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Scoring disease activity in myositis
Dr Hector Chinoy PhD FRCP@drhectorchinoy
Senior Lecturer / Honorary Consultant RheumatologistSalford Royal NHS Foundation Trust
Manchester Academic Health Science CentreThe University of Manchester, UK
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)
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
Different IIM subtypes with commonality of myositis
Extra-muscular features
eg skin, lung, cardiac, malignancy
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
Always worthChecking 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.
Treatment of IIM is challenging:diagnosis, assessing disease, treatment success?
Correct diagnosis
• other myopathies may have similar clinical presentation (also PM vs IBM)• inflammation on biopsy does not exclude other diagnoses• treatment resistance should prompt reappraisal of diagnosis
Assessing disease
• muscle weakness… is it activity (ongoing immune-mediated process), or damage (fatty replacement/ atrophy)?• poor prognostic features may direct drug selection/ treatment strategy (lung, cardiac, dysphagia, malignancy)
Treatment success measured as improvement in major manifestations of disease…by muscle strength & improvement in skin rash or organ involvement
DD, 66 year old male
• Referral from Rheumatology, Preston• 5 year history, gradual onset of proximal weakness, no dysphagia• Struggling to get out of car, low chairs, stairs• ESR normal, CK 829, improved on steroids to 101• EMG – complex repetitive discharges• ANA 1/2560 speckled, Ro/La positive, no sicca symptoms• Commenced on azathioprine & steroids – no worse & no better
Examination
• Deltoid and quadriceps wasting• Neck flexor weakness 9/10• Shoulder abduction, elbow flexion 8/10• Hip flexion/extension 8/10• Finger flexor weakness• No fasciculations
Review of muscle biopsy
• Initial report– CD8+ inflammatory cells– Regenerating muscle fibres– No inclusion bodies / vacuoles
• Further review and staining at Salford Royal– Positive staining for p62 and HLA-1
– COX negative fibres
What is the diagnosis?
A: PolymyositisB: Myofibrillary myopathyC: Sporadic inclusion body myositisD: Adult onset dystrophinopathyE: Miyoshi myopathy
What is the diagnosis?
A: PolymyositisB: Myofibrillary myopathyC: Sporadic inclusion body myositisD: Adult onset dystrophinopathyE: Miyoshi myopathy
Assumptions made
• Proximal weakness• +ANA/Ro• Positive muscle biopsy/EMG• Biochemical response to steroids• Patient subjectively felt better
Revised Diagnosis in UKMYONET Seronegative Cases
Initial diagnosis n (%) Diagnosis changed (%)Polymyositis 32 (45.1) 13 (40.6)Dermatomyositis 17 (23.9) 3 (17.6)Inclusion Body Myositis 15 (21.1) 1 (6.7)JDM 1 (1.4) 0 (0)Others 6 (8.4) 2 (33)Totals (%) 71 (100) 19 (26.8)Revised final diagnosis (n=19) n (%)
Inclusion body myositis 6 (31.6)Non-myositic/myopathic diagnosis 4 (21.1)
Unspecified (probably genetic) myopathy 4 (21.1)Becker muscular dystrophy 2 (10.5)
Oculopharyngeal muscular dystrophy 1 (5.3)Polymyositis 1 (5.3)
Tubular aggregate myopathy 1 (5.3)Courtesy of Dr James Lilleker
• >50, male predominance• CK < 5x ULN (15 ULN)• Antibody negative (Ro)• Fatty atrophy at presentations• Assymmetrical weakness• Finger flexor/distal
involvement• CK but no clinical response
Inclusion bodiesRimmed vacuoles
HLA-1 upregulation Protein accumulation
COX negative fibres Endomysial inflammation
Histopathology courtesy of Dr Daniel DuPlessis, SRFT
Think about Inclusion Body Myositis…
• >50, male predominance• CK < 5x ULN (15 ULN)• Antibody negative (Ro)• Fatty atrophy at presentations• Assymmetrical weakness• Finger flexor/distal
involvement• CK but no clinical response
Inclusion bodiesRimmed vacuoles
HLA-1 upregulation Protein accumulation
COX negative fibres Endomysial inflammation
Histopathology courtesy of Dr Daniel DuPlessis, SRFTAlso seen in polymyositis
Think about Inclusion Body Myositis…
Treatment of IIM is challenging:diagnosis, assessing disease, treatment success?
Correct diagnosis
• other myopathies may have similar clinical presentation (also PM vs IBM)• inflammation on biopsy does not exclude other diagnoses• treatment resistance should prompt reappraisal of diagnosis
Assessing disease
• muscle weakness… is it activity (ongoing immune-mediated process), or damage (fatty replacement/ atrophy)?• poor prognostic features may direct drug selection/ treatment strategy (lung, cardiac, dysphagia, malignancy)
Treatment success measured as improvement in major manifestations of disease…by muscle strength & improvement in skin rash or organ involvement
MR thighs – axial T1 / STIR
T1 – marked fatty replacementLikely to taken place over many years
STIR – ongoing inflammatory processMR sensitive at picking up inflammationbut not specific for autoimmune disease
MR thighs – axial T1 / STIR
T1 – marked fatty replacementLikely to taken place over many years
STIR – ongoing inflammatory processMR sensitive at picking up inflammationbut not specific for autoimmune disease
Treatment of IIM is challenging:diagnosis, assessing disease, treatment success?
Correct diagnosis
• other myopathies may have similar clinical presentation (also PM vs IBM)• inflammation on biopsy does not exclude other diagnoses• treatment resistance should prompt reappraisal of diagnosis
Assessing disease
• muscle weakness… is it activity (ongoing immune-mediated process), or damage (fatty replacement/ atrophy)?• poor prognostic features may direct drug selection/ treatment strategy (lung, cardiac, dysphagia, malignancy)
Treatment success measured as improvement in major manifestations of disease…by muscle strength & improvement in skin rash or organ involvement
« How do we assess disease activity?« Not just by using CK« Requirement to test more than one muscle group to assess
strength, and also to quantify the result« Parameters are a requirement of the NHS England RTX
MYOACT registry
6 Core Set Measures: Validated and reliable
Domain Core Set Measure Range
Physician Global
ActivityPhysician global VAS (10 cm scale) 0-10
Patient Global ActivityPatient/Parent global VAS (10 cm scale) 0-10
Muscle Strength Composite score of 8 muscle groups
( MMT-8 )0-80
Physical Function Health Assessment Questionnaire (HAQ) score0-3
Laboratory Enzymes Most abnormal enzyme among CK, LDH, AST, ALT, Aldolase Depends on muscle
enzymes
Extramuscular Disease
Activity
Global extramuscular disease activity VAS (10 cm):
constitutional, cutaneous, articular, GI, pulm, cardiac0-10
Slide courtesy of Rohit Aggarwal
Rider LG, Giannini EH, Harris-Love M, Joe G, Isenberg D,
Pilkington C, Lachenbruch PA, Miller FW; International
Myositis Assesment and Clinical Studies Group. Defining
Clinical Improvement in Adult and Juvenile Myositis. J
Rheumatol. 2003 Mar;30(3):603-17. PMID: 12610824.
https://www.niehs.nih.gov/research/resources/imacs/diseaseactivity/
Manual Muscle Testing - 8
Total Score = 80 (One side + Axial) Slide courtesy of Rohit Aggarwal
1. Manual Muscle Testing - MMT8/MMT26
Kendall Scale
« MRC Scale– 1976– Grade 0-5 - blunt– Informally adapted
with “+” and “-” designations
« Kendall Scale– Florence Kendall– “MRC-plus”– Grade 0-10
2. Patient global disease activity VAS
3. Physician global disease activity VAS
4. Extramuscular disease activity
Extra-muscular global disease activity
Visual Analogue Scale (VAS) 0 – 10 cm
uConstitutional uCutaneousuPulmonaryuGIuJointsuCardiac
= Extra-Muscular Disease Activity
Slide courtesy of Rohit Aggarwal
Health Assessment Questionnaire
W ithout any d ifficu lty
W ith som e d ifficu lty W ith m uch d ifficu lty U nable to do
D ressing/G room ing
Arising
Eating
W alking
H ygiene
Reach
G rip
Activities
Slide courtesy of Rohit Aggarwal
Muscle Enzymes
« Creatine Kinase (CK)« Aldolase« AST« ALT« LDH
FI-3 – measure of endurance
The Functional Index-3 in Adult Dermatomyositis and Polymyositis: Validity and Reliability of an Outcome Measure
for Muscle Endurance. Floranne Ernste, Christopher Chong, Orla Ni Mhuircheartaigh, Tanaz Kermani, Cynthia Crowson, Helene Alexanderson, Ann Reed.
ACR/ARHP Annual Meeting November 11, 2012
Performed FI-3 tasks with as many repetitions possible in 3 minutes
Cutaneous dermatomyositis disease area and severity index
(CDASIv2)
1: Yassaee M, Fiorentino D, Okawa J, Taylor L, Coley C, Troxel AB, Werth VP. Modification of the cutaneous dermatomyositis disease area and severity index,
an outcome instrument. Br J Dermatol. 2010 Mar;162(3):669-73. PubMed PMID: 19863510
2: Anyanwu CO, Fiorentino DF, Chung L, Dzuong C, Wang Y, Okawa J, Carr K, Propert KJ, Werth VP. Validation of the Cutaneous Dermatomyositis Disease Area and Severity Index: characterizing
disease severity and assessing responsiveness to clinical change. Br J Dermatol. 2015 Oct;173(4):969-74. PubMed PMID: 25994337;
Useful to use as outcome measurein patients with predominant
skin involvement
Recent patient with MDA5 disease
Correlation with disease activityCreatine
kinase
Cardiac
troponin T
Cardiac
troponin I
Absolute
CK-MB
Physician global
disease activity VAS
rho 0.042 0.260 0.218 0.168p 0.776 0.082 0.138 0.271
Patient global disease
activity VAS
rho 0.071 0.106 0.179 0.139p 0.628 0.483 0.224 0.363
HAQrho 0.209 0.330 0.192 0.306p 0.149 0.025 0.192 0.041
Extramuscular global
VAS
rho -0.255 0.036 0.150 -0.076p 0.080 0.812 0.316 0.620
Manual muscle testrho -0.188 -0.403 -0.195 -0.222p 0.196 0.005 0.183 0.142
Rho=Spearman’s ranked correlation coefficient
Lilleker JB, Diederichsen ACP, Jacobsen S, Guy M, Roberts ME, Sergeant JC, Cooper RG, Diederichsen LP, Chinoy H. Using serum troponins to screen for cardiac involvement and assess disease activity in the idiopathic inflammatory myopathies. Rheumatology
(Oxford). 2018 Mar 12. doi: 10.1093/rheumatology/key031. [Epub ahead of print] PubMed PMID: 29538753
“We have concluded that there is enough evidence to consider making the treatment available”
• Recommendations largely mirror RIM study inclusion criteria etc.
• ~60 patients per year• 500 incident cases• 80% of these will have a relevant
autoantibody• RA protocol for Rituximab
administration
https://www.england.nhs.uk/commissioning/wp-content/uploads/sites/12/2013/04/16036_FINAL.pdf
Is my patient eligible?
« Have myositis…
« Failed steroids
« Failed ≥2 steroid-sparing drugs
« Have myositis relevant autoantibodies
« MMT <125/150 + 2 CSMs (if MMT>125, then 3 CSMs)– Patient global VAS >2/10– Physician global VAS >2/10– HAQ > 0.25– Raised muscle enzyme >1.3 ULN– Global extramuscular activity VAS >1– Active ILD
« Registered with the MYOACT registry
Summary of opportunities for myositis
research
« (UKMYONET) MYOPROSP cross-sectional study– Any myositis patient
« MYOPROSP prospective study– Ideally patients within 2 years of diagnosis or newly
diagnosed– MYOACT – specifically for patients starting RTX
UKMYONET
« Cross-sectional study – understanding of genetic and antibody associations in myositis
« CRN study« Blood test x1« 1 page clinical proforma« >1,600 patients recruited
MYOPROSP« Multi-centre UK study,
commenced Sep 2016« MRC/industry funded« ~80 prospective cases /year« Also opportunity to collect data
cross-sectionally
« Defined workstreams– MYOACT registry – additional
prospective patients commencing on RTX
– Biomarkers– Imaging
– Patient recorded measures (PROMS)
Baseline dataClinical activityBiomarkersPROMS
FU dataClinical activityBiomarkersPROMS
FU dataClinical activityBiomarkersPROMS
FU dataClinical activityBiomarkersPROMS
FU dataClinical activityBiomarkersPROMS
0 3 6 12 24
Acknowledgements
The patients!The University of ManchesterJanine Lamb
Paul New
Robert G. Cooper
William Ollier
Simon Rothwell
Joanna Parkes
James Lilleker
Alex Oldroyd
Philip Day
Fiona MarriageJoanna Cobb
John Bowes
Hazel Platt
Nicolas Pipis
Federico Roncaroli
Mark Roberts
MYOGENIngrid E. Lundberg
Frederick W. Miller
Peter K. GregersenJiri Vencovsky
KatalinDanko
VidyaLimaye
Albert Selva-O'Callaghan
Lauren M. Pachman
Ann M. Reed
Lisa G. Rider
ØyvindMolberg
Olivier Benveniste
PernilleMathiesen
Timothy Radstake
Andrea Doria
Jan De Bleecker
Boel De Paepe
Britta Maurer
Leonid Padyukov
Terrance P. O'Hanlon
Annette Lee
Euromyositis CommitteeLucy Wedderburn
Gouchun Wang
Louise Diedrichson
Jens SchmidtJiri Vencovsky
Paula Oakley
Olivier Benveniste
Ingrid Lundberg
ZitelabNielsKrogh
Mikkel Abildtoft
UKMYONET / MYOPROSPPatrick GordonDavid Isenberg
Mike Hanna
Pedro Machado
Harsha Gunawardena
David Isenberg
Patrick Kiely
James Miller
BathNeil McHugh
Zoe Betteridge