposed to play a role in the AD pathogenesis. Because the chemo-morphologic muscle phenotype of sporadic inclusion-body myositis (s-IBM) has several similarities with the phenotype of AD brain, including abnormal accumulation of A, deposits, we studied expression and localization of CC in muscle biopsies of 10 s-IBM, and 16 disease- and five normal-control muscle biopsies. Physical interaction of CC with amyloid-, precursor protein (A,PP) was studied by a combined immunoprecipitation/immunoblotting technique in the s-IBM muscle biopsies and in A,PP-overexpressing cultured human muscle fibers. In all s-IBM muscle biopsies, CC-immunoreactivity either colocalized with, or was adjacent to, the A,-immunoreactive inclusions in 80,90% of the vacuolated muscle fibers, mostly in non-vacuolated regions of their cytoplasm. Ultrastructurally, CC immunoreactivity-colocalized with A, on 6,10 nm amyloid-like fibrils and floccular material. By immunoblotting, CC expression was strongly increased in IBM muscle as compared to the controls. By immunoprecipitation/immunoblotting experiments, CC coimmunoprecipitated with A,PP, both in s-IBM muscle and in A,PP-overexpressing cultured normal human muscle fibers. Our studies (i) demonstrate for the first time that CC physically associates with A,PP, and (ii) suggest that CC may play a novel role in the s-IBM pathogenesis, possibly by influencing A,PP processing and A, deposition. [source] Review article: the gastrointestinal complications of myositisALIMENTARY PHARMACOLOGY & THERAPEUTICS, Issue 3 2010E. C. EBERT Aliment Pharmacol Ther,31, 359,365 Summary Background, The inflammatory myopathies are a group of acquired diseases characterized by a proximal myopathy caused by an inflammatory infiltrate of the skeletal muscle. The three major diseases are dermatomyositis, polymyositis and inclusion body myositis. Aims, To review the gastrointestinal manifestations of myositis. Methods, Over 110 articles in the English literature were reviewed. Results, Dysphagia to solids and liquids occurs in patients with myositis. The pharyngo-oesophageal muscle tone is lost and therefore patients develop nasal speech, hoarseness, nasal regurgitation and aspiration pneumonia. There is tongue weakness, flaccid vocal cords, poor palatal motion and pooling of secretions in the distended hypopharynx. Proximal oesophageal skeletal muscle dysfunction is demonstrated by manometry with low amplitude/absent pharyngeal contractions and decreased upper oesophageal sphincter pressures. Patients exhibit markedly elevated creatine kinase and lactate dehydrogenase levels consistent with muscle injury. Myositis can be associated with inflammatory bowel disease, coeliac disease and interferon treatment of hepatitis C. Corticosteroids and other immunosuppressive drugs comprise the mainstay of treatment. Inclusion body myositis responds poorly to these agents and therefore a myotomy is usually indicated. Conclusion, Myositis mainly involves the skeletal muscles in the upper oesophagus with dysphagia, along with proximal muscle weakness. [source] Inhibition of myostatin with emphasis on follistatin as a therapy for muscle diseaseMUSCLE AND NERVE, Issue 3 2009Louise R. Rodino-Klapac PhD Abstract In most cases, pharmacologic strategies to treat genetic muscle disorders and certain acquired disorders, such as sporadic inclusion body myositis, have produced modest clinical benefits. In these conditions, inhibition of the myostatin pathway represents an alternative strategy to improve functional outcomes. Preclinical data that support this approach clearly demonstrate the potential for blocking the myostatin pathway. Follistatin has emerged as a powerful antagonist of myostatin that can increase muscle mass and strength. Follistatin was first isolated from the ovary and is known to suppress follicle-stimulating hormone. This raises concerns for potential adverse effects on the hypothalamic,pituitary,gonadal axis and possible reproductive capabilities. In this review we demonstrate a strategy to bypass off-target effects using an alternatively spliced cDNA of follistatin (FS344) delivered by adeno-associated virus (AAV) to muscle. The transgene product is a peptide of 315 amino acids that is secreted from the muscle and circulates in the serum, thus avoiding cell-surface binding sites. Using this approach our translational studies show increased muscle size and strength in species ranging from mice to monkeys. Adverse effects are avoided, and no organ system pathology or change in reproductive capabilities has been seen. These findings provide the impetus to move toward gene therapy clinical trials with delivery of AAV-FS344 to increase size and function of muscle in patients with neuromuscular disease. Muscle Nerve 39: 283,296, 2009 [source] Annexin expression in inflammatory myopathiesMUSCLE AND NERVE, Issue 1 2004Stefan Probst-Cousin MD Abstract The pathogenesis of the inflammatory myopathies is still unclear, making their treatment largely empirical. Improved understanding of the molecular mechanisms of inflammatory muscle injury may, however, lead to the development of more specific immunotherapies. To elucidate a possible pathogenic contribution of calcium-binding proteins such as the annexins, we immunohistochemically investigated muscle biopsy specimens from patients with dermatomyositis (10 cases), polymyositis (9 cases), and inclusion-body myositis (4 cases), compared to control cases comprising sarcoid myopathy (3 cases), Duchenne muscular dystrophy (DMD; 4 cases), and normal muscle (3 cases). We found expression of annexins A1, A2, A4, and A6 in the vascular endothelium of all cases. Myofibers expressed annexins A5, A6, and A7 diffusely and weakly in the cytosol, whereas annexins A5 and A7 were also particularly localized to the sarcolemma. In the inflammatory myopathies, in areas of myonecrosis in DMD, and in granulomatous lesions of sarcoid myopathy, reactivity of annexins A1, A2, A4, A5, and A6 was observed in macrophages and T-lymphocytes. Whereas the latter annexins appear to be nonspecific indicators of activation, annexin A1 upregulation may represent endogenous anti-inflammatory mechanisms that merit further investigation. Muscle Nerve 30: 102,110, 2004 [source] Inflammatory myopathies: Clinical, diagnostic and therapeutic aspectsMUSCLE AND NERVE, Issue 4 2003Frank L. Mastaglia MD Abstract The three major forms of immune-mediated inflammatory myopathy are dermatomyositis (DM), polymyositis (PM), and inclusion-body myositis (IBM). They each have distinctive clinical and histopathologic features that allow the clinician to reach a specific diagnosis in most cases. Magnetic resonance imaging is sometimes helpful, particularly if the diagnosis of IBM is suspected but has not been formally evaluated. Myositis-specific antibodies are not helpful diagnostically but may be of prognostic value; most antibodies have low sensitivity. Muscle biopsy is mandatory to confirm the diagnosis of an inflammatory myopathy and to allow unusual varieties such as eosinophilic, granulomatous, and parasitic myositis, and macrophagic myofasciitis, to be recognized. The treatment of the inflammatory myopathies remains largely empirical and relies upon the use of corticosteroids, immunosuppressive agents, and intravenous immunoglobulin, all of which have nonselective effects on the immune system. Further controlled clinical trials are required to evaluate the relative efficacy of the available therapeutic modalities particularly in combinations, and of newer immunosuppressive agents (mycophenolate mofetil and tacrolimus) and cytokine-based therapies for the treatment of resistant cases of DM, PM, and IBM. Improved understanding of the molecular mechanisms of muscle injury in the inflammatory myopathies should lead to the development of more specific forms of immunotherapy for these conditions. Muscle Nerve 27:407,425, 2003 [source] Adhesion molecule expression in experimental myositisMUSCLE AND NERVE, Issue 3 2002Tomoko Ito MD Abstract Experimental allergic myositis (EAM) in Lewis rats, induced with partially purified myosin, is regarded as a model of human polymyositis. To clarify the role of adhesion molecules in the pathogenesis of EAM in Lewis rats, we investigated intramysial expressions of the intercellular adhesion molecule (ICAM)-1 and vascular cell adhesion molecule (VCAM)-1, and the serum level of soluble ICAM-1 in EAM rats. All the EAM rat muscles had scattered inflammatory foci, as well as cell infiltration and necrosis, by week 4 after the initial immunization (i.e., day 0 after the last immunization). As compared with the control muscles, ICAM-1 and VCAM-1 were strongly expressed immunohistochemically in the endothelium of vessels in the endomysium and perimysium, and to lesser extents in the inflammatory infiltrates and on the sarcolemma of nonnecrotic muscle fibers adjacent to the inflammatory infiltrates or invaded muscle fibers. ICAM-1 in the muscle extracts and sera from EAM rats increased on each test day, as compared with extracts from the normal controls. The values peaked on day 0 after the last immunization, then gradually decreased with time. ICAM-1 elevations in the muscle extracts were correlated with the percent of sections that had inflammatory lesions (P = 0.032) and the histological scores (P = 0.005) on day 0, whereas there was no significance on days 3 and 7. These findings suggest that the adhesion molecules ICAM-1 and VCAM-1 increase in the early stage of EAM, and function in the initiation of the inflammatory process of myositis. © 2002 Wiley Periodicals, Inc. Muscle Nerve 25: 000,000, 2002 [source] Patterns of muscle involvement in inclusion body myositis: Clinical and magnetic resonance imaging studyMUSCLE AND NERVE, Issue 11 2001Beverley A. Phillips PhD Abstract The differential patterns of muscle involvement in the upper and lower limbs in sporadic inclusion body myositis (sIBM) were examined in 18 patients using both quantitative and manual muscle testing as well as magnetic resonance imaging (MRI) in 9 patients. Weakness of the quadriceps femoris and the forearm flexors was present in most patients, but there was considerable variability in the patterns and severity of muscle involvement. MRI disclosed preferential patterns of muscle involvement within functional groups such as the quadriceps femoris, in which there was severe involvement of the vasti with relative sparing of the rectus femoris, and the triceps surae, in which selective involvement of the medial gastrocnemius was common. Involvement of flexor digitorum profundus on MRI was found in only one third of patients. The results emphasize the variability in the clinical phenotype and differential susceptibility of muscles to the disease process in sIBM. © 2001 John Wiley & Sons, Inc. Muscle Nerve 24: 1526,1534, 2001 [source] McArdle disease and sporadic inclusion body myositisNEUROPATHOLOGY & APPLIED NEUROBIOLOGY, Issue 4 2009M. Scarpelli First page of article [source] Myostatin precursor protein is increased and associates with amyloid-, precursor protein in inclusion-body myositis culture modelNEUROPATHOLOGY & APPLIED NEUROBIOLOGY, Issue 2 2007S. Wojcik First page of article [source] Systematic review and meta-analysis of clinically relevant adverse events from HMG CoA reductase inhibitor trials worldwide from 1982 to present,PHARMACOEPIDEMIOLOGY AND DRUG SAFETY, Issue 2 2007David L. McClure PhD Abstract Purpose Our objective was to determine the association of clinically relevant adverse events from a systematic review and meta-analysis of statin randomized controlled trials (RCT). Methods We performed the meta-analysis in the manner of a Cochrane Collaboration systematic review. Outcomes were discontinuances of therapy or muscle-related symptoms due to adverse events. We searched for articles from 1982 through June 2006 in MEDLINE and other databases. The main inclusion criteria were double blind, placebo controlled RCTs with a monotherapy intervention of any marketed statin and active surveillance of adverse events. We excluded studies of drug interactions, organ transplants, or exercise, or those not meeting all of the study quality criteria. The primary analysis was a statin formulation stratified fixed-effect model using Peto odds-ratios (POR). Secondary analyses explored the stability of the primary results. Results Over 86,000 study participants from 119 studies were included. Available statins were associated with a lower POR of discontinuance (overall: 0.88 [0.84, 0.93], largest effect with pravastatin: 0.79 [0.74, 0.84]), an elevated POR of rhabdomyolysis (1.59 [0.54, 4.70]) and myositis (2.56 [1.12, 5.85]), and null odds of myalgia (1.09 [0.97, 1.23]). Cerivastatin by comparison demonstrated larger PORs for discontinuances and muscle-related adverse events. Secondary analyses demonstrated the stability of the results. Conclusions Overall, discontinuation of statin therapy due to adverse events was no worse than placebo. The risks of muscle-related adverse events were in general agreement with the known risks of statins. Copyright © 2006 John Wiley & Sons, Ltd. [source] The prion protein in human neuromuscular diseasesTHE JOURNAL OF PATHOLOGY, Issue 3 2004Gábor G Kovács Abstract The basis of human prion diseases affecting the nervous system is accumulation of a disease-associated conformer (PrPSc) of the normal cellular prion protein (PrPC). Earlier studies demonstrated increased expression of PrPC in inclusion body myositis (IBM), dermato-, and polymyositis, as well as neurogenic muscle atrophy. To define the spectrum and reliability of PrPC immunoreactivity, its expression was examined systematically in a series of pathologically characterized muscular disorders by means of immunohistochemistry, confocal laser microscopy, and immunogold electron microscopy. Anti-PrPC immunolabelling of rimmed vacuoles was observed in IBM, inclusions of myofibrillary myopathy, targets, regenerating, and atrophic fibres, mononuclear cells, in addition to ragged red fibres in mitochondrial myopathies, and focal sarcolemmal immunostaining in non-diseased controls. Quantitative analysis demonstrated that, in neurogenic muscle lesions, anti-PrPC staining detects a significantly broader spectrum of fibres than anti-vimentin or anti-NCAM. In dystrophic muscle, PrPC expression was mainly restricted to regenerating fibres. In IBM, PrPC expression was not confined to rimmed vacuoles or vacuolated fibres and only a small percentage (7.1%) of rimmed vacuoles were PrPC positive. Ultrastructurally, PrPC was observed in the cytoplasm of lymphocytes, in the myofibrillar network of targets, and in rimmed vacuoles. Knowledge of disease circumstances with altered expression of PrPC is important in the setting of a potentially increased chance for extraneural PrPC,PrPSc conversion. In addition, our observations suggest that PrPC may have a general stress,response effect in various neuromuscular disorders. Copyright © 2004 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. [source] Sporadic inclusion body myositis: Pathogenic considerations,ANNALS OF NEUROLOGY, Issue 1 2009FRCP(C), George Karpati OC Sporadic inclusion body myositis is the commonest acquired disease of skeletal muscles after 50 years of age, and as such it has commanded a great deal of attention of investigators over the past 25 years. As a result, a large amount of information has accumulated concerning its clinical profile, myopathology, and immunopathology. In the myopathology and immunopathology, there is general agreement that the characteristic features could be divided into a degenerative and an inflammatory group. However, there has been controversy about the possible role of these changes in the pathogenesis of muscle fiber damage. In particular, there is no agreement whether a cause-and-effect relationship exists between these two groups of changes, and if so, which is the primary one. In this brief overview, we examine the validity of the various controversial observations and critically review the justification for the two major hypotheses for the primary role of inflammation versus degeneration. Ann Neurol 2009;65:7,11 [source] Definitive engagement of cytotoxic CD8 T cells in C protein,induced myositis, a murine model of polymyositisARTHRITIS & RHEUMATISM, Issue 10 2010Takahiko Sugihara Objective To substantiate a pathogenic role of cytotoxic CD8 T cells in the development of a murine polymyositis model, C protein,induced myositis (CIM). Methods Beta2 -microglobulin,null mutant, perforin-null mutant, and wild-type (WT) C57BL/6 mice were immunized with skeletal muscle C protein fragments to provoke CIM. Regional lymph node CD8 or CD4 T cells stimulated with C protein,pulsed dendritic cells were transferred adoptively to naive mice. Inflammation and damage of the muscle tissues were evaluated histologically. Results The incidence of myositis development was significantly lower in ,2 -microglobulin,null and perforin-null mutant mice compared with WT mice. Inflammation was less severe in mutant mice, and the incidence of muscle injury was reduced significantly. Adoptive transfer of lymph node T cells from mice with CIM induced myositis in naive recipient mice. The CD8 T cell,induced muscle injuries were significantly more severe than the CD4 T cell,induced muscle injuries. Conclusion Perforin-mediated cytotoxicity by CD8 T cells is definitively responsible for muscle injury in CIM. [source] Damage extent and predictors in adult and juvenile dermatomyositis and polymyositis as determined with the myositis damage indexARTHRITIS & RHEUMATISM, Issue 11 2009Lisa G. Rider Objective We undertook this study to validate the Myositis Damage Index (MDI) in juvenile and adult myositis, to describe the degree and types of damage and to develop predictors of damage. Methods Retrospective MDI evaluations and prospective assessment of disease activity and illness features were conducted. Patients with juvenile-onset disease (n = 143) were evaluated a median of 18 months after diagnosis; 135 patients were assessed 7,9 months later, and 121 were last assessed a median of 82 months after diagnosis. Ninety-six patients with adult-onset dermatomyositis or polymyositis had a baseline assessment a median of 30 months after diagnosis; 77 patients had a 6-month followup evaluation, and 55 had a final assessment a median of 60 months after diagnosis. Results Damage was present in 79% of juvenile patients and in 97% of adult patients. In juveniles, scarring, contractures, persistent weakness, muscle dysfunction, and calcinosis were most frequent (23,30%) at the last evaluation. In adults, muscle atrophy, muscle dysfunction, and muscle weakness were most frequent (74,84%). MDI severity correlated with physician-assessed global damage, serum creatinine, and muscle atrophy on magnetic resonance imaging, and in juveniles also with functional disability and weakness. MDI damage scores and frequency were highest in patients with a chronic illness course and in adult patients who died. Predictors of damage included functional disability, duration of active disease, disease severity at diagnosis, physician-assessed global disease activity, and illness features, including ulcerations in children and pericarditis in adults. Conclusion Damage is common in myositis after a median duration of 5 years in patients with adult-onset disease and 6.8 years in patients with juvenile-onset disease. The MDI has good content, construct, and predictive validity in juvenile and adult myositis. [source] Retinoid ameliorates experimental autoimmune myositis, with modulation of Th cell differentiation and antibody production in vivoARTHRITIS & RHEUMATISM, Issue 10 2009Naho Ohyanagi Objective Polymyositis and dermatomyositis are chronic inflammatory muscle diseases. Retinoids are compounds that bind to the retinoic acid binding site of retinoic acid receptors and have biologic activities similar to those of vitamin A. Recent studies indicate that retinoids promote Th2 differentiation and suppress Th1 and Th17 differentiation in vitro. The present study was undertaken to examine the effects of a synthetic retinoid, Am80, on experimental autoimmune myositis as well as on Th phenotype development and antibody production. Methods Experimental autoimmune myositis was induced in SJL/J mice by immunization with rabbit myosin. Am80 was administered orally once daily. Its effects were evaluated by measurement of the numbers of infiltrating inflammatory cells, production of inflammatory cytokines in muscle, production of Th-specific cytokines by myosin-stimulated splenic T cells, and production of antimyosin antibodies in serum. Results In mice with experimental autoimmune myositis, orally administered Am80 significantly reduced the number of infiltrating inflammatory cells and the expression of tumor necrosis factor , and interleukin-1, (IL-1,) in muscle. Moreover, Am80 increased production of interferon-,, IL-4, and IL-10, but not IL-17, by myosin-stimulated splenic T cells of mice with experimental autoimmune myositis, suggesting that it could enhance differentiation into Th1 and Th2, but not Th17, in vivo. Am80 also decreased serum levels of IgG2a and IgG2b antimyosin antibodies, but did not affect levels of IgG1 antimyosin antibodies. In addition, it suppressed chemokine expression and activator protein 1 activity in myoblasts in vitro. Conclusion The synthetic retinoid Am80 has an inhibitory effect on experimental autoimmune myositis. It might regulate the development of Th phenotype and antibody production in vivo, in addition to its effects on cytokine and chemokine production. [source] Ultraviolet radiation intensity predicts the relative distribution of dermatomyositis and anti,Mi-2 autoantibodies in womenARTHRITIS & RHEUMATISM, Issue 8 2009Lori A. Love Objective Because studies suggest that ultraviolet (UV) radiation modulates the myositis phenotype and Mi-2 autoantigen expression, we conducted a retrospective investigation to determine whether UV radiation may influence the relative prevalence of dermatomyositis and anti,Mi-2 autoantibodies in the US. Methods We assessed the relationship between surface UV radiation intensity in the state of residence at the time of onset with the relative prevalence of dermatomyositis and myositis autoantibodies in 380 patients with myositis from referral centers in the US. Myositis autoantibodies were detected by validated immunoprecipitation assays. Surface UV radiation intensity was estimated from UV Index data collected by the US National Weather Service. Results UV radiation intensity was associated with the relative proportion of patients with dermatomyositis (odds ratio [OR] 2.3, 95% confidence interval [95% CI] 0.9,5.8) and with the proportion of patients expressing anti,Mi-2 autoantibodies (OR 6.0, 95% CI 1.1,34.1). Modeling of these data showed that these associations were confined to women (OR 3.8, 95% CI 1.3,11.0 and OR 17.3, 95% CI 1.8,162.4, respectively) and suggests that sex influences the effects of UV radiation on autoimmune disorders. Significant associations were not observed in men, nor were UV radiation levels related to the presence of antisynthetase or anti,signal recognition particle autoantibodies. Conclusion This first study of the distribution of myositis phenotypes and UV radiation exposure in the US showed that UV radiation may modulate the clinical and immunologic expression of autoimmune disease in women. Further investigation of the mechanisms by which these effects are produced may provide insights into pathogenesis and suggest therapeutic or preventative strategies. [source] Therapeutic effects of interleukin-6 blockade in a murine model of polymyositis that does not require interleukin-17AARTHRITIS & RHEUMATISM, Issue 8 2009Naoko Okiyama Objective To explore new molecular targets in the treatment of polymyositis (PM) by examining a recently established murine model of PM, C protein,induced myositis (CIM), for involvement of an interleukin-6 (IL-6)/IL-17A pathway. Methods CIM was induced by immunizing wild-type mice as well as IL-6,null and IL-17A,null C57BL/6 mice with recombinant mouse skeletal C protein fragments. Some mice were treated with anti,IL-6 receptor (anti,IL-6R) monoclonal antibodies or control antibodies. Muscle tissue samples were examined histologically and immunohistochemically. Results The syngeneic C protein fragments successfully induced inflammation in the skeletal muscles of wild-type mice. IL-6 was expressed by mononuclear cells, especially in macrophages, infiltrating in the muscles. IL-6,null mice developed myositis with significantly lower incidence and milder severity than wild-type mice. In contrast, IL-17A,null mice were as susceptible to CIM as wild-type mice. Intraperitoneal administration of anti,IL-6R monoclonal antibodies, but not of control monoclonal antibodies, ameliorated CIM both preventively and therapeutically. Conclusion Our findings indicate that IL-6 is critically involved in the development of CIM. Although many other autoimmune models require IL-6 for differentiation of pathogenic T cells producing IL-17A, IL-17A was dispensable in CIM. Nevertheless, treatment with anti,IL-6R antibodies was effective. IL-6 blockade is potentially a new approach to the treatment of autoimmune myositis, via processes distinct from interference in the IL-6/IL-17A pathway. [source] Amelioration of alphavirus-induced arthritis and myositis in a mouse model by treatment with bindarit, an inhibitor of monocyte chemotactic proteinsARTHRITIS & RHEUMATISM, Issue 8 2009Nestor E. Rulli Objective Alphaviruses such as chikungunya virus, Sindbis virus, o'nyong-nyong virus, Mayaro virus, and Ross River virus (RRV), are commonly associated with arthralgias and overt arthritides worldwide. Understanding the processes by which arthritogenic viruses cause disease is a prerequisite in the quest for better treatments. In this regard, we have recently established that monocyte/macrophages are mediators of alphavirus-induced arthritis in mice. We hypothesized that chemokines associated with monocyte/macrophage recruitment may play an important role in disease. The aim of the present investigations was to determine whether bindarit, an inhibitor of monocyte chemotactic protein (MCP) synthesis, could ameliorate alphavirus-induced rheumatic disease in mice. Methods Using our recently developed mouse model of RRV-induced arthritis, which has many characteristics of RRV disease (RRVD) in humans, the effects of bindarit treatment on RRVD in mice were determined via histologic analyses, immunohistochemistry, flow cytometry, real-time polymerase chain reaction analysis, enzyme-linked immunosorbent assay, and electrophoretic mobility shift assay. Results Bindarit-treated RRV-infected mice developed mild disease and had substantially reduced tissue destruction and inflammatory cell recruitment as compared with untreated RRV-infected mice. The virus load in the tissues was not affected by bindarit treatment. Bindarit exhibited its activity by down-regulating MCPs, which in turn led to inhibition of cell infiltration and lower production of NF-,B and tumor necrosis factor ,, which are involved in mediating tissue damage. Conclusion Our data support the use of inhibitors of MCP production in the treatment of arthritogenic alphavirus syndromes and suggest that bindarit may be useful in treating RRVD and other alphavirus-induced arthritides in humans. [source] Sera from anti,Jo-1,positive patients with polymyositis and interstitial lung disease induce expression of intercellular adhesion molecule 1 in human lung endothelial cellsARTHRITIS & RHEUMATISM, Issue 8 2009Sevim Barbasso Helmers Objective To investigate whether sera or purified IgG from patients with polymyositis (PM) and patients with dermatomyositis (DM), with or without interstitial lung disease (ILD), can activate endothelial cells (ECs). Methods Patients' sera were selected based on the presence or absence of anti,Jo-1, anti-SSA, or anti,U1 small nuclear RNP autoantibodies. The presence of autoantibodies was determined by line blot assays. Cultured human microvascular ECs derived from lung tissue (HMVEC-L) were incubated with sera or purified IgG from 22 patients with PM, 7 patients with DM, and 10 healthy individuals as controls. Assessment of intercellular adhesion molecule 1 (ICAM-1) expression was conducted by immunofluorescence (n = 22) and by cell-based enzyme-linked immunosorbent assay (ELISA) (n = 20). Serum levels of soluble ICAM-1 (sICAM-1) were determined by ELISA. Results Sera from PM patients with ILD who were positive for anti,Jo-1 autoantibodies had a significantly stronger effect on the expression of ICAM-1 by HMVEC-L in comparison with sera from healthy controls and patients with other autoantibodies. Purified IgG did not induce ICAM-1 expression. Higher serum levels of sICAM-1 were found in patients with myositis compared with healthy controls. Conclusion EC activation with ICAM-1 expression could contribute to the multiorgan involvement, including the development of myositis and ILD, in patients carrying anti,Jo-1 autoantibodies. The EC-activating factors are not the autoantibodies themselves, but might be systemic factors associated with these autoantibodies. [source] Characterization and peripheral blood biomarker assessment of anti,Jo-1 antibody,positive interstitial lung diseaseARTHRITIS & RHEUMATISM, Issue 7 2009Thomas J. Richards Objective Using a combination of clinical, radiographic, functional, and serum protein biomarker assessments, this study was aimed at defining the prevalence and clinical characteristics of interstitial lung disease (ILD) in a large cohort of patients with anti,Jo-1 antibodies. Methods A review of clinical records, pulmonary function test results, and findings on imaging studies determined the existence of ILD in anti,Jo-1 antibody,positive individuals whose data were accumulated in the University of Pittsburgh Myositis Database from 1982 to 2007. Multiplex enzyme-linked immunosorbent assays (ELISAs) for serum inflammation markers, cytokines, chemokines, and matrix metalloproteinases in different patient subgroups were performed to assess the serum proteins associated with anti,Jo-1 antibody,positive ILD. Results Among the 90 anti,Jo-1 antibody,positive individuals with sufficient clinical, radiographic, and/or pulmonary function data, 77 (86%) met the criteria for ILD. While computed tomography scans revealed a variety of patterns suggestive of underlying usual interstitial pneumonia (UIP) or nonspecific interstitial pneumonia, a review of the histopathologic abnormalities in a subset of patients undergoing open lung biopsy or transplantation or whose lung tissue was obtained at autopsy (n = 22) demonstrated a preponderance of UIP and diffuse alveolar damage. Analysis by multiplex ELISA yielded statistically significant associations between anti,Jo-1 antibody,positive ILD and elevated serum levels of C-reactive protein (CRP), CXCL9, and CXCL10, which distinguished this disease entity from idiopathic pulmonary fibrosis and anti,signal recognition particle antibody,positive myositis. Recursive partitioning further demonstrated that combinations of these and other serum protein biomarkers can distinguish these disease subgroups at high levels of sensitivity and specificity. Conclusion In this large cohort of anti,Jo-1 antibody,positive individuals, the incidence of ILD approached 90%. Multiplex ELISA demonstrated disease-specific associations between anti,Jo-1 antibody,positive ILD and serum levels of CRP as well as the interferon-,,inducible chemokines CXCL9 and CXCL10, highlighting the potential of this approach to define biologically active molecules contributing to the pathogenesis of myositis-associated ILD. [source] | |||||||||||||||||||||||||||||||