Initial treatment of rheumatoid arthritis in adults

INTRODUCTION — The treatment of rheumatoid arthritis (RA) is directed toward the control of synovitis and the prevention of joint injury. Support for an early aggressive approach to treatment is based upon the observations that joint damage, which may ultimately result in disability, begins early in the course of disease and that the longer active disease persists, the less likely the patient is to respond to therapy [1]. Improved outcomes have resulted from the use of potent and well-tolerated nonbiologic (traditional), biologic, and targeted small molecule disease-modifying antirheumatic drugs (DMARDs) used alone or in combination to induce and maintain tight control of disease [2-10]. These medications and strategies have the potential to control synovitis and slow or stop radiographic progression [2,9,11,12].

These observations regarding the course of disease and the efficacy of these therapeutic approaches, coupled with limits in the ability to accurately identify individuals with a poor prognosis, support our view that every patient with established active RA should be treated with DMARDs at the earliest stage of disease, ideally within three months of symptom onset. (See "General principles and overview of management of rheumatoid arthritis in adults".)

The treatment of patients with active RA with methotrexate (MTX) as initial DMARD monotherapy and regardless of duration will be reviewed here. The diagnosis and differential diagnosis, the general principles of management, and an overview of the therapy of RA, the initial treatment of RA using DMARD therapy other than MTX, and the treatment of disease resistant to initial therapy are presented separately. (See "Diagnosis and differential diagnosis of rheumatoid arthritis" and "General principles and overview of management of rheumatoid arthritis in adults" and "Alternatives to methotrexate for the initial treatment of rheumatoid arthritis in adults" and "Treatment of rheumatoid arthritis in adults resistant to initial conventional synthetic (nonbiologic) DMARD therapy" and "Treatment of rheumatoid arthritis in adults resistant to initial biologic DMARD therapy".)

GENERAL PRINCIPLES — There are several general principles important in the management of all patients with rheumatoid arthritis (RA). These principles are discussed in detail elsewhere. (See "General principles and overview of management of rheumatoid arthritis in adults".)

Briefly, these include:

●Evaluation and ongoing care by a rheumatologist

●Achievement and maintenance of tight control of disease activity, defined as remission or a state of low disease activity, without compromising safety

●Treatment of all patients diagnosed with RA with disease-modifying antirheumatic drug (DMARD) therapy following a shared decision-making process

●Use of antiinflammatory therapies, including nonsteroidal antiinflammatory drugs (NSAIDs) and glucocorticoids, to help control symptoms until DMARDs take effect

●Identification, management, and prevention of comorbid conditions that can complicate the disease course

NONPHARMACOLOGIC AND PREVENTIVE THERAPIES — A number of nonpharmacologic measures and other medical interventions are important in the comprehensive management of rheumatoid arthritis (RA), in addition to antiinflammatory and antirheumatic drug therapies. These interventions, including patient education, exercise, rehabilitation, vaccinations, and others, are discussed in detail elsewhere. (See "Nonpharmacologic therapies for patients with rheumatoid arthritis".)

APPROACH TO DRUG THERAPY — Our approach to therapy is based upon the widely accepted view that all patients diagnosed with active rheumatoid arthritis (RA) should receive disease-modifying antirheumatic drugs (DMARDs) to prevent, arrest, or retard disease-related injury (see 'General principles' above). Recommendations of major groups support the early use of DMARDs, usually methotrexate (MTX), for most patients with active disease [13-17].

The following is our general approach to the selection of drug therapies for the initial therapy of patients with active RA. It is broadly consistent with the 2021 American College of Rheumatology (ACR) recommendations and with the 2022 recommendations of the European Alliance of Associations for Rheumatology (EULAR; formerly known as European League Against Rheumatism) [17,18].

●We initiate therapy with a DMARD or combinations of DMARDs. We suggest MTX as the initial DMARD. (See 'Initial therapy with methotrexate' below.)

●In patients unable or unwilling to take MTX at the initiation of DMARD therapy, we use monotherapy with leflunomide, sulfasalazine, hydroxychloroquine, or a tumor necrosis factor (TNF) inhibitor, depending upon comorbidities, patient preferences, regulatory guidance, and disease severity. (See "Alternatives to methotrexate for the initial treatment of rheumatoid arthritis in adults".)

●We add nonsteroidal antiinflammatory drugs (NSAIDs) and/or glucocorticoids (systemic and/or intraarticular) for initial symptomatic control of inflammation while awaiting the response to DMARD therapy. We do not use NSAIDs or glucocorticoids as the sole or primary treatments. (See 'NSAIDs' below and 'Glucocorticoids' below.)

●In patients not achieving remission or low disease activity with appropriate doses of MTX monotherapy after three to six months, our preferred approach is to initiate combination therapy. (See 'Inadequate treatment response' below and 'Monitoring and reevaluation' below and "Treatment of rheumatoid arthritis in adults resistant to initial conventional synthetic (nonbiologic) DMARD therapy".)

DMARD THERAPY — We initially use one of the more effective disease-modifying antirheumatic drugs (DMARDs), usually methotrexate (MTX), both to suppress synovitis and other signs and symptoms of active disease and to prevent articular bone erosions and joint space narrowing. We initiate DMARD therapy as early in the treatment of rheumatoid arthritis (RA) as possible because delayed use of such medications results in poorer physical function and increased joint injury [19-21]. Alternatives to MTX for initial DMARD therapy are described separately. (See "Alternatives to methotrexate for the initial treatment of rheumatoid arthritis in adults".)

Numerous meta-analyses and randomized controlled trials support the use of nonbiologic (traditional) and biologic DMARDs in patients with active RA [13,22-30]. These trials included a mix of patients with a range of severity and a mean duration of illness of 6 to 12 months [3,6,19,29-32]. The applicability of these studies to the initial treatment of patients with active disease is addressed together with the other evidence described below.

Pretreatment interventions — We take a number of important precautions before using DMARDs, including:

●Laboratory assessment (eg, complete blood count, serum creatinine, aminotransferases)

●Screening for hepatitis C, hepatitis B, and latent tuberculosis

●Ensuring that the patient has received standard immunizations

●Chest radiograph for patients initiating MTX therapy

Although not conclusive, observational data have suggested that there may be an increased risk of MTX hypersensitivity pneumonitis in patients with underlying pulmonary disease, and having a baseline chest radiograph in these patients would be helpful for subsequent comparison if needed. These issues are discussed in detail elsewhere. (See "Major side effects of low-dose methotrexate", section on 'Pulmonary toxicity' and "Methotrexate-induced lung injury", section on 'Risk factors'.)

Initial therapy with methotrexate — We suggest MTX as the DMARD of choice for the initial treatment of patients with active RA. MTX typically serves as the "anchor" drug for the most commonly used DMARD combinations [33-35]. The major issues regarding the use of MTX in RA will be briefly reviewed here but are discussed in further detail elsewhere. (See "Use of methotrexate in the treatment of rheumatoid arthritis" and "Safety of rheumatic disease medication use during pregnancy and lactation", section on 'Methotrexate' and "Effects of antiinflammatory and immunosuppressive drugs on gonadal function and teratogenicity in men with rheumatic diseases".)

MTX is contraindicated in several groups of patients. These include:

●Women who are contemplating becoming pregnant or women not using adequate contraception

●Women who are pregnant

●Patients with liver disease or excessive alcohol intake

●Patients with severe renal impairment (estimated glomerular filtration rate [eGFR] less than 30 mL/min)

Issues related to the use of MTX and reproductive health are described in detail separately. (See "Safety of rheumatic disease medication use during pregnancy and lactation", section on 'Methotrexate' and "Effects of antiinflammatory and immunosuppressive drugs on gonadal function and teratogenicity in men with rheumatic diseases".)

Methotrexate dosing — MTX is given in a single weekly dose, usually orally. The optimal starting dose and schedule for dose escalation are uncertain. We suggest initiating therapy at a dose between 7.5 and 15 mg once weekly for most patients, depending upon the degree of disease activity, the size and age of the patient, the presence of comorbidities, and renal function. As examples, we would treat a 70-year-old patient weighing 55 kg with moderately active disease with an initial dose of 7.5 mg once weekly, while an otherwise healthy 30-year-old patient weighing 80 kg with highly active disease would be started on 15 mg once weekly. A lower initial dose is essential in patients with reduced renal function, defined as an eGFR <60 mL/min. Initial subcutaneous dosing is an alternative favored by some experts [36]. (See "Use of methotrexate in the treatment of rheumatoid arthritis", section on 'Dosing and administration' and "Use of methotrexate in the treatment of rheumatoid arthritis", section on 'Dose titration'.)

The MTX dose is increased as tolerated and as needed to control symptoms and signs of arthritis. Our usual approach is to increase the dose after four weeks by 2.5 mg (one tablet) to 5 mg per week at intervals no more frequent than every month, as indicated by disease activity and as tolerated (eg, from 10 mg initially to 15 mg once weekly after four weeks of initial therapy, then after a month on the higher dose it can be increased as tolerated to 17.5 or 20 mg once weekly if the response has been inadequate). In patients with continued high disease activity, we may increase by up to 5 mg/week if few comorbidities are present and if the increase in the dose continues to be well-tolerated. The usual target dose is at least 15 mg/week; the usual maximum dose is 25 mg/week. Alternative dose titration strategies may also be employed. (See "Use of methotrexate in the treatment of rheumatoid arthritis", section on 'Dose titration'.)

In early RA trials in which the dose of MTX is rapidly increased to 20 mg/week and in which the drug is continued for at least three months, approximately 30 percent of patients achieve a Disease Activity Score 28 (DAS28) less than or equal to 3.2, consistent with low disease activity, within three to six months [37,38].

For patients in whom 15 to 25 mg of MTX orally once weekly is ineffective or is poorly tolerated because of gastrointestinal symptoms, a trial of subcutaneous MTX administration is an alternative to switching to another DMARD or to adding other conventional DMARDs or a tumor necrosis factor (TNF) inhibitor. As an alternative to subcutaneous dosing, a dose of 15 mg or greater of MTX can be administered orally in a split dose with both doses taken on the same day of the week to enhance absorption, as MTX is better absorbed when administered in lower individual doses [39]. It is imperative to tell the patient to take all the MTX over a single 24-hour period once a week, as spreading the dose out further may produce significant liver toxicity. (See "Use of methotrexate in the treatment of rheumatoid arthritis", section on 'Dosing and administration' and "Use of methotrexate in the treatment of rheumatoid arthritis", section on 'Parenteral therapy' and "Use of methotrexate in the treatment of rheumatoid arthritis", section on 'Pharmacology' and "Use of methotrexate in the treatment of rheumatoid arthritis", section on 'Split dosing'.)

Side effects, monitoring, and other considerations — MTX treatment requires meticulous monitoring for bone marrow, liver, and lung toxicity. The toxicities associated with MTX in the doses used in RA are very rarely life-threatening in patients receiving recommended monitoring. MTX is generally well-tolerated, although most patients experience at least one or more of the more common side effects, such as gastrointestinal upset or stomatitis, over their course of therapy. Although concomitant use of certain medicines (such as nonsteroidal antiinflammatory drugs [NSAIDs] or proton pump inhibitors) can increase MTX drug levels, this typically has little clinical consequence given the relatively low weekly doses used in RA compared with the substantially higher doses used in the treatment of some cancers. MTX is discontinued due to adverse effects after two and five years of treatment in up to 20 and 35 percent of patients, respectively [24]. The major side effects of low-dose MTX are discussed in detail elsewhere. (See "Major side effects of low-dose methotrexate" and "Hepatotoxicity associated with chronic low-dose methotrexate for nonmalignant disease" and "Methotrexate-induced lung injury".)

Patients receiving MTX should also receive daily supplementation with folic acid. The use of folic acid and additional considerations with the use of MTX that are discussed in more detail separately include alcohol ingestion and dosing in renal insufficiency. (See "Use of methotrexate in the treatment of rheumatoid arthritis".)

Methotrexate versus other DMARDs — Randomized head-to-head trials have found that MTX has a faster onset of action, comparable or greater efficacy, and better long-term tolerance compared with other nonbiologic DMARD monotherapy [24]. MTX has also been shown to improve survival (both cardiovascular and all-cause mortality) in patients with RA compared with other nonbiologic DMARDs [40,41]. Leflunomide, sulfasalazine, and hydroxychloroquine have been used as alternatives to MTX due to intolerance or when MTX is contraindicated.

Two trials that supported the initial regulatory approval of leflunomide for RA that were conducted in the 1990s compared leflunomide (20 mg daily after a loading dose of 100 mg daily for three days) with MTX at 10 to 15 mg once weekly, a dose lower than that subsequently both widely used and considered as optimal [42,43]. One trial demonstrated similar efficacy of leflunomide to MTX with both being superior to placebo, and the second, larger head-to-head study demonstrated that MTX was superior to leflunomide in the individual components of the American College of Rheumatology (ACR) clinical response. Due to the greater cost of leflunomide and the side effect profile, MTX has remained the preferred initial DMARD. Sulfasalazine had similar efficacy to leflunomide in a single randomized trial, but persistence on therapy was poor [44].

MTX has been shown to be beneficial both in patients with longstanding and earlier disease. As an example, in the Treatment of Early Aggressive Rheumatoid Arthritis (TEAR) study, which compared initiation of combination therapies with initiating MTX monotherapy and stepping up therapy in patients who did not achieve low disease activity at six months, patients were enrolled with disease duration of only three to four months. Twenty-eight percent of patients treated with MTX monotherapy achieved low disease activity (LDA), defined as DAS28-erythrocyte sedimentation rate (ESR) <3.2 [45]. Similar clinical efficacy has been noted in multiple randomized trials that compared MTX monotherapy with MTX combination therapies.

The benefits and safety of MTX have also been documented in multiple other randomized trials and long-term observational studies, including in comparison with placebo and with other DMARD therapies [46-55].

In randomized trials, initial therapy with MTX results in comparable clinical benefit compared with initial therapy with TNF inhibitor monotherapy, but radiographic benefit may be numerically less [29,30]. Trials have also demonstrated superior efficacy to MTX in early RA of the Janus kinase inhibitors tofacitinib, baricitinib, and upadacitinib, but these therapies have rarely been used in early RA due to their substantially greater cost and side effect profile demonstrated in comparisons with TNF inhibitors [56-59]. A recent open-label phase IV trial (NORDSTAR) compared methotrexate rapidly escalated to 25 mg along with prednisone taper or as triple therapy with abatacept, tocilizumab, or certolizumab in combination with methotrexate in early seropositive RA patients. Adjusted 24-week Clinical Disease Activity Index (CDAI) remission rates were 42.7 percent (95% CI 36.1-49.3 percent) for active conventional treatment, 46.5 percent (95% CI 39.9-53.1 percent) for certolizumab pegol, 52.0 percent (45.5-58.6 percent) for abatacept, and 42.1 percent (35.3-48.8 percent) for tocilizumab with abatacept demonstrating superiority compared with conventional therapy. Adjusted CDAI remission rates at week 48 were 59.3 percent (abatacept), 52.3 percent (certolizumab), 51.9 percent (tocilizumab), and 39.2 percent (active conventional therapy), with both abatacept and certolizumab statistically superior. Radiographic progression was low with no group differences [60]. Tight control treatment strategies have also shown significant benefit without the use of biologics for initial therapy [61]. (See "General principles and overview of management of rheumatoid arthritis in adults", section on 'Tight control'.)

Methotrexate versus initial combination therapy — Combinations of MTX with either sulfasalazine or hydroxychloroquine, with both sulfasalazine and hydroxychloroquine (commonly referred to as "triple therapy" or "triple DMARD therapy"), or with a biologic DMARD also have proven efficacy for initial treatment of highly active RA [13,62]. (See "Treatment of rheumatoid arthritis in adults resistant to initial conventional synthetic (nonbiologic) DMARD therapy", section on 'General approach'.)

However, we prefer MTX monotherapy for initial treatment rather than in combination with other nonbiologic or biologic DMARDs or a biologic DMARD alone, despite the fact that a greater proportion of patients respond well when treated initially with combination therapies or biologics, and observations that MTX and biologics have a similar frequency of long-term side effects [62]. This is principally because:

●Initial MTX monotherapy is adequate in many patients with early, moderately to severely active RA; those with an inadequate response can be quickly identified and subsequently treated with combination therapy prior to the development of irreversible injury [29,30,37,61,63,64].

●Clinical outcomes after several years of treatment are similar in trials that compared patients initially receiving MTX, who then stepped up to combination therapy after an inadequate response, with patients initially treated with combination therapy. This was best demonstrated in a post-hoc analysis of the TEAR trial, a blinded randomized trial of this approach [65]. In this analysis, the clinical outcomes from weeks 48 to 102 in patients who had been stepped up from MTX alone, based upon clinical findings after six months (DAS28-ESR ≥3.2), to receive combination therapy (either triple therapy with traditional DMARDs or MTX plus etanercept) were comparable to patients started on combination therapy initially. Longer-term clinical outcomes between such groups are otherwise not well-studied.

In the TEAR trial, there was also no difference at two years in radiographic outcomes between the patients initially assigned to MTX only and those assigned to combination therapy [65]. When differences between these approaches have been described, they have tended to favor the combination groups, but have been very small and of uncertain clinical significance [4,37,66,67]. (See "Treatment of rheumatoid arthritis in adults resistant to initial conventional synthetic (nonbiologic) DMARD therapy", section on 'Efficacy of triple DMARD therapy versus methotrexate/TNF inhibitor'.)

●There are widespread regulatory or cost barriers to the use of biologic therapies for initial DMARD treatment for most DMARD-naïve patients, even with severely active RA.

Alternatives to methotrexate — In patients unable or unwilling to take MTX, we use leflunomide, sulfasalazine, hydroxychloroquine, or a TNF inhibitor (eg, etanercept or adalimumab). Tofacitinib, baricitinib, and upadacitinib are also effective in such patients. There are insufficient data to identify the optimal initial therapy in patients who are unable to take MTX. The choice of agent is largely based upon indirect comparisons; limited head-to-head comparisons; regulatory or insurance requirements; comorbidities; disease severity; and patient preferences regarding relative risks and benefits, route of administration, and cost. (See "Alternatives to methotrexate for the initial treatment of rheumatoid arthritis in adults".)

SYMPTOMATIC TREATMENT WITH ANTIINFLAMMATORY DRUGS — Nonsteroidal antiinflammatory drugs (NSAIDs) and/or glucocorticoids act rapidly to control inflammation but do not provide adequate benefit for longer-term control of disease or prevention of joint injury in most patients. Moreover, chronic use of these agents, particularly glucocorticoids in moderate to high doses, is associated with significant risk of adverse effects, with some data suggesting that the risk of serious infection associated with chronic glucocorticoid use is increased even at daily prednisone doses ≤5 mg [68]. (See "Major adverse effects of systemic glucocorticoids" and "Nonselective NSAIDs: Overview of adverse effects" and "Overview of COX-2 selective NSAIDs", section on 'Toxicities and possible toxicities'.)

We thus use these medications primarily for temporary control of disease activity in patients in whom treatment is being started with disease-modifying antirheumatic drugs (DMARDs) or in whom adjunctive treatment is needed for persistent or flaring disease until treatment with DMARDs is sufficiently effective. Some patients require ongoing use of such agents despite other therapies, but neither NSAIDs nor glucocorticoids should be considered as substitutes for effective treatment with DMARDs. (See "General principles and overview of management of rheumatoid arthritis in adults".)

We use NSAIDs initially in most patients with active disease. We also initiate therapy with glucocorticoids in patients on the more severe end of this spectrum, while patients with less active disease who do not respond adequately to NSAIDs within two weeks should also receive treatment with glucocorticoids.

NSAIDs — NSAIDs should be used at full therapeutic antiinflammatory doses for initial therapy of patients with active rheumatoid arthritis (RA), unless contraindicated by gastrointestinal, renal, or cardiovascular disease. NSAIDs also provide analgesic benefit.

NSAIDs are continued for at least two weeks before switching agents, because maximal analgesic and antiinflammatory effect is usually achieved within 10 to 14 days. The dose and duration of NSAIDs previously tried by the patient should be identified to determine if an adequate trial of one or more NSAIDs has already been attempted. The dose of a given medication required by different patients may vary. Examples of effective total daily doses include 2400 to 3200 mg of ibuprofen, 1000 mg of naproxen, or a single daily dose of a longer-acting agent such as 15 mg of meloxicam.

A reduced dose and more frequent monitoring may be needed in older patients and in others who may be at greater risk of adverse effects, including renal insufficiency due to comorbidities or other medication use and those with increased cardiovascular risk. The use and safety of NSAIDs in patients with renal disease and in those with cardiovascular disease and increased cardiovascular risk are discussed in detail separately. (See "NSAIDs: Adverse cardiovascular effects" and "Nonselective NSAIDs: Overview of adverse effects", section on 'Renal effects'.)

With usual drug safety monitoring, NSAIDs can be used with concomitant DMARDs, including methotrexate (MTX), without dose adjustment. (See "NSAIDs: Therapeutic use and variability of response in adults" and "Overview of COX-2 selective NSAIDs".)

In patients at increased risk of NSAID gastropathy, such as those who are also receiving glucocorticoids or who have a history of peptic ulcer disease, appropriate measures should be undertaken to decrease the risk of gastrointestinal complications such as use of a proton pump inhibitor, misoprostol, or possibly use of a selective cyclooxygenase (COX)-2 inhibitor (eg, celecoxib) rather than a nonselective NSAID. Alternatives to the non-salicylate NSAIDs in such patients also include the non-acetylated salicylates (eg, salsalate at 2000 to 3000 mg/day), which have proven antiinflammatory activity with fewer adverse gastrointestinal effects. (See "NSAIDs (including aspirin): Primary prevention of gastroduodenal toxicity" and "NSAIDs (including aspirin): Treatment and secondary prevention of gastroduodenal toxicity".)

Patients should be cautioned regarding the risks of chronic use of NSAIDs. Effective management with DMARDs should allow for the discontinuation of daily full-dose NSAID use. (See "Nonselective NSAIDs: Overview of adverse effects".)

Therapeutic trials of individual NSAIDs can continue until the patient has achieved adequate control of the inflammation with minimal side effects. Clinical experience indicates that there are relatively little or no benefits and an increased risk of gastrointestinal toxicity when adding one NSAID to another. Treatment with glucocorticoids should be offered if adequate symptomatic relief is not achieved within 10 to 14 days on NSAIDs alone while awaiting benefit from DMARD therapy. (See "NSAIDs (including aspirin): Pathogenesis and risk factors for gastroduodenal toxicity".)

Glucocorticoids — Glucocorticoids act to rapidly reduce symptoms due to inflammatory synovitis in patients with RA. Oral glucocorticoids are commonly used in RA, and some patients may benefit from intraarticular or intramuscular glucocorticoid administration in this setting. Glucocorticoid use is discussed briefly below. A more detailed discussion of glucocorticoid use in RA and of the data supporting its efficacy is presented elsewhere. (See "Use of glucocorticoids in the treatment of rheumatoid arthritis" and 'Therapy for resistant disease and flares' below and 'Intraarticular glucocorticoids' below and 'Intramuscular glucocorticoids' below and 'Oral glucocorticoids' below.)

There is also evidence that glucocorticoids retard radiographic progression in patients with RA in the short to medium term [69-71]. However, these agents should not be used alone for an extended period, and long-term treatment with glucocorticoids should be minimized since their use may be associated with increased morbidity and mortality [72]. (See "Major adverse effects of systemic glucocorticoids" and "Use of glucocorticoids in the treatment of rheumatoid arthritis", section on 'Efficacy of chronic use'.)

Oral glucocorticoids — We suggest the use of oral glucocorticoids to help control disease activity in the initial treatment of severely active RA, particularly in early disease, and in the treatment of patients with less severe disease in whom a trial of NSAIDs has been inadequate. We use glucocorticoids in addition to (or sometimes in place of) NSAIDs because of their extremely rapid onset of action and the greater effectiveness in controlling symptoms for most patients with active RA [73]. Based upon our clinical experience, we usually initiate therapy with prednisone 5 to 20 mg/day, depending upon the severity of joint inflammation and upon the minimal dose required to obtain initial control. Most patients can be adequately controlled on 5 to 10 mg/day while initiating DMARDs.

Glucocorticoids should then be tapered as rapidly as tolerated with the goal of further tapering and eventual discontinuation, if possible, once disease control is achieved and can be maintained. In general, the beneficial effects of DMARD therapy will permit reduction and discontinuation of the glucocorticoids, a goal of successful DMARD therapy, within four to six months. (See "Glucocorticoid withdrawal".)

The efficacy of glucocorticoids in this setting has been shown in randomized trials and in a large number of observational studies [73]. Some studies have used relatively high-dose glucocorticoids for initial therapy (prednisone 60 mg/day or equivalent) [3,74]. However, lower doses are usually adequate when combined with effective DMARDs. (See "Use of glucocorticoids in the treatment of rheumatoid arthritis".)

There are numerous risks associated with glucocorticoid use, and appropriate monitoring and precautions should be performed in all patients on these medications with respect to risks for osteoporosis, diabetes, infection [75], and other adverse effects of hypercortisolism. 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 adverse effects of systemic glucocorticoids".)

Intramuscular glucocorticoids — In patients who must avoid daily oral glucocorticoids or who require an extremely rapid antiinflammatory response, an alternative to oral glucocorticoids is a single initial intramuscular injection of a depot preparation of methylprednisolone (80 to 120 mg), administered by deep intramuscular injection into the gluteal muscle [76-78]. Based upon the overall clinical response, up to two subsequent injections may be required at intervals of every four weeks to maintain improvement in symptoms, signs, and physical function, while slower-acting DMARDs exert their expected effect on controlling disease activity. Longer-term use is avoided to prevent harmful effects of glucocorticoids [76].

Intraarticular glucocorticoids — Intraarticular injections of long-acting glucocorticoids (eg, triamcinolone hexacetonide) are used to reduce synovitis in particular joints that are more inflamed than others. In such patients, it may be difficult to distinguish between active joint inflammation due to RA alone and that due to infection. Thus, when clinically indicated, joint fluid should be obtained to exclude infection. (See "Use of glucocorticoids in the treatment of rheumatoid arthritis" and "Intraarticular and soft tissue injections: What agent(s) to inject and how frequently?".)

ANALGESICS — In addition to the medications noted above, we use analgesic medications, such as acetaminophen, for additional pain relief if required. We avoid the use of opioids because pain can be controlled in most patients with rheumatoid arthritis (RA) by effective use of nonsteroidal antiinflammatory drugs (NSAIDs), glucocorticoids, and disease-modifying antirheumatic drugs (DMARDs) that control the disease process. Patients without evidence of very significant joint injury who appear to require opioids for adequate pain relief despite good control of disease activity should be evaluated for other comorbid conditions.

MONITORING AND REEVALUATION — Disease activity and the response to therapy should be regularly reassessed, along with monitoring for drug toxicities, every three to five weeks until the patient is stable and disease is under control [9,69,79,80]. Subsequently, frequency of assessments should generally be no fewer than every three months. Well-controlled patients who are seen less frequently may require laboratory monitoring beyond that performed at scheduled visits and should be counseled, as should all patients, to contact their treating clinician if the arthritis flares. Laboratory testing for the monitoring of disease activity and for the monitoring and prevention of drug toxicity is discussed separately. (See "General principles and overview of management of rheumatoid arthritis in adults", section on 'Drug monitoring and prevention of drug toxicity'.)

We periodically reevaluate and track disease activity using a quantitative composite measure at each assessment. Recommended measures are described in detail separately. (See "Assessment of rheumatoid arthritis disease activity and physical function" and "General principles and overview of management of rheumatoid arthritis in adults", section on 'Tight control'.)

Adaptations of measures for the assessment of disease activity and function have been proposed for the monitoring of patients receiving care during telehealth visits [81].

More frequent laboratory monitoring may be required depending on the medications being used and following increases in dosing; more frequent clinical assessments may be required in patients with comorbidity or in those experiencing a flare of disease or undergoing changes in therapy. We alter therapy if the disease remains active or progresses. (See 'Disease resistant to initial methotrexate therapy' below.)

THERAPY FOR RESISTANT DISEASE AND FLARES

Disease resistant to initial symptomatic treatment — We take the following approaches in patients who exhibit a persistent inflammatory synovitis that is resistant to the initial symptomatic therapies described above:

●We add oral glucocorticoids in patients begun on nonsteroidal antiinflammatory drugs (NSAIDs) and disease-modifying antirheumatic drugs (DMARDs) who continue to experience significant symptoms after 10 to 14 days of therapy. (See 'Oral glucocorticoids' above.)

●We use intraarticular glucocorticoids in individual joints when only a small number are resistant to therapy with systemic agents, or if it is anticipated that a local injection may preclude the need for NSAIDs or systemic glucocorticoids. (See 'Intraarticular glucocorticoids' above.)

Flares — Rheumatoid arthritis (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 physical and laboratory findings of increased inflammatory synovitis, from noninflammatory causes of local or generalized increased pain. The severity of the flare and background drug therapy influence the choice of therapies. Drug therapy for flares is discussed in detail elsewhere. (See "General principles and overview of management of rheumatoid arthritis in adults", section on 'Drug therapy for flares'.)

Disease resistant to initial methotrexate therapy — In patients resistant to initial DMARD therapy with methotrexate (MTX), we either add additional DMARDs or switch the patient to a different DMARD or DMARD combination, while also treating the active inflammation with antiinflammatory drug therapy. (See "Treatment of rheumatoid arthritis in adults resistant to initial conventional synthetic (nonbiologic) DMARD therapy".)

DURATION OF THERAPY

Inadequate treatment response — We suggest that patients who fail to achieve remission or low disease activity within three to six months of initiating therapy, or who require more than approximately 5 to 7.5 mg/day of prednisone or equivalent glucocorticoid chronically to maintain a state of remission or low disease activity, undergo a change in therapeutic regimen. The decision to intensify or modify treatment also depends, in part, upon the patient's functional capacity and quality of life. We would typically make a change in therapy in patients who continue to have moderate to high disease activity despite optimized methotrexate (MTX) dosing after three months, even if they have had some benefit. Patients with a substantial reduction in disease activity both proportionally (eg, over 50 percent) and in absolute terms (eg, reduction in a Disease Activity Score 28 [DAS28] of >1.2) might have such changes deferred to six months, even if minimal disease activity has not yet been achieved, depending upon their goals and preferences. (See "Treatment of rheumatoid arthritis in adults resistant to initial conventional synthetic (nonbiologic) DMARD therapy".)

Adequate treatment response — Most patients with active rheumatoid arthritis (RA) will require sustained therapy and adjustments in their treatment regimen over months to years to achieve treatment goals. In the minority of patients who achieve a sustained clinical remission of greater than one year, we cautiously try to reduce disease-modifying antirheumatic drug (DMARD) doses while maintaining close monitoring to facilitate recognition of any recurrence of disease activity. Although some patients may tolerate a reduced dose of medications, whether or not to discontinue DMARDs in patients in remission remains controversial [14,82,83]. We prefer to continue nonbiologic or biologic DMARD therapy at reduced doses, if possible, but do not discontinue DMARD therapy in most patients who have had active RA. Cautious reduction of biologic DMARD doses can be performed by increasing the interval between doses or by reducing the medication dose [14]. (See "General principles and overview of management of rheumatoid arthritis in adults", section on 'Assessment and monitoring' and "General principles and overview of management of rheumatoid arthritis in adults", section on 'Tight control'.)

As an example, in a patient in clinical remission being treated with prednisone (7.5 mg/day) and MTX (20 mg/week), we would first try to reduce prednisone because of the risk of long-term adverse effects with glucocorticoids. In such a patient, we would lower the glucocorticoid dose slowly (no faster than an average of 1 mg every two to four weeks), as long as there was no recurrence of disease activity. If prednisone can be discontinued, or cannot but can be lowered to a dose no greater than 5 mg/day, we next decrease MTX. We reduce the MTX dose in 2.5 mg increments every two to three months as tolerated but generally to no lower than 15 mg/week. A lower dose of MTX (eg, 10 to 12.5 mg/week) may be adequate to maintain remission in patients who are older or who have diminished renal function.

Continued close monitoring is required in patients who discontinue their medications and who enter a period of possible drug-free remission. The risk of disease recurrence in such patients is high, and flares of disease may occur even several years after stopping therapy [82,84-88]. Additionally, clinical remission may be difficult to achieve upon resumption of DMARD therapy in patients who have discontinued all DMARDs. The best candidates for achieving a drug-free remission appear to be patients with the following characteristics: a short duration of symptoms when treatment is started, male sex, the absence of autoantibodies, and receipt of early intensive therapy [74,86,88,89].

PREGNANCY, COMORBIDITIES, AND OTHER SPECIAL CONSIDERATIONS — Pregnancy and 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. A number of medical conditions that often coexist with or result from rheumatoid arthritis (RA) may influence the choice of medications. The approach to treatment in the presence of these conditions is discussed in more detail separately. (See "General principles and overview of management of rheumatoid arthritis in adults", section on 'Tight control' and "Rheumatoid arthritis and pregnancy".)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Rheumatoid arthritis".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

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

●Basics topics (see "Patient education: Rheumatoid arthritis (The Basics)" and "Patient education: Disease-modifying antirheumatic drugs (DMARDs) (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

●Approach to management – In all patients with active rheumatoid arthritis (RA), we recommend treatment with a disease-modifying antirheumatic drug (DMARD), rather than use of antiinflammatory agents and/or glucocorticoids alone and delaying DMARD therapy (Grade 1B). Additional principles for the treatment of RA include achievement and maintenance of tight control of disease activity, with the ideal goal of remission; use of antiinflammatory agents, including nonsteroidal antiinflammatory drugs (NSAIDs) and glucocorticoids, only as adjunctive agents; and participation of a rheumatologist in the evaluation and ongoing care of the patient. (See 'General principles' above and "General principles and overview of management of rheumatoid arthritis in adults".)

Patient education and other nonpharmacologic and preventive therapies are needed for all patients with RA. (See 'Nonpharmacologic and preventive therapies' above and "Nonpharmacologic therapies for patients with rheumatoid arthritis".)

●Initial immunosuppressive therapy – In patients with active RA we suggest methotrexate (MTX) as the initial DMARD, rather than another single nonbiologic or biologic DMARD or combination therapy (Grade 2B). Doses are increased as tolerated and as needed, up to 25 mg/week, to control symptoms and signs of arthritis. Subcutaneous administration may be of benefit in patients with an inadequate response to orally administered MTX at a dose of 15 to 25 mg/week of MTX. (See 'Initial therapy with methotrexate' above.)

In patients who are unable or unwilling to take MTX, we use an alternative nonbiologic or biologic DMARD therapy. (See 'Alternatives to methotrexate' above.)

●Symptom management – In patients with active RA, we use antiinflammatory drug therapy with NSAIDs or glucocorticoids, preferably on a temporary basis, to quickly achieve control of signs and symptoms of disease. We use NSAIDs in all patients without contraindications to their use. In patients with more severe disease or with moderate disease resistant to a brief course of NSAIDs, we suggest the use of glucocorticoids (Grade 2B). We then taper and withdraw these medications once DMARDs have taken effect. We use intraarticular injections of long-acting glucocorticoids to reduce synovitis in particular joints that are more inflamed than others. When clinically indicated, joint fluid should be obtained to exclude infection. (See 'NSAIDs' above and 'Glucocorticoids' above.)

●Monitoring – During the initial treatment of patients with active RA, the patient should be reevaluated every three to five weeks for the effectiveness of therapy and for the monitoring of possible drug toxicity. We advise regular reevaluation of disease activity using a quantitative composite measure at each assessment. In patients who fail to achieve remission within three to six months of initiating optimal therapy, or who require more than approximately 5 to 7.5 mg/day of prednisone or equivalent glucocorticoid on a chronic basis to maintain a state of remission or low disease activity, we use a more potent DMARD or combination of DMARDs rather than continuing the same treatment regimen for a longer period of time. The approach to these patients is described in detail separately. (See 'Monitoring and reevaluation' above and 'General principles' above and "Treatment of rheumatoid arthritis in adults resistant to initial conventional synthetic (nonbiologic) DMARD therapy".)

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