The new ACR/EULAR remission criteria: rationale for developing new criteria for remission

RHEUMATOLOGY Rheumatology 2012;51:vi16 vi20 doi:10.1093/rheumatology/kes281 The new ACR/EULAR remission criteria: rationale for developing new criteria for remission Vivian P. Bykerk 1,2 and Elena M. Massarotti 3 Abstract As more effective treatments for RA have become available, studies have demonstrated that in patients who attained remission, defined as a simplified disease activity index (SDAI) 43.3, not only disease activity but radiographic progression was reduced. The feasibility and the benefit of attaining remission led to the development of the ACR/European League Against Rheumatism (EULAR) 2011 remission criteria. These criteria employ either a Boolean definition, including tender and swollen joint counts 41, and CRP 41 mg/dl, or an index-based definition, SDAI 43.3, in combination with patient-reported outcomes on a scale of 0 10. It is expected that the ACR/EULAR criteria will be used as secondary outcomes in clinical trials. Some questions about the implementation of the new criteria include the availability of CRP values, and the possibility that patient-reported outcomes may skew the outcome if patients cannot distinguish other musculoskeletal conditions from RA. Several issues require further study, including the role of imaging, fatigue and the impact of the involvement of joints other than the 28 counted in the ACR/ EULAR criteria. Key words: rheumatoid arthritis, ACR/EULAR remission criteria, radiographic progression, DAS, DAS28, SDAI, tender/swollen joint counts. Introduction Advances in the treatment of RA have made it possible in some patients for the target of treatment to be remission, however remission may be defined. Recent treatment recommendations for RA have advocated early institution of DMARD therapy to preserve joint function, maintain optimal quality of life and minimize comorbid conditions associated with this disease [1 3]. Sustained elevations in disease activity are associated with progressive joint damage, whereas sustained remission is associated with less radiographic damage [4 6]. Achieving a state of low disease activity, the lowest being a state of remission, is associated with favourable outcomes [6]. Remission is associated with halting of disease activity and maintenance of function in real-world practice [4]. The ability of a new therapy to initiate a state of remission has been 1 Inflammatory Arthritis Center, Hospital for Special Surgery, 2 Department of Medicine, Weill Cornell Medical School, New York, NY and 3 Division of Rheumatology, Brigham and Women s Hospital, Boston, MA, USA. Submitted 10 January 2012; revised version accepted 14 September 2012. Correspondence to: Vivian Bykerk, Hospital for Special Surgery, 535 East 70th Street, 6th Floor, New York, NY 10021, USA. E-mail: bykerkv@hss.edu increasingly appreciated such that this has become a recommended outcome for clinical trials [7]. This review summarizes the data supporting the development of updated remission criteria for the treatment of RA. Rationale for developing new remission criteria Definitions of remission in RA have varied over time. In 1981 Pinals et al. [8] published what was until recently deemed by the ACR to be the official definition of remission. The authors defined remission as sustained total absence of inflammation and associated manifestations of inflammation. These 1981 criteria required that five of the following six criteria be met for at least two consecutive months in order for remission to be achieved: (i) morning stiffness <15 min, (ii) no fatigue, (iii) no joint pain, (iv) no joint tenderness or pain on motion, (v) no soft tissue swelling in joints or tendon sheaths and (vi) normal ESR. These criteria were to be met in the absence of any other disease feature attributable to RA that would! The Author 2012. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: journals.permissions@oup.com

The new ACR/EULAR remission criteria prohibit a designation of complete clinical remission. Few patients met these criteria, limiting the widespread use of the remission criteria, especially in the pre-biologic era, when fewer long-lasting treatments were available. Over time the concept of remission allowed for the persistence of some disease activity, making remission achievable [9]. The most frequently used definition of remission employed the DAS using either 44- or 28-joint counts; the latter is referred to as DAS28. DAS and DAS28 are calculated indices that take into account parameters other than the number of tender and swollen joints. DAS scores <1.6 or DAS28 <2.6 are commonly considered as indications that the patient is in remission [10]. The DAS was reported in a number of clinical trials of new biologic therapies tested in early RA [11]. However, in clinical practice decisions, treatment changes based upon the DAS can be difficult to make in real time unless results of the serum measure of inflammation are immediately available [12]. Furthermore, the use of DAS-based remission has been criticized because patients can be in remission but still have active synovitis [13]. In order for remission to be an implementable target both in clinical studies and in practice it needs to be easy to calculate at the bedside in patients with RA. To this end, Aletaha et al. [14] demonstrated that simpler composite indices correlated well with the DAS and derived definitions of remission using an arithmetic sum of the same components. Examples of these indices included the simplified disease activity index (SDAI, incorporating inflammatory markers) and clinical disease activity index (CDAI). Nonetheless, with the advent of new, more effective therapies for the treatment of RA, the concept of remission has again swung back to one invoking more stringent criteria. Methodology utilized to develop the 2011 ACR/EULAR remission criteria The definition of remission was based on a mandate from the ACR/EULAR committee on quality measures, which put forward a number of requirements for a definition of remission and wanted this definition to be developed for use in clinical trials (with subsequent modification). The definition was to be stringent, allow for little if any residual active disease, include measures of tender joint count (TJC) plus swollen joint count (SJC), acute-phase reactants and patient-reported outcomes. It was not to include measures of physical function, as these can be affected by disease duration or type of treatment (if any). The definition had to be able to predict the absence of radiographic damage and stable good function. The new ACR/EULAR 2011 criteria for remission were derived using a consensus approach followed by a data-driven approach. Rheumatologists experienced in the management of RA identified domains important in defining remission: SJC, TJC, acute-phase reactants (e.g. CRP), patient and physician assessments of global health and patient assessment of pain. Using consensus techniques, the committee agreed to cut-offs for each domain considered as being compatible with remission. These domains were evaluated by logistic regression, and by classification and regression tree analysis, using data from four clinical trials, to determine which of these domains best predicted a SJC 41. Although three objective domains (SJC, TJC, CRP) showed good predictive validity for preventing radiographic damage and optimizing function, higher predictive validity was achieved when they were combined with patient and physician assessments of health and patient assessment of pain. Remission was ultimately defined using a Boolean-based definition where patients would be considered to be in remission at a single point in time if they satisfied all of the criteria shown below. The ACR/EULAR definition of remission is as follows: Boolean-based definition: At any time point, a patient must satisfy all of the following: TJC 41, SJC 41, CRP 41 mg/dl and patient global assessment (PGA) 41 (on a 0 10 scale) OR Index-based definition At any time point, a patient must have SDAI 43.3. Furthermore, the following wording should be used to elicit the PGA: considering all of the ways your arthritis has affected you, how do you feel your arthritis is today? (0 10, where 0 = very well and 10 = very poorly) [15]. Note that the Boolean criteria appear more stringent than the DAS28 remission. It is possible to have up to five swollen joints and still be in remission using the DAS28 criteria if the other variables used to calculate the DAS28 are nearly normal. Use of the 2011 ACR/EULAR remission criteria in the clinic and in randomized clinical trials It is expected that a remission definition will be used as a secondary outcome in randomized controlled trials. To date, most clinical trials of early RA report remission rates using the DAS28 in the range of 30 50% when a biologic is combined with MTX, but this rate is lower in patients with established disease, where remission rates are closer to 15 30%. It may be some time before we see this definition used as an a priori outcome measure for new therapeutic regimens for RA. Studies of observational cohorts have reported outcomes using the SDAI and CDAI, but again this has not been reported in clinical trials except in post hoc analyses. No clinical trials have yet been published in the literature showing remission rates using the new Boolean remission criteria. However, in abstract form, Emery et al. [16] showed that a significantly greater proportion of patients achieved remission when receiving a combination of a TNF inhibitor (golimumab) in combination with MTX as compared with those receiving MTX and placebo, based on a post hoc analysis from the Golimumab Before Employing Methotrexate as the First-line Option (GO-BEFORE) and vi17

Vivian P. Bykerk and Elena M. Massarotti Golimumab for Subjects with Active RA Despite MTX (GO-FORWARD) studies. As would be expected, these authors reported that fewer patients receiving golimumab MTX treatment met the new ACR Boolean remission or SDAI criteria as compared with DAS28-ESR remission criteria (13.2%/11.2% by Boolean criteria, 15.4%/12.9% by SDAI criteria vs 26.7%/28.7% by DAS28 criteria in the GO-BEFORE and GO-FORWARD studies, respectively) [16]. Recently Shahouri et al. [17] have reported that remission in the Veterans Affairs RA (VARA) cohort and a community practice cohort is found to occur 5 10% of the time when doing cross-sectional analyses. This suggests that in cohorts with patients who have long-standing disease particularly those that include patients who had disease long before the advent of biological therapies that remission rates using the newer stringent criteria will be low. As O Dell and Mikuls [18] point out, the new ACR/ EULAR definition of remission in RA provides a uniform means to report remission for future clinical trials. They also note that it will be important to determine whether the new ACR/EULAR definition in short-term clinical trials will translate into improved long-term outcomes in patients who have this life-long disease. Particularly, it remains to be determined if this remission target is too stringent (leading to overtreatment) without appreciable gain in other elements important to patients, including elimination of fatigue, quality of life, long-term function and physical deformity. Whether or not these criteria will stand the test of time will be based on how achievable they are for all patients and whether or not they reflect other measures of good outcome. If so these should be the new target of therapy. Validation of the ACR/EULAR remission criteria studies to date Very few studies have yet been done to validate the new remission criteria. O Dell and Mikuls [18] examined the new criteria using data from patients enrolled in the VARA registry. In this analysis they found that 86 of 815 patients (10.6%) with evaluable data satisfied the proposed criteria for remission as of their most recent clinic visit. They observed that an ESR of 410 mm/h might be a reasonable surrogate for a CRP level of 41.0 mg/dl. They noted that among patients with an ESR of 410 mm/h, 89% had concomitant CRP concentrations 41.0 mg/dl, but suggested that this finding needs to be replicated in additional observational data sets. These observations may not be applicable to elderly patients, considering the association between ESR level and age. Barriers to implementation of the new remission criteria Both sets of remission criteria are easy to calculate and thus potentially easy to implement. In practice, a CRP is not always available at the patient visit, thus calculating whether a patient is in remission or not will usually need to be done in retrospect unless the patient had it measured recently. Validation studies need to be done to determine if eliminating the CRP from the definition will yield similar results to the definition with the CRP included. It is also possible that the main limitation to meeting the Boolean definition of remission may be the PGA. This can be high if patients have other musculoskeletal conditions (OA, back pain, FM), particularly since many patients may not be able to readily distinguish between these conditions and RA. Some of the specifics of the ACR/EULAR remission criteria have the potential of leading to overtreatment. Wolfe and Michaud [19] have shown that influences on patient-reported global health include pain due to inflammation and/or damage, fatigue and comorbid conditions like FM. The presence of these factors may cause some patients to persistently score high on the PGA component despite a low number of active joints and normal acutephase reactants. Thus ACR/EULAR remission may not be achieved because the criterion of a PGA score 41 is not met. If remission is used as a target of therapy and the PGA is higher for other reasons, then there is a risk of overtreatment if patients are misclassified as not being in remission for an unrelated reason. Furthermore, there is significant variability in assessing SJCs and TJCs [12]. This is in part based on assessor variability, but may also reflect the relapsing nature of the disease. Thus discrete measures of remission may not represent the true ongoing state of the patient. It is possible that a definition of remission may need to include the absence of flares or worsening. Are the new criteria stringent enough? Patients can have one tender and one swollen joint and be defined as being in remission. Using the SDAI (43.3) a patient could theoretically have three swollen joints (assuming all other variables in the index are zero) and still be categorized as being in remission [15]. A recent study from Kuriya et al. [20] compared the frequency of remission at 12 months based on eight definitions, including the new ACR/EULAR criteria in 369 patients with early RA. Remission at 12 months ranged from 18% according to the ACR/EULAR clinical trial criteria to 40% according to the DAS28 <2.6. Higher TJC, SJC, physician global scores and PGA scores were observed among patients who were in remission based on the DAS28 definitions. From this standpoint, one could argue that these criteria are an indicator of very low disease activity rather than of remission. The adoption of the new ACR/EULAR definition may limit the number classified as in remission, especially if the PGA criteria are rated high for reasons other than RA. An attempt to understand factors associated with PGA is needed when applying these new remission definitions because these factors may have implications for treatment [20]. Furthermore, the criteria have not addressed the issue of time in remission. It is assumed that the longer patients remain in remission the less likely they will have radiographic progression or loss of function. Is the ability to achieve remission on one occasion, but with some degree of disease activity, sufficient to prevent damage and improve other outcomes if treatment is continued? It remains to be determined if these criteria are vi18

The new ACR/EULAR remission criteria stringent enough to result in an increase in the number of patients who will be able to achieve sustained (and sustained drug-free) remission. Using the DAS-based definition of remission, at most only 15% of patients have been able to achieve sustained drug-free remission in two large observational cohort studies [21]. Some issues that require further study The role of imaging in the definition of remission remains to be determined. High-sensitivity imaging was not included in the current definition. At this time, a high rate of synovitis is still reported in joints where synovitis cannot be clinically detected, even in patients in whom either definition of remission is met [22]. It remains to be determined if the additional degree of synovitis detected using high-sensitivity imaging in patients meeting these new definitions of synovitis is clinically important over time in terms of predicting further radiographic damage and loss of function. Fatigue had not been well studied in the data sets available and thus was not incorporated into the current definition of remission. Further study is still needed on the impact of the involvement of joints other than the 28 joints assessed in the new ACR/EULAR remission criteria. It is conceivable that other joints could be active and should be examined. If other joints are to be measured this needs to be reported. Using a longitudinal observational RA data set, Kapral et al. [23] evaluated RA disease activity and remission among 767 patients, with a total of 2754 combined visits. Composite indices involving a 28- or 32-joint count (the latter includes ankles and combined MTP joints) were used in evaluation [23]. However, it was found that the difference in the joint count was not relevant for composite disease activity assessment, as the frequency of remission was the same whether the 28- or 32-joint count was used. When the ankles and/or combined MTP joints were found to be swollen using the 32-joint count, the PGA of disease activity was higher, preventing mischaracterization of disease activity. Will it be feasible to incorporate an acute-phase reactant to define remission in clinical practice? CRP is not always available at the bedside. Felson et al. [15] commented that the Boolean definition without CRP or CDAI (consisting of SJC + TJC + evaluator and PGAs 42.8) provided results similar to those obtained using the Boolean or SDAI criteria. These definitions of remission may be used in clinical practice until better measures become available. Finally, the current criteria have not addressed the concept of sustained remission. Questions to be addressed A number of questions will be raised by rheumatology researchers and practitioners as they determine whether these new criteria will service the needs of people living with arthritis, those developing new therapies for them, and those treating patients with RA in daily clinical practice [22]. The new Boolean remission criteria are intended for use in clinical trials. However, rheumatologists at the bedside also need to treat their patients to a target of remission. It remains to be determined if the new criteria are cost effective, safe and feasible to implement at the bedside. This raises a number of questions. Are these criteria strict enough to define remission such that patients who achieve remission will not experience further joint damage, maintain function and/or achieve drug-free sustained remission? Recently Saleem et al. [24] evaluated whether or not patients meeting the new stringent definition of remission would have less evidence of synovitis as detected by US power Doppler studies. These authors showed this to be the case but still noted that most patients meeting the most stringent criteria of remission based on physical examination still had a significant number or joints that showed synovitis defined by a power Doppler signal >1 and grey-scale score >1 [24]. Other questions for future study might include: Will we need to treat patients to the point that even subclinical synovitis needs to be eliminated? Might there be less fatigue in patients who have no subclinical synovitis? Are there patients in whom escalation of therapy to achieve remission or subclinical remission will cause an increased risk of infection or other adverse events? Will other comorbidities lessen in patients who meet more stringent definitions of remission? Will treatment to the target of a stricter definition of remission be cost-effective and for which patient? Should this definition of remission become a benchmark for new therapies in development? Will remission only be achievable in patients with early disease? It is hoped that data from observational studies and upcoming trials, including those studying new agents and strategies for RA disease management, will answer these important questions moving forward such that clinicians can safely and confidently target remission as the state their patients should achieve. Rheumatology key messages. The ACR/EULAR 2011 RA remission criteria allow for little, if any, residual active disease.. The new RA remission criteria include measures of acute-phase reactants and patient-reported outcomes.. The implementation of the new RA remission criteria is questionable when CRP is not available. Supplement: This paper forms part of the supplement Reducing the toll of autoimmune disease: a focus on rheumatoid arthritis. This supplement was supported by unrestricted education grants from Centocor and Genentech. Disclosure statement: E.M.M. is an investigator for BMS, Astra Zeneca and Human Genome Sciences and a consultant for Sanofi, UCB and the Goodwin Group. V.B. is a consultant for Bristol-Myers Squibb, Roche and UCB. vi19

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