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01/06/2017 Planned Layout Planned Layout what is myositis? what is myositis? Connective tissue disorders how do we classify myositis? how do we classify myositis? myositis disease spectrum antibodies myositis disease spectrum antibodies Dr Hector Chinoy PhD FRCP case presentations case presentations @drhectorchinoy Senior Lecturer / Honorary Consultant Rheumatologist how do we assess and treat myositis? how do we assess and treat myositis? Salford Royal NHS Foundation Trust Manchester Academic Health Science Centre The University of Manchester, UK Idiopathic inflammatory myopathy (IIM): How do patients’ present with inflammatory myopathy? Creatine Features of Myositis A heterogeneous group of rare autoimmune muscle disorders Insidious onset of proximal ATP ATP weakness Myalgia Creatine Kinase Rare disease, annual Different IIM subtypes with ADP + H + ADP incidence 5-10/million commonality of myositis Fatigue 2 peaks of onset: Extra-muscular features Dysphagia Creatine phosphate (5-15 years) eg skin, lung, cardiac, Dyspnoea (30-50 years) malignancy Weight loss Skin abnormalities Patterns of disease (including ulceration) Lack of evidence base for Raynaud’s (rule of 1/3’s) : treatment Monogenic Dry, cracked hands Steroid & immunoresponsive Relapsing/remitting Treatment phases: Arthralgia/arthritis induction/maintenance of remission Chronic persistent Many causes of raised CK! Differential diagnosis of muscle weakness Clues on bloods 1. Muscle trauma a) Muscle injury / Needle stick Inherited myopathies Muscular dystrophies: Duchenne’s , fascioscapulohumeral , limb girdle, Becker’s, b) EMG Emery Dreifuss, distal, ocular c) Surgery Congenital myopathies: nemaline, mitochondrial, centronuclear, central core d) Convulsions, delirium tremens Neurologic Denervating conditions: spinal muscular atrophies, amyotrophic lateral sclerosis  Low creatinine 2. Diseases affecting muscle a) Myocardial infarction f) Dystrophinopathies Neuromuscular junction disorders: Eaton-Lambert syndrome, myasthenia gravis b) Rhabdomyolysis h) Amyotrophic lateral sclerosis Myotonic disease: dystrophia myotonica, myotonia congenita, PROMM  High ferritin g) Infectious myositis i) Neuromyotonias Other: Guillain-Barre syndrome, chronic autoimmune polyneuropathy c) Metabolic myopathies h) Idiopathic inflammatory d) Carnitine palmityltransferase myopathy Metabolic Glycogen storage diseases: acid maltase deficiency, McArdle’s , PFK  High ALT II deficiency Lipid storage myopathies: carnitine palmityltransferase II deficiency e) Mitochondrial myopathies Nutritional: vitamin E deficiency, malabsorption Other: uraemia, hepatic failure, alcoholism, acute intermittent porphyria, diabetic  Raised Troponin T 3. Drug/toxin-induced a) Lipid-lowering agents, especially statins plexopathy myopathy b) Alcoholic myopathy Endocrine Hyper/hypothyroidism, acromegaly, Cushing’s syndrome, Addison’s disease, c) Drugs of abuse: e.g. cocaine, amphetamines, phencyclidine  Negative ANA d) Malignant hyperthermia / neuroleptic malignant syndrome myopathies vitamin D deficiency, hyper/hypocalcaemia, hypokalaemia e) Other meds: e.g. zidovudine, colchicine, chloroquine, ipecac Drug-induced Statins, D-penicillamine, clofibrate, chloroquine, amiodarone, vincristine, zidovudine myopathies 4. Drug-induced CK elevation Inhibition of excretion: e.g. barbiturates, morphine, diazepam Infections Acute viral: influenza, hep B, echovirus, rickettsia, coxsackie, rubella, vaccines Bacterial pyomyositis: s taphylococcus, streptococcus, clostridium perfringens , 5. Endocrine and metabolic a) Hypothyroidism leprosy abnormalities b) Hypokalemia Parasites: toxoplasma, trichinella, schistosoma, cysticercus c) Hyperosmolar state or ketoacidosis Other CTDs Rheumatoid arthritis, systemic sclerosis, systemic lupus erythematosus d) Diabetic nephrotic syndrome with oedema e) Renal failure Miscellaneous Periodic paralyses, carcinomatous neuromyopathy, acute rhabdomyolysis, myositis 6. Elevation without disease a) Strenuous, prolonged, and/or unaccustomed exercise ossificans, microembolisation by atheroma or carcinoma b) Ethnic group (black > white) Oddis CV, Rheum Dis Clin North Am 2002;28:979-1001 c) Increased muscle mass Adapted from Targoff 2002 1

01/06/2017 Bohan and Peter diagnostic criteria for Necrotizing Myopathy Polymyositis Dermatomyositis polymyositis / dermatomyositis Inclusion Body Myositis 1 Symmetrical weakness of limb-girdle muscles and anterior what is myositis? neck flexors 2 Muscle biopsy evidence typical of myositis how do we classify myositis? 3 Elevation of serum skeletal muscle enzymes, particularly CK Idiopathic Malignancy 4 Typical EMG features of myositis myositis disease spectrum antibodies Inflammatory 5 Typical DM rash, including heliotrope and Gottron’s papules Myopathy For the diagnosis of PM: For the diagnosis of DM: case presentations Definite: All of items 1-4 Definite: Item 5 plus 3 of items 1-4 . Probable: 3 of items 1-4 Probable: Item 5 plus 2 of items 1-4 Possible: 2 of items 1-4 Possible: Item 5 plus 1 of items 1-4 how do we assess and treat myositis? Exclusion criteria: congenital muscular dystrophies, central or peripheral neurological disease, Juvenile dermatomyositis infectious myositis, metabolic/endocrine myopathies and myasthenia gravis. Myositis-CTD overlap Bohan A, Peter JB, N Eng J Med 1975 Extra-muscular features of Inflammatory Myopathy Gottron’s papules Nail changes Erythematous to violaceous papules and plaques over the extensor surfaces of MCP and IP joints & other large joints in a symmetric distribution Hughes M, Lilleker JB, Herrick AL, Chinoy H. 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. Slides courtesy of IMACS, Prof Oddis & McHugh Ann Rheum Dis. 2015 May;74(5):795-8 http://www.cytoskeleton.com/tropomyosin-troponin-complex-cs-tt05 Source: IMACS Always worth Myositis-Spectrum Disease Autoantibodies Checking ANA pattern for clues what is myositis? Autoantibody how do we classify myositis? formation HLA myositis disease spectrum antibodies Other genes Specific signs Infections & symptoms case presentations UV how do we assess and treat myositis? Environmental risk factors Gunawardena H. The Clinical Features of Myositis-Associated Autoantibodies: a Review. Slide adapted from Dr Gunawardena Hood E: Environ Health Perspect 2003, 111:A274 – A276. Clin Rev Allergy Immunol. 2017 Feb;52(1):45-57. 2

01/06/2017 Anti-TIF1g: diagnostic utility in cancer associated myositis Myositis Spectrum Disease Antibodies & Clinical Associations in Adult Myositis Pooled sensitivity for cancer-associated myositis SENSITIVITY SPECIFICITY what is myositis? how do we classify myositis? myositis disease spectrum antibodies case presentations how do we assess and treat myositis? 0.78 0.89 Betteridge Z, McHugh N. Myositis-specific autoantibodies: an important tool to support diagnosis of myositis. Trallero-Araguás et al , Arthritis Rheum 2012;64:523 – 532 J Intern Med. 2016 Jul;280(1):8-23 MR images Case 1: Mrs SH Muscle biopsy • 57 year old female, type II DM • 1 year post-simvastatin • 3 month history of marked proximal weakness • CK 11,384 • EMG: fibrillations & brief duration simple and complex motor unit potentials T1 STIR H&E stained section showing necrotic fibres with macrophage infiltrates Clinical features of anti-HMG CoA reductase (HMGCR) Statin-related myotoxicity phenotype classification Statin-related myotoxicity phenotype classification positive patients (45/750, 6%) Features Anti-HMGCR Ab not Age 52 ± 16 years found in majority of Female 58% statin-treated Statin exposure 30/45 (67%) subjects, including (24/26, 92% >50 years) those with self- CPK 9,718 ± 7,383 iu/l limited statin- Proximal weakness 96% associated Necrosis on biopsy 100% myopathy Inflammation on 20% biopsy Alfirevic A, Neely D, Armitage J, Chinoy H, Cooper RG, Laaksonen R, et al. Alfirevic A, Neely D, Armitage J, Chinoy H, Cooper RG, Laaksonen R, et al. Mammen A et al . Arthritis Rheum 2011;63:713-721 Clin Pharmacol Ther. 2014 Oct;96(4):470-6. doi: 10.1038/clpt.2014.121. Clin Pharmacol Ther. 2014 Oct;96(4):470-6. doi: 10.1038/clpt.2014.121. Mammen A et al . Arthritis Care Res (Hoboken). 2012;64:269-72 3