American College of Rheumatology/European League against Rheumatism Preliminary Definition of Remission in Rheumatoid Arthritis for Clinical Trials
1 Clinical Epidemiology Research and Training Unit, Boston University School of Medicine, USA.
2 Division of Rheumatology, Department of Medicine 3, Medical University of Vienna, and 2nd Department of Medicine, Center of Rheumatic Diseases, Hietzing Hospital, Vienna, Austria.
3 Department of Epidemiology and Community Medicine, University of Ottawa, Canada.
4 The Department of Epidemiology and Biostatistics and the Department of Rheumatology, VU University Medical Center, Amsterdam, Netherlands
5 Division of Rheumatology, Department of Medicine 3, Medical University of Vienna, Vienna, Austria.
6 Leiden University Medical Center, Netherlands.
7 Johns Hopkins University School of Medicine, Baltimore, USA.
8 University of Pisa, Italy.
9 University of Melbourne, Melbourne, Australia.
10 Hull York Medical School, University of York, UK.
11 University of Florence, Italy.
12 Division Hopital Lapeyronie, Montpellier University Hospital Montpellier, France.
13 Department of Medical Humanities, VU University Medical Center, Amsterdam, Netherlands.
14 Paris-Descartes University, Medicine Faculty; UPRES-EA ; AP-HP, Cochin Hospital, Rheumatology B Department, Paris, France.
15 University of Leeds and Leeds Teaching Hospitals NHS Trust, UK.
16 David Geffen School of Medicine at the University of California in Los Angeles, USA.
17 Hospital Clinico Universitario at the Universidad de Santiago de Compostela, Santiago, Spain.
18 Women's College Hospital, Toronto, Canada.
19 University of Toronto, Canada.
20 University of Bristol, Bristol, UK.
21 Diakonhjemmet Hospital, Oslo, Norway.
22 Department of Internal Medicine/Rheumatology, University Hospital Maastricht, Netherlands.
23 Deutsches Rheuma-Forschungszentrum, Berlin, Germany.
24 University of Nebraska, Omaha, USA.
25 Hospital Universitario La Paz, Madrid, Spain.
26 Arthritis Research Centre of Canada, Vancouver, Canada.
27 New York University School of Medicine, New York, USA.
28 Food and Drug Administration, Center for Drug Evaluation and Research, Washington DC, USA.
29 SDG LLC, Cambridge, USA.
30 Jyväskylä Central Hospital, Jyväskylä, Finland.
31 Stanford University School of Medicine, Palo Alto, USA.
32 University of Ottawa, Canada.
33 University of Basel, Switzerland
34 Arthritis Research UK Epidemiology Unit, The University of Manchester, UK.
35 MedImmune, Gaithersburg, USA.
36 National Data Bank for Rheumatic Diseases, Wichita, USA.
37 German Rheumatism Research Center, Berlin, Germany.
With the advent of new therapies and therapeutic strategies for rheumatoid arthritis (RA), remission has become a realistic goal (1
) and has recently become a secondary or even primary endpoint for clinical studies and trials(4
). Remission is also regarded as a major therapeutic target in clinical practice(9
) and can be achieved in a significant proportion of patients followed in routine care(13
). However, the formal definition of remission differs between studies.
The current American College of Rheumatology (ACR) definition of remission in RA(16
) was developed in 1981 prior to the introduction of the core set measures(17
). In this classic paper, Pinals et al. stated: ‘…”complete remission” implies the total absence of all articular and extraarticular inflammation and immunologic activity related to rheumatoid arthritis (RA).’ Recognizing that detecting such a state could entail documentation by ‘extraordinary measures’, they settled on the concept of ‘complete clinical remission’ aiming to achieve ‘uniformity in clinical application using generally acceptable and convenient measures.’ Even though this concept is of considerable value for trials and clinical practice as a therapeutic target, the 1981 ACR definition has not been widely used in clinical trials in RA because it contains some elements not in the core set (morning stiffness, swelling in tendon sheaths) and a time requirement. Also, this original version was so stringent that few patients met the criteria. Subsequently many modifications of the ACR criteria were developed, usually omitting one or more of the measures as well as the time requirement.
The development of composite indices of disease activity allowed the definition of cutpoint values representing remission(18
), but their validation was often limited to comparisons with such modified ACR criteria. For instance, we now know that the widely used definition of remission based on the Disease Activity Score (DAS28) of less than 2.6(18
) better represents minimal disease activity than remission as multiple joints can remain swollen or tender at that score(19
). This is further exemplified by the fact that in many recent clinical trials the proportion of patients with ACR70 response is around, or even lower than, the proportion of patients attaining DAS28 remission(5
). Thus, the 1981 statement by Pinals et al. remains relevant today: “Substantial variation appears to exist in the concept of remission within the group of participating rheumatologists”(16
In the meantime, effective treatments for rheumatoid arthritis have led to more exacting criteria for improvement (e.g. ACR 50, 70 and even 90 percent improvement) and have led to recently proposed definitions of minimal disease activity(27
). In light of the heterogeneity of definitions of remission , the time has come for consensus on a new definition, a uniform definition of remission. Therefore, the ACR and European League Against Rheumatism (EULAR) together with the Outcome Measures in Rheumatology Initiative (OMERACT) jointly constituted a committee to redefine remission in rheumatoid arthritis. This committee subsequently published a systematic review of prognostic validity of current remission definitions(28
) as well as an outline of the goals of redefining remission and the methods by which we would attain them (2
In this outline of our goals already published, the committee decided by consensus to create a stringent definition for remission; and that any definition should include as a minimum tender and swollen joint counts and an acute phase reactant. Excluded were treatment, duration of remission (the committee felt that this should be specified in each trial), and measures of physical function and damage. The latter two were to be used to validate candidate remission definitions: the chosen definition should predict absence of X-ray damage progression and good functional outcomes in the future. Remission should also predict future remission and minimal disease activity, i.e. show stability. Finally, the requirement for full or 28-joint counts had to be studied.
The committee suggested that core set measures should be used to define remission and that any definition of remission in clinical trials should look toward and make possible a similar definition in clinical practice.
The selection of the optimal definition of remission was guided by the research agenda as put forward by the committee at the beginning of our deliberations. In general, the evidence-based consensus method adhered to was in line with similar activities previously performed by OMERACT and ACR and EULAR(29
) with the intent of deriving a definition that would pass the OMERACT filter of Truth, Discrimination and Feasibility(32
). In this paper we present the results of analyses addressing this research agenda, report on later meetings of the committee in which these results were evaluated and present a consensus definition of remission.