07.18 scoring disease activity - University of Manchester · Physical Function Health Assessment...

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

Follow-up summary audit sheet

http://bit.ly/2xvdDxK

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