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Home , Inclusion body myositis, Myopathy, Myositis

Recent advances in

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 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 (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 ?

Insidious onset of proximal

Fatigue

Dyspnoea Weight loss Skin abnormalities (including ulceration) Raynaud’s

Dry, cracked hands Arthralgia/arthritis Creatine Features of Myositis ATP ATP + 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) d) Convulsions, delirium tremens 2. affecting muscle a) Myocardial infarction f) Dystrophinopathies b) h) Amyotrophic lateral sclerosis g) Infectious myositis i) Neuromyotonias c) Metabolic h) Idiopathic inflammatory d) Carnitine palmityltransferase myopathy II deficiency e) Mitochondrial myopathies 3. Drug/toxin-induced a) Lipid-lowering agents, especially myopathy b) Alcoholic myopathy c) Drugs of abuse: e.g. cocaine, amphetamines, phencyclidine d) Malignant hyperthermia / neuroleptic malignant syndrome e) Other meds: e.g. , , 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

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 disorders: Eaton-Lambert syndrome, Myotonic disease: dystrophia myotonica, 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-, clofibrate, chloroquine, amiodarone, vincristine, zidovudine myopathies Infections Acute viral: , hep B, echovirus, rickettsia, coxsackie, rubella, vaccines Bacterial : staphylococcus, streptococcus, clostridium perfringens, leprosy Parasites: toxoplasma, trichinella, schistosoma, cysticercus Other CTDs Rheumatoid arthritis, systemic sclerosis, systemic erythematosus Miscellaneous Periodic paralyses, carcinomatous neuromyopathy, acute rhabdomyolysis, , 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? Necrotizing Myopathy

Idiopathic Malignancy Inflammatory Myopathy

Myositis-CTD overlap Bohan and Peter diagnostic criteria for polymyositis / dermatomyositis

1 Symmetrical weakness of limb-girdle muscles and anterior neck flexors 2 evidence typical of myositis 3 Elevation of serum 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/

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

SENSITIVITY Pooled sensitivity SPECIFICITY for cancer-associated myositis

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 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 - 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% 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 A, Neely D, Armitage J, Chinoy H, Cooper RG, Laaksonen R, et al. Clin Pharmacol Ther. 2014 Oct;96(4):470-6. doi: 10.1038/clpt.2014.121. Statin-related myotoxicity phenotype classification

Alfirevic A, Neely D, Armitage J, Chinoy H, Cooper RG, Laaksonen R, et al. Clin Pharmacol Ther. 2014 Oct;96(4):470-6. doi: 10.1038/clpt.2014.121. 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

MR thigh images

T1 STIR Two vacuolated fibres with basophilic rimming, one with an amphophilic inclusion body (H&E x60) Features of sporadic Inclusion Body Myositis

• >50, male predominance • Slowly progressive, affects distal & proximal musculature, often asymmetrically • Selective quads & flexor weakness • CK < 5x ULN • Tend to be antibody negative, but may be Ro+ • Not immunoresponsive what is myositis? how do we classify myositis? myositis disease spectrum antibodies case presentations how do we assess and treat myositis? 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;50:2281–90.12. Study ID: ______Study Visit Date: _ _ / _ _ / _ _ _ _ Study visit number (Circle): 1, 2, 3, 4, 5, 6, 7 Completed by: Consultant MANUAL MUSCLE TESTING Completed for: All patients Completed at: All study visits

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) - flexors (Hamstrings) - Knee extensors (Quadriceps) MMT8** - Distal (0-80) Wrist Extensors MMT8** - Wrist Flexors - Ankle Dorsiflexors MMT8** - Ankle Plantar Flexors -

MMT SCORING: MMT8 0 - 80 MMT8 highlighted in boxes (MMT8**) MMT24 0 - 260 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

Version 1.0 SEPT 2009 Induction of remission (1)

 40-60mg prednisolone / day (~0.75mg/kg) or if severe disease, initial methylprednisolone 250-500mg 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 7.5-10mg daily, then further gradual reductions once established on a 2nd line agent

Carstens PO, Schmidt J. Diagnosis, pathogenesis and treatment of myositis: recent advances. Clin Exp Immunol. 2014 Mar;175(3):349-58. doi: 10.1111/cei.12194. Induction of remission (2)

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

Maintanance of remission: Early introduction of disease modifying treatment

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

Acknowledgements

The patients! Boel De Paepe The University of Manchester Britta Maurer Janine Lamb Leonid Padyukov Hector Chinoy Terrance P. O'Hanlon Robert G. Cooper Annette Lee William Ollier Simon Rothwell Euromyositis Committee Joanna Parkes Lucy Wedderburn James Lilleker Gouchun Wang Alex Oldroyd Louise Diedrichson Philip Day Jens Schmidt Fiona Marriage Jiri Vencovsky Joanna Cobb Paula Oakley John Bowes Olivier Benveniste Hazel Platt Ingrid Lundberg Nicolas Pipis Zitelab MYOGEN Niels Krogh Ingrid E. Lundberg Mikkel Abildtoft Frederick W. Miller Peter K. Gregersen UKMYONET / MYOPROSP Jiri Vencovsky Patrick Gordon Katalin Danko David Isenberg Vidya Limaye Mike Hanna Albert Selva-O'Callaghan Pedro Machado Lauren M. Pachman Harsha Gunawardena Ann M. Reed David Isenberg Lisa G. Rider Patrick Kiely Øyvind Molberg James Miller Olivier Benveniste Pernille Mathiesen Bath Timothy Radstake Neil McHugh Andrea Doria Zoe Betteridge Jan De Bleecker Useful sites MYONET www.myonet.eu www.euromyositis.eu Manchester myositis research http://research.bmh.manchester.ac.uk/epidemiology/CIGMR/research/autoimmune//My ositis IMACS resources including muscle biopsy video http://www.niehs.nih.gov/research/resources/imacs/diseaseactivity/index.cfm http://www.niehs.nih.gov/research/resources/imacs/othertools/index.cfm Freely accessible reviews on myositis and Abs Antibodies http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3874450/ http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3132021/ http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4386580/ Myositis review http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4104537/ Statin myotoxicitiy and classification http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4172546/ Treatment reviews http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4581266/ http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3927896/ Free resources 1st myositis international conference http://onlinelibrary.wiley.com/doi/10.1111/joim.12525/full