Recent advances in myositis

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1 Recent advances in myositis Dr Hector Chinoy PhD Senior Lecturer / Honorary Consultant Rheumatologist Salford Royal NHS Foundation Trust Manchester Academic Health Science Centre The University of Manchester, UK

2 Planned Layout what is myositis? how do we classify myositis? myositis disease spectrum antibodies case presentations how do we assess and treat myositis?

3 Planned Layout what is myositis? how do we classify myositis? myositis disease spectrum antibodies case presentations how do we assess and treat myositis?

4 Idiopathic inflammatory myopathy (IIM): A heterogeneous group of rare autoimmune muscle disorders Rare disease, annual incidence 5-10/million 2 peaks of onset: (5-15 years) (30-50 years) Different IIM subtypes with commonality of myositis Extra-muscular features eg skin, lung, cardiac, malignancy Patterns of disease (rule of 1/3 s): Monogenic Relapsing/remitting Chronic persistent Lack of evidence base for treatment Steroid & immunoresponsive Treatment phases: induction/maintenance of remission

5 How do patients present with inflammatory myopathy? Insidious onset of proximal weakness Dyspnoea Fatigue Skin abnormalities (including ulceration) Myalgia Dysphagia Weight loss Raynaud s Dry, cracked hands Arthralgia/arthritis

6 ATP ADP Creatine ATP ADP + H + Features of Myositis Creatine Kinase Creatine phosphate

7 Clues on bloods Low creatinine High ferritin High ALT Raised Troponin T Negative ANA

8 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 b) Rhabdomyolysis g) Infectious myositis c) Metabolic myopathies d) Carnitine palmityltransferase II deficiency e) Mitochondrial myopathies 3. Drug/toxin-induced myopathy f) Dystrophinopathies h) Amyotrophic lateral sclerosis i) Neuromyotonias h) Idiopathic inflammatory myopathy a) Lipid-lowering agents, especially statins 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 abnormalities a) Hypothyroidism 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

9 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 Endocrine myopathies Drug-induced myopathies Infections Other CTDs Miscellaneous 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 Hyper/hypothyroidism, acromegaly, Cushing s syndrome, Addison s disease, vitamin D deficiency, hyper/hypocalcaemia, hypokalaemia Statins, D-penicillamine, clofibrate, chloroquine, amiodarone, vincristine, zidovudine Acute viral: influenza, hep B, echovirus, rickettsia, coxsackie, rubella, vaccines Bacterial pyomyositis: staphylococcus, streptococcus, clostridium perfringens, leprosy Parasites: toxoplasma, trichinella, schistosoma, cysticercus Rheumatoid arthritis, systemic sclerosis, systemic lupus erythematosus Periodic paralyses, carcinomatous neuromyopathy, acute rhabdomyolysis, myositis ossificans, microembolisation by atheroma or carcinoma Oddis CV, Rheum Dis Clin North Am 2002;28:

10 what is myositis? how do we classify myositis? myositis disease spectrum antibodies case presentations how do we assess and treat myositis?

11 Polymyositis Inclusion Body Myositis Necrotizing Myopathy Dermatomyositis Idiopathic Inflammatory Myopathy Malignancy Myositis-CTD overlap Juvenile dermatomyositis

12 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: Definite: Probable: Possible: All of items of items of items 1-4 For the diagnosis of DM: Definite: Probable: Possible: Item 5 plus 3 of items 1-4 Item 5 plus 2 of items 1-4 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

13 New classification criteria for myositis Tjarnlund et al, Ann Rheum Dis 2013 Vol 72, suppl 3, p60 biostatistics/calculators/iim/

14 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. Ann Rheum Dis May;74(5):795-8 Slides courtesy of IMACS, Prof Oddis & McHugh

15 Myositis: effects of muscle damage Photo courtesy of Prof R Coop

16 Heliotrope rash Violaceous to erythematous discrete or confluent macules confined to the upper eyelids

17 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

18 Nail changes

19 V / Shawl sign Discrete, confluent macular erythema over lower anterior neck, upper anterior chest & shawl distribution V SIGN SHAWL SIGN

20 what is myositis? how do we classify myositis? myositis disease spectrum antibodies case presentations how do we assess and treat myositis?

21 Myositis-Spectrum Disease Autoantibodies Autoantibody HLA formation Other genes Infections UV Specific signs & symptoms Environmental risk factors Slide adapted from Dr Gunawardena Hood E: Environ Health Perspect 2003, 111:A274 A276.

22 Always worth Checking ANA pattern for clues Gunawardena H. The Clinical Features of Myositis-Associated Autoantibodies: a Review. Clin Rev Allergy Immunol Feb;52(1):45-57.

23 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 Jul;280(1):8-23

24 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

25 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

26 Reported Clinical Associations ILD (67-100%) Rapidly Progressing ILD (RP-ILD) (22-100%) Anti-MDA5 (anti-cadm140) Skin manifestations Gottron s Papules Periungal Ulceration (skin and mouth) Hand Swelling Arthritis Palmar Papules Mechanics Hands Panniculitis Alopecia Fiorentino et al J Am Acad Dermatol 2011;65:25-34 Sato et al Arthritis Rheum 2005;52: Nakashima et al Rheumatol 2010;49: Kobayashi et al J Pediatr 2011;158:675-7 JDM Associations Skin and Oral Ulcers No known association with Periungal, Gottron s Papules, Arthritis or Alopecia ILD? Slide adapted from Dr Betteridge

27 Anti-TIF1g: diagnostic utility in cancer associated myositis SENSITIVITY Pooled sensitivity for cancer-associated myositis SPECIFICITY Trallero-Araguás et al, Arthritis Rheum 2012;64:

28 what is myositis? how do we classify myositis? myositis disease spectrum antibodies case presentations how do we assess and treat myositis?

29 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

30 MR images T1 STIR

31 Muscle biopsy H&E stained section showing necrotic fibres with macrophage infiltrates

32 Clinical features of anti-hmg CoA reductase (HMGCR) positive patients (45/750, 6%) Features Age Female 58% 52 ± 16 years Statin exposure 30/45 (67%) (24/26, 92% >50 years) CPK Proximal weakness 96% Irritable EMG 73% Necrosis on biopsy 100% Inflammation on biopsy 9,718 ± 7,383 iu/l 20% Anti-HMGCR Ab not found in majority of statintreated subjects, including those with self-limited statin-associated myopathy Strong HLA association Cases v controls analysis (41:164) HLA-DRB1*11 p=4.29x10-5, OR=5.60, 95% CI= (unpublished data, our lab) Mammen A et al. Arthritis Rheum 2011;63: Mammen A et al. Arthritis Care Res (Hoboken). 2012;64:269-72

33 Statin-related myotoxicity phenotype classification Alfirevic A, Neely D, Armitage J, Chinoy H, Cooper RG, Laaksonen R, et al. Clin Pharmacol Ther Oct;96(4): doi: /clpt

34 Statin-related myotoxicity phenotype classification Alfirevic A, Neely D, Armitage J, Chinoy H, Cooper RG, Laaksonen R, et al. Clin Pharmacol Ther Oct;96(4): doi: /clpt

35 Case 2: Mr HW 81 year old male 2 year history progressive muscle weakness Unable to dress himself, loss of grip CK 450 Quads / forearm wasting Wrist flexor weakness Prednisolone 30mg for 6/52 no difference

36 MR thigh images T1 STIR

37 Two vacuolated fibres with basophilic rimming, one with an amphophilic inclusion body (H&E x60)

38 Features of sporadic Inclusion Body Myositis >50, male predominance Slowly progressive, affects distal & proximal musculature, often asymmetrically Selective quads & finger flexor weakness CK < 5x ULN Tend to be antibody negative, but may be Ro+ Not immunoresponsive

39 what is myositis? how do we classify myositis? myositis disease spectrum antibodies case presentations how do we assess and treat myositis?

40 Myositis Core Set Measures 1. Manual muscle testing (MMT-8) 2. Patient global visual analogue scale recorded on a 10cm scale 3. Physician global visual analogue scale recorded on a 10cm scale 4. Health Assessment Questionnaire disability index 5. At least one muscle enzyme (CK, AST, ALT, aldolase, LDH) 6. Global extramuscular disease activity (composite of constitutional, cutaneous, skeletal, gastrointestinal, pulmonary and cardiac activity) score recorded on 10cm VAS scale on Myositis Disease Activity Assessment Tool (MDAAT)) Rider LG et al. Arthritis Rheum 2004;50:

41 Version 1.0 SEPT 2009 Study ID: Study Visit Date: / / Study visit number (Circle): 1, 2, 3, 4, 5, 6, 7 MANUAL MUSCLE TESTING Completed by: Consultant Completed for: All patients Completed at: All study visits MMT SCORING: Muscle groups Left (0-10) Right (0-10) Axial (0-10) Axial (0-20) Neck Flexors - - MMT8** Neck Extensors - - Proximal (0-160) Shoulder elevators (Trapezius) - Shoulder abductors (Deltoid Middle) MMT8** - Elbow flexors (Bicepts Brachii) MMT8** - Hip extensors (Gluteus Maximus) MMT8** - Hip abductors (Gluteus Medius) MMT8** - Hip flexors (Iliopsoas) - Knee flexors (Hamstrings) - Knee extensors (Quadriceps) MMT8** - Distal (0-80) Wrist Extensors MMT8** - Wrist Flexors - Ankle Dorsiflexors MMT8** - Ankle Plantar Flexors - MMT MMT8 highlighted in boxes (MMT8**) MMT Axial + Proximal + Distal (all 26) MMT GRADING: FUNCTION OF THE MUSCLE GRADE No No contraction felt in muscle 0 / 0 Movement Feeble contraction felt in muscle, but no movement of part T / 1 MOVEMENT IN HORIZONTAL PLANE Test Moves through partial range of motion 1 / 2- Movement Moves through complete range of motion 2 / 2 ANTIGRAVITY POSITION Moves through partial range of motion 3 / 2+ Test Gradual release from test position 4 / 3- Position Holds test position (no added pressure) 5 / 3 Holds test position against slight pressure 6 / 3+ Holds test position against slight to moderate pressure 7 / 4- Holds test position against moderate pressure 8 / 4 Holds test position against moderate to strong pressure 9 / 4+ Holds test position against strong pressure 10 / 5

42 Induction of remission (1) 40-60mg prednisolone / day (~0.75mg/kg) or if severe disease, initial methylprednisolone mg 2-3 doses alternate days Continue dose until CK <2x ULN Then reduce by 10mg/wk to 40mg, then 5mg/wk to 15mg, then 2.5mg/wk to mg daily, then further gradual reductions once established on a 2 nd line agent Carstens PO, Schmidt J. Diagnosis, pathogenesis and treatment of myositis: recent advances. Clin Exp Immunol Mar;175(3): doi: /cei

43 Induction of remission (2) If CK not improving after 4-5 weeks Check diagnosis (?+antibody, biopsy, EMG, 2 nd opinion) Add in methylprednisolone if not done so already IV cyclophosphamide EUROLUPUS or CYCLOPS (gauge severity) IVIG 2g/kg over 5 days IV Rituximab

44 Maintanance of remission: Early introduction of disease modifying treatment Early introduction of DMARDs (may overlap with induction of remission) Disease resistance Methotrexate 10-25mg/wk Azathioprine 2.5-3mg/kg (check TPMT levels) Consider adding ciclosporin 3mg/kg to MTX Consider adding MTX/AZA to MMF Mycophenolate mofetil 2-3g/day Tacrolimus 2-5mg bd Cyclophosphamide Rituximab Tocilizumab

45 Inflammatory myopathy: useful hints to help clinical judgement in diagnostics and treatment course Heterogenous collection of diseases Awareness of antibody status may be helpful Help predict clinical phenotype Aid planned investigations / treatment type, length and intensity Use combination of modalities, including MR, to aid diagnostics/assessment of disease activity Evidence base for treatment slowly improving, still unmet need in tailoring treatments

46 Acknowledgements The patients! The University of Manchester Janine Lamb Hector Chinoy Robert G. Cooper William Ollier Simon Rothwell Joanna Parkes James Lilleker Alex Oldroyd Philip Day Fiona Marriage Joanna Cobb John Bowes Hazel Platt Nicolas Pipis MYOGEN Ingrid E. Lundberg Frederick W. Miller Peter K. Gregersen Jiri Vencovsky Katalin Danko Vidya Limaye Albert Selva-O'Callaghan Lauren M. Pachman Ann M. Reed Lisa G. Rider Øyvind Molberg Olivier Benveniste Pernille Mathiesen Timothy Radstake Andrea Doria Jan De Bleecker Boel De Paepe Britta Maurer Leonid Padyukov Terrance P. O'Hanlon Annette Lee Euromyositis Committee Lucy Wedderburn Gouchun Wang Louise Diedrichson Jens Schmidt Jiri Vencovsky Paula Oakley Olivier Benveniste Ingrid Lundberg Zitelab Niels Krogh Mikkel Abildtoft UKMYONET / MYOPROSP Patrick Gordon David Isenberg Mike Hanna Pedro Machado Harsha Gunawardena David Isenberg Patrick Kiely James Miller Bath Neil McHugh Zoe Betteridge

47 MYONET Manchester myositis research Useful sites ositis IMACS resources including muscle biopsy video Freely accessible reviews on myositis and Abs Antibodies Myositis review Statin myotoxicitiy and classification Treatment reviews Free resources 1 st myositis international conference