1. Redefining remission in rheumatoid arthritis a joint ACR/EULAR/OMERACT initiative Maarten Boers Department of Clinical Epidemiology and Biostatistics VU University Medical Center Amsterdam

2. redefining remission in RA2 Outline Background/Task Decisions and research agenda made at ACR 2007 Progress to date

3. redefining remission in RA3 Remission team George Wells, Ottawa Josef Smolen, Vienna Lilian van Tuyl, Amsterdam Bin Zhang, Boston Julia Funovits, Vienna ACR-EULAR ad hoc committee (40+ members) co-chairs: Maarten Boers, Amsterdam David Felson, Boston

4. redefining remission in RA4 Background Increasing numbers of patients reach remission Abundance of remission definitions ‘strict’ definitions:ACR, CDAI/SDAI, PAS/RAPID3 ‘loose’ definitions:DAS, DAS28, mACR, SJC0/TJC0/ESR10, MDA Need for a uniform definition (RA trials, practice)

5. redefining remission in RA5 OMERACT Filter to select measures To be applicable in its intended setting, a measure must be truthfuldiscriminativefeasible

6. redefining remission in RA6 OMERACT Filter Truth free from bias criterion, construct validityrelevant content, face validity

7. redefining remission in RA7 OMERACT Filter Discrimination able to distinguish between states that are of interest: at one time point at different time points reliability, reproducibility, sensitivity to change

8. redefining remission in RA8 OMERACT Filter Feasibilitytimecostsinterpretability

9. redefining remission in RA9 Etymology Remittere (L): to send back; to decrease; to relax... Remission (med dictionary): An abatement or lessening of the manifestations of a disease. (Wiki): The state of absence of disease activity in patients with a chronic illness, with the possibility of return of disease activity.

10. redefining remission in RA10 Concept: key points State, not change or transition Pattern of transitions interesting research area Time spent in state not part of concept Absence of disease activity How to be sure?

11. redefining remission in RA11 Concept: key points State, not change or transition Absence of disease activity Related but not identical: Cure: disease does not return Arrest: disease process is stopped Intermission: period of no activity between two periods of active diseaseAntithetical Relapse: return of disease activity Flare: substantial increase of disease activity

12. redefining remission in RA12 Current definitions: Pinals (1981) 5 or more must be fulfilled for at least 2 consecutive months: Morning stiffness not exceeding 15 minutes No fatigue No joint pain (by history) No joint tenderness or pain on motion No soft tissue swelling in joints or tendon sheaths ESR (W) <30 mm/h (f); <20 mm/h (m)

13. redefining remission in RA13 Pinals 3 groups classified according to the rheumatologist: complete remission, partial remission, active disease Sensitivity 72%, specificity 90% against partial remission Using 4 out of 6: sens 90%, spec 62% Read the discussion!

14. redefining remission in RA14 Pinals “A major obstacle to developing criteria for remission in RA is the difficulty in ascertaining the absence of inflammation by methods that are reliable and also convenient in clinical settings...”

15. redefining remission in RA15 Pinals “A major obstacle...” “Substantial variation appears to exist in the concept of remission within the group of participating rheumatologists...”

16. redefining remission in RA16 DAS/DAS28 DAS: Ritchie joint index and 44 swollen joint ct DAS28: 28 tender & swollen joint count Both use a ‘general health’ VAS (0-100) DAS28 = 0.56 sqrt (TJC) + 0.28 sqrt (SJC) + 0.70 ln (ESR) + 0.014 GH. DAS28 remission: 2.6 DAS remission: 1.6

17. redefining remission in RA17 DAS28 remission (1996) Validation against ARA criteria in Nijmegen obs. data, moderately active disease ‘mACR’: Fatigue not assessed Remission defined as 4 out of 5 remaining criteria 3 months instead of 2 months period; single visit data used Sens and Spec against mACR 87%

18. redefining remission in RA18 SDAI/CDAI remission (2005) SDAI = (28TJC) + (28SJC) + MDGA + PGA + CRP CDAI = (28TJC) + (28SJC) + MDGA + PGA SDAI remission = 3.3 CDAI remission = 2.8 Developed in patient profile exercise and validated in observational datasets

19. redefining remission in RA19 PAS/RAPID3 (2005) PAS = 1/3 [(HAQ * 3.33) + pain + PGA] PAS remission: 1.25 (judgment) RAPID3 = 1/3 [(HAQ * 3.33) + pain + PGH] RAPID3 remission: 1.0 (judgment)

20. redefining remission in RA20 MDA (minimal disease activity; 2003) State of disease activity deemed a useful target of treatment by patient and physician, given current treatment possibilities and limitations. Derived from profile exercises at OMERACT Initial ‘remission’ decision node: TJC = 0, SJC = 0, ESR = 10 or less

21. redefining remission in RA21 MDA (minimal disease activity) Initial ‘remission’ decision node: TJC = 0, SJC = 0, ESR = 10 or less. If not in remission, choose system: DAS 2.85 or less 5 out of 7 core set criteria Pain  2 SJC  1 TJC  1 HAQ  0.5 MDGA  1.5 PGA  2 ESR  20

22. redefining remission in RA22 Remission in Kansas ESR missing in about 50% of 849 patients Kappa’s between def’s 0.09 - 0.51

23. redefining remission in RA23QUEST-RA 5519 patients from 62 sites in 22 countries Tetrachor. correlation between def’s 0.63-0.91

24. redefining remission in RA24Vienna 948 patients in obs database, most with low disease activity Kappa’s between def’s 0,36 - 0,89

25. redefining remission in RA25 Background: Conclusion ACR, CDAI/SDAI, PAS/RAPID3 ‘strict’ Applying the 2 month duration requirement in the ACR criteria probably decreases prevalence by at least 50% mACR and SJC0/TJC0/ESR10 ‘lax’ These and DAS28 remission criterion resemble DAS28 MDA

26. redefining remission in RA26 Task A joint ACR / EULAR / OMERACT initiative to: Study current remission definitions Explore the theoretical concept of remission Re-define remission in RA

27. redefining remission in RA27 Decisions made at ACR 2007* Conceptual issues: A strict definition: no clinical disease lack of damage progression over time Not in the definition: Long term outcomes (phys. function, damage): used to determine validity of a new definition Therapy *Van Tuyl, LHD et al. Arthritis Rheum (AC&R) 2009;61:704-10.

28. redefining remission in RA28 Decisions made at ACR 2007 (2) Measurement issues Definition should include as a minimum: Tender joint count (full joint count preferred) Swollen joint count (idem) An acute phase reactant Definition should not include: Duration of remission

29. redefining remission in RA29 Decisions made at ACR 2007 (3) Potential setting and use A remission definition for practice settings is needed and part of the task Trial and practice definitions should be closely linked

30. redefining remission in RA30 Research agenda – ACR 2007 Conceptual issues: Assessment of reliability/reproducibility of the remission definition Predictive validity of candidate definition against X-rays and physical function Relationship between remission and MDA and longer term outcome (function, disability) The role of new imaging (eg. US and MRI) in the definition, measurement, assessment and monitoring of the remission

31. redefining remission in RA31 Research agenda – ACR 2007 (2) Measurement issues What disease activity measures to include? Exact question in physician and patient globals? What about between-physician variability? Do we need 28 joints or more? Should we give priority to specific joints? Should we ask patients directly if they feel they are in remission? For patients in remission at one time point, what is the likelihood to be in remission at adjacent time points?

32. redefining remission in RA32 Research agenda – ACR 2007 (3) Potential settings and uses Are there equivalent measures, easier to use in practice, which give the same information? Can the practice setting definition include fewer measures whilst retaining a strong resemblance to the trial definition?

33. redefining remission in RA33 Progress to date Challenges* No good previous example on how to do this... Initial delays caused by difficulties in obtaining datasets Trial datasets only contain information on the core set No observational datasets in current exercise Systematic review of evidence for validity of current definitions Formulation of candidate definitions Cutpoints chosen from survey by Aletaha Sparse and comprehensive combinations of core measures

34. redefining remission in RA34 Progress to date Challenges* Systematic review of evidence for validity of current definitions Formulation of candidate definitions predict a good outcome? Validation: How well does presence of remission by this candidate definition predict a good outcome? stability in damage stability in physical function Further validation: analyses in subsets of patients with a poor prognosis good outcome defined as stability in BOTH damage and function

35. redefining remission in RA35 Progress to date Challenges* Systematic review of evidence for validity of current definitions Formulation of candidate definitions Validation: Further validation: Committee survey on acceptable levels of residual activity in measures Determination of residual disease activity in candidate definitions This Saturday: selection of short list/provisional def.

36. redefining remission in RA36 Systematic review of evidence for validity of current definitions Search: 1138 records, 14 studies (!) In all included studies: Relationship between remission and long term structural damage or disability Patients in remission (various definitions) showed less deterioration of function and radiographic progression compared to patients not in remission. *Van Tuyl, LHD et al. Arthritis Rheum (AC&R) 2009;in press.

37. redefining remission in RA37 Formulation of candidate definitions indices: DAS28, CDAI, SDAI original cut points plus stricter cut points for DAS28 plus more relaxed cut points for CDAI/SDAI core set: TJC, SJC, CRP/ESR +/– other measures at cut points 0 and 1

38. redefining remission in RA38 Validation: Gold standard outcome between y1 and y2: no damage progression (SvdH =< 0) HAQ good (=<0.5) and no deterioration (=<0) Does presence of remission by definition # at 6 months lead to increased prevalence of the gold standard outcome? Answer: yes, better for HAQ than damage, but no choice between definitions possible

39. redefining remission in RA39 Challenges Lack of damage progression frequently seen in patients not in remission, and even more so in intensive treatment & biological trials... Normal HAQ difficult to attain in longstanding disease (irreversibility and comorbidity)

40. redefining remission in RA40 Datasets Randomized controlled trials ASPIRE, ERA, PREMIER, TEMPO (MTX, biologicals; 1-2 years) Extension trials PREMIER (5 years; no treatment assignment, from year 3 onward all patients received adalimumab)COBRA

41. redefining remission in RA41 Likelihood Ratio – PREMIER/ERA/TEMPO Remission Criteria HAQ6moHAQ 12 mo SHARP6mo SHARP12mo DAS28< 2.0 2.32.61.51.8 < 2.2 2.52.91.61.7 < 2.6 2.63.61.82.2 CDAI<= 2.8 4.55.31.91.4 <= 3.5 2.94.22.11.7 <= 4.0 2.63.31.81.8 SDAI<= 3.3 3.95.42.21.7 <= 4.0 2.94.32.21.8 <= 5.0 2.63.72.01.8 SJC28= 0 1.72.41.21.4 TJC28= 0 2.11.51.82.0 CRP<= 1 1.21.21.21.1 Pain= 0 4.25.51.51.6

42. redefining remission in RA42 Residual disease activity 1 core set measure: 30-40 (CRP 60-70) 2 measures: 20-30 3 measures: 15-20 4 measures: 10-15 5 measures: 8-12 6 measures: <10

43. redefining remission in RA43 Further validation: Repeat exercise in poor prognosis patients RF/aCCP+, damage at baseline Repeat exercise in MTX treated patients Redefine outcome: no damage progression AND HAQ good & stable Does presence of remission by definition # at 6 months lead to increased prevalence of the gold standard outcome? Answer: yes, better for HAQ than damage, but no choice between definitions possible

44. redefining remission in RA44 Face validity Describe the residual disease activity that each definition allows in term of: Swollen joint count Tender joint count ESR / CRP Physician global assessment Patient global assessment Pain

45. redefining remission in RA45 Committee survey Two questions: If this were the ONLY measure to define remission, what is the maximum level of disease activity you are willing to accept? If there were other measures in the definition and these all point to remission, what is the maximum level of disease activity you are willing to accept in this measure?

46. redefining remission in RA46 Methods 25 respondents VAS scales from 0 to 100 75 th percentiles

47. redefining remission in RA47 If this were the ONLY measure : If this were the ONLY measure : TJC282joints TJC full2joints SJC281joints SJC full1joints ESR25mm CRP10Mg/l Physician global10mm Patient global20mm Pain20mm HAQ0.5points Fatigue25mm 75th percentiles; VAS 0 to 100

48. redefining remission in RA48 If there were other measures in the definition and these all point to remission : If there were other measures in the definition and these all point to remission : TJC283joints TJC full3joints SJC282joints SJC full2joints ESR30mm CRP15Mg/l Physician global20mm Patient global30mm Pain30mm HAQ1.0points Fatigue40mm 75th percentiles; VAS 0 to 100

49. redefining remission in RA49 Cut points strictmiddlerelaxed TJC28≤1≤2≤3joints SJC28≤1 ≤2joints ESR≤20≤25≤30mm CRP≤10 ≤15mg/l Physician global≤10 ≤20mm Patient global≤10≤20≤30mm Pain≤10≤20≤30mm

50. redefining remission in RA50 Residual disease activity Strict cutpointsTJC28SJC28CRPPhGPtGPain TJC+SJC+CRP1110608081 TJC+SJC+CRP+PhG1110107377 TJC+SJC+CRP+PtG1110201015 TJC+SJC+CRP+pain1110406010 TJC+SJC+CRP+PhG+PtG1110101027 TJC+SJC+CRP+PhG+pain1110104710 TJC+SJC+CRP+PtG+pain1110201010 TJC+SJC+CRP+PhG+PtG+pain1110101010 DAS28<2.672125508095 SDAI ≤ 3.32227202327

51. redefining remission in RA51 Residual disease activity Middle cutpointsTJC28SJC28CRPPhGPtGPain TJC+SJC+CRP2110608088 TJC+SJC+CRP+PhG2110107388 TJC+SJC+CRP+PtG2110482049 TJC+SJC+CRP+pain2110506020 TJC+SJC+CRP+PhG+PtG2110102037 TJC+SJC+CRP+PhG+pain2110104720 TJC+SJC+CRP+PtG+pain2110302020 TJC+SJC+CRP+PhG+PtG+pain2110102020 DAS28<2.672125508095 SDAI ≤ 3.32227202327

52. redefining remission in RA52 Residual disease activity Relaxed cutpointsTJC28SJC28CRPPhGPtGPain TJC+SJC+CRP3214609088 TJC+SJC+CRP+PhG3214207388 TJC+SJC+CRP+PtG3214543049 TJC+SJC+CRP+pain3214547030 TJC+SJC+CRP+PhG+PtG3214203049 TJC+SJC+CRP+PhG+pain3214207029 TJC+SJC+CRP+PtG+pain3214543030 TJC+SJC+CRP+PhG+PtG+pain3214203029 DAS28<2.672125508095 SDAI ≤ 3.32227202327

53. redefining remission in RA53 Residual disease activity Strict cutpointsTJC28SJC28CRPPhGPtGPain TJC+SJC+CRP1110608081 TJC+SJC+CRP+PhG1110107377 TJC+SJC+CRP+PtG1110201015 TJC+SJC+CRP+pain1110406010 TJC+SJC+CRP+PhG+PtG1110101027 TJC+SJC+CRP+PhG+pain1110104710 TJC+SJC+CRP+PtG+pain1110201010 TJC+SJC+CRP+PhG+PtG+pain1110101010 DAS28<2.672125508095 SDAI ≤ 3.32227202327

54. redefining remission in RA54 Residual disease activity Middle cutpointsTJC28SJC28CRPPhGPtGPain TJC+SJC+CRP2110608088 TJC+SJC+CRP+PhG2110107388 TJC+SJC+CRP+PtG2110482049 TJC+SJC+CRP+pain2110506020 TJC+SJC+CRP+PhG+PtG2110102037 TJC+SJC+CRP+PhG+pain2110104720 TJC+SJC+CRP+PtG+pain2110302020 TJC+SJC+CRP+PhG+PtG+pain2110102020 DAS28<2.672125508095 SDAI ≤ 3.32227202327

55. redefining remission in RA55 Percentage in remission Total DMARD mono Biological mono Combi 1230380330520 TJC+SJC+CRP+PhG1410926 TJC+SJC+CRP+PtG12 9722 TJC+SJC+CRP+PhG+PtG10 8720 TJC+SJC+CRP+PhG+pain10 8620 TJC+SJC+CRP+PhG+PtG+pain9 7618 1510925 DAS28 < 2.621191735 SDAI ≤ 3.31410826 number of patients

56. redefining remission in RA56 Last Saturday TJC+SJC+CRP+PtG got highest marks 5 def’s to remain for further testing in observational datasets agenda at OMERACT 10 presentation of final validation exercises stability/reliability start development of patient ‘absence of disease’ definition and measurement collaborate with OMERACT RA Flare group

57. redefining remission in RA57 Conclusion Process characteristic of OMERACT* Data-driven consensus OMERACT Filter of Truth, Discrimination, Feasibility Continuum of remission, minimal disease activity, active disease along the same feasible scale Strong impetus to start development of patient definition in collaboration with RA flare group OMERACT 10 in Borneo May 3-8, 2010: www.omeract.org