Assessment of rheumatoid arthritis activity in clinical trials and clinical practice

Assessment of rheumatoid arthritis activity in clinical trials and clinical practice

Authors
Josef S Smolen, MD
Daniel Aletaha, MD

Section Editor
Ravinder N Maini, BA, MB BChir, FRCP, FMedSci, FRS

Deputy Editor
Paul L Romain, MD

All topics are updated as new evidence becomes available and our peer review process is complete.

Literature review current through: May 2016. &#124 This topic last updated: Feb 28, 2016.

INTRODUCTION — Approaches to the management of rheumatoid arthritis (RA) have evolved as an increasing number of effective disease-modifying antirheumatic drugs (DMARDs) have become available. The early introduction of DMARDs has become standard of care, and depends upon early diagnosis [1]. Such early diagnosis is facilitated by the 2010 American College of Rheumatology (ACR)/European League Against Rheumatism (EULAR) rheumatoid arthritis classification criteria [2].
The goals of DMARD use are not only to ameliorate the symptoms and signs of active RA, but also to prevent structural joint damage and avoid functional impairment or enable its restoration. The development of new antirheumatic therapies, including biologic and synthetic agents targeted against specific components of the immunoinflammatory system, has required the availability of instruments that permit the assessment of disease activity and the response to therapy. Regardless of whether patients are evaluated in the context of a clinical trial or longitudinal clinical practice, the successful application of DMARD therapy requires that the goals of therapy be specified in advance and that the specific choice of DMARDs be revisited on a regular basis [3,4].
Clinical indicators employed in the assessment of RA activity are discussed here. The roles of both individual variables (eg, swollen joint counts and acute phase reactant measurements) and composite indices for disease activity assessment are considered, as are definitions of remission and criteria for clinically significant responses. Although much of the discussion centers on clinical trial outcome measures, we also provide recommendations for clinical practice.
A number of other topic reviews are related to the discussion of RA disease activity and complement the information provided here. As examples:
●The clinical features of RA, including the importance of distinguishing disease activity from structural joint damage are discussed elsewhere. (See "Clinical manifestations of rheumatoid arthritis".)
●Functional capacity and functional disability indices, which relate to a large extent to the degree of RA disease activity, are reviewed separately. (See "Disease outcome and functional capacity in rheumatoid arthritis".)
●Descriptions of a variety of biologic markers of disease activity, including those with established clinical utility and those that are of investigational interest are presented elsewhere. (See "Biologic markers in the diagnosis and assessment of rheumatoid arthritis" and "Investigational biologic markers in the diagnosis and assessment of rheumatoid arthritis".)
●The management of RA, including pharmacologic and nonpharmacologic as well as surgical interventions is surveyed separately. (See "General principles of management of rheumatoid arthritis in adults" and "Nonpharmacologic therapies and preventive measures for patients with rheumatoid arthritis".)
GENERAL PRINCIPLES — The conceptual framework for the assessment of disease activity in rheumatoid arthritis (RA) is defined by several principles. (See "General principles of management of rheumatoid arthritis in adults".)
●Active RA leads to severe joint destruction, functional disability, and impaired health status [5-12], particularly if sustained at high levels for prolonged periods of time. Thus, reduction of clinical disease activity through prudent DMARD use is an essential therapeutic aim.
●Functional impairment may relate to both active RA, manifested by symptoms such as pain, swelling, and stiffness of the joints, and to structural joint damage occurring as the consequence of previously active disease [7,9,13-15].
●With few exceptions [16], clinically active RA and the processes leading to joint destruction are linked, such that damage usually progresses in the presence of active disease [16-23].
●Monitoring disease activity at regular, short-term intervals (not to exceed three months when disease is active) and appropriate modifications of disease-modifying antirheumatic drug (DMARD) therapy to establish and maintain control of disease result in improved radiographic and functional outcomes in patients with RA [24-26]. To this end, the European League Against Rheumatism (EULAR) recommendations on the management of RA provide a treatment strategy, including recommendations for an approach to the institution of various therapeutic agents [3].
●The response to disease-modifying therapy in RA can be assessed by use of one of several response criteria that allow for an assessment of the degree of disease activity that is present, the extent of improvement that has occurred, and whether a state of remission has been achieved. (See 'Response criteria' below and 'Remission' below.)
●Therapeutic goals are the achievement of remission (ie, the virtual absence of disease activity) or a state of low disease activity as the second-best option. These goals are consistent with the recommendations of an international task force [4]. In the majority of RA patients, the achievement of sustained disease remission is associated with the cessation of joint damage [8,18,27-29]. However, in the majority of patients with longstanding disease, remission may not be an achievable goal, and therefore low disease activity is an acceptable alternative.

While some progression of damage and residual impairment of physical function may occur in association with low disease activity [30,31], a state of moderate disease activity, as defined by composite measures, is generally not acceptable, as it leads to much worse outcomes by comparison with low disease activity. Nevertheless, patient-specific factors and other risks need to be taken into account when adapting therapy to attain a good outcome. (See 'Composite indices for disease activity assessment' below.)
The following sections describe individual elements that are assessed in order to determine RA activity, the concepts of composite indices and response criteria, and the definitions of low disease activity and remission.
INDIVIDUAL VARIABLES OF DISEASE ACTIVITY — Common indicators of disease activity in rheumatoid arthritis (RA) include the following measurements (reviewed in [32]):
●Swollen and tender joint counts
●Pain
●Patient and evaluator global assessments of disease activity
●Erythrocyte sedimentation rate and C-reactive protein (ESR, CRP)
●Duration of morning stiffness
●Fatigue
Additional measures, which partly reflect disease activity and partly reflect disease outcome, include:
●Measures of function (eg, the Health Assessment Questionnaire)
●Health status measures (eg, the Short Form 36)
Core sets of disease activity variables — Beginning in the 1990s, several groups defined core sets of disease activity variables. The American College of Rheumatology (ACR), European League Against Rheumatism (EULAR), and a group of investigators representing both the World Health Organization (WHO) and International League of Associations of Rheumatology (ILAR) all published similar core sets of activity variables [33-35]. The methods used to identify these variables were driven by clinical data and met several criteria for validity [36-38].
All three core sets include swollen and tender joint counts, patient assessment of pain, patient global assessment of disease activity, and a measure of the acute phase response. As an example, the ACR core data set includes a total of seven measures: three performed by the evaluator (swollen joint count, tender joint count, and global assessment of disease activity); three collected by patient self-report (functional status, pain, and global assessment of disease activity); and a laboratory measure (either an ESR or CRP). The ACR and WHO/ILAR core sets both include evaluator global assessments of disease activity and physical function. In contrast, in the EULAR core set, physical function is regarded as an outcome variable rather than a process variable.
Swollen and tender joint counts — Joints are typically assessed according to two characteristics: 1) soft tissue swelling and effusion (the swollen joint count); and 2) pain on pressure or motion (the tender joint count). In general, neither the weighting of joints by their size (ie, the cartilage surface area) nor grading them by degree of swelling or tenderness confers validity and reliability [39,40].
The 28 joint count has become a standard for use in both clinical practice and clinical trials [40-43]. The 28 joint count excludes assessments of the foot and ankle joints, because the interpretation of swelling and tenderness in these joints is confounded frequently by disorders other than RA [40,42,43]. Although the 28 joint count has been criticized for leaving out assessment of the feet, it has been thoroughly validated and employed reliably in clinical trials and other analyses [44-46]. It is the basis of today’s most frequently employed composite measures of disease activity. Importantly, employing a 28-joint count for determining levels of disease activity and response does not obviate the responsibility to also assess ankles and feet in clinical practice.
Pain — Pain is usually measured by visual analog scales [43-45], which most often use horizontal 100 mm lines. Patients indicate their degree of pain (typically over the preceding week) by placing a mark between "no pain" (left end, 0 mm) and excruciating pain (right end, 100 mm). Alternatives to visual analog scales include numerical rating scales (ranging from 0 to 10 in steps of 1 or 0.5) and categorical scales (eg, 5-point Likert scales), both of which are also reliable and sensitive to change [47-49].
Patient and evaluator global assessments — Global disease activity rated by the patient, the evaluator, or both (and termed, respectively, the PGA or EGA, as appropriate) is assessed in a similar manner using visual analog scales, numerical rating scales, or Likert scales. Measuring the PGA acknowledges the importance of patient-reported outcomes. Whereas the EGA typically integrates information from both subjective and objective variables, the PGA is considered a subjective measure, which is strongly weighted for pain [50]. Because patients are more likely than medically-trained evaluators to construe functional disability as a manifestation of active disease, and because medically-trained evaluators have greater context for comparison with other RA patients, PGAs are usually scored at higher levels than are EGAs.
The typical question asked of the patient for a PGA is: "Considering all the ways your arthritis has affected you, how do you feel your arthritis is today?" This assessment is presumed to also take into account aspects of disease activity that might be less well appreciated by the clinician (eg, fatigue or sleep disturbances).
Acute phase reactants — Acute phase reactant levels, particularly the ESR and CRP, constitute the most objective disease activity measures. Acute phase reactant levels correlate well with both clinical disease activity measurements and radiographic progression of joint damage [6,10,51-54]. The ESR and CRP are the two biomarkers used most widely to assess disease activity. These tests are widely available, relatively inexpensive, and reflective of the cascade of inflammatory events associated with active RA; the CRP in particular is well standardized. Measurements of individual components of this response, eg, levels of the interleukin (IL)-1 beta, IL-6, or tumor necrosis factor (TNF)-alpha, are not more useful in assessing RA activity and are prone to greater variation from laboratory to laboratory. Moreover, among these cytokines, only IL-6 can be consistently and reliably measured in patient sera.
Other variables — Other variables associated with disease activity include the duration of morning stiffness, degree of fatigue, and the reduction in functional capacity. Morning stiffness is not contained among the core set variables because of its higher variability and lower sensitivity to change compared with other measures. A variety of patient-reported instruments are available to measure levels of fatigue, including the vitality/fatigue scales that constitute part of the short form (SF)-36. A specific measure for fatigue, the Functional Assessment of Chronic Illness Therapy (FACIT) fatigue measure, has been developed. More commonly, however, fatigue is assessed simply through the use of a visual analog scale.
COMPOSITE INDICES FOR DISEASE ACTIVITY ASSESSMENT — The individual variables outlined above reflect major characteristics of the disease within the population of rheumatoid arthritis (RA) patients as a whole. Given the heterogeneity of RA, however, the predominance of these indicators may be highly variable across individual patients, and may even vary with time within individual patients. As a result, the evaluation of a single core variable (eg, the erythrocyte sedimentation rate) in patients with RA would not reflect accurately the full spectrum of the disease. In addition, the evaluation of all variables within core sets often leads to heterogeneous responses and substantial methodological problems [36-38,55]. Thus, "composite" indices combining several core set variables have been developed. Several composite indices are in common use (table 1).
Formulas for calculating the indices vary in complexity, some are challenging to compute [10,41,56-59]. The Disease Activity Score (DAS), its derivative (the DAS28), the Simplified Disease Activity Index (SDAI), and the Clinical Disease Activity Index (CDAI) are described in greater detail below. Interestingly, baseline disease activity by these composite scores, and especially disease activity after three months of therapy with DMARDs is highly predictive of disease activity at later points in time (one year) [60] allowing to adopt treatment strategies that allow rapid, dynamic changes of therapeutic agents in patients who continue with high (or sometimes moderate) disease activity by three to six months from start of therapy.
Disease activity score (DAS) — The basis of the DAS was the clinician's decision to raise or lower disease-modifying antirheumatic drug (DMARD) doses based on a largely qualitative assessment of disease activity, and reflected clinical practice in about 1990 [56]. Several features make the DAS challenging to use in clinical trial and practice settings. First, the DAS employs the Ritchie Articular Index [57], a measure with major shortcomings in terms of feasibility and reliability, to evaluate joint tenderness. Second, the DAS employs an extensive 44 joint count to record the number of swollen joints. Finally, once the data required to complete the DAS are accumulated, the formula for calculating the score is quite complex, using different weights for each of the variables as well as square roots or logarithmic transformations in the case of some (table 1). In summary, the original DAS is complicated and not very user friendly, and therefore not ideally suited to wide use.
DAS28 score — The development of the DAS was important because it provided a global summative and continuous score for disease activity assessment [56]. A modification of the DAS, the DAS28, eliminated the grading of joints and reduced the number of joints evaluated to 28 [41,59]; it has been widely used in clinical trials and in practice. A calculator for the DAS28 is available (calculator 1).
Ranges of DAS28 scores that correspond to high, moderate, and low disease activity have been proposed (table 1 and figure 1). High disease activity relates to DAS28 >5.1, moderate to DAS28 of >3.2 to 5.1, low disease activity is regarded in the range of 2.6 to 3.2. A cut-off point for “remission” has also been proposed (DAS28 <2.6). However, studies find that nearly 15 percent of patients with DAS28 scores of 2.6 (the cut-point for remission) continue to have at least two swollen joints; some may have more than 10 swollen joints yet still be categorized as in "remission" using this composite index [11,61-63] (see 'Remission' below). Other composite measures also permit a number of inflamed joints among patients who fulfill criteria for remission.
The greater relative weight the DAS28 gives to acute phase measures can result in a disproportionately lower estimate of disease activity compared with other measures, such as the SDAI or CDAI (see 'Simplified disease activity index (SDAI)' below and 'Clinical disease activity index (CDAI)' below) when used to assess disease activity in patients receiving agents such as tocilizumab that have more pronounced effects on acute phase reactants relative to their overall clinical benefit [64]. As revealed by the formula of the DAS28, it also gives half as much weight to a swollen joint as it does to a tender joint, although both have a similar level of severity of inflammation.
Simplified disease activity index (SDAI) — The SDAI, which employs five of the core set variables (table 1) is calculated using a linear sum of unweighted, untransformed variables [59].
The SDAI is defined as the simple sum of the following:
●Tender joint count (using 28 joints)
●Swollen joint count (using 28 joints)
●Patient global assessment (0 to 10 scale)
●Physician global assessment (0 to 10 scale)
●C-reactive protein level (mg/dL)
The SDAI has been validated for use in both clinical trials and clinical practice [11,65,66]. Moreover, it has been shown to have the highest sensitivity and specificity for predicting clinicians' decisions to change DMARD therapy in 2005 when compared with other composite scores [66,67] and to correlate best with sonographic outcomes. A calculator for the SDAI is available, although the SDAI (and the CDAI (see 'Clinical disease activity index (CDAI)' below)) can potentially be performed without the use of a calculator in daily practice (calculator 2).
Cutpoints have been established for the various activity states (table 1 and figure 1). A cutpoint of 15 for the SDAI had the best combination of sensitivity and specificity (90 percent and 86 percent, respectively) when compared with the treating clinicians' decisions to change DMARDs because of active disease [66]. The cutpoint for remission, an SDAI of ≤3.3, does not allow the presence of more than two joints that are swollen or tender; because of its stringency, it also constitutes the index-based American College of Rheumatology (ACR)-European League Against Rheumatism (EULAR) remission definition [68,69]. The established cutpoints of 11 and 26 separate low disease activity (≤11) from moderate (≤26) and high (>26) disease activity [11,70].
Clinical disease activity index (CDAI) — A further simplification of the SDAI, the CDAI does not require the measurement of an acute phase reactant, but otherwise uses the same measures as the SDAI (table 1 and figure 1). (See 'Simplified disease activity index (SDAI)' above.)
The CDAI correlates well with other disease activity scores and response criteria, as well as with progression of joint damage and functional impairment [10,59,70]. The cutpoint for remission is 2.8 and that for low disease activity is 10. The advantage of the CDAI is that it facilitates immediate treatment decisions based entirely on clinical criteria and includes assessment of the joints, the principle “target organ" in RA. This attribute is useful in clinical trials and practice, since it circumvents the potential problem of lab to lab variation in the measurement of acute phase reactants. A calculator for the CDAI is available (calculator 3).
Since the CDAI does not incorporate measures of acute phase reactants, it presumably constitutes the most valid measure across all agents, including drugs that interfere directly with the acute phase reactants. However, the contribution of CRP to the SDAI is only minimal [10] and, therefore, these two scores give very similar results irrespective of the type of drug used.
PHYSICAL FUNCTION ASSESSMENTS AS MEASURES OF DISEASE ACTIVITY — Because active rheumatoid arthritis (RA) exerts a substantial effect on physical function, instruments designed to measure physical function are also useful indicators of disease activity. Such instruments, developed for generic use, are employed commonly in clinical trials, less often in clinical practice. The two physical function assessment tools used most frequently are the Health Assessment Questionnaire (HAQ) and the Medical Outcomes Study Short Form-36 (SF-36) [71-74].
Health Assessment Questionnaire (HAQ) — The complete HAQ is a comprehensive instrument designed to assess patient disability, discomfort, medication side effects, costs, and mortality. Of these components, only the HAQ Disability Index (HAQ-DI) is used frequently in clinical trials and clinical practice. The HAQ-DI, a component of the American College of Rheumatology (ACR) core data set for the evaluation of RA disease activity and outcome, evaluates patients' ability to perform activities of daily living through their answers to 20 questions designed to assess upper or lower extremity use. These questions are organized into eight categories: dressing, rising, eating, walking, hygiene, reach, grip, and usual activities. Each question is answered on a four-level scale of impairment ranging from 0 to 3: 0 = no difficulty; 1 = some difficulty; 2 = much difficulty; and 3 = inability to do.
The final HAQ index, which ranges from 0 to 3, is the mean of scores from all eight categories. HAQ scores <0.3 are considered normal, however, the mean HAQ of the population rises with age [75]. Higher HAQ scores indicate increasing disability. The minimal clinically important difference in serial HAQ scores has been suggested to be 0.22 on the group level. Several modifications of the HAQ have been employed in clinical trials and practice [73].
Although the primary influence on the HAQ is disease activity [9,72], the score reflects both joint damage and disease activity. Therefore, results of the HAQ require careful interpretation when used for disease activity assessment, as the irreversible, damage-related component of disability as assessed by HAQ increases with the degree of joint damage and with disease duration [14,15]. Thus, it has been proposed that the activity-related HAQ (ACT-HAQ) should be distinguished from its damage-related component (DAM-HAQ).
The short form-36 — The short form (SF)-36 is a patient-reported instrument designed to assess overall health status; it is not disease-specific [74]. The SF-36, usually utilized to measure patients' quality of life, has been validated in numerous diseases, including RA. The instrument consists of 36 questions organized into 8 domains: physical function, physical role, general health, bodily pain, mental health, social function, vitality/fatigue, and emotional role. Data from these eight domains can be summarized into two categories: a physical component score and a mental component score. SF-36 results are particularly useful for comparing quality of life across cohorts of patients with different diseases, but also correlate well with other measures of RA activity. Increasing SF-36 scores are indicative of improving health status.
PATIENT-REPORTED INSTRUMENTS — Several self-reported instruments are available for the assessment of RA activity. These include the Rheumatoid Arthritis Disease Activity Index (RADAI), the Rapid Assessment of Disease Activity inRheumatology (RADAR), and a modification of the Routine Assessment of Patient Index Data (RAPID3) [76-78].
RADAI and RADAR — The RADAI encompasses five items, including patient-assessed joint counts [76]. A major detraction of the RADAI, similar to that of the Disease Activity Score (DAS), is the need for a calculator. In contrast, the RADAR is a brief, two-page questionnaire that includes six items related to arthritis symptoms, physical function, work impact, psychological status, social health, and satisfaction with health status [77]. Although the use of patient-reported indices of disease activity such as the RADAI or RADAR is appealing in rheumatoid arthritis (RA), a condition associated with large personal dimensions, these instruments are rarely used in clinical trials and almost never in clinical practice. The patient-reported instruments used most often in clinical trials are global assessments of disease activity (eg, visual analog scales), Health Assessment Questionnaire (HAQ) scores, and the short form (SF)-36.
RAPID3 score — The RAPID3, as an expansion of the RAPID, constitutes an index that is based upon patient self-reported outcomes only and is simple to administer. It includes the HAQ, physical function, pain, and patient global estimate, all normalized to 0 to 10, counted together, and divided by 3 to yield a score on a scale of 0 to 10 [78,79]. It does not require a formal joint count, although swollen joint counts correlate with progression of joint damage [5,12]. It does provide similar quantitative information to the DAS28 or the Clinical Disease Activity Index (CDAI) regarding disease activity [78]. However, in established disease where functional impairment, to a large extent, is irreversible due to the accrued joint damage, the RAPID3 likely does not correlate well with the actual clinical improvement.
COMPOSITE BIOMARKER SCORING — A multi-biomarker disease activity (MBDA) assay and score has been developed which is suggested to reflect disease activity using a blood test based on a variety of biomarkers [80]. It is not clear when and how to use this blood test, since while it reflects clinical disease activity, it may be misleading in patients with infections or other comorbidities, and further study needs to be done in this regard. Indeed, since it shows good correlation with clinical activity, clinical assessment remains the gold standard and such tests, if sufficiently validated in various populations, may be useful for research studies but do not replace clinical assessment. (See "Biologic markers in the diagnosis and assessment of rheumatoid arthritis", section on 'Multi-protein biomarker algorithms'.)
RESPONSE CRITERIA — Response criteria, defined for both moderate and major changes in disease activity, have been developed for all of the major rheumatoid arthritis (RA) activity assessment indices. Such criteria can be applied to large numbers of patients in the context of clinical trials, and also in gauging the treatment responses of individual patients over time. Response criteria may involve either the comparison of a patient's activity score to a baseline value for that same patient, or the achievement of a certain disease activity state (eg, either remission or low disease activity).
ACR response criteria — An early attempt to define minimal response requirements was provided by the Paulus criteria [81]. These criteria formed the basis for the American College of Rheumatology (ACR) response criteria [82], which (in their initial iteration) outlined the variables of a 20 percent improvement. The ACR20 response, a standard measure for many clinical trials performed since 1995, is defined as improvement of at least 20 percent in the number of both swollen and tender joints, as well as at least 20 percent improvement in three or more of the five remaining core set variables (table 2).
The categorical response criteria embodied in the ACR20, ACR50, and ACR70 measure the frequency of benefit (ie, the proportion of patients receiving a certain treatment that achieve a defined response). In contrast, measuring the mean or median ACR-N (N for numeric) improvement facilitates an estimation of the cumulative magnitude of benefit that may be anticipated for a typical patient relative to the baseline disease activity. Both types of measures are useful for certain situations, and in many cases the information they provide are complementary. The hybrid-ACR response requires further validation. These measures are described below.
ACR20 response — The ACR20 response discriminates accurately between the effects of active medications and those of placebo. However, because of improvements in RA treatment, the ACR20 is no longer considered an optimal measure of clinically meaningful change: patients who achieve only ACR20 responses may still have substantial disease burdens from active RA. Moreover, the ACR20 has other potential weaknesses in some applications: 1) it does not measure directly any responses >20 percent in magnitude over baseline; 2) it characterizes the percentage of patients who meet this cutoff, rather than the response of the average patient; and 3) it measures the change in patients' disease activity compared with baseline, but does not quantify disease activity at the end of the period of interest.
ACR50 and ACR70 responses — More ambitious criteria for improvements in disease activity have been proposed; namely, the ACR50 and ACR70 responses [83], corresponding to 50 and 70 percent improvements, respectively. In contrast to ACR20 responses, patients notice dramatic differences following the achievement of ACR50 and ACR70 responses. In clinical trials of biologic agents, disease-modifying antirheumatic drugs (DMARDs), or various combinations, the percentage of patients achieving ACR20, 50, and 70 responses with the study agent (or combination of agents) have been on the order of 40 to 80 percent, 25 to 60 percent, and 10 to 40 percent, respectively. An ACR70 response corresponds well with achievement of a low disease activity state [84].
ACR-N response — However, as categorical variables, the ACR50 and ACR70 suffer from some of the same drawbacks as the ACR20. Thus, some investigators have attempted to express changes in the ACR core set variables as a continuous measure. One such effort, the ACR-N, judges changes in the following three variables: swollen joint count, tender joint count, and the median of the 5 remaining core set variables, using the 0 to 100 percent improvement that is the smallest among these three measures [59]. Thus, the ACR-N quantifies the patient response in terms of a single number, providing a continuous variable rather than a categorical one.
Hybrid-ACR response — Another attempt to expand the ACR response criteria is the Hybrid-ACR measure. To calculate the Hybrid-ACR, first the average improvement in core set measure is determined as percent improvement (with maximizing and thus censoring worsening at 100 percent). Then, (i) the mean of the percent changes across all core set measures, and (ii) the traditional ACR response (ie, ACR20, ACR50, or ACR70 response or non-response) is determined. The Hybrid-ACR is the first of these (ie, the mean percent change across all core set variables), unless it falls within the respective range of the traditional ACR response. Under these circumstances, the response is categorized as values of 19.99, 49.99, or 69.99 as long as mean core set changes lie above the traditional ACR categories that were achieved; if, however, the mean core set data lie below these traditional ACR categories, they are set to 20, 50, or 70. Thus, calculation of the Hybrid-ACR measure requires a variety of assessments to be accounted for, including the traditional ACR response evaluation. It requires additional validation.
EULAR response criteria — The European League Against Rheumatism (EULAR) response criteria are based upon the Disease Activity Score (DAS)28. These criteria categorize improvement into either good or moderate responses (table 1) [85,86].
●EULAR good response – For a good response, the decline in score must exceed 1.2 and result in the achievement of low disease activity (ie, DAS28 <3.2).
●EULAR moderate response – A moderate response, on the other hand, may be achieved by a decline in the DAS28 by >1.2 (without reaching low disease activity); or by a decline of 0.6 to 1.2, plus reaching at least moderate disease activity (ie, DAS28 <5.1).
Comparisons of the ACR and EULAR Response Criteria indicate that moderate EULAR responses are achieved more often than ACR20 responses in most studies. Good EULAR responses are observed more frequently than are ACR70 responses. (See 'ACR response criteria' above.)
SDAI and CDAI response criteria — Response cutoffs have been defined for the Simplified Disease Activity Index (SDAI) and the Clinical Disease Activity Index (CDAI) that correspond with the traditional ACR responses; these definitions of minor, moderate, and major response have been defined as relative improvements of SDAI or CDAI of 50, 70, or 85 percent, respectively [87]. (See 'Simplified disease activity index (SDAI)' above and 'Clinical disease activity index (CDAI)' above.)
REMISSION — Provisional definitions of remission were developed jointly by the American College of Rheumatology (ACR) and the European League Against Rheumatism (EULAR) for use in clinical trials and in clinical practice [68,69]. These definitions were considered provisional at the time of their publication, but now have undergone validation in several additional studies, also in comparisons with other criteria [63,88-90], and have also been adopted by the US Food and Drug Administration (FDA) draft guidance to industry for developing drugs products for treatment of rheumatoid arthritis (RA) and European Medicines Agency (EMA) Guideline on clinical investigation of medicinal products other than nonsteroidal antiinflammatory drugs (NSAIDs) for treatment of RA.
For clinical trials, the ACR/EULAR remission criteria recommend use of either of the following definitions as the primary and the other as a secondary outcome measure:
●Simplified Disease Activity Index (SDAI) ≤3.3 (calculator 2) (see 'Simplified disease activity index (SDAI)' above)

OR
●All of the following:
•Swollen and tender joint counts (using 28 joint count) each ≤1
•Patient global assessment (on a 0 to 10 scale) ≤1
•C-reactive protein (CRP) (expressed in mg/dL) ≤1
For clinical practice, either of the clinical trial criteria, modified by exclusion of the CRP, may be used:
●Clinical Disease Activity Index (CDAI) ≤2.8 (calculator 3) (see 'Clinical disease activity index (CDAI)' above)

OR
●All of the following:
•Swollen and tender joint counts (using 28 joint count) each ≤1
•Patient global assessment (on a 0 to 10 scale) ≤1
In concept, the state of remission constitutes a clinical condition in which no active disease is present. As noted, definitions of disease remission technically permit within their parameters some degree of active disease (table 1) [11,66,68,69,91,92]. The identification of remission is hampered practically by the presence of irreversible joint damage, which may lead to abnormalities confused with residual disease activity. In a similar manner, comorbidities such as fibromyalgia or osteoarthritis may confound the designation of remission.
Because progressive joint destruction may occur and function may decline, albeit at comparatively slow rates, when disease activity persists even at a low level, stringent criteria are important as a means of distinguishing remission from low disease activity [8,11,25,93]. In this regard, as briefly noted above, remission criteria by SDAI and CDAI, as well as Boolean-based criteria, are not only more stringent but also more reliable than Disease Activity Score (DAS)28 remission criteria and constitute the index-based ACR/EULAR provisional definitions of remission [68,69].
The above new remission definition has meanwhile been widely validated to convey better outcomes than other measures [63,88-90].
SUMMARY
●The three major points supporting the use of disease activity measures in clinical practice to try to achieve a goal of remission are the following: 1) Active rheumatoid arthritis (RA) leads to severe joint destruction, functional disability, and impaired health status; 2) monitoring disease activity at regular, short-term intervals and appropriate modifications of disease-modifying antirheumatic drug (DMARD) therapy leads to significant functional and radiologic improvements; and 3) joint destruction progresses only at a slow rate and much less than in moderate or high disease activity states; therefore, low disease activity is an alternative treatment target, especially in established disease.
●Several indicators of disease activity are typically assessed in clinical trials of therapeutic agents in patients with RA. Among them, the most often measured are: swollen and tender joint counts, pain, patient and evaluator global assessments, acute phase reactants (erythrocyte sedimentation rate [ESR] and C-reactive protein [CRP]), duration of morning stiffness, fatigue, measures of function (eg, the Health Assessment Questionnaire), and of health status (eg, the Short Form 36). (See 'Individual variables of disease activity' above.)
●Various sets of individual measures have been characterized that are useful for assessing the efficacy of drug treatment of RA. These core sets include those developed by the American College of Rheumatology (ACR), European League Against Rheumatism (EULAR), and World Health Organization (WHO)/International League of Associations of Rheumatology (ILAR). (See 'Core sets of disease activity variables' above.)
●Composite indices of disease activity (Simplified Disease Activity Index [SDAI], and Clinical Disease Activity Index [CDAI]) represent indices that provide a timely aid to clinical decision making. The Disease Activity Score using 28 joint counts (DAS28) is a good score for higher disease activity, but not sufficiently stringent nor reproducible across different agents when aiming at a good outcome such as remission. The SDAI and CDAI are also easier to calculate than the DAS or DAS28 and define remission more stringently. Measures that do not include joint counts may not reflect disease activity sufficiently in patients with longstanding disease and may not be as well correlated with joint damage as the other indices. (See 'Composite indices for disease activity assessment' above.)
●Responses of groups of patients to treatment in clinical trials may be based on a categorical criterion (eg, an ACR50 response, a EULAR good response, or a CDAI/SDAI major response) or the mean change of a numeric index of disease activity (eg, DAS, SDAI, CDAI, ACR-N [N for numeric], or Hybrid ACR). DAS, SDAI, and CDAI provide measures of actual disease activity, while the ACR-N and Hybrid ACR represent improvements from a series of baseline values. (See 'Response criteria' above.)
●With some preparation and minor modifications of the usual work flow in clinical settings, all of the variables comprising core data sets for RA activity assessment can be collected in a standard fashion: 1) Tender and swollen joint counts can be obtained by any health professional with appropriate training; 2) visual analogue scales for patient and evaluator global assessments of disease activity require less than one minute to complete (figure 2); 3) routine laboratory testing of the ESR, CRP, or both is inexpensive and widely available; 4) HAQ-DI assessments may be completed by patients in the waiting room.
●We suggest use of the CDAI to help guide treatment decisions by clinicians caring for patients with RA. The CDAI is calculated as a simple numerical sum of swollen and tender joints (using the 28 joint count), the patient global assessment, and the evaluator global assessments. It can be used for clinical decision-making purposes even in the absence of information about acute phase reactants. It is easy to obtain and calculate, despite the inclusion of formal joint counts. The ESR or CRP, if available, may be useful in validating the clinician's impressions based on the CDAI or other composite index of choice. (See 'Clinical disease activity index (CDAI)' above.)
●Definitions of remission that may be used in clinical trials and clinical practice, respectively, have been developed by a joint committee of the ACR and the EULAR and meanwhile widely validated. (See 'Remission' above.)
●Optimal management of patients with RA and some degree of active disease requires serial assessments. We suggest intervals not greater than every three months, in line with the recommendations on treating RA to targeting remission or low disease activity.