Pitfalls in the Diagnosis of Myositis



Pitfalls in the Diagnosis of MyositisProf. Hector Chinoy PhD FRCP BMBS MSc BMedSciNational Institute for Health Research Manchester Biomedical Research Centre, Manchester University NHS Foundation Trust, The University of Manchester, Manchester, UK.Department of Rheumatology, Salford Royal NHS Foundation Trust, Manchester Academic Health Science Centre, Salford, UK.Dr James B Lilleker PhD MRCP MBChBCentre for Musculoskeletal Research, Division of Musculoskeletal and Dermatological Sciences, School of Biological Sciences, Faculty of Biology, Medicine and Health, Manchester Academic Health Science Centre, The University of Manchester, Manchester, UK.Manchester Centre for Clinical Neurosciences, Salford Royal NHS Foundation Trust, Salford, UK.Conflicts of interestNone declaredFinding statementNo relevant funding declaredAbstractThe idiopathic inflammatory myopathies are a group of heterogenous autoimmune connective tissue diseases. Despite increase in the understanding of these conditions, securing a timely diagnosis and accurate subtype classification remains difficult in some cases. This has important implications for patients, where delayed or inappropriate treatments can have a negative effect on outcomes.Several conditions can mimic myositis, including metabolic myopathies, genetic myopathies and neurologic disease. In addition, the heterogeneity within the idiopathic inflammatory myopathy spectrum can also create diagnostic confusion, referred to here as ‘myositis chameleons’. This includes inclusion body myositis, immune-mediated necrotising myopathy, hypomyopathic variants of anti-synthetase syndrome and overlap disease. We highlight the importance of a thorough diagnostic workup, refer to updated classification criteria and emphasize the importance of myositis autoantibody testing. Where diagnostic doubt exists, involvement of a specialist centre and a multidisciplinary team is vital.Key wordsMYOSITISDIAGNOSISAUTOANTIBODIESCLASSIFICATION CRITERIAIntroductionThe idiopathic inflammatory myopathies (IIM) are a heterogenous group of rare autoimmune diseases characterised by proximal muscle weakness, raised serum levels of skeletal muscle enzymes, abnormal electromyography (EMG), inflammatory infiltrates on muscle biopsy, and circulating autoantibodies. A particular challenge in the diagnosis of IIM is the variety of differential diagnoses to be considered in patients presenting with one or more of the core clinical features, the so called ‘myositis mimics’. In addition, the significant disease heterogeneity within IIM and occurrence of atypical features can lead to diagnostic confusion, referred to here as ‘myositis chameleons’. The ramifications of an IIM misdiagnosis are high, as treatment involves use of potentially toxic immunosuppressants and possible iatrogenic harm. Furthermore, emerging treatments for metabolic myopathies and the prospect of tailored gene therapy in genetic myopathies emphasise the importance of such conditions being on the diagnostic radar. Conversely, but less common, patients initially diagnosed with an alternative muscle disease may later turn out to have IIM; such patients may not receive timely immunosuppressive treatment, increasing the risk of irreversible muscle damage.This review is not meant to be a comprehensive review covering the differential diagnosis of raised skeletal enzymes and/or muscle weakness, but will instead concentrate on specific conditions and scenarios that may present in a similar such fashion to IIM or create diagnostic confusion. Overview of epidemiologyUsing the ?2017 EULAR/ACR classification criteria,ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1002/art.40320","ISSN":"2326-5205","PMID":"29106061","abstract":"OBJECTIVE To develop and validate new classification criteria for adult and juvenile idiopathic inflammatory myopathies (IIM) and their major subgroups. METHODS Candidate variables were assembled from published criteria and expert opinion using consensus methodology. Data were collected from 47 rheumatology, dermatology, neurology, and pediatric clinics worldwide. Several statistical methods were utilized to derive the classification criteria. RESULTS Based on data from 976 IIM patients (74% adults; 26% children) and 624 non-IIM patients with mimicking conditions (82% adults; 18% children), new criteria were derived. Each item is assigned a weighted score. The total score corresponds to a probability of having IIM. Subclassification is performed using a classification tree. A probability cutoff of 55%, corresponding to a score of 5.5 (6.7 with muscle biopsy) \"probable IIM,\" had best sensitivity/specificity (87%/82% without biopsies, 93%/88% with biopsies) and is recommended as a minimum to classify a patient as having IIM. A probability of ≥90%, corresponding to a score of ≥7.5 (≥8.7 with muscle biopsy), corresponds to \"definite IIM.\" A probability of <50%, corresponding to a score of <5.3 (<6.5 with muscle biopsy), rules out IIM, leaving a probability of ≥50-<55% as \"possible IIM.\" CONCLUSION The European League Against Rheumatism/American College of Rheumatology (EULAR/ACR) classification criteria for IIM have been endorsed by international rheumatology, dermatology, neurology, and pediatric groups. They employ easily accessible and operationally defined elements, and have been partially validated. They allow classification of \"definite,\" \"probable,\" and \"possible\" IIM, in addition to the major subgroups of IIM, including juvenile IIM. They generally perform better than existing criteria.","author":[{"dropping-particle":"","family":"Lundberg","given":"Ingrid E.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Tj?rnlund","given":"Anna","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Bottai","given":"Matteo","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Werth","given":"Victoria P.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Pilkington","given":"Clarissa","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Visser","given":"Marianne","non-dropping-particle":"de","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Alfredsson","given":"Lars","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Amato","given":"Anthony 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G.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"International Myositis Classification Criteria Project Consortium, the Euromyositis Register","given":"and the Juvenile Dermatomyositis Cohort Biomarker Study and Repository (UK and Ireland)","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Arthritis & rheumatology (Hoboken, N.J.)","id":"ITEM-1","issued":{"date-parts":[["2017","10"]]},"title":"2017 European League Against Rheumatism/American College of Rheumatology Classification Criteria for Adult and Juvenile Idiopathic Inflammatory Myopathies and Their Major Subgroups.","type":"article-journal"},"uris":["",""]}],"mendeley":{"formattedCitation":" (1)","plainTextFormattedCitation":" (1)","previouslyFormattedCitation":" (1)"},"properties":{"noteIndex":0},"schema":""} (1) our research group has estimated mean incidence of adult IIM at 17.6 per million person years, higher in females than males (25.2 versus 10.0 per million person years).ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1093/rap/rky035","ISSN":"2514-1775","author":[{"dropping-particle":"","family":"Parker","given":"Matthew J S","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Oldroyd","given":"Alexander","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Roberts","given":"Mark E","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Ollier","given":"William E","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"New","given":"Robert P","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Cooper","given":"Robert G","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Chinoy","given":"Hector","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Rheumatology Advances in Practice","id":"ITEM-1","issue":"2","issued":{"date-parts":[["2018","7"]]},"title":"Increasing incidence of adult idiopathic inflammatory myopathies in the City of Salford, UK: a 10-year epidemiological study","type":"article-journal","volume":"2"},"uris":["",""]}],"mendeley":{"formattedCitation":" (2)","plainTextFormattedCitation":" (2)","previouslyFormattedCitation":" (2)"},"properties":{"noteIndex":0},"schema":""} (2) A significant increase in the incidence of IIM over a 10-year period is also apparent (2007-11: 13.6 versus 2012-16: 21.4 per million person years). Thus, a challenge of dealing with such a rare disease is the lack of familiarity with IIM and conditions which may mimic it.Overview of clinical and antibody subtypesSeveral conditions form part of the IIM spectrum (Table 1). If a patient has the pathognomonic rash of dermatomyositis (DM), signs of the anti-synthetase syndrome (e.g. arthritis, myositis, interstitial lung disease) and/or circulating myositis-specific autoantibodies (MSAs), then the diagnosis can be made even without the requirement for muscle biopsy or EMG. The latest criteria for immune-mediated necrotizing myopathy (IMNM) also do not require a muscle biopsy to be performed if characteristic clinical features, high CK levels, and signal recognition particle (SRP) or 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase (HMGCR) autoantibodies are found.ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1016/j.nmd.2017.09.016","ISSN":"18732364","abstract":"The objective of this study was to investigate the mechanical properties (% elongation and puncture strength) of poly(D,L‐lactide) (PLA) and poly(D,L‐lactide‐co‐glycolide) (PLGA) films as a function of exposure time to an aqueous medium and to correlate the mechanical properties to the degradation/erosion of the polymer as a function of the type of polymer [PLA, weight‐average molecular weight (MW) 270,300, or PLGA 50:50, MW 56,500], the type of plasticizer [(triethyl citrate (TEC) or acetyltributyl citrate (ATBC)], and the exposure time to pH 7.4 phosphate buffer. The glass transition temperature of the films was measured by differential scanning calorimetry (DSC), the molecular weight by size exclusion chromatography (SEC), and the polymer erosion and hydration gravimetrically. The mechanical properties were strongly affected by the type of polymer and plasticizer. PLGA films showed a faster loss of mechanical integrity. TEC, the water‐soluble plasticizer, leached from the films, resulting in major differences in the mechanical properties (flexibility) when compared with films plasticized with the more permanent, water‐insoluble ATBC. A significant difference in MW decrease was seen between plasticizer‐free and plasticizer‐containing PLA films, but not for PLGA films. Plasticized PLA films, which were above their glass transition temperature in the rubbery state, showed a faster decrease in MW than plasticizer‐free PLA ones, which were in the glassy state. The plasticizer addition to the lower MW PLGA did not enhance the polymer degradation; the plasticizer‐free PLGA was already in the rubbery state. Major differences between the two polymers were also seen in the mass loss and the water uptake studies. After 4 weeks, the mass loss was between 2.6 and 7.0% and the water uptake between 10.1 and 21.1% for PLA films, whereas for PLGA films, the mass loss was between 40.3 and 51.3% and the water uptake between 221.9 and 350.6%. 2000 Wiley‐Liss, Inc. and the American Pharmaceutical Association J Pharm Sci 89:1558–1566, 2000","author":[{"dropping-particle":"","family":"Allenbach","given":"Yves","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Mammen","given":"Andrew L.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Benveniste","given":"Olivier","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Stenzel","given":"Werner","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Allenbach","given":"Yves","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Amato","given":"Anthony","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Aussey","given":"Audrey","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Benveniste","given":"Olivier","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Bleecker","given":"Jan","non-dropping-particle":"De","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Groot","given":"Ingrid","non-dropping-particle":"de","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Visser","given":"Marianne","non-dropping-particle":"de","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Goebel","given":"Hans","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Hervier","given":"Baptiste","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Fischer","given":"Norina","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Hilton-Jones","given":"David","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Lamb","given":"Janice","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Lundberg","given":"Ingrid","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Mammen","given":"Andrew","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Mozaffar","given":"Tahseen","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Nishino","given":"Ichizo","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Pestronk","given":"Alan","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Schara","given":"Ulrike","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Stenzelr","given":"Werner","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Neuromuscular Disorders","id":"ITEM-1","issued":{"date-parts":[["2018"]]},"title":"224th ENMC International Workshop:: Clinico-sero-pathological classification of immune-mediated necrotizing myopathies Zandvoort, The Netherlands, 14–16 October 2016","type":"paper-conference"},"uris":["",""]}],"mendeley":{"formattedCitation":" (3)","plainTextFormattedCitation":" (3)","previouslyFormattedCitation":" (3)"},"properties":{"noteIndex":0},"schema":""} (3)The wide spectrum of MSA testing now available allows greater ease of securing IIM diagnosis and can help when opining on prognosis. However, whilst MSAs are extremely specific to IIM, the positive predictive value may be reduced with new commercial line blot assays compared to traditional immunoprecipitation. Therefore, positive antibody results should not be taken at face value outside of the correct clinical context or where “low positive” results are obtained. It is now firmly established that MSAs occur mutually exclusively.ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1016/j.jaut.2019.04.001","ISSN":"1095-9157","PMID":"30992170","abstract":"OBJECTIVES To determine prevalence and co-existence of myositis specific autoantibodies (MSAs) and myositis associated autoantibodies (MAAs) and associated clinical characteristics in a large cohort of idiopathic inflammatory myopathy (IIM) patients. METHODS Adult patients with confirmed IIM recruited to the EuroMyositis registry (n = 1637) from four centres were investigated for the presence of MSAs/MAAs by radiolabelled-immunoprecipitation, with confirmation of anti-MDA5 and anti-NXP2 by ELISA. Clinical associations for each autoantibody were calculated for 1483 patients with a single or no known autoantibody by global linear regression modelling. RESULTS MSAs/MAAs were found in 61.5% of patients, with 84.7% of autoantibody positive patients having a sole specificity, and only three cases (0.2%) having more than one MSA. The most frequently detected autoantibody was anti-Jo-1 (18.7%), with a further 21 specificities each found in 0.2-7.9% of patients. Autoantibodies to Mi-2, SAE, TIF1, NXP2, MDA5, PMScl and the non-Jo-1 tRNA-synthetases were strongly associated (p < 0.001) with cutaneous involvement. Anti-TIF1 and anti-Mi-2 positive patients had an increased risk of malignancy (OR 4.67 and 2.50 respectively), and anti-SRP patients had a greater likelihood of cardiac involvement (OR 4.15). Interstitial lung disease was strongly associated with the anti-tRNA synthetases, anti-MDA5, and anti-U1RNP/Sm. Overlap disease was strongly associated with anti-PMScl, anti-Ku, anti-U1RNP/Sm and anti-Ro60. Absence of MSA/MAA was negatively associated with extra-muscular manifestations. CONCLUSIONS Myositis autoantibodies are present in the majority of patients with IIM and identify distinct clinical subsets. Furthermore, MSAs are nearly always mutually exclusive endorsing their credentials as valuable disease biomarkers.","author":[{"dropping-particle":"","family":"Betteridge","given":"Z.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Tansley","given":"S.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Shaddick","given":"G.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Chinoy","given":"H.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Cooper","given":"R G","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"New","given":"R P","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Lilleker","given":"J B","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Vencovsky","given":"J.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Chazarain","given":"L.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Danko","given":"K.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Nagy-Vincze","given":"M.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Bodoki","given":"L.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Dastmalchi","given":"M.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Ekholm","given":"L.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Lundberg","given":"I E","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"McHugh","given":"N.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"UKMyonet contributors","given":"","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Journal of autoimmunity","id":"ITEM-1","issued":{"date-parts":[["2019","4"]]},"title":"Frequency, mutual exclusivity and clinical associations of myositis autoantibodies in a combined European cohort of idiopathic inflammatory myopathy patients.","type":"article-journal"},"uris":["",""]}],"mendeley":{"formattedCitation":" (4)","plainTextFormattedCitation":" (4)","previouslyFormattedCitation":" (4)"},"properties":{"noteIndex":0},"schema":""} (4) Thus, careful interpretation is mandated in cases where multiple MSA specificities are detected. About 38% of IIM patients remain seronegative following MSA and myositis-associated autoantibody (MAA) testing.ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1016/j.jaut.2019.04.001","ISSN":"1095-9157","PMID":"30992170","abstract":"OBJECTIVES To determine prevalence and co-existence of myositis specific autoantibodies (MSAs) and myositis associated autoantibodies (MAAs) and associated clinical characteristics in a large cohort of idiopathic inflammatory myopathy (IIM) patients. METHODS Adult patients with confirmed IIM recruited to the EuroMyositis registry (n = 1637) from four centres were investigated for the presence of MSAs/MAAs by radiolabelled-immunoprecipitation, with confirmation of anti-MDA5 and anti-NXP2 by ELISA. Clinical associations for each autoantibody were calculated for 1483 patients with a single or no known autoantibody by global linear regression modelling. RESULTS MSAs/MAAs were found in 61.5% of patients, with 84.7% of autoantibody positive patients having a sole specificity, and only three cases (0.2%) having more than one MSA. The most frequently detected autoantibody was anti-Jo-1 (18.7%), with a further 21 specificities each found in 0.2-7.9% of patients. Autoantibodies to Mi-2, SAE, TIF1, NXP2, MDA5, PMScl and the non-Jo-1 tRNA-synthetases were strongly associated (p < 0.001) with cutaneous involvement. Anti-TIF1 and anti-Mi-2 positive patients had an increased risk of malignancy (OR 4.67 and 2.50 respectively), and anti-SRP patients had a greater likelihood of cardiac involvement (OR 4.15). Interstitial lung disease was strongly associated with the anti-tRNA synthetases, anti-MDA5, and anti-U1RNP/Sm. Overlap disease was strongly associated with anti-PMScl, anti-Ku, anti-U1RNP/Sm and anti-Ro60. Absence of MSA/MAA was negatively associated with extra-muscular manifestations. CONCLUSIONS Myositis autoantibodies are present in the majority of patients with IIM and identify distinct clinical subsets. Furthermore, MSAs are nearly always mutually exclusive endorsing their credentials as valuable disease biomarkers.","author":[{"dropping-particle":"","family":"Betteridge","given":"Z.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Tansley","given":"S.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Shaddick","given":"G.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Chinoy","given":"H.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Cooper","given":"R G","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"New","given":"R P","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Lilleker","given":"J B","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Vencovsky","given":"J.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Chazarain","given":"L.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Danko","given":"K.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Nagy-Vincze","given":"M.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Bodoki","given":"L.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Dastmalchi","given":"M.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Ekholm","given":"L.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Lundberg","given":"I E","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"McHugh","given":"N.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"UKMyonet contributors","given":"","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Journal of autoimmunity","id":"ITEM-1","issued":{"date-parts":[["2019","4"]]},"title":"Frequency, mutual exclusivity and clinical associations of myositis autoantibodies in a combined European cohort of idiopathic inflammatory myopathy patients.","type":"article-journal"},"uris":["",""]}],"mendeley":{"formattedCitation":" (4)","plainTextFormattedCitation":" (4)","previouslyFormattedCitation":" (4)"},"properties":{"noteIndex":0},"schema":""} (4) Serological testing cannot therefore be relied upon alone as confirmation of a clinical diagnosis of IIM. A further description of individual myositis autoantibodies and the associated clinical phenotypes has been covered in a previous review.ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1016/j.berh.2019.03.012","ISSN":"15321770","abstract":"Novel classification schemes for idiopathic inflammatory myopathy are based on serologic and histopathologic features. The presence of specific myositis autoantibodies may correspond to particular clinical phenotypes. Patients with a known diagnosis of inflammatory myopathy require a prompt clinical evaluation and the assessment of myositis-associated autoantibodies. Patients possessing autoantibodies associated with ILD or those with any pulmonary symptoms should undergo pulmonary functions tests and high-resolution computed tomography scanning of their lungs. Despite the lack of placebo-controlled trials, systemic glucocorticoids are considered the mainstay of initial treatment of myositis-associated ILD. Glucocorticoid-sparing agents are often started concomitantly with glucocorticoids, particularly in patients with moderate or severe disease. The first-line conventional immunosuppressive drugs include either mycophenolate mofetil or azathioprine, and when they fail or if the features are rapidly progressive, more aggressive therapy includes tacrolimus or cyclosporine, rituximab, intravenous immunoglobulin, or cyclophosphamide used either alone or in various combinations.","author":[{"dropping-particle":"","family":"Moghadam-Kia","given":"Siamak","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Aggarwal","given":"Rohit","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"V.","family":"Oddis","given":"Chester","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Best Practice and Research: Clinical Rheumatology","id":"ITEM-1","issued":{"date-parts":[["2019"]]},"title":"Myositis in clinical practice—relevance of new antibodies","type":"article"},"uris":["",""]}],"mendeley":{"formattedCitation":" (5)","plainTextFormattedCitation":" (5)","previouslyFormattedCitation":" (5)"},"properties":{"noteIndex":0},"schema":""} (5)Changes in classificationThe 2017 EULAR/ACR classification criteria for IIM has represented a step change from the prior widely used Bohan and Peter criteria in the way patients can be identified for research studies, and also allow for subdivision into defined IIM subtypes.ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1056/NEJM197502132920706","ISSN":"0028-4793","PMID":"1089199","author":[{"dropping-particle":"","family":"Bohan","given":"A","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Peter","given":"J B","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"The New England journal of medicine","id":"ITEM-1","issue":"7","issued":{"date-parts":[["1975","2"]]},"page":"344-7","title":"Polymyositis and dermatomyositis (first of two parts).","type":"article-journal","volume":"292"},"uris":["",""]}],"mendeley":{"formattedCitation":" (6)","plainTextFormattedCitation":" (6)","previouslyFormattedCitation":" (6)"},"properties":{"noteIndex":0},"schema":""} (6) However, issues with the criteria do remain, as only one of the existing MSAs, anti-Jo-1, is incorporated, and patients with IMNM get classified as polymyositis (PM), for example.ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1093/rheumatology/key343","ISSN":"1462-0332","PMID":"30496561","abstract":"Objectives To assess the performance of the EULAR/ACR idiopathic inflammatory myopathies (IIMs) classification criteria in a cohort of incident IIM cases and examine how criteria-assigned IIM subtype correlates with expert opinion. Methods Adults with newly diagnosed IIM attending Salford Royal NHS Foundation Trust were identified over a 10 year period. A retrospective review of all putative cases was performed and those fulfilling a consensus expert opinion diagnosis of IIM were included. Clinical, serological and histological data were collected and each case was assigned a single IIM subtype. The EULAR/ACR classification criteria were then applied and sensitivity, specificity and positive and negative predictive values were calculated, presented with 95% CIs. Results A total of 1637 cases were screened, with 255 consensus expert opinion IIM cases ultimately identified. Applying the EULAR/ACR classification criteria, the sensitivity to diagnose an IIM was 99.6% (95% CI 97.2, 100) and 80.9% (95% CI 76.0, 85.8) for the criteria cut-points of probable and definite diagnoses, respectively. In 94/255 cases the IIM subtype differed between consensus expert opinion and classification criteria, most strikingly in the group subtyped as PM by the EULAR/ACR criteria, where there was discrepancy in the majority (i.e. in 87/161). Conclusion The EULAR/ACR criteria performed with high sensitivity in identifying IIM in this external cohort of incident IIM. However, substantial disagreements arose between consensus expert opinion and the criteria regarding IIM subtype assignments, resulting in a large proportion of criteria-assigned cases of PM having heterogeneous features. These results may have important implications for future use of these criteria in subsequent research.","author":[{"dropping-particle":"","family":"Parker","given":"Matthew J S","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Oldroyd","given":"Alexander","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Roberts","given":"Mark E","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Lilleker","given":"James B","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Betteridge","given":"Zoe E","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"McHugh","given":"Neil J","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Herrick","given":"Ariane L","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Cooper","given":"Robert G","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Chinoy","given":"Hector","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Rheumatology (Oxford, England)","id":"ITEM-1","issued":{"date-parts":[["2018","11"]]},"title":"The performance of the European League Against Rheumatism/American College of Rheumatology idiopathic inflammatory myopathies classification criteria in an expert-defined 10 year incident cohort.","type":"article-journal"},"uris":["",""]}],"mendeley":{"formattedCitation":" (7)","plainTextFormattedCitation":" (7)","previouslyFormattedCitation":" (7)"},"properties":{"noteIndex":0},"schema":""} (7) In clinical practice, once a patient has been classified according to appropriate clinical features (including presence of rash and/or features of anti-synthetase syndrome or connective tissue disease [CTD]) and autoantibody positivity, few patients with IIM remain. The remaining patients may have ‘seronegative polymyositis’, but should be treated with extra suspicion regarding the possibility of a myositis mimic explaining the presentation.Myositis mimicsSeveral conditions can present with what might be considered core features of IIM (e.g. proximal weakness, CK elevation, myopathic EMG) and may be regarded as ‘myositis mimics’ (Table 2). Isolated hyper-CK-aemia can also occur in the absence of disease, including following trauma, surgery and strenuous exercise. Reference CK levels also vary according to gender, ethnic group and relative muscle mass. For example, the normal CK level in black individuals is higher than in non-black individuals.ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1111/j.1468-1331.2010.03012.x","ISSN":"1468-1331","PMID":"20402744","abstract":"OBJECTIVE: To provide evidence-based guidelines to general neurologists for the assessment of patients with pauci- or asymptomatic hyperCKemia.\n\nBACKGROUND: Recent epidemiologic studies show that up to 20% of 'normal' individuals have an elevated creatine kinase activity in the serum (sCK). The possibility of a subclinical myopathy is often raised, and patients may be unnecessarily denied treatment with statins.\n\nSEARCH STRATEGY: Electronic databases including Medline, the Cochrane Library and the American Academy of Neurology were searched for existing guidelines. Articles dealing with series of patients investigated for asymptomatic/pauci-symptomatic hyperCKemia and articles dealing with myopathies that can present with asymptomatic hyperCKemia were identified and reviewed.\n\nRESULTS: The only guidelines found were those approved by the Italian Association of Myology Committee, and the only relevant articles identified describe class IV studies.\n\nRECOMMENDATIONS: HyperCKemia needs to be redefined as values beyond 1.5 times the upper limit of normal (which itself needs to be appropriately defined). Pauci- or asymptomatic hyperCKemia with no apparent medical explanation may be investigated with a muscle biopsy if one or more of the following are present; the sCK is >or=3x normal, the electromyogram is myopathic or the patient is <25 years of age. In addition, women with sCK<3 times normal may be offered DNA testing because of the possibility of carrying a dystrophin mutation.","author":[{"dropping-particle":"","family":"Kyriakides","given":"T","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Angelini","given":"C","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Schaefer","given":"J","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Sacconi","given":"S","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Siciliano","given":"G","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Vilchez","given":"J J","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Hilton-Jones","given":"D","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"European journal of neurology : the official journal of the European Federation of Neurological Societies","id":"ITEM-1","issue":"6","issued":{"date-parts":[["2010","6","1"]]},"page":"767-73","title":"EFNS guidelines on the diagnostic approach to pauci- or asymptomatic hyperCKemia.","type":"article-journal","volume":"17"},"uris":[""]}],"mendeley":{"formattedCitation":" (8)","plainTextFormattedCitation":" (8)","previouslyFormattedCitation":" (8)"},"properties":{"noteIndex":0},"schema":""} (8)In highly sub-specialised practice, a patient with IIM may be reviewed in a neurology clinic and a diagnosis of a genetic myopathy pursued. Conversely, a patient with a condition mimicking IIM may present to a rheumatologist who will naturally be more likely to consider a diagnosis of IIM. This phenomenon may be referred to as “looking down the wrong end of the telescope”.ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1136/practneurol-2015-001311","ISSN":"1474-7758","author":[{"dropping-particle":"","family":"Bloem","given":"B R","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Voermans","given":"N C","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Aerts","given":"M B","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Bhatia","given":"K P","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Engelen","given":"B G M","non-dropping-particle":"van","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Warrenburg","given":"B P","non-dropping-particle":"van de","parse-names":false,"suffix":""}],"container-title":"Practical Neurology","id":"ITEM-1","issue":"4","issued":{"date-parts":[["2016","8"]]},"page":"264-269","title":"The wrong end of the telescope: neuromuscular mimics of movement disorders (and vice versa)","type":"article-journal","volume":"16"},"uris":["","",""]}],"mendeley":{"formattedCitation":" (9)","plainTextFormattedCitation":" (9)","previouslyFormattedCitation":" (9)"},"properties":{"noteIndex":0},"schema":""} (9) We encourage close multidisciplinary working between rheumatologists, neurologists, internists, pulmonologists, pathologists, neurophysiologists and an awareness of the ‘red flags’ for alternative conditions (Table 3) to reduce the likelihood of diagnostic error.Metabolic myopathiesA detailed discussion of metabolic myopathies is beyond the scope of this article, and we recommend consulting other reviews on this topic.ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1136/practneurol-2017-001708","ISSN":"1474-7758","author":[{"dropping-particle":"","family":"Lilleker","given":"James B","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Keh","given":"Yann Shern","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Roncaroli","given":"Federico","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Sharma","given":"Reena","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Roberts","given":"Mark","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Practical Neurology","id":"ITEM-1","issue":"1","issued":{"date-parts":[["2018","2"]]},"page":"14-26","title":"Metabolic myopathies: a practical approach","type":"article-journal","volume":"18"},"uris":["","",""]}],"mendeley":{"formattedCitation":" (10)","plainTextFormattedCitation":" (10)","previouslyFormattedCitation":" (10)"},"properties":{"noteIndex":0},"schema":""} (10) However, an understanding of key features of the metabolic myopathies is important in order to avoid diagnostic error. First, the magnitude of CK elevation is usually much greater in patients with metabolic myopathies experiencing an exacerbation in symptoms, often >100,000 IU/L. Ensuing hospital admissions may occur and the temptation to use oral or intravenous steroids should be avoided. Such high CK levels are not seen in IIM. Similarly, the occurrence of rhabdomyolysis and frank myoglobinuria, particularly if repeated, is very unusual in IIM.Second, understanding the temporal relationship between exertion (and other provoking factors such as fasting or fever) is key. In those with glycogen storage disorders such as McArdle’s disease, myalgia and painful muscle contracture is experienced within a few minutes of intense exertion, usually forcing the person to rest. After around 10 minutes, when activation of alternative metabolic pathways have produced substrates for cellular respiration, a ‘second wind’ phenomenon is observed where the patient is able to return to exercise. In fatty acid oxidation defects, long periods of low intensity exertion are more likely to trigger episodes of rhabdomyolysis, which can occur several days after the inciting event. Third, patients with mitochondrial disease can present with exercise intolerance, but in such cases other clinical features may be evident, including short stature, lipomas, learning difficulties, epilepsy, diabetes, ophthalmoplegia and retinopathy. Finally, it is important to recognise that a family history may not be present in those with a metabolic myopathy, given the autosomal recessive nature of most of the conditions. The maternal inheritance pattern of mitochondrial DNA mutations may be missed, and genetic heteroplasmy (variable mutation burden in different body tissues) can make the presentation highly variable between family members with the same mutation.Genetic myopathies A multitude of genetic myopathies may present in adulthood and may mimic IIM. A particularly vexing issue is young females presenting with myalgia and unexplained hyper-CK-aemia, where ultimately the diagnosis of manifesting carrier of Duchenne muscular dystrophy is made. One clinical clue can be the presence of subtle calf pseudohypertrophy. We would suggest a relatively low threshold for muscle biopsy in such circumstances. Several other factors may also contribute to the misdiagnosis of a genetic myopathy as IIM. First, the muscle biopsy in several genetic myopathies may show inflammatory features. These myopathies include dysferlinopathies, calpainopathies and facioscapulohumeral muscular dystrophy. In other cases, those with genetic conditions resembling of inclusion body myositis (IBM) may have degenerative features on muscle biopsy such as rimmed vacuoles, which are assumed to represent the sporadic form of the disease. In genetic myopathies however, the widespread HLA class I upregulation expected in sporadic IBM and other IIMs is not usually seen.ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"PMID":"6228350","abstract":"Biopsy specimens from patients with treated or untreated polymyositis and muscular dystrophy controls were examined by indirect immunoperoxidase staining with a panel of monoclonal antibodies to human leucocyte antigens. In untreated polymyositis, helper/inducer T cells were the predominant T cell subset. In treated cases few T cells were seen. Overall, few T cells were seen in dystrophic cases, most infiltrating cells being dendritic and lacking T cell antigens. Staining of sarcolemma with anti-HLA class 1 antibody is weak or negative except in areas adjacent to infiltrating leucocytes or where muscle fibre damage is apparent","author":[{"dropping-particle":"","family":"Rowe","given":"D","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Isenberg","given":"D A","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Beverley","given":"P C","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Clin Exp Immunol","id":"ITEM-1","issue":"0009-9104 (Print)","issued":{"date-parts":[["1983","11"]]},"language":"eng PT - Journal Article","page":"327-336","title":"Monoclonal antibodies to human leucocyte antigens in polymyositis and muscular dystrophy","type":"article-journal","volume":"54"},"uris":["",""]}],"mendeley":{"formattedCitation":" (11)","plainTextFormattedCitation":" (11)","previouslyFormattedCitation":" (11)"},"properties":{"noteIndex":0},"schema":""} (11) Second, inadvertent treatment of a genetic myopathy patient with glucocorticoids can be associated with an apparent response, particularly reductions in the CK level ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1016/S0140-6736(03)14368-1","ISSN":"1474-547X","PMID":"14511932","abstract":"The inflammatory myopathies, commonly described as idiopathic, are the largest group of acquired and potentially treatable myopathies. On the basis of unique clinical, histopathological, immunological, and demographic features, they can be differentiated into three major and distinct subsets: dermatomyositis, polymyositis, and inclusion-body myositis. Use of new diagnostic criteria is essential to discriminate between them and to exclude other disorders. Dermatomyositis is a microangiopathy affecting skin and muscle; activation and deposition of complement causes lysis of endomysial capillaries and muscle ischaemia. In polymyositis and inclusion-body myositis, clonally expanded CD8-positive cytotoxic T cells invade muscle fibres that express MHC class I antigens, which leads to fibre necrosis via the perforin pathway. In inclusion-body myositis, vacuolar formation with amyloid deposits coexists with the immunological features. The causative autoantigen has not yet been identified. Upregulated vascular-cell adhesion molecule, intercellular adhesion molecule, chemokines, and their receptors promote T-cell transgression, and various cytokines increase the immunopathological process. Early initiation of therapy is essential, since both polymyositis and dermatomyositis respond to immunotherapeutic agents. New immunomodulatory agents currently being tested in controlled trials may prove promising for difficult cases.","author":[{"dropping-particle":"","family":"Dalakas","given":"Marinos C","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Hohlfeld","given":"Reinhard","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Lancet (London, England)","id":"ITEM-1","issue":"9388","issued":{"date-parts":[["2003","9","20"]]},"note":"Rash in DM may not be present (but more likely missed due to dark skin).\n\n\nRash in DM may be present without muscle disease (amyotrophic)\n\n\nRash usually preceeds muscle weakness in DM\n\n\nPM is a diagnosis of exclusion - particularly consider metabolic myopathy.\n\n\nAnti Jo-1 disease is associated more commonly with respiratory muscle weakness","page":"971-82","title":"Polymyositis and dermatomyositis.","type":"article-journal","volume":"362"},"uris":["","",""]}],"mendeley":{"formattedCitation":" (12)","plainTextFormattedCitation":" (12)","previouslyFormattedCitation":" (12)"},"properties":{"noteIndex":0},"schema":""} (12). The treating clinician may therefore be falsely reassured that the diagnosis of IIM is correct, even leading to a cascade of more aggressive treatment. Third, patients with a genetic myopathy often do not have a positive family history. This is primarily related to the autosomal recessive nature of many genetic myopathies, but also because our predecessors likely did not have access to advanced genetic techniques to secure the diagnosis. The increasing availability of muscle magnetic resonance imaging (MRI) has led to an increase in referrals to our service with apparent IIM diagnoses made on imaging grounds, without muscle biopsy or other investigations. However, whilst myo-oedematous change on MRI (usually seen using the short tau inversion recovery [STIR] sequence) is often felt to represent inflammatory change, it can occur for several other reasons, including muscle trauma and denervation (e.g. due to lumbar sacral radiculopathy). Apparent inflammatory changes on MRI imaging may be observed in genetic myopathies, although usually with accompanying fatty infiltration of selected muscles. Established fatty change and/or atrophy at initial disease presentation, best appreciated on the T1 sequence, should alert to an underlying myositis mimic. Overall, we recommend that muscle MRI should be regarded as similar to the serum CK level; abnormalities may be supportive of a diagnosis of IIM, but they are not specific for it. Neurologic diseasePatients with amyotrophic lateral sclerosis (ALS) may present with indolent muscle weakness, bulbar involvement and mild-moderate elevations in serum CK, mimicking IIM (particularly IBM). Involvement of an expert neurophysiologist is critical in such cases, with a mix of acute and chronic denervation on EMG a key feature of ALS, which should not be seen in IIM. However, ‘myogenic denervation’ may sometimes occur in IBM, creating a confusing electrophysiological picture and highlighting that EMG features alone should not be used to secure a diagnosis.ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1002/mus.880131010","ISSN":"0148-639X","PMID":"2172812","abstract":"We present electrodiagnostic data on 30 patients with inclusion body myositis (IBM) in order to better delineate its electrophysiological features. Comprehensive electromyography (EMG) and nerve conduction studies (NCS) were performed in all cases. Twelve patients had single fiber electromyography (SFEMG). EMG showed abundant short-small motor unit potentials (MUP) with fibrillations and positive sharp waves in 56.6% of patients, and a mixed pattern of large and small MUP in 36.7%. In 6.7%, only \"neurogenic\" features were seen. NCS were slow in 33.3%. SFEMG revealed a mildly abnormal jitter and a slightly increased fiber density. IBM demonstrates a heterogeneous EMG profile. A pattern of large and small MUP is highly suggestive of IBM but is seen in only about one third of cases.","author":[{"dropping-particle":"","family":"Joy","given":"J L","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Oh","given":"S J","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Baysal","given":"A I","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Muscle & nerve","id":"ITEM-1","issue":"10","issued":{"date-parts":[["1990","10"]]},"page":"949-51","title":"Electrophysiological spectrum of inclusion body myositis.","type":"article-journal","volume":"13"},"uris":["","",""]}],"mendeley":{"formattedCitation":" (13)","plainTextFormattedCitation":" (13)","previouslyFormattedCitation":" (13)"},"properties":{"noteIndex":0},"schema":""} (13) Spinobulbar muscular atrophy (Kennedy’s disease) is an X-linked condition caused by an expansion mutation in the androgen receptor gene.ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1007/s00415-018-8968-7","ISSN":"0340-5354","author":[{"dropping-particle":"","family":"Breza","given":"Marianthi","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Koutsis","given":"Georgios","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Journal of Neurology","id":"ITEM-1","issue":"3","issued":{"date-parts":[["2019","3","13"]]},"page":"565-573","title":"Kennedy’s disease (spinal and bulbar muscular atrophy): a clinically oriented review of a rare disease","type":"article-journal","volume":"266"},"uris":["","",""]}],"mendeley":{"formattedCitation":" (14)","plainTextFormattedCitation":" (14)","previouslyFormattedCitation":" (14)"},"properties":{"noteIndex":0},"schema":""} (14) The diagnosis should be considered in males presenting with limb weakness and atrophy, bulbar involvement (often with prominent peri-oral fasciculations), raised CK, and endocrine features including diabetes, gynaecomastia and testicular atrophy. Genetic testing is easily available to confirm the diagnosis. Acquired neuropathies may also mimic a myopathy, particularly motor-predominant variants of chronic inflammatory demyelinating polyneuropathy (CIDP).ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1016/S1474-4422(19)30144-9","ISSN":"14744422","author":[{"dropping-particle":"","family":"Bunschoten","given":"Carina","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Jacobs","given":"Bart C","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Bergh","given":"Peter Y K","non-dropping-particle":"Van den","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Cornblath","given":"David R","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Doorn","given":"Pieter A","non-dropping-particle":"van","parse-names":false,"suffix":""}],"container-title":"The Lancet Neurology","id":"ITEM-1","issue":"8","issued":{"date-parts":[["2019","8"]]},"page":"784-794","title":"Progress in diagnosis and treatment of chronic inflammatory demyelinating polyradiculoneuropathy","type":"article-journal","volume":"18"},"uris":["","",""]}],"mendeley":{"formattedCitation":" (15)","plainTextFormattedCitation":" (15)","previouslyFormattedCitation":" (15)"},"properties":{"noteIndex":0},"schema":""} (15) In such cases, proximal and distal weakness as well as clinical signs of neuropathy (e.g. absent reflexes) are evident. Involvement of an expert neurophysiologist is again critical and patients will often require further investigations including lumbar puncture (to demonstrate raised cerebrospinal fluid protein), and testing for paraproteins and IgG4 autoantibodies directed against proteins within or around the nodes of Ranvier.ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1016/S1474-4422(19)30144-9","ISSN":"14744422","author":[{"dropping-particle":"","family":"Bunschoten","given":"Carina","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Jacobs","given":"Bart C","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Bergh","given":"Peter Y K","non-dropping-particle":"Van den","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Cornblath","given":"David R","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Doorn","given":"Pieter A","non-dropping-particle":"van","parse-names":false,"suffix":""}],"container-title":"The Lancet Neurology","id":"ITEM-1","issue":"8","issued":{"date-parts":[["2019","8"]]},"page":"784-794","title":"Progress in diagnosis and treatment of chronic inflammatory demyelinating polyradiculoneuropathy","type":"article-journal","volume":"18"},"uris":["","",""]}],"mendeley":{"formattedCitation":" (15)","plainTextFormattedCitation":" (15)","previouslyFormattedCitation":" (15)"},"properties":{"noteIndex":0},"schema":""} (15) Clinical features of the peripheral nerve hyperexcitability syndromes may also mimic IIM, with the cramping and myalgia misattributed to a myopathy.ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1212/CON.0000000000000520","ISSN":"1080-2371","author":[{"dropping-particle":"","family":"Sawlani","given":"Komal","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Katirji","given":"Bashar","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"CONTINUUM: Lifelong Learning in Neurology","id":"ITEM-1","issue":"5","issued":{"date-parts":[["2017","10"]]},"page":"1437-1450","title":"Peripheral Nerve Hyperexcitability Syndromes","type":"article-journal","volume":"23"},"uris":[""]}],"mendeley":{"formattedCitation":" (16)","plainTextFormattedCitation":" (16)","previouslyFormattedCitation":" (16)"},"properties":{"noteIndex":0},"schema":""} (16) These diseases may be autoimmune or paraneoplastic and represent a spectrum from relatively minor symptoms (cramp fasciculation syndrome), to severe disease with multi-system involvement (Morvan syndrome). Around half of patients have detectable antibodies against the voltage gated potassium channel complex (usually the CASPR2 subunit). Neurophysiological testing can be helpful to confirm the clinical suspicion of this disorder.Focal diseaseSignificant uncertainties remain regarding the diagnostic entity of focal myositis. We would urge readers to carefully consider differentials before finalising this diagnosis.ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1016/j.nmd.2016.08.014","ISSN":"18732364","abstract":"Amongst the heterogeneous group of inflammatory myopathies, focal myositis stands as a rare and benign dysimmune disease. Although it can be associated with root and/or nerve lesions, traumatic muscle lesions and autoimmune diseases, its triggering factors remain poorly understood. Defined as an isolated inflammatory pseudotumour usually restricted to one skeletal muscle, clinical presentation of focal myositis is that of a rapidly growing solitary mass within a single muscle, usually in the lower limbs. Electromyography shows spontaneous activity associated with a myopathic pattern. MRI reveals a contrast enhanced enlarged muscle appearing hyper-intense on FAT-SAT T2 weighted images. Adjacent structures are spared and there are no calcifications. Serum creatine kinase (CK) levels are usually moderately augmented and biological markers of systemic inflammation are absent in most cases. Pathological histological features include marked variation in fibre size, inflammatory infiltrates mostly composed of T CD4+ lymphocytes and macrophages, degenerating/regenerating fibres and interstitial fibrosis. Differential diagnoses are numerous and include myositis of other origin with focal onset. Steroid treatment should be reserved for patients who present with major pain, nerve lesions, associated autoimmune disease, or elevated C reactive protein or CK.","author":[{"dropping-particle":"","family":"Devic","given":"P.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Gallay","given":"L.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Streichenberger","given":"N.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Petiot","given":"P.","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Neuromuscular Disorders","id":"ITEM-1","issued":{"date-parts":[["2016"]]},"title":"Focal myositis: A review","type":"article"},"uris":["",""]}],"mendeley":{"formattedCitation":" (17)","plainTextFormattedCitation":" (17)","previouslyFormattedCitation":" (17)"},"properties":{"noteIndex":0},"schema":""} (17) Asymmetrical myo-oedematous change in lower limb muscle may alternatively be caused by radiculopathies (e.g. due to spinal disease), lumbosacral plexopathies (e.g. due to diabetes) or neuropathies (e.g. due to nerve compression). Alternatively, muscle infarction due to vascular disease (including haemoglobinopathies/hyperviscosity syndromes, vasculitis or cardioembolic disease) may be the explanation.Myositis ChameleonsMuch like the Old-World lizards, myositis chameleons are situations where a patient with IIM has atypical clinical features which resemble another disease. This can cause diagnostic confusion and lead to administration of inappropriate treatment. Such instances include patients with pauci-myopathic IIM and overlap syndromes where presenting clinical features are primarily extra-muscular, including arthritis, Raynaud’s, interstitial lung disease or skin disease. Inclusion body myositisSporadic IBM is considered the most common acquired myopathy in those over the age of 50. Initial descriptions and classification criteria for IIM did not make specific reference to IBM and the Bohan and Peter criteria are unable to distinguish between IBM and PM.ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1056/NEJM197502202920807","ISSN":"0028-4793","PMID":"1089199","author":[{"dropping-particle":"","family":"Bohan","given":"A","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Peter","given":"J B","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"The New England journal of medicine","id":"ITEM-1","issue":"8","issued":{"date-parts":[["1975","2"]]},"page":"403-7","title":"Polymyositis and dermatomyositis (second of two parts).","type":"article-journal","volume":"292"},"uris":["",""]},{"id":"ITEM-2","itemData":{"DOI":"10.1056/NEJM197502132920706","ISSN":"0028-4793","PMID":"1089199","author":[{"dropping-particle":"","family":"Bohan","given":"A","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Peter","given":"J B","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"The New England journal of medicine","id":"ITEM-2","issue":"7","issued":{"date-parts":[["1975","2"]]},"page":"344-7","title":"Polymyositis and dermatomyositis (first of two parts).","type":"article-journal","volume":"292"},"uris":["",""]}],"mendeley":{"formattedCitation":" (6,18)","plainTextFormattedCitation":" (6,18)","previouslyFormattedCitation":" (6,18)"},"properties":{"noteIndex":0},"schema":""} (6,18) However, the entity of ‘steroid-resistant PM’ slowly gained recognition and the core clinical and pathological features of IBM were subsequently summarised by Griggs et al in 1995.ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1002/ana.410380504","ISSN":"0364-5134","PMID":"7486861","author":[{"dropping-particle":"","family":"Griggs","given":"R C","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Askanas","given":"V","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"DiMauro","given":"S","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Engel","given":"A","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Karpati","given":"G","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Mendell","given":"J R","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Rowland","given":"L P","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Annals of neurology","id":"ITEM-1","issue":"5","issued":{"date-parts":[["1995","11"]]},"page":"705-13","title":"Inclusion body myositis and myopathies.","type":"article-journal","volume":"38"},"uris":[""]}],"mendeley":{"formattedCitation":" (19)","plainTextFormattedCitation":" (19)","previouslyFormattedCitation":" (19)"},"properties":{"noteIndex":0},"schema":""} (19) IBM remains grouped with the other IIM subtypes, and some clinical and pathological features are shared. However, IBM is unique amongst the IIM spectrum, characterised by a treatment resistant course, highly stereotyped pattern of muscle weakness (finger flexors, quadriceps) and canonical muscle biopsy features including the presence of misfolded protein aggregates and rimmed vacuoles. Such features may lead the clinician to conclude that the patient may have some other condition, perhaps a genetic myopathy or even ALS.ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1016/j.jocn.2008.01.011","ISSN":"0967-5868","PMID":"18815046","abstract":"The prevalence of sporadic inclusion body myositis (sIBM) is variable in different populations and ethnic groups. A previous survey in Western Australia in 2000 found a prevalence of 9.3 per million population. We have now performed a follow-up survey to determine whether there has since been any change in prevalence. The current prevalence was found to be 14.9 per million population, with a prevalence of 51.3 per million population in people over 50 years of age. This is the highest reported prevalence of sIBM and correlates with a high frequency of HLA-DR3 and the 8.1 major histocompatibility complex ancestral haplotype in this population. Review of a combined cohort of 57 sIBM cases from three Australian centres revealed a high rate of initial misdiagnosis and a mean time to diagnosis of 5.2 years, which suggests that even the latest prevalence figure may be an underestimate, and emphasising the need to increase the level of awareness of the condition among the medical community.","author":[{"dropping-particle":"","family":"Needham","given":"Merrilee","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Corbett","given":"Alastair","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Day","given":"Timothy","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Christiansen","given":"Frank","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Fabian","given":"Vicki","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Mastaglia","given":"Frank L","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Journal of clinical neuroscience : official journal of the Neurosurgical Society of Australasia","id":"ITEM-1","issue":"12","issued":{"date-parts":[["2008","12"]]},"page":"1350-3","title":"Prevalence of sporadic inclusion body myositis and factors contributing to delayed diagnosis.","type":"article-journal","volume":"15"},"uris":["","",""]}],"mendeley":{"formattedCitation":" (20)","plainTextFormattedCitation":" (20)","previouslyFormattedCitation":" (20)"},"properties":{"noteIndex":0},"schema":""} (20) Making a positive diagnosis of IBM is important for two reasons. First, accurately distinguishing IBM from other IIM subtypes ensures that patients are not unnecessarily exposed to potentially toxic immunosuppressive treatments, which have consistently been shown to have no sustained positive effect in IBM, accepting that many clinical trials in this area have been small and of low quality.ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1002/14651858.CD001555.pub5","ISSN":"1469-493X","PMID":"26125437","abstract":"BACKGROUND: Inclusion body myositis (IBM) is a late-onset inflammatory muscle disease (myopathy) associated with progressive proximal and distal limb muscle atrophy and weakness. Treatment options have attempted to target inflammatory and atrophic features of this condition (for example with immunosuppressive and immunomodulating drugs, anabolic steroids, and antioxidant treatments), although as yet there is no known effective treatment for reversing or minimising the progression of inclusion body myositis. In this review we have considered the benefits, adverse effects, and costs of treatment in targeting cardinal effects of the condition, namely muscle atrophy, weakness, and functional impairment.\n\nOBJECTIVES: To assess the effects of treatment for IBM.\n\nSEARCH METHODS: On 7 October 2014 we searched the Cochrane Neuromuscular Disease Group Specialized Register, the Cochrane Central Register for Controlled Trials (CENTRAL), MEDLINE, and EMBASE. Additionally in November 2014 we searched clinical trials registries for ongoing or completed but unpublished trials.\n\nSELECTION CRITERIA: We considered randomised or quasi-randomised trials, including cross-over trials, of treatment for IBM in adults compared to placebo or any other treatment for inclusion in the review. We specifically excluded people with familial IBM and hereditary inclusion body myopathy, but we included people who had connective tissue and autoimmune diseases associated with IBM, which may or may not be identified in trials. We did not include studies of exercise therapy or dysphagia management, which are topics of other Cochrane systematic reviews.\n\nDATA COLLECTION AND ANALYSIS: We used standard Cochrane methodological procedures.\n\nMAIN RESULTS: The review included 10 trials (249 participants) using different treatment regimens. Seven of the 10 trials assessed single agents, and 3 assessed combined agents. Many of the studies did not present adequate data for the reporting of the primary outcome of the review, which was the percentage change in muscle strength score at six months. Pooled data from two trials of interferon beta-1a (n = 58) identified no important difference in normalised manual muscle strength sum scores from baseline to six months (mean difference (MD) -0.06, 95% CI -0.15 to 0.03) between IFN beta-1a and placebo (moderate-quality evidence). A single trial of methotrexate (MTX) (n = 44) provided moderate-quality evidence that MTX did not arrest or slow disease progression,…","author":[{"dropping-particle":"","family":"Rose","given":"Michael R","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Jones","given":"Katherine","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Leong","given":"Kevin","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Walter","given":"Maggie C","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Miller","given":"James","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Dalakas","given":"Marinos C","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Brassington","given":"Ruth","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Griggs","given":"Robert","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"The Cochrane database of systematic reviews","id":"ITEM-1","issued":{"date-parts":[["2015","1"]]},"page":"CD001555","title":"Treatment for inclusion body myositis.","type":"article-journal","volume":"6"},"uris":["","",""]}],"mendeley":{"formattedCitation":" (21)","plainTextFormattedCitation":" (21)","previouslyFormattedCitation":" (21)"},"properties":{"noteIndex":0},"schema":""} (21) Second, accurate diagnosis facilitates involvement of the patient in clinical trials and other research endeavours. This, for example includes the recently completed bimagrumab trial (a myostatin inhibitor).ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1016/S1474-4422(19)30200-5","ISSN":"1474-4465","PMID":"31397289","abstract":"BACKGROUND Inclusion body myositis is an idiopathic inflammatory myopathy and the most common myopathy affecting people older than 50 years. To date, there are no effective drug treatments. We aimed to assess the safety, efficacy, and tolerability of bimagrumab-a fully human monoclonal antibody-in individuals with inclusion body myositis. METHODS We did a multicentre, double-blind, placebo-controlled study (RESILIENT) at 38 academic clinical sites in Australia, Europe, Japan, and the USA. Individuals (aged 36-85 years) were eligible for the study if they met modified 2010 Medical Research Council criteria for inclusion body myositis. We randomly assigned participants (1:1:1:1) using a blocked randomisation schedule (block size of four) to either bimagrumab (10 mg/kg, 3 mg/kg, or 1 mg/kg) or placebo matched in appearance to bimagrumab, administered as intravenous infusions every 4 weeks for at least 48 weeks. All study participants, the funder, investigators, site personnel, and people doing assessments were masked to treatment assignment. The primary outcome measure was 6-min walking distance (6MWD), which was assessed at week 52 in the primary analysis population and analysed by intention-to-treat principles. We used a multivariate normal repeated measures model to analyse data for 6MWD. Safety was assessed by recording adverse events and by electrocardiography, echocardiography, haematological testing, urinalysis, and blood chemistry. This trial is registered with , number NCT01925209; this report represents the final analysis. FINDINGS Between Sept 26, 2013, and Jan 6, 2016, 251 participants were enrolled to the study, of whom 63 were assigned to each bimagrumab group and 62 were allocated to the placebo group. At week 52, 6MWD change from baseline did not differ between any bimagrumab dose and placebo (least squares mean treatment difference for bimagrumab 10 mg/kg group, 17·6 m, SE 14·3, 99% CI -19·6 to 54·8; p=0·22; for 3 mg/kg group, 18·6 m, 14·2, -18·2 to 55·4; p=0·19; and for 1 mg/kg group, -1·3 m, 14·1, -38·0 to 35·4; p=0·93). 63 (100%) participants in each bimagrumab group and 61 (98%) of 62 in the placebo group had at least one adverse event. Falls were the most frequent adverse event (48 [76%] in the bimagrumab 10 mg/kg group, 55 [87%] in the 3 mg/kg group, 54 [86%] in the 1 mg/kg group, and 52 [84%] in the placebo group). The most frequently reported adverse events with bimagrumab were muscle spasms (32 [51%] in the bimag…","author":[{"dropping-particle":"","family":"Hanna","given":"Michael G","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Badrising","given":"Umesh A","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Benveniste","given":"Olivier","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Lloyd","given":"Thomas 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Group","given":"","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"The Lancet. Neurology","id":"ITEM-1","issue":"9","issued":{"date-parts":[["2019","9"]]},"page":"834-844","title":"Safety and efficacy of intravenous bimagrumab in inclusion body myositis (RESILIENT): a randomised, double-blind, placebo-controlled phase 2b trial.","type":"article-journal","volume":"18"},"uris":["","",""]}],"mendeley":{"formattedCitation":" (22)","plainTextFormattedCitation":" (22)","previouslyFormattedCitation":" (22)"},"properties":{"noteIndex":0},"schema":""} (22) Whilst this trial did not meet the primary endpoint, several beneficial outputs were achieved, including: i) proof that large, high quality, studies can be performed in IBM, ii) detailed natural history data, and iii) the validation of the first patient reported outcome measure for IBM, the sporadic IBM physical functioning assessment.ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1002/mus.25079","ISSN":"0148639X","PMID":"26872556","abstract":"INTRODUCTION Sporadic inclusion body myositis (sIBM) is a progressive idiopathic inflammatory myopathy characterized by atrophy and weakness of proximal and distal muscle groups that results in a loss of independence and the need for assistive devices and supportive care. To assess treatment benefit of new therapies, a patient-reported outcome measure of physical function was developed. METHODS The tool was rigorously developed in accordance with the United States Food and Drug Administration (FDA) patient-reported outcomes (PRO) guidance. A single-visit, observational study was conducted. Standard qualitative analytical methods were employed to analyze interview data and generate questionnaire items. RESULTS Twenty concept elicitation and 19 cognitive debriefing interviews were conducted, and 6 expert physicians were consulted. The tool consists of 11 items scored on a 0-10 numerical rating scale. Subjects completed the questionnaire utilizing either paper or electronic administration. CONCLUSION We have developed a PRO tool in alignment with FDA PRO guidance for use in the functional assessment of treatment benefit in sIBM. Muscle Nerve, 2016 Muscle Nerve 54: -, 2016 Muscle Nerve 54: 653-657, 2016.","author":[{"dropping-particle":"","family":"DeMuro","given":"Carla","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Lewis","given":"Sandy","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Lowes","given":"Linda","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Alfano","given":"Lindsay","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Tseng","given":"Brian","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Gnanasakthy","given":"Ari","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Muscle & Nerve","id":"ITEM-1","issue":"4","issued":{"date-parts":[["2016","10"]]},"page":"653-657","title":"Development of the sporadic inclusion body myositis physical functioning assessment","type":"article-journal","volume":"54"},"uris":["","",""]}],"mendeley":{"formattedCitation":" (23)","plainTextFormattedCitation":" (23)","previouslyFormattedCitation":" (23)"},"properties":{"noteIndex":0},"schema":""} (23) Other interventional studies are ongoing, including of arimoclomol (upregulator of the heat shock response) and rapamycin (inhibits mTOR, stimulating autophagy).ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1126/scitranslmed.aad4583","ISSN":"1946-6242","PMID":"27009270","abstract":"Sporadic inclusion body myositis (sIBM) is the commonest severe myopathy in patients more than 50 years of age. Previous therapeutic trials have targeted the inflammatory features of sIBM but all have failed. Because protein dyshomeostasis may also play a role in sIBM, we tested the effects of targeting this feature of the disease. Using rat myoblast cultures, we found that up-regulation of the heat shock response with arimoclomol reduced key pathological markers of sIBM in vitro. Furthermore, in mutant valosin-containing protein (VCP) mice, which develop an inclusion body myopathy, treatment with arimoclomol ameliorated disease pathology and improved muscle function. We therefore evaluated arimoclomol in an investigator-led, randomized, double-blind, placebo-controlled, proof-of-concept trial in sIBM patients and showed that arimoclomol was safe and well tolerated. Although arimoclomol improved some IBM-like pathology in the mutant VCP mouse, we did not see statistically significant evidence of efficacy in the proof-of-concept patient trial.","author":[{"dropping-particle":"","family":"Ahmed","given":"Mhoriam","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Machado","given":"Pedro 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myositis.","type":"article-journal","volume":"8"},"uris":[""]},{"id":"ITEM-2","itemData":{"author":[{"dropping-particle":"","family":"Benveniste","given":"O","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Hogrel","given":"JY","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Annoussamy","given":"M","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Bachasson","given":"D","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Rigolet","given":"A","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Servais","given":"L","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Salem","given":"JE","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Hervier","given":"B","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Landon Cardinal","given":"O","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Mariampillai","given":"K","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Hulot","given":"JS","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Carlier","given":"P","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Allenbach","given":"Y","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Arthritis Rheumatol.","id":"ITEM-2","issue":"Suppl 10","issued":{"date-parts":[["2017"]]},"title":"Rapamycin Vs. Placebo for the Treatment of Inclusion Body Myositis: Improvement of the 6 Min Walking Distance, a Functional Scale, the FVC and Muscle Quantitative MRI [abstract]","type":"article-journal","volume":"69"},"uris":["","",""]}],"mendeley":{"formattedCitation":" (24,25)","plainTextFormattedCitation":" (24,25)","previouslyFormattedCitation":" (24,25)"},"properties":{"noteIndex":0},"schema":""} (24,25) Several modern diagnostic criteria for IBM have been produced, including those recently recommended by Lloyd et al.ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1212/WNL.0000000000000642","ISSN":"1526-632X","PMID":"24975859","abstract":"OBJECTIVE: To use patient data to evaluate and construct diagnostic criteria for inclusion body myositis (IBM), a progressive disease of skeletal muscle. METHODS: The literature was reviewed to identify all previously proposed IBM diagnostic criteria. These criteria were applied through medical records review to 200 patients diagnosed as having IBM and 171 patients diagnosed as having a muscle disease other than IBM by neuromuscular specialists at 2 institutions, and to a validating set of 66 additional patients with IBM from 2 other institutions. Machine learning techniques were used for unbiased construction of diagnostic criteria. RESULTS: Twenty-four previously proposed IBM diagnostic categories were identified. Twelve categories all performed with high (≥97%) specificity but varied substantially in their sensitivities (11%-84%). The best performing category was European Neuromuscular Centre 2013 probable (sensitivity of 84%). Specialized pathologic features and newly introduced strength criteria (comparative knee extension/hip flexion strength) performed poorly. Unbiased data-directed analysis of 20 features in 371 patients resulted in construction of higher-performing data-derived diagnostic criteria (90% sensitivity and 96% specificity). CONCLUSIONS: Published expert consensus-derived IBM diagnostic categories have uniformly high specificity but wide-ranging sensitivities. High-performing IBM diagnostic category criteria can be developed directly from principled unbiased analysis of patient data. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that published expert consensus-derived IBM diagnostic categories accurately distinguish IBM from other muscle disease with high specificity but wide-ranging sensitivities.","author":[{"dropping-particle":"","family":"Lloyd","given":"Thomas E","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Mammen","given":"Andrew L","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Amato","given":"Anthony a","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Weiss","given":"Michael D","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Needham","given":"Merrilee","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Greenberg","given":"Steven a","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Neurology","id":"ITEM-1","issue":"5","issued":{"date-parts":[["2014","7","29"]]},"page":"426-33","title":"Evaluation and construction of diagnostic criteria for inclusion body myositis.","type":"article-journal","volume":"83"},"uris":[""]}],"mendeley":{"formattedCitation":" (26)","plainTextFormattedCitation":" (26)","previouslyFormattedCitation":" (26)"},"properties":{"noteIndex":0},"schema":""} (26) Each set of criteria is highly specific, although variable levels of sensitivity are observed, especially where there is emphasis on demonstration of protein aggregates on muscle biopsy. Studies have demonstrated that clinical assessment determines the diagnosis of IBM independently of pathological features, and therefore recognition of the typical IBM pattern of weakness is key.ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1136/jnnp-2013-305690","ISSN":"1468-330X","PMID":"23864699","abstract":"BACKGROUND AND OBJECTIVE: Historically, the diagnosis of sporadic inclusion body myositis (IBM) has required the demonstration of the presence of a number of histopathological findings on muscle biopsy--namely, rimmed vacuoles, an inflammatory infiltrate with invasion of non-necrotic muscle fibres (partial invasion) and amyloid or 15-18 nm tubulofilamentous inclusions (Griggs criteria). However, biopsies of many patients with clinically typical IBM do not show all of these histopathological findings, at least at presentation. We compared the clinical features at presentation and during the course of disease in 67 patients with histopathologically diagnosed IBM and clinically diagnosed IBM seen within a single UK specialist muscle centre. METHODS AND RESULTS: At presentation, using clinically focused diagnostic criteria (European Neuromuscular Centre (ENMC) 2011), a diagnosis of IBM was made in 88% of patients whereas 76% fulfilled the 1997 ENMC criteria and only 27% satisfied the histopathologically focused Griggs criteria. There were no differences in clinical features or outcomes between clinically and histopathologically diagnosed patients, but patients lacking the classical histopathological finding of rimmed vacuoles were younger, suggesting that rimmed vacuoles may be a later feature of the disease. CONCLUSIONS: These findings have important implications for diagnosis and future studies or trials in IBM as adherence to histopathologically focused diagnostic criteria will exclude large numbers of patients with IBM. Importantly, those excluded may be at an earlier stage of the disease and more amenable to treatment.","author":[{"dropping-particle":"","family":"Brady","given":"Stefen","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Squier","given":"Waney","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Hilton-Jones","given":"David","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Journal of neurology, neurosurgery, and psychiatry","id":"ITEM-1","issue":"11","issued":{"date-parts":[["2013","11"]]},"note":"patients with IBM+RV did not get IBM later, but the biopsy WAS DONE LATER.","page":"1240-6","title":"Clinical assessment determines the diagnosis of inclusion body myositis independently of pathological features.","type":"article-journal","volume":"84"},"uris":["","",""]}],"mendeley":{"formattedCitation":" (27)","plainTextFormattedCitation":" (27)","previouslyFormattedCitation":" (27)"},"properties":{"noteIndex":0},"schema":""} (27) There has been recent interest in the identification of cytosolic 5`-nucleotidase 1A (cN-1A) autoantibodies, which are found in approximately 1/3 of patients with IBM, where antibody positivity is associated with a worse prognosis.ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1136/annrheumdis-2016-210282","ISSN":"1468-2060","PMID":"28122761","abstract":"OBJECTIVES Autoantibodies directed against cytosolic 5'-nucleotidase 1A have been identified in many patients with inclusion body myositis. This retrospective study investigated the association between anticytosolic 5'-nucleotidase 1A antibody status and clinical, serological and histopathological features to explore the utility of this antibody to identify inclusion body myositis subgroups and to predict prognosis. MATERIALS AND METHODS Data from various European inclusion body myositis registries were pooled. Anticytosolic 5'-nucleotidase 1A status was determined by an established ELISA technique. Cases were stratified according to antibody status and comparisons made. Survival and mobility aid requirement analyses were performed using Kaplan-Meier curves and Cox proportional hazards regression. RESULTS Data from 311 patients were available for analysis; 102 (33%) had anticytosolic 5'-nucleotidase 1A antibodies. Antibody-positive patients had a higher adjusted mortality risk (HR 1.89, 95% CI 1.11 to 3.21, p=0.019), lower frequency of proximal upper limb weakness at disease onset (8% vs 23%, adjusted OR 0.29, 95% CI 0.12 to 0.68, p=0.005) and an increased prevalence of excess of cytochrome oxidase deficient fibres on muscle biopsy analysis (87% vs 72%, adjusted OR 2.80, 95% CI 1.17 to 6.66, p=0.020), compared with antibody-negative patients. INTERPRETATION Differences were observed in clinical and histopathological features between anticytosolic 5'-nucleotidase 1A antibody positive and negative patients with inclusion body myositis, and antibody-positive patients had a higher adjusted mortality risk. Stratification of inclusion body myositis by anticytosolic 5'-nucleotidase 1A antibody status may be useful, potentially highlighting a distinct inclusion body myositis subtype with a more severe phenotype.","author":[{"dropping-particle":"","family":"Lilleker","given":"J B","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Rietveld","given":"A","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Pye","given":"S R","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Mariampillai","given":"K","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Benveniste","given":"O","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Peeters","given":"M T J","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Miller","given":"J A L","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Hanna","given":"M G","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Machado","given":"P M","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Parton","given":"M J","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Gheorghe","given":"K R","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Badrising","given":"U A","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Lundberg","given":"I E","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Sacconi","given":"S","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Herbert","given":"M K","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"McHugh","given":"N J","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Lecky","given":"B R F","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Brierley","given":"C","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Hilton-Jones","given":"D","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Lamb","given":"J A","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Roberts","given":"M E","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Cooper","given":"R G","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Saris","given":"C G J","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Pruijn","given":"G J M","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Chinoy","given":"H","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Engelen","given":"B G M","non-dropping-particle":"van","parse-names":false,"suffix":""},{"dropping-particle":"","family":"all UKMYONET contributors","given":"","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Annals of the rheumatic diseases","id":"ITEM-1","issue":"5","issued":{"date-parts":[["2017","5","25"]]},"page":"862-868","title":"Cytosolic 5'-nucleotidase 1A autoantibody profile and clinical characteristics in inclusion body myositis.","type":"article-journal","volume":"76"},"uris":[""]}],"mendeley":{"formattedCitation":" (28)","plainTextFormattedCitation":" (28)","previouslyFormattedCitation":" (28)"},"properties":{"noteIndex":0},"schema":""} (28) However, whilst this discovery may be useful in understanding the pathogenesis of IBM, the clinical utility appears restricted. In addition to limited sensitivity, anti-cN-1A autoantibodies are found in similar proportions of patients with Sj?gren’s syndrome and system lupus erythematosus (SLE), also limiting diagnostic specificity. However, as anti-cN-1A autoantibodies are not present in PM, serological testing could potentially be used to support differentiation between IBM and PM in cases where biopsy and clinical features do not allow so.ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1136/annrheumdis-2014-206691","ISSN":"1468-2060","PMID":"25714931","abstract":"OBJECTIVES The diagnosis of inclusion body myositis (IBM) can be challenging as it can be difficult to clinically distinguish from other forms of myositis, particularly polymyositis (PM). Recent studies have shown frequent presence of autoantibodies directed against cytosolic 5'-nucleotidase 1A (cN-1A) in patients with IBM. We therefore, examined the autoantigenicity and disease specificity of major epitopes of cN-1A in patients with sporadic IBM compared with healthy and disease controls. METHODS Serum samples obtained from patients with IBM (n=238), PM and dermatomyositis (DM) (n=185), other autoimmune diseases (n=246), other neuromuscular diseases (n=93) and healthy controls (n=35) were analysed for the presence of autoantibodies using immunodominant cN-1A peptide ELISAs. RESULTS Autoantibodies directed against major epitopes of cN-1A were frequent in patients with IBM (37%) but not in PM, DM or non-autoimmune neuromuscular diseases (<5%). Anti-cN-1A reactivity was also observed in some other autoimmune diseases, particularly Sj?gren's syndrome (SjS; 36%) and systemic lupus erythematosus (SLE; 20%). CONCLUSIONS In summary, we found frequent anti-cN-1A autoantibodies in sera from patients with IBM. Heterogeneity in reactivity with the three immunodominant epitopes indicates that serological assays should not be limited to a distinct epitope region. The similar reactivities observed for SjS and SLE demonstrate the need to further investigate whether distinct IBM-specific epitopes exist.","author":[{"dropping-particle":"","family":"Herbert","given":"Megan K","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Stammen-Vogelzangs","given":"Judith","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Verbeek","given":"Marcel M","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Rietveld","given":"Anke","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Lundberg","given":"Ingrid E","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Chinoy","given":"Hector","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Lamb","given":"Janine A","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Cooper","given":"Robert G","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Roberts","given":"Mark","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Badrising","given":"Umesh A","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Bleecker","given":"Jan L","non-dropping-particle":"De","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Machado","given":"Pedro M","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Hanna","given":"Michael G","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Plestilova","given":"Lenka","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Vencovsky","given":"Jiri","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Engelen","given":"Baziel G","non-dropping-particle":"van","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Pruijn","given":"Ger J M","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Annals of the rheumatic diseases","id":"ITEM-1","issue":"4","issued":{"date-parts":[["2016","4","24"]]},"page":"696-701","title":"Disease specificity of autoantibodies to cytosolic 5'-nucleotidase 1A in sporadic inclusion body myositis versus known autoimmune diseases.","type":"article-journal","volume":"75"},"uris":[""]}],"mendeley":{"formattedCitation":" (29)","plainTextFormattedCitation":" (29)"},"properties":{"noteIndex":0},"schema":""} (29)Immune mediated necrotizing myopathyAnother recently described entity within the IIM spectrum is IMNM. In such cases, the paucity of inflammatory features on muscle biopsy and lack of cutaneous involvement or other CTD features, can lead clinicians to erroneously conclude that an inflammatory myopathy is unlikely. The CK level is also usually very high in IMNM, usually >2,000 IU/L, leading to concern about rhabdomyolysis or perhaps a metabolic myopathy. However, levels >30-40,000 IU/L in the author’s experience should suggest an alternative diagnosis. Previous statin exposure is not required for a diagnosis of IMNM and it is interesting to note that exposure to naturally occurring sources of statin (e.g. Chinese red yeast rice, oyster mushroom extract, Pu-erh tea) may be the explanation for the occurrence in some cases. Finally, more indolent forms of IMNM are recognised with initial dystrophic-like features at presentation, potentially leading to misdiagnosis.ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1097/MD.0000000000000028","ISBN":"0000000000000","ISSN":"1536-5964","PMID":"24797170","abstract":"Necrotizing autoimmune myopathy (NAM) is a group of acquired myopathies characterized by prominent myofiber necrosis with little or no muscle inflammation. Recently, researchers identified autoantibodies (aAb) against 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR) in patients with NAM, especially in statin-exposed patients. Here we report what is to our knowledge the first European cohort of patients with NAM.The serum of 206 patients with suspicion of NAM was tested for detection of anti-HMGCR aAb using an addressable laser bead immunoassay. Forty-five patients were found to be anti-HMGCR positive. Their mean age was 48.9 ± 21.9 years and the group was predominantly female (73.3%). Statin exposure was recorded in 44.4% of patients. Almost all patients had a muscular deficit (97.7%), frequently severe (Medical Research Council [MRC] 5 ≤3 in 75.5%). Subacute onset (<6 mo) was noted for most of them (64.4%). Nevertheless, 3 patients (6.6%) had a slowly progressive course over more than 10 years. Except for weight loss (20%), no extramuscular sign was observed. The mean CK level was high (6941 ± 8802 IU/L) and correlated with muscle strength evaluated by manual muscle testing (r = -0.37, p = 0.03). Similarly, anti-HMGCR aAb titers were correlated with muscular strength (r = -0.31; p = 0.03) and CK level (r = 0.45; p = 0.01). Mean duration of treatment was 34.1 ± 40.8 months, and by the end of the study no patient had been able to stop treatment.This study confirms the observation and description of anti-HMGCR aAb associated with NAM. The majority of patients were statin naive and needed prolonged treatments. Some patients had a dystrophic-like presentation. Anti-HMGR aAb titers correlated with CK levels and muscle strength, suggesting their pathogenic role.","author":[{"dropping-particle":"","family":"Allenbach","given":"Yves","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Drouot","given":"Laurent","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Rigolet","given":"Aude","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Charuel","given":"Jean Luc","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Jouen","given":"Fabienne","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Romero","given":"Norma 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Autoantibodies in European Patients With Autoimmune Necrotizing Myopathies: Inconstant Exposure to Statin.","type":"article-journal","volume":"93"},"uris":["",""]}],"mendeley":{"formattedCitation":" (30)","plainTextFormattedCitation":" (30)","previouslyFormattedCitation":" (29)"},"properties":{"noteIndex":0},"schema":""} (30)It is important to recognise IMNM as distinct from PM, particularly as more aggressive treatment may be required in the former, with intravenous immunoglobulin (IVIg) shown to be potentially effective.ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1056/NEJMc1506163","ISBN":"3642118526","ISSN":"1533-4406","PMID":"26488714","abstract":"Ischemic optic neuropathy, often referred to as a stroke of the optic nerve, is one of the major causes of visual impairment or loss of vision. Yet it is a highly controversial and confusing subject because of the general lack of in-depth scientific understanding of the subject. In this book the leading authority in the field describes in detail the current knowledge about the different forms of the often devastating disease. Insights into the underlying pathogenesis and peculiar clinical features are given, leading the reader to the most appropriate way of management. This information will help any physician dealing with patients who suffer from sudden loss of vision.","author":[{"dropping-particle":"","family":"Mammen","given":"Andrew L","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Tiniakou","given":"Eleni","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"The New England journal of medicine","id":"ITEM-1","issue":"17","issued":{"date-parts":[["2015","10"]]},"page":"1680-2","title":"Intravenous Immune Globulin for Statin-Triggered Autoimmune Myopathy.","type":"article-journal","volume":"373"},"uris":["",""]},{"id":"ITEM-2","itemData":{"DOI":"10.1016/j.nmd.2017.09.016","ISSN":"18732364","abstract":"The objective of this study was to investigate the mechanical properties (% elongation and puncture strength) of poly(D,L‐lactide) (PLA) and poly(D,L‐lactide‐co‐glycolide) (PLGA) films as a function of exposure time to an aqueous medium and to correlate the mechanical properties to the degradation/erosion of the polymer as a function of the type of polymer [PLA, weight‐average molecular weight (MW) 270,300, or PLGA 50:50, MW 56,500], the type of plasticizer [(triethyl citrate (TEC) or acetyltributyl citrate (ATBC)], and the exposure time to pH 7.4 phosphate buffer. The glass transition temperature of the films was measured by differential scanning calorimetry (DSC), the molecular weight by size exclusion chromatography (SEC), and the polymer erosion and hydration gravimetrically. The mechanical properties were strongly affected by the type of polymer and plasticizer. PLGA films showed a faster loss of mechanical integrity. TEC, the water‐soluble plasticizer, leached from the films, resulting in major differences in the mechanical properties (flexibility) when compared with films plasticized with the more permanent, water‐insoluble ATBC. A significant difference in MW decrease was seen between plasticizer‐free and plasticizer‐containing PLA films, but not for PLGA films. Plasticized PLA films, which were above their glass transition temperature in the rubbery state, showed a faster decrease in MW than plasticizer‐free PLA ones, which were in the glassy state. The plasticizer addition to the lower MW PLGA did not enhance the polymer degradation; the plasticizer‐free PLGA was already in the rubbery state. Major differences between the two polymers were also seen in the mass loss and the water uptake studies. After 4 weeks, the mass loss was between 2.6 and 7.0% and the water uptake between 10.1 and 21.1% for PLA films, whereas for PLGA films, the mass loss was between 40.3 and 51.3% and the water uptake between 221.9 and 350.6%. 2000 Wiley‐Liss, Inc. and the American Pharmaceutical Association J Pharm Sci 89:1558–1566, 2000","author":[{"dropping-particle":"","family":"Allenbach","given":"Yves","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Mammen","given":"Andrew L.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Benveniste","given":"Olivier","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Stenzel","given":"Werner","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Allenbach","given":"Yves","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Amato","given":"Anthony","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Aussey","given":"Audrey","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Benveniste","given":"Olivier","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Bleecker","given":"Jan","non-dropping-particle":"De","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Groot","given":"Ingrid","non-dropping-particle":"de","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Visser","given":"Marianne","non-dropping-particle":"de","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Goebel","given":"Hans","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Hervier","given":"Baptiste","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Fischer","given":"Norina","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Hilton-Jones","given":"David","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Lamb","given":"Janice","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Lundberg","given":"Ingrid","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Mammen","given":"Andrew","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Mozaffar","given":"Tahseen","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Nishino","given":"Ichizo","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Pestronk","given":"Alan","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Schara","given":"Ulrike","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Stenzelr","given":"Werner","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Neuromuscular Disorders","id":"ITEM-2","issued":{"date-parts":[["2018"]]},"title":"224th ENMC International Workshop:: Clinico-sero-pathological classification of immune-mediated necrotizing myopathies Zandvoort, The Netherlands, 14–16 October 2016","type":"paper-conference"},"uris":["",""]}],"mendeley":{"formattedCitation":" (3,31)","plainTextFormattedCitation":" (3,31)","previouslyFormattedCitation":" (3,30)"},"properties":{"noteIndex":0},"schema":""} (3,31) In order to avoid such diagnostic pitfalls we suggest having a low threshold for testing for the HMGCR and SRP autoantibodies in all patients with possible IIM (except those with a typical DM rash). DermatomyositisTwo unusual DM subtypes are described. First, dermatomyositis sine dermatitis refers to a patient with myositis, muscle biopsy appearances indicative of an inflammatory process and features seen more frequently in DM (e.g. perivascular inflammatory infiltrates, perifascicular atrophy), but without any skin rash. The classification tree accompanying the 2017 EULAR/ACR IIM criteria would likely classify such patients as PM.ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1002/art.40320","ISSN":"2326-5205","PMID":"29106061","abstract":"OBJECTIVE To develop and validate new classification criteria for adult and juvenile idiopathic inflammatory myopathies (IIM) and their major subgroups. METHODS Candidate variables were assembled from published criteria and expert opinion using consensus methodology. Data were collected from 47 rheumatology, dermatology, neurology, and pediatric clinics worldwide. Several statistical methods were utilized to derive the classification criteria. RESULTS Based on data from 976 IIM patients (74% adults; 26% children) and 624 non-IIM patients with mimicking conditions (82% adults; 18% children), new criteria were derived. Each item is assigned a weighted score. The total score corresponds to a probability of having IIM. Subclassification is performed using a classification tree. A probability cutoff of 55%, corresponding to a score of 5.5 (6.7 with muscle biopsy) \"probable IIM,\" had best sensitivity/specificity (87%/82% without biopsies, 93%/88% with biopsies) and is recommended as a minimum to classify a patient as having IIM. A probability of ≥90%, corresponding to a score of ≥7.5 (≥8.7 with muscle biopsy), corresponds to \"definite IIM.\" A probability of <50%, corresponding to a score of <5.3 (<6.5 with muscle biopsy), rules out IIM, leaving a probability of ≥50-<55% as \"possible IIM.\" CONCLUSION The European League Against Rheumatism/American College of Rheumatology (EULAR/ACR) classification criteria for IIM have been endorsed by international rheumatology, dermatology, neurology, and pediatric groups. They employ easily accessible and operationally defined elements, and have been partially validated. They allow classification of \"definite,\" \"probable,\" and \"possible\" IIM, in addition to the major subgroups of IIM, including juvenile IIM. They generally perform better than existing criteria.","author":[{"dropping-particle":"","family":"Lundberg","given":"Ingrid E","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Tj?rnlund","given":"Anna","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Bottai","given":"Matteo","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Werth","given":"Victoria P","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Pilkington","given":"Clarissa","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Visser","given":"Marianne","non-dropping-particle":"de","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Alfredsson","given":"Lars","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Amato","given":"Anthony A","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Barohn","given":"Richard J","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Liang","given":"Matthew H","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Singh","given":"Jasvinder A","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Aggarwal","given":"Rohit","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Arnardottir","given":"Snjolaug","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Chinoy","given":"Hector","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Cooper","given":"Robert G","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Dankó","given":"Katalin","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Dimachkie","given":"Mazen M","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Feldman","given":"Brian M","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Garcia-De La Torre","given":"Ignacio","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Gordon","given":"Patrick","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Hayashi","given":"Taichi","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Katz","given":"James D","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kohsaka","given":"Hitoshi","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Lachenbruch","given":"Peter A","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Lang","given":"Bianca A","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Li","given":"Yuhui","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"V","family":"Oddis","given":"Chester","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Olesinska","given":"Marzena","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Reed","given":"Ann M","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Rutkowska-Sak","given":"Lidia","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Sanner","given":"Helga","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Selva-O'Callaghan","given":"Albert","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Song","given":"Yeong-Wook","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Vencovsky","given":"Jiri","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Ytterberg","given":"Steven R","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Miller","given":"Frederick W","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Rider","given":"Lisa G","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"International Myositis Classification Criteria Project Consortium, the Euromyositis Register","given":"and the Juvenile Dermatomyositis Cohort Biomarker Study and Repository (UK and Ireland)","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Arthritis & rheumatology (Hoboken, N.J.)","id":"ITEM-1","issue":"12","issued":{"date-parts":[["2017"]]},"page":"2271-2282","title":"2017 European League Against Rheumatism/American College of Rheumatology Classification Criteria for Adult and Juvenile Idiopathic Inflammatory Myopathies and Their Major Subgroups.","type":"article-journal","volume":"69"},"uris":[""]}],"mendeley":{"formattedCitation":" (32)","plainTextFormattedCitation":" (32)","previouslyFormattedCitation":" (31)"},"properties":{"noteIndex":0},"schema":""} (32) There remains uncertainty regarding this entity and whether disease risk factors or outcomes differ from other IIM subtypes. However, in many cases the skin rash is simply very subtle and evades detection on routine examination or may have disappeared before the patient reaches the specialist clinic.Second, clinically amyopathic DM refers to a patient with a DM specific skin rash but with little or no muscle involvement. This entity is more common and is specified in the 2017 criteria and classification tree. The CK may be slightly elevated in such cases, but muscle weakness is not a feature. Patients with SAE1 positive DM may present initially with skin before going on to develop muscle involvement.ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"PMID":"18930994","abstract":"OBJECTIVES: We have previously identified autoantibodies to a novel autoantigen small ubiquitin-like modifier activating enzyme (SAE) associated with dermatomyositis (DM). The aim of this study was to establish the frequency of anti-SAE autoantibodies in a UK myositis cohort and investigate clinico-immunogenetic associations. METHODS: Clinical data and sera were studied from 266 patients recruited to the Adult Onset Myositis Immunogenetic Collaboration. Myositis sera, control sera including 250 patients with other connective tissue diseases and 50 healthy subjects were screened using radio-immunoprecipitation. Immunodepletion was performed on all sera immunoprecipitating 40 and 90 kDa bands to confirm the presence of anti-SAE. DNA from 202 myositis patients was genotyped for HLA-DRB1 and DQB1; DQA1 data were inferred. RESULTS: Eleven out of 266 myositis patients (4%) were positive for anti-SAE which was found exclusively in DM with a frequency of 8%. Anti-SAE patients had a high frequency of cutaneous lesions including heliotrope (82%) and Gottron's rash (82%). Nine/11 (82%) had systemic features and 7/9 (78%) developed dysphagia. Seven/9 (78%) presented with skin disease before myositis onset. All anti-SAE patients possessed at least one copy of HLA-DQB1*03. HLA-DRB1*04-DQA1*03-DQB1*03 was a significant risk factor in anti-SAE positive vs. anti-SAE negative patients (haplotype frequency 18% vs. 6%, p=0.0001, OR 5.7, 95% CI 1.9-17.3). CONCLUSIONS: Anti-SAE is a myositis specific autoantibody that identifies a subset of patients with adult DM. The majority of anti-SAE patients presented with cutaneous disease and progressed to myositis with systemic features including dysphagia. This novel autoantibody has a strong association with the HLA-DRB1*04-DQA1*03-DQB1*03 haplotype","author":[{"dropping-particle":"","family":"Betteridge","given":"Z E","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Gunawardena","given":"H","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Chinoy","given":"H","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"North","given":"J","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Ollier","given":"W E","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Cooper","given":"R G","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"McHugh","given":"N J","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Ann.Rheum.Dis.","id":"ITEM-1","issue":"1468-2060 (Electronic)","issued":{"date-parts":[["2008","10"]]},"language":"ENG PT - JOURNAL ARTICLE","publisher-place":"University of Bath, United Kingdom","title":"Clinical and HLA-class II haplotype associations of autoantibodies to small ubiquitin-like modifier enzyme, a dermatomyositis-specific autoantigen target, in UK adult-onset Caucasian myositis","type":"article-journal"},"uris":["",""]}],"mendeley":{"formattedCitation":" (33)","plainTextFormattedCitation":" (33)","previouslyFormattedCitation":" (32)"},"properties":{"noteIndex":0},"schema":""} (33) MDA5 and TIF1g positive DM patients also commonly present with amyopathic disease.Anti-synthetase syndrome and overlap syndromesPatients can have elements of the anti-synthetase syndrome (ASS) but without prominent (or any) muscle involvement. This is particularly relevant in non-Jo-1 antibody disease: 56-65% of PL7 or PL12 antibody positive patients will present with sole lung involvement at presentation.ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1093/rheumatology/kex021","ISSN":"14620332","abstract":"? The Author 2017. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. Objective. The aim was to study the prevalence, rate of appearance and severity of clinical features in patients with different anti-synthetase syndrome (ASyS) autoantibodies. Methods. All Johns Hopkins Myositis Longitudinal Cohort subjects positive for any ASyS autoantibodies were included. Clinical information, including symptoms, signs, strength, creatine kinase concentrations and pulmonary function tests, were prospectively collected. The standardized mortality and cancer rates and the rate of appearance and intensity of the different organ manifestations were assessed using univariate and multivariate analysis and compared between ASyS autoantibodies. Results. One hundred and twenty-four (73.4%) patients were positive for anti-Jo1, 23 (13.6%) for anti-PL12, 16 for anti-PL7 (9.5%) and 3 (1.8%) for anti-EJ or anti-OJ, respectively. The mean length of follow-up was 4.1 years. Anti-PL12 was more frequent in black subjects. Anti-PL12 and anti-PL7 were associated with more prevalent and severe lung involvement, often without muscle involvement. Anti-Jo1 displayed more severe muscle involvement compared with anti-PL12 patients. Concurrent anti-Ro52 was more prevalent in anti-Jo1 patients and was associated with earlier development of mechanic's hands, DM-specific skin findings and arthritis. Independent of ASyS antibody status, black patients demonstrated more severe lung involvement than white patients. There was no significant increase in mortality or cancer risk in ASyS patients compared with the general US population. Conclusion. Different ASyS autoantibodies are associated with phenotypically distinct subgroups within the ASyS spectrum. Anti-PL7 and anti-PL12 are characterized by more severe lung involvement, whereas anti-Jo1 is associated with more severe muscle involvement. Black race is a major prognostic factor associated with lung disease severity.","author":[{"dropping-particle":"","family":"Pinal-Fernandez","given":"Iago","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Casal-Dominguez","given":"Maria","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Huapaya","given":"Julio A.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Albayda","given":"Jemima","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Paik","given":"Julie J.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Johnson","given":"Cheilonda","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Silhan","given":"Leann","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Christopher-Stine","given":"Lisa","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Mammen","given":"Andrew L.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Danoff","given":"Sonye K.","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Rheumatology (United Kingdom)","id":"ITEM-1","issue":"6","issued":{"date-parts":[["2017"]]},"page":"999-1007","title":"A longitudinal cohort study of the anti-synthetase syndrome: Increased severity of interstitial lung disease in black patients and patients with anti-PL7 and anti-PL12 autoantibodies","type":"article-journal","volume":"56"},"uris":["",""]}],"mendeley":{"formattedCitation":" (34)","plainTextFormattedCitation":" (34)","previouslyFormattedCitation":" (33)"},"properties":{"noteIndex":0},"schema":""} (34) With the lack of established diagnostic or classification criteria for ASS, confusion arises regarding what to label such patients as – PM, amyopathic PM, ASS sine myositis or myositis-spectrum disease. Including these patients within IIM highlights the tensions between classification systems that focus on clinical, serological or histopathological features. However, such patients may go on to develop other ASS features later in their disease course, including myositis. Retaining classification of such patients within the IIM umbrella does at least keep this possibility in the mind of the treating clinician.Myositis can occur in the context of other CTDs, including SLE, systemic sclerosis (SSc) and mixed connective tissue disease. In these overlap syndromes management will usually follow that of the primary CTD. “Scleromyositis” (SSc-PM overlap) is probably the most well known overlap syndrome and is associated with PM-Scl autoantibodies. In such cases, muscle involvement can take either an inflammatory or a fibrosing form. In the latter, CK levels are normal or only slightly elevated, the muscle biopsy shows prominent perimysial and endomysial fibrosis without inflammatory infiltrates, and poor responses to immunosuppression and higher mortality rates are observed.ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1002/acr.23291","ISSN":"2151464X","author":[{"dropping-particle":"","family":"Paik","given":"Julie J.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Wigley","given":"Fredrick M.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Shah","given":"Ami A.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Corse","given":"Andrea M.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Casciola-Rosen","given":"Livia","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Hummers","given":"Laura K.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Mammen","given":"Andrew L.","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Arthritis Care & Research","id":"ITEM-1","issue":"11","issued":{"date-parts":[["2017","11"]]},"page":"1764-1770","title":"Association of Fibrosing Myopathy in Systemic Sclerosis and Higher Mortality","type":"article-journal","volume":"69"},"uris":[""]}],"mendeley":{"formattedCitation":" (35)","plainTextFormattedCitation":" (35)","previouslyFormattedCitation":" (34)"},"properties":{"noteIndex":0},"schema":""} (35)Seronegative and treatment-resistant myositisA particularly difficult scenario is the IIM patient with refractory disease activity. This inevitably raises concern about whether the diagnosis is correct. Of course, the alternative is that treatment that is more aggressive is required, but such “raising of the stakes” requires careful thought and discussion with other members of the MDT and the patient. It is important not to rely on the CK level in isolation as a marker of treatment response, as this can improve in patients with other myopathies in response to glucocorticoids (so called ‘chemical improvement’). Instead, the wider clinical picture should be examined, ideally with an emphasis on reliable outcome measures, such as those produced by the International Myositis Assessment & Clinical Studies Group (IMACS).ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"PMID":"12867580","abstract":"OBJECTIVE: To devise new tools to assess activity and damage in patients with idiopathic myopathies (IIM). METHODS: An international multidisciplinary consensus effort to standardize the conduct and reporting of the myositis clinical trials has been established. Two tools, known as the myositis intention to treat index (MITAX) and the myositis disease activity assessment visual analogue scale (MYOACT), have been developed to capture activity in patients with IIM. In addition, the myositis damage index (MDI) has been devised to assess the extent and severity of damage developing in different organs and systems. These measures have been reviewed by the myositis experts participating in the International Myositis Assessment and Clinical Studies (IMACS) group and have been found to have good face validity and to be comprehensive. The instruments were assessed in two real patient exercises involving patients with adult dermatomyositis and inclusion body myositis. RESULTS: The reliability of MITAX, MYOACT and MDI, measured by the intraclass correlation coefficient among the physicians, and the inter-rater reliability, as assessed by variation in the physicians' rating of patients, was fair to good for most aspects of the tools. Reliability and inter-rater agreement improved at the second exercise after the participants had completed additional training. CONCLUSIONS: The MITAX, MYOACT and MDI tools, which are now undergoing validity testing, should enhance the consistency, comprehensiveness and reliability of disease activity and damage assessment in patients with myositis","author":[{"dropping-particle":"","family":"Isenberg","given":"D A","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Allen","given":"E","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Farewell","given":"V","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Ehrenstein","given":"M R","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Hanna","given":"M G","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Lundberg","given":"I E","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Oddis","given":"C","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Pilkington","given":"C","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Plotz","given":"P","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Scott","given":"D","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Vencovsky","given":"J","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Cooper","given":"R","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Rider","given":"L","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Miller","given":"F","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Rheumatology.(Oxford)","id":"ITEM-1","issue":"1462-0324","issued":{"date-parts":[["2004"]]},"language":"eng PT - Consensus Development Conference PT - Journal Article PT - Multicenter Study PT - Review SB - AIM SB - IM","page":"49-54","publisher-place":"Center for Rheumatology, Department of Medicine, The Middlesex Hospital, University College London, London, UK. d.isenberg@ucl.ac.uk","title":"International consensus outcome measures for patients with idiopathic inflammatory myopathies. Development and initial validation of myositis activity and damage indices in patients with adult onset disease","type":"article-journal","volume":"43"},"uris":["",""]}],"mendeley":{"formattedCitation":" (36)","plainTextFormattedCitation":" (36)","previouslyFormattedCitation":" (35)"},"properties":{"noteIndex":0},"schema":""} (36) Some patients with IIM do require intensive treatment, including with IVIg and cyclophosphamide. Additional options are increasingly becoming available, including biologic therapies such as rituximab, abatacept, tocilizumab, JAK inhibitors.ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1038/nrrheum.2018.42","ISSN":"1759-4790","PMID":"29593343","abstract":"Many immunosuppressive and immunomodulatory therapies are available to clinicians for managing myositis, and numerous biologic and small-molecule therapies are emerging that target implicated pathogenic targets. However, care must be taken when considering the numerous extramuscular complications of this disease.","author":[{"dropping-particle":"V.","family":"Oddis","given":"Chester","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Aggarwal","given":"Rohit","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Nature Reviews Rheumatology","id":"ITEM-1","issue":"5","issued":{"date-parts":[["2018"]]},"page":"279-289","publisher":"Nature Publishing Group","title":"Treatment in myositis","type":"article-journal","volume":"14"},"uris":["",""]},{"id":"ITEM-2","itemData":{"DOI":"10.1093/brain/awy105","ISSN":"1460-2156","PMID":"29741608","abstract":"Dermatomyositis is an acquired auto-immune disease characterized by skin lesions and muscle-specific pathological features such as perifascicular muscle fibre atrophy and vasculopathy. Dermatomyositis patients display an upregulation of type I interferon-inducible genes in muscle fibres, endothelial cells, skin and peripheral blood. However, the effect of type I interferon on muscle tissue has not yet been determined. Our aim was to study the pathogenicity of type I interferon in vitro and to evaluate the efficacy of the type I interferon pathway blockade for therapeutic purposes. The activation of type I interferon in differentiating myoblasts abolished myotube formation with reduced myogenin expression while in differentiated myotubes, we observed a reduction in surface area and an upregulation of atrophy-associated genes. In vitro endothelial cells exposure to type I interferon disrupted vascular network organization. All the pathogenic effects observed in vitro were abolished by ruxolitinib. Finally, four refractory dermatomyositis patients were treated with ruxolitinib and improvement ensued in skin lesions, muscle weakness and a reduced serum type I interferon levels and interferon-inducbile genes scores. We propose JAK inhibition as a mechanism-based treatment for dermatomyositis, a finding that is relevant for the design of future clinical trials targeting dermatomyositis.","author":[{"dropping-particle":"","family":"Ladislau","given":"Leandro","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Suárez-Calvet","given":"Xavier","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Toquet","given":"Ségolène","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Landon-Cardinal","given":"Océane","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Amelin","given":"Damien","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Depp","given":"Marine","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Rodero","given":"Mathieu P","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Hathazi","given":"Denisa","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Duffy","given":"Darragh","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Bondet","given":"Vincent","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Preusse","given":"Corinna","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Bienvenu","given":"Boris","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Rozenberg","given":"Flore","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Roos","given":"Andreas","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Benjamim","given":"Claudia F","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Gallardo","given":"Eduard","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Illa","given":"Isabel","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Mouly","given":"Vincent","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Stenzel","given":"Werner","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Butler-Browne","given":"Gillian","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Benveniste","given":"Olivier","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Allenbach","given":"Yves","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Brain : a journal of neurology","id":"ITEM-2","issue":"6","issued":{"date-parts":[["2018","6"]]},"page":"1609-1621","title":"JAK inhibitor improves type I interferon induced damage: proof of concept in dermatomyositis.","type":"article-journal","volume":"141"},"uris":["",""]}],"mendeley":{"formattedCitation":" (37,38)","plainTextFormattedCitation":" (37,38)","previouslyFormattedCitation":" (36,37)"},"properties":{"noteIndex":0},"schema":""} (37,38)ConclusionsOne must remain vigilant for the presence of myositis mimickers in patients presenting with a raised CK, muscle weakness, and/or non-specific CTD symptoms, who do not possess other more specific IIM features. In addition, IIM is highly heterogenous and the variability within the syndrome may lead the clinician to wonder about the possibility of alternative diagnoses. We have discussed some of the ramifications of making an erroneous diagnosis and advise that the reader considers diagnostic re-appraisal as part of the management pathway in treatment resistant IIM cases. Where diagnostic doubt exists, involvement of a specialist centre can be vital in helping to make the correct diagnosis. Finally, close working between neurology, rheumatology and other sub-specialities remains essential. DermatomyositisImmune mediated necrotizing myopathyInclusion body myositisPolymyositis and overlap syndromesAnti-synthetase syndromeClinical featuresCharacteristic skin rash (e.g. Heliotrope, Gottron’s papules and sign, Shawl sign, V sign).Proximal upper and lower limb weaknessSevere proximal upper and lower limb weakness.Neck flexor weakness.Very high CK levels.Age usually >50 years. Distal upper limb weakness.Proximal lower limb weakness.Dysphagia.Proximal upper and lower limb weakness.Features of associated connective tissue disease (e.g. SSc, SLE, MCTD).Myositis.Mechanics’ hands.Raynaud’s phenomenon.Arthritis.Interstitial lung disease.Muscle biopsy findingsPerivascular and perimysial inflammation with perifascicular atrophy.Reduced capillary density with membrane attack complex deposition on capillaries.Necrotic fibres predominate.Sparse perivascular inflammatory cells.Endomysial CD8+ T cells surrounding and invading non-necrotic muscle fibres.Widespread HLA class I upregulation.Protein aggregates and rimmed vacuoles.Mitochondrial dysfunction.Endomysial CD8+ T cells surrounding and invading non-necrotic muscle fibres.Widespread HLA class I upregulation.Rounded fibres, internalised nuclei, necrosis.Perimysial macrophage and CD8+ T cell infiltrates.Associated autoantibodiesSAE, Mi2, MDA5, NXP2, TIF1SRP, HMGCRCN-1APM-Scl, Scl-70, Ku, RNP, Ro/LaJo-1, PL-7, PL-12, OJ, Zo, KS, EJ, HaTable 1: Typical clinical features, biopsy findings and autoantibody profiles of the idiopathic inflammatory myopathy subtypesCK = creatine kinase, SSc = systemic sclerosis, SLE = systemic lupus erythematosus, MCTD = mixed connective tissue disease, HLA = human leukocyte antigenTable 2: Idiopathic inflammatory myopathy mimics and chameleonsIIM Mimics: other conditions masquerading as IIMIIM Chameleons: patients with IIM that may appear to have a different conditionMetabolic myopathies: Glycogen storage disorders (e.g. McArdle’s disease, Pompe disease), fatty acid oxidation defects (e.g. carnitine palmityltransferase II deficiency), mitochondrial diseaseInclusion body myositis: “Unusual” pattern of muscle weakness (distal upper limbs, proximal lower limbs), older age of onset (usually >50 years), treatment resistant courseGenetic myopathies: Limb girdle muscular dystrophy, facioscapulohumeral muscular dystrophy, myotonic dystrophy, myofibrillar myopathies, congenital myopathies, dystrophinopathies, hereditary inclusion body myopathies, skeletal muscle channelopathiesImmune-mediated necrotizing myopathy: Very high CK level, paucity of inflammatory features on muscle biopsy, indolent forms may resemble a limb girdle muscular dystrophyNeurologic disease: Amyotrophic lateral sclerosis, spinobulbar muscular atrophy (Kennedy’s disease), motor variants of chronic inflammatory demyelinating polyneuropathy, peripheral nerve hyperexcitability, spinal disease/radiculopathiesDermatomyositis: Sine myopathy and sine dermatitis variants. Other acquired diseases with myopathic manifestations: Infective and post-infective myositis, endocrinopathies (e.g. hyper/hypothyroidism, acromegaly, Cushing’s syndrome, Addison’s disease, vitamin D deficiency, hyper/hypocalcaemia, hypokalaemia), pyonecrosis, traumaAnti-synthetase syndrome: Manifestations may primarily be extramuscular (especially pulmonary) Drugs/toxins: Statin-related myotoxicity, fibrates, colchicine, hydroxychloroquine, zidovudine, cocaine, alcohol, D-penicillamineSeronegative IIM: Additional myositis-specific autoantibodies are likely to be discoveredIIM = idiopathic inflammatory myopathy, CK = creatine kinaseTable 3: Red flags for alternative diagnoses in patients with apparent idiopathic inflammatory myopathyRed flagKey alternative diagnoses to considerPositive family history for myopathic symptomsGenetic myopathies, neuropathies or metabolic myopathiesAsymmetric and distal weakness (except sporadic IBM)Genetic myopathies (e.g. facioscapulohumeral muscular dystrophy, myotonic dystrophy, hereditary forms of IBM)Muscle hypertrophyGenetic myopathies (e.g. caveolinopathy, sarcoglycanopathy). Manifesting carriers of dystrophinopathiesEarly muscle atrophyGenetic myopathies (many), neurologic disease (e.g. amyotrophic lateral sclerosis), metabolic myopathy (e.g. Pompe disease)Fasciculations or crampingNeurologic disease (e.g. amyotrophic lateral sclerosis or peripheral nerve hyperexcitability) or metabolic abnormality (e.g. hypocalcaemia)Enzymes >100x normal upper limitMetabolic myopathies (e.g. McArdle’s disease, carnitine palmityltransferase II deficiency)No non-muscle symptomsPure myopathy syndromes have wide differential. Genetic myopathies should be considered.No response to therapy (except sporadic IBM)Genetic myopathies, neuropathies or metabolic myopathiesNo abnormal gammaglobulins or autoantibodiesGenetic myopathies, neuropathies or metabolic myopathiesMuscle magnetic resonance imaging demonstrating severe selective fatty replacement of individual musclesGenetic myopathies, neurologic disease (e.g. spinal disease/radiculopathy)Muscle magnetic resonance imaging normal or demonstrating atrophy onlyMetabolic myopathies, sarcopenia of ageing Rhabdomyolysis, especially if recurrentMetabolic myopathiesIBM = inclusion body myositis. The authors thank Rohit Aggarwal for kindly providing a version of this table, which has been adapted for this publication.Practice pointsThe spectrum of idiopathic inflammatory myopathy (IIM) includes the traditional subtypes of polymyositis and dermatomyositis, but also immune-mediated necrotising myopathy (IMNM), anti-synthetase syndrome (ASS), overlap syndromes and inclusion body myositis (IBM). Each IIM subtype has characteristic clinical, serological, pathological and genetic associations.Testing for myositis-specific autoantibodies (MSA) and myositis-associated autoantibodies (MAA) remains an important part of the work-up of patients with suspected IIM, helping to confirm diagnosis, define disease subtype and inform prognosis.Interpretation of MSA/MAA results requires correlation with the clinical phenotype and should be performed cautiously in those with multiple specificities and “low/weak positive” results.Non-inflammatory myopathies can mimic IIM. Red flags alerting the clinician to an alternative diagnosis include positive family history, serum muscle enzyme level >100x upper limit of normal, and episode(s) of rhabdomyolysis.The IIM spectrum is heterogeneous and several atypical presentations are recognised, including IMNM (where inflammatory features on muscle biopsy are scarce), ASS (where muscle involvement may be minimal and extramuscular involvement including interstitial lung disease can predominate), and restricted forms such as DM sine myopathy and DM sine dermatitis. IBM is the most common acquired myopathy in those >50 years of age and should be considered in those with distal upper limb weakness, proximal lower limb weakness and inflammatory features on muscle biopsy. IBM does not respond to treatment with immunosuppressive treatment which should be avoided. A diagnosis of IBM should be alerted to when patients prove refractory to treatment.Multidisciplinary teamwork is vital to ensure patients receive timely accurate diagnosis and appropriate treatment, maximising the opportunity for muscle recovery.Research agendaThe retention of the traditional IIM subtype category of PM is increasingly difficult to justify. Most patients now classified differently (e.g. as IMNM) in clinical practice. There is a pressing requirement to update classification and inclusion criteria for clinical trials. Further work is required to understand disease mechanisms in those with seronegative IIM. It is likely that further autoantibodies are yet to be discovered.The development of biomarkers able to distinguish between IBM (which should not be treated with immunosuppression) and the other IIM subtypes accurately at an early stage of disease are required.The evidence base for IIM treatment is remarkably sparse and recommendations are often based on case series or expert opinion. Further clinical trials in IIM and evidence-based treatment guidelines are required.ReferencesADDIN Mendeley Bibliography CSL_BIBLIOGRAPHY 1. Lundberg IE, Tj?rnlund A, Bottai M, Werth VP, Pilkington C, Visser M de, et al. 2017 European League Against Rheumatism/American College of Rheumatology Classification Criteria for Adult and Juvenile Idiopathic Inflammatory Myopathies and Their Major Subgroups. Arthritis Rheumatol (Hoboken, NJ) 2017.2. Parker MJS, Oldroyd A, Roberts ME, Ollier WE, New RP, Cooper RG, et al. 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Ladislau L, Suárez-Calvet X, Toquet S, Landon-Cardinal O, Amelin D, Depp M, et al. JAK inhibitor improves type I interferon induced damage: proof of concept in dermatomyositis. Brain 2018;141:1609–1621. ................
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