University of Manchester



Idiopathic inflammatory myopathies Matthew JS ParkerJames B LillekerMark E RobertsHector ChinoyMatthew JS Parker MBChB MRCP FRACP Clinical Research Fellow, Rheumatology Department, Manchester Academic Health Science Centre, Salford Royal NHS Foundation Trust, Salford, UK. Competing interests: NoneJames B Lilleker MBChB (Hons) MRCP Clinical Research Fellow, The National Institute for Health Research Manchester Musculoskeletal Biomedical Research Unit, Central Manchester University Hospitals NHS Foundation Trust, Manchester Academic Health Science Centre, the University of Manchester, Manchester, UK. Competing interests: NoneMark E Roberts BSc MBChB FRCP MD,Consultant Neurologist, Greater Manchester Neurosciences Centre, Salford Royal NHS Foundation Trust, Manchester Academic Health Science Centre, Salford, UK. Competing interests: NoneHector Chinoy PhD FRCP BMBS MSc BMedSci Honorary Consultant Rheumatologist and Senior Clinical Lecturer, Rheumatology Department, Manchester Academic Health Science Centre, Salford Royal NHS Foundation Trust, Salford, UK and University of Manchester, UK. Competing interests: NoneAbstractIdiopathic inflammatory myopathies represent a rare group of diseases characterized by a central role of autoimmune processes and the inflammation of skeletal muscle. There has been significant recent progress in understanding disease pathogenesis, phenotyping subtypes of disease and investigating effective therapeutic options. Patients typically present with progressive, proximal weakness and functional impairment, and elevated muscle enzymes. There can also have extramuscular manifestations, including skin, respiratory, articular, gastrointestinal and cardiovascular involvement, which can precede or occur in the absence of clinically detectable muscle involvement. There are therefore a multitude of potential differential diagnoses to consider. A conscientious initial evaluation supported by pragmatically structured investigations remains critical to accurate diagnosis and appropriate management of these complex conditions. Key WordsAutoantibodies; dermatomyositis; diagnosis; drug therapy; myositis; polymyositis; prognosisKey PointsIdiopathic inflammatory myopathies (IIM) are characterized by symmetrical inflammatory involvement of the proximal skeletal musclesExtramuscular manifestations include cutaneous, gastrointestinal, articular, pulmonary and cardiovascular involvementSerum autoantibodies are useful in identifying particular IIM subtypes and are helping in the further investigation of pathogenesisCurrent pharmacological treatments are directed at a range of immunological targets, although non-inflammatory pathways can also be important in causing muscle weakness and consequent disabilityIntroductionThe term ‘idiopathic inflammatory myopathies’ (IIM) refers to a group of rare clinico-pathological syndromes characterized by inflammatory damage to skeletal muscle, hence the more commonly employed but less specific synonym ‘myositis’. However, there are often a range of additional multisystem manifestations, and extramuscular manifestations can occur in the absence of skeletal muscle inflammation. Research into these conditions is rapidly advancing understanding, and this review is intended as a clinically focused integration of the currently relevant literature. Aetiology, pathogenesis and risk factorsMuch work has been done to accurately describe the cause of IIM, but a complete understanding has proven elusive. Current working models include the interaction of predisposing genetic influences with largely obscure environmental factors. Worthy of particular mention is the increased frequency of anti-Jo-1 antibodies in patients who are current or previous smokers, and the increased risk of developing anti-HMGCR antibody positive immune-mediated necrotizing myopathy (IMNM) in patients with HLA-DRB1:11*01 who are taking statins. Other observations include an increased incidence of dermatomyositis (DM) in low-latitude areas (closer to the equator), probably because of increased ultraviolet light exposure. There are also reported associations after exposures such as infections, drugs, vaccines, medical devices, physical exertion and emotional stress. The strongest genetic associations identified so far are concentrated in the major histocompatibility complex (MHC) on chromosome 6. These, when combined with identification of disease-specific serum autoantibodies and typical muscle histopathological findings of inflammatory cell infiltrates and upregulated MHC expression, helps to corroborate the central role of autoimmune processes. Although the clinical features of the various IIM subtypes show considerable overlap, the aberrant pathogenic pathways implicated (including type I interferon pathways, protein transcription, translation and post-translational processes, and altered B and T cell function) can be strikingly different.1 EpidemiologyThe rarity of the IIM and variability of classification methods makes their epidemiology challenging to study and to compare over time or between populations. However, IIMs have been described globally and can be considered ubiquitous. Taken collectively, a systematic review estimates the annual incidence of IIM to be 7.98 per million and the prevalence to be 14 per 100,000 persons. There is a general female predominance, with a bi-modal distribution of disease onset in childhood and then in the fifth and sixth decades. Nomenclature and classification criteriaOur understanding of IIM has changed considerably over the last few decades. The most widely applied criteria of Bohan and Peter importantly made the distinction between DM and polymyositis (PM). These criteria were updated in various forms to also discriminate patients with inclusion body myositis (IBM), a subtype of myositis not amenable to immunosuppression. Others have incorporated the now widely available myositis-specific autoantibodies (MSAs; see below) or particular discriminating histological findings to generate criteriaADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1111/joim.12524", "ISSN" : "13652796", "PMID" : "27320359", "abstract" : "The idiopathic inflammatory myopathies (IIMs) are a heterogeneous group of diseases, collectively termed myositis, sharing symptoms of muscle weakness, fatigue and inflammation. Other organs are frequently involved, supporting the notion that these are systemic inflammatory diseases. The IIMs can be subgrouped into dermatomyositis, polymyositis and inclusion body myositis. The myositis-specific autoantibodies (MSAs) identify other and often more distinct clinical phenotypes, such as the antisynthetase syndrome with antisynthetase autoantibodies and frequent interstitial lung disease and anti-SRP and anti-HMGCR autoantibodies that identify necrotizing myopathy. The MSAs are important both to support myositis diagnosis and to identify subgroups with different patterns of extramuscular organ involvement such as interstitial lung disease. Another cornerstone in the diagnostic procedure is muscle biopsy to identify inflammation and to exclude noninflammatory myopathies. Treatment effect and prognosis vary by subgroup. To develop new and better therapies, validated classification criteria that identify distinct subgroups of myositis are critical. The lack of such criteria was the main rationale for the development of new classification criteria for IIMs, which are summarized in this review; the historical background regarding previous diagnostic and classification criteria is also reviewed. As the IIMs are rare diseases with a prevalence of 10 in 100\u00a0000 individuals, an international collaboration was essential, as was the interdisciplinary effort including experts in adult and paediatric rheumatology, neurology, dermatology and epidemiology. The new criteria have been developed based on data from more than 1500 patients from 47 centres worldwide and are based on clinically easily available variables.", "author" : [ { "dropping-particle" : "", "family" : "Lundberg", "given" : "I. E.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Miller", "given" : "F. W.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Tj\u00e4rnlund", "given" : "A.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Bottai", "given" : "M.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Journal of Internal Medicine", "id" : "ITEM-1", "issue" : "1", "issued" : { "date-parts" : [ [ "2016" ] ] }, "page" : "39-51", "title" : "Diagnosis and classification of idiopathic inflammatory myopathies", "type" : "article-journal", "volume" : "280" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "¹⁰", "plainTextFormattedCitation" : "10", "previouslyFormattedCitation" : "¹⁰" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }. A long-running international project (International Myositis Classification Criteria Project) currently has a list of classification criteria undergoing review. Varying nomenclature of IIM subtypes is encountered in the literature and clinical practice; for adult disease, the groups include DM, anti-(tRNA)-synthetase syndrome, IMNM, IBM, myositis with overlap features and PM.AutoantibodiesOne of the most exciting recent developments has been the identification of a range of novel serum autoantibodies in IIM, many of which can be linked to different phenotypes and outcomes. Autoantibodies can now be identified in a large majority of patients with IIM and can be of great help in the initial work-up as well as in providing clues for further research into pathogenic mechanisms. Table 1 lists the relevant autoantibodies; it is beyond the scope of this article to describe their individual significance in more detail, so readers are directed to Betteridge and McHugh’s review.2 Autoantibodies are traditionally separated into MSAs and myositis-associated autoantibodies (MAAs). The latter are present in around 20% of patients and have a lower positive predictive value or indicate another related co-morbid (or ‘overlap’) autoimmune rheumatic condition (e.g. systemic sclerosis, mixed connective tissue disease). Clinical featuresAlthough muscle disease is implicit in the diagnosis of myositis, the extent of muscle disease can be highly variable, and a range of other organ systems can be involved. These should be actively investigated when considering an individual patient. A summary of typical findings is provided in Table 2. Skeletal-muscular – IIM typically cause a symmetrical proximal distribution of weakness with elevated muscle enzymes or proteins (including creatine kinase (CK), lactate deyhdrogenase, alanine aminotransferase and troponin T). There are also typical electromyography (EMG) findings, myoedema on magnetic resonance imaging (MRI) and evidence of an inflammatory infiltrate with muscle damage on biopsy.Cutaneous – a wide variety of different skin manifestation can be present and are usually helpful in identifying the IIM subset of DM. These include the widely appreciated pathognomonic Gottron’s papules (or sign) over the extensor surface of the fingers, the heliotrope rash over the eyelids and the so-called ‘shawl’ or ‘holster’ signs (Figure 1). In clinical practice, the range of abnormalities is much more varied; readers are directed to an excellent review of the topic for further discussion.ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1097/00002281-200311000-00006", "ISBN" : "1040-8711", "ISSN" : "1040-8711", "PMID" : "14569200", "abstract" : "PURPOSE OF REVIEW: Dermatomyositis (DM) is a rare multisystem autoimmune disorder of adults and children that primarily affects skin and skeletal muscle. Classification systems of dermatomyositis, polymyositis, and the other idiopathic inflammatory myopathies focus primarily on features of muscle involvement. However, cutaneous disease does not always parallel muscle disease in its onset, activity, or response to therapy. This review will describe the distinct cutaneous clinical and histopathologic presentation of DM and the relation between these cutaneous findings, pathogenesis of DM, and serological subsets of DM. RECENT FINDINGS: This review discusses recent findings that have begun to elucidate the pathogenesis of DM, including polymorphism of tumor necrosis factor-alpha 308A allele and maternal fetal microchimerism. The recent description of other systemic diseases and drugs causing DM-like eruptions and the recognition that DM can resemble other common dermatoses highlights the need for a cutaneous biopsy to diagnose and distinguish the cutaneous features of DM. Once diagnosed, a number of noninvasive imaging modalities and new cutaneous assessment instruments can be used to follow and evaluate patients with DM. SUMMARY: Recognition of cutaneous and histopathologic findings in DM is essential for prompt and accurate diagnosis and treatment of DM.", "author" : [ { "dropping-particle" : "", "family" : "Santmyire-Rosenberger", "given" : "Beth", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Dugan", "given" : "Elizabeth M", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Current opinion in rheumatology", "id" : "ITEM-1", "issue" : "6", "issued" : { "date-parts" : [ [ "2003" ] ] }, "page" : "714-22", "title" : "Skin involvement in dermatomyositis.", "type" : "article-journal", "volume" : "15" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "¹²", "plainTextFormattedCitation" : "12", "previouslyFormattedCitation" : "¹²" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }3 Gastrointestinal – dysphagia is present in around one-third of IIMs, especially in the subtypes of anti-synthetase syndrome and IBM. When present, dysphagia is responsible for a large burden of morbidity and a substantial proportion of direct disease-related mortality. It is also one of the most treatment-resistant manifestations.Articular – when present, joint involvement usually takes the form of a symmetrical small joint, typically non-erosive polyarthritis. This is more frequent in patients who have myositis with an overlap connective tissue disease or have anti-synthetase syndrome. Pulmonary – interstitial lung disease is present in many patients with IIM and is the most common cause of disease-related death.4 In particular, it is common in anti-synthetase syndrome, detected in as many as 90% of individuals with anti-Jo-1 antibodies; sometimes it is the only clinical manifestation, especially in those with anti-PL-12 and anti-PL-7 antibodies. Cardiovascular – significant confusion can occur when assessing patients for cardiac involvement with IIM as troponins (and other traditionally considered ‘cardiac enzymes’) are also components of the myocyte and are released when skeletal muscle is damaged. In particular, troponin T is expressed by regenerating myocytes and is elevated in active myositis; cardiac-specific troponin I is more discriminatingADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1136/annrheumdis-2014-206812", "ISSN" : "1468-2060", "PMID" : "25732174", "abstract" : "Primary cardiac involvement, an under-recognised manifestation of the idiopathic inflammatory myopathies (IIM) and systemic sclerosis (SSc)-spectrum disorders, is associated with significant mortality. Within these two conditions, traditional skeletal muscle enzyme testing may not effectively distinguish between skeletal and cardiac muscle involvement, especially in patients with subclinical cardiac disease. Accurate biomarkers are thus required to screen for cardiac disease, to better inform both therapeutic decision-making and treatment response. The widespread uptake of cardiac troponin testing has revolutionised the management of acute coronary syndromes. While cardiac troponin I (cTnI) appears specific to the myocardium, cardiac troponin T (cTnT) is also expressed by skeletal muscle, including regenerating skeletal muscle tissue. There is increasing interest about the role of cardiac troponins as a putative biomarker of primary cardiac involvement in IIM and SSc-spectrum disorders. Herewith we discuss subclinical cardiac disease in IIM and SSc-spectrum disorders, the respective roles of cTnI and cTnT testing, and the re-expression of cTnT within regenerating skeletal muscle tissue. There remains wide variation in access to cardiac troponin testing nationally and internationally. We propose two pragmatic clinical pathways using cardiac troponins, preferably measuring concomitant cTnT followed by confirmatory (cardiac) cTnI to screen patients for subclinical cardiac disease and/or low-grade skeletal muscle disease activity, and also an agenda for future research.", "author" : [ { "dropping-particle" : "", "family" : "Hughes", "given" : "Michael", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Lilleker", "given" : "James B", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Herrick", "given" : "Ariane L", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Chinoy", "given" : "Hector", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Annals of the rheumatic diseases", "id" : "ITEM-1", "issue" : "5", "issued" : { "date-parts" : [ [ "2015" ] ] }, "page" : "795-8", "title" : "Cardiac troponin testing in idiopathic inflammatory myopathies and systemic sclerosis-spectrum disorders: biomarkers to distinguish between primary cardiac involvement and low-grade skeletal muscle disease activity.", "type" : "article-journal", "volume" : "74" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "¹⁸", "plainTextFormattedCitation" : "18", "previouslyFormattedCitation" : "¹⁸" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }. Despite this common dilemma, true cardiac involvement in the form of atrioventricular conduction defects, tachyarrhythmias, myocarditis and heart failure is described and more common in, for example, individuals with anti-SRP antibody positive IMNM. This is not an exhaustive description of the extramuscular manifestations of IIM, and any new symptom should prompt an open investigation into the potential involvement of other systems. In particular, approximately 10% of IIMs are associated with malignancy. This is most prevalent in older men with DM, and when specific autoantibodies,particularly against TIF1-γ (transcriptional intermediary factor-1-γ), NXP-2 (nuclear matrix protein-2) and SAE (small ubiquitin-like modifier activating enzyme), are present. Screening for occult malignancy should be patient-specific and informed by local population factors.Differential diagnosisGiven the myriad of possible clinical features and investigation findings, there are many potential diagnoses to actively consider while assessing a patient with possible IIM (often termed ‘myositis mimics’); Table 3 outlines some of these. Easily remedial systemic causes (e.g. thyroid dysfunction, electrolyte disturbance, drug-related myotoxicity) should be excluded in every patient. Other diagnoses are usually hinted at by clues that can be gleaned from a thorough history and shrewd examination; however, further investigation of these patients should usually be by a specialist with an interest in muscle disease. Worthy of special mention is the characteristic pattern of weakness predominantly affecting the finger flexors and knee extensors in patients with IBM. Immunosuppression is of limited or no benefit in these patients and risks substantial adverse effects. InvestigationsWhen considering a patient with possible IIM, investigations should be pragmatically structured to help support the diagnosis and if possible identify the IIM subtype, to exclude important mimics, to establish disease activity and organ-specific complications and to help plan potential treatments. A non-comprehensive list of commonly ordered investigations is provided in Table 4. TreatmentGiven the rarity of and wide clinical spectrum encompassed by IIM, as well as the consequent almost complete lack of randomized controlled placebo or head-to-head trials, it is challenging to develop a unifying treatment approach. There are no widely accepted treatment guidelines, although this is a priority for the future, so clinicians must make choices using the available evidence. Pharmacotherapy is the mainstay of treatment but there is a role for non-pharmacological treatments (including meticulous nursing care, management of aspiration risk and nutrition, exercise regimens and psychosocial support) at all stages of disease. It is salient to stress once more the importance of an accurate diagnosis before instigating pharmacotherapy. It is not uncommon to find that the reason for apparent treatment inefficacy is in fact an alternative diagnosis less modifiable by immunosuppression, for example IBM, a late presentation of inherited or metabolic myopathy or cancer-associated myositis.Treatment can be considered as targeting either remission induction or remission maintenance. Corticosteroids remain the backbone of all but exceptional treatment regimens. However, particular attention must be directed to minimizing their cumulative dose and stopping them once adequate disease control is achieved. Additional treatments can be broadly considered as first line or reserved as second or third line for treatment-refractory disease, intolerance to treatment and treatments with less established evidence for use or an increased incidence of adverse reactions. Figure 2 summarises our approach; however, this is a particularly complex aspect of management, and individual treatment decisions should be carefully considered, ideally by a multidisciplinary specialist team. Readers are also directed to a more comprehensive discussion surrounding the evidence for many of these treatment modalities.5OutcomeMost patients respond well to immunotherapy but do not usually return to full strength on monotherapy and may require long term immune-targeted treatment. Patients with, for example, established fatty infiltration of muscles on MRI or advanced pulmonary fibrosis have unfortunately acquired irreversible damage, so measures of treatment response should be moderated appropriately.Mortality in IIM in general has improved considerably over the last few decades owing to better understanding and awareness of the disease and increasingly effective treatment modalities. However, there remains an increased mortality associated with these conditions. The cumulative 2-year survival rate in a recent Norwegian study was 87% compared with 96% in age- and gender-matched controls, and survival rates continue to be significantly below matched controls at 5- and 10-year intervals. This is largely because of the increased incidence of malignancy in this cohort (see above) as well as organ-specific complications such as aspiration and respiratory failure. However, it also reflects an increased risk of infection related to immunosuppression, and of ischaemic heart disease related to chronic inflammation.KEY REFERENCESADDIN Mendeley Bibliography CSL_BIBLIOGRAPHY 1. Longo DL, Dalakas MC. Inflammatory muscle diseases. N Engl J Med 2015; 372: 1734–47.2. Betteridge Z, McHugh N. Myositis-specific autoantibodies: an important tool to support diagnosis of myositis. J Intern Med 2016; 280: 8–23.3. Dugan EM, Huber AM, Miller FW, Rider LG; International Myositis Assessment and Clinical Studies (IMACS) group. Photoessay of the cutaneous manifestations of the idiopathic inflammatory myopathies. Dermatol Online J 2009; 15: 1.4. Miller SA, Glassberg MK, Ascherman DP. Pulmonary complications of inflammatory myopathy. Rheum Dis Clin North Am 2015; 41: 249–62.5. Moghadam-Kia S, Aggarwal R, Oddis CV. Treatment of inflammatory myopathy: emerging therapies and therapeutic targets. Expert Rev Clin Immunol 2015; 11: 1265–75. Autoantibodies relevant to IIMsMSAs?Anti-synthetase antibodiesAnti-Jo-1, -PL-12, -PL-7, -OJ, -EJ, -KS, -Zo, -Ha?DM-specificAnti-Mi-2, -MDA-5, -NXP2, -TIF1, -SAE ?IMNM-specificAnti-SRP, -HMGCRMAAsAnti-Ro52, -Ro60, -PmScl, -La, -dsDNA, -Sm, -U1-RNP, -Ku, -cN-1ATable 1 MSAs and MAAs Clinical systemHistoryExaminationLocomotorWeakness (usually painless); impaired physical function (difficulty getting out of chair/bed, falls, head drop, impaired ADLs); arthralgia/arthritisProximal > distal weakness and wasting; neck flexion > extension weakness; camptocormia; ‘waddling’ gait; synovitisCardiorespiratoryBreathlessness on exertion; cough; orthopnoea (implying respiratory muscle involvement or congestive cardiac failure); symptoms of CO2 retentionSigns of pulmonary fibrosis and/or respiratory failure; dysphonia; arrhythmia or signs of congestive cardiac failureGastrointestinal Dysphagia (both pharyngeal and distal oesophageal characteristics); altered bowel habit; weight lossUnusual to have specific findings except features of malnutritionCutaneousPhotosensitivity, new rash, cutaneous ulcersRash on extensor surfaces, scalp, face (especially ‘heliotrope’ distribution), chest and back; calcinosisTable 2 Typical history and examination findings in IIMADL, activities of daily living.Differential diagnosisInheritedMuscular dystrophies*, myotonic dystrophies*, channelopathies*MetabolicMitochondrial*, glycogen storage disorders*, fatty acid oxidation defects*EndocrinopathiesHyper/hypothyroidism*, Cushing’s syndrome, Addison’s syndrome, acromegalyToxicCorticosteroids, statins*, antimalarials*, colchicine*, penicillamine*, antiretrovirals*, alcohol*InfectiveHIV*, acute viral or bacterial infections*, trichinellosis*Neuromuscular junctionMyasthenia gravis, Lambert–Eaton syndromeMiscellaneousMalignant hyperthermia*, motor neurone disease*, certain neuropathies*, diabetic amyotrophy/plexopathy*, sarcoidosis*, amyloidosis*, neuroleptic malignant syndrome*, exertional*, ethnic variation*, chronic graft-versus-host disease*Table 3 Differential diagnosis of IIM – ‘muscle mimics’*Conditions that also typically cause a raised CK (>1.5 × upper limit of normal)Investigation category Specific Investigation and/or findingsBlood testsCK, ESR, CRP, ANA, ENAs, ANCA, MSAs, MAAsFull blood count, urea and electrolytes (including Ca2+ and Mg2+), liver and thyroid function tests, 25-OH-vitamin D EMGMyopathic features (small motor unit action potentials, abnormal fibrillation potentials, positive sharp waves, etc) MRIInclude axial fat-suppressed STIR sequence for myoedema and T1-weighted sequences for fatty replacementMuscle biopsyFindings vary considerably but usually include myopathic features (e.g. fibre size variation), signs of inflammation (e.g. upregulated MHC, inflammatory cell infiltrate, complement deposition) and/or fibre necrosisOrgan specific Involvement:CutaneousGastrointestinalPulmonaryCardiacSkin biopsy, nailfold capillaroscopySwallow assessment, barium swallowChest X-ray, pulmonary function tests, high-resolution computed tomography,Troponin I, ECG, echocardiogram, cardiac MRITable 4 Suggested initial investigations in suspected IIMANA, antinuclear antibody; ANCA, antineutrophil cytoplasmic antibody; ENA, extractable nuclear antigens; ESR, erythrocyte sedimentation rate; STIR, short-tau inversion recoveryFigure 1 Typical cutaneous manifestations of dermatomyositis. (a) Gottron’s papules. (b) ‘Shawl sign’. (c) Gottron’s sign over the extensor aspect of both knees. (d) ‘Heliotrope’ rash. Adapted with permission from Dugan et al.ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "author" : [ { "dropping-particle" : "", "family" : "Dugan", "given" : "EM", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Huber", "given" : "AM", "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" : "" } ], "container-title" : "Dermatology online journal", "id" : "ITEM-1", "issue" : "2", "issued" : { "date-parts" : [ [ "2009" ] ] }, "page" : "1", "title" : "Photoessay of the idiopathic inflammatory myopathies", "type" : "article-journal", "volume" : "15" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "²³", "plainTextFormattedCitation" : "23" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }3Figure 2 Step-wise approach to remission induction and maintenance pharmacotherapy in IIM. ‘Early’ relapse occurs if the patient at the time remains on prednisolone ≥20 mg daily or equivalent; ‘late’ relapse occurs when the patient is taking <20 mg prednisolone daily or equivalent. IVIg, intravenous immunoglobulin.TEST YOURSELFTo test your knowledge based on the article you have just read, please complete the questions below. The answers can be found at the end of the issue or online hereQuestion 1A 74-year-old man presented with a number of recent falls. He also had difficulty carrying his shopping bags, often slinging them over his elbow, and opening jars of food. He had experienced a choking sensation when eating and occasional regurgitation of food. On clinical examination, he had weakness predominantly affecting the flexor muscles of his forearms and the quadriceps. There was no evidence of fasciculations, and his reflexes were normal bilaterally.What is the most likely diagnosis?A PolymyositisB Inclusion body myositisC Motor neurone diseaseD Myasthenia gravisE HypothyroidismCorrect answer: B. This is a classic presentation for inclusion body myositis (IBM) with distal upper limb and proximal lower limb weakness and a lack of other features suggesting an alternative differential diagnosis. Specifically, the pattern of distal upper limb involvement is unusual for polymyositis. The absence of fasciculations and normal reflexes makes motor neurone disease less likely. Although an important differential, myasthenia gravis is also less likely given the distal upper limb involvement and no mention of fatiguability or extra-ocular muscle involvement. Hypothyroidism would classically result in the delayed relaxation of deep tendon reflexes (‘Woltman’s sign’). This is an important subtype of IIM that does not respond to immunosuppression.Question 2A 50-year-old woman presented with breathlessness, most pronounced when lying flat, and a new headache, especially in the morning. She had been found to have dermatomyositis based upon findings of a pathognomonic rash, a proximal pattern of muscular weakness, positive anti-Mi-2 antibody and a supportive muscle biopsy. On examination, she did not appear dyspnoeic, and auscultation of her precordium and chest did not reveal any abnormality. Investigation?Serum troponin T 650 microgram/litre (<0.01) What is the most likely cause of her breathlessness?A Interstitial lung diseaseB Pulmonary artery hypertensionC MyopericarditisD Respiratory muscle weaknessE Multiple small pulmonary emboliCorrect answer: D. The patient described symptoms that are classic for respiratory muscle weakness and diaphragmatic involvement in particular. The raised troponin T concentration is most likely caused by skeletal muscle involvement given the clinical features described. Specifically, interstitial lung disease and myopericarditis would be expected to have particular findings on clinical examination which are absent in this case. Pulmonary artery hypertension, myopericarditis if it results in pulmonary oedema and pulmonary emboli would usually not be associated with hypercapnoea which is implied with her symptom of early morning headaches. This is an important presentation to recognize to avoid iatrogenic harm or missing impending respiratory failure.Question 3A 68-year-old woman presented with a 2-month history of difficulty climbing stairs and reaching up to her kitchen shelves. The statin she had been taking for secondary cardiovascular protection was implicated and had been stopped 6 weeks previously; however, her symptoms had worsened. Investigations?Serum creatine kinase 8000 U/litre (24–170) ?Alanine aminotransferase 430 U/litre (5–35) ?Anti-HMGCR antibody positiveWhat is the most appropriate treatment strategy at this stage?A Conservative – having ceased the statin, she should improve spontaneouslyB Co-enzyme Q10 supplementationC Oral prednisolone 0.75 mg/kg dailyD Urgent gastroenterology referralE Rituximab (anti-CD20 monoclonal antibody) 1 g intravenously, repeated in 2 weeksCorrect answer: C. The patient has the features of a statin-induced immune-mediated necrotizing myopathy (IMNM), recently described as being associated with the anti-HMGCR antibody. First-line immunotherapy with glucocorticoids is appropriate while further investigations are undertaken, although many cases of IMNM ultimately require more aggressive immunotherapy. Specifically, in contrast to the other significantly more common statin-induced myotoxicities, the positive antibody result and implicit triggering of autoimmune processes infers that the presentation will not improve spontaneously with statin cessation. Although opinion on the utility of Co-enzyme Q10 in managing certain statin associated symptoms is divided, there is no clear indication for it in this case. Muscle damage from any process releases alanine aminotransferase; it is not uncommon for such patients to present first to gastroenterologists with abnormal ‘liver function tests’ before creatine kinase levels are checked and the cause becomes apparent. Rituximab is currently considered a second or third line treatment and it would be unusual to use it as monotherapy first line, especially as it can take weeks before resulting in clinical improvements. ................
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