Overview of the management of rheumatoid arthritis in adults

INTRODUCTION — 

Management strategies for patients with rheumatoid arthritis (RA) are directed toward controlling synovitis, preventing joint damage, relieving pain, and preserving musculoskeletal function.

Treatment approaches aim to achieve and maintain remission (or low disease activity) by using disease-modifying antirheumatic drug (DMARD) therapy early in the disease course.

Common management principles have been developed based on evidence from clinical studies and our increasing understanding of disease pathogenesis. (See "Epidemiology of, risk factors for, and possible causes of rheumatoid arthritis" and "Pathogenesis of rheumatoid arthritis".)

An overview of the management of RA is reviewed here. The initial therapy of RA, the treatment of patients resistant to initial and subsequent DMARDs, and nonpharmacologic treatment strategies are discussed in detail elsewhere:

●(See "Initial pharmacologic management of rheumatoid arthritis in adults".)

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

●(See "Treatment of rheumatoid arthritis in adults resistant to initial biologic DMARD therapy".)

●(See "Nonpharmacologic therapies for patients with rheumatoid arthritis".)

MANAGEMENT STRATEGIES — 

Our approach to treatment involves the timely and judicious use of several management strategies. These strategies are based on general principles that have been widely accepted by major professional organizations and other expert groups [1-4]. Improvements in outcomes among patients with rheumatoid arthritis (RA) may owe more to the application of these management strategies than to advances in pharmacotherapy [5].

Early recognition and diagnosis — Achieving the benefits of early intervention with disease-modifying antirheumatic drugs (DMARDs) depends on making the diagnosis of RA as early as possible, before irreversible injury has occurred [5-8]. 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 during the first two years of disease [9,10]. For example, in a study of 42 patients with RA for less than two years, more than 80 percent of patients already had joint space narrowing on plain radiographs of the hands and wrists, and two-thirds had joint erosions [10]. More sensitive imaging techniques (eg, magnetic resonance imaging [MRI], high-resolution ultrasonography) would likely detect even higher rates of joint damage among patients with early RA [11-13]. (See "Pathogenesis of rheumatoid arthritis".)

Early use of DMARDs — We suggest starting all patients diagnosed with RA on DMARD therapy as soon as possible, consistent with the recommendations of major professional organizations [2-4]. There is widespread expert consensus regarding this approach, which is based on several observational studies and a more limited number of randomized trials [6,14-19]. Our choice of drug therapies in patients with RA and the evidence supporting these choices are described in detail separately. (See 'Overview of drug therapy' below and "Initial pharmacologic management of rheumatoid arthritis in adults".)

Early intervention with DMARDs is associated with better outcomes (both in terms of treatment response and joint damage) among patients with RA, compared with patients who are treated later [6,14-20]. (See "Initial pharmacologic management of rheumatoid arthritis in adults", section on 'DMARD therapy'.)

Tight control of disease activity — Tight control of disease activity is associated with improved radiographic and functional outcomes compared with less aggressive approaches [7,21-30].

The "treat-to-target" approach uses frequent adjustments of DMARD therapy to reach a target of remission (or low disease activity).

This approach is supported by multiple expert groups, including the American College of Rheumatology (ACR), the European Alliance of Associations for Rheumatology (EULAR; formerly known as European League Against Rheumatism), and the Canadian Rheumatology Association (CRA) [2-4].

●Treat to target approach – The treat-to-target approach has two components [1]:

•Frequent reassessment – Disease activity is reassessed frequently, on a fixed schedule, using a quantitative composite measure (see 'Frequency of monitoring' below and 'Structured disease assessment' below)

•DMARD adjustment – DMARD regimens are adjusted at each assessment (if needed)

As an example, in patients who fail to respond to initial DMARD therapy (eg, methotrexate [MTX]) after three to six months of treatment, we usually transition the patient to a combination of DMARDs (eg, MTX plus sulfasalazine [SSZ] and hydroxychloroquine [HCQ]) or MTX plus a tumor necrosis factor [TNF] inhibitor rather than continuing therapy with the initial DMARD. (See "Treatment of rheumatoid arthritis in adults resistant to initial conventional synthetic (nonbiologic) DMARD therapy", section on 'Resistant to methotrexate'.)

●Efficacy of treat-to-target approach – The treat-to-target approach, more than the specific agents used, results in better outcomes for patients with RA [31].

A number of randomized trials and related studies demonstrate the efficacy of a treat-to-target approach. Excellent treatment responses are 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 [21-27,32-34].

For example, a meta-analysis of six heterogeneous trials that evaluated tight control strategies in comparison with usual care for RA demonstrated the following benefits [35]:

•Greater improvement in disease activity from baseline to one year was seen in the patients randomly allocated to tight control strategies compared with usual care (mean difference in reduction in Disease Activity Score 28 [DAS28] of 0.59). (See "Assessment of rheumatoid arthritis disease activity and physical function", section on 'Disease Activity Score using 28 joints (DAS28)'.)

•Greater reduction in disease activity was observed in the trials in which tight control was achieved with protocolized treatment adjustments compared with trials without such protocols.

•Greater improvement in Health Assessment Questionnaire (HAQ; a questionnaire that measures functional status) scores in the tight control groups was seen in two of four trials. In the other two trials, improvements in the HAQ scores did not differ significantly between the treatment arms. (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 [21,22]; the Finnish Rheumatoid Arthritis Combination Therapy (FIN-RACo) trial [24-26,32]; the New Finnish Rheumatoid Arthritis Combination Therapy (NEO-RACo) trial [33]; the Treatment of Early Aggressive Rheumatoid Arthritis (TEAR) trial [34]; and the Tight Control of Rheumatoid Arthritis (TICORA) trial [27].

●Treatment target – While remission is the initial target, for some patients, a target of low disease activity is more easily achieved than remission and is adequate to improve quality of life and limit disability [36]. Individual factors may affect the selection of remission versus low disease activity as the treatment target [1,37]. For example:

•Disability and function – For some patients, specific vocational requirements, family responsibilities, or recreational interests may make low disease activity inadequate as a treatment goal and affect a patient's willingness to accept the risks of treatment intensification.

Additionally, an overall assessment of low disease activity may not capture specific joint involvement that may be more impactful for an individual patient.

•Comorbidities – The presence of comorbidities, such as kidney or hepatic disease, may affect medication choices and influence the degree of risk inherent in attempting to reach a goal of remission versus low disease activity in a given patient. (See 'Comorbidities' below.)

•Joint damage – In patients with low disease activity but with worsening joint injury on imaging studies, achieving remission may slow the progression of joint damage.

Care by a rheumatologist — Patients with inflammatory arthritis in whom RA is suspected or diagnosed benefit from ongoing care by an expert in the rheumatic diseases, usually a rheumatologist [38,39]. Compared with care rendered primarily by other clinicians, early and ongoing care of such patients by a rheumatologist is associated with better disease outcomes, including reduced joint injury and less functional disability [40-45].

In the initial consultation, the rheumatologist can confirm or reassess the diagnosis, determine the severity of disease, and initiate a plan of care. 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 with the patient's comorbidities, the preferences of the patient and primary care clinician, and the availability of such care.

PRETREATMENT ASSESSMENTS AND INTERVENTIONS — 

Before starting or resuming a disease-modifying antirheumatic drug (DMARD), we perform pretreatment assessments and interventions [46,47].

For all patients

Routine laboratories — For all patients, we obtain a baseline complete blood count, serum creatinine, aminotransferases, erythrocyte sedimentation rate (ESR), and C-reactive protein (CRP). These tests are broadly helpful for monitoring disease activity and drug toxicity. (See 'Clinical assessment of disease' below and 'Monitoring for drug toxicity' below.)

Baseline radiographs — Early in the course of rheumatoid arthritis (RA), we obtain plain radiographs of the hands and wrists (two films, an anteroposterior [AP] view and a posteroanterior or ball catcher's view), as well as at least one AP view of both forefeet, including the metatarsophalangeal joints. These radiographs serve as a baseline for evaluating change in the joints during treatment. We do not obtain more advanced imaging (eg, MRI, ultrasound) for all patients. (See 'Imaging for select patients' below.)

Hepatitis virus screening — We screen all patients for hepatitis B and C before initiating therapy with any DMARDs.

●Hepatitis B – Screening for hepatitis B is discussed in detail elsewhere. (See "Hepatitis B virus: Screening and diagnosis in adults", section on 'Approach to screening and testing'.)

For patients with evidence of prior or active hepatitis B infection, we use the following approach:

•Prior infection – In patients with natural immunity to hepatitis B virus (HBV; HBV core antibody [positive, normal liver chemistries, HBV surface antibody positive, and HBV surface antigen negative), treatment for RA (other than with rituximab) should be the same as for HBV-unexposed RA patients. However, viral loads should be monitored every 6 to 12 months to ensure there is no reactivation.

We avoid using rituximab in patients with a history of hepatitis B infection due to the high risk of HBV reactivation, unless under the supervision of a hepatologist.

Additionally, some patients may require antiviral treatment before initiating immunosuppressive therapy, depending upon their level of risk for HBV reactivation.

Prevention of immunosuppression-associated HBV reactivation is described in detail separately. (See "Hepatitis B virus reactivation associated with immunosuppressive therapy".)

•Active hepatitis B – For patients with active untreated hepatitis, antiviral therapy should be initiated before immunosuppressive therapy, and patients should be treated in collaboration with their hepatologist. (See "Hepatitis B virus: Overview of management", section on 'Antiviral therapy'.)

●Hepatitis C – We screen all patients for hepatitis C virus (HCV). Screening for hepatitis C is described in detail separately. (See "Screening and diagnosis of chronic hepatitis C virus infection", section on 'Initial testing'.)

Patients with HCV infection should be managed in collaboration with their hepatologist, infectious disease specialist, or internist (depending on the severity of the underlying liver disease). (See "Overview of the management of chronic hepatitis C virus infection".)

Patients with previously treated HCV infection and normal liver function may be treated with the usual DMARD therapies. If underlying liver disease is present, we prefer non-hepatotoxic DMARDs.

Cardiovascular risk assessment — We perform a risk assessment for cardiovascular disease in all patients with RA. Comorbid cardiovascular disease can occur in patients with RA and may also be a complication of therapy [48]. Active RA is associated with an increased risk of cardiovascular disease, but good control of disease activity has been associated with reduced cardiovascular complications. Both glucocorticoids and nonsteroidal antiinflammatory drugs (NSAIDs) may increase cardiovascular risk. The connection between RA and coronary artery disease as well as strategies for risk stratification and management of cardiovascular risk are described in detail separately. (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 "Overview of primary prevention of cardiovascular disease in adults".)

Fracture risk assessment — We perform a fracture risk assessment in all patients with RA. Both RA and glucocorticoid exposure are independent risk factors for osteoporotic fracture.

Both the assessment of fracture risk and the management of glucocorticoid-induced osteoporosis are described in detail separately. (See "Osteoporotic fracture risk assessment", section on 'Assessment of fracture risk' and "Prevention and treatment of glucocorticoid-induced osteoporosis".)

Immunizations — We offer all patients with RA immunizations to decrease the risk of infectious complications of immunosuppressive therapies and disease-associated immune dysregulation. These issues are described in detail separately. (See "Immunizations in autoimmune inflammatory rheumatic disease in adults".)

Nonpharmacologic interventions — Selected patients may benefit from one or more nonpharmacologic interventions. Briefly, these include:

●Patient education regarding RA and its management

●Psychosocial interventions

●Rest, exercise, and physical and occupational therapy

●Nutritional and dietary counseling

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

For selected patients — Precautions relevant to each DMARD prescribed should be reviewed before initiating therapy to confirm that all appropriate precautions have been taken. Some common examples include:

Chest radiograph for methotrexate use — We obtain a baseline chest radiograph before methotrexate (MTX) use. Although not conclusive, observational data suggest that there may be an increased risk of MTX hypersensitivity pneumonitis in patients with underlying pulmonary disease; having a baseline chest radiograph for comparison may be helpful to differentiate complications of MTX use from preexisting findings. These issues are discussed elsewhere. (See "Major adverse effects of low-dose methotrexate", section on 'Pulmonary toxicity' and "Methotrexate-induced lung injury", section on 'Risk factors'.)

Eye screening for hydroxychloroquine use — We perform a complete baseline ophthalmologic examination within the first year of treatment with hydroxychloroquine (HCQ), including optical coherence tomography, examination of the retina through a dilated pupil, and/or automated visual field testing. Retinopathy is a known complication of HCQ use, and a baseline examination is useful for subsequent comparison. Our approach to screening and subsequent monitoring for ocular toxicity among patients using HCQ is described in detail separately. (See "Antimalarial drugs in the treatment of rheumatic disease", section on 'Routine eye examinations for all patients'.)

Tuberculosis screening for biologics/Janus kinase inhibitor use

●Standard screening options – We screen for tuberculosis (TB) infection (ie, latent TB) with an interferon-gamma release assay. Skin testing may be used if an interferon-gamma release assay is not available. Both biologics and Janus kinase (JAK) inhibitors may increase the risk of mycobacterial infection [49,50]. (See "Risk of mycobacterial infection associated with biologic agents and JAK inhibitors".)

The approach to latent TB screening varies by country; these issues are discussed in detail elsewhere. (See "Tuberculosis infection (latent tuberculosis) in adults: Approach to diagnosis (screening)", section on 'Diagnostic approach'.)

●Chest radiograph in high-risk patients – In addition to standard screening, we also obtain a chest radiograph in patients with risk factors for latent TB before using a biologic DMARD or JAK inhibitor, even if screening tests are negative. Glucocorticoids and other factors may make false-negative TB tests more common among patients with RA [51].

●Approach to patients with latent TB – In patients in whom latent TB is diagnosed (and TB disease has been excluded), we treat for at least one month before initiating immunosuppressive agents. (See "Treatment of tuberculosis infection (latent tuberculosis) in nonpregnant adults without HIV infection".)

In patients with latent TB who are unable to complete TB therapy, we prefer to use nonbiologic DMARDs. In patients with persistent disease activity despite such intervention, we may use biologic DMARDs but avoid tumor necrosis factor (TNF) and JAK inhibitors. We also review the risks of using biologic DMARDs in detail with the patient when deciding upon therapy and consult with an infectious disease specialist for additional assistance in management.

Lipid screening for interleukin-6/Janus kinase inhibitor use — We check a complete lipid panel, including total cholesterol, low-density lipoprotein, high-density lipoprotein, and triglycerides, before initiating therapy with either an interleukin 6 (IL-6) or JAK inhibitor.

Both IL-6 and JAK inhibitors have been associated with dyslipidemia. Patients using an IL-6 or JAK inhibitor who have dyslipidemia should be managed according to available guidelines. These issues are discussed elsewhere. (See "Interleukin 6 inhibitors: Biology, principles of use, and adverse effects", section on 'Gastrointestinal' and "Overview of the Janus kinase inhibitors for rheumatologic and other inflammatory disorders", section on 'Cardiovascular' and "Low-density lipoprotein cholesterol-lowering therapy in the primary prevention of cardiovascular disease", section on 'CVD risk assessment'.)

OVERVIEW OF DRUG THERAPY

●Disease-modifying antirheumatic drugs (DMARDs) for all patients – We suggest that all patients diagnosed with rheumatoid arthritis (RA) be started on DMARD therapy as soon as possible. (See 'Early use of DMARDs' above.)

•DMARD classification – DMARDs are immunosuppressive or immunomodulatory agents that reduce or prevent joint damage and preserve joint integrity and function. Examples of DMARDs include:

-Nonbiologic (traditional or conventional synthetic) DMARDs – Nonbiologic DMARDs are broadly immunosuppressive and do not target a specific immune pathway; nonbiologic DMARDs are typically administered orally.

Examples of nonbiologic DMARDs include methotrexate (MTX), hydroxychloroquine (HCQ), sulfasalazine (SSZ), and leflunomide (LEF).

-Biologic DMARDs – Biologic DMARDs are produced by cultured cells that target cytokines, cytokine receptors, or other cell surface molecules; biologic DMARDs are typically administered parenterally.

Examples of bDMARDs include anticytokine therapies, such as the tumor necrosis factor (TNF) inhibitors etanercept, infliximab, adalimumab, golimumab, and certolizumab pegol; and the interleukin 6 (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.

A biosimilar is a biologic DMARD that is similar in structure and function to the original biologic DMARD. Biosimilars are widely available and are used interchangeably with the original product (ie, the bio-originator).

-Targeted synthetic DMARDs – Targeted synthetic DMARDs are small, synthetic molecules that, like biologic DMARDs, target specific immune pathways; unlike biologic DMARDs, targeted synthetic DMARDs are typically administered orally.

This class includes Janus kinase (JAK) inhibitors, which inhibit cytokine and growth factor signaling through interference with a family of non-receptor tyrosine kinases known as JAK. JAK inhibitors are available for use in RA and other disorders in the United States and several other countries.

Examples of JAK inhibitors include tofacitinib, baricitinib, upadacitinib, filgotinib, and peficitinib.

•Factors affecting DMARD selection – Choices between treatment options are based upon multiple factors, including:

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

-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 indicators

Several medical conditions that often coexist with or result from RA may also influence the choice of medications (table 1).

In some patients, the extraarticular features of RA may require treatment that is distinct from and at times even more aggressive than the treatment needed for the articular features. In such cases, drug therapy is based on the extraarticular features, such as vasculitis or interstitial lung disease, which may require more aggressive immunosuppressive therapy. The treatment of these specific features is reviewed in detail elsewhere. (See "Overview of the systemic and nonarticular manifestations of rheumatoid arthritis" and "Interstitial lung disease in rheumatoid arthritis" and "Treatment of rheumatoid vasculitis".)

The approach to the selection of DMARDs is discussed in detail separately:

•(See "Initial pharmacologic management of rheumatoid arthritis in adults", section on 'DMARD therapy'.)

•(See "Treatment of rheumatoid arthritis in adults resistant to initial conventional synthetic (nonbiologic) DMARD therapy", section on 'Approach to pharmacotherapy'.)

•(See "Treatment of rheumatoid arthritis in adults resistant to initial biologic DMARD therapy", section on 'Approach to pharmacotherapy'.)

●Symptomatic therapy – In addition to DMARDs, most patients will require symptomatic (adjunctive) therapy, which may include nonsteroidal antiinflammatory drugs (NSAIDs), low-dose glucocorticoids, and/or analgesics, to address symptoms until the patient has adequate symptom relief from DMARD therapy, which may take weeks to months.

Some patients will require chronic symptomatic treatment to address symptoms that persist despite adequate DMARD therapy (eg, pain due to structural joint damage).

Unlike DMARDs, these symptomatic therapies do not prevent structural joint damage or improve long-term outcomes.

The approach to symptomatic therapy is discussed in detail elsewhere. (See "Initial pharmacologic management of rheumatoid arthritis in adults", section on 'Adjunctive symptomatic treatment'.)

ASSESSMENT AND MONITORING DURING TREATMENT

Frequency of monitoring — Routine monitoring is a cornerstone of the "treat-to-target" strategy to achieve tight control of rheumatoid arthritis (RA) disease activity. (See 'Tight control of disease activity' above.)

We use the following intervals as a guideline:

●Initial monitoring – Patients with active disease should be regularly reassessed every three months until the patient is stable and their disease is in remission (or only low disease activity is present) [27,52-54].

●Long-term monitoring – After the RA is in remission and well-controlled, patients may be seen every three to six months.

●Other considerations

•More frequent clinical assessments may be required in patients with comorbidity or in those experiencing a flare of disease or undergoing changes in therapy. Patients should also be counseled to contact their treating clinician if the arthritis flares. The management of disease flares is discussed elsewhere. (See "Initial pharmacologic management of rheumatoid arthritis in adults", section on 'Recurrent disease (disease flares)'.)

•Patients may require additional laboratory monitoring between scheduled visits. More frequent laboratory monitoring may be necessary depending on the medications being used and following increases in dosing. (See 'Monitoring for drug toxicity' below.)

At these routine monitoring visits, we suggest performing clinical and laboratory assessments, screening for drug toxicities, and obtaining quantitative composite measures of disease activity, as outlined below.

Clinical assessment of disease — Clinical assessment includes the following major elements:

●Patient history

•Articular manifestations – We ask the patient about the degree of joint pain and swelling and the duration of morning stiffness, which may indicate active RA [47,55].

The articular symptoms associated with RA are described in detail elsewhere. (See "Articular manifestations of rheumatoid arthritis".)

•Extraarticular manifestations – We ask patients about changes in extraarticular manifestations of RA, including systemic signs such as fever, anorexia, malaise, weight loss, fatigue, and symptoms of ocular, pulmonary, and cardiovascular disease. (See "Overview of the systemic and nonarticular manifestations of rheumatoid arthritis".)

Because fever is not a common feature of RA in adults, infection should be excluded before ascribing fever to RA. An approach to the evaluation of fever is described in detail elsewhere. (See "Fever of unknown origin in adults: Evaluation and management", section on 'Initial evaluation and management'.)

•Functional capacity – We ask patients about their functional capacity, including the performance of activities of daily living, vocational activities, and avocational activities (eg, hobbies, participation in sports).

We routinely use a self-report questionnaire that measures function. (See 'Structured disease assessment' below.)

Functional assessment also helps to identify therapeutic needs for additional interventions such as counseling, exercise, and occupational therapy. These interventions are described in detail elsewhere. (See "Nonpharmacologic therapies for patients with rheumatoid arthritis".)

●Physical examination

•Musculoskeletal examination – As part of every clinical assessment, we perform a detailed musculoskeletal examination.

The joints should be evaluated for warmth, swelling, tenderness, loss of motion, and malalignment. Changes in previously affected joints or the appearance of inflammation in previously uninvolved joints may indicate active RA.

Examined joints include the wrists, elbows, shoulders, and knees as well as the metacarpophalangeal and proximal interphalangeal joints of the hands [56]. If the feet are involved, the ankles, the metatarsophalangeal joints, and the proximal interphalangeal joints of the feet should also be assessed.

The physical findings of joint inflammation, including the distribution of involved joints, are discussed in detail elsewhere. (See "Articular manifestations of rheumatoid arthritis".)

•Extraarticular examination – In addition to the articular examination, we perform a general physical examination, with particular attention to the skin for rheumatoid nodules (which may be a harbinger of more severe disease) 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.

The extraarticular manifestations of RA are reviewed in detail elsewhere. (See "Overview of the systemic and nonarticular manifestations of rheumatoid arthritis".)

●Laboratory monitoring — We assess acute phase reactants (eg, erythrocyte sedimentation rate [ESR] and C-reactive protein [CRP]) at every evaluation. These tests are useful for assessing systemic inflammation and are components of several of the formal composite measures used for evaluating the level of disease activity. (See 'Structured disease assessment' below.)

Other tests primarily obtained for medication monitoring may also help track systemic inflammation potentially indicative of RA activity. For example, decreases in hemoglobin and serum albumin may occur in response to increased disease activity and/or inflammation. Additionally, platelet counts may be mildly elevated (typically up to 400,000 to 450,000/microL) in patients with ongoing inflammation.

Laboratory tests used to monitor for treatment-associated toxicities are discussed below. (See 'Monitoring for drug toxicity' below.)

Structured disease assessment — We use a disease activity measure and a functional status measure (eg, Clinical Disease Activity Index [CDAI] and Health Assessment Questionnaire [HAQ]) at every visit. Effective implementation of tight control strategies involves reassessing disease activity and functional status on a regular, planned basis using quantitative composite measures. The use of structured measures helps quantify disease activity and functional status and facilitates timely adjustment of treatment regimens. (See 'Tight control of disease activity' above.)

●Disease activity measures – We use the CDAI as a measure of disease activity. The American College of Rheumatology (ACR) notes that all of the following are appropriate for use in clinical practice [57]:

•CDAI (calculator 1)

•Disease Activity Score derivative for 28 joints (DAS28) with the ESR (calculator 2)

•DAS28 with the CRP (calculator 3)

•Simplified Disease Activity Index (SDAI) (calculator 4)

•Routine Assessment of Patient Index Data 3 (RAPID3) [58]

•Patient Activity Scale (PAS) II [59]

All of these 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 [57,60]. The choice between these measures is based on clinician preference.

The authors do not use the RAPID3 and PAS-II, which require only patient-reported data; the other indices require input from the patient and the provider. Adaptations of measures for assessing disease activity and function have been proposed for monitoring patients receiving care during telehealth visits [61].

These disease activity measures (and the individual components used to calculate these disease activity measures) are described in detail separately. (See "Assessment of rheumatoid arthritis disease activity and physical function", section on 'Composite indices for disease activity assessment'.)

●Functional status assessment measures – In addition to the medical history and inferences drawn from clinical assessment, functional status can be quantitatively assessed and followed using patient-reported functional status assessment measures. Several of these are available and have been used in clinical practice and research.

The ACR has identified three measures as the most appropriate options for routine clinical use. These include [62]:

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

•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'.)

Monitoring for 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 [63,64].

●For DMARDs – We generally follow the ACR's recommendations for drug monitoring in the treatment of RA [46,47,54,55,65], which are also consistent with the recommendations of other experts [66].

In addition, for azathioprine, we obtain liver function tests at baseline and every three months thereafter.

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.)

●For glucocorticoids – Patients on glucocorticoids should be monitored for adverse effects, such as osteoporosis, diabetes, and hypertension, and appropriate preventive measures should be undertaken.

Glucocorticoid-associated toxicities are discussed in detail elsewhere. (See "Major adverse effects of systemic glucocorticoids", section on 'General treatment considerations and monitoring'.)

Imaging for select patients — We do not perform imaging at every assessment. Imaging is most useful for identifying evidence of disease activity when the clinical assessment is not clear.

●Plain radiography – After baseline radiographs have been obtained, we obtain radiographs when there is clinical evidence of disease progression to guide clinical decisions, but we do not routinely obtain them for asymptomatic patients. Radiologic evidence of disease progression (eg, periarticular osteopenia, joint space narrowing, or bone erosions) indicates that the current DMARD regimen is inadequate and requires modification. However, coexistent osteoarthritis may also account, in part, for joint space narrowing in older patients with RA [66].

●Ultrasonography and MRI – We use musculoskeletal ultrasound and MRI to confirm the presence of synovitis when the joint examination is equivocal. We do not use these modalities for the routine management of RA. However, some clinicians routinely employ musculoskeletal ultrasound and/or MRI to follow patients and to detect early changes.

Musculoskeletal ultrasound and MRI are more sensitive for detecting cartilage and bone abnormalities and can reveal subclinical inflammation [67,68]. However, these sensitive imaging techniques do not provide greater clinical benefit and may be associated with increased adverse effects and potentially with greater cost [69-71].

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 (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 [69]. However, 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 musculoskeletal ultrasound to guide therapy in patients with early RA has also been described [70,71].

TAPERING MEDICATIONS IN PATIENTS WITH SUSTAINED REMISSION

Approach to reducing immunosuppression — In patients who achieve sustained clinical remission for more than one year, we suggest cautiously reducing nonbiologic and biologic disease-modifying antirheumatic drug (DMARD) doses. We closely monitor the patient for evidence of disease flare, and we halt the taper if there is evidence of increased disease activity.

As an example of our approach, in a patient in clinical remission for over one year, we would sequentially:

●Taper chronic glucocorticoids – For a patient taking chronic prednisone therapy (eg, ≤10 mg daily), we decrease the dose no faster than 1 mg every two to four weeks.

We suggest reducing the prednisone dose first because of the risk of long-term adverse effects of glucocorticoids. In general, patients who are unable to taper prednisone without a flare of rheumatoid arthritis (RA) are not in remission, and we would not recommend tapering other agents.

●Taper biologic/targeted synthetic DMARD – If the prednisone can be tapered and discontinued, we then try to taper the biologic DMARD. This may be accomplished either by decreasing the dose or increasing the interval between doses every three to six months.

For example, we try to reduce etanercept (which is administered subcutaneously) by slowly decreasing the dosing frequency (eg, to every 10 to 14 days, then gradually to every three to four weeks, if tolerated). In patients on infliximab (which is administered intravenously), we would try to incrementally reduce the dose to as low as 3 mg/kg and then increase the interval between infusions. However, there are limited data to guide these decisions, which therefore depend heavily on patient preference and clinical response.

●Taper nonbiologic DMARD – If the patient remains in remission without a biologic DMARD for at least one year, we will try to taper the nonbiologic DMARD without discontinuing the drug entirely.

For example, with methotrexate (MTX), we decrease the dose in 2.5 mg increments every 1 to 2 months.

Our approach is based upon the available data and our clinical experience:

●Tapering and clinical outcomes – Multiple studies suggest that RA patients who have achieved sustained clinical remission may tolerate a reduction in immunosuppression without a significantly increased risk of relapse.

In a meta-analysis of randomized trials including 1430 patients with RA who had achieved a prolonged remission after treatment with a biologic or targeted synthetic DMARD plus MTX, stopping MTX did not affect the remission rate [72].

Similarly, in a cohort study of 437 patients who had been in remission for at least six months, reducing immunosuppression (either conventional and/or biologic DMARDs) did not increase the risk of flare (hazard ratio [HR] 0.88) or loss of remission (HR 1.04) when compared with patients who remained on chronic immunosuppression [73].

●Tapering and radiographic outcomes – There is relatively limited evidence regarding radiographic outcomes of tapering of DMARDs in patients who are started on DMARDs early in their disease course and those who have been treated with biologic DMARDs [38,74-81]. In general, randomized trials have demonstrated that gradual reduction of immunosuppression is associated with some increased risk of flare but not necessarily progression of radiographic damage.

For example, in a trial involving initial therapy of early RA (ie, symptoms less than one year) with etanercept (50 mg weekly) and MTX (up to 25 mg weekly administered orally), 193 patients achieving remission after one year of therapy were randomly assigned to receive either etanercept 25 mg weekly plus MTX, MTX alone, or placebo in a blinded fashion for the next 39 weeks [82]. After 39 additional weeks of follow-up, there was no difference in radiographic outcomes among the three groups.

Avoid discontinuing all DMARD therapy — We generally avoid discontinuing all DMARD treatment. Although some patients may tolerate a reduced dose of medications, there are insufficient data to prospectively identify which patients will be able to successfully discontinue therapy without clinical recurrence or radiographic progression [28,76,83,84].

The decision to discontinue DMARDs in patients in remission remains controversial [85]. It is generally not recommended by the American College of Rheumatology (ACR) or the European Alliance of Associations for Rheumatology (EULAR) based on multiple studies demonstrating an increased risk of flare associated with DMARD discontinuation [79,86,87].

Patients who successfully discontinue their medications and enter a period of possible drug-free remission require close monitoring. The risk of disease recurrence in such patients is high, and disease flares may occur even several years after stopping therapy [74-78,83,88]. Additionally, clinical remission may be difficult to achieve upon resumption of DMARD therapy in patients who have discontinued all DMARDs.

Monitoring of RA disease activity is discussed in detail elsewhere. (See "Assessment of rheumatoid arthritis disease activity and physical function", section on 'Composite indices for disease activity assessment'.)

APPROACH TO REFRACTORY DISEASE

●Resistant disease and disease flares – Some patients with rheumatoid arthritis (RA) have sustained disease activity despite appropriate disease-modifying antirheumatic drug (DMARD) therapy; others will experience exacerbations (known as "flares") after first achieving disease remission. The management of these issues is discussed elsewhere. (See "Treatment of rheumatoid arthritis in adults resistant to initial conventional synthetic (nonbiologic) DMARD therapy", section on 'Definition of resistance to initial therapy'.)

●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 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 — 

Comorbidities among patients with rheumatoid arthritis (RA) may be the direct result of the disease or the drugs used to manage it. Patients with RA often have multimorbidity (defined as the coexistence of at least two long-term comorbid conditions). In a study of 154,391 patients with RA, the adjusted odds of multimorbidity for patients with RA versus controls were 2.19 (95% CI 2.16-2.23) [89].

Multimorbidity is associated with increased mortality and decreased functional status and quality of life [90]. In a study of 1558 patients with RA who had initiated therapy with a new disease-modifying antirheumatic drug (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) [91]. Patients with RA with multimorbidity have longer and more frequent hospitalizations when compared with patients without RA or patients with RA without multimorbidity [92].

Some common disease- and treatment-related issues are discussed below.

Acute infection — In patients with a minor infection (eg, urinary tract infection, upper respiratory tract infection), we continue DMARDs without interruption.

In patients with an active serious infection, we temporarily hold DMARDs until resolution of infection and completion of antimicrobial therapy. However, we continue chronic glucocorticoid therapy at the lowest dose necessary to prevent adrenal insufficiency and/or disease flare.

In patients with a history of serious or recurrent infections, we use conventional DMARDs over biologic agents. Conventional DMARDs have a shorter half-life and can be stopped or adjusted more quickly than biologic agents. This feature may be particularly important when there is a heightened concern for serious or recurrent infections.

The assessment and management of hepatitis B, hepatitis C, and tuberculosis are described above. (See 'Hepatitis virus screening' above and 'Tuberculosis screening for biologics/Janus kinase inhibitor use' above.)

Chronic comorbidities — The relationship between RA and cardiovascular disease is discussed above. (See 'Cardiovascular risk assessment' above.)

Other chronic comorbid conditions associated with RA include the following:

●Lung disease – Comorbid interstitial lung disease and chronic obstructive pulmonary disease (COPD) are common in patients with RA [93].

Pneumonitis may also be a complication of many different RA therapeutic agents [48]. The limited available data for drug toxicity are often prone to confounding and selection bias. Drugs with the potential to cause adverse pulmonary effects include methotrexate (MTX), leflunomide (LEF), tumor necrosis factor (TNF) inhibitors, sulfasalazine (SSZ), abatacept, and rituximab [94].

The pleuropulmonary manifestations of RA are discussed in detail elsewhere. (See "Overview of pleuropulmonary diseases associated with rheumatoid arthritis" and "Interstitial lung disease in rheumatoid arthritis".)

●Neurologic disease – Impingement neuropathies such as carpal tunnel syndrome are common in patients with RA. However, other neurologic manifestations of RA and/or coexisting neurologic disease are uncommon. (See "Neurologic manifestations of rheumatoid arthritis".)

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 the 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 [48]. (See "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 may worsen control of the diabetes [48]. By contrast, patients being treated with hydroxychloroquine (HCQ) or TNF inhibitors for RA have a lower risk of diabetes [95], and HCQ and SSZ may have glucose-lowering effects [96].

The association between glucocorticoids and diabetes is discussed in detail elsewhere. (See "Major adverse effects of systemic glucocorticoids", section on 'Metabolic and endocrine effects'.)

●Kidney disease – RA infrequently affects the kidney, but, if kidney disease coexists, it increases mortality risk [48].

Nonsteroidal antiinflammatory drugs (NSAIDs), which are used for symptomatic therapy of RA, are commonly associated with kidney toxicity. Appearance of proteinuria in a patient with severe, longstanding RA should prompt consideration of amyloidosis.

Some nonbiologic DMARDs, particularly MTX and cyclosporine, should be avoided or used with particular caution in patients with significantly decreased kidney function. (See "Use of methotrexate in the treatment of rheumatoid arthritis", section on 'Dosing and limits to use with reduced kidney function' and "Cyclosporine and tacrolimus nephrotoxicity".)

●Gastrointestinal perforation – RA causes direct effects on the intestines only in very rare cases of rheumatoid vasculitis, but upper and lower gastrointestinal perforation has been associated with some drugs (ie, glucocorticoids, NSAIDs, interleukin 6 [IL-6] inhibitors), particularly when used in combination and in older patients [97,98].

Treatment-associated gastrointestinal toxicities are discussed in detail elsewhere. (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".)

PREGNANCY — 

Rheumatoid arthritis (RA) often improves or remits completely during pregnancy. However, disease flares of RA are common for several months after parturition.

Issues related to pregnancy 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 — 

Several factors have been associated with poorer outcomes in patients with rheumatoid arthritis (RA). The following four markers of adverse prognosis can be used to identify patients who may require more aggressive pharmacotherapy, especially in the early stages of the disease [47]:

●Functional limitation

●Extraarticular disease

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

●Bony erosions documented radiographically

Other factors associated with a worse prognosis include concurrent medical disorders, cigarette smoking, lack of formal education, lower socioeconomic status (SES), older age, female sex, and the presence of the inherited RA-predisposing major histocompatibility complex (MHC) allele known as the shared epitope. However, we do not suggest routine testing for the shared epitope due to cost, limited availability, and lack of data supporting its clinical use [47,99,100].

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 6th-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 12th-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.)

●Basics topics (See "Patient education: Rheumatoid arthritis (The Basics)" and "Patient education: How to give a subcutaneous injection (The Basics)" and "Patient education: How to dispose of needles and other sharps (The Basics)".)

●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

●Early diagnosis – In patients with rheumatoid arthritis (RA), affected areas may be irreversibly damaged or destroyed if inflammation persists. Thus, prompt diagnosis and early recognition of active disease are central to modifying disease outcomes. (See 'Early recognition and diagnosis' above.)

●Rapid initiation of disease-modifying antirheumatic drug (DMARD) therapy – We suggest starting all patients with RA on 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 associated with early compared with delayed intervention with DMARDs. (See "Initial pharmacologic management of rheumatoid arthritis in adults", section on 'Early DMARD therapy for all patients'.)

DMARDs may be nonbiologic (conventional synthetic), biologic, or targeted synthetic. Factors that may influence the choice of DMARD include the disabilities or functional limitations important to a given patient, progressive joint injury, comorbidities (table 1), and the presence of adverse prognostic factors. (See 'Early use of DMARDs' above and 'Overview of drug therapy' above.)

●Tight control of disease activity – We assess 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. This "treat to target" approach allows us to achieve tight control of disease activity, which is associated with improved radiographic and functional outcomes compared with less aggressive approaches. (See 'Tight control of disease activity' above and 'Assessment and monitoring during treatment' above.)

●Expert management – 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.).

●Pretreatment evaluation – Laboratory testing before therapy should include a complete blood count, erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), aminotransferases, and creatinine. All patients should receive routine immunizations, screening for hepatitis B and C, and assessment of both cardiovascular and fracture risk. Nonpharmacologic interventions, including psychosocial interventions and dietary counseling, are important adjuncts to therapy. Patients taking specific DMARDs may require additional screening measures. (See 'Pretreatment assessments and interventions' above.)

●Symptomatic therapy – 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 symptomatic therapy. Patients with end-stage disease may require surgical intervention to alleviate symptoms. (See 'Overview of drug therapy' above and 'Approach to refractory disease' above.)

●Monitoring – We monitor patients every three months until the patient is stable and their disease is in remission; subsequently, we monitor patients every three to six months. This monitoring includes a history and physical examination, testing specific to evaluating the safety of the drugs being used (table 2), periodic assessments of disease activity with composite measures, and monitoring for extraarticular manifestations of RA as well as other disease complications. We limit the use of imaging to identify evidence of disease activity when these assessments are not adequate. (See 'Assessment and monitoring during treatment' above.)

●Therapy duration – In patients who are in remission for over one year, we suggest tapering the DMARD therapy (Grade 2C). We prioritize reduction and discontinuation of chronic glucocorticoids. However, we avoid discontinuing all DMARD therapy entirely, which is associated with an increased risk of relapse. (See 'Tapering medications in patients with sustained remission' above.)

●Specific treatment recommendations – Initial pharmacotherapy and subsequent management decisions are discussed separately:

•(See "Initial pharmacologic management of rheumatoid arthritis in adults".)

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

•(See "Treatment of rheumatoid arthritis in adults resistant to initial biologic DMARD therapy".)

●Comorbid disease – Comorbidities among patients with RA may be the direct result of the disease or the drugs used to manage it. Patients with RA often have multiple comorbidities, including cardiovascular disease, lung disease, and infection. DMARDs also increase the risk of infection.

In patients with a minor infection, we continue DMARD therapy without interruption. We temporarily hold DMARDs in patients with active serious infections until resolution of the infection and completion of antimicrobial therapy; however, we continue glucocorticoids at the lowest dose required to prevent adrenal insufficiency and/or disease flare. (See 'Comorbidities' above.)

ACKNOWLEDGMENT — 

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