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American College of Rheumatology/European League Against Rheumatism Provisional Definition of Remission in Rheumatoid Arthritis for Clinical Trials
  1. David T Felson1,2,
  2. Josef S Smolen3,
  3. George Wells4,
  4. Bin Zhang5,
  5. Lilian H D van Tuyl1,
  6. Julia Funovits6,
  7. Daniel Aletaha6,
  8. Cornelia F Allaart7,
  9. Joan Bathon8,*,
  10. Stefano Bombardieri9,
  11. Peter Brooks10,
  12. Andrew Brown11,
  13. Marco Matucci-Cerinic12,
  14. Hyon Choi4,
  15. Bernard Combe13,
  16. Maarten de Wit14,
  17. Maxime Dougados15,
  18. Paul Emery16,
  19. Daniel Furst17,
  20. Juan Gomez-Reino18,
  21. Gillian Hawker19,
  22. Edward Keystone20,
  23. Dinesh Khanna17,
  24. John Kirwan21,
  25. Tore K. Kvien22,
  26. Robert Landewé23,
  27. Joachim Listing24,
  28. Kaleb Michaud25,
  29. Emilio Martin-Mola26,
  30. Pamela Montie27,
  31. Theodore Pincus28,
  32. Pamela Richards29,
  33. Jeffrey N Siegel30,,
  34. Lee S Simon31,
  35. Tuulikki Sokka32,
  36. Vibeke Strand33,
  37. Peter Tugwell3,
  38. Alan Tyndall34,
  39. Desirée van der Heijde7,
  40. Suzan Verstappen35,
  41. Barbara White36,
  42. Frederick Wolfe37,38,
  43. Angela Zink24,
  44. Maarten Boers5
  1. 1Boston University School of Medicine, Boston, Massachusetts, USA
  2. 2University of Manchester, Manchester, UK
  3. 3Medical University of Vienna and Hietzing Hospital, Vienna, Austria
  4. 4University of Ottawa, Ottawa, Ontario, Canada
  5. 5VU University Medical Center, Amsterdam, The Netherlands
  6. 6Medical University of Vienna, Vienna, Austria
  7. 7Leiden University Medical Center, Leiden, The Netherlands
  8. 8Johns Hopkins University School of Medicine, Baltimore, Maryland
  9. 9University of Pisa, Pisa, Italy
  10. 10University of Melbourne, Melbourne, Victoria, Australia
  11. 11University of York, York, UK
  12. 12University of Florence, Florence, Italy
  13. 13Montpellier University Hospital, Montpellier, France
  14. 14Amsterdam, The Netherlands
  15. 15Paris-Descartes University, UPRES-EA, Assistance Publique Hôpi- taux de Paris, and Cochin Hospital, Paris, France
  16. 16University of Leeds and NIHR Leeds Musculoskeletal Biomedical Research Unit, Leeds, UK
  17. 17David Geffen School of Medicine, University of California, Los Angeles, California, USA
  18. 18Hospital Clinico Universitario and Universidad de Santiago de Compostela, Santiago, Spain
  19. 19Wom- en's College Hospital and University of Toronto, Toronto, Ontario, Canada
  20. 20University of Toronto, Toronto, Ontario, Canada
  21. 21University of Bristol, Bristol, UK
  22. 22Diakonhjemmet Hospital, Oslo, Norway
  23. 23University Hospital Maas- tricht, Maastricht, The Netherlands
  24. 24German Rheumatology Research Center, Berlin, Ger- many
  25. 25National Data Bank for Rheumatic Diseases, Wichita, Kansas and University of Nebraska Medical Center, Omaha
  26. 26Hospital Universitario La Paz, Madrid, Spain
  27. 27Vancouver, British Columbia, Canada
  28. 28New York University School of Medicine, New York, New York
  29. 29Bristol, UK
  30. 30US Food and Drug Administration, Washington, DC, USA
  31. 31SDG LLC, Cambridge, Massachusetts, USA
  32. 32Jyväskylä Central Hospital, Jyväskylä, Finland
  33. 33Stanford University School of Medicine, Palo Alto, California, USA
  34. 34University of Basel, Basel, Switzerland
  35. 35University of Manchester, Manchester, UK
  36. 36Medlmmune, Gaithersburg, Maryland, USA
  37. 37National Data Bank for Rheumatic Diseases, Wichita, Kansas, USA
  38. 38University of Kansas, Wichita, Kansas, USA
  1. Correspondence to Maarten Boers, Department of Epidemiology and Biostatistics, VU University Medical Center, PK 6Z 165, PO Box 7057, 1007 MB Amsterdam, The Netherlands; eb{at}vumc.nl

Abstract

Objective Remission in rheumatoid arthritis (RA) is an increasingly attainable goal, but there is no widely used definition of remission that is stringent but achievable and could be applied uniformly as an outcome measure in clinical trials. This work was undertaken to develop such a definition.

Methods A committee consisting of members of the American College of Rheumatology, the European League Against Rheumatism, and the Outcome Measures in Rheumatology Initiative met to guide the process and review prespecified analyses from RA clinical trials. The committee requested a stringent definition (little, if any, active disease) and decided to use core set measures including, as a minimum, joint counts and levels of an acute-phase reactant to define remission. Members were surveyed to select the level of each core set measure that would be consistent with remission. Candidate definitions of remission were tested, including those that constituted a number of individual measures of remission (Boolean approach) as well as definitions using disease activity indexes. To select a definition of remission, trial data were analysed to examine the added contribution of patient-reported outcomes and the ability of candidate measures to predict later good radiographic and functional outcomes.

Results Survey results for the definition of remission suggested indexes at published thresholds and a count of core set measures, with each measure scored as 1 or less (eg, tender and swollen joint counts, C reactive protein (CRP) level, and global assessments on a 0–10 scale). Analyses suggested the need to include a patient-reported measure. Examination of 2-year follow-up data suggested that many candidate definitions performed comparably in terms of predicting later good radiographic and functional outcomes, although 28-joint Disease Activity Score–based measures of remission did not predict good radiographic outcomes as well as the other candidate definitions did. Given these and other considerations, we propose that a patient's RA can be defined as being in remission based on one of two definitions: (1) when scores on the tender joint count, swollen joint count, CRP (in mg/dl), and patient global assessment (0–10 scale) are all ≤1, or (2) when the score on the Simplified Disease Activity Index is ≤3.3.

Conclusion We propose two new definitions of remission, both of which can be uniformly applied and widely used in RA clinical trials. The authors recommend that one of these be selected as an outcome measure in each trial and that the results on both be reported for each trial.

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Footnotes

  • * Columbia University, New York, New York, USA

  • Genentech, South San Francisco, California

  • DTF and JSS contributed equally to this work.

  • This criteria set has been approved by the American College of Rheumatology (ACR) Board of Directors and the European League Against Rheumatism (EULAR) Executive Committee as provisional period. This signifies that the criteria set has been quantitatively validated using patient data, but it has not undergone validation based on an external data set. All ACR/EULAR-approved criteria sets are expected to undergo intermittent updates.

  • The American College of Rheumatology is an independent, professional, medical and scientific society which does not guarantee, warrant, or endorse any commercial product or service.

  • This article is published simultaneously in the March 2011 issue of Arthritis & Rheumatism.

  • The views presented in this article do not necessarily reflect those of the United States Food and Drug Administration.

  • Funding The American College of Rheumatology, the European League Against Rheumatism, and the NIH (grant AR-47785). Dr. Smolen has received consulting fees, speaking fees, and/or honoraria from Amgen, Abbott, Centocor, Schering-Plough, Wyeth, Bristol-Myers Squibb, Roche, UCB, and AstaZeneca (less than $10 000 each); he has received grants from Schering-Plough, Roche, UCB, Bristol-Myers Squibb, and Abbott. Dr. Aletaha has received consulting fees, speaking fees, and/or honoraria from Abbott, Roche, UCB, Bristol- Myers Squibb, Schering-Plough, and Wyeth (less than $10 000 each). Dr. Allaart has received consulting fees, speaking fees, and/or honoraria from Schering-Plough, Centocor, and UCB (less than $10 000 each). Dr. Bathon has received consulting fees, speaking fees, and/or honoraria from Crescendo Biosciences and Roche (less than $10 000 each); she has received research contracts from Biogen Idec. Dr. Brown has received speaking fees and/or honoraria from Schering-Plough, Abbott, and Pfizer (less than $10 000 each). Dr. Matucci-Cerinic has provided paid consul- tation to Pfizer, Actelion, and Schering (less than $10 000 each). Dr. Choi has received honoraria for serving on advisory boards for TAP Pharma- ceuticals and Savient (less than $10 000 each). Dr. Furst has received consulting fees, speaking fees, and/or honoraria from Abbott, Actelion, Amgen, Bristol-Myers Squibb, Biogen Idec, Centocor, Genentech, Gilead, GlaxoSmithKline, Merck, Nitec, Novartis, UCB, Wyeth, and Xoma (less than $10 000 each); he has received research funding from Abbott, Actelion, Amgen, Bristol-Myers Squibb, Genentech, Gilead, GlaxoSmithKline, Nitec, Novartis, Roche, UCB, Wyeth, and Xoma. Dr. Gomez-Reino has received consulting fees, speaking fees, and/or hono- raria from Schering-Plough, Bristol-Myers Squibb, Wyeth, Roche, and UCB (less than $10 000 each). Dr. Khanna has received consulting fees, speaking fees, and/or honoraria from Abbott and UCB (less than $10 000 each). Dr. Landewé has received consulting fees, speaking fees, and/or honoraria from Abbott, Centocor, Schering-Plough, Wyeth, Pfizer, UCB, Merck, Bristol-Myers Squibb, and Amgen (less than $10 000 each). Dr. Martin-Mola has received consulting fees from Merck, Sharp, and Dohme, Pfizer, and Roche (less than $10 000 each). Dr. Pincus has received consulting fees, speaking fees, and/or honoraria from Amgen, Abbott, Bristol-Myers Squibb, Centocor, UCB, Wyeth, and Genentech (less than $10 000 each) and research grants from Amgen, Bristol-Myers Squibb, UCB, and Centocor. Dr. Simon has received consulting fees from Affinergy, AstraZeneca, Abraxis, Alpha Rx, Nuvo/Dimethaid Research, Roche, Pfizer, Novartis, PLx Pharma, Hisamitsu, Dr Reddys, Avanir, Cerimon, Alimera, Paraexel, Nitec, Bayer, Rigel, Chelsea, Regeneron, Cypress Biosciences, Nicox, Biocryst, Extera, Wyeth, Solace, Puretech- ventures, White Mountain Pharma, Abbott, Omeros, Jazz, Takeda, Teva, Zydus, Proprius, Alder, Cephalon, Seprecor, Purdue, EMD Merck Se- rono, Altea, Talagen, TiGenix, Antigenics, Forest, Genzyme, CaloSyn, King, Pozen, IL Pharma, Analgesic Solutions, and US WorldMeds (less than $10 000 each) and from Savient and Horizon (more than $10 000 each); owns stock or stock options in Savient; and has provided paid consultation to Leerink Swann, Luxor, Nomura, and Fidelity, investment analysis firms. Dr. Sokka has received consulting fees, speaking fees, and/or honoraria from Abbott, Pfizer, and UCB (less than $10 000 each). Dr. Tugwell has received consulting fees from Bristol-Myers Squibb, Chelsea, and UCB (more than $10 000 each); he has received research grants from Aventis (HMR), Biomatrix, Cigna, Genzyme, Merck, Novar- tis, Parke Davis, Pfizer, Rhone-Poulenc, Sandoz, and SmithKline Beecham. Dr. Zink has received speaking fees from Abbott, Bristol- Myers Squibb, Roche, Wyeth, and UCB (less than $10,000 each).

  • Provenance and peer review Not commissioned; externally peer reviewed.

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