American College of Rheumatology/European League Against Rheumatism provisional definition of remission in rheumatoid arthritis for clinical trials

Authors

  • David T. Felson,

    1. Boston University School of Medicine, Boston, Massachusetts
    2. University of Manchester, Manchester, UK
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    • Drs. Felson and Smolen contributed equally to this work.

  • Josef S. Smolen,

    1. Medical University of Vienna and Hietzing Hospital, Vienna, Austria
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    • Drs. Felson and Smolen contributed equally to this work.

    • 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.

  • George Wells,

    1. University of Ottawa, Ottawa, Ontario, Canada
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  • Bin Zhang,

    1. Boston University School of Medicine, Boston, Massachusetts
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  • Lilian H. D. van Tuyl,

    1. VU University Medical Center, Amsterdam, The Netherlands
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  • Julia Funovits,

    1. Medical University of Vienna, Vienna, Austria
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  • Daniel Aletaha,

    1. Medical University of Vienna, Vienna, Austria
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    • 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).

  • Cornelia F. Allaart,

    1. Leiden University Medical Center, Leiden, The Netherlands
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    • Dr. Allaart has received consulting fees, speaking fees, and/or honoraria from Schering-Plough, Centocor, and UCB (less than $10,000 each).

  • Joan Bathon,

    1. Johns Hopkins University School of Medicine, Baltimore, Maryland
    Current affiliation:
    1. Columbia University, New York, New York
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    • 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.

  • Stefano Bombardieri,

    1. University of Pisa, Pisa, Italy
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  • Peter Brooks,

    1. University of Melbourne, Melbourne, Victoria, Australia
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  • Andrew Brown,

    1. University of York, York, UK
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    • Dr. Brown has received speaking fees and/or honoraria from Schering-Plough, Abbott, and Pfizer (less than $10,000 each).

  • Marco Matucci-Cerinic,

    1. University of Florence, Florence, Italy
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    • Dr. Matucci-Cerinic has provided paid consultation to Pfizer, Actelion, and Schering (less than $10,000 each).

  • Hyon Choi,

    1. Boston University School of Medicine, Boston, Massachusetts
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    • Dr. Choi has received honoraria for serving on advisory boards for TAP Pharmaceuticals and Savient (less than $10,000 each).

  • Bernard Combe,

    1. Montpellier University Hospital, Montpellier, France
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  • Maarten de Wit,

    1. Amsterdam, The Netherlands
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  • Maxime Dougados,

    1. Paris-Descartes University, UPRES-EA, Assistance Publique Hôpitaux de Paris, and Cochin Hospital, Paris, France
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  • Paul Emery,

    1. University of Leeds and NIHR Leeds Musculoskeletal Biomedical Research Unit, Leeds, UK
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  • Daniel Furst,

    1. David Geffen School of Medicine at the University of California in Los Angeles
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    • 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.

  • Juan Gomez-Reino,

    1. Hospital Clinico Universitario and Universidad de Santiago de Compostela, Santiago, Spain
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    • Dr. Gomez-Reino has received consulting fees, speaking fees, and/or honoraria from Schering-Plough, Bristol-Myers Squibb, Wyeth, Roche, and UCB (less than $10,000 each).

  • Gillian Hawker,

    1. Women's College Hospital and University of Toronto, Toronto, Ontario, Canada
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  • Edward Keystone,

    1. University of Toronto, Toronto, Ontario, Canada
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  • Dinesh Khanna,

    1. David Geffen School of Medicine at the University of California in Los Angeles
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    • Dr. Khanna has received consulting fees, speaking fees, and/or honoraria from Abbott and UCB (less than $10,000 each).

  • John Kirwan,

    1. University of Bristol, Bristol, UK
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  • Tore K. Kvien,

    1. Diakonhjemmet Hospital, Oslo, Norway
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  • Robert Landewé,

    1. University Hospital Maastricht, Maastricht, The Netherlands
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    • 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).

  • Joachim Listing,

    1. German Rheumatology Research Center, Berlin, Germany
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  • Kaleb Michaud,

    1. National Data Bank for Rheumatic Diseases, Wichita, Kansas and University of Nebraska Medical Center, Omaha
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  • Emilio Martin-Mola,

    1. Hospital Universitario La Paz, Madrid, Spain
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    • Dr. Martin-Mola has received consulting fees from Merck, Sharp, and Dohme, Pfizer, and Roche (less than $10,000 each).

  • Pamela Montie,

    1. Vancouver, British Columbia, Canada
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  • Theodore Pincus,

    1. New York University School of Medicine, New York, New York
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    • 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.

  • Pamela Richards,

    1. Bristol, UK
    Current affiliation:
    1. Genentech, South San Francisco, California
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  • Jeffrey N. Siegel,

    1. US Food and Drug Administration, Washington, DC
    Current affiliation:
    1. Genentech, South San Francisco, California
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  • Lee S. Simon,

    1. SDG LLC, Cambridge, Massachusetts
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    • 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, Puretechventures, White Mountain Pharma, Abbott, Omeros, Jazz, Takeda, Teva, Zydus, Proprius, Alder, Cephalon, Seprecor, Purdue, EMD Merck Serono, 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.

  • Tuulikki Sokka,

    1. Jyväskylä Central Hospital, Jyväskylä, Finland
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    • Dr. Sokka has received consulting fees, speaking fees, and/or honoraria from Abbott, Pfizer, and UCB (less than $10,000 each).

  • Vibeke Strand,

    1. Stanford University School of Medicine, Palo Alto, California
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  • Peter Tugwell,

    1. University of Ottawa, Ottawa, Ontario, Canada
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    • 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, Novartis, Parke Davis, Pfizer, Rhone-Poulenc, Sandoz, and SmithKline Beecham.

  • Alan Tyndall,

    1. University of Basel, Basel, Switzerland
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  • Desirée van der Heijde,

    1. Leiden University Medical Center, Leiden, The Netherlands
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  • Suzan Verstappen,

    1. University of Manchester, Manchester, UK
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  • Barbara White,

    1. MedImmune, Gaithersburg, Maryland
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  • Frederick Wolfe,

    1. National Data Bank for Rheumatic Diseases and University of Kansas, Wichita, Kansas
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  • Angela Zink,

    1. German Rheumatology Research Center, Berlin, Germany
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    • Dr. Zink has received speaking fees from Abbott, Bristol-Myers Squibb, Roche, Wyeth, and UCB (less than $10,000 each).

  • Maarten Boers

    Corresponding author
    1. VU University Medical Center, Amsterdam, The Netherlands
    • Department of Epidemiology and Biostatistics, VU University Medical Center, PK 6Z 165, PO Box 7057, 1007 MB Amsterdam, The Netherlands
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  • This article is published simultaneously in the March 2011 issue of Annals of the Rheumatic Diseases.

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

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 analyzed 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 (e.g., 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 followup 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: (a) 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 (b) 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. We 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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