General principles and overview of management of rheumatoid arthritis in adults

INTRODUCTION — Management strategies for patients with rheumatoid arthritis (RA) are directed toward the control of synovitis and the prevention of joint injury. Treatment approaches aim to achieve and maintain remission or low disease activity by use of disease-modifying antirheumatic drug (DMARD) therapy that is initiated early in the disease course. Common principles that guide management have been developed based upon evidence from randomized trials and other studies and from an increasing but incomplete understanding of the disease. (See "Epidemiology of, risk factors for, and possible causes of rheumatoid arthritis" and "Pathogenesis of rheumatoid arthritis".)

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 and subsequent DMARDs are discussed in detail elsewhere. (See "Initial treatment of rheumatoid arthritis in adults" and "Alternatives to methotrexate for the initial treatment of rheumatoid arthritis in adults" and "Treatment of rheumatoid arthritis in adults resistant to initial conventional synthetic (nonbiologic) DMARD therapy" and "Treatment of rheumatoid arthritis in adults resistant to initial biologic DMARD therapy".)

GENERAL PRINCIPLES — Our approach to treatment involves the timely and judicious use of several types of therapeutic interventions and is based upon general principles that have been widely accepted by major professional organizations and other expert groups [1-7]. The application of these principles has resulted in significant improvements in treatment outcomes since the 1980s; such progress may owe even more to the therapeutic strategies that have been adopted than to the development and use of newer and more potent drugs [8].

These general principles, discussed in greater detail below, 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 rheumatoid arthritis (RA) (see 'Early use of DMARDs' below)

●Efforts toward 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 DMARD therapy (see 'Adjunctive role of antiinflammatory agents' below)

MANAGEMENT STRATEGIES

Early recognition and diagnosis — Achieving the benefits of early intervention with disease-modifying antirheumatic drugs (DMARDs) depends upon making the diagnosis of rheumatoid arthritis (RA) as early as possible, before irreversible injury has occurred [5,8-10]. The diagnosis and differential diagnosis of RA are reviewed in detail separately. (See "Diagnosis and differential diagnosis of rheumatoid arthritis".)

Persistent synovial inflammation, which is associated with a proliferative and destructive process in joint tissues, can lead to significant and irreversible joint injury as early as during the first two years of disease. (See 'Early use of DMARDs' below and "Pathogenesis of rheumatoid arthritis".)

Care by a rheumatologist — Patients with inflammatory arthritis who are suspected of RA and those diagnosed with it benefit from ongoing care by an expert in the rheumatic diseases, such as a rheumatologist [11,12]. Early and ongoing care of such patients by a rheumatologist, compared with care rendered primarily by other clinicians, is associated with better disease outcomes, including reduced joint injury and less functional disability [13-18].

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 of and risks associated with the therapy, the preferences of the patient and primary care clinician, and the availability of such care.

Early use of DMARDs — We suggest that all patients diagnosed with RA be started on disease-modifying antirheumatic drug (DMARD) therapy as soon as possible, consistent with the recommendations of major professional organizations [3,6]. There is widespread expert consensus regarding this approach, which is based upon a number of observational studies and a more limited number of randomized trials [3,6,9,19-25]. Our choice of drug therapies in patients with RA and the evidence supporting these choices are described in detail separately. (See 'Choice of therapy' below and "Initial treatment of rheumatoid arthritis in adults" and "Alternatives to methotrexate for the initial treatment of rheumatoid arthritis in adults".)

Much of the joint damage that ultimately results in disability begins early in the course of the disease [26,27]. As an example, in a study from 1989, 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 [27]. 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 [28-30].

Better outcomes are achieved by early compared with delayed intervention with DMARDs in patients with RA [9,19-25]. Some evidence suggests that the effect upon outcomes is not linear with time, and that there may be an early "window of opportunity" for optimal DMARD treatment benefit [25]. As examples:

●Disability is greater in patients for whom therapy is delayed. One study in Texas found that low socioeconomic status (SES) was associated with a substantial delay in starting DMARD therapy; and both the delay and low SES were independently associated with greater disease activity, joint damage, and physical disability [24].

●There may be a limited period of several months following symptom onset during which RA is most susceptible to intervention with DMARDs. The effect on the likelihood of DMARD-free sustained remission of symptom duration prior to DMARD therapy was examined in two large European cohorts [25]. 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 patients were anti-citrullinated peptide antibody (ACPA) positive.

●Response rates to drug intervention decrease over time. An observational study of 1435 patients involved in 14 trials, primarily of methotrexate (MTX) or other nonbiologic DMARDs, found a progressive decrease in the likelihood of a significant response to DMARD therapy with increasing disease duration [19]. 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).

Tight control — Tight control treatment strategies help to quickly minimize inflammation and disease progression; our therapeutic target is remission or a state of minimal disease activity, without compromising safety. As an example, in patients resistant to initial DMARD therapy (eg, MTX), we usually treat with a combination of DMARDs (eg, MTX plus sulfasalazine [SSZ] and hydroxychloroquine [HCQ] or MTX plus a tumor necrosis factor [TNF] inhibitor), while also treating the active inflammation with antiinflammatory drug 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). 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 "Treatment of rheumatoid arthritis in adults resistant to initial conventional synthetic (nonbiologic) DMARD therapy".)

Tight control strategies involve frequent periodic reassessment of disease activity using a quantitative composite measure, 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 as bridging therapies 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 [5,31-40]. (See 'Assessment and monitoring' below and 'Adjunctive role of antiinflammatory agents' below.)

This approach is supported by American College of Rheumatology (ACR) and European Alliance of Associations for Rheumatology (EULAR; formerly known as European League Against Rheumatism) treatment recommendations and in the recommendations of an international task force that were presented in 2010 and updated in 2021 [1,2,5,6,11,40-45].

●Efficacy of treat-to-target strategy – The treat-to-target strategy, more than the specific agents used, results in better outcomes for patients with RA [46]. A number of randomized trials and related studies illustrate the range of medications and approaches that demonstrate the efficacy of a treat-to-target approach, with excellent treatment responses being 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 [31-37,47-49].

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 RA [50]. 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 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 trials 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 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 disease activity and physical function", section on 'Health Assessment Questionnaire (HAQ)'.)

Examples of individual trials supporting this approach include the BehandelStrategieën voor Reumatoïde Artritis (Dutch for "treatment strategies for rheumatoid arthritis" or BeSt) trial [31,32]; the Finnish Rheumatoid Arthritis Combination Therapy (FIN-RACo) trial [34-36,47]; the New Finnish Rheumatoid Arthritis Combination Therapy (NEO-RACo) trial [48]; the Treatment of Early Aggressive Rheumatoid Arthritis (TEAR) trial [49]; and the Tight Control of Rheumatoid Arthritis (TICORA) trial [37].

●Role of imaging to detect joint injury and/or inflammatory disease activity – The use of sensitive imaging techniques, including either MRI or musculoskeletal ultrasound (MSUS), may be better than the clinical exam for diagnosing joint involvement and predicting disease relapse [51]. However, these imaging modalities do not appear to provide greater clinical benefit and may be associated with increased adverse effects and potentially with greater cost [52-54]. As an example, in a randomized trial involving 200 patients in clinical remission on conventional DMARDs, patients assigned to receive protocol-driven treatment adjustments every four months that were guided by MRI imaging (for bone marrow edema) plus composite clinical assessments had similar clinical and radiographic outcomes at two years compared with those guided by the clinical assessments alone [52]. Treatment escalation was more frequent in the MRI-driven group (73 versus 17 percent), with more of these patients receiving biologic agents (46 versus 2 percent). Serious adverse events occurred in 17 percent of the MRI group and 6 percent of the conventional treat-to-target group. Similarly, in other studies, a lack of additional benefit from using MSUS to guide therapy in patients with early RA has also been described [53,54].

●Other considerations in the selection of treatment targets – Although the focus of therapeutic decision-making is control of disease activity, additional factors, such as the degree of joint injury or disability, may influence the choice of specific therapies in individual patients [2,55]. Additionally, the efficacy of particular medications may be affected by the presence or absence of comorbidities and other factors. (See 'Comorbidities and disease management' below and 'Prognosis' below.)

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.

•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. (See 'Comorbidities and disease management' below.)

•Joint damage – Good clinical 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 joint injury 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 of joint damage alone provides additional benefit for long-term outcomes, compared with targets based upon measures of disease activity alone.

NONPHARMACOLOGIC THERAPIES — A number of nonpharmacologic measures are important in the comprehensive management of rheumatoid arthritis (RA) in all stages of disease. Briefly, these measures include:

●Patient education regarding RA and its management

●Psychosocial interventions

●Rest, exercise, and physical and occupational therapy

●Nutritional and dietary counseling

These therapies are discussed in detail separately. (See "Nonpharmacologic therapies for patients with rheumatoid arthritis".)

PHARMACOLOGIC THERAPY

Pretreatment evaluation — Prior to starting, resuming, or a significant dose increase of therapy with any nonbiologic, targeted synthetic (small molecule), or biologic disease-modifying antirheumatic drug (DMARD), we do the following baseline studies [3,41]:

●General testing for all patients – Baseline complete blood count, serum creatinine, aminotransferases, erythrocyte sedimentation rate (ESR), and C-reactive protein (CRP). In patients receiving interleukin 6 (IL-6) inhibitors and Janus kinase (JAK) inhibitors, lipids are also monitored.

●Hepatitis virus screening – 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 JAK inhibitors.

•Hepatitis B – We obtain testing for hepatitis B virus (HBV) surface antigen (HBsAg) and HBV core antibody (HBc) prior to initiating these drugs and prior to treatment with prednisone at doses of ≥20 mg daily. 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".)

•Hepatitis C – Although we perform such testing in all patients without a known history of hepatitis, 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 health care workers [3,41].

●Ophthalmologic screening for hydroxychloroquine use – A complete baseline ophthalmologic examination should be performed within the first year of treatment with hydroxychloroquine (HCQ), including examination of the retina through a dilated pupil and automated visual field testing. Our approach to screening and subsequent monitoring for ocular toxicity is described in detail separately. (See "Antimalarial drugs in the treatment of rheumatic disease", section on 'Routine eye examinations'.)

●Testing for latent tuberculosis – We screen for latent tuberculosis (TB), consistent with the Centers for Disease Control and Prevention (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 a JAK inhibitor; such screening is based upon evidence that these medications, including the tumor necrosis factor (TNF) inhibitors, other biologics, and JAK inhibitors, may increase the risk of mycobacterial infection [3,56,57].

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 "Use of interferon-gamma release assays for diagnosis of tuberculosis infection (tuberculosis screening) in adults".)

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, screening 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 "Risk of mycobacterial infection associated with biologic agents and JAK inhibitors" and "Tuberculosis infection (latent tuberculosis) in adults: Approach to diagnosis (screening)".)

Pretreatment interventions

●Interventions to reduce risks of cardiovascular disease – Strategies for cardiovascular risk reduction (eg, smoking cessation and management of dyslipidemia) are described in detail separately. (See "Overview of smoking cessation management in adults" and "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".)

●Immunizations – Immunization with appropriate vaccines is indicated to decrease risk of infectious complications of immunosuppressive therapies and disease-associated immunosuppression and is described in detail separately. (See "Immunizations in autoimmune inflammatory rheumatic disease in adults".)

Choice of therapy — Our specific drug choices for patients with rheumatoid arthritis (RA) and the evidence supporting these choices are described in detail separately. (See "Initial treatment of rheumatoid arthritis in adults" and "Alternatives to methotrexate for the initial treatment of rheumatoid arthritis in adults" and "Treatment of rheumatoid arthritis in adults resistant to initial conventional synthetic (nonbiologic) DMARD therapy" and "Treatment of rheumatoid arthritis in adults resistant to initial biologic DMARD therapy".)

●Factors affecting drug choices – 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, fertility planning)

•Presence of adverse prognostic signs

●DMARDs – Drugs classified as disease-modifying antirheumatic drugs (DMARDs), which all have the potential to reduce or prevent joint damage and to preserve joint integrity and function, include:

•Nonbiologic (traditional or conventional) DMARDs, including MTX, HCQ, sulfasalazine (SSZ), and LEF. (See "Initial treatment of rheumatoid arthritis in adults" and "Alternatives to methotrexate for the initial treatment of rheumatoid arthritis in adults".)

•Biologic DMARDs, which are produced by recombinant deoxyribonucleic acid (DNA) technology and 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; and the IL-6 receptor antagonists tocilizumab and sarilumab. 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 "Treatment of rheumatoid arthritis in adults resistant to initial conventional synthetic (nonbiologic) DMARD therapy" and "Treatment of rheumatoid arthritis in adults resistant to initial biologic DMARD therapy".)

•Targeted synthetic DMARDs, including several JAK inhibitors, which are available for use in RA and other disorders in the United States and several other countries. These include tofacitinib, baricitinib, upadacitinib, filgotinib, and peficitinib, which are orally administered small molecule DMARDs that inhibit cytokine and growth factor signaling through interference with JAKs. (See "Treatment of rheumatoid arthritis in adults resistant to initial conventional synthetic (nonbiologic) DMARD therapy" and "Treatment of rheumatoid arthritis in adults resistant to initial biologic DMARD therapy".)

●Approach to drug therapy – Briefly, we take the following approach:

•In patients with active RA, we initiate antiinflammatory therapy with either a nonsteroidal antiinflammatory drug (NSAID) or glucocorticoid, depending upon the degree of disease activity, and generally start DMARD therapy with MTX. NSAIDs and systemic and intraarticular glucocorticoids can act rapidly to reduce disease activity, while DMARDs, including MTX, may take weeks to months to achieve optimal effects. (See "Initial treatment of rheumatoid arthritis in adults" and 'Adjunctive role of antiinflammatory agents' below.)

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 usually treat with a combination of DMARDs (eg, MTX plus SSZ and HCQ, or MTX plus a TNF inhibitor), while also treating the active inflammation with antiinflammatory drug therapy. The 2021 ACR recommendations conditionally recommend the addition of a biologic or targeted synthetic DMARD in these patients, although they acknowledged that the safety issues reported with JAK inhibitors may require a modification of this recommendation. (See "Treatment of rheumatoid arthritis in adults resistant to initial conventional synthetic (nonbiologic) DMARD therapy".)

•In patients resistant to initial or subsequent combination therapy or subsequent treatment that includes a biologic or targeted synthetic DMARD (ie, a JAK inhibitor), we switch to an alternative biologic or targeted synthetic DMARD. Treatment with antiinflammatories may also be required in such patients. (See "Treatment of rheumatoid arthritis in adults resistant to initial biologic DMARD therapy".)

Our approach to therapy is generally consistent with that of major professional organizations, including the ACR and the European Alliance of Associations for Rheumatology (EULAR) [1,4,6,11,41,44].

Assessment and monitoring

Overview of assessment and monitoring — Patients should be seen on a regular basis for clinical and laboratory monitoring of disease and for screening for drug toxicities. The initial evaluation and subsequent periodic monitoring should also include a quantitative composite measure of disease activity. The use of periodic structured assessments of disease activity is complementary to the ongoing regular monitoring of disease manifestations, including extraarticular manifestations and complications of the disease; disease progression and joint injury, including use of selected imaging studies; and functional status and disability. (See 'Clinical assessment of disease and related testing' below and 'Structured measures of disease activity and functional status' below and 'Drug monitoring and prevention of drug toxicity' below.)

Clinical assessment of disease and related testing — Patients should be seen at regular intervals that vary with disease activity and severity. As an example, patients starting new medications or with severely active disease may be seen at one- to two-month intervals, while those with mildly active or well-controlled disease could be seen every three to six months, with appropriate laboratory monitoring in the interim. Clinical assessment includes the following major elements:

●Patient history – Patients should be questioned regarding the degree of joint pain, the duration of morning stiffness, and the severity of fatigue [41,58]. 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 ocular, pulmonary, and cardiovascular disease. Because fever is not a common feature of RA in adults, infection should be excluded before ascribing fever to RA. (See "Clinical manifestations of rheumatoid arthritis".)

Patients should be queried regarding their functional capacity, including the performance of activities of daily living; vocational activities; and avocational activities, such as hobbies or participation in sports. Serial use of a self-report questionnaire that measures function is helpful for this purpose (see 'Structured measures of disease activity and functional status' below). Functional assessment also helps to identify therapeutic needs for additional interventions such as counseling, exercise, and occupational therapy. (See "Nonpharmacologic therapies for patients with rheumatoid arthritis".)

●Physical examination – A detailed musculoskeletal exam and a general physical exam are part of the periodic clinical assessment. Changes in previously affected joints or the appearance of inflammation in previously uninvolved joints should be assessed. A 28-joint examination is appropriate if the hands but not the feet are involved [59]. 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 CRP or 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 (see 'Structured measures of disease activity and functional status' below). In addition to these studies, we obtain other tests primarily for medication monitoring that may also reflect changes or levels of disease activity (see 'Drug monitoring and prevention of drug toxicity' below). 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 "Hematologic complications of rheumatoid arthritis".)

●Imaging

•Plain radiography – Early in the course of RA, we 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 may be repeated when needed to guide clinical decisions but are not advocated on a routine basis for asymptomatic patients. 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 from baseline and may intensify or modify the treatment regimen. Coexistent osteoarthritis may also account, in part, for joint space narrowing near the joints involved with RA in older patients [60].

•Ultrasonography and MRI – We prefer to use musculoskeletal ultrasound (MSUS) and MRI to answer specific clinical questions in an individual patient but not in the routine management of RA. MSUS and MRI are more sensitive for the detection of cartilage and bone abnormalities and can reveal subclinical inflammation [61,62]. However, use of these techniques for routine monitoring does not result in improved outcomes (see 'Tight control' above). Nonetheless, some clinicians routinely employ MSUS and MRI to follow patients and to detect early changes.

Structured measures of disease activity and functional status — Effective implementation of tight control strategies involves reassessment of disease activity on a regularly planned basis with the use of quantitative composite measures to facilitate timely adjustment of treatment regimens as part of a treat-to-target approach (see 'Tight control' above). Measurement of functional status is also of particular value.

●Disease activity measures – Several disease activity measures have been identified by the ACR as being preferred options to choose from for this purpose in clinical practice [63]:

•Disease Activity Score derivative for 28 joints (DAS28) with the ESR (calculator 1)

•DAS28 with the CRP (calculator 2)

•Simplified Disease Activity Index (SDAI) (calculator 3)

•Clinical Disease Activity Index (CDAI) (calculator 4)

•Routine Assessment of Patient Index Data 3 (RAPID3) [64]

•Patient Activity Scale (PAS) II [65]

The choice between these measures is based upon clinician preference. The RAPID3 and PAS-II require only patient-reported data, and the CDAI includes patient and provider data. All of the measures 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 [63,66]. These and other activity measures, including instruments used in clinical research, are described in detail separately. (See "Assessment of rheumatoid arthritis disease activity and physical function".)

●Functional status assessment measures – As a complement to the medical history and inferences drawn from clinical assessment, functional status can be quantitatively assessed and followed by use of patient-reported functional status assessment measures. A number of these are available and have been used in both clinical practice and for research purposes. The ACR has identified three measures as those options most appropriate to choose from for routine clinical use. These include [67]:

•Physical function 10-item short form (Patient-Reported Outcomes Measurement Information System physical function 10-item short form [PROMIS PF10a])

•Health assessment questionnaire (HAQ) II

•Multidimensional HAQ

Functional assessment and measures used for this purpose are discussed in more detail separately. (See "Disease outcome and functional capacity in rheumatoid arthritis", section on 'Functional capacity' and "Assessment of rheumatoid arthritis disease activity and physical function", section on 'Assessment of physical function'.)

Drug 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 [68,69]. We generally follow the recommendations of the ACR for drug monitoring in the treatment of RA (table 1) [1,3,41,58,70], which are also consistent with the recommendations of other experts [71]. 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 (see "Overview of the systemic and nonarticular manifestations of rheumatoid arthritis", section on 'Osteopenia'), 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 adverse effects of systemic glucocorticoids".)

Adjunctive therapies and flare management

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 starting or changing DMARDs and in patients who are experiencing disease flares (see 'Drug therapy for flares' below). Although these agents act rapidly to control inflammation, they do not provide adequate benefit on their own for longer-term control of disease or prevention of joint injury. We taper glucocorticoids as rapidly as tolerated once disease control is achieved and can be maintained, with the ideal goal of discontinuing systemic glucocorticoid therapy.

Glucocorticoids can retard radiographic progression in patients with RA in the short to medium term (ie, up to two years of therapy), but we avoid long-term use, when possible, because chronic use for inflammatory disease is often associated with adverse effects. However, some patients with severe RA require sustained therapy with low doses of glucocorticoids (less than 10 mg/day) together with DMARD therapy; such doses in RA are generally well tolerated and may also have some benefit in retarding disease progression. More detailed discussions of NSAIDs and glucocorticoids in RA, including the evidence supporting their use, 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'.)

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?" and "Use of glucocorticoids in the treatment of rheumatoid arthritis" and "Initial treatment of rheumatoid arthritis in adults", section on 'Symptomatic treatment with antiinflammatory drugs'.)

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".)

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 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 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 [72]. (See "Use of methotrexate in the treatment of rheumatoid arthritis", section on 'Dosing and administration'.)

●Patients initially controlled with a regimen that includes infliximab may benefit from a decrease in the interval between infliximab doses or from higher doses [73,74]. However, increasing the dose from 3 to 5 mg/kg was not beneficial in one well-designed trial [75,76].

●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 [77,78].

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

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 [79].

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" and "Overview of chronic widespread (centralized) pain in the rheumatic diseases".)

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

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 evaluation and management of patients with apparent end-stage RA are discussed in detail separately. (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 and other important issues relating to joint replacement in RA are discussed separately. (See "Surgical management of end-stage rheumatoid arthritis".)

COMORBIDITIES AND DISEASE MANAGEMENT — 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 (table 2) [1,3,41,80].

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, other than with rituximab, 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 being treated with rituximab, antiviral therapy is administered for at least 12 months following rituximab therapy, consistent with guidance from the ACR and the American Association for the Study of Liver Diseases (AASLD) [45,81]. 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 antiviral treatment. (See "Hepatitis B virus: Screening and diagnosis in adults" and "Hepatitis B virus: Overview of management".)

●Hepatitis C – Patients with hepatitis C virus (HCV) infection should be managed in collaboration with their hepatologist. If underlying liver disease is present, non-hepatotoxic DMARDs (sulfasalazine [SSZ] or hydroxychloroquine [HCQ]) are preferred initially. Patients with previously treated HCV infection and normal liver function may tolerate usual RA treatment as in patients without HCV. (See "Overview of the management of chronic hepatitis C virus infection".)

●Tuberculosis – Prior to initiation of immunomodulatory therapy, all patients who will be receiving a biologic DMARD, a targeted synthetic DMARD (ie, a Janus kinase [JAK] inhibitor), and any other 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.

In patients with latent TB who are unable to complete anti-TB therapy, we prefer to use conventional synthetic DMARDs as monotherapy or in combinations. In patients with persistent disease activity despite such intervention, it may be necessary to use a biologic DMARD, in which case we prefer agents other than tumor necrosis factor (TNF) inhibitors. We also review the risks of such intervention in detail with the patient when deciding upon therapy and consult with a specialist in infectious disease for additional assistance in management. (See "Treatment of tuberculosis infection (latent tuberculosis) in nonpregnant adults without HIV infection".)

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 [3,82-86].

●Nonmelanoma skin cancer (basal cell and squamous cell carcinoma) – In patients with a history of nonmelanoma skin cancer, we use conventional DMARDs over biologic DMARDs or JAK inhibitors. There is no contraindication to escalation of therapy to include biologics, but routine skin cancer surveillance is indicated. (See "Basal cell carcinoma: Epidemiology, pathogenesis, clinical features, and diagnosis" and "Cutaneous squamous cell carcinoma (cSCC): Clinical features and diagnosis".)

●Melanoma skin cancer – In patients with a history of melanoma, we use conventional DMARDs over biologic DMARDs or JAK inhibitors. Approaches including monoclonal antibody treatments that activate T cells have shown benefit in treating melanoma (see "Systemic treatment of metastatic melanoma lacking a BRAF mutation"); therefore, some clinicians avoid the use of abatacept in patients with a prior history of melanoma [87]. Routine skin cancer surveillance is indicated. (See "Screening for melanoma in adults and adolescents".)

●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.

Lung disease — Comorbid interstitial lung disease (RA-ILD) and chronic obstructive pulmonary disease (COPD) are common in patients with RA. Pneumonitis may also be a complication of many different RA therapeutic agents [80]. The limited available data for drug toxicity are often prone to confounding and selection bias. Drugs with the potential for causing adverse pulmonary effects include methotrexate (MTX), leflunomide (LEF), TNF inhibitors, SSZ, parenteral gold, abatacept, and rituximab [88]. In general, we avoid the use of MTX in patients with clinically significant or progressive RA-ILD. Although abatacept has had a safety concern for exacerbation of COPD when compared with placebo, subsequent data have not shown it to be increased when compared with other biologic DMARDs. These agents should be used cautiously in patients with severe COPD [89,90]. (See "Overview of pleuropulmonary diseases associated with rheumatoid arthritis".)

Cardiovascular disease — Comorbid cardiovascular disease can occur in patients with RA and may also be a complication of therapy [80]. 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 adverse effects of systemic glucocorticoids", section on 'Cardiovascular effects' 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 a JAK inhibitor. (See "Tumor necrosis factor-alpha inhibitors: An overview of adverse effects", section on 'Heart failure' and "Heart failure in rheumatoid arthritis".)

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 [80]. (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 [80]. By contrast, patients being treated with HCQ or TNF inhibitors for RA have a lower risk of diabetes [91], and SSZ may have glucose-lowering effects [92]. (See "Antimalarial drugs in the treatment of rheumatic disease", section on 'Noninfectious indications for antimalarials' and "Major adverse effects of systemic glucocorticoids", section on 'Metabolic and endocrine effects'.)

Renal disease — RA infrequently affects the kidney, but, if renal disease coexists, it increases mortality risk [80]. 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" and "Cyclosporine and tacrolimus nephrotoxicity" and "Membranous nephropathy: Pathogenesis and etiology", section on 'Drugs'.)

Diverticulitis and gastrointestinal perforation — RA does not cause direct effects on the bowels, but upper and lower gastrointestinal (GI) perforation can be seen and is driven by use of drugs, especially glucocorticoids and NSAIDs, and particularly when used in combination and in older patients [93,94]. For patients with a history of diverticulitis, but not diverticulosis, lower GI perforation is significantly higher with interleukin 6 (IL-6) inhibitors, and likely with targeted synthetic DMARDs (eg, JAK inhibitors) when compared with TNF inhibitors. Although data are limited, the risk does not appear to be increased with the use of abatacept or rituximab. (See "NSAIDs (including aspirin): Pathogenesis and risk factors for gastroduodenal toxicity" and "Major adverse effects of systemic glucocorticoids", section on 'Gastrointestinal effects' and "Interleukin 6 inhibitors: Biology, principles of use, and adverse effects".)

Multimorbidity — Patients with RA often have multimorbidity (defined as the coexistence of at least two long-term conditions). In a study of 154,391 patients with RA, the adjusted odds of multimorbidity for patients with RA versus controls was 2.19 (95% CI 2.16-2.23) [95].

Multimorbidity is associated with increased mortality and decreased functional status and quality of life [96]. In a study of 1558 patients with RA who had initiated therapy with a new DMARD, patients with the highest burden of multimorbidity had the lowest odds of achieving low disease activity or remission, as measured by the Routine Assessment of Patient Index Data 3 (RAPID3; odds ratio [OR] 0.54, 95% CI 0.34, 0.85) [97]. Patients with RA with multimorbidity have longer and more frequent hospitalizations when compared with patients without RA or patients with RA without multimorbidity [98].

PREGNANCY — Rheumatoid arthritis (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 "Safety of rheumatic disease medication use during pregnancy and lactation".)

PROGNOSIS — Clinical outcomes have improved significantly since the 1980s with changes in drug therapy and in the approach to treatment [10,99,100]. Rheumatoid arthritis (RA) was historically associated with a high degree of economic loss, morbidity, and early mortality; these have all improved with 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 [101,102]. More severe RA was associated with higher mortality rates prior to these developments due to higher rates of myocardial infarction, infection, and certain malignancies than at present; mortality had been comparable to that for three-vessel coronary artery disease or with stage IV Hodgkin lymphoma [103]. (See "Disease outcome and functional capacity in rheumatoid arthritis".)

These improvements have decreased the need for joint surgery and reduced disability in patients with RA. As an example, 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 [104]. In another study, 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 [105].

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 [41]:

●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 (SES), older age, female sex, and the presence of the shared epitope. We do not suggest routine testing for the shared epitope due to cost, limited availability, and lack of data supporting its clinical use [41,106,107]. 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 "HLA and other susceptibility genes in rheumatoid arthritis".)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: 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 education: Rheumatoid arthritis symptoms and diagnosis (Beyond the Basics)" and "Patient education: Rheumatoid arthritis treatment (Beyond the Basics)" and "Patient education: Disease-modifying antirheumatic drugs (DMARDs) in rheumatoid arthritis (Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS

●Principles and goals of therapy – 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.)

●Care by a rheumatologist – 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 – 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 therapies' above and 'Pretreatment interventions' above.)

●Initiation of DMARD therapy soon after RA diagnosis – We suggest 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 2C). Better outcomes are achieved by early compared with delayed intervention with DMARDs. (See 'Early use of DMARDs' above.)

●Tight control of disease activity – Tight control treatment strategies to "treat to target" are associated with improved radiographic and functional outcomes compared with less aggressive approaches. Such strategies involve 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) have not been achieved. (See 'Tight control' above and 'Assessment and monitoring' above.)

●Pretreatment evaluation – 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 or Janus kinase (JAK) inhibitor 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.)

●Adjunctive use of antiinflammatory agents – 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.)

●Drug therapy for flares – 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.)

●Monitoring – The monitoring that we perform on a regular basis includes testing that is specific to evaluation of the safety of the drugs being used (table 1); 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 affecting target and choice of therapy – 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 (table 2), and the presence of adverse prognostic factors. (See 'Tight control' above and 'Comorbidities and disease management' above and 'Prognosis' above.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Peter Schur, MD, who contributed to an earlier version of this topic review.