Recent advances in myositis Dr Hector Chinoy PhD FRCP @drhectorchinoy Senior Lecturer / Honorary Consultant Rheumatologist Salford Royal NHS Foundation Trust Manchester Academic Health Science Centre The University of Manchester, UK Planned Layout what is myositis? how do we classify myositis? myositis disease spectrum antibodies case presentations how do we assess and treat myositis? Planned Layout what is myositis? how do we classify myositis? myositis disease spectrum antibodies case presentations how do we assess and treat myositis? Idiopathic inflammatory myopathy (IIM): A heterogeneous group of rare autoimmune muscle disorders Rare disease, annual Different IIM subtypes with incidence 5-10/million commonality of myositis 2 peaks of onset: Extra - muscular features (5-15 years) eg skin, lung, cardiac, (30-50 years) malignancy Patterns of disease Lack of evidence base for (rule of 1/3’s): treatment Monogenic Steroid & immunoresponsive Relapsing/remitting Treatment phases: induction/maintenance of remission Chronic persistent How do patients’ present with inflammatory myopathy? Insidious onset of proximal weakness Myalgia Fatigue Dysphagia Dyspnoea Weight loss Skin abnormalities (including ulceration) Raynaud’s Dry, cracked hands Arthralgia/arthritis Creatine Features of Myositis ATP ATP Creatine Kinase + ADP ADP + H Creatine phosphate Clues on bloods Low creatinine High ferritin High ALT Raised Troponin T Negative ANA Many causes of raised CK! 1. Muscle trauma a) Muscle injury / Needle stick b) EMG c) Surgery d) Convulsions, delirium tremens 2. Diseases affecting muscle a) Myocardial infarction f) Dystrophinopathies b) Rhabdomyolysis h) Amyotrophic lateral sclerosis g) Infectious myositis i) Neuromyotonias c) Metabolic myopathies h) Idiopathic inflammatory d) Carnitine palmityltransferase myopathy II deficiency e) Mitochondrial myopathies 3. Drug/toxin-induced a) Lipid-lowering agents, especially statins myopathy b) Alcoholic myopathy c) Drugs of abuse: e.g. cocaine, amphetamines, phencyclidine d) Malignant hyperthermia / neuroleptic malignant syndrome e) Other meds: e.g. zidovudine, colchicine, chloroquine, ipecac 4. Drug-induced CK elevation Inhibition of excretion: e.g. barbiturates, morphine, diazepam 5. Endocrine and metabolic a) Hypothyroidism abnormalities b) Hypokalemia c) Hyperosmolar state or ketoacidosis d) Diabetic nephrotic syndrome with oedema e) Renal failure 6. Elevation without disease a) Strenuous, prolonged, and/or unaccustomed exercise b) Ethnic group (black > white) c) Increased muscle mass Adapted from Targoff 2002 Differential diagnosis of muscle weakness Inherited myopathies Muscular dystrophies: Duchenne’s, fascioscapulohumeral, limb girdle, Becker’s, Emery Dreifuss, distal, ocular Congenital myopathies: nemaline, mitochondrial, centronuclear, central core Neurologic Denervating conditions: spinal muscular atrophies, amyotrophic lateral sclerosis Neuromuscular junction disorders: Eaton-Lambert syndrome, myasthenia gravis Myotonic disease: dystrophia myotonica, myotonia congenita, PROMM Other: Guillain-Barre syndrome, chronic autoimmune polyneuropathy Metabolic Glycogen storage diseases: acid maltase deficiency, McArdle’s, PFK Lipid storage myopathies: carnitine palmityltransferase II deficiency Nutritional: vitamin E deficiency, malabsorption Other: uraemia, hepatic failure, alcoholism, acute intermittent porphyria, diabetic plexopathy Endocrine Hyper/hypothyroidism, acromegaly, Cushing’s syndrome, Addison’s disease, myopathies vitamin D deficiency, hyper/hypocalcaemia, hypokalaemia Drug-induced Statins, D-penicillamine, clofibrate, chloroquine, amiodarone, vincristine, zidovudine myopathies Infections Acute viral: influenza, hep B, echovirus, rickettsia, coxsackie, rubella, vaccines Bacterial pyomyositis: staphylococcus, streptococcus, clostridium perfringens, leprosy Parasites: toxoplasma, trichinella, schistosoma, cysticercus Other CTDs Rheumatoid arthritis, systemic sclerosis, systemic lupus erythematosus Miscellaneous Periodic paralyses, carcinomatous neuromyopathy, acute rhabdomyolysis, myositis ossificans, microembolisation by atheroma or carcinoma Oddis CV, Rheum Dis Clin North Am 2002;28:979-1001 what is myositis? how do we classify myositis? myositis disease spectrum antibodies case presentations how do we assess and treat myositis? Polymyositis Necrotizing Myopathy Dermatomyositis Inclusion Body Myositis Idiopathic Malignancy Inflammatory Myopathy Myositis-CTD overlap Juvenile dermatomyositis Bohan and Peter diagnostic criteria for polymyositis / dermatomyositis 1 Symmetrical weakness of limb-girdle muscles and anterior neck flexors 2 Muscle biopsy evidence typical of myositis 3 Elevation of serum skeletal muscle enzymes, particularly CK 4 Typical EMG features of myositis 5 Typical DM rash, including heliotrope and Gottron’s papules For the diagnosis of PM: For the diagnosis of DM: 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 Exclusion criteria: congenital muscular dystrophies, central or peripheral neurological disease, infectious myositis, metabolic/endocrine myopathies and myasthenia gravis. Bohan A, Peter JB, N Eng J Med 1975 New classification criteria for myositis Tjarnlund et al, Ann Rheum Dis 2013 Vol 72, suppl 3, p60 http://www.imm.ki.se/ biostatistics/calculators/iim/ Extra-muscular features of Inflammatory Myopathy 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 Myositis: effects of muscle damage Photo courtesy of Prof R Cooper Heliotrope rash Violaceous to erythematous discrete or confluent macules confined to the upper eyelids Gottron’s papules Erythematous to violaceous papules and plaques over the extensor surfaces of MCP and IP joints & other large joints in a symmetric distribution Nail changes V / Shawl sign Discrete, confluent macular erythema over lower anterior neck, upper anterior chest & shawl distribution V SIGN SHAWL SIGN what is myositis? how do we classify myositis? myositis disease spectrum antibodies case presentations how do we assess and treat myositis? Myositis-Spectrum Disease Autoantibodies Autoantibody formation HLA Other genes Specific signs Infections & symptoms UV Environmental risk factors Slide adapted from Dr Gunawardena Hood E: Environ Health Perspect 2003, 111:A274–A276. Always worth Checking ANA pattern for clues Gunawardena H. The Clinical Features of Myositis-Associated Autoantibodies: a Review. Clin Rev Allergy Immunol. 2017 Feb;52(1):45-57. Myositis Spectrum Disease Antibodies & Clinical Associations in Adult Myositis Betteridge Z, McHugh N. Myositis-specific autoantibodies: an important tool to support diagnosis of myositis. J Intern Med. 2016 Jul;280(1):8-23 Anti-synthetase / anti-PM-Scl: Remember Interstitial Lung Disease Jo-1: anti-synthetase syndrome PM-Scl: myositis/scleroderma overlap syndrome Pictures courtesy of Drs Herrick, Oddis & Wedderburn Anti-synthetase / anti-PM-Scl: Remember Interstitial Lung Disease Jo-1: anti-synthetase syndrome REMEMBER - PATIENTS MAY PRESENT WITHOUT CLINICAL MYOSITIS PM-Scl: myositis/scleroderma overlap syndrome Pictures courtesy of Drs Herrick, Oddis & Wedderburn Anti-MDA5 (anti-CADM140) Reported Clinical Associations ILD (67-100%) Rapidly Progressing ILD (RP-ILD) (22- 100%) Skin manifestations Gottron’s Papules Periungal Ulceration (skin and mouth) Hand Swelling Arthritis JDM Associations Palmar Papules Skin and Oral Ulcers Mechanics’ Hands No known association with Periungal, Gottron’s Papules, Arthritis or Alopecia Panniculitis ILD? AlopeciaFiorentino et al J Am Acad Dermatol 2011;65:25-34 Sato et al Arthritis Rheum 2005;52:1571-6 Nakashima et al Rheumatol 2010;49:433-40 Slide adapted from Dr Betteridge Kobayashi et al J Pediatr 2011;158:675-7 Anti-TIF1g: diagnostic utility in cancer associated myositis Pooled sensitivity for cancer-associated myositis SENSITIVITY SPECIFICITY 0.78 0.89 Trallero-Araguás et al, Arthritis Rheum 2012;64:523–532 what is myositis? how do we classify myositis? myositis disease spectrum antibodies case presentations how do we assess and treat myositis? Case 1: Mrs SH • 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 MR images T1 STIR Muscle biopsy H&E stained section showing necrotic fibres with macrophage infiltrates Clinical features of anti-HMG CoA reductase (HMGCR) positive patients (45/750, 6%) Features Anti-HMGCR Ab not found Age 52 ± 16 years in majority of statin- treated subjects, including Female 58% those with self-limited Statin exposure 30/45 (67%) statin-associated myopathy (24/26, 92% >50 years) CPK 9,718 ± 7,383 iu/l Strong HLA association Cases v controls analysis (41:164) Proximal weakness 96% HLA-DRB1*11 Irritable EMG 73% p=4.29X10-5, OR=5.60, 95% CI=2.62-12.63 (unpublished data, our lab) Necrosis on biopsy 100% Inflammation on 20% biopsy Mammen A et al. Arthritis Rheum 2011;63:713-721 Mammen A et al. Arthritis Care Res (Hoboken). 2012;64:269-72 Statin-related myotoxicity phenotype classification Alfirevic