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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 Determination of patient global assessment Axial assessment Enthesial assessment Dactylitis assessment PsA treatment guidelines PsA: Classification Schema Moll & Wright, Vasey and Espinosa, Fournie, Bennett, Gladman, McGonagle CASPAR (Philip Helliwell) Psoriatic arthritis – disease classification and diagnosis Psoriatic arthritis Inflammatory arthritis – Oligoarticular, polyarticular, DIP, axial, mutilans Psoriasis (Usually) negative rheumatoid factor Moll and Wright 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 CASPAR – development and validation of classification criteria for PsA A prospective multicentre international case control study 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 – 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) Clinical features Case Control 35 30 % 25 20 15 10 5 0 Dactylitis Enthesitis DIP involvement 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 Psoriasis Psoriasis DOR = 581 Nail dystrophy DOR = 59 Family history of psoriasis DOR = 9.2 Dactylitis Dactylitis DOR = 19.3 DIP disease DIP disease DOR = 6.4 Clinical enthesitis Any tender enthesis DOR = 3.8 Inflammatory heel pain DOR = 2.7 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 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; chisquare) ROC changes DAS28 4 Variables youden .784 cutoff1 1.27 sens .880 spec .904 ROC changes 68 Tender Joint Count youden .513 cutoff1 6.00 sens .753 spec .759 ROC changes 66 swollen joint count youden .464 cutoff1 6.00 sens .654 spec .810 ROC changes CRP youden .324 cutoff1 -.10 sens .935 spec .389 Discrimination IMPACT Criterium EULAR28 Good + moderate Good EULAR28 (DAS28 crp) Good + moderate Good Placebo (n=52) Drug (n=52) %improved %improved 26% 0% 92% 60% 30% 7% 88% 52% 2 MH 53.4 p-value <0.0001 35.4 <0.0001 48.6 <0.0001 EULAR Good + moderate Good 26% 0% 88% 63% ACR20 ACR50 ACR70 10% 0% 0% 67% 48% 29% 36.2 32.6 17.4 <0.0001 <0.0001 <0.0001 PsARC 30% 82% 27.9 <0.0001 Discrimination Etanercept Criterium EULAR28 Good + moderate Good Placebo (n=30) Drug (n=30) %improved %improved 2 MH 15% 8% EULAR28 (DAS28 crp) Good + moderate 15% Good 4% p-value 26.2 <0.0001 23.3 <0.0001 22.9 <0.0001 93% 52% 86% 39% EULAR Good + moderate Good 12% 4% 81% 44% ACR20 ACR50 ACR70 15% 4% 0% 73% 50% 13% 19.6 14.8 3.8 <0.0001 0.0001 0.05 PsARC 33% 90% 19.3 <0.0001 Inflammatory Enthesopathy Enthesitis Periosteal new bone formation Subchondral bone inflammation and resorption Bone McGonagle D. Arthritis Rheum. 1999. 42:1080-1086. MASES Index .. .. .. .. 13 sites 0 = no pain ... . . Heuft-Dorenbosch Ann Rheum Dis 2003 1 = pain 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) 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 Methods (derived from Etanercept Phase III trial in PsA) Patient Rating-Based MCID Not At All Important How important to you is the amount of change in your physical limitations (such as limitations in walking, standing, gripping reaching, etc.) 1 Extremely Important 2 3 4 5 Minimally Important 6 7 Very Important Mean change from baseline in HAQ Disability Score for those who improved 0.0 0.5 1.0 1.5 2.0 2.5 3.0 Methods Data-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 Results Threshold 95% for delta in Confidence Type of MCID HAQ Scores Interval SEM-Based MCID Patient Rating-Based MCID Patient Rating-Based Major Clinically Important Difference 0.40 0.30 N.A. 0.24-0.35 2.2.5 2.1.5 0.65 0.57-0.72 2.1.5 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 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 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) 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) Immunohistochemistry 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 Guidelines Peripheral Arthritis Skin and Nail Disease Axial Disease Dactylitis Enthesitis Initiate Therapy Initiate Therapy Initiate Therapy Initiate Therapy Initiate Therapy NSAIDs, IA steroids, DMARDs (MTX, CsA, SSZ, LEF), Biologics (anti-TNF) Topicals PUVA/UVB DMARDs (MTX, CsA) Biologics (anti-TNF, etc) NSAID PT Biologics (anti-TNF) NSAID Injection Biologics (anti-TNF) 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. Quality of evidence Evidence Recommendation 1A meta-analysis of RCT 1B one or more RCT 2A one or more CT 2B well-designed studies Grade A Grade B 3 non-experimental studies Grade C 4 expert opinions, clinical experience Grade D Soriano ER, McHugh GRAPPA, San Antonio, 2004 MJ. Level evidence: effect size, side-effect profile 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 Xray -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: negligible effect; SE: Small effect; ME: Medium effect; LE: Large effect; HE: Huge effect 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?