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 incidence 5-10/million
Different IIM subtypes with commonality of myositis
2 peaks of onset: (5-15 years)
Extra-muscular features
(30-50 years) Patterns of disease
eg skin, lung, cardiac, malignancy
(rule of 1/3’s):
Lack of evidence base for 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 ATP
ATP
Features of Myositis
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 b) Rhabdomyolysis g) Infectious myositis c) Metabolic myopathies d) Carnitine palmityltransferase II deficiency e) Mitochondrial myopathies
3. Drug/toxin-induced 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) Adapted from Targoff 2002 c) Increased muscle mass
f) Dystrophinopathies h) Amyotrophic lateral sclerosis i) Neuromyotonias h) Idiopathic inflammatory myopathy
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 myopathies
Hyper/hypothyroidism, acromegaly, Cushing’s syndrome, Addison’s disease, vitamin D deficiency, hyper/hypocalcaemia, hypokalaemia
Drug-induced myopathies
Statins, D-penicillamine, clofibrate, chloroquine, amiodarone, vincristine, zidovudine
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 Inclusion Body Myositis
Necrotizing Myopathy
Dermatomyositis
Idiopathic Inflammatory
Malignancy
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: Probable: Possible:
All of items 1-4 3 of items 1-4 2 of items 1-4
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
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. Ann Rheum Dis. 2015 May;74(5):795-8
Slides courtesy of IMACS, Prof Oddis & McHugh
http://www.cytoskeleton.com/tropomyosin-troponin-complex-cs-tt05
Myositis: effects of muscle damage
Photo courtesy of Prof R Coop
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 HLA
formation
Other genes Infections
Specific signs & 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) (22100%) 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;52:1571-6 Nakashima et al Rheumatol 2010;49:433-40 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
Anti-TIF1g: diagnostic utility in cancer associated myositis SENSITIVITY
0.78
Pooled sensitivity for cancer-associated myositis
SPECIFICITY
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 Age Female Statin exposure
52 ± 16 years 58% 30/45 (67%) (24/26, 92% >50 years)
CPK 9,718 ± 7,383 iu/l Proximal weakness 96%
Irritable EMG 73% Necrosis on biopsy 100% Inflammation on 20% biopsy
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=2.62-12.63 (unpublished data, our lab)
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 & finger 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. 2. 3. 4. 5. 6.
Manual muscle testing (MMT-8) Patient global visual analogue scale recorded on a 10cm scale Physician global visual analogue scale recorded on a 10cm scale Health Assessment Questionnaire disability index At least one muscle enzyme (CK, AST, ALT, aldolase, LDH) 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): Completed by: Consultant Completed for: All patients Completed at: All study visits
MANUAL MUSCLE TESTING Muscle groups
Left (0-10)
Axial (0-20) Neck Flexors Neck Extensors Proximal (0-160) Shoulder elevators Shoulder abductors Elbow flexors Hip extensors Hip abductors Hip flexors Knee flexors Knee extensors
1, 2, 3, 4, 5, 6, 7
Right (0-10)
-
-
Axial (0-10)
MMT8**
-
(Trapezius) (Deltoid Middle)
MMT8**
(Bicepts Brachii)
MMT8**
(Gluteus Maximus)
MMT8**
(Gluteus Medius)
MMT8**
(Iliopsoas) (Hamstrings) (Quadriceps)
MMT8**
Distal (0-80) Wrist Extensors Wrist Flexors Ankle Dorsiflexors Ankle Plantar Flexors
-
MMT8**
MMT8**
MMT SCORING: MMT8
0 - 80
MMT8 highlighted in boxes
MMT24
0 - 260
Axial + Proximal + Distal (all 26)
(MMT8**)
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
/
Holds test position against strong pressure
10
4+ /
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 Azathioprine 2.5-3mg/kg (check TPMT levels) Mycophenolate mofetil 2-3g/day
Consider adding ciclosporin 3mg/kg to MTX Consider adding MTX/AZA to MMF 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! 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
Useful sites MYONET www.myonet.eu www.euromyositis.eu Manchester myositis research http://research.bmh.manchester.ac.uk/epidemiology/CIGMR/research/autoimmune/Autoimmunity/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