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Redefining remission in rheumatoid arthritis a joint ACR/EULAR/OMERACT initiative

This article discusses the background and progress made in redefining remission in rheumatoid arthritis (RA) through the collaboration of various organizations. The focus is on developing a uniform definition of remission that is truthful, discriminative, and feasible. The concept of remission and current definitions are explored, highlighting the need for more accurate and reliable methods of assessing disease activity.

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Redefining remission in rheumatoid arthritis a joint ACR/EULAR/OMERACT initiative

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  1. Redefining remissionin rheumatoid arthritisa joint ACR/EULAR/OMERACT initiative Maarten Boers Department of Clinical Epidemiology and Biostatistics VU University Medical Center Amsterdam

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

  3. 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 redefining remission in RA

  4. 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) redefining remission in RA

  5. OMERACT Filter to select measures To be applicable in its intended setting, a measure must be • truthful • discriminative • feasible redefining remission in RA

  6. OMERACT Filter Truth • free from bias • criterion, construct validity • relevant • content, face validity redefining remission in RA

  7. 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 redefining remission in RA

  8. OMERACT Filter Feasibility • time • costs • interpretability redefining remission in RA

  9. 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. redefining remission in RA

  10. 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? redefining remission in RA

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

  12. 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) redefining remission in RA

  13. 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! redefining remission in RA

  14. 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...” redefining remission in RA

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

  16. 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 redefining remission in RA

  17. 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% redefining remission in RA

  18. 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 redefining remission in RA

  19. 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) redefining remission in RA

  20. 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 redefining remission in RA

  21. 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 redefining remission in RA

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

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

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

  25. 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 redefining remission in RA

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

  27. 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. redefining remission in RA

  28. 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 redefining remission in RA

  29. 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 redefining remission in RA

  30. 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 redefining remission in RA

  31. 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? redefining remission in RA

  32. 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? redefining remission in RA

  33. 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 redefining remission in RA

  34. Progress to date • Challenges* • Systematic review of evidence for validity of current definitions • Formulation of candidate definitions • 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 redefining remission in RA

  35. 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. redefining remission in RA

  36. 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. redefining remission in RA

  37. 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 redefining remission in RA

  38. 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 redefining remission in RA

  39. 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) redefining remission in RA

  40. 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 redefining remission in RA

  41. Likelihood Ratio – PREMIER/ERA/TEMPO redefining remission in RA

  42. 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 redefining remission in RA

  43. 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 redefining remission in RA

  44. 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 redefining remission in RA

  45. 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? redefining remission in RA

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

  47. If this were the ONLY measure : 75th percentiles; VAS 0 to 100 redefining remission in RA

  48. If there were other measures in the definition and these all point to remission : 75th percentiles; VAS 0 to 100 redefining remission in RA

  49. Cut points redefining remission in RA

  50. Residual disease activity redefining remission in RA

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