General principles of management of rheumatoid arthritis in adults

General principles of management of rheumatoid arthritis in adults

Authors
Peter H Schur, MD
Larry W Moreland, MD

Section Editor
James R O'Dell, MD

Deputy Editor
Paul L Romain, MD

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

Literature review current through: May 2016. &#124 This topic last updated: Dec 07, 2015.

INTRODUCTION — The treatment of rheumatoid arthritis (RA) is directed toward the control of synovitis and the prevention of joint injury. The choice of therapies depends upon several factors, including the severity of disease activity when therapy is initiated and the response of the patient to prior therapeutic interventions.
Common principles that guide management strategies and the choice of agents have been derived from an increased understanding of the disease and from evidence from clinical trials and other studies. These strategies include approaches directed at achieving remission or low disease activity by more rapid and sustained control of inflammation and by the institution of disease-modifying antirheumatic drug (DMARD) therapy early in the disease course.
The general principles and treatment strategies that should be applied to the management of RA are reviewed here. The initial therapy of RA and the treatment of patients resistant to initial disease-modifying antirheumatic drugs are discussed in greater detail elsewhere. (See "Nonpharmacologic therapies and preventive measures for patients with rheumatoid arthritis" and "Initial treatment of mildly active rheumatoid arthritis in adults" and "Initial treatment of moderately to severely active rheumatoid arthritis in adults" and "Treatment of rheumatoid arthritis in adults resistant to initial nonbiologic DMARD therapy".)
GENERAL PRINCIPLES — Our overall approach to the treatment of patients with rheumatoid arthritis (RA) depends upon the timely and judicious use of several types of therapeutic interventions. The appropriate use of these therapies is based upon an understanding of a group of general principles that have been widely accepted by major working groups and by professional organizations of rheumatologists [1-5]. (See 'Recommendations by major groups' below.)
These principles include:
●Early recognition and diagnosis (see 'Early recognition and diagnosis' below)
●Care by an expert in the treatment of rheumatic diseases, such as a rheumatologist (see 'Care by a rheumatologist' below)
●Early use of disease-modifying antirheumatic drugs (DMARDs) for all patients diagnosed with RA (see 'Early use of DMARDs' below)
●Importance of tight control with target of remission or low disease activity (see 'Tight control' below)
●Use of antiinflammatory agents, including nonsteroidal antiinflammatory drugs (NSAIDs) and glucocorticoids, only as adjuncts to therapy (see 'Adjunctive role of antiinflammatory agents' below)
The application of these principles has resulted in significant improvement in the outcomes of treatment, although the etiology and pathogenesis of RA are complex and are not fully understood [6-8]. Such improvements may owe even more to the therapeutic strategies that have been adopted than to the development and use of newer and more potent drugs [9].
RA is characterized by acute and chronic inflammation in the synovium, which is associated with a proliferative and destructive process in joint tissues [8,10,11]. Many elements of innate and adaptive immunity are involved in this process, and evidence of significant and irreversible joint injury may occur as early as during the first two years of disease if inflammation persists. Measures aimed at identifying early active disease and at markedly reducing inflammation are, therefore, essential for modifying disease outcome [7,9,12,13]. (See "Pathogenesis of rheumatoid arthritis" and 'Tight control' below.)
Early recognition and diagnosis — Achieving the benefits of early intervention with disease-modifying antirheumatic drugs (DMARDs) depends upon making the diagnosis of RA as early as possible. The recognition of RA early in the course of inflammatory arthritis, before irreversible injury has occurred, is thus an important element of effective management. (See 'Early use of DMARDs' below.)
International collaborative efforts led in 2010 to the development of new classification criteria for RA, which have identified factors that support the early diagnosis of RA among patients presenting with inflammatory arthritis [14]. These criteria are directed at the recognition of patients with early arthritis who are most likely to develop progressive and erosive disease. The diagnosis and differential diagnosis of RA are reviewed in detail elsewhere. (See "Diagnosis and differential diagnosis of rheumatoid arthritis" and "Clinical manifestations of rheumatoid arthritis".)
Care by a rheumatologist — An expert in the treatment of rheumatic diseases, such as a rheumatologist, should participate in the care of patients with inflammatory arthritis who are suspected of having RA and in the ongoing care of patients diagnosed with this condition [4,15]. The early and ongoing care of patients with RA by a rheumatologist is associated with better disease outcomes compared with care rendered primarily by other clinicians [16-20].
As an example, in one study of 598 patients from an early arthritis cohort (symptoms for less than two years), those in whom assessment by a rheumatologist had been delayed at least 12 weeks from symptom onset, compared with those evaluated within less than 12 weeks, were significantly more likely not to achieve DMARD-free remission (hazard ratio 1.87, 95% CI 1.18-2.99) and had a significantly higher rate of joint destruction (calculated as 1.34-fold greater) over six years of follow-up [21].
The initial rheumatology consultation allows the diagnosis to be made or reassessed, the severity of disease to be estimated, and a plan of care to be developed and initiated. The frequency of subsequent specialist care depends upon the severity of symptoms and joint inflammation, upon the patient’s response to treatment, upon the complexity and risks associated with the therapy, and upon the preferences of the patient and primary care clinician.
NONPHARMACOLOGIC AND PREVENTIVE THERAPIES — A number of nonpharmacologic measures and other medical interventions are important in the comprehensive management of rheumatoid arthritis (RA) in all stages of disease, in addition to antiinflammatory and antirheumatic drug therapies. Patient education that addresses issues related to the disease and its management is indicated for all patients with RA. Attention to health promotion and specific strategies aimed at minimizing the adverse effects of RA and of agents used to treat it are also appropriate. These therapies are discussed in detail elsewhere. (See "Nonpharmacologic therapies and preventive measures for patients with rheumatoid arthritis".)
Briefly, these measures include:
●Patient education
●Psychosocial interventions
●Rest, exercise, and physical and occupational therapy
●Nutritional and dietary counseling
●Interventions to reduce risks of cardiovascular disease, including smoking cessation, and of osteoporosis
●Immunizations to decrease risk of infectious complications of immunosuppressive therapies
PHARMACOLOGIC THERAPY
Pretreatment evaluation — Prior to starting, resuming, or significantly increasing therapy with nonbiologic or biologic disease-modifying antirheumatic drugs (DMARDs), we do the following baseline studies [1]:
●General testing for all patients — We obtain a baseline complete blood count, serum creatinine, aminotransferases, erythrocyte sedimentation rate (ESR), and C-reactive protein (CRP) in all patients.
●Serologic testing for hepatitis prior to methotrexate, leflunomide, or biologic DMARDs – Patients should be screened for hepatitis B with testing for hepatitis B virus (HBV) surface antigen and HBV core antibody prior to initiating DMARD (conventional or biologic) therapy and prior to treatment with prednisone at doses of ≥20 mg daily. All patients at increased risk of hepatitis, such as those who have a history of intravenous drug abuse, those who have had multiple sex partners in the previous six months, and those who are healthcare workers, should be screened for hepatitis C before starting these medications [1]. Some experts, including the authors, prefer to screen for hepatitis B and C in all patients without a known history of hepatitis before initiating therapy with these medications. Some patients may require antiviral treatment prior to initiating DMARD or immunosuppressive therapy, depending upon their level of risk for HBV reactivation. (See "Hepatitis B virus reactivation associated with immunosuppressive therapy".)
●Ophthalmologic screening for hydroxychloroquine use – A complete baseline ophthalmologic examination should be performed within the first year of treatment, including examination of the retina through a dilated pupil and automated visual field testing. (See "Antimalarial drugs in the treatment of rheumatic disease", section on 'Monitoring for toxicity'.)
●Testing for latent tuberculosis – We screen for latent tuberculosis (TB), consistent with the US Centers for Disease Control (CDC) and 2008 American College of Rheumatology (ACR) guidelines, with skin testing or an interferon-gamma release assay prior to all biologic DMARDs and prior to use of the Janus kinase inhibitor, tofacitinib; such screening is based upon evidence that these medications, including the tumor necrosis factor (TNF) inhibitors, other biologics, and tofacitinib, may increase the risk of mycobacterial infection [1,22,23].

We also screen for latent TB in patients about to receive methotrexate (MTX), but some experts do not perform testing in such patients, given the lack of sufficient evidence to document the benefit of this approach. A possible exception is rituximab, since there is no clear evidence of an increased risk of TB with this agent [24]. We obtain a chest radiograph in patients with a history of other risk factors for latent TB, even if screening tests are negative, given the risks of false-negative testing. Additionally, skin testing should be repeated in patients with new TB exposures. Glucocorticoids and other factors may cause false-negative results. Screening for latent TB is discussed in detail separately. (See "Tumor necrosis factor-alpha inhibitors and mycobacterial infections" and "Diagnosis of latent tuberculosis infection (tuberculosis screening) in HIV-uninfected adults".)

Interferon-gamma release assays can be used in place of tuberculin skin testing in the United States, according to CDC recommendations, and may be preferred in patients who have previously received vaccination with Bacillus Calmette-Guerin (BCG). However, in some countries, tuberculin skin testing is preferred. (See "Interferon-gamma release assays for diagnosis of latent tuberculosis infection".)
Choice of therapy — Choices between treatment options are based upon multiple factors, including:
●Level of disease activity (eg, mild versus moderate to severe)
●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)
A combination of the following types of therapies may be used:
●Rapidly acting antiinflammatory medications, including nonsteroidal antiinflammatory drugs (NSAIDs) and systemic and intraarticular glucocorticoids. (See 'Adjunctive role of antiinflammatory agents' below.)
●Disease-modifying antirheumatic drugs (DMARDs), including nonbiologic (traditional small molecule or synthetic) and biologic DMARDs, and an orally-administered small molecule kinase inhibitor, which all have the potential to reduce or prevent joint damage and to preserve joint integrity and function. (See "Overview of immunosuppressive and conventional (non-biologic) disease-modifying drugs in the rheumatic diseases".)

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

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

Targeted synthetic DMARDs, including several kinase inhibitors, are in development for use in rheumatoid arthritis (RA); one of these, tofacitinib, is available for such clinical use in the United States and several other countries. Tofacitinib is an orally-administered small molecule DMARD that inhibits cytokine and growth factor signalling through interference with Janus kinases. (See "Cytokine networks in rheumatic diseases: Implications for therapy", section on 'JAK inhibition'.)
Early use of DMARDs — We recommend that all patients diagnosed with RA be started on disease-modifying antirheumatic drug (DMARD) therapy as soon as possible. The choice of initial drug therapy depends in large part upon the degree of disease activity. We distinguish between those patients with mildly active disease and the majority of patients with more active disease. Our choice of drug therapies in patients with RA and the evidence supporting these choices is described in detail separately. Briefly, we take the following approach (see 'Assessment of disease activity' below):
●In patients with mildly active RA, we initiate antiinflammatory therapy with a NSAID for rapid symptomatic relief and begin DMARD treatment with either hydroxychloroquine (HCQ) or sulfasalazine (SSZ). (See "Initial treatment of mildly active rheumatoid arthritis in adults".)
●In patients with moderately to severely active RA, we initiate antiinflammatory therapy with either a NSAID or glucocorticoid, depending upon the degree of disease activity, and generally start DMARD therapy with methotrexate (MTX). (See "Initial treatment of moderately to severely active rheumatoid arthritis in adults".)
●In patients resistant to initial DMARD therapy (eg, MTX), we treat with a combination of DMARDs (eg, MTX plus either a TNF inhibitor or SSZ and HCQ) or, alternatively, we switch the patient to a different DMARD of potentially comparable efficacy (eg, leflunomide or a TNF inhibitor), while also treating the active inflammation with antiinflammatory drug therapy. (See "Treatment of rheumatoid arthritis in adults resistant to initial nonbiologic DMARD therapy".)
Much of the joint damage that ultimately results in disability begins early in the course of the disease [25,26]. As an example, more than 80 percent of patients with RA of less than two years’ duration had joint space narrowing on plain radiographs of the hands and wrists, while two-thirds had erosions [26]. The use of more sensitive imaging techniques, such as magnetic resonance imaging (MRI) and high resolution ultrasonography, can identify even earlier damage than that which is recognized by radiography, although the prognostic implications of such findings are unknown [27-29].
Better outcomes are achieved by early compared with delayed intervention with DMARDs in patients with RA [12,30-35]. As an example, one study in Texas found that low socioeconomic status was associated with a significant delay in starting DMARD therapy; both factors were independently associated with greater disease activity, joint damage, and physical disability [35]. Some evidence suggests that the effect upon outcomes is not linear with time, but that there may be an early “window of opportunity” for optimal DMARD treatment benefit [36]. As examples:
●The effect of symptom duration prior to DMARD therapy on the likelihood of DMARD-free sustained remission was examined during five years of follow-up in patients with RA from two cohorts, the Leiden Early Arthritis Clinic (EAC, n = 738) and Evaluation et Suivi de POlyarthrites Indifferenciées Récentes (ESPOIR, n = 533) [36]. Remission was maintained in 11.5 and 5.4 percent of patients from the two cohorts, respectively. The symptom durations that optimally discriminated between greater and lesser likelihood of remission were between 11.4 and 19.1 weeks, depending upon the cohort and whether or not patients were ACPA-positive, suggesting there is a limited period of several months following symptom onset during which RA is most susceptible to intervention with DMARDs.
●An observational study of 1435 patients involved in 14 trials, primarily of MTX or other nonbiologic DMARDs, found a progressive decrease over time in the likelihood of a significant response to DMARD therapy. Response rates were higher in patients with no more than one year of disease than in those with one to two years of disease, and response rates were lowest in the group with greater than 10 years of disease (53 versus 43 versus 35 percent) [30].
●A further observational study comparing very early (median disease duration of three months) with late early (median disease duration of 12 months) initiation of nonbiologic (traditional) DMARD therapy showed significantly greater improvement in disease activity in the very early group within three months after starting DMARDs; the greater degree of improvement in the very early treatment group remained statistically and clinically significant after 36 weeks of DMARD therapy (Disease Activity Score for 28 joints [DAS28] improvement of 2.8 versus 1.7) [32].
●Another study found that the combination of MTX with etanercept was more effective upon evaluation after one year of treatment in patients begun on therapy less than four months after diagnosis compared with those begun on therapy from four months to two years after diagnosis (DAS28 remission rates of 70 versus 48 percent) [34].
ASSESSMENT AND MONITORING — Patients should be seen on a regular basis for clinical evaluation and monitoring of clinical and laboratory assessment of disease activity and for screening for drug toxicities. The initial evaluation and subsequent monitoring should also include periodic assessment of disease activity using a quantitative composite measure of disease activity. (See 'Assessment of disease activity' below.)
Additionally, the ongoing evaluation and monitoring of patients with rheumatoid arthritis (RA) following the initiation of therapy also involves:
●Patient and clinician assessment of symptoms and functional status (see 'Symptoms and functional status' below)
●Evaluation of joint involvement and extraarticular manifestations (see 'Physical examination' below)
●Laboratory markers (see 'Laboratory monitoring of disease activity' below and 'Monitoring and prevention of drug toxicity' below)
●Imaging (see 'Imaging' below)
Assessment of disease activity — Disease activity should be evaluated initially and at all subsequent visits. We recommend that a structured assessment of disease activity using a composite measure, such as those described here, should be performed initially, and most patients should be seen at least every three months to monitor the response to therapy using the same measure. Adjustments to treatment regimens should be made to quickly achieve and maintain control of disease activity if targeted treatment goals (remission or low disease activity), rather than an undefined degree of improvement, have not been achieved. (See "Assessment of rheumatoid arthritis activity in clinical trials and clinical practice", section on 'Composite indices for disease activity assessment' and 'Tight control' below.)
The initial assessment, made once the diagnosis is established, helps to distinguish the smaller group of patients who present with mild disease from the majority of patients who present with moderately to severely active disease and who are usually treated initially with methotrexate. (See "Initial treatment of mildly active rheumatoid arthritis in adults" and "Initial treatment of moderately to severely active rheumatoid arthritis in adults".)
The use of periodic structured assessments of disease activity is complementary to ongoing regular monitoring of disease manifestations, disease progression, joint injury, disability, and complications of the disease and to monitoring for adverse effects of medications. (See 'Assessment and monitoring' above.)
Multiple composite measures employing different combinations and weighting of these variables have been developed for use in clinical research and practice. Among the greater than 60 activity measures available for evaluation of patients with RA, the six measures noted below have been identified by the American College of Rheumatology (ACR) as having the greatest utility in clinical practice because they accurately reflect disease activity; are sensitive to change; discriminate well between low, moderate, and high disease activity; have remission criteria; and are feasible to perform in clinical settings [37]. The choice of measure is based upon clinician preference; some measures require both patient and clinician input, while others are based only upon patient-reported data. (See "Assessment of rheumatoid arthritis activity in clinical trials and clinical practice", section on 'Composite indices for disease activity assessment'.)
Measures that require both patient and clinician input, as well as calculators for these measures, include the following:
●The Disease Activity Score derivative for 28 joints (DAS28) (calculator 1)
●The Simplified Disease Activity Index (SDAI) (calculator 2)
●The Clinical Disease Activity Index (CDAI) (calculator 3)
The patient-reported outcome measures include:
●The Routine Assessment of Patient Index Data 3 (RAPID3) [38]
●The Patient Activity Scale (PAS) and PAS-II [39]
The RAPID3 correlates well with the results obtained by use of the DAS28 or CDAI [38]. (See "Assessment of rheumatoid arthritis activity in clinical trials and clinical practice", section on 'RAPID3 score'.)
Symptoms and functional status — The clinical assessment of disease activity should include questions concerning the degree of joint pain, the duration of morning stiffness, and the severity of fatigue [1,40]. In addition, evidence for and changes in extraarticular manifestations of RA should be actively sought, including systemic signs such as fever, anorexia, malaise, weight loss, and symptoms of cardiovascular disease. (See "Clinical manifestations of rheumatoid arthritis".)
Fever is not a common feature of RA in adults. Infection must be excluded before ascribing fever to RA.
Patients should be queried regarding their functional capacity, including the performance of activities of daily living, of vocational activities, and of avocational activities, such as hobbies or participation in sports. A self-report questionnaire that measures function can also be often helpful for this purpose. The Stanford Health Assessment Questionnaire (HAQ) is one of the best known and tested of these questionnaires [41,42]; others include the Functional Independence Measure [43], the Arthritis Impact Measurement Scale (AIMS), the Short Form 36 (SF36), and the Modified Health Assessment Questionnaire (MHAQ) [44]. (See "Disease outcome and functional capacity in rheumatoid arthritis", section on 'Functional capacity'.)
We use the evaluation of functional capacity to identify which of a variety of interventions may be required in addition to pharmacologic therapy, especially in patients with diminished functional capacity, such as counseling, exercise, and occupational therapy. (See "Nonpharmacologic therapies and preventive measures for patients with rheumatoid arthritis".)
Physical examination — A physical examination should be performed at regular intervals that vary with disease activity and severity. As an example, patients with severely active disease may be seen at four-week intervals, while those with mildly active or well-controlled disease could be seen every two to four months. At these visits, an examination should be performed to assess changes in previously affected joints or the appearance of inflammation in previously uninvolved joints.
A 28 joint examination is appropriate if the hands but not the feet are involved [45]. Examined joints include the wrists, elbows, shoulders, and knees, as well as the metacarpophalangeal and proximal interphalangeal joints of the hands. If the feet are involved, the metatarsophalangeal joints and proximal interphalangeal (PIP) joints of the feet should also be assessed. The joints should be evaluated for the presence of swelling, tenderness, loss of motion, and deformity.
In addition to the articular examination, a periodic general physical examination should be performed, with particular attention to the skin for rheumatoid nodules or other dermal manifestations of RA and to the lungs for signs of pleural or interstitial disease, to detect evidence of systemic or extraarticular involvement. (See "Overview of the systemic and nonarticular manifestations of rheumatoid arthritis".)
Laboratory monitoring of disease activity — The acute phase reactants, such as C-reactive protein (CRP) or erythrocyte sedimentation rate (ESR), are useful for assessment of disease activity and are components of several of the formal composite measures used for evaluating the level of disease activity. In addition to these studies, we obtain other tests primarily for medication monitoring that may also reflect changes or levels of disease activity. Examples of the latter include serum hemoglobin, decreases in which may reflect anemia of chronic inflammation, and serum albumin, which may also be reduced in association with increased disease activity. Additionally, platelet counts may be mildly elevated (typically up to 400,000 to 450,000/microL) in patients with ongoing inflammation. (See 'Pretreatment evaluation' above and "Assessment of rheumatoid arthritis activity in clinical trials and clinical practice", section on 'Acute phase reactants' and "Acute phase reactants" and "Biologic markers in the diagnosis and assessment of rheumatoid arthritis" and "Anemia of chronic disease/inflammation" and "Hematologic manifestations of rheumatoid arthritis".)
Monitoring and prevention of drug toxicity — Because of the potential risks of serious adverse effects and the frequency of common side effects of antirheumatic drugs, a careful balance must be struck between the risks and potential benefits of these agents [46,47]. We generally follow the recommendations of the American College of Rheumatology (ACR) for drug monitoring in the treatment of RA (table 1) [1,40,48]. Additional precautions, warnings, and the manufacturer’s recommendations for clinical and laboratory monitoring are provided in the individual UpToDate drug information topics for each medication. (See appropriate topic reviews.)
Monitoring for adverse effects, such as osteoporosis, diabetes, and hypertension, should be performed in patients on glucocorticoids, and appropriate preventive measures should be undertaken. RA is considered an independent risk factor for osteoporotic fracture, and a fracture risk assessment should be performed to help guide treatment decisions. (See "Prevention and treatment of glucocorticoid-induced osteoporosis" and "Osteoporotic fracture risk assessment", section on 'Assessment of fracture risk' and "Major side effects of systemic glucocorticoids" and "Antimalarial drugs in the treatment of rheumatic disease", section on 'Monitoring for toxicity' and "Leflunomide in the treatment of rheumatoid arthritis", section on 'Liver'.)
Imaging — Early in the course of RA, it is appropriate to obtain plain radiographs of the hands and wrists (one film, postero-anterior [PA] view), as well as at least one anterio-posterior (AP) view of both forefeet to include the metatarsophalangeal joints. These radiographs serve as a baseline for evaluating change in the joints during treatment. Radiographs should be repeated every two years in patients in remission or with low disease activity. We view the therapy in use by the patient as insufficient if radiologic evidence of disease progression, such as periarticular osteopenia, joint space narrowing, or bone erosions, appears or worsens during this interval, despite good control of disease activity by other measures. In such patients, based upon our clinical experience, we may intensify or modify the treatment regimen. The clinician must be aware that, in hand radiographs of older patients, coexistent osteoarthritis may account, in part, for joint space narrowing noted near the joints involved with RA [49].
Computerized tomographic (CT) scanning, ultrasonography, computerized image analysis, and magnetic resonance imaging (MRI) are more sensitive for the detection of cartilage and bone abnormalities, and their role in the process of making therapeutic decisions is under investigation [27,50,51]. We do not use these techniques for routine clinical assessment.
TIGHT CONTROL — We recommend the use of tight control treatment strategies to quickly minimize inflammation and disease progression; our therapeutic target is remission or a state of minimal disease activity, without compromising safety. In patients resistant to initial disease-modifying antirheumatic drug (DMARD) therapy, we either add additional DMARDs to the ongoing regimen or switch the patient to a different DMARD, while also treating the active inflammation with antiinflammatory drug therapy. A description of our treatment approach and the evidence supporting use of particular medications in patients with active disease despite initial DMARD therapy are discussed in detail separately. (See 'Drug therapy for flares' below and "Treatment of rheumatoid arthritis in adults resistant to initial nonbiologic DMARD therapy".)
In patients with disease exacerbations despite a preceding period of better control of disease activity (a “disease flare”), a temporary increase in antiinflammatory therapies, including the use of glucocorticoids, may be required. (See 'Drug therapy for flares' below.)
The use of strategies for tight control involves frequent periodic reassessment of disease activity, usually at least every three months; adjustment of DMARD regimens every three to six months, if needed, as the primary tool to achieve treatment goals; and administration of antiinflammatory therapies (eg, nonsteroidal antiinflammatory drugs [NSAIDs] and oral and intraarticular glucocorticoids) as an adjunct to DMARDs to maintain control of disease activity until DMARD therapies are sufficiently effective to discontinue glucocorticoids or to reduce their use to an acceptably low level. Treatment protocols based upon this general approach are associated with improved radiographic and functional outcomes compared with less aggressive approaches [7,52-61].
The periodic reevaluation of disease activity using a quantitative composite measure and the use of antiinflammatory drugs, including nonsteroidal antiinflammatory drugs and glucocorticoids, as bridging therapies are both important elements in the strategy of tight control. Glucocorticoids can rapidly achieve control of inflammation until disease-modifying antirheumatic drugs (DMARDs) are sufficiently effective. (See 'Assessment of disease activity' above and "Assessment of rheumatoid arthritis activity in clinical trials and clinical practice" and 'Adjunctive role of antiinflammatory agents' below.)
Taken together, studies that have compared tight control with less aggressive approaches support the following observations:
●Most patients should receive a DMARD as soon as possible after diagnosis. Achieving and maintaining low disease activity using a DMARD or DMARD combinations as quickly as possible improve long-term outcomes and are cost-effective compared with older, more gradual approaches to initiating DMARD therapy. (See 'Early use of DMARDs' above.)
●Excellent treatment responses can be achieved with a wide variety of nonbiologic and biologic DMARDs and with regimens that combine either nonbiologic DMARDs alone or nonbiologic DMARDs with a biologic agent, as described below.
●Escalation in the treatment regimen is needed for patients resistant to initial treatment; both intraarticular glucocorticoids and oral or intramuscular glucocorticoids help minimize disease activity until DMARDs are sufficient. (See 'Adjunctive role of antiinflammatory agents' below.)
●Regular assessment with composite measures of disease activity is critical to optimize clinical decision-making. (See 'Assessment of disease activity' above.)
These observations are reflected in the 2008, 2012, and 2015 American College of Rheumatology (ACR) and 2010 European League Against Rheumatism (EULAR) treatment recommendations and in the recommendations of an international task force that were presented in 2010 and updated in 2014 [1-4,7,61-64].
The benefits of tight control have been shown in a meta-analysis of six heterogeneous trials that evaluated tight control strategies in comparison with usual care for rheumatoid arthritis (RA) [65]. Significantly greater improvement from baseline to one year in the DAS28 composite measure of disease activity was seen in the patients randomly allocated to tight control strategies compared with usual care (mean difference in reduction in DAS28 of 0.59, 95% CI 0.22-0.97). A statistically significantly greater reduction compared with usual care was observed in the trials in which tight control was achieved with protocolized treatment adjustments compared with trials without such protocols (mean difference in DAS28 of 0.91, 95% CI 0.72-1.11, versus 0.25, 95% CI 0.03-0.46). Four of the six studies analyzed compared functional ability in the two treatment arms using the Health Assessment Questionnaire (HAQ). Greater improvement in HAQ scores in the tight control groups that were statistically significant were seen in two of these trials, while improvements in the HAQ scores did not differ significantly between the treatment arms in the other two trials. (See "Assessment of rheumatoid arthritis activity in clinical trials and clinical practice", section on 'Health Assessment Questionnaire (HAQ)'.)
The following trials and related studies best illustrate the range of medications and approaches that support these conclusions [52-58,66]:
●BeSt trial – In the Behandel-Strategieën voor Reumatoide Artritis (Dutch for “treatment strategies for rheumatoid arthritis” or BeSt) trial, 508 patients with early active RA were randomly assigned to sequential monotherapy (group one), to initial monotherapy with step-up combination therapy as required (group two), to combination therapy plus high-dose prednisone (group three), or to combination therapy including infliximab (group four) [52,53]. Regimens in this trial were adjusted in all groups based upon assessment of disease activity every three months. The next intervention in the defined sequence was assigned if the DAS44 score was >2.4. The treatment sequence in each group was:
•Group one (sequential monotherapy) – Initially methotrexate (MTX) 15 mg weekly, followed, if needed, by switching sequentially to MTX 25 to 30 mg weekly, sulfasalazine (SSZ), leflunomide (LEF), MTX plus infliximab, gold plus methylprednisolone, and MTX plus cyclosporine A (CSA) and prednisone.
•Group two (step-up combination therapy) – Initially MTX 15 mg weekly, followed, if needed, by increasing MTX to 25 to 30 mg weekly, adding SSZ, adding hydroxychloroquine (HCQ), adding prednisone, and switching to MTX plus infliximab, to MTX plus CSA and prednisone, and to LEF.
•Group three (initial combination therapy with prednisone) – Combination of MTX 7.5 mg weekly plus SSZ and prednisone (60 mg daily tapered gradually to 7.5 mg daily), then MTX 25 to 30 mg weekly plus SSZ and prednisone, MTX plus CSA and prednisone, MTX plus infliximab, LEF, gold plus methylprednisolone, and azathioprine plus prednisone.
•Group four (initial combination therapy) – MTX 25 to 30 mg weekly plus infliximab (3 mg/kg per infusion), MTX plus infliximab (6 mg/kg), MTX plus infliximab (7.5 mg/kg), MTX plus infliximab (10 mg/kg), then SSZ monotherapy, LEF monotherapy, MTX plus CSA and prednisone, gold plus methylprednisolone, and azathioprine plus prednisone.
•At 3 and 12 months, functional improvement was significantly better in those who received initial combination therapy (groups three and four). Significantly less radiographic progression was observed at two and four years in the combination groups compared with the initial monotherapy groups [53,59]. Remission at four years was achieved in 43 percent of all patients, and drug-free remission was seen in 13 percent.
●FIN-RACo and NEO-RACo trials
•FIN-RACo – The Finnish Rheumatoid Arthritis Combination Therapy (FIN-RACo) trial evaluated the outcomes of 199 patients randomly assigned for at least two years to monotherapy (initially SSZ 2 g daily) and then sequentially switched every three months, if criteria for an inadequate response were met, to SSZ (3 g daily), MTX (7.5 to 15 mg weekly), azathioprine, auranofin, hydroxychloroquine, injectable gold, penicillamine, or podophyllotoxin (which could be used alternatively after azathioprine), respectively, or to combination therapy (SSZ, MTX, hydroxychloroquine [HCQ], and prednisolone, with dose adjustment at three months based upon criteria for active disease and with subsequent dose adjustments as needed within defined limits) [55-57].

The treatment target after the first two years remained remission, but medication choices were not restricted. At follow-up at 11 years following the initial randomization, a significantly greater proportion of patients in the initial combination group had achieved minimal disease activity (63 versus 43 percent) and remission by ACR criteria (37 versus 19 percent) [57]. Additionally, radiographic progression at 11 years was significantly less in the group receiving initial combination therapy compared with the group on monotherapy for at least two years (increase in Larsen score of 17, 95% CI 12-26, versus 27, 95% CI 22-33) [66].
•NEO-RACo – Biologic agents may not add further benefit in most patients who achieve very tight control with traditional DMARDs. In patients with early RA (symptoms for less than one year), tighter control than that accomplished by the FIN-RACo regimen was achieved in the NEO-RACo trial. This was accomplished by intensification of the FIN-RACo regimen, by more rapid escalation of the MTX dose to a target of MTX 25 mg weekly, combined with SSZ 2 g daily, HCQ 35 mg/kg in total per week, and prednisone 7.5 mg daily [67]. This regimen resulted in high rates of clinical remission and minimal joint damage at two years. At two years, there was less radiologic progression in patients randomly assigned to also receive infliximab (3mg/kg) during the first six months of therapy. After two years, the patients were followed off protocol; although the goal of therapy remained strict ACR remission. At five-year follow-up, it was found that the initial period of infliximab therapy did not improve the clinical and radiographic outcomes compared with the group initially treated with the intensified FIN-RACo regimen without a biologic agent [68]. Few patients in either group received a biologic agent between years two and five. It is not clear whether as needed use of intraarticular glucocorticoids, which was allowed by the treatment protocols, significantly affected the outcomes.
●TICORA trial – In the Tight Control of Rheumatoid Arthritis (TICORA) trial, 111 patients were randomly assigned to intensive or routine management [58]. Intensively-managed patients in this trial had monthly visits, with calculation of disease activity scores (a validated composite score based upon the erythrocyte sedimentation rate, Ritchie articular index, joint swelling count, and patients’ global assessment of disease activity defining high, moderate, and low disease activity levels of ≥3.6, of ≥2.4 to <3.6, and of ≥1.6 to <2.4, respectively); glucocorticoid injections of swollen joints; and, every three months, adjustment of their treatment regimen by a predefined protocol if moderate or highly active disease was present. Routinely managed patients were seen every three months, with no formal measurement of disease activity performed, and glucocorticoid injections and other treatment adjustments were made at the discretion of the rheumatologist.

After 18 months, the patients receiving intensive management demonstrated a significantly greater decrease in their disease activity scores compared with the routine management group (-3.5 versus -1.9), and a higher proportion achieved a good response by European League Against Rheumatism criteria (82 versus 44 percent). Additionally, physical function assessed by the HAQ was improved to a statistically and clinically significantly greater degree in the patients receiving intensive management (change in HAQ of -0.97 versus -0.47).
Adjunctive role of antiinflammatory agents — We use antiinflammatory therapies, including systemic and intraarticular glucocorticoids and nonsteroidal antiinflammatory drugs (NSAIDs), primarily as adjuncts for temporary control of disease activity in patients in whom treatment is being started with disease-modifying antirheumatic drugs (DMARDs), in patients in whom the DMARD regimen requires modification, or in patients who are experiencing disease flares. Although NSAIDs and/orglucocorticoids act rapidly to control inflammation, they do not provide adequate benefit on their own for longer-term control of disease or for prevention of joint injury. More detailed discussions of NSAID and glucocorticoids in RA are presented elsewhere. (See "Use of glucocorticoids in the treatment of rheumatoid arthritis" and "Initial treatment of mildly active rheumatoid arthritis in adults", section on 'Symptomatic treatment'.)
In patients who receive glucocorticoids, we taper the medication as rapidly as tolerated once disease control is achieved and can be maintained, with the ideal goal of discontinuing systemic glucocorticoid therapy.
Intraarticular injections of long-acting glucocorticoids (eg, triamcinolone hexacetonide) 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?".)
There is strong evidence that glucocorticoids retard radiographic progression in patients with RA in the short to medium term (ie, up to two years of therapy) [69-71]. However, these agents should not be used alone for an extended period. We avoid long-term use, if possible, because chronic use for inflammatory disease is often associated with adverse effects [72]. However, patients with severe RA sometimes require sustained therapy with low doses of glucocorticoids (less than 10mg/day); such doses in RA are generally well-tolerated and may have some benefit in retarding disease progression [71,73]. (See "Use of glucocorticoids in the treatment of rheumatoid arthritis", section on 'Efficacy of chronic use'.)
Drug therapy for flares — RA has natural exacerbations (also known as flares) and reductions of continuing disease activity. It is important to distinguish a disease flare, characterized by symptoms and by physical and laboratory findings of increased inflammatory synovitis, from noninflammatory causes of local or generalized increased pain. Patients with recurrent flares may require adjustment in the background DMARD therapy. (See "Clinical manifestations of rheumatoid arthritis" and 'Assessment of disease activity' above.)
The severity of the flare and background drug therapy influence the choice of therapies. The following is a brief summary of glucocorticoid therapy, which is discussed in detail separately. (See "Use of glucocorticoids in the treatment of rheumatoid arthritis".)
With respect to the severity of the flare:
●In patients with a single or few affected joints, intraarticular glucocorticoid injections may be effective and avoid the need for additional or prolonged systemic therapy.
●More widespread flares may be treated by initiating glucocorticoid therapy or by increasing the dose of oral glucocorticoid, with the intention of reducing the dose once the flare is under control. The magnitude of dose increase varies with the baseline dose and with the severity of the flare. An alternative to an increase in the oral dose is the administration of a single deep intramuscular injection of methylprednisolone acetate (120 mg in 3 mL), which is available in the United Kingdom (UK) and other European countries.
●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:
●Patients on methotrexate (MTX) who will tolerate a slower resolution of their flare may respond to an increase in the dose of MTX or to a switch from oral to subcutaneous therapy [74].
●Patients initially controlled with a regimen that includes infliximab may benefit from a decrease in the interval of infliximab dosing or from higher doses [75,76]. However, increasing the dose from 3 to 5 mg/kg was not beneficial in one well-designed trial [77,78].
●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 [79,80].
Patients who require multiple treatment courses with glucocorticoids for recurrent disease flares and whose medication doses have been increased to the maximally tolerated or acceptable level should be treated as patients with sustained disease activity. (See "Treatment of rheumatoid arthritis in adults resistant to initial nonbiologic DMARD therapy".)
OTHER CONSIDERATIONS IN RA MANAGEMENT — The focus of therapeutic decision-making is control of disease activity, as described above, but additional factors, such as the degree of joint injury or disability, may influence the choice of specific therapies in individual patients [3,8]. Additionally, the efficacy of particular medications may be affected by the presence or absence of some of these factors, which are associated with an adverse prognosis. (See 'Prognosis' below.)
The relative importance of these factors depends upon the individual treatment choice; these are discussed in more detail in the appropriate individual treatment topics. We consider the following factors, depending upon the specific treatment decision:
●Disability and function – General scales that measure disability may not identify specific limitations of greater impact on an individual patient. As an example, specific vocational requirements, family responsibilities, or recreational interests may affect a patient’s willingness to accept the risks of a given intervention that would help to achieve a greater degree of disease control than low disease activity. We therefore incorporate patient-specific needs in our assessment of the severity of disease-related disability.
●Joint injury – Good control of disease activity may not result in complete elimination of progressive joint injury in all patients. In patients with low disease activity but with worsening findings on imaging studies, either changes in medications or increased dosing may be of benefit. However, there is insufficient evidence to determine whether treating to targets that are based upon imaging findings provides additional benefit for long-term outcomes, compared with targets based upon measures of disease activity alone.
●Comorbidities – The presence of comorbidities, such as renal or hepatic disease, may affect medication choices and may influence the degree of risk inherent in attempting to reach a goal of remission or of low disease activity in a given patient.
Comorbidities — A number of medical conditions that often coexist with or result from rheumatoid arthritis (RA) may influence the choice of medications [1,2,81]. (See appropriate treatment and drug information topics.)
Pregnancy — RA often improves or remits completely during pregnancy. Issues related to the pregnant woman with RA, including the use of immunosuppressive drugs, are discussed separately. (See "Rheumatoid arthritis and pregnancy" and "Use of antiinflammatory and immunosuppressive drugs in rheumatic diseases during pregnancy and lactation".)
Lung disease — Comorbid pulmonary disease is common in patients with RA and may also be a complication of therapy or of the disease [81]. Therapeutic agents with potential for causing adverse pulmonary effects include methotrexate, leflunomide, tumor necrosis factor (TNF) inhibitors, sulfasalazine, parenteral gold, abatacept, and rituximab. (See "Overview of lung disease associated with rheumatoid arthritis".)
Cardiovascular disease — Comorbid cardiovascular disease can occur in patients with RA and may also be a complication of therapy [81]. Both glucocorticoids and nonsteroidal antiinflammatory drugs (NSAIDs) may increase cardiovascular risk. TNF inhibitors should be avoided in patients with moderate or severe heart failure (HF), as they can worsen HF. Active RA is associated with an increased risk of cardiovascular disease, but good control of disease activity has been associated with reduced cardiovascular complications. (See "Coronary artery disease in rheumatoid arthritis: Pathogenesis, risk factors, clinical manifestations, and diagnostic implications" and "Coronary artery disease in rheumatoid arthritis: Implications for prevention and management" and "Major side effects of systemic glucocorticoids", section on 'Cardiovascular disease' and "Nonselective NSAIDs: Overview of adverse effects", section on 'Cardiovascular effects' and "Tumor necrosis factor-alpha inhibitors: An overview of adverse effects", section on 'Heart failure'.)
Neurologic manifestations — Neurologic manifestations of RA and the presence of coexistent neurologic disease are generally uncommon, other than the occurrence of impingement neuropathies such as carpal tunnel syndrome. However, TNF inhibitors should be avoided in those with a history of or with 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 [81]. (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 [81]. In contrast, patients being treated with hydroxychloroquine or with TNF inhibitors for RA have a lower risk of diabetes [82], and sulfasalazine may have glucose-lowering effects [83]. (See "Major side effects of systemic glucocorticoids", section on 'Glucose metabolism' and "Antimalarial drugs in the treatment of rheumatic disease", section on 'Reduction of diabetes risk'.)
Renal disease — RA infrequently affects the kidney, but, if renal disease coexists, it increases mortality risk [81]. 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 disease-modifying antirheumatic drugs (DMARDs), particularly methotrexate and cyclosporine, should be avoided or used with particular caution in patients with significantly decreased renal function. (See "NSAIDs: Acute kidney injury (acute renal failure)" and "Causes and diagnosis of membranous nephropathy", section on 'Drugs, particularly penicillamine and gold' and "Cyclosporine and tacrolimus nephrotoxicity".)
Extraarticular disease — Rheumatoid arthritis has many extraarticular manifestations. The treatment of these specific features, such as vasculitis, interstitial lung disease, and others, is reviewed in detail elsewhere. (See "Overview of the systemic and nonarticular manifestations of rheumatoid arthritis" and "Treatment of rheumatoid vasculitis".)
Use of analgesics — Drugs that primarily or only provide analgesia, including topical medications (eg, capsaicin) and oral agents, such as acetaminophen (paracetamol), tramadol, and more potent opioids (eg, oxycodone, hydrocodone), have a limited role in most patients with active disease but may be helpful in patients with end-stage disease and, occasionally, in patients with more severe involvement or during disease flares for added temporary benefit. These medications should not be used as the sole or primary therapy in patients with active inflammatory disease. An additional concern regarding opioid analgesics is an increased risk of hospitalization for serious infection, which has been associated with their use by patients with RA and may be due to impairment of certain immune functions by these agents [84].
Apparent need for additional analgesic medications when inflammatory disease is well-controlled (other than acetaminophen or occasional NSAIDs) should prompt a search for alternative comorbid diagnoses, such as fibromyalgia, to explain the patient’s symptoms. (See "Clinical manifestations and diagnosis of fibromyalgia in adults".)
THERAPY OF END-STAGE DISEASE — Despite therapeutic intervention, some patients progress to disabling, destructive joint disease. Symptoms in such patients may be present in the absence of active inflammatory joint disease and may be due to the secondary degenerative changes alone. The accurate evaluation of such patients is essential since deterioration associated with mechanical problems of the muscle or joint is treated much differently from ongoing inflammation or systemic manifestations of rheumatoid arthritis (RA). Disease exacerbations and their systemic effects are usually easily recognized by the presence of many inflamed joints, fever, anemia, an elevated erythrocyte sedimentation rate (ESR), or an elevated serum C-reactive protein (CRP) concentration.
The goals of therapy in the patient with end-stage disease are:
●Pain relief
●Protection of remaining articular structures
●Maintenance of function
●Relief from fatigue and weakness
In the absence of inflammation, which requires antiinflammatory medications and disease-modifying antirheumatic drugs (DMARDs), treatments other than medications may be particularly important in management. These include nonpharmacologic interventions, such as physical and occupational therapy, use of adaptive devices, and surgery. (See "Evaluation and medical management of end-stage rheumatoid arthritis".)
The indications for surgical intervention in patients with RA include intractable pain or severe functional disability due to joint destruction, as well as impending tendon rupture. The timing of surgery is often critical. If one waits too long, there may be so much muscle atrophy from disuse that postoperative rehabilitation is unsuccessful. On the other hand, a decision about joint replacement should take into account the average life of the artificial joint. (See "Total joint replacement for severe rheumatoid arthritis".)
RECOMMENDATIONS BY MAJOR GROUPS — Recommendations for the management of patients with rheumatoid arthritis (RA) have been developed by major professional organizations, including the American College of Rheumatology (ACR) and the European League Against Rheumatism (EULAR) [1,2,4,5,64]. In addition, an international task force has developed recommendations for treating RA to targeted goals [3,7,61,63]. Our approach to treatment is generally consistent with these recommendations. The 2015 ACR recommendations and supporting documents can be accessed online.
The EULAR recommendations for the management of RA represent a European consensus on the management of RA with disease-modifying antirheumatic drugs (DMARDs) and glucocorticoids and on the strategies to reach optimal outcomes, based upon evidence and expert opinion [4,5]. The evidence used was detailed in a series of systematic literature reviews, and the recommendations were updated in 2013 [5,6,85-88]. The 2013 recommendations include three overarching principles for the care of patients with RA and a set of 14 recommendations covering major issues in disease management. The 2013 EULAR recommendations can be accessed online.
PROGNOSIS — Rheumatoid arthritis (RA) was associated with a high degree of economic loss, morbidity, and early mortality prior to the widespread use of methotrexate that began in the 1980s, to more aggressive treatment of early disease, and to the availability of targeted biologic agents since the later part of the 1990s. As an example, almost 20 percent of patients in one center were severely disabled after 20 years of follow-up (from 1967 to 1987); an additional one-third had died [89]. Patients with RA that required hospital care had at least a twofold increased mortality when compared with those without disease [90], and more severe RA was associated with higher mortality rates due to higher rates of myocardial infarction, infection, and certain malignancies, comparable to three vessel coronary artery disease or to stage IV Hodgkin lymphoma [91].
Clinical outcomes have improved significantly with changes in drug therapy and in the approach to treatment. These improvements have decreased the need for joint surgery and reduced disability in patients with RA. As an example, in a study involving data from 57 hospitals in Ireland, the number of total hip and knee joint arthroplasties in patients with RA decreased from 1995 to 2010, despite substantial increases in these procedures among the general population [92].
An analysis of 1007 patients with RA diagnosed between 1993 and 2011 in the Leiden Early Arthritis Clinic found that more intensive treatment strategies adopted over the years of study increased the chances for disease-modifying antirheumatic drug (DMARD)-free sustained remissions [93]. Moreover, those patients achieving DMARD-free remission had normal functional status when compared with the general population. The average level of disability in RA was found in a longitudinal study of over 3000 patients to have declined by about 40 percent from 1977 to 1998, even prior to the introduction of the biologic DMARDs [94]. Similarly, patients with RA seen in a single university clinic from 1984 through 1986 had significantly more disability and greater radiographic evidence of joint injury compared with a cohort from the same clinic seen from 1999 through 2001 (modified Health Assessment Questionnaire disability score on a 0 to 3 scale of 1 versus 0.4, respectively, and Larsen radiographic score on a 0 to 100 scale of 20 versus 3, respectively) [13]. Patients able to achieve remission with combination therapy had significantly less work disability over five years of follow-up compared with patients with incomplete responses to treatment [95]. (See "Disease outcome and functional capacity in rheumatoid arthritis".)
A number of factors have been associated with poorer outcomes in patients with RA. The following four markers of adverse prognosis can be used to identify patients who may require more aggressive pharmacotherapy, especially in early stages of disease [1]:
●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 [96]. Older age, female sex, and the presence of the shared epitope have also been associated with a poorer prognosis [1]. Some studies have derived models to estimate prognosis, such as persistent erosive disease [97]. However, these models have not been validated in other cohorts. The individual factors associated with a poor prognosis are discussed in detail separately. (See "Epidemiology of, risk factors for, and possible causes of rheumatoid arthritis" and "Disease outcome and functional capacity in rheumatoid arthritis" and "Biologic markers in the diagnosis and assessment of rheumatoid arthritis" and "Overview of the systemic and nonarticular manifestations of rheumatoid arthritis" and "HLA and other susceptibility genes in rheumatoid arthritis".)
INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, “The Basics” and “Beyond the Basics.” The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.
Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on “patient info” and the keyword(s) of interest.)
●Beyond the Basics topics (see "Patient information: Rheumatoid arthritis symptoms and diagnosis (Beyond the Basics)" and "Patient information: Rheumatoid arthritis treatment (Beyond the Basics)" and "Patient information: Disease-modifying antirheumatic drugs (DMARDs) (Beyond the Basics)" and "Patient information: Complementary and alternative therapies for rheumatoid arthritis (Beyond the Basics)")
SUMMARY AND RECOMMENDATIONS
●In patients with rheumatoid arthritis (RA), affected areas may be irreversibly damaged or destroyed if inflammation persists. Thus, prompt diagnosis, early recognition of active disease, and measures to quickly achieve and maintain control of inflammation and the underlying disease process, with the goal of remission or low disease activity, are central to modifying disease outcome. The application of these principles in the management of patients with RA, together with the development and use of newer and more potent drugs, has resulted in significant improvement in the outcomes of treatment. (See 'General principles' above and 'Early recognition and diagnosis' above.)
●An expert in the care of rheumatic disease, such as a rheumatologist, should participate in the care of patients suspected of having RA and in the ongoing care of patients diagnosed with this condition. The treatment of patients with RA by a rheumatologist is associated with better disease outcomes compared with care rendered primarily by other clinicians. (See 'Care by a rheumatologist' above.)
●Nonpharmacologic measures, such as patient education, psychosocial interventions, and physical and occupational therapy, should be used in addition to drug therapy. Other medical interventions that are important in the comprehensive management of RA in all stages of disease include cardiovascular risk reduction and immunizations to decrease the risk of complications of drug therapies. (See 'Nonpharmacologic and preventive therapies' above.)
●We recommend that all patients diagnosed with RA be started on disease-modifying antirheumatic drug (DMARD) therapy as soon as possible following diagnosis, rather than using antiinflammatory drugs alone, such as nonsteroidal antiinflammatory drugs (NSAIDs) and glucocorticoids (Grade 1B). Better outcomes are achieved by early compared with delayed intervention with DMARDs. (See 'Early use of DMARDs' above.)
●We recommend the use of tight control treatment strategies to guide adjustments in the treatment regimen, rather than less aggressive approaches (Grade 1B). Tight control involves reassessment of disease activity on a regularly planned basis with the use of quantitative composite measures and adjustment of treatment regimens to quickly achieve and maintain control of disease activity if targeted treatment goals (remission or low disease activity), rather than an undefined degree of improvement, have not been achieved. Such tight control treatment strategies are associated with improved radiographic and functional outcomes compared with less aggressive approaches. (See 'Tight control' above and 'Assessment of disease activity' above.)
●Laboratory testing prior to therapy should include a complete blood count, erythrocyte sedimentation rate, C-reactive protein, aminotransferases, blood urea nitrogen, and creatinine. Patients receiving hydroxychloroquine should have a baseline ophthalmologic examination, and most patients who will receive a biologic agent should be tested for latent tuberculosis infection. Screening for hepatitis B should be performed in all patients, and screening for hepatitis C should be performed in all patients at increased risk of hepatitis. Some patients may require antiviral treatment prior to initiating DMARD or immunosuppressive therapy, depending upon their level of risk for hepatitis B virus (HBV) reactivation. (See 'Pretreatment evaluation' above.)
●We use antiinflammatory drugs, including nonsteroidal antiinflammatory drugs and glucocorticoids, as bridging therapies to rapidly achieve control of inflammation until disease-modifying antirheumatic drugs are sufficiently effective. Some patients may benefit from longer-term therapy with low doses of glucocorticoids. (See 'Adjunctive role of antiinflammatory agents' above.)
●RA has natural exacerbations (also known as flares) and reductions of continuing disease activity. The severity of the flare and background drug therapy influence the choice of therapies. Patients who require multiple treatment courses with glucocorticoids for recurrent disease flares and whose medication doses have been increased to the maximally tolerated or acceptable level should be treated as patients with sustained disease activity. Such patients require modifications of their baseline drug therapies. (See 'Drug therapy for flares' above.)
●The monitoring that we perform on a regular basis includes testing that is specific to evaluation of the safety of the drugs being used; periodic assessments of disease activity with composite measures; monitoring for extraarticular manifestations of RA, other disease complications, and joint injury; and functional assessment. (See 'Assessment and monitoring' above.)
●Other factors in RA management that may influence the target or choice of therapy include the disabilities or functional limitations important to a given patient, progressive joint injury, comorbidities, and the presence of adverse prognostic factors. (See 'Other considerations in RA management' above and 'Prognosis' above.)