The New RA Criteria: Impact on clinical trials and patients

1. The New RA Criteria: Impact on clinical trials and patients Yusuf Yazıcı, MD Assistant Professor of Medicine, NYU School of Medicine Director, Seligman Center for Advanced Therapeutics & Behcet’s Syndrome Evaluation, Treatment and Research Center NYU Hospital for Joint Diseases

2. Outline • Why do we need a new criteria? • How the new criteria were developed? • ACR/EULAR classification criteria for RA • What are the possible shortcomings/consequences of the new criteria?

3. RA Classification Criteria 1987 Morning stiffness Arthritis in three or more joint areas Soft tissue swelling or fluid (not bony overgrowth) observed by a physician, present simultaneously for at least 6 weeks Arthritis of hand joints Swelling of wrist, metacarpophalangeal (MCP) or proximal interphalangeal (PIP) joints for at least 6 weeks Symmetric arthritis Simultaneous involvement of the same joint areas (defined in 2) on both sides of the body (bilateral involvement of PIP, MCP or metatarsophalangeal [MTP] joints is acceptable without absolute symmetry) for at least 6 weeks ARA 1987 revised criteria. Arthritis Rheum 1988.

4. RA Classification Criteria 1987 (2) 5. Rheumatoid nodules Subcutaneous nodules over bony prominences, extensor surfaces or in juxta-articular regions, observed by a physician 6. Rheumatoid factor (RF) Detected by a method positive in fewer than 5% of normal controls 7. Radiographic changes Typical of RA on posteroanterior hand and wrist radiographs; it must include erosions or unequivocal bony decalcification localized in or most marked adjacent to the involved joints (osteoarthritis [OA] changes alone do not qualify) Feet erosions

5. RA criteria • 1987 • Distinguish RA patients with established disease from those with a combination of other definite rheumatologic diagnosis • ACR 1987 criteria are not helpful in achieving the goal of EARLY and EFFECTIVE intervention • 2010 • Focus on early disease to try to determine features that lead to earlier treatment • “most predictive leading to DMARD use”

7. New RA Classification Criteria • 2010 revised ACR/EULAR criteria for the classification of RA were developed to enable earlier diagnosis

8. PhasesofDevelopment

9. Cohorts • 3115 pt from 9 cohorts, “not thought to have evidence of another possible diagnosis” • Analysis • Amsterdam • Austria • ESPOIR • Manchester • Norway • REACH • Gold standard • “MTX start in the next 12 months” • Validation • Leeds • Leiden • Toronto

10. Entrycriteria Inclusion Exclusion Definitive diagnosis at baseline Disease duration >3 yr • After yr 2000 (widespread use of MTX) • >1 swollen joint • MTX decision depends on physician (not treatment rule of cohort)

11. Phase 1 Baselinedata • Gender • Age • SJC • TJC • Joint swelling by region • Joint tenderness by region • HAQ • Morning stiffness • RF • ACPA • ESR • CRP

12. Univariateanalysis Funovits J et al. Ann Rheum Dis 2010;69:1589-1595

13. Univariateanalysis No association Associated Individual joint regions SJC/TJC ESR CRP RF Anti-CCP HAQ • Large joints (S/T) • Elbows • Shoulders • Knees • MTP (T) • Ankle involvement (S/T) • Morning stiffness • Symmetry of involvement • Except: MCP/wrist (S)

14. Factor analysis SwollenMCP Swollen PIP Swollen wrist Hand tenderness (MCP, PIP, wrist) Acute phase response Serology (RF/ACPA)

15. Multivariate logistic regression model

16. Phase2 • Ensure that experts’ perspectives were captured • Important factors not captured in cohort data might be identified

17. Expertpanel 12 12

18. Phase2

20. Phase 2 Consensus meeting • Each case was discussed • Reasons for disagreement were identified • Evidence from Phase 1 was used for discussion and decision • List of factors will be in the final criteria set identified

21. Draft criteria and categories • Joint involvement (pattern and distribution) • 1 medium large joint • Asymmetric medium large joints • Symmetric medium large joints • 1-3 small joints • >=4 asymmetric small joints • >=4 symmetric small joints • Serology (ACPA and RF) • Negative • Low positive • High positive • Acute phase reactants (ESR and CRP) • Normal • abnormal • Duration of synovitis • <4 weeks • 4-8 weeks • >8 weeks

22. Consensus was considered achieved when all participants either indicated “agreement” or indicated they could accept the “majority decision” Derives point values/ weights that reflect decision maker’s preferences

24. Phase3Determine the optimal cut point for definite RA Consensus based 65.7 Expert panel was asked to examine the rankings of paper cases based on new scoring and indicate their opinion at which the cases changed from probable to definite RA

25. Phase3Determine the optimal cut point for definite RA Consensus based Data driven New scoring system was applied to 3 cohorts ROC curves of the scoring system discriminating those who did and who did not receive MTX 65.7 Expert panel was asked to examine the rankings of paper cases based on new scoring and indicate their opinion at which the cases changed from probable to definite RA

26. Phase3Determine the optimal cut point for definite RA Consensus based Data driven New scoring system was applied to 3 cohorts ROC curves of the scoring system in 3 cohorts discriminating those who did and who did not receive MTX 65.7 Expert panel was asked to examine the rankings of paper cases based on new scoring and indicate their opinion at which the cases changed from probable to definite RA France 0.66 Norway 0.82 Rotter 0.69

27. Phase3 Validation Among participants who received MTX within year from symptom onset The proportion score >=6

28. New ACR/EULAR RA Criteria RA can be classifiable or diagnosed with a score ≥6: • Joints (0–5) • 1 large joint 0 • 2–10 large joints 1 • 1–3 small joints (large jts excluded) 2 • 4–10 small joints (large jts excluded) 3 • >10 joints (at least 1 small joint) 5 • Serology (0–3) • Negative RF and negative anti-CCP 0 • Low positive RF or anti-CCP 2 • High positive RF or anti-CCP 3 • Symptom duration (0–1) • <6 weeks 0 • ≥6 weeks 1 • Acute phase reactants (APR) (0–1) • Normal CRP and ESR 0 • Abnormal CRP or ESR 1 Aletaha D. Ann Rheum Dis 2010

31. In addition… • Instead of having 2 sets of criteria • New criteria can be applied historically • Erosion • Long standing disease with historical evidence • Early disease may not fulfill but later may

32. Applying the New Classification Criteria for Clinical Trial Eligibility • Study aimed to determine: • Proportion of patients with recent onset EIA* the revised criteria identify as having RA • Patients’ eligibility for ERA clinical trials • N=1146 patients enrolled in CATCH • New criteria were applied to determine what proportion of EIA patients fulfill new criteria at BL • Identified patients with DAS28 ≥3.2 considered potentially eligible for ERA clinical trial Bykerk et al. Abstract #659 *early inflammatory arthritis, < 1 year

33. New Criteria Identify More Patients Eligible for ERA Clinical Trials • Applying 1987 criteria on 648 eligible patients: • 441 (68%) met 1987 criteria ERA at BL • 201 (31%) had undifferentiated IA (UIA) • Applying 2010 criteria: • 82% of the 441 who met 1987 criteria now met new 2010 criteria for ERA at BL • 57% of the 201 with UIA now diagnosed with ERA; 79% of these patients had DAS28>3.2 • According to new criteria, new patients previously diagnosed with UIA actually have ERA Bykerk et al. Abstract #659

34. Agreement Between 1987 and 2010 Classification Criteria • ESPOIR cohort • N=813 pt ERA followed for 6 m during the first 2 y • Agreement based on Kappa coefficient calculation • Of 811 patients with available data at baseline • 579 (71.4%) met 1987 criteria • 641 (79.0 %) met 2010 criteria • Kappa coefficient remained fair: 0.42 [95% CI: 0.33; 0.51]. •  2010 criteria identify more patients than 1987 criteria as having RA. • 2010 set failed to identify as RA patients with symmetrical sero-negative arthritis with limited joint involvement. Fautrel et al. Abstract #1760

35. Problems with the new criteria • Definition of RA • Is “decision to initiate MTX” the best surrogate marker? • “all other possible causes for synovitis need to be excluded” • From classification to diagnosis • Early vs old • No validation in non-RA patients • Circular reasoning • Databases used were of “different origins” and “highly variable” • Should factor analysis also include (and compare) pts initiated MTX and pts not given MTX? • Can consensus be (really) achieved with choices of ”agree” and “accept the majority decision”? • Can ROC curve analysis (Phase 3) help to distinguish patients with RA from those of having other diagnosis?

36. Discussion • Extrapolation of current literature • Planning of future trials • Basic research with new criteria • Absence of erosions • Absence of symmetric joint involvement • New treatment goals • New remission criteria • Aggressive Tx for less active disease • Cost of early Tx with biologicals • Use of local ref values for acute phase reactants

38. New ACR/EULAR RA remission criteria • Developed by committee using data from clinical trials • Assessed ability of candidate measures to predict: damage (change 0 in vdH/S score) and function (change in HAQ 0; HAQ 0.5) over 2 ys • Best results obtained by 2 proposed definitions: • TJC and SJC and CRP and Pt Global all 1 OR • SDAI 3.3 [SDAI = TJC (28) + SJC (28) + Phys global (0–10 cm VAS) + Pt global (0–10 cm VAS) + CRP (mg/dL). Cutpoints: 3.3/11/26 (Smolen J, et al. Rheumatology. 2003;42:244–57.)] Stringent new RA remission criteria proposed Felson DT, et al. ACR 2010, Atlanta, #2108

39. Conclusions • In God we trust, all others must bring data • Edwards Deming 1900-1993 • New criteria are not ready for prime time • Not clear how it helps the practicing MD