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Due to advances in therapies for rheumatoid arthritis (RA) over the last years, an increasing proportion of patients are able to achieve a state of ‘remission’. But what exactly is remission? At the moment, randomized controlled trials around the world use different remission definitions and consequently measure different aspects of a patient’s disease state. For research findings to be correctly interpreted, the need for a uniform definition of remission is vital. The ACR constituted a committee to redefine remission in RA that included international clinical researchers, trialists and clinical epidemiologists. This group was asked to study current definitions of remission, explore the theoretical underpinning of the concept of ‘remission’, and develop a research agenda that would inform future work in the development of an ACR definition of remission.
In its first meeting, the committee preferred to develop a ‘strict’ definition, implying no or very low disease activity. Such a definition would need to be validated against long-term outcome e.g. physical function and damage. The committee decided to consider both a definition for trials and a modified version for clinical practice.
At the time of this development relatively few patients achieved remission, in part because there were few highly effective treatments for disease. Since this time, randomized controlled trials have focused on whether drugs could be shown to improve disease, prompting the development and widespread use of a single core set of endpoints for trials (WHO-ILAR core set) (2), and validated measures of disease improvement (ACR20, EULAR criteria). At the time of its development, showing a significant ACR20 improvement compared to placebo represented a significant advance in improving disease outcomes (3;4).
With the evolution of more effective treatments for RA, these improvement measures have been stretched. RA trials now routinely use ACR50, ACR70 and sometimes even ACR90 responses as secondary outcomes, and increasing numbers of trial subjects achieve these endpoints (5–7). Within the Outcome Measures in Rheumatology Clinical Trials (OMERACT) initiative, the importance of achieving an acceptable state of low disease activity has resulted in a preliminary definition of what is termed ‘minimal disease activity’(8). With emerging new treatment strategies, developments are rapid, and trials where remission is the primary outcome are becoming more and more prevalent (7;9–11).
However, there are problems with the current definitions of remission. While the ACR remission criteria might be used to characterize persons attaining remission, they are problematic, since they are so restrictive that few patients, even in current trials attain this state (12). Further, they include measures not in the core set (fatigue, morning stiffness; tendon sheath swelling) and others that are not always routinely assessed in trials (ESR). To account for some of these issues, modified ACR criteria (mACR) have been employed where fatigue is omitted and the presence of 4 of the remaining 5 items is required (13;14).
Amongst all disease activity scoring systems that are available today, the most commonly used measures for remission are based on the Disease Activity Score (DAS). A (full joint count) DAS < 1.6 correlates well with the ACR remission criteria (15), but it is the 28-joint count DAS (DAS28) that is currently most commonly used. A DAS28 with a cut-off point of 2.6 corresponded best to the fulfilment of the modified ACR criteria for clinical remission, which means that patients who meet the modified ACR remission criteria will meet the DAS28 cut-off (although because the DAS cut-off is less stringent, those who meet DAS cut-off will not necessarily meet modified ACR remission criteria) (13). However, a DAS < 1.6 may constitute a more stringent measure of remission than DAS28 < 2.6 (16). Indeed it has been reported that up to 20% of patients in DAS28 remission have 2 or more residual swollen joints, and the number of swollen joints can reach more than a dozen (17–20). These findings suggest that patients in DAS28 remission may actually be in a ‘minimal disease activity state’ rather than in a true remission (8). However, also in DAS remission there can be a considerable number of swollen joints (20). Further, in recent clinical trials DAS28 remission rates exceeded those of ACR70 response rates (7;9;21;22), meaning that more patients achieved a state of DAS28 remission than the proportion of patients reaching a 70% or higher decrease in tender and swollen joints.
Since neither the ACR remission criteria nor the full DAS definition is often used and the DAS28 may not be stringent enough to define true remission, there appears to be a need for an easy to use definition that is suitable as either a secondary or primary outcome in clinical trials. Given these concerns, the ACR constituted a committee joint by EULAR representation, to redefine remission in RA. This group met initially in November 2007, and consisted of an international group of rheumatoid arthritis (RA) clinical researchers, trialists and clinical epidemiologists. Their charge was to study current definitions of remission, explore the theoretical underpinning of the concept of ‘remission’, and develop a research agenda that would inform future work in the development of an ‘authorized’ ACR clinical trial definition. This document summarizes their considerations, conclusions and research agenda for the coming period and aims to give readers insight into the complexity of the process by raising many questions that have to be taken into account.
The format of the meeting is shown in Table 2. Three presentations were given by the committee chairpersons to clarify the issues involved. The whole group was then divided into three breakout groups, each charged with exploring a series of questions concerning remission: (1) conceptual issues, (2) measurement issues or (3) potential setting and uses (Table 2). Members of each group were encouraged to develop additional questions in their areas.
Dr. Boers began the meeting by reminding the group of the “OMERACT filter”, that requires that measures used should be truthful, discriminative, and feasible in their intended setting (23). He expanded on this core definition, suggesting that being truthful implied that the definition was free from bias and relevant, that discriminative implied that the definition could distinguish between states reliably and reproducibly at multiple time points and was sensitive to change, and that feasibility applied to time for implementation of the definition, cost of use, and ease of interpretability.
He then presented the concept that remission could be defined as absence of disease activity, but with the possibility that disease could return in time. In this way it was to be distinguished from a ‘cure’ or ‘arrest’ of the disease. In this concept, remission is a state, not a change or a transition between states. In his opinion, the concept of remission is independent of the time spent in the state, although time may be of use in defining a sustained state of remission. He asked the group to consider how one could be sure that RA disease activity was absent and suggested that the definition of remission could change depending on the setting (trial vs. clinic).
Turning to current definitions of remission, he reviewed Pinals’ 1981 definition of remission (Table 1) and other definitions including:
Evaluation of these definitions in large cross-sectional studies (14;25;26) suggest that they can roughly be categorised as either ‘strict’ (ACR, CDAI/SDAI, PAS/RAPID3) or ‘lax’ (the mACR criteria and the DAS28 definition), with the latter being very similar to the OMERACT definition for minimal disease activity (MDA) (8); MDA is a different, though related concept than that of remission because by definition, everyone in remission will also be in MDA. During the OMERACT 6 and 7 meetings, participants agreed to a preliminary MDA definition: a decision node places all patients without tender and swollen joints and an ESR <10 in MDA; furthermore, patients with either a DAS28≤2.85 or meeting 5 out of 7 core set criteria were placed in MDA (27;28).
Besides the unfavourable situation that different proportions of patients are classified as MDA or remission depending on the definition that is used (29;30), there are also aspects of feasibility and acceptability to patients and health professionals that should be taken into account (25;31); How much time/effort does it take to obtain a complete measure of remission? What is an acceptable burden for patients in obtaining a measure of remission?
Dr. Felson suggested that a definition or measurement should have ‘content validity’; i.e. it should represent all facets of a concept. With content validity in mind, he challenged the group to consider what elements would be required for a definition of remission by presenting the following questions:
Discrimination implies that a measurement is able to distinguish between different states that are of interest at a certain time point and on different time points, in a reliable, reproducibly and sensitive way. Using actual data from a group of randomized controlled trials, Dr Wells conducted preliminary studies to determine how current definitions of remission discriminate between placebo and active treatment (either DMARD’s or biologic agents) in trials. A number of definitions did this well, including the DAS, physician global, and PAS II. Also of note, remission rates varied markedly depending on the remission definition, with the DAS28 and PAS II giving the highest rates of remission and the SDAI, CDAI and ACR criteria giving the lowest.
These factors will be important for the issue of feasibility. The sample size necessary in a trial depends on the discriminative ability of a measure. At a given level of alpha (probability of a type I error) and beta (probability of a type II error) the better the discrimination of a measure then the smaller the number of subjects needed to show a significant difference between control and active medication.
The following results (Table 3) are based on the feedback from the three breakout groups and the subsequent plenary session.
There was unanimous agreement on the need for a strict definition of remission with stringent criteria (to differentiate remission from low disease activity). These criteria should include: (1) no clinical disease (although the participants acknowledged that an absence of disease activity and of / pain may not always be possible); and (2) lack of progression over time. It would be wise to create a separate remission definition with a similar structure as used for the minimal disease activity definition. The group also felt it was important to continue to work separately on the validation of a minimal disease activity definition in relation to the new remission definition.
It was felt that the definition of remission should be independent of long term outcomes such as radiographic damage, but that the validity of the definition should be tested using x-ray/ultrasonography/MRI damage indices and HAQ function. Those in remission should have no/reduced progression of joint damage and should have less deterioration or more improvement in functional status (using HAQ) over time (remission definition should have predictive validity). However, the definition of remission should be based largely on clinical and biochemical parameters at this stage, and not include definitions that require imaging. It was felt that at present there is not enough data on the use of imaging such as ultrasonography and MRI in this field to formulate a precise imaging based definition of remission but that this is an important area for future research.
All agreed that therapy should not be a part of the definition of remission.
One question concerned the best cut-off points for each current definition that predicts lack of damage progression. Can we explore existing data to find the best cut-off points?
The three most important variables were felt to be: (1) tender joint count, (2) swollen joint count and (3) an acute phase reactant. For all other possible variables it was felt that more data are needed; first with a focus on pain (for example, how should one deal with non-RA pain?), and then focusing on fatigue, physician global assessment (utility of continuous vs dichotomous scale), patient global assessment, sleep, and the HAQ.
It was felt that while a 28 joint count may be sufficient to assess disease activity, more joints should be included if a stringent remission definition is desirable. Further data were felt to be needed about how many patients in a DAS28 remission state still have activity in non DAS28 joints. Based on these data, it should then be decided whether this is an important issue (in trials the issue may be less important than in clinical practice). With current knowledge, most attendants felt that a 28-joint count was not sufficient for the purpose of developing a stringent definition of remission.
The group felt that sustained remission was a critical outcome but that time was not necessarily a part of the trial definition of remission (although it might be a secondary outcome). Some felt that it would be valuable to ask patients about their perception of the importance of ‘time in remission’. The patient-attendee stressed the importance of time for her in the definition of remission: she saw it as a permanent state, from which there should be no recurrence of disease, especially not within a limited time. The relevance of time was also discussed in the light of damage progression: Can we calculate what period of time in remission is needed so as not to see any future damage progression?
No conclusion was reached on this topic. There is a need to collect prospective data including a wide range of variables to make sure we are not locked into previous decisions about what variables to include.
All participants agreed that there should also be a remission definition for clinical practice. Trials differ from clinical practice in aspects such as restricted time, measures that lead to additional health care cost, patient characteristics that differ from those in clinical trials, and physicians’ needs. These differences may result in different definitions of remission in trial versus practice settings. A patient based measure could be developed for this environment.
The trial definition should be closely linked with the practice definition, taking into account clinical trials’ need for accuracy, and the need for feasibility and cost in clinical practice. A trial definition should maximize the efficiency of the trial while a modified or lower efficiency version might be used in clinical practice.
The needs of a trial should determine whether remission is the primary or a secondary outcome in a study.
No conclusion was reached.
The first ACR remission workshop concluded that a new remission definition should be strict, based on no or very low disease activity and should be validated against long-term outcome, specifically physical function and radiographic progression. Treatment should not be part of the remission definition, nor should long term absence of disease activity, although the latter could be used for validation purposes. The definition should at least include the tender and swollen joint counts, probably include non-DAS28 joints, and an acute phase reactant. Besides an efficient trial remission definition, there is also a need for a modified version for use in clinical practice.
Similar work has been done by experts in the field of Juvenile Inflammatory Arthritis (JIA), who using consensus approaches, formulated preliminary remission definitions in JIA. Similarities between the JIA definition and the RA definition are the need for stringency: the JIA criteria for a patient to qualify for inactive disease are: no joints with active arthritis; no fever, rash, serositis, spenomegaly, or generalized lymphadenopathy attributable to JIA; normal ESR or CRP; and physician’s global assessment of 0. Important differences with the RA definition of remission are the incorporation of drug use and duration in JIA: in JIA, a patient is in remission if criteria for inactive disease are met for 6 continuous months for a patient on medication, and for 12 continuous months off medication. Unlike JIA, the construction of the RA remission definition started with expert consensus on the main elements of a new definition, but will be guided by analysis of data from clinical trials (32).
This initial workshop has raised many important research questions that will be addressed by a research agenda and subsequent meetings of the committee to evaluate findings from the data analysis that is part of the research agenda. ACR and EULAR have decided to sponsor this initiative as an official ACR-EULAR collaboration.
This project is funded by the American College of Rheumatology. Dr Felson’s effort was supported by NIH AR47785
Daniel Aletaha, MD, MSc, Division of Rheumatology, Department of Internal Medicine, Medical University Vienna, Austria
Claire Bombardier, MD, Division of rheumatology and Department of Health Policy, Management, and Evaluation, University of Toronto, Division of Clinical Decision Making & Health Care, Toronto General Research Institute, University Health Network, Institute for Work and Health, Mount Sinai Hospital, Toronto, Ontario, Canada.
Stefano Bombardieri, Rheumatology Unit, Department of Internal Medicine, University of Pisa, Italy.
Peter Brooks, Faculty of Health Sciences, The University of Queensland, Brisbane, Queensland, Australia
Andrew K Brown, MBCHB, MRCP, PhD, Hull & York Medical School, University of York; York Hospital Foundation Trust, United Kingdom.
Hyon K Choi, MD, DrPH, Rheumatology Unit, Department of Medicine, University of British Columbia, Arthritis Research Centre of Canada, Vancouver, Canada
Bernard Combe, MD, PhD, Immuno-humatologie, Hopital Lapeyronie CHU Montpellier, Université Montpellier 1, France
Maxime Dougados, MD, Hopital Cochin, Service de Rhumatologie B, Paris, France
Paul Emery, MA, MD, FRCP, Leeds Institute of Molecular Medicine, University of Leeds, Leeds Teaching Hospitals Trust, Chapel Allerton Hospital, United Kingdom
Daniel E Furst, MD, Geffen School of Medicine, University of California, Los Angeles
Juan J Gomez-Reino, MD, Hospital Clinico Universitario, Department of Medicine, USC, Spain
Gillian Hawker, MD, Women’s College Hospital, Departments of Medicine and Health Policy, Management and Evaluation, University of Toronto, Toronto, Ontario, Canada
Désirée van der Heijde, MD, PhD, Leiden University Medical Center, Leiden, the Netherlands
Kent Johnson, MD, Dept of Clinical Pharmacology, University of Newcastle NSW, Australia
Thomas Karonitsch, Medical University of Vienna, Vienna, Austria
Ed Keystone, MD, FRCP(C), University of Toronto, Canada
John Richard Kirwan, MD, University of Bristol Academic Rheumatology Unit, Bristol Royal Infirmary, Bristol, UK
Tore K Kvien, MD, PhD, Department of Rheumatology, Diakonhjemmet Hospital, University of Oslo, Norway
Robert B.M. Landewé, MD, Department of Medicine, Division of Rheumatology, Maastricht University Medical Center, Maastricht, The Netherlands
Michael LaValley, PhD, Department of Biostatistics, School of Public Health, Boston University, USA
Joachim Listing, PhD, German Rheumatism Research Centre, Berlin
Emilio Martin Mola, MD, Department of Rheumatology, Hospital Universitario La Paz, Madrid, Spain
Marco Matucci Cerinic, MD PhD, Dept Biomedicine, Div Rheumatology AOUC, Univ Florence, Italy
Kaleb Michaud, PhD, University of Nebraska Medical Center, Omaha, NE, National Data Bank for Rheumatic Diseases, Wichita, KS, USA
Larry W Moreland, MD, University of Pittsburgh, Pittsburgh, USA
Harold E. Paulus, MD, Division of Rheumatology, UCLA David Geffen School of Medicine
Theodore Pincus, MD, New York University Hospital for Joint Diseases, New York, USA
Pam Richards, University of Bristol, Bristol, UK
Piet LCM van Riel, MD, PhD, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands
Vibeke Strand, MD, FACP, FACR, Division of Immunology/Rheumatology, Stanford University School of Medicine
Tuulikki Sokka, MD, PhD, Jyväskylä Central Hospital, Jyväskylä Finland
Lee S Simon, MD, Harvard Medical School, Beth Israel Deaconess Medical Center, USA
Peter Tugwell, MD, MSc, FRCPC, Canada Research Chair in Health Equity, University Of Ottawa, Ottawa, Ontario Canada
Alan Tyndall, MD, PhD, Department of Rheumatology, University of Basle, Switzerland
Jeffrey N. Siegel, MD, Division of Analgesia, Anesthesia and Rheumatology Products (DAARP), Food and Drug Administration (FDA), Silver Spring, MD, USA
Josef S. Smolen, MD, Division of Rheumatology, Department of Internal Medicine III, Medical University of Vienna, Austria
E. William St. Clair, MD, Department of Medicine, Division of Rheumatology and Immunology, Duke University Medical Center, Durham,
Ronald F. van Vollenhoven, MD, PhD, The Karolinska Institute, Stockholm Sweden
Michael M. Ward, MD, MPH, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD, USA.
Fred Wolfe, MD, National Data Bank for Rheumatic Diseases Wichita, Kansas NDB Office
Bin Zhang, DSc, Clinical Epidemiology Research & Training Unit, Boston University School of Medicine, Boston, USA
Angela Zink, PhD Charité Medical School, Berlin, Germany
No conflicts of interest.