1. GRAPPA Examples 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 – disease classification and diagnosis Moll and Wright Psoriatic arthritis Inflammatory arthritis – Oligoarticular, polyarticular, DIP, axial, mutilans Psoriasis (Usually) negative rheumatoid factor

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. CASPAR – development and validation of classification criteria for 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 control study

7. CASPAR – validation of classification 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)

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

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

11. Dactylitis DOR = 19.3 Dactylitis

12. DIP disease DOR = 6.4 DIP disease

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

14. Outcome Measurements in PSA preliminary results from IMPACT and Etanercept PhaseII trials OMERACT 7 C. Antoni J. Fransen W. Uter P. Mease on behalf of GRAPPA

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 changes DAS28 4 Variables youdencutoff1sensspec.7841.27.880.904

17. ROC changes 68 Tender Joint Count youdencutoff1sensspec.5136.00.753.759

18. ROC changes 66 swollen joint count youdencutoff1sensspec.4646.00.654.810

19. ROC changes CRP youdencutoff1sensspec.324-.10.935.389

20. Discrimination IMPACT Placebo (n=52)Drug (n=52) Criterium%improved%improved  2 MHp-value EULAR2853.4<0.0001 Good + moderate26%92% Good0%60% EULAR28 (DAS28 crp) Good + moderate30%88%35.4<0.0001 Good7%52% EULAR48.6<0.0001 Good + moderate26%88% Good0%63% ACR2010%67%36.2<0.0001 ACR500%48%32.6<0.0001 ACR700%29%17.4<0.0001 PsARC30%82%27.9<0.0001

21. Discrimination Etanercept Placebo (n=30) Drug (n=30) Criterium%improved%improved  2 MHp-value EULAR2826.2<0.0001 Good + moderate15%93% Good8%52% EULAR28 (DAS28 crp)23.3<0.0001 Good + moderate15%86% Good4%39% EULAR22.9<0.0001 Good + moderate12%81% Good4%44% ACR2015%73%19.6<0.0001 ACR504%50%14.80.0001 ACR700%13%3.80.05 PsARC33%90%19.3<0.0001

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

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

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 Mease 1 Rita Ganguly 2, L. Wanke 3, Amitabh Singh 2 1 Seattle Rheumatology Associates, Seattle, WA; 2 Wyeth Research, Collegeville, PA; 3 Amgen, Thousand Oaks, CA

26. Methods (derived from Etanercept 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.) 12345671234567 Not AtExtremely All Important Important 0.0 0.51.01.52.02.53.0 Mean change from baseline in HAQ Disability Score for those who improved Minimally Important Very Important

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- r baseline HAQ where σ=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

31. 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

32. 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)

33. 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)

34. 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

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

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

37. SSZMTXCyALFNGoldAZAETNINF Evidence symptom control 1A2B1B -1A2B1B Effect sizeSENEMELESEMEHE Evidence X- ray -3 34 –1B– ToxicityLow HighLowMedLow Recomm. grade? A-BB A-ABAA Means evidence against. NE: negligible effect; SE: Small effect; ME: Medium effect; LE: Large effect; HE: Huge effect Level evidence: effect size, side-effect profile

38. 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?