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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: Jun 2016. | 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)/EuropeanLeague 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 RapidAssessment of Disease Activity in Rheumatology (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.

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GENERAL PRINCIPLES OF MANAGEMENT OF RHEUMATOID ARTHRITIS IN ADULTS

Authors Larry W Moreland, MD Amy Cannella, MD, MS, RhMSUS Section Editor James R O'Dell, MD 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: Jun 2016. | This topic last updated: Jun 10, 2016. INTRODUCTION The treatment of rheumatoid arthritis (RA) is directed toward the control of synovitis and the prevention of joint injury. The choice of therapies depends upon several factors, including the severity of disease activity when therapy is initiated and the response of the patient to prior therapeutic interventions.

Common principles that guide management strategies and the choice of agents have been derived from an increased understanding of the disease and evidence from clinical trials and other studies. These strategies include approaches directed at achieving remission or low disease activity by more rapid and sustained control of inflammation by the institution of disease-modifying antirheumatic drug (DMARD) therapy early in the disease course.

The general principles and treatment strategies that should be applied to the management of RA are reviewed here. The initial therapy of RA and the treatment of patients resistant to initial DMARDs are discussed in greater detail elsewhere. (See "Nonpharmacologic therapies and preventive measures for patients with rheumatoid arthritis" and "Alternatives to methotrexate for the initial treatment of rheumatoid arthritis in adults" and "Initial treatment of rheumatoid arthritis in adults" and "Treatment of rheumatoid arthritis in adults resistant to

initial nonbiologic DMARD therapy" and "Treatment of rheumatoid arthritis in adults resistant to initial biologic DMARD therapy".)

GENERAL PRINCIPLES Our overall approach to the treatment of patients with rheumatoid arthritis (RA) depends upon the timely and judicious use of several types of therapeutic interventions. The appropriate use of these therapies is based upon an understanding of a group of general principles that have been widely accepted by major working groups and by professional organizations of rheumatologists [1-5]. (See 'Recommendations by major groups' below.)

These principles include:

Early recognition and diagnosis (see 'Early recognition and diagnosis' below)

Care by an expert in the treatment of rheumatic diseases, such as a rheumatologist (see 'Care by a rheumatologist' below)

Early use of disease-modifying antirheumatic drugs (DMARDs) for all patients diagnosed with RA (see 'Early use of DMARDs' below)

Importance of tight control, utilizing a treat-to-target strategy, with a goal of remission or low disease activity (see 'Tight control' below)

Use of antiinflammatory agents, including nonsteroidal antiinflammatory drugs (NSAIDs) and glucocorticoids, only as adjuncts to therapy (see 'Adjunctive role of antiinflammatory agents' below)

The application of these principles has resulted in significant improvement in the outcomes of treatment, although the etiology and pathogenesis of RA are complex and are not fully understood [6-8]. Such improvements may owe even more to the therapeutic strategies that have been adopted than to the development and use of newer and more potent drugs [9].

RA is characterized by acute and chronic inflammation in the synovium, which is associated with a proliferative and destructive process in joint tissues [8,10,11]. Many elements of innate and adaptive immunity are involved in this process, and persistent inflammation may lead to significant and irreversible joint injury as early as the first two years of disease. Therefore, measures aimed at identifying early active disease and at markedly reducing inflammation are essential for modifying disease outcome [7,9,12,13]. (See "Pathogenesis of rheumatoid arthritis" and 'Tight control' below.)

Early recognition and diagnosis Achieving the benefits of early intervention with DMARDs depends upon making the diagnosis of RA as early as possible. The recognition of RA early in the course of inflammatory arthritis, before irreversible injury has occurred, is thus an important element of effective management. (See 'Early use of DMARDs' below.)

In 2010, international collaborative efforts led to the development of new classification criteria for RA, which have identified factors that support the early diagnosis of RA among patients presenting with inflammatory arthritis [14]. These criteria are directed at the recognition of patients with early arthritis who are most likely to develop progressive and erosive disease. The diagnosis and differential diagnosis of RA are reviewed in detail elsewhere. (See "Diagnosis and differential diagnosis of rheumatoid arthritis" and "Clinical manifestations of rheumatoid arthritis".)

Care by a rheumatologist An expert in the treatment of rheumatic diseases, such as a rheumatologist, should participate in the care of patients with inflammatory arthritis who are suspected of having RA and in the ongoing care of patients diagnosed with this condition [3,15]. The early and ongoing care of patients with RA by a rheumatologist is associated with better disease outcomes, such as reduced joint injury and less functional disability, compared with care rendered primarily by other clinicians [16-21].

The initial rheumatology consultation allows the diagnosis to be made or reassessed, the severity of disease to be estimated, and a plan of care to be developed and initiated. The frequency of subsequent specialist care depends upon the severity of symptoms and joint inflammation, the patient’s response to treatment, the complexity and risks associated with the therapy, and the preferences of the patient and primary care clinician.

NONPHARMACOLOGIC AND PREVENTIVE THERAPIES A number of nonpharmacologic measures and other medical interventions are important in the comprehensive management of rheumatoid arthritis (RA) in all stages of disease, in addition to antirheumatic drug therapies. Patient education that addresses issues related to the disease and its management is indicated for all patients with RA. Attention to health promotion and specific strategies aimed at minimizing the adverse effects of RA and of agents used to treat it are also appropriate. These therapies are discussed in detail elsewhere. (See "Nonpharmacologic therapies and preventive measures for patients with rheumatoid arthritis".)

Briefly, these measures include:

Patient education

Psychosocial interventions

Rest, exercise, and physical and occupational therapy

Nutritional and dietary counseling

Interventions to reduce risks of cardiovascular disease, including smoking cessation and lipid control

Screening for and treatment of osteoporosis

Immunizations to decrease risk of infectious complications of immunosuppressive therapies

PHARMACOLOGIC THERAPY

Pretreatment evaluation Prior to starting, resuming, or significantly increasing therapy with nonbiologic or biologic disease-modifying antirheumatic drugs (DMARDs), we do the following baseline studies [22]:

General testing for all patients We obtain a baseline complete blood count, serum creatinine, aminotransferases, erythrocyte sedimentation rate (ESR), and C-reactive protein (CRP) in all patients.

Hepatitis B and C In all patients without a known history of hepatitis, we screen for hepatitis B and C before initiating therapy with conventional DMARDs, including methotrexate (MTX) and leflunomide (LEF); biologic DMARDs; and tofacitinib. Patients should be screened for hepatitis B with testing for hepatitis B virus (HBV) surface antigen and HBV core antibody prior to initiating these drugs and prior to treatment with prednisone at doses of ≥20 mg daily. Some experts limit screening for hepatitis C to patients at increased risk of hepatitis, such as those who have a history of intravenous drug abuse, have had multiple sex partners in the previous six months, or who are healthcare workers. [5,22]. Some patients may require antiviral treatment prior to initiating DMARD or immunosuppressive therapy, depending upon their level of risk for HBV reactivation. (See "Hepatitis B virus reactivation associated with immunosuppressive therapy".)

Ophthalmologic screening for hydroxychloroquine use A complete baseline ophthalmologic examination should be performed within the first year of treatment, including examination of the retina through a dilated pupil and automated visual field testing. (See "Antimalarial drugs in the treatment of rheumatic disease", section on 'Monitoring for toxicity'.)

Testing for latent tuberculosis We screen for latent tuberculosis (TB), consistent with the US Centers for Disease Control (CDC) and 2015 American College of Rheumatology (ACR)

guidelines, with skin testing or an interferon-gamma release assay prior to all biologic DMARDs and prior to use of the Janus kinase inhibitor, tofacitinib; such screening is based upon evidence that these medications, including the tumor necrosis factor (TNF) inhibitors, other biologics, and tofacitinib, may increase the risk of mycobacterial infection [5,23,24].

We also screen for latent TB in patients about to receive MTX who live, travel or work in areas with likely TB exposure, although some clinicians prefer to screen all patients starting DMARD therapy. We obtain a chest radiograph in patients with a history of other risk factors for latent TB, even if screening tests are negative, given the risks of false-negative testing. Additionally, skin testing should be repeated in patients with new TB exposures. Glucocorticoids and other factors may cause false-negative results. Screening for latent TB is discussed in detail separately. (See "Tumor necrosis factor-alpha inhibitors and mycobacterial infections" and "Diagnosis of latent tuberculosis infection (tuberculosis screening) in HIV-uninfected adults".)

Interferon-gamma release assays can be used in place of tuberculin skin testing in the United States, according to CDC recommendations, and may be preferred in patients who have previously received vaccination with Bacillus Calmette-Guerin (BCG). However, in some countries, tuberculin skin testing is preferred. (See "Interferon-gamma release assays for diagnosis of latent tuberculosis infection".)

Choice of therapy Choices between treatment options are based upon multiple factors, including:

Level of disease activity (eg, mild versus moderate to severe)

Presence of comorbid conditions

Stage of therapy (eg, initial versus subsequent therapy in patients resistant to a given intervention)

Regulatory restrictions (eg, governmental or health insurance company coverage limitations)

Patient preferences (eg, route and frequency of drug administration, monitoring requirements, personal cost)

Presence of adverse prognostic signs

A combination of the following types of therapies may be used:

Rapidly acting antiinflammatory medications, including nonsteroidal antiinflammatory drugs (NSAIDs) and systemic and intraarticular glucocorticoids. (See 'Adjunctive role of antiinflammatory agents' below.)

DMARDs, including nonbiologic (traditional small molecule or synthetic) and biologic DMARDs, and an orally administered small molecule kinase inhibitor, which all have the potential to reduce or prevent joint damage and to preserve joint integrity and function. (See "Overview of immunosuppressive and conventional (non-biologic) disease-modifying drugs in the rheumatic diseases".)

The nonbiologic (or conventional synthetic) DMARDs most frequently used include hydroxychloroquine (HCQ), sulfasalazine (SSZ), MTX, and LEF. (See "Overview of immunosuppressive and conventional (non-biologic) disease-modifying drugs in the rheumatic diseases", section on 'Disease-modifying antirheumatic drugs' and "Antimalarial drugs in the treatment of rheumatic disease" and "Sulfasalazine in the treatment of rheumatoid arthritis" and "Use of methotrexate in the treatment of rheumatoid arthritis" and "Leflunomide in the treatment of rheumatoid arthritis".)

Biologic DMARDs, produced by recombinant DNA technology, generally target cytokines or their receptors or are directed against other cell surface molecules. These include anticytokine therapies, such as the TNF-alpha inhibitors, etanercept, infliximab, adalimumab, golimumab, and certolizumab pegol; the interleukin (IL)-1 receptor antagonist anakinra; and the IL-6 receptor antagonist tocilizumab. They also include other biologic response modifiers such as the T-cell costimulation blocker abatacept (CTLA4-Ig) and the anti-CD20 B-cell depleting monoclonal antibody rituximab. (See "Overview of biologic agents in the rheumatic diseases" and "T-cell targeted therapies for rheumatoid arthritis", section on 'Abatacept' and "Rituximab and other B cell targeted therapies for rheumatoid arthritis", section on 'Rituximab' and "Randomized clinical trials in rheumatoid arthritis of biologic agents that inhibit IL-1, IL-6, and RANKL", section on 'Tocilizumab'.)

Targeted synthetic DMARDs, including several kinase inhibitors, are in development for use in rheumatoid arthritis (RA); one of these, tofacitinib, is available for such clinical use in the United States and several other countries. Tofacitinib is an orally administered small molecule DMARD that inhibits cytokine and growth factor signalling through interference with Janus kinases. (See "Cytokine networks in rheumatic diseases: Implications for therapy", section on 'JAK inhibition'.)

Early use of DMARDs We recommend that all patients diagnosed with RA be started on DMARD therapy as soon as possible. Our choice of drug therapies in patients with RA and the

evidence supporting these choices is described in detail separately. Briefly, we take the following approach (see 'Assessment of disease activity' below):

In patients with active RA, we initiate antiinflammatory therapy with either a NSAID or glucocorticoid, depending upon the degree of disease activity, and generally start DMARD therapy with MTX. (See "Initial treatment of rheumatoid arthritis in adults".)

Patients unable to take MTX may require an alternative agent, such as HCQ, SSZ, or LEF. (See "Alternatives to methotrexate for the initial treatment of rheumatoid arthritis in adults".)

In patients resistant to initial DMARD therapy (eg, MTX), we treat with a combination of DMARDs (eg, MTX plus either SSZ and HCQ or a TNF inhibitor), while also treating the active inflammation with antiinflammatory drug therapy. (See "Treatment of rheumatoid arthritis in adults resistant to initial nonbiologic DMARD therapy".)

Much of the joint damage that ultimately results in disability begins early in the course of the disease [25,26]. As an example, more than 80 percent of patients with RA of less than two years’ duration had joint space narrowing on plain radiographs of the hands and wrists, while two-thirds had erosions [26]. The use of more sensitive imaging techniques, such as magnetic resonance imaging (MRI) and high-resolution ultrasonography, can identify even earlier damage than that which is recognized by radiography, although the prognostic implications of such findings are unknown [27-29].

Better outcomes are achieved by early compared with delayed intervention with DMARDs in patients with RA [12,30-35]. As an example, one study in Texas found that low socioeconomic status was associated with a significant delay in starting DMARD therapy; both factors were independently associated with greater disease activity, joint damage, and physical disability [35]. Some evidence suggests that the effect upon outcomes is not linear with time, but that there may be an early “window of opportunity” for optimal DMARD treatment benefit [36]. As examples:

The effect of symptom duration prior to DMARD therapy on the likelihood of DMARD-free sustained remission was examined during five years of follow-up in patients with RA from two cohorts, the Leiden Early Arthritis Clinic (EAC; n = 738) and Étudeet Suivi de POlyarthrites Indifférenciées Récentes (ESPOIR; n = 533) [36]. Remission was maintained in 11.5 and 5.4 percent of patients from the two cohorts, respectively. The symptom durations that optimally discriminated between greater and lesser likelihood of remission were between 11.4 and 19.1 weeks, depending upon the cohort and whether or not patients were anti-citrullinated peptide antibody (ACPA)-positive, suggesting there is a limited period of several months following symptom onset during which RA is most susceptible to intervention with DMARDs.

An observational study of 1435 patients involved in 14 trials, primarily of MTX or other nonbiologic DMARDs, found a progressive decrease over time in the likelihood of a significant response to DMARD therapy. Response rates were higher in patients with no more than one year of disease than in those with one to two years of disease, and response rates were lowest in the group with greater than 10 years of disease (53 versus 43 versus 35 percent)

[30].

ASSESSMENT AND MONITORING Patients should be seen on a regular basis for clinical evaluation and monitoring of clinical and laboratory assessment of disease activity and for screening for drug toxicities. The initial evaluation and subsequent monitoring should also include periodic assessment of disease activity using a quantitative composite measure of disease activity. (See 'Assessment of disease activity' below.)

Additionally, the ongoing evaluation and monitoring of patients with rheumatoid arthritis (RA) following the initiation of therapy also involves:

Patient and clinician assessment of symptoms and functional status (see 'Symptoms and functional status' below)

Evaluation of joint involvement and extraarticular manifestations (see 'Physical examination' below)

Laboratory markers (see 'Laboratory monitoring of disease activity' below and 'Monitoring and prevention of drug toxicity' below)

Imaging (see 'Imaging' below)

Assessment of disease activity Disease activity should be evaluated initially and at all subsequent visits. We recommend that a structured assessment of disease activity using a composite measure, such as those described here, should be performed initially, and most patients should be seen at least every three months to monitor the response to therapy using the same measure. Adjustments to treatment regimens should be made to quickly achieve and maintain control of disease activity if targeted treatment goals (remission or low disease activity), rather than an undefined degree of improvement, have not been achieved. (See "Assessment of rheumatoid arthritis activity in clinical trials and clinical practice", section on 'Composite indices for disease activity assessment' and 'Tight control' below.)

The initial assessment, made once the diagnosis is established, helps to distinguish the smaller group of patients who present with mild disease from the majority of patients who present with moderately to severely active disease and who are usually treated initially with

methotrexate (MTX). (See "Alternatives to methotrexate for the initial treatment of rheumatoid arthritis in adults" and "Initial treatment of rheumatoid arthritis in adults".)

The use of periodic structured assessments of disease activity is complementary to ongoing regular monitoring of disease manifestations, disease progression, joint injury, disability, and complications of the disease and to monitoring for adverse effects of medications. (See 'Assessment and monitoring' above.)

Multiple composite measures employing different combinations and weighting of these variables have been developed for use in clinical research and practice. Among the more than 60 activity measures available for evaluation of patients with RA, the six measures noted below have been identified by the American College of Rheumatology (ACR) as having the greatest utility in clinical practice because they accurately reflect disease activity; are sensitive to change; discriminate well between low, moderate, and high disease activity; have remission criteria; and are feasible to perform in clinical settings [37]. The choice of measure is based upon clinician preference; some measures require both patient and clinician input, while others are based only upon patient-reported data. (See "Assessment of rheumatoid arthritis activity in clinical trials and clinical practice", section on 'Composite indices for disease activity assessment'.)

Measures that require both patient and clinician input, as well as calculators for these measures, include the following:

Disease Activity Score derivative for 28 joints (DAS28) (calculator 1)

Simplified Disease Activity Index (SDAI) (calculator 2)

Clinical Disease Activity Index (CDAI) (calculator 3)

The patient-reported outcome measures include:

Routine Assessment of Patient Index Data 3 (RAPID3) [38]

Patient Activity Scale (PAS) [39]

PAS-II [39]

The RAPID3 correlates well with the results obtained by use of the DAS28 or CDAI [38]. (See "Assessment of rheumatoid arthritis activity in clinical trials and clinical practice", section on 'RAPID3 score'.)

Symptoms and functional status The clinical assessment of disease activity should include questions concerning the degree of joint pain, the duration of morning stiffness, and the severity of fatigue [22,40]. In addition, evidence for and changes in extraarticular manifestations of RA should be actively sought, including systemic signs such as fever, anorexia, malaise, weight loss, and symptoms of cardiovascular disease. (See "Clinical manifestations of rheumatoid arthritis".)

Fever is not a common feature of RA in adults. Infection must be excluded before ascribing fever to RA.

Patients should be queried regarding their functional capacity, including the performance of activities of daily living, of vocational activities, and of avocational activities, such as hobbies or participation in sports. A self-report questionnaire that measures function can also be often helpful for this purpose. The Stanford Health Assessment Questionnaire (HAQ) is one of the best known and tested of these questionnaires [41,42]; others include the Functional Independence Measure [43], the Arthritis Impact Measurement Scale (AIMS), the Short Form 36 (SF36), and the Modified Health Assessment Questionnaire (MHAQ) [44]. (See "Disease outcome and functional capacity in rheumatoid arthritis", section on 'Functional capacity'.)

We use the evaluation of functional capacity to identify which of a variety of interventions may be required in addition to pharmacologic therapy, especially in patients with diminished functional capacity, such as counseling, exercise, and occupational therapy. (See "Nonpharmacologic therapies and preventive measures for patients with rheumatoid arthritis".)

Physical examination A physical examination should be performed at regular intervals that vary with disease activity and severity. As an example, patients with severely active disease may be seen at four-week intervals, while those with mildly active or well-controlled disease could be seen every two to four months. At these visits, an examination should be performed to assess changes in previously affected joints or the appearance of inflammation in previously uninvolved joints.

A 28-joint examination is appropriate if the hands but not the feet are involved [45]. Examined joints include the wrists, elbows, shoulders, and knees, as well as the metacarpophalangeal and proximal interphalangeal joints of the hands. If the feet are involved, the metatarsophalangeal joints and proximal interphalangeal joints of the feet should also be assessed. The joints should be evaluated for the presence of swelling, tenderness, loss of motion, and deformity.

In addition to the articular examination, a periodic general physical examination should be performed, with particular attention to the skin for rheumatoid nodules or other dermal manifestations of RA and to the lungs for signs of pleural or interstitial disease, to detect evidence of systemic or extraarticular involvement. (See "Overview of the systemic and nonarticular manifestations of rheumatoid arthritis".)

Laboratory monitoring of disease activity The acute phase reactants, such as C-reactive protein (CRP) or erythrocyte sedimentation rate (ESR), are useful for assessment of disease activity and are components of several of the formal composite measures used for evaluating the level of disease activity. In addition to these studies, we obtain other tests primarily for medication monitoring that may also reflect changes or levels of disease activity. Examples of the latter include serum hemoglobin, decreases in which may reflect anemia of chronic inflammation, and serum albumin, which may also be reduced in association with increased disease activity. Additionally, platelet counts may be mildly elevated (typically up to 400,000 to 450,000/microL) in patients with ongoing inflammation. (See 'Pretreatment evaluation' above and "Assessment of rheumatoid arthritis activity in clinical trials and clinical practice", section on 'Acute phase reactants' and "Acute phase reactants" and "Biologic markers in the diagnosis and assessment of rheumatoid arthritis" and "Anemia of chronic disease/inflammation" and "Hematologic manifestations of rheumatoid arthritis".)

Monitoring and prevention of drug toxicity Because of the potential risks of serious adverse effects and the frequency of common side effects of antirheumatic drugs, a careful balance must be struck between the risks and potential benefits of these agents [46,47]. We generally follow the recommendations of the ACR for drug monitoring in the treatment of RA (table 1) [1,5,22,40,48]. Additional precautions, warnings, and the manufacturer’s recommendations for clinical and laboratory monitoring are provided in the individual UpToDate drug information topics for each medication. (See appropriate topic reviews.)

Monitoring for adverse effects, such as osteoporosis, diabetes, and hypertension, should be performed in patients on glucocorticoids, and appropriate preventive measures should be undertaken. RA is considered an independent risk factor for osteoporotic fracture, and a fracture risk assessment should be performed to help guide treatment decisions. (See "Prevention and treatment of glucocorticoid-induced osteoporosis" and "Osteoporotic fracture risk assessment", section on 'Assessment of fracture risk' and "Major side effects of systemic glucocorticoids" and "Antimalarial drugs in the treatment of rheumatic disease", section on 'Monitoring for toxicity' and "Leflunomide in the treatment of rheumatoid arthritis", section on 'Liver'.)

Imaging Early in the course of RA, it is appropriate to obtain plain radiographs of the hands and wrists (one film, posteroanterior [PA] view), as well as at least one anteroposterior (AP)

view of both forefeet to include the metatarsophalangeal joints. These radiographs serve as a baseline for evaluating change in the joints during treatment. Radiographs should be repeated every two years in patients in remission or with low disease activity. We view the therapy in use by the patient as insufficient if radiologic evidence of disease progression, such as periarticular osteopenia, joint space narrowing, or bone erosions, appears or worsens during this interval, despite good control of disease activity by other measures. In such patients, based upon our clinical experience, we may intensify or modify the treatment regimen. The clinician must be aware that, in hand radiographs of older patients, coexistent osteoarthritis may account, in part, for joint space narrowing noted near the joints involved with RA [49].

Musculoskeletal ultrasonography (MSUS) and magnetic resonance imaging (MRI) are more sensitive for the detection of cartilage and bone abnormalities. MSUS is increasingly utilized at the point of care by rheumatologists for diagnosis and monitoring disease progression and therapeutic response [27,50]. Likewise, MRI has become increasingly employed to demonstrate subclinical synovitis, early erosive changes, and therapeutic response [27,51,52]. Some clinicians routinely employ these modalities to follow patients over time. The authors prefer to use MSUS and MRI to answer specific clinical questions in an individual patient, but not in the routine management of RA.

TIGHT CONTROL We recommend the use of tight control treatment strategies to quickly minimize inflammation and disease progression; our therapeutic target is remission or a state of minimal disease activity, without compromising safety. In patients resistant to initial disease-modifying antirheumatic drug (DMARD) therapy, we either add additional DMARDs to the ongoing regimen or switch the patient to a different DMARD, while also treating the active inflammation with antiinflammatory drug therapy. A description of our treatment approach and the evidence supporting use of particular medications in patients with active disease despite initial DMARD therapy are discussed in detail separately. (See 'Drug therapy for flares' below and "Treatment of rheumatoid arthritis in adults resistant to initial nonbiologic DMARD therapy".)

In patients with disease exacerbations despite a preceding period of better control of disease activity (a “disease flare”), a temporary increase in antiinflammatory therapies, including the use of glucocorticoids, may be required. (See 'Drug therapy for flares' below.)

The use of strategies for tight control involves frequent periodic reassessment of disease activity, usually at least every three months; adjustment of DMARD regimens every three to six months, if needed, as the primary tool to achieve treatment goals; and administration of antiinflammatory therapies (eg, nonsteroidal antiinflammatory drugs [NSAIDs] and oral and intraarticular glucocorticoids) as an adjunct to DMARDs to maintain control of disease activity until DMARD therapies are sufficiently effective to discontinue glucocorticoids or reduce their

use to an acceptably low level. Treatment protocols based upon this general approach are associated with improved radiographic and functional outcomes compared with less aggressive approaches [7,53-62].

The periodic reevaluation of disease activity using a quantitative composite measure and the use of antiinflammatory drugs, including NSAIDs and glucocorticoids, as bridging therapies are both important elements in the strategy of tight control. Glucocorticoids can rapidly achieve control of inflammation until DMARDs are sufficiently effective. (See 'Assessment of disease activity' above and "Assessment of rheumatoid arthritis activity in clinical trials and clinical practice" and 'Adjunctive role of antiinflammatory agents' below.)

Taken together, studies that have compared tight control with less aggressive approaches support the following observations:

Most patients should receive a DMARD as soon as possible after diagnosis. Achieving and maintaining low disease activity using a DMARD or DMARD combinations as quickly as possible improve long-term outcomes and are cost-effective compared with older, more gradual approaches to initiating DMARD therapy. (See 'Early use of DMARDs' above.)

Excellent treatment responses can be achieved with a wide variety of nonbiologic and biologic DMARDs and with regimens that combine either nonbiologic DMARDs alone or nonbiologic DMARDs with a biologic agent, as described below.

Escalation in the treatment regimen is needed for patients resistant to initial treatment; both intraarticular glucocorticoids and oral or intramuscular glucocorticoids help minimize disease activity until DMARDs are sufficient. (See 'Adjunctive role of antiinflammatory agents' below.)

Regular assessment with composite measures of disease activity is critical to optimize clinical decision-making. (See 'Assessment of disease activity' above.)

These observations are reflected in the 2008, 2012, and 2015 American College of Rheumatology (ACR) and 2010 European League Against Rheumatism (EULAR) treatment recommendations and in the recommendations of an international task force that were presented in 2010 and updated in 2014 [1-3,7,22,62-65].

The benefits of tight control have been shown in a meta-analysis of six heterogeneous trials that evaluated tight control strategies in comparison with usual care for rheumatoid arthritis (RA) [66]. Significantly greater improvement from baseline to one year in the Disease Activity Score derivative for 28 joints (DAS28) composite measure of disease activity was seen in the

patients randomly allocated to tight control strategies compared with usual care (mean difference in reduction in DAS28 of 0.59, 95% CI 0.22-0.97). A statistically significantly greater reduction compared with usual care was observed in the trials in which tight control was achieved with protocolized treatment adjustments compared with trials without such protocols (mean difference in DAS28 of 0.91, 95% CI 0.72-1.11, versus 0.25, 95% CI 0.03-0.46). Four of the six studies analyzed compared functional ability in the two treatment arms using the Health Assessment Questionnaire (HAQ). Greater improvement in HAQ scores in the tight control groups that were statistically significant were seen in two of these trials, while improvements in the HAQ scores did not differ significantly between the treatment arms in the other two trials. (See "Assessment of rheumatoid arthritis activity in clinical trials and clinical practice", section on 'Health Assessment Questionnaire (HAQ)'.)

A number of randomized trials and related studies illustrate the range of medications and

approaches that provide evidence favoring a treat-to target approach [53-59,67-69]. Especially notable examples include the Behandel-Strategieën voor Reumatoide Artritis (Dutch for “treatment strategies for rheumatoid arthritis” or BeSt) trial [53,54]; the Finnish Rheumatoid Arthritis Combination Therapy (FIN-RACo) trial [56-58,67]; the NEO-RACo trial [68]; the Treatment of Early Aggressive Rheumatoid Arthritis (TEAR) trial [69]; and the Tight Control of Rheumatoid Arthritis (TICORA) trial [59]. Taken together, these reports provide strong support for the view that it is the treat-to-target strategy, more than the specific agents used, that results in better outcomes for patients with RA [70].

As an example, in the TICORA trial, 111 patients were randomly assigned to intensive or routine management [59]. Intensively managed patients in this trial had monthly visits, with calculation of disease activity scores (a validated composite score based upon the erythrocyte sedimentation rate [ESR], Ritchie articular index, joint swelling count, and patients’ global assessment of disease activity defining high, moderate, and low disease activity levels of ≥3.6, of ≥2.4 to <3.6, and of ≥1.6 to <2.4, respectively); glucocorticoid injections of swollen joints; and, every three months, adjustment of their treatment regimen by a predefined protocol if moderate or highly active disease was present. Routinely managed patients were seen every three months, with no formal measurement of disease activity performed, and glucocorticoid injections and other treatment adjustments were made at the discretion of the rheumatologist. After 18 months, the patients receiving intensive management demonstrated

a significantly greater decrease in their disease activity scores compared with the routine

management group (-3.5 versus -1.9), and a higher proportion achieved a good response by EULAR criteria (82 versus 44 percent). Additionally, physical function assessed by the HAQ was improved to a statistically and clinically significantly greater degree in the patients receiving intensive management (change in HAQ of -0.97 versus -0.47).

Adjunctive role of antiinflammatory agents We use antiinflammatory therapies, including systemic and intraarticular glucocorticoids and NSAIDs, primarily as adjuncts for temporary control of disease activity in patients in whom treatment is being started with DMARDs, in patients in whom the DMARD regimen requires modification, or in patients who are experiencing disease flares. Although NSAIDs act rapidly to control inflammation, they do not provide adequate benefit on their own for longer-term control of disease or for prevention of joint injury.

There is strong evidence that glucocorticoids retard radiographic progression in patients with RA in the short to medium term (ie, up to two years of therapy) [71-73]. However, these agents should not be used alone for an extended period. We avoid long-term use, if possible, because chronic use for inflammatory disease is often associated with adverse effects [74]. However, patients with severe RA sometimes require sustained therapy with low doses of glucocorticoids (less than 10 mg/day); such doses in RA are generally well-tolerated and may have some benefit in retarding disease progression [73,75] (see "Use of glucocorticoids in the treatment of rheumatoid arthritis", section on 'Efficacy of chronic use'). More detailed discussions of NSAID and glucocorticoids in RA are presented elsewhere. (See "Use of glucocorticoids in the treatment of rheumatoid arthritis" and "Initial treatment of rheumatoid arthritis in adults", section on 'Symptomatic treatment with antiinflammatory drugs'.)

In patients who receive glucocorticoids, we taper the medication as rapidly as tolerated once disease control is achieved and can be maintained, with the ideal goal of discontinuing systemic glucocorticoid therapy.

Intraarticular injections of long-acting glucocorticoids are used to reduce synovitis in particular joints that are more inflamed than others. Occasional patients benefit from intramuscular rather than oral administration. (See "Intraarticular and soft tissue injections: What agent(s) to inject and how frequently?".)

Drug therapy for flares RA has natural exacerbations (also known as flares) and reductions of continuing disease activity. It is important to distinguish a disease flare, characterized by symptoms and by physical and laboratory findings of increased inflammatory synovitis, from noninflammatory causes of local or generalized increased pain. Patients with recurrent flares may require adjustment in the background DMARD therapy. (See "Clinical manifestations of rheumatoid arthritis" and 'Assessment of disease activity' above.)

The severity of the flare and background drug therapy influence the choice of therapies. The following is a brief summary of glucocorticoid therapy, which is discussed in detail separately. (See "Use of glucocorticoids in the treatment of rheumatoid arthritis".)

With respect to the severity of the flare:

In patients with a single or few affected joints, intraarticular glucocorticoid injections may be effective and avoid the need for additional or prolonged systemic therapy.

More widespread flares may be treated by initiating glucocorticoid therapy or by increasing the dose of oral glucocorticoid, with the intention of reducing the dose once the flare is under control. The magnitude of dose increase varies with the baseline dose and with the severity of the flare. An alternative to an increase in the oral dose is the administration of a single deep intramuscular injection of methylprednisolone acetate (120 mg in 3 mL) or triamcinolone acetonide (60 mg in 1.5 mL).

Pulse intravenous methylprednisolone therapy, usually consisting of three daily infusions of up to 1000 mg, is generally limited to severe flares, particularly those associated with systemic manifestations, such as rheumatoid vasculitis.

With respect to background drug therapy, an escalation in dose or a modification in drugs is warranted if the patient is flaring frequently or severely. The strategy depends upon the background DMARDs being used. As examples:

Patients on methotrexate (MTX) who will tolerate a slower resolution of their flare may respond to optimization of the MTX dose by either an increase in the dose of MTX or switching from oral to subcutaneous therapy [76]. (See "Use of methotrexate in the treatment of rheumatoid arthritis", section on 'Dosing of MTX'.)

Patients initially controlled with a regimen that includes infliximab may benefit from a decrease in the interval between infliximab doses or from higher doses [77,78]. However, increasing the dose from 3 to 5 mg/kg was not beneficial in one well-designed trial [79,80].

Increases in doses of etanercept (greater than 50 mg weekly) or adalimumab (weekly rather than every two weeks), with or without MTX, do not appear to increase efficacy [81,82].

Patients who require multiple treatment courses with glucocorticoids for recurrent disease flares and whose medication doses have been increased to the maximally tolerated or acceptable level should be treated as patients with sustained disease activity. (See "Treatment of rheumatoid arthritis in adults resistant to initial nonbiologic DMARD therapy" and "Treatment of rheumatoid arthritis in adults resistant to initial biologic DMARD therapy".)

OTHER CONSIDERATIONS IN RA MANAGEMENT The focus of therapeutic decision-making is control of disease activity, as described above, but additional factors, such as the degree of

joint injury or disability, may influence the choice of specific therapies in individual patients [2,8]. Additionally, the efficacy of particular medications may be affected by the presence or absence of some of these factors, which are associated with an adverse prognosis. (See 'Prognosis' below.)

The relative importance of these factors depends upon the individual treatment choice; these are discussed in more detail in the appropriate individual treatment topics. We consider the following factors, depending upon the specific treatment decision:

Disability and function General scales that measure disability may not identify specific limitations of greater impact on an individual patient. As an example, specific vocational requirements, family responsibilities, or recreational interests may affect a patient’s willingness to accept the risks of a given intervention that would help to achieve a greater degree of disease control than low disease activity. We therefore incorporate patient-specific needs in our assessment of the severity of disease-related disability.

Joint injury Good control of disease activity may not result in complete elimination of progressive joint injury in all patients. In patients with low disease activity but with worsening findings on imaging studies, either changes in medications or increased dosing may be of benefit. However, there is insufficient evidence to determine whether treating to targets that are based upon imaging findings provides additional benefit for long-term outcomes, compared with targets based upon measures of disease activity alone.

Comorbidities The presence of comorbidities, such as renal or hepatic disease, may affect medication choices and may influence the degree of risk inherent in attempting to reach a goal of remission or of low disease activity in a given patient.

Comorbidities A number of medical conditions that often coexist with or result from rheumatoid arthritis (RA) may influence the choice of medications; our approach is consistent with expert opinion, including the American College of Rheumatology (ACR) treatment guidelines [1,5,22,83].

Infection

Serious infection In patients with an active serious infection, conventional and biologic disease-modifying antirheumatic drugs (DMARDs) and tofacitinib should be temporarily held until resolution of infection and completion of antimicrobial therapy. In patients with a history of a serious infection, we recommend conventional DMARDs over biologic agents. Medications administered more frequently are preferred in patients in whom there is

heightened concern regarding infection or with recurrent infections because of the relative greater ease of discontinuing the therapy and its immunomodulatory effect if needed.

Hepatitis B In patients with natural immunity to hepatitis B virus (HBV; HBV core antibody [HBc]-positive, normal liver chemistries, HBV surface antibody [HBs]-positive, and HBV surface antigen [HBsAg]-negative), treatment for RA should be the same as for HBV-unexposed RA patients, but viral loads should be monitored every 6 to 12 months to ensure there is no reactivation. For patients with active untreated hepatitis, referral for antiviral therapy should be obtained before immunosuppressive therapy, and patients should be treated in collaboration with their hepatologist. In the absence of additional harms, RA treatment may proceed for patients with active HBV on concomitant antiretroviral treatment. (See "Diagnosis of hepatitis B virus infection" and "Overview of the management of hepatitis B and case examples".)

Hepatitis C Patients with active hepatitis C virus (HCV) and normal liver function should not be treated differently than RA patients without HCV. If underlying liver disease is present, non-hepatotoxic DMARDs (sulfasalazine [SSZ] or hydroxychloroquine [HCQ]) are preferred initially. Patients with HCV infection should be managed in collaboration with their hepatologist. (See "Overview of the management of chronic hepatitis C virus infection".)

Tuberculosis Prior to initiation of immunomodulatory therapy, patients with risk factors for tuberculosis (TB) should be screened for latent TB and treated if indicated (see 'Pretreatment evaluation' above). In patients in whom latent TB is diagnosed, at least one month of treatment should be completed prior to the initiation of immunosuppressive agents.

Malignancy Management of RA in patients with malignancy or a history of malignancy is based upon findings from observational studies involving relatively small numbers of patients with typically imprecise results, together with expert opinion [5,84-88].

Non-melanoma skin cancer (basal cell and squamous cell carcinoma) In patients with a history of non-melanoma skin cancer, we use conventional DMARDs over biologic DMARDs or tofacitinib. There is no contraindication to escalation of therapy to include biologics, but routine skin cancer surveillance is indicated. (See "Epidemiology and clinical features of basal cell carcinoma" and "Clinical features and diagnosis of cutaneous squamous cell carcinoma (SCC)".)

Melanoma skin cancer In patients with a history of melanoma, we use conventional DMARDs over biologic DMARDs or tofacitinib. If a biologic agent is needed, the first choice would be rituximab, and we would avoid use of abatacept. Routine skin cancer surveillance is indicated. (See "Screening and early detection of melanoma".)

History of lymphoproliferative disorder In patients with a history of a lymphoproliferative disorder, we prefer conventional DMARDs, and if a biologic agent is needed, the first choice would be rituximab, given its use in the treatment of lymphoproliferative disorders and a lack of evidence for increased cancer risk with its use.

Solid organ malignancy In patients with a treated solid organ malignancy within the past five years, we use conventional DMARDs over biologic DMARDs. If a biologic agent is needed, the first choice would be rituximab, given the lack of evidence for increased cancer risk with its use.

In patients who are more than five years out from a treated solid organ malignancy, excluding melanoma, RA treatment is no different than from those without malignancy.

Pregnancy RA often improves or remits completely during pregnancy. Issues related to the pregnant woman with RA, including the use of immunosuppressive drugs, are discussed separately. (See "Rheumatoid arthritis and pregnancy" and "Use of antiinflammatory and immunosuppressive drugs in rheumatic diseases during pregnancy and lactation".)

Lung disease Comorbid pulmonary disease is common in patients with RA and may also be a complication of therapy or of the disease [83]. Therapeutic agents with potential for causing adverse pulmonary effects include methotrexate (MTX), leflunomide (LEF), tumor necrosis factor (TNF) inhibitors, SSZ, parenteral gold, abatacept, and rituximab. (See "Overview of lung disease associated with rheumatoid arthritis".)

Cardiovascular disease Comorbid cardiovascular disease can occur in patients with RA and may also be a complication of therapy [83]. Both glucocorticoids and nonsteroidal antiinflammatory drugs (NSAIDs) may increase cardiovascular risk. Active RA is associated with an increased risk of cardiovascular disease, but good control of disease activity has been associated with reduced cardiovascular complications. (See "Coronary artery disease in rheumatoid arthritis: Pathogenesis, risk factors, clinical manifestations, and diagnostic implications" and "Coronary artery disease in rheumatoid arthritis: Implications for prevention and management" and "Major side effects of systemic glucocorticoids", section on 'Cardiovascular disease' and "Nonselective NSAIDs: Overview of adverse effects", section on 'Cardiovascular effects'.)

TNF inhibitors should be avoided in patients with moderate or severe heart failure (HF), as they can worsen HF. Such patients should be treated instead with traditional nonbiologic DMARDs, non-TNF inhibitor biologics, or tofacitinib. (See "Tumor necrosis factor-alpha inhibitors: An overview of adverse effects", section on 'Heart failure'.)

Neurologic manifestations Neurologic manifestations of RA and the presence of coexistent neurologic disease are generally uncommon, other than the occurrence of impingement neuropathies such as carpal tunnel syndrome. However, TNF inhibitors should be avoided in those with a history of or an ongoing demyelinating disorder because of case reports of such disorders in patients being treated for RA and because of increased risk of disease worsening in trials of TNF blockade in patients with multiple sclerosis (MS). Some RA experts are also cautious about using TNF-alpha inhibitors in patients with family histories of MS [83]. (See "Neurologic manifestations of rheumatoid arthritis" and "Tumor necrosis factor-alpha inhibitors: An overview of adverse effects", section on 'Demyelinating disease'.)

Diabetes The risk of diabetes mellitus is not increased in patients with RA. However, in patients with both diabetes and RA, glucocorticoids should be used with particular caution because they may worsen control of the diabetes [83]. By contrast, patients being treated with HCQ or with TNF inhibitors for RA have a lower risk of diabetes [89], and SSZ may have glucose-lowering effects [90]. (See "Major side effects of systemic glucocorticoids", section on 'Glucose metabolism' and "Antimalarial drugs in the treatment of rheumatic disease", section on 'Reduction of diabetes risk'.)

Renal disease RA infrequently affects the kidney, but, if renal disease coexists, it increases mortality risk [83]. In addition to NSAIDs, the use of some medications occasionally or only historically used in the treatment of patients with RA may adversely affect renal function, including gold, penicillamine, and cyclosporine. Some nonbiologic DMARDs, particularly MTX and cyclosporine, should be avoided or used with particular caution in patients with significantly decreased renal function. (See "NSAIDs: Acute kidney injury (acute renal failure)" and "Causes and diagnosis of membranous nephropathy", section on 'Drugs, particularly penicillamine and gold' and "Cyclosporine and tacrolimus nephrotoxicity".)

Extraarticular disease RA has many extraarticular manifestations. The treatment of these specific features, such as vasculitis, interstitial lung disease, and others, is reviewed in detail elsewhere. (See "Overview of the systemic and nonarticular manifestations of rheumatoid arthritis" and "Treatment of rheumatoid vasculitis".)

Use of analgesics Drugs that primarily or only provide analgesia, including topical medications (eg, capsaicin) and oral agents, such as acetaminophen (paracetamol), tramadol, and more potent opioids (eg, oxycodone, hydrocodone), have a limited role in most patients with active disease but may be helpful in patients with end-stage disease and, occasionally, in patients with more severe involvement or during disease flares for added temporary benefit. These medications should not be used as the sole or primary therapy in patients with active inflammatory disease. An additional concern regarding opioid analgesics is an increased risk of

hospitalization for serious infection, which has been associated with their use by patients with RA and may be due to impairment of certain immune functions by these agents [91].

Apparent need for additional analgesic medications when inflammatory disease is well- controlled (other than acetaminophen or occasional NSAIDs) should prompt a search for alternative comorbid diagnoses, such as fibromyalgia, to explain the patient’s symptoms. (See "Clinical manifestations and diagnosis of fibromyalgia in adults".)

THERAPY OF END-STAGE DISEASE Despite therapeutic intervention, some patients progress to disabling, destructive joint disease. Symptoms in such patients may be present in the absence of active inflammatory joint disease and may be due to the secondary degenerative changes alone. The accurate evaluation of such patients is essential, since deterioration associated with mechanical problems of the muscle or joint is treated much differently from ongoing inflammation or systemic manifestations of rheumatoid arthritis (RA). Disease exacerbations and their systemic effects are usually easily recognized by the presence of many inflamed joints, fever, anemia, an elevated erythrocyte sedimentation rate (ESR), or an elevated serum C-reactive protein (CRP) concentration.

The goals of therapy in the patient with end-stage disease are:

Pain relief

Protection of remaining articular structures

Maintenance of function

Relief from fatigue and weakness

In the absence of inflammation, which requires antiinflammatory medications and disease- modifying antirheumatic drugs (DMARDs), treatments other than medications may be particularly important in management. These include nonpharmacologic interventions, such as physical and occupational therapy and the use of adaptive devices, and surgery. (See "Evaluation and medical management of end-stage rheumatoid arthritis".)

The indications for surgical intervention in patients with RA include intractable pain or severe functional disability due to joint destruction, as well as impending tendon rupture. The timing of surgery is often critical. If one waits too long, there may be so much muscle atrophy from disuse that postoperative rehabilitation is unsuccessful. On the other hand, a decision about joint replacement should take into account the average life of the artificial joint. (See "Total joint replacement for severe rheumatoid arthritis".)

RECOMMENDATIONS BY MAJOR GROUPS Recommendations for the management of patients with rheumatoid arthritis (RA) have been developed by major professional organizations, including the American College of Rheumatology (ACR) and the European League Against Rheumatism (EULAR) [1,3,4,22,65]. In addition, an international task force has developed recommendations for treating RA to targeted goals [2,7,62,64]. Our approach to treatment is generally consistent with these recommendations. The 2015 ACR recommendations and supporting documents can be accessed online.

The EULAR recommendations for the management of RA represent a European consensus on the management of RA with disease-modifying antirheumatic drugs (DMARDs) and glucocorticoids and on the strategies to reach optimal outcomes, based upon evidence and expert opinion [3,4]. The evidence used was detailed in a series of systematic literature reviews, and the recommendations were updated in 2013 [4,6,92-95]. The 2013 recommendations include three overarching principles for the care of patients with RA and a set of 14 recommendations covering major issues in disease management. The 2013 EULAR recommendations can be accessed online.

PROGNOSIS Rheumatoid arthritis (RA) was associated with a high degree of economic loss, morbidity, and early mortality prior to the widespread use of methotrexate (MTX) that began in the 1980s, more aggressive treatment of early disease, and the availability of targeted biologic agents since the later part of the 1990s. As an example, almost 20 percent of patients in one center were severely disabled after 20 years of follow-up (from 1967 to 1987); an additional one-third had died [96]. Patients with RA that required hospital care had at least a twofold increased mortality when compared with those without disease [97], and more severe RA was associated with higher mortality rates due to higher rates of myocardial infarction, infection, and certain malignancies, comparable to three-vessel coronary artery disease or to stage IV Hodgkin lymphoma [98].

Clinical outcomes have improved significantly with changes in drug therapy and in the approach to treatment. These improvements have decreased the need for joint surgery and reduced disability in patients with RA. As an example, in a study involving data from 57 hospitals in Ireland, the number of total hip and knee joint arthroplasties in patients with RA decreased from 1995 to 2010, despite substantial increases in these procedures among the general population [99].

An analysis of 1007 patients with RA diagnosed between 1993 and 2011 in the Leiden Early Arthritis Clinic found that more intensive treatment strategies adopted over the years of study increased the chances for DMARD-free sustained remissions [100]. Moreover, those patients achieving DMARD-free remission had normal functional status when compared with the general population. The average level of disability in RA was found in a longitudinal study of

over 3000 patients to have declined by about 40 percent from 1977 to 1998, even prior to the introduction of the biologic DMARDs [101]. Similarly, patients with RA seen in a single university clinic from 1984 through 1986 had significantly more disability and greater radiographic evidence of joint injury compared with a cohort from the same clinic seen from 1999 through 2001 (modified Health Assessment Questionnaire [HAQ] disability score on a 0 to 3 scale of 1 versus 0.4, respectively, and Larsen radiographic score on a 0 to 100 scale of 20 versus 3, respectively) [13]. Patients able to achieve remission with combination therapy had significantly less work disability over five years of follow-up compared with patients with incomplete responses to treatment [102]. (See "Disease outcome and functional capacity in rheumatoid arthritis".)

A number of factors have been associated with poorer outcomes in patients with RA. The

following four markers of adverse prognosis can be used to identify patients who may require more aggressive pharmacotherapy, especially in early stages of disease [22]:

Functional limitation

Extraarticular disease

Rheumatoid factor positivity or presence of anticyclic citrullinated peptide (CCP) antibodies

Bony erosions documented radiographically

Other factors associated with a worse prognosis include concurrent medical disorders, cigarette smoking, lack of formal education, and lower socioeconomic status [103]. Older age, female sex, and the presence of the shared epitope have also been associated with a poorer prognosis [22]. Some studies have derived models to estimate prognosis, such as persistent erosive disease [104]. However, these models have not been validated in other cohorts. The individual factors associated with a poor prognosis are discussed in detail separately. (See "Epidemiology of, risk factors for, and possible causes of rheumatoid arthritis" and "Disease outcome and functional capacity in rheumatoid arthritis" and "Biologic markers in the diagnosis and assessment of rheumatoid arthritis" and "Overview of the systemic and nonarticular manifestations of rheumatoid arthritis" and "HLA and other susceptibility genes

in rheumatoid arthritis".)

INFORMATION FOR PATIENTS UpToDate offers two types of patient education materials, “The Basics” and “Beyond the Basics.” The Basics patient education pieces are written in plain language, at the 5 th to 6 th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient

education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10 th to 12 th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on “patient info” and the keyword(s) of interest.)

Beyond the Basics topics (see "Patient information: Rheumatoid arthritis symptoms and diagnosis (Beyond the Basics)" and "Patient information: Rheumatoid arthritis treatment (Beyond the Basics)" and "Patient information: Disease-modifying antirheumatic drugs (DMARDs) (Beyond the Basics)" and "Patient information: Complementary and alternative therapies for rheumatoid arthritis (Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS

In patients with rheumatoid arthritis (RA), affected areas may be irreversibly damaged or destroyed if inflammation persists. Thus, prompt diagnosis, early recognition of active disease, and measures to quickly achieve and maintain control of inflammation and the underlying disease process, with the goal of remission or low disease activity, are central to modifying disease outcome. The application of these principles in the management of patients with RA, together with the development and use of newer and more potent drugs, has resulted in significant improvement in the outcomes of treatment. (See 'General principles' above and 'Early recognition and diagnosis' above.)

An expert in the care of rheumatic disease, such as a rheumatologist, should participate in the care of patients suspected of having RA and in the ongoing care of patients diagnosed with this condition. The treatment of patients with RA by a rheumatologist is associated with better disease outcomes compared with care rendered primarily by other clinicians. (See 'Care by a rheumatologist' above.)

Nonpharmacologic measures, such as patient education, psychosocial interventions, and physical and occupational therapy, should be used in addition to drug therapy. Other medical interventions that are important in the comprehensive management of RA in all stages of disease include cardiovascular risk reduction and immunizations to decrease the risk of complications of drug therapies. (See 'Nonpharmacologic and preventive therapies' above.)

We recommend that all patients diagnosed with RA be started on disease-modifying antirheumatic drug (DMARD) therapy as soon as possible following diagnosis, rather than using antiinflammatory drugs alone, such as nonsteroidal antiinflammatory drugs (NSAIDs)

and glucocorticoids (Grade 1B). Better outcomes are achieved by early compared with delayed intervention with DMARDs. (See 'Early use of DMARDs' above.)

We recommend the use of tight control treatment strategies to guide adjustments in the treatment regimen, rather than less aggressive approaches (Grade 1B). Tight control involves reassessment of disease activity on a regularly planned basis with the use of quantitative composite measures and adjustment of treatment regimens to quickly achieve and maintain control of disease activity if targeted treatment goals (remission or low disease activity), rather than an undefined degree of improvement, have not been achieved. Such tight control treatment strategies are associated with improved radiographic and functional outcomes compared with less aggressive approaches. (See 'Tight control' above and 'Assessment of disease activity' above.)

Laboratory testing prior to therapy should include a complete blood count, erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), aminotransferases, blood urea nitrogen, and creatinine. Patients receiving hydroxychloroquine (HCQ) should have a baseline ophthalmologic examination, and most patients who will receive a biologic agent should be tested for latent tuberculosis (TB) infection. Screening for hepatitis B and C should be performed in all patients. Some patients may require antiviral treatment prior to initiating DMARD or immunosuppressive therapy, depending upon their level of risk for hepatitis B virus (HBV) reactivation. (See 'Pretreatment evaluation' above.)

We use antiinflammatory drugs, including NSAIDs and glucocorticoids, as bridging therapies to rapidly achieve control of inflammation until DMARDs are sufficiently effective. Some patients may benefit from longer-term therapy with low doses of glucocorticoids. (See 'Adjunctive role of antiinflammatory agents' above.)

RA has natural exacerbations (also known as flares) and reductions of continuing disease activity. The severity of the flare and background drug therapy influence the choice of therapies. Patients who require multiple treatment courses with glucocorticoids for recurrent disease flares and whose medication doses have been increased to the maximally tolerated or acceptable level should be treated as patients with sustained disease activity. Such patients require modifications of their baseline drug therapies. (See 'Drug therapy for flares' above.)

The monitoring that we perform on a regular basis includes testing that is specific to evaluation of the safety of the drugs being used; periodic assessments of disease activity with composite measures; monitoring for extraarticular manifestations of RA, other disease complications, and joint injury; and functional assessment. (See 'Assessment and monitoring' above.)

Other factors in RA management that may influence the target or choice of therapy include the disabilities or functional limitations important to a given patient, progressive joint injury, comorbidities, and the presence of adverse prognostic factors. (See 'Other considerations in RA management' above and 'Prognosis' above.)

ACKNOWLEDGMENT The editorial staff at UpToDate would like to acknowledge Peter Schur, MD, who contributed to an earlier version of this topic review.

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REFERENCES

McDowell I, Newell C. health: A guide to rating scales and questionnaires, 2nd, Oxford
43 University Press, New York 1996. p.106.

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