GRAPPAGRAPPAExamples of Work ProjectsExamples of Work Projects

Philip Mease

Examples of GRAPPA Work Examples of GRAPPA Work ProjectsProjects

Classification and diagnosis of PsA (CASPAR) Evaluation of PsA composite outcomes Determination of minimal clinically important

difference of function in PsA “Participation” measure Determination of patient global assessment Axial assessment Enthesial assessment Dactylitis assessment PsA treatment guidelines

PsA: Classification SchemaPsA: Classification Schema

Moll & Wright, Vasey and Espinosa, Fournie, Bennett, Gladman, McGonagle

CASPAR (Philip Helliwell)

Psoriatic arthritis – diseasePsoriatic arthritis – diseaseclassification and diagnosisclassification and diagnosis

Moll and WrightMoll and Wright

Psoriatic arthritis Inflammatory arthritis

– Oligoarticular, polyarticular, DIP, axial, mutilans

Psoriasis (Usually) negative rheumatoid factor

Psoriatic arthritis – disease Psoriatic arthritis – disease classification and diagnosisclassification and diagnosis

New classification criteria are required: Reduce contamination with other

conditions More precise epidemiology Improved prognostic information Facilitate research into aetiology and

pathophysiology

CASPAR – development and CASPAR – development and validation of classification criteria validation of classification criteria

for PsAfor PsA

600 consecutive patients with PsA

600 next available controls with inflammatory arthritis and inflammatory osteoarthritis (OA)

At least 50% with RA

Matched for disease duration

Standardized proforma

Clinical and historic data

Radiographic data

DNA samples

Serum sample

A prospective multicentre international case A prospective multicentre international case control studycontrol study

CASPAR – validation of CASPAR – validation of classification criteria for PsAclassification criteria for PsA

Analysis by:– Univariate analyses

– Comparison of existing criteria

– Conditional logistic regression

– Latent class analysis

– Classification and regression trees

International study All major ‘players’ Consensus criteria Based on sound

methodology (cf RA and ESSG)

Clinical featuresClinical features

0

5

10

15

20

25

30

35

Dactylitis Enthesitis DIP involvement

Case Control

0

5

10

15

20

25

30

35

Dactylitis Enthesitis DIP involvement

Case Control

%%

CASPAR – individual featuresCASPAR – individual features

Diagnostic Odds Ratio (DOR) Ratio of odds of positivity in disease

relative to odds of positivity in non-disease DOR = true positive / false negative ÷

false positive / true negative– Sensitivity / (1-sens) ÷ (1-specificity) /

specificity– LR*(+) / LR(-)

Glas et al. Glas et al. J Clin EpidJ Clin Epid 2003; 56:1129–35 2003; 56:1129–35*LR = Likelihood Ratio*LR = Likelihood Ratio

Psoriasis Psoriasis DOR = 581DOR = 581

Nail dystrophyNail dystrophy DOR = 59DOR = 59

Family history of psoriasis Family history of psoriasis DOR = 9.2DOR = 9.2

PsoriasisPsoriasis

Psoriasis Psoriasis DOR = 581DOR = 581

Nail dystrophyNail dystrophy DOR = 59DOR = 59

Family history of psoriasis Family history of psoriasis DOR = 9.2DOR = 9.2

DactylitisDactylitis

DOR = 19.3DOR = 19.3

DactylitisDactylitis

DIP diseaseDIP disease

DOR = 6.4DOR = 6.4

DIP diseaseDIP disease

Inflammatory heel painInflammatory heel pain

DOR = 2.7DOR = 2.7

Any tender enthesisAny tender enthesis

DOR = 3.8DOR = 3.8

Clinical enthesitisClinical enthesitis

Outcome Measurements in Outcome Measurements in PSAPSA

preliminary results from preliminary results from IMPACT and Etanercept IMPACT and Etanercept

PhaseII trialsPhaseII trialsOMERACT 7OMERACT 7

C. AntoniJ. FransenW. Uter P. Mease on behalf ofGRAPPA

MethodsMethods Data resources

– Etanercept PhaseII week 0-12 n=60– IMPACT week 0-16 n=104

Combined SAS data base Erlangen Analysis

– ROC receiver operating characteristic in combined data base

– Responsiveness analysis in seperated data bases (standardised response mean SRM; t-value; chi-square)

ROC changesROC changesDAS28 4 VariablesDAS28 4 Variables

youden cutoff1 sens spec.784 1.27 .880 .904

ROC changesROC changes68 Tender Joint Count68 Tender Joint Count

youden cutoff1 sens spec.513 6.00 .753 .759

ROC changesROC changes66 swollen joint count66 swollen joint count

youden cutoff1 sens spec.464 6.00 .654 .810

ROC changesROC changesCRPCRP

youden cutoff1 sens spec.324 -.10 .935 .389

Discrimination IMPACTDiscrimination IMPACT

Placebo (n=52) Drug (n=52)Criterium %improved %improved 2 MH p-valueEULAR28 53.4 <0.0001Good + moderate 26% 92%Good 0% 60%

EULAR28 (DAS28 crp)Good + moderate 30% 88% 35.4 <0.0001Good 7% 52%

EULAR 48.6 <0.0001Good + moderate 26% 88%Good 0% 63%

ACR20 10% 67% 36.2 <0.0001ACR50 0% 48% 32.6 <0.0001ACR70 0% 29% 17.4 <0.0001

PsARC 30% 82% 27.9 <0.0001

Discrimination EtanerceptDiscrimination Etanercept

Placebo (n=30) Drug (n=30)Criterium %improved %improved 2 MH p-value

EULAR28 26.2 <0.0001Good + moderate 15% 93%Good 8% 52%

EULAR28 (DAS28 crp) 23.3 <0.0001Good + moderate 15% 86%Good 4% 39%

EULAR 22.9 <0.0001Good + moderate 12% 81%Good 4% 44%

ACR20 15% 73% 19.6 <0.0001ACR50 4% 50% 14.8 0.0001ACR70 0% 13% 3.8 0.05

PsARC 33% 90% 19.3 <0.0001

Inflammatory Enthesopathy

Periosteal new bone formation

Subchondral bone inflammation and resorption

Bone

Enthesitis

McGonagle D. McGonagle D. Arthritis Rheum.Arthritis Rheum. 1999. 42:1080-1086. 1999. 42:1080-1086.

MASES IndexMASES Index

Heuft-Dorenbosch Ann Rheum Dis 2003Heuft-Dorenbosch Ann Rheum Dis 2003

13 sites13 sites

0 = no pain0 = no pain

1 = pain1 = pain

..

.. .. . . .

..

. .

..

.. .. . . .

..

. .

MCID BackgroundMCID Background

Key question: In a given disease parameter, how much change is clinically important to the patient as opposed to “statistically significantly different”

> 20 different methodologies to measure minimal clinically important difference

MCID for RA for Health Assessment Questionnaire (HAQ) is 0.22 (out of total of 3.0)

How Much Improvement in How Much Improvement in Functional Status Is Considered Functional Status Is Considered

Important by Patients With Important by Patients With Active Psoriatic Arthritis: Active Psoriatic Arthritis:

Applying the Outcome Measures Applying the Outcome Measures in Rheumatoid Arthritis Clinical in Rheumatoid Arthritis Clinical

Trials (OMERACT) Group Trials (OMERACT) Group GuidelinesGuidelines

Philip Mease1 Rita Ganguly2, L. Wanke3, Amitabh Singh2

1Seattle Rheumatology Associates, Seattle, WA; 2Wyeth Research, Collegeville, PA; 3Amgen, Thousand Oaks, CA

Methods (derived from Etanercept Methods (derived from Etanercept Phase III trial in PsA)Phase III trial in PsA)

Patient Rating-Based MCID

How important to you is the amount of change in your physical limitations (such

as limitations in walking, standing, gripping reaching, etc.) 1 2 3 4 5 6 7

Not At ExtremelyAll Important

Important

0.0 0.5 1.0 1.5 2.0 2.5 3.0

Mean change from baselinein HAQ Disability Score for

those who improved

Minimally ImportantMinimally Important Very ImportantVery Important

MethodsMethods

Data-Driven Approach MCIDData-Driven Approach MCID Upper bound of 95% confidence interval of

standard error of measurement (SEM) for HAQ

SEM = σ baseline HAQ 1- rbaseline HAQ

where σ=standard deviation

r = Cronbach’s alpha coefficient

ResultsResults

Threshold 95%for delta in Confidence Type of MCID

HAQ Scores Interval

SEM-Based MCID 0.40 N.A. 2.2.5Patient Rating-Based MCID 0.30 0.24-0.35 2.1.5Patient Rating-Based MajorClinically Important Difference

0.65 0.57-0.72 2.1.5

ParticipationParticipation

Measurement of“Participation” in all aspects of life: work, family, social, religious, etc.

Mandate from WHO International Classification of Function (ICF) group regarding all disease groups

Seen as involvement in a life situation, not merely the execution of a task or action

Action PlanAction Plan

Agreement that this is a worthwhile project Identify rheumatology and dermatology leaders: Will Taylor,

Henning Boehncke Project1: Map items from existing measurement tools to ICF

categories Project2: Delphi exercise (includes non-rheumatologists,

non-medical health professionals) Project3: Patient survey using ICF checklist (funding

required for training and patient assessments); validate WHODAS at same time

Project4: 3-day consensus development meeting possibly adjacent to EULAR 2006 (Netherlands)

Project5: Further patient survey to validate the core-set (?) Project6: Development of the core-set into a

psychometrically sound measurement tool

Patient Global QuestionPatient Global Question

Please place a mark on each line below to indicate your answer to each question relating to the past week (or 3 days?/ or day of assessment?)

GlobalIn all the ways in which your PSORIASIS and ARTHRITIS, as a whole, affects you, how would you rate the way you feel at this time? (10 cm line) (from “wellness” to “the worse I can feel”)

Joints In all the ways your ARTHRITIS affects you, how would you rate the way you feel at this time? (10 cm line)

SkinIn all the ways your PSORIASIS affects you, how would you rate the way you feel at this time? (10 cm line)

Biomarkers in PsA and PsoriasisBiomarkers in PsA and Psoriasis

Goal: Standardization of histologic and immunohistochemical analyses used in skin synovial biopsies before and after treatment with various agents

Committee lead: Oliver Fitzgerald (Dublin)

ImmunohistochemistryImmunohistochemistry

Inflammatory cells– CD3, CD38, CD55, CD68, granzyme B

Adhesion molecules

– ICAM-1, VCAM-1, E-selectin

Angiogenesis– vWF, VEGF, v3, bFGF

Matrix metalloproteinases– MMP1, MMP3, MMP13, TIMP

Cytokines– IL-1, TNF, IL-6, IL-18

GRAPPA PsA Treatment GRAPPA PsA Treatment GuidelinesGuidelines

Reassess Response to Therapy and Toxicity

Axial Axial DiseaseDisease

Initiate TherapyNSAIDPTBiologics(anti-TNF)

Peripheral Arthritis

Initiate TherapyNSAIDs, IA steroids, DMARDs(MTX, CsA, SSZ, LEF),Biologics(anti-TNF)

Skin and Nail Disease

Initiate TherapyTopicalsPUVA/UVBDMARDs (MTX, CsA)Biologics (anti-TNF, etc)

DactylitisDactylitis

Initiate TherapyNSAIDInjectionBiologics(anti-TNF)

EnthesitisEnthesitis

Initiate TherapyNSAIDInjectionBiologics(anti-TNF)

GRAPPA=Group for Research and Assessment of Psoriasis and Psoriatic Arthritis;NSAIDs=nonsteroidal anti-inflammatory drugs; IA=intra-articular; DMARDs=disease-modifying antirheumatic drugs; MTX=methotrexate; CsA=cyclosporin A; SSZ=sulfasalazine; LEF=leflunomide; anti-TNF=tumor necrosis factor inhibitor; PUVA=psoralen plus ultraviolet light A; UVB=ultraviolet light B; PT=physiotherapy.

Quality of evidenceQuality of evidence

Soriano ER, McHugh GRAPPA, San Antonio, 2004 MJ.Soriano ER, McHugh GRAPPA, San Antonio, 2004 MJ.

RecommendationRecommendation

Grade AGrade A1A meta-analysis of RCT

1B one or more RCT

Grade BGrade B2A one or more CT

2B well-designed studies

Grade DGrade D4 expert opinions,

clinical experience

EvidenceEvidence

Grade CGrade C3 non-experimental studies

SSZ MTX CyA LFN Gold AZA ETN INF

Evidence symptom control

1A 2B 1B 1B -1A 2B 1B 1B

Effect size SE NE ME LE SE ME HE HE

Evidence X-ray

-3 -3 3 4 -3 – 1B –

Toxicity Low Low High Low Med Low Low Low

Recomm. grade?

A-B B A-B A -A B A A

Means evidence against. NE: Means evidence against. NE: negligible effect; SE: Small effect; negligible effect; SE: Small effect; ME: Medium effect; LE: Large effect; HE: Huge effectME: Medium effect; LE: Large effect; HE: Huge effect

Level evidence: Level evidence: effect size, side-effect profileeffect size, side-effect profile

A few unanswered questionsA few unanswered questions

Why do skin and joint disease coexist in PsA? What is behind the difference in clinical expression

between SpAs and RA What is the enthesopathy process trying to teach

us about the central pathophysiology of the SpAs and how does this influence our assessment and therapy?

What implication will differential cellular activity and cytokine expression have on our approach to therapy of SpAs?

Are the lessons being learned about the ability to inhibit disease progression in RA transferable to SpAs?