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Initial pharmacologic management of rheumatoid arthritis in adults

Initial pharmacologic management of rheumatoid arthritis in adults
Authors:
Stanley Cohen, MD
Ted R Mikuls, MD, MSPH
Section Editor:
James R O'Dell, MD
Deputy Editor:
Philip Seo, MD, MHS
Literature review current through: May 2025. | This topic last updated: Jun 10, 2025.

INTRODUCTION — 

The treatment of rheumatoid arthritis (RA) is directed toward control of synovitis, prevention of joint damage, preservation of musculoskeletal function, and relief of pain.

Every patient with active RA should be treated with disease-modifying antirheumatic drugs (DMARDs) at the earliest stage of the disease, ideally within three months of symptom onset. Joint damage begins early in the course of disease, and patients with prolonged disease activity are less likely to respond to therapy [1].

Early, aggressive use of DMARDs is used to induce and maintain tight control of disease [2-10]. This strategy improves outcomes by controlling synovitis and slowing or stopping permanent joint damage [2,9,11,12].

The initial treatment of patients with active RA will be reviewed here. An overview of the management of RA (including nonpharmacologic strategies) and the treatment of disease resistant to initial therapy are presented separately.

●(See "Overview of the management of rheumatoid arthritis in adults".)

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

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

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

APPROACH TO INITIAL THERAPY — 

An overview of the basic principles underlying the management of rheumatoid arthritis (RA) is discussed in detail elsewhere. (See "Overview of the management of rheumatoid arthritis in adults", section on 'Management strategies'.)

Pretreatment interventions — A number of interventions are required before using disease-modifying antirheumatic drugs (DMARDs). These include screening for viral hepatitis; interventions to reduce the risk of cardiovascular disease and osteoporosis; immunizations; and nonpharmacologic interventions [13]. Some patients may require additional pretreatment interventions, depending on the specific DMARDs used. These issues are discussed in detail elsewhere. (See "Overview of the management of rheumatoid arthritis in adults", section on 'Pretreatment assessments and interventions'.)

DMARD therapy

Early DMARD therapy for all patients — We suggest using a DMARD, usually methotrexate (MTX), to treat all patients with active RA. DMARDs treat synovial inflammation, alleviate signs and symptoms of active RA, and prevent articular bone erosions and joint space narrowing due to loss of cartilage. There is widespread expert consensus regarding this approach, which is largely based on observational studies.

We initiate DMARD therapy as early in the treatment of RA as possible (rather than the use of symptomatic treatment alone) for the following reasons: [14-16].

●Delayed therapy is associated with increased disability – Delayed use of DMARDs results in poorer physical function and increased joint injury. One study found that low socioeconomic status (SES) was associated with a substantial delay in starting DMARD therapy, and both the delay and low SES were independently associated with more disease activity, joint damage, and physical disability [17].

●Prompt therapy is more likely to lead to sustained remission – Some evidence suggests that the effect on outcomes is not linear with time, and there may be an early "window of opportunity" for optimal DMARD treatment benefit [18]. In two large European cohorts, patients with RA treated with DMARDs early (ie, after 14.9 to 19.1 weeks of symptoms) were more likely to achieve a sustained remission than patients treated later in their disease course [18].

Furthermore, an observational study of 1435 patients involved in 14 trials, primarily of MTX or other nonbiologic DMARDs, found a progressive decrease in the likelihood of a significant response to DMARD therapy with increasing disease duration [1]. 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). (See "Overview of the management of rheumatoid arthritis in adults", section on 'Early use of DMARDs'.)

Methotrexate for most patients — We suggest MTX for the initial treatment of patients with active RA. Initial MTX monotherapy is adequate in many patients with early, active RA; those with an inadequate response can be quickly identified and subsequently treated with combination therapy prior to the development of irreversible injury [19-24]. MTX typically serves as the "anchor" drug for the most commonly used DMARD combinations [25-27].

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

●Patients who are pregnant (or may become pregnant)

●Patients with liver disease

●Patients who consume more than one alcoholic drink daily [28]

●Patients with moderate to severe impairment of kidney function (estimated glomerular filtration rate [eGFR] less than 30 mL/min/1.73 m2)

We treat such patients with an alternate agent, discussed below. (See 'Other alternative agents' below.)

Issues regarding the use of MTX for the treatment of RA, including dosing, administration, precautions, adverse effects, and implications for pregnancy, are discussed in detail elsewhere:

●(See "Use of methotrexate in the treatment of rheumatoid arthritis".)

●(See "Major adverse effects of low-dose methotrexate".)

●(See "Safety of rheumatic disease medication use during pregnancy and lactation", section on 'Methotrexate'.)

Our reasons for preferring the use of MTX for the initial therapy of RA are discussed below.

●MTX versus other nonbiologic DMARDs – Multiple studies have demonstrated that MTX has several advantages over other nonbiologic DMARDs for the treatment of RA, including [29-38] (see 'Preferred alternatives to methotrexate' below):

•Faster onset of action

•Comparable or greater efficacy

•Better long-term tolerance

•Less erosive joint damage

•Improved patient survival (both cardiovascular and all-cause mortality)

•Lower cost

●MTX versus TNF inhibitors – We generally do not use tumor necrosis factor (TNF) inhibitors for the initial treatment of RA due to their greater cost and side effect profile. However, in randomized trials, initial therapy with MTX results in comparable clinical benefit compared with initial therapy with TNF inhibitor monotherapy for the treatment of RA [19,20]. For example, in a randomized trial of 632 patients with early RA, treatment with a TNF inhibitor was associated with a greater clinical response than treatment with MTX at six months, but the difference between the two groups was insignificant thereafter [19].

MTX and TNF inhibitors are associated with a similar overall frequency of side effects, although their side effect profiles are distinct. In a systematic review of 15 trials of early RA, MTX and the combination of MTX with a TNF inhibitor were associated with similar rates of withdrawals for drug toxicity (9 versus 6 percent) [39]. Although overall rates of side effects are similar among those treated with MTX and TNF inhibitors, studies suggest higher rates of serious infection (particularly opportunistic infections) with the latter [40].

Initial therapy with TNF inhibitor monotherapy may be more effective at preventing structural joint damage than initial therapy with MTX, although the clinical significance of this observation is unclear [19,20]. (See 'Other alternative agents' below.)

●MTX versus JAK inhibitors – In randomized trials, initial therapy with oral modestly dosed MTX is less effective than initial therapy with a Janus kinase (JAK) inhibitor (eg, tofacitinib, baricitinib, upadacitinib) for the treatment of RA [41-43]. However, due to safety concerns with JAK inhibitors noted in post-approval clinical trials, regulatory agencies recommend JAK inhibitors only after treatment with TNF inhibitors. (See "Overview of the Janus kinase inhibitors for rheumatologic and other inflammatory disorders", section on 'Adverse effects'.)

●MTX versus initial combination therapy – We prefer MTX monotherapy for initial treatment rather than starting with combinations of biologic and/or nonbiologic DMARDs. Initiation of multiple medications concurrently can confound the attribution of a side effect to a specific medication.

Moreover, 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 by the Treatment of Early Aggressive Rheumatoid Arthritis (TEAR) trial, which enrolled 755 patients who had RA for only three to four months [44]. In this trial, initial treatment with combination therapies was compared with initiating MTX monotherapy and "stepping up" therapy in patients who did not achieve low disease activity at six months.

•Twenty-eight percent of patients treated with MTX monotherapy achieved low disease activity, defined as Disease Activity Score 28 for patients with RA based on erythrocyte sedimentation rate (DAS28-ESR) <3.2 [44]. (See "Assessment of rheumatoid arthritis disease activity and physical function", section on 'Disease Activity Score using 28 joints (DAS28)'.)

•The clinical outcomes from weeks 48 to 102 in patients who had been stepped up from MTX alone were comparable to patients started on combination therapy initially [45].

•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 [45].

Combinations of MTX with either sulfasalazine (SSZ) or hydroxychloroquine (HCQ), with both SSZ and HCQ (commonly referred to as "triple therapy" or "triple DMARD therapy"), or with a biologic DMARD are also effective for initial treatment of highly active RA [39,46]. While some studies have demonstrated that these strategies are more effective than initial therapy with MTX, the differences in outcomes tend to be small and of uncertain clinical significance [4,24,47,48]. (See "Treatment of rheumatoid arthritis in adults resistant to initial conventional synthetic (nonbiologic) DMARD therapy", section on 'Efficacy of triple therapy'.)

Preferred alternatives to methotrexate — Alternatives to MTX are sometimes used for the initial treatment of rheumatoid arthritis (RA), either because of comorbidities that present an absolute or relative contraindication to MTX, the initial DMARD usually employed for treating RA, or because of patient or clinician preferences.

The choice of the alternative agent to MTX is ultimately based upon the following considerations: disease severity; comorbidities; contraindications for the use of specific drugs; patient preferences regarding relative risks and benefits and route of administration; and regulatory, insurance, and cost limitations. It is further shaped by evidence from indirect comparisons and limited head-to-head comparisons.

Numerous meta-analyses and randomized studies demonstrate that a broad range of nonbiologic (traditional) and biologic/targeted synthetic DMARDs are effective for the initial treatment of RA [3,6,14,19,20,29,46,49-56]. Our approach, which is based on disease activity, is outlined below. The assessment of disease activity is discussed elsewhere (calculator 1). (See "Assessment of rheumatoid arthritis disease activity and physical function", section on 'Composite indices for disease activity assessment'.)

●Leflunomide (LEF) for moderate to severe activity – We suggest LEF monotherapy for the initial therapy of moderate to severe RA in patients who cannot use MTX. The use of LEF for the treatment of rheumatoid arthritis, including dosing, adverse effects, monitoring, and precautions regarding its use, is discussed in greater detail elsewhere. (See "Pharmacology, dosing, and adverse effects of leflunomide in the treatment of rheumatoid arthritis".)

Leflunomide is contraindicated in patients with chronic liver disease and patients who may become pregnant. Such patients can be treated with a TNF inhibitor unless active viral hepatitis is present. Additionally, a TNF inhibitor is a reasonable alternative to leflunomide for patients with significant impairment of kidney function. (See 'Other alternative agents' below.)

A systematic review of six randomized trials (including comparisons of LEF with placebo and/or MTX) suggested that LEF was twice as likely as placebo to achieve an ACR20 response at 6 or 12 months, and was as effective as MTX using the same criteria (table 1) [57]. However, these trials have been criticized for using lower maximum doses of MTX (up to 15 mg/week) than those that have subsequently been commonly employed (up to 25 mg/week) [58-61].

Additionally, the adverse effect profile of LEF is generally similar to that of MTX, with similar rates of withdrawal for drug toxicity at two years [57,62].

●Hydroxychloroquine (HCQ) for low disease activity – In patients with low disease activity, we suggest HCQ in patients who cannot use MTX. We also use HCQ in patients with findings limited to mild inflammatory arthritis and a positive antinuclear antibody (ANA) test who lack autoantibodies associated with RA (ie, rheumatoid factor, anticitrullinated peptide antibodies), since distinguishing early RA from undifferentiated immune-inflammatory disease and early systemic lupus erythematosus (SLE) may not be straightforward. The dosing, adverse effects of HCQ and recommendations for drug monitoring, including baseline and follow-up ophthalmologic evaluation, are discussed in detail separately. (See "Antimalarial drugs in the treatment of rheumatic disease", section on 'Adverse effects' and "Antimalarial drugs in the treatment of rheumatic disease", section on 'Routine eye examinations for all patients' and "Antimalarial drugs in the treatment of rheumatic disease", section on 'Administration, dosing, and monitoring'.)

We prefer HCQ in these patient populations because this agent is very well tolerated, is effective, and has a very low risk of significant toxicity. However, HCQ may be less effective than other DMARDs for patients with RA who have moderate to high disease activity. There are no major contraindications to initiating therapy.

The clinical response to HCQ may be slower than the response to other DMARDs. While HCQ administration generally results in clinical improvement within two to three months, maximum effects may require up to four to six months of therapy. Whether measurement of HCQ drug concentrations might prove helpful in optimizing dosing and/or patient compliance in RA (as has been reported in SLE) remains unknown. (See "Antimalarial drugs in the treatment of rheumatic disease", section on 'Dosing'.)

HCQ has been compared with placebo in randomized trials in patients with active RA, where it exhibits moderate efficacy in RA compared with placebo and is very well tolerated [63-66]. A 2000 systematic review and meta-analysis of four trials, which involved 592 patients randomized to receive either HCQ or placebo, showed significant benefit from HCQ compared with placebo [67]. There were no differences between groups in withdrawals for toxicity, but withdrawals for lack of efficacy were significantly less frequent in the HCQ group. In one study, as an example, withdrawals for lack of efficacy at six months were significantly fewer with HCQ compared with placebo (16 versus 34 percent) [63].

Radiographic deterioration was comparable at 12 months in patients randomized to either HCQ or placebo in the one study that examined this question [63].

Other alternative agents — We generally reserve other agents for people who cannot use methotrexate, leflunomide or hydroxychloroquine.

●Sulfasalazine (SSZ) – We use SSZ for the initial therapy of RA when the patient prefers an oral agent, and the oral DMARDs discussed above are contraindicated. Dosing, adverse effects, and recommendations for monitoring SSZ are discussed in detail separately. (See "Sulfasalazine: Pharmacology, administration, and adverse effects in the treatment of rheumatoid arthritis".)

SSZ can also be used as an alternative to HCQ in patients with mild disease. SSZ works more quickly than HCQ and has greater clinical efficacy. However, it is not as well tolerated as HCQ [68].

Treatment adherence with SSZ regimens can be more difficult than with other DMARDs, given the need for two to three times daily administration of a total of four to six pills, as well as the occurrence of side effects, which may also limit its use in some patients [69,70]. One study demonstrated that 30 and 50 percent of patients stopped treatment due to adverse effects over two and five years of follow-up, respectively [29]. Patients who find adherence to SSZ challenging, and cannot use another oral DMARD, can be treated with a TNF inhibitor (see below).

The efficacy of SSZ monotherapy in the treatment of RA has been evaluated and documented in numerous randomized trials [68,71-80]. In a meta-analysis of eight randomized trials involving 903 patients, active therapy with SSZ was significantly more effective than placebo [75]. SSZ, compared with placebo, was more likely to significantly reduce the duration of morning stiffness (61 versus 33 percent), the number of painful joints (59 versus 33 percent), the number of swollen joints (51 versus 26 percent), and the amount of joint pain (42 versus 15 percent).

Among nonbiologic DMARDs, we prefer LEF over SSZ for patients with moderate to severe RA because of its potentially greater efficacy, especially for the treatment of moderate to severely active RA [46,51,52]. Some randomized trials suggest that LEF is more effective than SSZ in achieving a clinical response, decreasing functional disability, and reducing the progression of erosive changes [79,81-83]; others indicate comparable efficacy of the two agents [57,84].

Whether SSZ alone can retard the rate or prevent the development of erosive disease is less well established [68,77-80]. Studies from two major centers found a reduction in the development of new erosions in the first three years of disease in patients receiving SSZ, compared with placebo and with HCQ [68,77,85]. Another trial showed a statistically significantly lower eroded joint count and slower radiographic disease progression with SSZ compared with placebo and showed similar benefit from LEF [79].

●Tumor necrosis factor (TNF) inhibitor – We use TNF inhibitor monotherapy for the initial treatment of RA with moderate to high disease activity when MTX and LEF are contraindicated. We use etanercept for most patients. However, other TNF inhibitors, except for infliximab, can also be used (table 2). Issues regarding the use of TNF inhibitors for the treatment of RA, including dosing, administration, and implications for pregnancy, are discussed in detail elsewhere. (See "Treatment of rheumatoid arthritis in adults resistant to initial conventional synthetic (nonbiologic) DMARD therapy", section on 'TNF inhibitor plus methotrexate' and "Safety of rheumatic disease medication use during pregnancy and lactation", section on 'Tumor necrosis factor inhibitors'.)

We prefer TNF inhibitors over nonbiologic DMARDs in this population because, in our experience, TNF inhibitors are more efficacious than nonbiologic DMARDs for patients with RA who have high disease activity. TNF inhibitor monotherapy has been demonstrated to be effective (compared with placebo or MTX) in randomized trials of patients with RA who have moderate or high disease activity, including patients who were naïve to MTX and other DMARDs [19,20,39].

Etanercept is our first choice because it has a lower probability of developing drug-neutralizing antibodies and may have a lower risk of severe infection than other TNF inhibitors [86,87].

We do not use infliximab monotherapy due to the increased likelihood of developing neutralizing human antichimeric antibodies (HACA) when this chimeric monoclonal antibody is given without other immunosuppressive drugs. (See "Tumor necrosis factor-alpha inhibitors: Induction of antibodies, autoantibodies, and autoimmune diseases", section on 'Infliximab-induced human antichimeric antibodies'.)

DMARDs to avoid — We typically do not use azathioprine or minocycline for the initial treatment of RA, given the availability of more effective alternatives. We also do not use rituximab or sarilumab, given that they have not been evaluated in randomized trials for DMARD-naïve patients with early RA, although these agents would likely be an effective alternative to MTX.

Adjunctive symptomatic treatment — We use symptomatic treatment (eg, nonsteroidal antiinflammatory drugs [NSAIDs] and/or glucocorticoids) primarily for rapid control of disease activity until treatment with DMARDs brings the disease under control. However, while these treatments alleviate symptoms, they are less effective than DMARDs at preventing the long-term consequences of RA.

NSAIDs for most patients — We use NSAIDs in many patients with active RA (in the absence of contraindications to NSAID therapy) for control of symptoms when initiating DMARD therapy.

●Selection – There may be variability in the individual response to any given NSAID; therefore, the selection of a specific NSAID should be based on prior history of response, side effects, cost, and clinician and patient preference (table 3). We often start with meloxicam or celecoxib due to dosing convenience and lower gastrointestinal toxicity compared with other NSAIDs.

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 is no benefit from using multiple NSAIDs simultaneously; simultaneous use of multiple NSAIDs also increases the risk of gastrointestinal toxicity.

We generally continue treatment with a specific NSAID for two weeks prior to switching to another NSAID, because the maximal analgesic and antiinflammatory effect is usually achieved within 10 to 14 days.

●Dosing – We initiate NSAIDs at maximum allowed dose for the specific NSAID used, unless contraindicated by gastrointestinal, kidney, or cardiovascular disease; then, at two to three weeks, we taper when patient is doing better (table 3).

With usual drug safety monitoring, NSAIDs can be used with concomitant DMARDs, including MTX, without dose adjustment.

Older patients and others who may be at greater risk of adverse effects (eg, due to cardiovascular risk or kidney impairment) may need a reduced dose and more frequent monitoring.

Issues regarding the use of NSAIDs, including dosing, administration, monitoring, drug interactions, adverse effects, minimizing gastroduodenal toxicity, and implications for pregnancy, are discussed in detail elsewhere:

●(See "NSAIDs: Therapeutic use and variability of response in adults".)

●(See "Nonselective NSAIDs: Overview of adverse effects".)

●(See "Overview of COX-2 selective NSAIDs".)

Glucocorticoids for selected patients

●Indications – We use glucocorticoids for symptomatic treatment in the following scenarios:

•Patients with moderately to severely active disease (figure 1) (see "Assessment of rheumatoid arthritis disease activity and physical function", section on 'Composite indices for disease activity assessment')

•Patients with an inadequate response to 10 to 14 days of NSAID therapy or contraindications to NSAIDs

We avoid using glucocorticoids in combination with NSAIDs due to the increased risk of gastrointestinal toxicity. However, some patients may also require the use of NSAIDs for symptomatic relief; in such cases, we limit the NSAID dose and duration to the minimum required, given the increased risk of gastrointestinal toxicity.

Glucocorticoids have an extremely rapid onset of action and are often more effective than NSAIDs in controlling symptoms of active RA [88]. However, glucocorticoids are associated with a broader range of toxicities than NSAIDs, particularly when used repeatedly or continuously. (See "Major adverse effects of systemic glucocorticoids".)

●Oral glucocorticoids in most scenarios – For most patients, we suggest using prednisone 5 to 10 mg daily while initiating DMARDs. Some patients with severe disease may require up to 20 mg daily. Some studies have used relatively high-dose glucocorticoids for initial therapy (prednisone 60 mg daily or equivalent) [3,89]. However, lower doses are usually adequate when combined with effective DMARDs.

Glucocorticoids should be tapered as rapidly as tolerated, with the goal of discontinuing glucocorticoids entirely once disease control is achieved with DMARD therapy. In general, glucocorticoids can be discontinued entirely after four to six months of DMARD therapy.

Strategies for tapering oral glucocorticoids are discussed elsewhere. (See "Approach to discontinuing systemic glucocorticoid therapy in adults and children".)

●Parenteral glucocorticoids in specific scenarios

•Intramuscular glucocorticoids – We use intramuscular methylprednisolone (80 to 120 mg), administered as a single injection into the gluteal muscle, in patients who must avoid daily oral glucocorticoids (eg, due to severe gastritis) or who would benefit from an extremely rapid antiinflammatory response [90-92].

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 desired effect on controlling disease activity.

Longer-term use is avoided to prevent the harmful effects of glucocorticoids [90].

•Intraarticular glucocorticoids – We use intraarticular injections of long-acting glucocorticoids when synovitis is limited to one or two accessible joints.

In such patients, it may be difficult to distinguish between active joint inflammation due to RA alone and joint inflammation due to infection. Thus, when clinically indicated (presence of systemic signs or symptoms suggestive of infection or articular inflammation that is clearly disproportionate from the remainder of the joint examination), joint fluid should be obtained to exclude infection.

Indications, contraindications, and approach to joint aspiration and injection, as well as specific considerations regarding the use of intraarticular glucocorticoids, are discussed elsewhere. (See "Joint aspiration and injection in adults: Indications and technique" and "Intraarticular and soft tissue injections: What agent(s) to inject and how frequently?", section on 'Use of glucocorticoid injections'.)

Issues regarding the use of oral and parenteral glucocorticoids for RA, including efficacy, dosing, administration, and adverse effects, are discussed in detail elsewhere:

●(See "Use of glucocorticoids in the treatment of rheumatoid arthritis".)

●(See "Approach to discontinuing systemic glucocorticoid therapy in adults and children".)

●(See "Overview of the pharmacologic use of glucocorticoids", section on 'Choosing a glucocorticoid regimen'.)

Limited role for other analgesics — In addition to the medications noted above, we use analgesic medications, such as acetaminophen, for additional pain relief if required.

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 severe disease 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 with opioid analgesics is their association with an increased risk of hospitalization for serious infection in patients with RA. This has been attributed to impaired immune function [93], but respiratory depression and a sedentary level of activity may also be contributing factors.

Patients who need additional analgesia despite good control of their inflammatory disease should be evaluated for alternate or concurrent diagnoses, such as fibromyalgia, to explain the patient's symptoms. (See "Fibromyalgia: Clinical manifestations and diagnosis in adults" and "Overview of chronic widespread (centralized) pain in the rheumatic diseases".)

The evaluation of joint and musculoskeletal pain, as well as the use of analgesics, are discussed elsewhere:

●(See "Evaluation of the adult with polyarticular pain".)

●(See "Approach to the adult with unspecified knee pain".)

●(See "Overview of soft tissue musculoskeletal disorders".)

●(See "Approach to the management of acute pain in adults".)

REEVALUATION AND MONITORING — 

Disease activity and the response to therapy should be regularly reassessed, along with monitoring for drug toxicities, every three months following a change in the treatment regimen until the patient is stable and until the disease is under control [9,94-96]. The approach to monitoring patients with rheumatoid arthritis (RA) is discussed in detail elsewhere. (See "Overview of the management of rheumatoid arthritis in adults", section on 'Assessment and monitoring during treatment'.)

Monitoring and prevention of toxicities associated with methotrexate (MTX) are discussed in detail elsewhere. (See "Use of methotrexate in the treatment of rheumatoid arthritis" and "Major adverse effects of low-dose methotrexate".)

Monitoring and prevention of toxicities related to other disease-modifying antirheumatic drugs (DMARDs) are discussed in the relevant topic reviews. A general approach to monitoring patients with RA, including the assessment of RA activity and drug monitoring, is discussed in detail in the table (table 4).

THERAPY FOR RECURRENT OR RESISTANT DISEASE

Initial considerations — Prior to treatment for resistant disease or a flare, the clinician should examine the patient to confirm that the symptoms are due to rheumatoid arthritis (RA) and not another cause of musculoskeletal pain. When only one or two joints are affected, a joint aspiration may be needed to evaluate for the possibility of a septic arthritis.

Indications, contraindications, and approach to joint aspiration and injection, as well as the evaluation of other causes of joint and musculoskeletal pain (including septic arthritis), are presented elsewhere:

●(See "Joint aspiration and injection in adults: Indications and technique".)

●(See "Evaluation of the adult with polyarticular pain".)

●(See "Approach to the adult with unspecified knee pain".)

●(See "Overview of soft tissue musculoskeletal disorders".)

●(See "Septic arthritis in adults".)

Recurrent disease (disease flares) — Patients who have an increase in disease activity following a period of remission have recurrent disease (also known as a disease flare). We treat recurrent disease with glucocorticoids, using the approach described above, while maintaining their current disease-modifying antirheumatic drug (DMARD) regimen. If this is inadequate to achieve remission or low disease activity, we manage patients as having resistant disease (see below). (See 'Glucocorticoids for selected patients' above.)

Some patients may also require temporary use of nonsteroidal antiinflammatory drugs (NSAIDs) for symptom relief; in such cases, we limit the NSAID dose and duration to the minimum required, given the increased risk of gastrointestinal toxicity. Other analgesics are generally unnecessary. (See 'NSAIDs for most patients' above.)

Resistant disease — Patients are said to have resistant disease when they have persistent joint inflammation resistant to three or four months of therapy and therefore are not in remission or low disease activity or require more than 5 mg daily of prednisone to maintain low disease activity or remission.

For patients with resistant disease, we take the following stepwise approach:

●Add glucocorticoids – If not already in use, we add oral glucocorticoids to the patient’s current regimen, followed by a taper, as described above. (See 'Glucocorticoids for selected patients' above.)

●Optimize current DMARDs – For patients who have an incomplete response to glucocorticoids, or require repeated courses of glucocorticoids for disease control, we gradually titrate their current DMARDs to the maximum recommended dose.

For methotrexate (MTX), the maximum dose is 25 mg weekly. (See "Use of methotrexate in the treatment of rheumatoid arthritis", section on 'Dose titration'.)

For patients using MTX, we also optimize MTX absorption, either by administering it subcutaneously or splitting the oral dose into two smaller doses administered on the same day. The rationale supporting these strategies is described in detail elsewhere. (See "Use of methotrexate in the treatment of rheumatoid arthritis", section on 'Alternatives to once-weekly oral therapy'.)

With parenteral DMARDs, another strategy is to decrease the interval between doses. However, there may be payor restrictions on more frequent dosing, and more frequent dosing does not always lead to clinical benefit (in addition to possibly increasing the risk of adverse effects). For example, patients who have a suboptimal response to subcutaneous etanercept (50 mg weekly) do not benefit from receiving the etanercept 50 twice weekly [97].

●Add additional DMARDs – Some patients may require other DMARDs, in addition to MTX, to achieve remission. We suggest adding an additional DMARD to MTX in the following scenarios:

•Moderate to high disease activity despite optimized MTX dosing after three to four months (even if the patient has experienced some benefit)

•Need for chronic prednisone therapy (eg, more than prednisone 5 mg daily) to maintain remission or low disease activity despite three months of DMARD therapy

The decision to intensify or modify treatment also depends, in part, upon the patient's functional capacity, therapeutic goals, and quality of life. For example, 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) may prefer to remain on their current regimen, rather than adding an additional DMARD.

Selecting an appropriate DMARD for patients resistant to MTX (or other therapies) is discussed in detail elsewhere. (See "Treatment of rheumatoid arthritis in adults resistant to initial conventional synthetic (nonbiologic) DMARD therapy", section on 'Approach to pharmacotherapy' and "Treatment of rheumatoid arthritis in adults resistant to initial biologic DMARD therapy", section on 'Approach to pharmacotherapy'.)

DURATION OF THERAPY — 

In patients who achieve a sustained clinical remission for greater than one year, we cautiously try to reduce disease-modifying antirheumatic drug (DMARD) doses while closely monitoring the patient for evidence of disease flare or worsening. However, we generally avoid discontinuing all DMARD treatment. These issues are discussed in detail elsewhere. (See "Overview of the management of rheumatoid arthritis in adults", section on 'Tapering medications in patients with sustained remission'.)

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

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

●Basics topics (see "Patient education: Rheumatoid arthritis (The Basics)" and "Patient education: 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

●Pretreatment interventions – A number of interventions are required before using disease-modifying antirheumatic drugs (DMARDs); these include screening for viral hepatitis, interventions to reduce the risk of cardiovascular disease and osteoporosis, immunizations, and nonpharmacologic interventions. Some patients may require additional pretreatment interventions, depending on the specific DMARDs used. (See "Overview of the management of rheumatoid arthritis in adults", section on 'Pretreatment assessments and interventions'.)

●Initial therapy – In all patients with active rheumatoid arthritis (RA), we recommend early treatment with a DMARD, rather than using antiinflammatory agents and/or glucocorticoids alone and delaying DMARD therapy (Grade 2C). There is widespread expert consensus for this approach. (See 'Early DMARD therapy for all patients' above.)

•MTX for most patients – We suggest methotrexate (MTX) as the initial DMARD, rather than another single nonbiologic or biologic DMARD or combination therapy (Grade 2C). However, MTX is contraindicated in patients who are pregnant or contemplating pregnancy, have liver disease or kidney infection impairment, or consume more than one alcoholic drink daily. (See 'Methotrexate for most patients' above.)

•Alternative regimens – In patients who are unable or unwilling to take MTX, preferred alternative DMARD therapies include (see 'Preferred alternatives to methotrexate' above):

-Hydroxychloroquine (HCQ) or sulfasalazine (SSZ) – For patients with mild disease

-Leflunomide (LEF) or tumor necrosis factor (TNF) inhibitor – For patients with moderate to severe disease activity

●Symptom management – In patients with active RA, we use antiinflammatory drug therapy with nonsteroidal antiinflammatory drugs (NSAIDs) or glucocorticoids, preferably on a temporary basis, to quickly achieve control of signs and symptoms of disease. We then taper and withdraw these medications once DMARDs have taken effect. (See 'Adjunctive symptomatic treatment' above.)

•NSAIDs – We use NSAIDs in all patients unless contraindicated by gastrointestinal, kidney, or cardiovascular disease (table 3).

•Glucocorticoids – In patients with moderate to severe disease or who are resistant to 10 to 14 days of NSAID therapy, we suggest using glucocorticoids (Grade 2B).

When glucocorticoids are indicated, we generally use prednisone 5 to 10 mg daily, with a goal of tapering off over the subsequent four to six months. We use intraarticular injections of long-acting glucocorticoids when synovitis is limited to one or two accessible joints. We use intramuscular methylprednisolone (80 to 120 mg), administered as a single injection into the gluteal muscle, in patients who must avoid daily oral glucocorticoids (eg, due to severe gastritis) or who would benefit from an extremely rapid antiinflammatory response.

●Limited role for other analgesics – Analgesic medications (eg, acetaminophen, narcotics) are most useful for patients with end-stage disease that is unresponsive to DMARDs. Analgesics have a limited role in the management of severe, active disease. A need for analgesic medications when the inflammatory disease is well controlled should prompt a search for alternate diagnoses, such as fibromyalgia. (See 'Limited role for other analgesics' above.)

●Monitoring – During the initial treatment of patients with active RA, the patient should be reevaluated every three months for the effectiveness of therapy and for the monitoring of possible drug toxicity. Monitoring should continue at that frequency until the patient is stable and the disease is under control. (See "Overview of the management of rheumatoid arthritis in adults", section on 'Assessment and monitoring during treatment'.)

●Resistant disease and disease flares – We treat resistant disease and disease flares with glucocorticoids followed by a taper, as tolerated, with a goal of discontinuing them entirely. Some patients may also require the temporary use of NSAIDs for symptomatic relief; in such cases, we limit the NSAID dose and duration to the minimum required, given the increased risk of gastrointestinal toxicity.

For patients with resistant disease who have an incomplete response to glucocorticoids or require repeated courses of glucocorticoids to maintain disease control, we gradually titrate their current DMARDs to the maximum recommended dose. For patients using MTX, absorption can be optimized by administering it subcutaneously or splitting the oral dose into two smaller doses, administered on the same day. (See 'Therapy for recurrent or resistant disease' above.)

For patients who fail to respond to these strategies, we add additional DMARDs to MTX. (See "Treatment of rheumatoid arthritis in adults resistant to initial conventional synthetic (nonbiologic) DMARD therapy".)

●Therapy duration – In patients who achieve a sustained clinical remission for greater than one year, we cautiously try to reduce DMARD doses while closely monitoring the patient for evidence of disease flare. However, we generally avoid discontinuing all DMARD treatment. (See "Overview of the management of rheumatoid arthritis in adults", section on 'Tapering medications in patients with sustained remission'.)

ACKNOWLEDGMENT — 

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

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Topic 7491 Version 35.0

References

1 : Factors predicting response to treatment in rheumatoid arthritis: the importance of disease duration.

2 : Evidence for treating rheumatoid arthritis to target: results of a systematic literature search.

3 : Clinical and radiographic outcomes of four different treatment strategies in patients with early rheumatoid arthritis (the BeSt study): a randomized, controlled trial.

4 : Comparison of treatment strategies in early rheumatoid arthritis: a randomized trial.

5 : Progression of joint damage in early rheumatoid arthritis: association with HLA-DRB1, rheumatoid factor, and anti-citrullinated protein antibodies in relation to different treatment strategies.

6 : Comparison of combination therapy with single-drug therapy in early rheumatoid arthritis: a randomised trial. FIN-RACo trial group.

7 : Impact of initial aggressive drug treatment with a combination of disease-modifying antirheumatic drugs on the development of work disability in early rheumatoid arthritis: a five-year randomized followup trial.

8 : The good initial response to therapy with a combination of traditional disease-modifying antirheumatic drugs is sustained over time: the eleven-year results of the Finnish rheumatoid arthritis combination therapy trial.

9 : Effect of a treatment strategy of tight control for rheumatoid arthritis (the TICORA study): a single-blind randomised controlled trial.

10 : Intensive treatment with methotrexate in early rheumatoid arthritis: aiming for remission. Computer Assisted Management in Early Rheumatoid Arthritis (CAMERA, an open-label strategy trial).

11 : Rheumatoid arthritis.

12 : Radiographic progression is getting milder in patients with early rheumatoid arthritis. Results of 3 cohorts over 5 years.

13 : 2022 American College of Rheumatology Guideline for Exercise, Rehabilitation, Diet, and Additional Integrative Interventions for Rheumatoid Arthritis.

14 : Long-term impact of early treatment on radiographic progression in rheumatoid arthritis: A meta-analysis.

15 : Early versus delayed treatment in patients with recent-onset rheumatoid arthritis: comparison of two cohorts who received different treatment strategies.

16 : Benefit of very early referral and very early therapy with disease-modifying anti-rheumatic drugs in patients with early rheumatoid arthritis.

17 : Association of socioeconomic status with treatment delays, disease activity, joint damage, and disability in rheumatoid arthritis.

18 : Evaluating relationships between symptom duration and persistence of rheumatoid arthritis: does a window of opportunity exist? Results on the Leiden early arthritis clinic and ESPOIR cohorts.

19 : A comparison of etanercept and methotrexate in patients with early rheumatoid arthritis.

20 : The PREMIER study: A multicenter, randomized, double-blind clinical trial of combination therapy with adalimumab plus methotrexate versus methotrexate alone or adalimumab alone in patients with early, aggressive rheumatoid arthritis who had not had previous methotrexate treatment.

21 : Two-year clinical and radiographic results with combination etanercept-methotrexate therapy versus monotherapy in early rheumatoid arthritis: a two-year, double-blind, randomized study.

22 : Combination of infliximab and methotrexate therapy for early rheumatoid arthritis: a randomized, controlled trial.

23 : Rheumatoid arthritis: strategy more important than agent.

24 : TEAR: Treatment of early aggressive RA: A randomized, double-blind, 2-year trial comparing immediate triple DMARD versus MTX plus etanercept to step-up from initial MTX monotherapy

25 : Guidelines for the management of rheumatoid arthritis: 2002 Update.

26 : How Canadian and US rheumatologists treat moderate or aggressive rheumatoid arthritis: a survey.

27 : Treatment of rheumatoid arthritis: state of the art 2009.

28 : Quantifying the hepatotoxic risk of alcohol consumption in patients with rheumatoid arthritis taking methotrexate.

29 : Meta-analysis of treatment termination rates among rheumatoid arthritis patients receiving disease-modifying anti-rheumatic drugs.

30 : Methotrexate and mortality in patients with rheumatoid arthritis: a prospective study.

31 : Propensity-adjusted association of methotrexate with overall survival in rheumatoid arthritis.

32 : Efficacy of low-dose methotrexate in rheumatoid arthritis.

33 : Long-term prospective study of methotrexate in the treatment of rheumatoid arthritis. 84-month update.

34 : Methotrexate in rheumatoid arthritis. A five-year prospective multicenter study.

35 : Comparison of low-dose oral pulse methotrexate and placebo in the treatment of rheumatoid arthritis. A controlled clinical trial.

36 : Safety, efficacy, and mortality in a long-term cohort of patients with rheumatoid arthritis taking methotrexate: followup after a mean of 13.3 years.

37 : Methotrexate for treating rheumatoid arthritis.

38 : Comparing the long-term clinical outcome of treatment with methotrexate or sulfasalazine prescribed as the first disease-modifying antirheumatic drug in patients with inflammatory polyarthritis.

39 : A systematic comparison of combination DMARD therapy and tumour necrosis inhibitor therapy with methotrexate in patients with early rheumatoid arthritis.

40 : Association of methotrexate and tumour necrosis factor antagonists with risk of infectious outcomes including opportunistic infections in the CORRONA registry.

41 : Tofacitinib versus methotrexate in rheumatoid arthritis.

42 : Baricitinib, Methotrexate, or Combination in Patients With Rheumatoid Arthritis and No or Limited Prior Disease-Modifying Antirheumatic Drug Treatment.

43 : Efficacy and Safety of Upadacitinib Monotherapy in Methotrexate-Naive Patients With Moderately-to-Severely Active Rheumatoid Arthritis (SELECT-EARLY): A Multicenter, Multi-Country, Randomized, Double-Blind, Active Comparator-Controlled Trial.

44 : A randomized comparative effectiveness study of oral triple therapy versus etanercept plus methotrexate in early aggressive rheumatoid arthritis: the treatment of Early Aggressive Rheumatoid Arthritis Trial.

45 : Validation of the methotrexate-first strategy in patients with early, poor-prognosis rheumatoid arthritis: results from a two-year randomized, double-blind trial.

46 : American College of Rheumatology 2008 recommendations for the use of nonbiologic and biologic disease-modifying antirheumatic drugs in rheumatoid arthritis.

47 : Two-year radiographic results from the TEAR trial

48 : State-of-the-art: rheumatoid arthritis.

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55 : Randomised comparison of combined step-down prednisolone, methotrexate and sulphasalazine with sulphasalazine alone in early rheumatoid arthritis.

56 : Triple therapy in early active rheumatoid arthritis: a randomized, single-blind, controlled trial comparing step-up and parallel treatment strategies.

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67 : Antimalarials for treating rheumatoid arthritis.

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69 : Low Persistence Rates in Patients With Rheumatoid Arthritis Treated With Triple Therapy and Adverse Drug Events Associated With Sulfasalazine.

70 : Retention rates of disease-modifying anti-rheumatic drugs in patients with rheumatoid arthritis.

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88 : Meta-analysis of short-term low dose prednisolone versus placebo and non-steroidal anti-inflammatory drugs in rheumatoid arthritis.

89 : Drug-free remission, functioning and radiographic damage after 4 years of response-driven treatment in patients with recent-onset rheumatoid arthritis.

90 : Intramuscular methylprednisolone is superior to pulse oral methylprednisolone during the induction phase of chrysotherapy.

91 : A two year randomised controlled trial of intramuscular depot steroids in patients with established rheumatoid arthritis who have shown an incomplete response to disease modifying antirheumatic drugs.

92 : Beneficial effects of a 3-week course of intramuscular glucocorticoid injections in patients with very early inflammatory polyarthritis: results of the STIVEA trial.

93 : Opioid Analgesics and the Risk of Serious Infections Among Patients With Rheumatoid Arthritis: A Self-Controlled Case Series Study.

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