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GRAPPA Examples of Work Projects

GRAPPA Examples of Work Projects. Philip Mease. Examples of GRAPPA Work Projects. Classification and diagnosis of PsA (CASPAR) Evaluation of PsA composite outcomes Determination of minimal clinically important difference of function in PsA “Participation” measure

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GRAPPA Examples of Work Projects

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  1. GRAPPAExamples of Work Projects Philip Mease

  2. Examples of GRAPPA Work Projects • 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

  3. PsA: Classification Schema • Moll & Wright, Vasey and Espinosa, Fournie, Bennett, Gladman, McGonagle • CASPAR (Philip Helliwell)

  4. Psoriatic arthritis – diseaseclassification and diagnosis Psoriatic arthritis • Inflammatory arthritis • Oligoarticular, polyarticular, DIP, axial, mutilans • Psoriasis • (Usually) negative rheumatoid factor Moll and Wright

  5. Psoriatic arthritis – disease classification and diagnosis New classification criteria are required: • Reduce contamination with other conditions • More precise epidemiology • Improved prognostic information • Facilitate research into aetiology and pathophysiology

  6. 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 CASPAR – development and validation of classification criteria for PsA A prospective multicentre international case control study

  7. 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) CASPAR – validation of classification criteria for PsA

  8. Clinical features %

  9. CASPAR – 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(-) *LR = Likelihood Ratio Glas et al. J Clin Epid 2003; 56:1129–35

  10. Psoriasis Psoriasis DOR = 581 Nail dystrophy DOR = 59 Family history of psoriasis DOR = 9.2 Psoriasis DOR = 581 Nail dystrophy DOR = 59 Family history of psoriasis DOR = 9.2

  11. Dactylitis Dactylitis DOR = 19.3

  12. DIP disease DIP disease DOR = 6.4

  13. Clinical enthesitis Any tender enthesis DOR = 3.8 Inflammatory heel pain DOR = 2.7

  14. Outcome Measurements in PSApreliminary results from IMPACT and Etanercept PhaseII trialsOMERACT 7 C. AntoniJ. FransenW. Uter P. Mease on behalf ofGRAPPA

  15. Methods • 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)

  16. ROC changesDAS28 4 Variables youden cutoff1 sens spec .784 1.27 .880 .904

  17. ROC changes68 Tender Joint Count youden cutoff1 sens spec .513 6.00 .753 .759

  18. ROC changes66 swollen joint count youden cutoff1 sens spec .464 6.00 .654 .810

  19. ROC changesCRP youden cutoff1 sens spec .324 -.10 .935 .389

  20. Discrimination IMPACT Placebo (n=52) Drug (n=52) Criterium %improved %improved 2 MH p-value EULAR28 53.4 <0.0001 Good + moderate 26% 92% Good 0% 60% EULAR28 (DAS28 crp) Good + moderate 30% 88% 35.4 <0.0001 Good 7% 52% EULAR 48.6 <0.0001 Good + moderate 26% 88% Good 0% 63% ACR20 10% 67% 36.2 <0.0001 ACR50 0% 48% 32.6 <0.0001 ACR70 0% 29% 17.4 <0.0001 PsARC 30% 82% 27.9 <0.0001

  21. Discrimination Etanercept Placebo (n=30) Drug (n=30) Criterium %improved %improved 2 MH p-value EULAR28 26.2 <0.0001 Good + moderate 15% 93% Good 8% 52% EULAR28 (DAS28 crp) 23.3 <0.0001 Good + moderate 15% 86% Good 4% 39% EULAR 22.9 <0.0001 Good + moderate 12% 81% Good 4% 44% ACR20 15% 73% 19.6 <0.0001 ACR50 4% 50% 14.8 0.0001 ACR70 0% 13% 3.8 0.05 PsARC 33% 90% 19.3 <0.0001

  22. Inflammatory Enthesopathy • Periosteal new bone formation • Subchondral bone inflammation and resorption Enthesitis Bone McGonagle D. Arthritis Rheum. 1999. 42:1080-1086.

  23. MASES Index 13 sites 0 = no pain 1 = pain Heuft-Dorenbosch Ann Rheum Dis 2003

  24. MCID 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)

  25. How Much Improvement in Functional Status Is Considered Important by Patients With Active Psoriatic Arthritis: Applying the Outcome Measures in Rheumatoid Arthritis Clinical Trials (OMERACT) Group Guidelines Philip Mease1 Rita Ganguly2, L. Wanke3, Amitabh Singh2 1Seattle Rheumatology Associates, Seattle, WA; 2Wyeth Research, Collegeville, PA; 3Amgen, Thousand Oaks, CA

  26. Methods (derived from Etanercept Phase III trial in PsA) Patient Rating-Based MCID Not At Extremely All Important Important 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 Minimally Important Very Important Mean change from baseline in HAQ Disability Score for those who improved 0.5 1.0 1.5 2.0 2.5 3.0 0.0

  27. Methods Data-Driven Approach MCID • Upper bound of 95% confidence interval of standard error of measurement (SEM) for HAQ • SEM = σ baseline HAQ 1- rbaselineHAQ whereσ=standard deviation r = Cronbach’s alpha coefficient

  28. Results

  29. Participation • 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

  30. Action 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

  31. Patient 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?) • Global In 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) • Skin In all the ways your PSORIASIS affects you, how would you rate the way you feel at this time? (10 cm line)

  32. Biomarkers 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)

  33. Immunohistochemistry • Inflammatory cells • CD3, CD38, CD55, CD68, granzyme B • Adhesion molecules • ICAM-1, VCAM-1, E-selectin • Angiogenesis • vWF, VEGF, v3, bFGF • Matrix metalloproteinases • MMP1, MMP3, MMP13, TIMP • Cytokines • IL-1, TNF, IL-6, IL-18

  34. GRAPPA PsA Treatment Guidelines Peripheral Arthritis Skin and Nail Disease Axial Disease Dactylitis Enthesitis Initiate Therapy NSAIDs, IA steroids, DMARDs (MTX, CsA, SSZ, LEF), Biologics (anti-TNF) Initiate Therapy Topicals PUVA/UVB DMARDs (MTX, CsA) Biologics (anti-TNF, etc) Initiate Therapy NSAID PT Biologics (anti-TNF) Initiate Therapy NSAID Injection Biologics (anti-TNF) Initiate Therapy NSAID Injection Biologics (anti-TNF) Reassess Response to Therapy and Toxicity 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.

  35. Quality of evidence Evidence Recommendation 1A meta-analysis of RCT 1B one or more RCT Grade A 2A one or more CT 2B well-designed studies Grade B Grade C 3 non-experimental studies 4 expert opinions, clinical experience Grade D Soriano ER, McHugh GRAPPA, San Antonio, 2004 MJ.

  36. Level evidence: effect size, side-effect profile Means evidence against. NE: negligible effect; SE: Small effect; ME: Medium effect; LE: Large effect; HE: Huge effect

  37. A 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?

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