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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
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
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
..
.. .. . . .
..
. .
..
.. .. . . .
..
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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?