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

INTRODUCTION — The treatment of rheumatoid arthritis (RA) is directed toward the control of synovitis and the prevention of joint injury. In patients whose condition is resistant to an initial course of treatment with a nonbiologic (also termed conventional synthetic [cs] or traditional) disease-modifying antirheumatic drug (csDMARD), such as methotrexate (MTX), timely adjustments in the treatment regimen are required to achieve effective disease control and prevent damage to the joints. (See 'Principles of management' below and 'Definition of resistance to initial therapy with conventional synthetic DMARDs' below.)

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 disease activity persists, the less likely the patient is to respond to therapy [1]. Improved outcomes have resulted from the use of potent and well-tolerated csDMARDs and biologic DMARDs used alone and in combination to induce and maintain tight control of disease [2-10]. These medications and strategies have the potential to control synovitis and to slow or even stop radiographic progression [2,9,11,12].

The treatment of active RA in adults who are resistant to initial therapy with a csDMARD (eg, MTX monotherapy) will be reviewed here. The general principles of the management of RA, initial treatment of RA, the treatment of patients resistant to initial therapy with biologic DMARDs, and the approach to RA patients with severe structural damage are presented separately. (See "General principles and overview of management of rheumatoid arthritis in adults" and "Initial treatment of rheumatoid arthritis in adults" and "Alternatives to methotrexate for the initial treatment of rheumatoid arthritis in adults" and "Treatment of rheumatoid arthritis in adults resistant to initial biologic DMARD therapy" and "Evaluation and medical management of end-stage rheumatoid arthritis" and "Surgical management of end-stage rheumatoid arthritis".)

GENERAL PRINCIPLES AND APPROACH

Principles of management — There are several general principles, discussed in detail separately, that are important in the management of all patients with rheumatoid arthritis (RA) (see "General principles and overview of management of rheumatoid arthritis in adults"). Briefly, these include:

●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

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

●Evaluation and ongoing care by an expert in the treatment of RA, typically a rheumatologist

Definition of resistance to initial therapy with conventional synthetic DMARDs — Resistance to initial conventional synthetic (cs) DMARD therapy is defined as one of the following:

●Failure to achieve remission or low disease activity within three to six months of initiating methotrexate (MTX) or other csDMARD therapy in maximally tolerated doses within the usual therapeutic range. A therapeutic trial of greater than three months is generally used in patients with partial responses showing progressive improvement, particularly in those with low to moderate levels of disease activity and with limited functional impairment. Treatment should be appropriate for the patient's overall medical status and comorbidities and should take into consideration the patient's treatment goals and preferences. (See "Initial treatment of rheumatoid arthritis in adults" and "Assessment of rheumatoid arthritis disease activity and physical function", section on 'Criteria for remission'.)

●A requirement, in addition to DMARDs, for chronic glucocorticoid therapy in a dose of greater than approximately 5 mg/day of prednisone or equivalent to achieve or maintain remission or low disease activity after three to six months of treatment with DMARDs.

●A requirement for multiple courses of treatment with glucocorticoids, in excess of doses used for chronic therapy, for the treatment of recurrent disease flares in patients whose medication doses have been increased to the maximally tolerated or acceptable level.

●Continued progression of erosive disease or structural damage that is not accounted for by prior joint damage.

Resistance or an inadequate response to DMARD therapy may be defined similarly, depending upon the treatment goals in an individual patient. (See "General principles and overview of management of rheumatoid arthritis in adults", section on 'Tight control'.)

Determination of inflammatory disease activity must account for joint symptoms related to prior joint damage and disability, as well as a concomitant illness, such as fibromyalgia. Symptoms due to these other causes would not benefit from the addition of immunomodulatory therapy with DMARDs. (See "Assessment of rheumatoid arthritis disease activity and physical function" and "General principles and overview of management of rheumatoid arthritis in adults", section on 'Assessment and monitoring'.)

Nonpharmacologic and preventive therapies — In addition to pharmacologic therapy, a number of nonpharmacologic measures and other medical interventions are important in the comprehensive management of RA. These interventions, including patient education; instruction regarding rest, exercise, and nutrition; and others, are discussed in detail elsewhere. (See "Nonpharmacologic therapies for patients with rheumatoid arthritis".)

PRETREATMENT INTERVENTIONS — A number of important precautions should be taken before using disease-modifying antirheumatic drugs (DMARDs), including laboratory assessment (complete blood count, serum creatinine, aminotransferases, and other studies as indicated); evaluation of comorbidities; vaccinations; and screening for hepatitis C, hepatitis B, and latent tuberculosis infection. Precautions relevant to the use of each new agent being prescribed should be reviewed before initiating such therapy to confirm that all appropriate measures have been performed. Some experts also obtain a baseline chest radiograph prior to initiating treatment with methotrexate (MTX) in patients in whom a recent chest radiograph is not available. These issues are discussed in detail elsewhere. (See "Immunizations in autoimmune inflammatory rheumatic disease in adults" and "Hepatitis B virus reactivation associated with immunosuppressive therapy" and "Risk of mycobacterial infection associated with biologic agents and JAK inhibitors" and "Major side effects of low-dose methotrexate", section on 'Pulmonary toxicity' and "General principles and overview of management of rheumatoid arthritis in adults", section on 'Pretreatment evaluation' and "Tuberculosis infection (latent tuberculosis) in adults: Approach to diagnosis (screening)".)

PHARMACOTHERAPY

General approach — In patients resistant to initial disease-modifying antirheumatic drug (DMARD) therapy, 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 'Definition of resistance to initial therapy with conventional synthetic DMARDs' above and 'Symptomatic drug therapy' below). The choices include both conventional synthetic (cs) and biologic DMARDs. The specific approach is influenced by the treatments the patient has already received and the level of disease activity:

●Resistant to hydroxychloroquine or sulfasalazine – In patients with only mildly active disease when DMARDs were initiated, hydroxychloroquine (HCQ) or sulfasalazine (SSZ) may have been started, and the patient may not have received methotrexate (MTX). Such patients should then be started on MTX, either in place of or in addition to these agents. (See 'Resistant to hydroxychloroquine and/or sulfasalazine' below.)

●Resistant to methotrexate – In patients who have already been treated with MTX without achieving therapeutic goals, treatment combining MTX with other csDMARDs or with a biologic DMARD is the next step. (See 'Resistant to methotrexate' below.)

Drug choice should also be tailored to the individual patient based upon their comorbid conditions, fertility considerations, and preference for route of administration (oral versus parenteral), as well as regulatory or insurance limitations and cost to the patient. (See 'Choice of therapy' below.)

Resistant to hydroxychloroquine and/or sulfasalazine

●Treatment options – In patients with initially mildly active disease who are resistant to three to six months of therapy with HCQ or SSZ, we suggest adding MTX along with both HCQ and SSZ or switching to MTX monotherapy; the approach in these patients is generally similar to that for patients with moderately to severely active disease presenting for initial DMARD therapy. When MTX is added to the regimen of HCQ and SSZ, this is termed "triple therapy." The continued or added use of HCQ, SSZ, or both depends upon drug tolerance and patient willingness to take several oral agents. (See "Alternatives to methotrexate for the initial treatment of rheumatoid arthritis in adults", section on 'Monitoring and reevaluation' and "Initial treatment of rheumatoid arthritis in adults", section on 'Initial therapy with methotrexate' and 'DMARD triple therapy' below.)

A therapeutic trial of greater than three months can be used in patients with partial responses showing progressive improvement, particularly in those in this group with low levels of disease activity and limited functional impairment. In most cases, if there has not been a significant response after 12 weeks on a particular regimen, then a change in the therapeutic regimen is required. For example, patients receiving MTX can benefit from an increased dose or switching to subcutaneous administration if the dose has not already been optimized. (See "Use of methotrexate in the treatment of rheumatoid arthritis", section on 'Dosing and administration'.)

●Efficacy and rationale – We prefer MTX over alternative csDMARDs and biologic DMARDs in such patients for several reasons. MTX typically serves as the "anchor" drug for the most commonly used DMARD combinations [13-15]. Randomized head-to-head trials have found that MTX has a faster onset of action, comparable or greater efficacy, better long-term tolerance, and results in improved survival compared with other csDMARD monotherapy [16,17]. Direct comparisons of MTX with tumor necrosis factor (TNF) inhibitor monotherapy have also shown similar clinical benefit, with American College of Rheumatology (ACR) 20 percent (ACR20), ACR50, and ACR70 responses after 6 to 12 months of approximately 60, 40, and 20 percent, respectively [18,19].

Additionally, those patients with an inadequate response to MTX can be quickly identified and subsequently treated prior to the development of irreversible injury [18-23]. There is also some evidence that infectious risk may be greater with biologic agents, and there are frequently regulatory or cost barriers to the use of biologic therapies in patients who have not been treated with MTX.

Treatment with MTX is reviewed in detail separately. (See "Initial treatment of rheumatoid arthritis in adults", section on 'Initial therapy with methotrexate' and "Initial treatment of rheumatoid arthritis in adults", section on 'Methotrexate versus other DMARDs' and "Initial treatment of rheumatoid arthritis in adults", section on 'Methotrexate versus initial combination therapy'.)

The efficacy of "triple therapy" with this DMARD combination is discussed in further detail below. (See 'Efficacy of triple DMARD therapy versus methotrexate/TNF inhibitor' below.)

Resistant to methotrexate

Choice of therapy — In patients resistant to MTX after three to six months of treatment at optimal doses and route of administration (usually 25 mg/week), we suggest either the use of DMARD "triple therapy" with MTX plus SSZ and HCQ, or the combination of continued MTX plus the addition of a TNF inhibitor, rather than monotherapy with another csDMARD, biologic DMARD, or targeted synthetic (ts) DMARD. Professional society guidelines favor the addition of a biologic DMARD or tsDMARD over triple therapy in an MTX nonresponder [24]. That guideline was "vigorously debated," and ultimately advised based upon patient preference for faster resolution of symptoms than with csDMARD triple therapy. We continue to utilize both approaches, as triple therapy has shown equal long-term efficacy to the combination of MTX plus anti-TNF therapy. Concerning safety data on tsDMARDs (Janus kinase [JAK] inhibitor class) have led to guidance that they be used only after an inadequate response to a TNF inhibitor [25]. Optimization of MTX therapy is described in more detail separately (see "Use of methotrexate in the treatment of rheumatoid arthritis"). Reasonable alternatives to these approaches include a JAK inhibitor, which can be classified as a tsDMARD, or a non-TNF inhibitor biologic DMARD in combination with MTX. (See 'Alternatives to triple therapy and methotrexate/TNF inhibitor' below.)

In patients with partial responses or showing progressive improvement, we may continue therapy with MTX for greater than three months before switching to one of these approaches, particularly in those with low to moderate levels of disease activity and with limited functional impairment. Another option would be switching from oral to subcutaneous MTX to see if the response could be enhanced. Studies evaluating subcutaneous MTX have demonstrated greater bioavailability, and approximately 30 percent of patients who switched had improvement in clinical response. (See "Use of methotrexate in the treatment of rheumatoid arthritis", section on 'Parenteral therapy' and 'DMARD triple therapy' below and 'Methotrexate plus TNF inhibitor' below and 'Alternatives to triple therapy and methotrexate/TNF inhibitor' below.)

In patients begun on a biologic DMARD (eg, a TNF inhibitor) or tsDMARD (eg, a JAK inhibitor), we generally continue MTX, unless contraindicated; in this setting, MTX may improve the degree of clinical and radiographic benefit and, for certain biologics, can inhibit the development of antibodies directed at the biologic agent that can reduce efficacy, as demonstrated in multiple clinical trials [26] (see "Tumor necrosis factor-alpha inhibitors: Induction of antibodies, autoantibodies, and autoimmune diseases", section on 'Anti-drug antibodies'). However, in our experience and that of others, as many as 30 percent of patients discontinue their csDMARD, usually MTX, after they obtain benefit with biologic DMARDs or with a tsDMARD (eg, JAK inhibitor) therapy [27]. Continued MTX cotherapy may be less important in patients on the latter agents (see 'JAK inhibitor therapy' below). Short-term studies have shown largely similar clinical benefit, but little long-term data are available regarding comparative effects upon radiographic progression.

Most patients who escalate their therapy receive TNF inhibitors based upon substantial clinical experience with these agents since the late 1990s. Leflunomide (LEF) is an alternative for patients unable to take MTX. JAK inhibitors, including tofacitinib, baricitinib, upadacitinib, filgotinib, peficitinib; abatacept, the T-cell costimulation blocker; and tocilizumab and sarilumab, the interleukin (IL) 6 inhibitors are alternatives to TNF inhibitors for use in combination with MTX in patients with an inadequate response to MTX.

The choice of a drug regimen in such patients depends upon a combination of factors, including the level of disease activity, the presence of comorbid conditions, patient preferences for route of administration and frequency of dosing, the presence of adverse prognostic features, and regulatory and cost barriers to drug access. The role of specific comorbidities in the choice of therapy is discussed in more detail separately. (See "General principles and overview of management of rheumatoid arthritis in adults", section on 'Comorbidities and disease management'.)

We take the following general approach to choosing from the available treatment options:

●Preference for oral agents and/or regulatory or cost limits on biologic DMARD and tsDMARD use – We prefer triple therapy with MTX, SSZ, and HCQ in patients for whom personal drug cost, regulatory restrictions on the use of biologic agents and JAK inhibitors, or preference for an oral nonbiologic agent, rather than an injectable, is an important factor. The use of triple therapy has been shown to provide comparable or near-comparable benefit, depending upon the trial, and to do so at a markedly lower total cost, being highly cost-effective compared with combining a biologic with MTX [28,29]. In addition, concern regarding the risk of serious infections, uncertainty in the setting of previous or current malignancy, and other possible adverse effects may influence clinician or patient preference for conventional synthetic agents [30-33]. (See 'DMARD triple therapy' below and 'Efficacy of triple DMARD therapy versus methotrexate/TNF inhibitor' below.)

●High disease activity and adverse prognostic features – We prefer combination therapy with MTX plus a TNF inhibitor in patients who would benefit from a more rapid therapeutic response, particularly those with high levels of disease activity and with adverse prognostic features. These features, several or more of which are often present, include high titer rheumatoid factor or anti-citrullinated peptide antibody, elevated C-reactive protein (CRP), and baseline erosive disease. All of the available TNF inhibitors appear to provide comparable benefit. These regimens may have a faster onset of action compared with csDMARD triple therapy. (See 'Methotrexate plus TNF inhibitor' below.)

Reasonable alternatives include several other parenterally administered agents, including the anti-IL-6 receptor antibodies and abatacept; and the oral ts JAK inhibitors. However, use of a TNF inhibitor or other biologic requires subcutaneous injections or intravenous infusions, and regulatory or cost considerations may limit access to these agents and to the JAK inhibitors. (See 'Alternatives to triple therapy and methotrexate/TNF inhibitor' below.)

●Inadequate response to conventional nonbiologic DMARD triple therapy – The combination of MTX with a TNF inhibitor is also preferred for patients who do not achieve a satisfactory response within three to six months with csDMARD triple therapy following an inadequate response to MTX. In such patients, we either discontinue SSZ and HCQ and administer a TNF inhibitor with the MTX, or continue both the HCQ and SSZ (or just one of the agents, usually the HCQ) when adding a TNF inhibitor, particularly in patients who have experienced partial clinical benefit. (See 'Methotrexate plus TNF inhibitor' below and "Tumor necrosis factor-alpha inhibitors: An overview of adverse effects".)

●Unable to use methotrexate and without regulatory or cost limits on biologic agents – In patients who have ready access to biologic agents but are intolerant to or otherwise unable to use MTX (eg, during pregnancy), we use a biologic, such as a TNF inhibitor, as monotherapy. In some patients, csDMARDs other than MTX may be used as an alternative to help prevent anti-drug antibodies. Management of RA during pregnancy is described separately. (See 'Alternatives to triple therapy and methotrexate/TNF inhibitor' below and "Rheumatoid arthritis and pregnancy".)

●Unable to use methotrexate and regulatory or cost limits on biologic availability – LEF is an alternative for patients unable to take MTX; it is an orally administered nonbiologic DMARD and immunosuppressive agent, which may be used as monotherapy or in combination with nonbiologic or biologic DMARDs. LEF may be of particular benefit for patients in whom regulatory or cost considerations preclude use of a biologic agent, despite failure of MTX to adequately control disease activity. It can be used as an alternative to MTX in those patients who do not tolerate MTX, whose renal function is moderately impaired such that use of MTX is contraindicated, and in those for whom MTX is inadequate, particularly patients who prefer not to use a medication requiring subcutaneous or intravenous administration. It can be used in combination with MTX instead of adding a biologic agent, with appropriate monitoring of liver function tests. (See 'Leflunomide' below and "Initial treatment of rheumatoid arthritis in adults", section on 'Alternatives to methotrexate' and "Alternatives to methotrexate for the initial treatment of rheumatoid arthritis in adults", section on 'Choice of therapy'.)

●Alternatives to a TNF inhibitor as initial biologic or targeted synthetic DMARD

•Abatacept and IL-6 inhibitors – Abatacept, the T-cell costimulation blocker, and tocilizumab and sarilumab, the IL-6 receptor inhibitors, may be used as alternatives to a TNF inhibitor in patients in whom MTX plus a TNF inhibitor would otherwise be appropriate, particularly in patients unable to use a TNF inhibitor. They have similar efficacy to the TNF inhibitors; however, their use in this setting is supported by a smaller body of evidence than that for TNF inhibitor use. (See 'Methotrexate plus abatacept' below and 'Methotrexate plus IL-6 inhibitor/IL-6 inhibitor monotherapy' below.)

Both abatacept and tocilizumab can be administered intravenously or subcutaneously, and sarilumab is administered by subcutaneous injection. Usual practice since TNF inhibitors came into clinical use beginning in the late 1990s has been to add a TNF inhibitor to MTX in patients with an inadequate response to MTX or combinations of nonbiologic DMARDs. Abatacept and tocilizumab have each generally been used in practice only following inadequate responses to both MTX and TNF inhibitors, but both of these biologic agents are available for use in the United States for patients who have not responded adequately to MTX alone. Sarilumab, like tocilizumab, is an IL-6 inhibitor that can also be used in this population; the efficacy and adverse effects of these two agents are similar, although there is less experience with sarilumab. (See 'Methotrexate plus abatacept' below and 'Methotrexate plus IL-6 inhibitor/IL-6 inhibitor monotherapy' below.)

•JAK inhibitors – The JAK inhibitors, primarily tofacitinib, are increasingly used in this population, having been available since 2012 for clinical use, and given many patients' preference for an oral alternative to the biologic agents, which are all administered parenterally. Clinical trials with tofacitinib and baricitinib have demonstrated similar efficacy to adalimumab (ADA) in MTX-incomplete responders. In one trial upadacitinib was superior to ADA. These therapies can be used in combination with MTX or as monotherapy, although there is less experience with upadacitinib than the other agents. (See 'JAK inhibitor therapy' below.)

•Rituximab – Rituximab is another alternative that may have similar efficacy to a TNF inhibitor in seropositive patients, but regulatory restrictions may limit its availability in some patients before a TNF inhibitor has been tried. However, rituximab is preferred in the subset of patients with a prior lymphoproliferative malignancy. The use and efficacy of rituximab in patients with an inadequate response to csDMARD therapy are described below. (See 'Methotrexate plus rituximab' below.)

DMARD triple therapy

Triple DMARD administration and dosing — Drug dosing for triple therapy is as follows:

●MTX is continued at the maximum tolerated dose achieved with initial therapy up to 25 mg once weekly. The use of MTX in rheumatoid arthritis (RA) and the adverse effects of MTX are described in detail separately. (See "Use of methotrexate in the treatment of rheumatoid arthritis" and "Major side effects of low-dose methotrexate" and "Initial treatment of rheumatoid arthritis in adults".)

●SSZ is gradually increased from 500 mg twice daily to 1000 to 1500 mg twice daily. The use of SSZ in RA and the adverse effects of SSZ are described in detail separately. (See "Sulfasalazine: Pharmacology, administration, and adverse effects in the treatment of rheumatoid arthritis" and "Alternatives to methotrexate for the initial treatment of rheumatoid arthritis in adults", section on 'Sulfasalazine'.)

●HCQ is used at a dose of 400 mg daily in most patients but should not exceed 5 mg/kg/day calculated on the basis of real body weight. The use of HCQ in rheumatic disease, including RA, as well as the dosing, adverse effects, and monitoring of HCQ are discussed in detail separately. (See "Antimalarial drugs in the treatment of rheumatic disease" and "Alternatives to methotrexate for the initial treatment of rheumatoid arthritis in adults" and "Alternatives to methotrexate for the initial treatment of rheumatoid arthritis in adults", section on 'Hydroxychloroquine'.)

Treatment with the triple therapy regimen is usually well tolerated, with adverse effects comparable to MTX alone, and the available evidence indicates that switching to a regimen containing a biologic agent in patients who do not first respond adequately to a three- to six-month trial of triple therapy, including patients with high levels of disease activity or with adverse prognostic features, results in similar patient outcomes compared with initiation of a biologic agent sooner [34].

Efficacy of triple DMARD therapy versus methotrexate/TNF inhibitor — The triple therapy regimen (MTX plus SSZ plus HCQ) has been found to be of similar clinical efficacy to MTX plus a biologic in several randomized trials, including in patients with high levels of disease activity or with adverse prognostic features (see "General principles and overview of management of rheumatoid arthritis in adults", section on 'Prognosis'). As examples, three randomized trials have compared the combination of MTX plus a TNF inhibitor with DMARD triple therapy combining MTX plus SSZ and HCQ [34-37]; two of the trials found no significant differences in clinical efficacy using composite measures of disease activity (eg, ACR20 responses of approximately 35 to 60 percent after one or two years) [34,37], while one of the trials showed a significant difference at 12 months but not at 6, 9, or 24 months [35,36]. Radiographic outcomes only slightly favored TNF inhibitor use, but these differences did achieve statistical if not clinical significance in some of the trials.

Limitations in trial design and the use of different TNF inhibitors in the published reports preclude adequate direct comparisons of the regimens in the two trials of patients with early disease [35-37]; both trials included a step-up design for at least a portion of the patients, in which patients were randomly assigned (either before or after initial treatment with MTX) to receive one of the two treatment options following an inadequate response to MTX. The third trial had a double-blind design and enrolled patients with more longstanding disease (mean duration since diagnosis of 4.9 to 5.5 years) who had also had inadequate responses to MTX [34]:

●Swefot trial – The Swedish Pharmacotherapy (Swefot) trial compared the efficacy of MTX plus infliximab with that of triple therapy using MTX, SSZ, and HCQ [35,36,38]. This randomized but nonblinded trial involved 258 patients with RA of less than one year in duration who had not achieved low disease activity within three to four months of starting treatment with MTX alone (20 mg once weekly). Differences between the groups were not significant at six or nine months, but, by one year (nine months after randomization and one year after initiating DMARD therapy with MTX alone), there was a significantly higher proportion of good responders (by the European Alliance of Associations for Rheumatology [EULAR; formerly known as European League Against Rheumatism] response criteria) among the group receiving infliximab (39 versus 25 percent, risk ratio [RR] 1.59, 95% CI 1.10-2.30). However, by two years, this difference was not apparent, and the trend toward a higher frequency of good responders in the infliximab group was no longer statistically significant (38 versus 31 percent, RR 1.31, 95% CI 0.93-1.85). A similar proportion of each group achieved an ACR20 response at two years (40 versus 33 percent). Interpretation of these results is hampered by the open design of this trial and by the switching of some patients to alternate therapies within the trial, particularly since the initial switch in the triple-therapy group was to cyclosporine, while the initial switch in the infliximab group was to etanercept (ETN).

Radiographic outcomes at two years favored the infliximab group, but the treatment differences were of uncertain clinical significance [36]. At 24 months, the mean increases in the van der Heijde-modified Sharp score (score range 0 to 448, reflecting radiographic detection of joint damage) were statistically significantly lower in the patients receiving infliximab compared with those receiving conventional DMARD triple therapy (4 versus 7.23, for a treatment difference of 3.23, 95% CI 0.14-6.32). However, this difference between treatments was less than 5, which is considered the minimum clinically important difference using this scoring system [39]. Moreover, despite these radiographic differences, at 21 months after randomization, both the infliximab and the triple-therapy groups experienced similar reductions (numerically lower in the triple group) in time lost from work due to sick leave and disability compared with baseline (-4.9 and -6.2 days per month, adjusted mean difference 1.6 days per month, 95% CI -1.2 to 4.4) [40].

●TEAR trial – The Treatment of Early Aggressive Rheumatoid Arthritis (TEAR) trial, which included 755 patients with poor-prognosis early RA (mean disease duration 3.75 months), compared the efficacy of therapy for active RA in four groups over two years [37]. Previous receipt of a biologic agent was an exclusion criterion. Patients were randomly assigned in this double-blind trial to receive one of the following: immediate treatment with MTX plus ETN; immediate treatment with DMARD triple therapy (MTX plus SSZ and HCQ); step-up from MTX to MTX plus ETN at week 24, if the Disease Activity Score in 28 joints using erythrocyte sedimentation rate (DAS28-ESR) was ≥3.2 (moderate or greater disease activity); and step-up from MTX to triple therapy at week 24, if the DAS28-ESR was ≥3.2.

Clinical outcomes (DAS28 scores) were comparable at 24 weeks in the two immediate combination therapy groups, which together showed a significantly greater reduction in disease activity compared with the two step-up groups (DAS28-ESR decrease to 3.6 versus 4.2) at this time point (prior to stepping up to combination therapy). Patients on MTX alone who had not reached the target of low disease activity at 24 weeks stepped up either to MTX plus ETN or to triple therapy at that time. Clinical outcomes, measured by the DAS28-ESR scores, were comparable during weeks 48 to 102 in patients receiving MTX plus ETN or receiving triple therapy, regardless of whether they were initially assigned to immediate or step-up therapy. Similar proportions of all four groups achieved an ACR20 at two years (approximately 45 to 50 percent).

At two years, the immediate combination groups did not differ clinically or radiographically from the step-up combination groups, as confirmed in a post-hoc analysis of the data [41]. However, radiographic outcomes at week 102 slightly but statistically significantly favored those who received MTX plus ETN (increased van der Heijde-modified Sharp score of 0.64 versus 1.69 on a scale of 0 to 448). There was no difference in the frequency of overall adverse effects or of serious adverse effects between the treatment groups.

●RA comparison of active therapies trial (RACAT) – Comparable benefit was achieved in a blinded 48-week trial involving 353 patients with moderate to severely active RA (despite use of MTX) who were randomly assigned to next receive triple therapy (MTX plus SSZ plus HCQ) or the combination of MTX and ETN [34]. An equal proportion of patients in each group (27 percent) failed to meet predefined criteria for continuing the initially assigned therapy at week 24 (a reduction in the DAS28 of at least 1.2) and were switched to the alternate therapy. The strategy of initial assignment to triple therapy was clinically and statistically noninferior to initial assignment to MTX plus ETN with respect to the degree of improvement in disease activity at week 48 (change in DAS28 of -2.12 and -2.29).

At week 24, a lower proportion of patients receiving triple therapy had achieved an ACR70 response (5 versus 16 percent), consistent with a trend suggesting more rapid responses to MTX plus ETN. However, by week 48, differences between the triple therapy group and the MTX plus ETN group in the proportion of patients reaching ACR20, ACR50, and ACR70 were not statistically significant (57, 36, and 18 percent versus 66, 43, and 27 percent). Importantly, the majority of the improvement obtained in the second 24 weeks was among the patients who did not switch. Differences in the radiographic worsening in the van der Heijde-modified Sharp score (0.54 and 0.29, on a scale of 0 to 380) and in the level of functional improvement (reductions in Health Assessment Questionnaire [HAQ] scores of -0.46 and -0.64) were also not significant. There were four serious infections in patients receiving triple therapy and 12 serious infections in those receiving MTX plus ETN. Gastrointestinal symptoms were the most common cause of discontinuation in patients receiving triple therapy (7 of 12), while infections were the most common cause in patients receiving MTX plus ETN (four of five). Patients did equally well after switching from triple to MTX plus ETN and vice versa.

A subsequent analysis based upon the data from this trial found that use of triple therapy rather than the biologic combination with MTX was highly cost-effective [28].

The relative efficacy and safety of DMARD triple therapy in patients resistant to MTX monotherapy has also compared favorably with other nonbiologic DMARDs used singly or in combination, including further MTX monotherapy and the combination of SSZ plus HCQ [42]; the two-drug regimens of MTX plus HCQ and MTX plus SSZ [43]; and sequential DMARD monotherapy with different agents [44]. In the last trial, triple therapy was also associated with more limited joint damage at two and five years [44].

Other conventional nonbiologic DMARDs that have been evaluated in combination with MTX include gold [45]; SSZ [46-48]; the calcineurin inhibitors cyclosporine [49-53] and tacrolimus [54]; doxycycline [55]; and LEF (see 'Leflunomide' below). Other than MTX plus SSZ and HCQ or MTX plus LEF, these combinations are rarely employed because of the greater efficacy and availability of other more effective and/or safer drugs and drug regimens, as described in this topic review.

Methotrexate plus TNF inhibitor

Methotrexate plus TNF inhibitor: Drug choice and administration — The choice of tumor necrosis factor (TNF) inhibitor depends upon patient factors such as comorbidities and patient preferences (eg, for route of administration and frequency of treatment), regulatory or insurance restrictions on drug choice, and safety issues; there is no convincing evidence that any one of the TNF inhibitors has greater efficacy than the others [56].

●We usually use ETN (50 mg administered subcutaneously once weekly) or ADA (40 mg administered subcutaneously every two weeks) as the initial TNF inhibitor in combination with continued MTX therapy, after appropriate pretreatment measures have been performed, as these agents are those often preferred by insurers and government agencies as the initial drug for this class.

●Very infrequently, for select patients with an inadequate response to ADA, especially when options are limited or in the setting of a strong patient preference, the dose may be increased to 40 mg every week or 80 mg every other week. (See 'Nonpharmacologic and preventive therapies' above and 'Pretreatment interventions' above.)

●Alternative TNF inhibitors in patients who prefer therapy by intravenous infusions are infliximab (usually 3 to 5 mg/kg every four to eight weeks after an initial loading schedule at zero, two, and six weeks) and golimumab (2 mg/kg administered every eight weeks).

●A subcutaneous version of a biosimilar infliximab is available in Europe, Canada, and Korea, but not in the United States, for maintenance therapy (120 mg once every two weeks begin four weeks following intravenous induction therapy) [57].

●Other alternative TNF inhibitors administered by subcutaneous injection and that are effective in patients with ongoing disease activity despite MTX include golimumab (50 mg once monthly) and certolizumab pegol (CZP; initial dose of 400 mg [given as two injections] and repeat dose two and four weeks after initial dose; maintenance dose of 200 mg every other week or 400 mg every four weeks).

●Biosimilar agents for some TNF inhibitors are also available and may be the preferred agent for some insurance plans.

TNF inhibitor therapy is generally well tolerated, but these medications pose increased risk of reactivation of latent tuberculosis and of new infection with other granulomatous diseases (eg, histoplasmosis and coccidiomycosis) or with varicella zoster. Adverse effects include injection-site and infusion reactions; mildly reduced neutrophil counts and other cytopenias; serious common and opportunistic infections; reactivation of hepatitis B; autoimmune phenomena, including cutaneous vasculitis, drug-induced lupus syndromes, and demyelinating disorders; and hepatotoxicity. There is no proof of increased risk of malignancy with these agents in analyses of short-term randomized trial data, and results of a large population-based long-term study of patients with RA have failed to demonstrate an increased risk of malignancy. These findings are reassuring, but should be interpreted with caution, since many patients at high risk for malignancy, such as those with a prior malignancy, may not have been initiated on anti-TNF therapy [58-60]. TNF inhibitors should not be administered to patients with active infections, and they are contraindicated in patients with multiple sclerosis and those with decompensated congestive heart failure. The adverse effects of TNF inhibitor therapy are discussed in detail elsewhere. (See "Tumor necrosis factor-alpha inhibitors: An overview of adverse effects" and "Tumor necrosis factor-alpha inhibitors: Bacterial, viral, and fungal infections" and "Risk of mycobacterial infection associated with biologic agents and JAK inhibitors" and "Tumor necrosis factor-alpha inhibitors: Risk of malignancy" and "Tumor necrosis factor-alpha inhibitors: Induction of antibodies, autoantibodies, and autoimmune diseases".)

Efficacy of methotrexate plus TNF inhibitor — In patients with an inadequate response to MTX and other conventional DMARDs, the use of combination therapy with the addition of a tumor necrosis factor (TNF) inhibitor is supported by a number of meta-analyses [30,61-63] and multiple randomized trials of all five agents, including ETN [64-66], infliximab [67,68], ADA [69,70], golimumab [71-73], and CZP [74,75], which demonstrate the superiority of this approach, compared with adding placebo, while continuing MTX.

●Methotrexate plus TNF inhibitor versus methotrexate monotherapy – Trials of MTX plus a TNF inhibitor in patients who have not responded adequately to MTX alone typically result in ACR20, ACR50, and ACR70 response rates of approximately 60, 40, and 20 percent, respectively [76]. These composite measures reflect at least 20, 50, and 70 percent improvement in several defined measurements of disease activity [77]. Indirect comparisons of the biologic agents in meta-analyses of randomized trials involving patients with an inadequate response to MTX have shown a statistically nonsignificant trend suggesting that TNF inhibitors may be more likely to result in an ACR50 response compared with other biologic agents (odds ratio [OR] 1.30, 95% CI 0.91-1.86) [78]. (See "Assessment of rheumatoid arthritis disease activity and physical function", section on 'ACR response criteria'.)

The evidence comparing the efficacy and safety of MTX plus a TNF inhibitor with nonbiologic DMARD triple therapy and with MTX plus abatacept are described in more detail elsewhere in this topic. (See 'Efficacy of triple DMARD therapy versus methotrexate/TNF inhibitor' above and 'Methotrexate plus abatacept' below.)

●Methotrexate plus TNF inhibitor versus biologic monotherapy – Meta-analyses and randomized trials have also shown that combination therapy of MTX with a biologic agent, such as a TNF inhibitor, is superior to biologic or traditional DMARD monotherapy in patients who are naïve to DMARDs [19,30,62,79,80]. However, in patients who have had an inadequate response to MTX, most randomized trials have continued MTX while adding either a biologic or a placebo. A small number of randomized trials and retrospective studies have evaluated the relative benefits of adding a biologic agent to MTX compared with biologic monotherapy; results range from showing small, statistically nonsignificant advantages for combination therapy to demonstrating substantial added benefit that is both statistically and clinically significant [71,72,81-87]. Additionally, MTX (as well as azathioprine) have been shown to significantly decrease the incidence of anti-drug antibody formation to the monoclonal anti-TNF agents [88].

●Comparison of methotrexate plus TNF inhibitor safety and efficacy – Only one trial has directly compared the combination of MTX with either of two TNF inhibitors (ADA and CZP) and found neither combination superior to the other [89]. The two drugs were compared head-to-head in combination with MTX in a randomized trial involving 915 patients with active RA and an inadequate response to MTX alone. There was no statistically significant difference between the groups in the proportion of patients achieving an ACR20 at week 12, the number with low disease activity based upon the DAS28-ESR at week 104, or other major clinical outcome measures. Adverse effects were similar as well.

ETN and ADA might be safer than infliximab [31,61,90]. However, comparisons between these agents are largely indirect [31,61]; additionally, a case-control study suggesting greater safety with ETN, compared with infliximab or ADA, only addressed the risk of reactivation of latent tuberculosis in patients who had not received adequate chemoprophylaxis prior to therapy [90]. Indirect comparisons of randomized trial results in a 2011 meta-analysis suggested that patients receiving ETN, ADA, or golimumab had statistically significantly lower rates of withdrawal from trials due to adverse effects compared with infliximab (OR 0.63, 95% CI 0.41-0.95; OR 0.50, 95% CI 0.32-0.78; and OR 0.55, 95% CI 0.30-0.99) [31].

Alternatives to triple therapy and methotrexate/TNF inhibitor

Alternative treatment options — There are several reasonable treatment options that may serve as alternatives to triple csDMARD therapy and the combination of MTX with a tumor necrosis factor (TNF) inhibitor in patients in whom MTX fails to adequately control disease activity:

●Unable to use TNF inhibitor with high disease activity – In patients in whom MTX plus a TNF inhibitor would otherwise be appropriate (see 'Methotrexate plus TNF inhibitor' above), particularly those unable to use a TNF inhibitor and who have a high level of disease activity, we suggest the combinations of MTX plus abatacept, tocilizumab, or a JAK inhibitor as alternatives to a TNF inhibitor, rather than biologic monotherapy or other csDMARD or biologic DMARD combinations. Both abatacept and tocilizumab may be administered by intravenous infusion or subcutaneous injection; the JAK inhibitors are taken orally. Choices between these agents are based upon comorbidities and adverse event risk in individual patients; regulatory, insurance, and patient cost concerns; and patient and clinician preference. (See 'Methotrexate plus abatacept' below and 'Methotrexate plus IL-6 inhibitor/IL-6 inhibitor monotherapy' below and 'JAK inhibitor therapy' below.)

●Unable to use a biologic or targeted synthetic DMARD – In patients who are unable to use a biologic agent or tsDMARD (ie, a JAK inhibitor) because of regulatory or cost considerations or other factors, we suggest either switching from MTX to LEF or adding LEF to ongoing MTX, rather than using other nonbiologic DMARDs (see 'Leflunomide' below). However, other combinations of nonbiologic DMARDs are additional alternative therapeutic options.

Methotrexate plus abatacept — Abatacept is a soluble fusion protein that consists of cytotoxic T-lymphocyte-associated antigen 4 (CTLA4) and the Fc portion of immunoglobulin G1 (IgG1); thus, it is also termed CTLA4-Ig. Through its high-affinity binding to CD80 (B7-1) and CD86 (B7-2), it inhibits transmission to CD28, the receptor for these ligands, of the second signal required for T-cell activation [91,92].

●Dosing and precautions – In patients for whom MTX plus abatacept is the choice of therapy following an inadequate response to MTX, abatacept can be administered intravenously every four weeks (750 mg per dose for patients 60 to 100 kg, adjusted for lower or higher weight to 500 or 1000 mg, respectively) after the three initial doses given at two-week intervals, or it can be administered subcutaneously (125 mg once weekly, with or without an intravenous loading dose given on the first week before starting subcutaneous dosing a week later). The decision regarding route of administration can be based upon patient preference; the efficacy and safety of the subcutaneous and intravenous preparations of abatacept were comparable in a large randomized trial involving patients with a previous inadequate response to MTX [93]. We generally use abatacept in combination with continued MTX therapy, after appropriate pretreatment measures have been performed, but it may also be administered as monotherapy or in combination with other nonbiologic DMARDs. It should not be used in combination with other biologic DMARDs such as TNF inhibitors.

Potential adverse effects of abatacept include infusion reactions, which may occur within an hour after beginning the intravenous administration of the drug and which may be characterized by headache, dizziness, and hypertension; anaphylactoid reactions are rare. Abatacept, similar to other biologics and JAK inhibitors, appears to increase the risk of serious infections, including pneumonia, pyelonephritis, cellulitis, and diverticulitis. In patients with chronic obstructive pulmonary disease (COPD), if abatacept is used, it should be with particular caution because of the higher rates of COPD exacerbations and respiratory tract infections reported in such patients in the randomized trials of this agent. A definite association with tuberculosis has not been shown, although screening for latent tuberculosis prior to treatment is recommended. Treatment of RA patients with abatacept has not been associated with an increased frequency of malignancy in the abatacept clinical trials participants [94].

The overall safety of abatacept appears comparable to or possibly slightly better than that of the TNF inhibitors, although there are few direct comparisons. An indirect comparison of biologic agents in data from a 2011 meta-analysis of randomized trials and extension studies showed a statistically nonsignificant trend for abatacept compared with the other agents toward fewer serious adverse events (OR 0.65, 95% CI 0.42-1.01) and serious infections (OR 0.57, 95% CI 0.30-1.08), while other biologics generally showed similar risks compared with each other [31]. Additional evidence supporting the use and safety of abatacept in RA, including in patients resistant to a biologic DMARD, is reviewed in detail separately. (See "Treatment of rheumatoid arthritis in adults resistant to initial biologic DMARD therapy", section on 'Abatacept'.)

●Efficacy of methotrexate plus abatacept – Meta-analyses of multiple randomized trials have documented the benefits of abatacept compared with placebo for use either alone or in combination with nonbiologic DMARDs [31,95-97]. In a systematic review and in indirect comparisons of randomized trial results from a network meta-analysis of biologic agents in patients with an inadequate response to MTX, the combination of abatacept with MTX was significantly more effective compared with MTX alone (ACR50 at 24 weeks of 32 versus 12 percent) [95]. Abatacept was comparable to other biologic agents, including several TNF inhibitors, rituximab, and tocilizumab. Evidence describing the benefits of abatacept compared with placebo in patients who have had an inadequate response to a TNF inhibitor is further reviewed below.

Only a few trials have directly compared abatacept with another active DMARD. These include two randomized trials in patients with an inadequate response to MTX therapy, which showed comparable benefit of abatacept to TNF inhibitor therapy when either was combined with continued MTX, with 60 to 70 percent of patients achieving an ACR20 response [98,99]:

•ATTEST trial – In the "Abatacept or infliximab versus placebo, a Trial for Tolerability, Efficacy, and Safety in Treating rheumatoid arthritis" (ATTEST) trial, 431 patients with active RA and with an inadequate response to MTX were randomly assigned to receive abatacept (500, 750, or 1000 mg in patients weighing <60 kg, 60 to 100 kg, or >100 kg, respectively, by intravenous infusion on days 1, 15, and 29, then every four weeks), infliximab (3 mg/kg by intravenous infusion on days 1, 15, 43, and 85, then every eight weeks), or placebo infusions, while continuing background MTX [98]. After six months, use of either abatacept or infliximab resulted in significantly greater benefit compared with placebo (ACR20 responses of 67 and 59 percent versus 42 percent, respectively). After one year of treatment, the frequency of ACR20 responses with abatacept plus MTX was statistically significantly greater than with infliximab plus MTX (72 versus 56 percent). An increase in the dose or frequency of infliximab, which may occur in clinical practice in infliximab-inadequate responders, was not allowed in the trial, but the patients receiving abatacept had numerically fewer serious adverse events (10 versus 18 percent) and serious infections (2 versus 9 percent) compared with those receiving the trial dose of infliximab.

•AMPLE trial – A head-to-head comparison of abatacept and ADA in patients on background MTX suggests comparable efficacy and safety [100]. In this randomized trial, the Abatacept versus Adalimumab Comparison in Biologic-Naïve RA Subjects with Background Methotrexate (AMPLE) trial, involving 646 patients with active RA and with an inadequate response to MTX, there were comparable clinical and radiographic responses to MTX plus abatacept (125 mg administered subcutaneously weekly) and to MTX plus ADA (40 mg administered subcutaneously every two weeks) at one year (ACR20 of 65 and 63 percent, respectively). Comparably small increases in modified total Sharp scores of 0.58 and 0.38 on a scale of 0 to 448, respectively, were seen. Rates of adverse effects, including infections, were similar between the two groups. (See 'Efficacy of triple DMARD therapy versus methotrexate/TNF inhibitor' above.)

The efficacy and safety of subcutaneous and intravenous administration of abatacept were comparable in a randomized trial involving 1457 patients with a previously inadequate response to MTX [93]. The efficacy of abatacept subcutaneously (125 mg subcutaneously on days 1 and 8, then weekly, plus an intravenous loading dose on day 1 of approximately 10 mg/kg) was comparable to abatacept intravenously (approximately 10 mg/kg intravenously on days 1, 15, and 29, then every four weeks) in achieving an ACR20 response after six months of treatment (both 76 percent). The onset and magnitude of the responses, disease activity, improvements in physical function, and adverse effects were also comparable. Injection site reactions were mostly mild and were as frequent in patients receiving the active subcutaneous drug as in those receiving subcutaneous placebo (2.5 to 2.6 percent).

Methotrexate plus IL-6 inhibitor/IL-6 inhibitor monotherapy — There are two interleukin (IL) 6 inhibitors, tocilizumab and sarilumab, that are available for use together with MTX or as monotherapy that have shown efficacy in this clinical setting. However, although tocilizumab is available for use in RA patients with active disease despite treatment with MTX, we use it primarily in patients with RA who have not responded adequately to TNF inhibitors. A small number of trials with each agent, described below, have suggested greater benefit with IL-6 inhibitor monotherapy compared with the TNF inhibitor ADA in patients who have responded inadequately to MTX [101,102].

Similar to other biologic agents, anti-IL-6 inhibitor antibodies (anti-drug antibodies) have been observed. However, the occurrence rate is low and does not appear to interfere with efficacy or be offset by the use of MTX [103].

●Methotrexate plus tocilizumab and tocilizumab monotherapy

•Administration and precautions – Tocilizumab, a humanized IgG1 anti-human IL-6 receptor antibody, can be administered either by intravenous infusion or by subcutaneous injection. When administered intravenously, it is given every four weeks (at an initial dose of 4 mg/kg per infusion, which may be increased to 8 mg/kg per infusion, based upon the clinical response, to a maximum of 800 mg/infusion). When taken subcutaneously in patients <100 kg, the dose is 162 mg every other week, which may be increased to every week based upon the clinical response; in patients ≥100 kg, the dose is 162 mg every week. The subcutaneous route of administration (162 mg) has comparable efficacy and safety when compared with the intravenous route (8 mg/kg) [104]. We use tocilizumab in combination with MTX, unless MTX is contraindicated.

A dose adjustment or drug discontinuation may be required in patients with significant liver enzyme (aminotransferase) elevations, neutropenia, or thrombocytopenia. Other adverse effects include serious infections, including mycobacterial and other opportunistic infections. Dyslipidemia may occur and should be managed according to available guidelines. Despite this impact on lipids, the risk of cardiovascular events with tocilizumab was similar to etanercept in a phase 4 clinical trial in RA patients with cardiovascular risk factors [105]. Intestinal perforations have been reported, especially in older patients and in those with a history of diverticulitis, which is a contraindication to the use of tocilizumab. (See "Low-density lipoprotein cholesterol-lowering therapy in the primary prevention of cardiovascular disease" and "Management of low density lipoprotein cholesterol (LDL-C) in the secondary prevention of cardiovascular disease".)

The risk of adverse effects is greater in patients on concomitant immunosuppressive therapy. A meta-analysis of randomized trials found that adverse events were increased in patients receiving tocilizumab (8 mg/kg) plus MTX compared with placebo plus MTX (OR 1.5, 95% CI 1.3-1.9), as was the rate of infection (OR 1.3, 95% CI 1.1-1.6) [106]. However, there was no significant increase in the rates of malignancy, tuberculosis reactivation, or hepatitis.

•Efficacy and safety – The efficacy and safety of tocilizumab in RA have been characterized in multiple randomized trials [81,107-112] and in meta-analyses of randomized trials of the drug as monotherapy or together with MTX compared with placebo [106,113].

In a 16-week randomized trial of tocilizumab in patients resistant to MTX monotherapy, ACR20 responses were achieved by 61 and 63 percent of patients receiving 4 mg/kg and 8 mg/kg of tocilizumab as monotherapy, respectively, and by 63 and 74 percent of patients receiving those doses of tocilizumab plus MTX [81]. By contrast, only 41 percent of patients receiving MTX plus placebo achieved ACR20 responses. Similarly, in a six-month trial of patients resistant to MTX alone, ACR20 responses were achieved more often by patients receiving tocilizumab 4 mg/kg and tocilizumab 8 mg/kg, respectively, compared with placebo (48 and 59 versus 26 percent) [107].

Tocilizumab was compared directly with ADA as monotherapy for patients with active RA who were intolerant to MTX or who were considered inappropriate candidates for continued treatment with MTX [101]. In this randomized 24-week trial involving 326 patients, tocilizumab (8 mg/kg administered intravenously every four weeks plus subcutaneous placebo every two weeks) was compared with ADA (40 mg administered subcutaneously every two weeks plus intravenous placebo every four weeks). Tocilizumab use resulted in a significantly greater reduction in the DAS28-ESR (decrease of -3.3 versus -1.8, difference of -1.5, 95% CI -1.8 to -1.1). A proportionately smaller but statistically significant difference in the degree of improvement was noted using the Clinical Disease Activity Index (CDAI decrease of -23.8 versus -18.9, difference of -4.9, 95% CI -8.3 to -1.5), which is independent of the reduced levels of acute phase reactants that may occur disproportionately with tocilizumab, unlike the DAS28-ESR. A trend toward greater improvement in the HAQ score did not achieve statistical significance. Only the higher dose of tocilizumab was used in this trial; there was no comparison with the more standard 4 mg/kg dose. Serious adverse effects did not differ between the groups, but laboratory abnormalities were more common with tocilizumab.

Evidence supporting the use of tocilizumab in patients resistant to biologic therapies is described in detail separately. (See "Treatment of rheumatoid arthritis in adults resistant to initial biologic DMARD therapy", section on 'Tocilizumab'.)

One randomized trial has suggested that continuing tocilizumab alone, while withdrawing MTX, may be sufficient to maintain a response to tocilizumab plus MTX in patients with RA with a previous inadequate response to MTX monotherapy [114,115]. In this trial, those who subsequently achieved low disease activity with tocilizumab plus MTX were randomly assigned to continue either the combination or tocilizumab alone (without MTX); after 16 weeks, similar clinical and imaging outcomes were observed, as small differences that favored the combination were not statistically significant.

●Methotrexate plus sarilumab and sarilumab monotherapy – Another human monoclonal antibody, sarilumab, directed against the membrane-bound and soluble IL-6R, has been effective in several clinical trials, including use together with MTX [102,116,117]. It is available for use in the United States, particularly for patients resistant or intolerant to one or more nonbiologic DMARDs, and is also available in a number of other countries. Sarilumab may be substituted if tocilizumab is unavailable. The efficacy and safety of sarilumab is similar to tocilizumab, and the indications for utilization are the same.

•Dosing and administration – The usual dosing for patients with RA is 200 mg administered subcutaneously once every two weeks, although the dose can be reduced to 150 mg every two weeks for issues with toxicity. It can be used as monotherapy or in combination with nonbiologic DMARDs (eg, MTX). It should not be used in combination with other biologic DMARDs, and treatment should not be initiated in patients with an absolute neutrophil count <2,000/mm³, platelets <150,000/mm³, or if alanine aminotransferase (ALT) or aspartate aminotransferase (AST) are >1.5 times the upper limit of normal.

•Efficacy and safety – Efficacy was shown in a randomized trial involving 1369 patients with active RA and an inadequate response or intolerance to MTX; patients receiving sarilumab (150 or 200 mg administered subcutaneously every two weeks) plus continued MTX were more likely to respond than those receiving placebo plus MTX when assessed by the ACR20 response criteria at week 24 (58 and 66 versus 33 percent respectively) [116]. Improvements in physical functioning at week 16 and decreased progression of radiographic damage were also seen.

Sarilumab monotherapy (200 mg subcutaneously every two weeks) was superior to the TNF inhibitor ADA (40 mg subcutaneously every two weeks) in a randomized trial involving 369 patients with active RA who discontinued MTX because of an inadequate response or intolerance [102]. Patients receiving sarilumab had a greater reduction from baseline in the DAS28-ESR at week 24 (-3.28 versus -2.20) and were more likely to achieve ACR20, -50, and -70 responses (72, 46, and 23 versus 58, 30, and 12 percent).

As with tocilizumab and other biologics, there is a moderate increased risk of infection. Additionally, an increased likelihood of neutropenia, liver function test abnormalities, and hyperlipidemia is seen, requiring monitoring. Similar to tocilizumab, an increased frequency of colonic perforations have been reported, and sarilumab is relatively contraindicated in patients with a history of diverticulitis.

JAK inhibitor therapy — There are several Janus kinase (JAK) inhibitors marketed for inflammatory arthritis (including RA), including tofacitinib, baricitinib, upadacitinib, filgotinib, and peficitinib, which are all available as oral agents. Safety data have led the US Food and Drug administration (FDA) to recommend tsDMARD use only after intolerance or an inadequate response to at least one TNF inhibitor [118]. The FDA has also advised consideration of the benefits and risks for the individual patient prior to initiating or continuing therapy, particularly in patients who are current or past smokers, those with other cardiovascular risk factors, those who develop a malignancy, and those with a known malignancy other than a successfully treated nonmelanoma skin cancer.

Prior to these new constraints, most tsDMARDs were available for use in patients who were at least a MTX non-responder. tsDMARDs can be used as monotherapy or in combination with MTX. The FDA recommends against use of any of the JAK inhibitors with azathioprine or cyclosporine. The JAK inhibitors, which are classified as tsDMARDs, may be appropriate for patients who prefer to avoid medications requiring subcutaneous or intravenous administration. (See 'Tofacitinib' below and 'Baricitinib' below and 'Upadacitinib' below and 'Peficitinib' below.)

The biology, principles of use, and adverse effects of JAK inhibitors are discussed in detail separately. (See "Overview of the Janus kinase inhibitors for rheumatologic and other inflammatory disorders".)

A Bayesian network meta-analysis comparing the randomized controlled trials of the five available tsDMARDs concluded that all five were efficacious as monotherapy in active RA. Importantly, there were no differences in their efficacy and safety as monotherapy [119]. Given the benefit seen in these trials in active and difficult-to-treat RA, JAK inhibitors are comparable or superior in efficacy to biologic DMARDs. Overall safety in the clinical trial programs and observational registries have demonstrated comparable safety profiles with biologic DMARDs. However, the safety issues seen with tofacitinib in older patients with cardiovascular risk factors resulted in a class warning from the FDA, which recommended use only in patients intolerant or unresponsive to at least one TNF inhibitor. For patients failing an initial biologic DMARD who have cardiovascular/venous thromboembolic event (VTE) or malignancy risk factors such as smoking, we would not suggest a JAK inhibitor if alternatives exist. For younger patients without risk factors, we consider JAK inhibitors appropriate (see 'Upadacitinib' below). Further trials, including additional comparisons with other biologic DMARDs and comparisons with other JAK inhibitors, will be useful in better determining its place in therapy.

There is the greatest experience with tofacitinib, which we prefer if one of these agents is used. Baricitinib is commercially available for use in both Europe (at a dose of either 2 or 4 mg daily) and the United States, although only the lower dose received FDA approval. Upadacitinib has been approved for use in the United States and is under regulatory review in a number of other countries and regions. Peficitinib is only available for use in Japan, and not in the United States or Europe; it is under review or in development in several other countries.

Tofacitinib — Tofacitinib is an orally administered JAK inhibitor that decreases signaling by a number of cytokine and growth factor receptors. It is taken in a dose of 5 mg twice daily (immediate-release form) or 11 mg once daily (extended-release form). The latter formulation became available for use in 2016 based upon pharmacokinetic studies of the equivalence of drug exposure of the two formulations [120]. In the United States, 70 percent of new starts on tofacitinib are at the 11 mg once-daily dose, which is not available commercially in Japan or Europe. Tofacitinib is effective and can be used in patients with moderately to severely active RA who have had an inadequate response to MTX as monotherapy or in combination with MTX (our usual approach) or other nonbiologic DMARDs [121-126]. Other nonbiologic DMARDs may be used as an alternative to MTX in patients intolerant of MTX therapy. It should not be taken in combination with biologic agents or with other potent immunosuppressants, such as azathioprine or cyclosporine.

The efficacy and safety of tofacitinib in RA have been evaluated in a series of randomized trials in patients with an inadequate response to MTX or another conventional DMARD [121-125,127]. It has also been compared as monotherapy with MTX in patients who are naïve to this agent [126]. The evidence supporting the use of tofacitinib in patients with RA resistant to a biologic DMARD is discussed separately. (See "Treatment of rheumatoid arthritis in adults resistant to initial biologic DMARD therapy", section on 'Tofacitinib'.)

As examples in patients with an inadequate response to MTX and/or other conventional nonbiologic DMARDs:

●Tofacitinib monotherapy – In a randomized trial involving 611 patients with an inadequate response to at least one nonbiologic or biologic DMARD (usually MTX), tofacitinib monotherapy (5 mg twice daily) resulted significantly more often in reductions in signs and symptoms of active RA after three months of treatment, compared with placebo (ACR20 of 60 versus 27 percent) [121].

●Tofacitinib plus methotrexate – This combination has been effective in patients who have not had an adequate response to MTX alone [122-124,127]. As an example, a trial involving 797 patients with active RA and inadequate responses to MTX showed significantly greater benefit at six months for continued MTX plus 5 or 10 mg twice daily of tofacitinib compared with MTX plus placebo (ACR20 of 52 and 62 percent versus 25 percent) [123]. At six months, those treated with tofacitinib demonstrated improved HAQ disability indices (HAQ-DI –0.4 and -0.54 versus -0.15) and smaller increases in the degree of radiographic injury, although the reduction in radiographic change in those receiving the manufacturer's recommended dose for clinical use (5 mg twice daily) did not reach statistical significance.

●Methotrexate plus tofacitinib versus methotrexate plus TNF inhibitor – The combination of MTX with either tofacitinib or a TNF inhibitor have also been comparably effective in patients resistant to MTX [122,127]. In a randomized trial involving 717 patients, tofacitinib (5 mg twice daily) and ADA (40 mg administered subcutaneously every two weeks) showed similar benefit compared with placebo after six months in patients with active RA who had had an inadequate response to MTX and who continued MTX cotherapy (ACR20 of 52 and 47 percent versus 28 percent, respectively) [122]. Similarly, the combination of tofacitinib (5 mg twice daily) with MTX (15 to 25 mg per week) was compared with ADA (40 mg every two weeks) plus MTX and tofacitinib monotherapy in a randomized trial involving 1146 patients with active RA despite MTX therapy [127]. The combination of tofacitinib plus MTX was comparable to ADA plus MTX, and both combinations resulted in greater responses than with tofacitinib monotherapy at six months (ACR50 of 46 and 44 versus 38 percent and ACR20 of 73, 71, and 65 percent, respectively). Rates of discontinuation due to adverse events were similar (7, 9, and 6 percent).

The relative safety of tofacitinib has generally appeared similar to that of biologic DMARDs, with adverse effects including increased risk of infections and liver function test abnormalities; additional concerns that require attention in clinical use include neutropenia, lymphopenia, hyperlipidemia, and, possibly, increased serum creatinine [121,122,128-130]. Gastrointestinal perforations have also been reported. An increased risk of herpes zoster was reported compared with placebo and with ADA in trials comparing these agents. In the clinical trial program of tofacitinib, overall cardiovascular adverse effects, malignancies, and VTEs were similar to those reported with biologic DMARDs [131]. However, in a phase 3b/4 trial in patients older than age 50 with at least one cardiovascular risk factor that compared tofacitinib with TNF inhibitors, a numerical increase in major adverse cardiovascular events (MACE), malignancy, and pulmonary embolisms/VTEs was reported [132]. Patients at highest risk were males, smokers, and individuals over age 65. Approximately 80 percent of the MACE and malignancies occurred in patients >65 years old or who had ever smoked.

Pretreatment screening, precautions, restrictions, FDA and European Medicines Agency (EMA) warnings, and adverse effects are reviewed in detail separately. (See "Overview of the Janus kinase inhibitors for rheumatologic and other inflammatory disorders", section on 'Pretreatment screening and precautions' and "Overview of the Janus kinase inhibitors for rheumatologic and other inflammatory disorders", section on 'Adverse effects'.)

The relative safety of tofacitinib was evaluated in an analysis of the data from patients in the randomized trials and long-term extension studies of tofacitinib, including 7061 patients with 23,194 patient-years of exposure to the drug, with safety data followed for up to 9.5 years [86,133]. Adverse event frequencies, expressed as events/100 patient-years, were serious infections, 2.5, which was stable over time; herpes zoster, 3.6; all-cause mortality, 0.3; and adverse events leading to discontinuation, 7.1. These rates were comparable with those previously reported in patients with RA receiving biologic DMARDs. Factors independently associated with an increased risk of serious infection with tofacitinib use were age, glucocorticoid dose, diabetes, tofacitinib dose, and lymphocyte counts of less than 0.5 x 10³/mm³. Patients should discontinue tofacitinib if lymphocyte counts drop below this level.

Herpes zoster was reported in 5 percent of patients (239 cases) in the trials and extension studies; the risk of herpes zoster was significantly increased in patients receiving tofacitinib compared with those receiving placebo (incidence ratio 4.4 per 100 patient-years, 95% CI 3.8-4.9) [134]. Only one case was multidermatomal, and none involved visceral dissemination or death. The only factors independently associated with increased risk of herpes zoster with tofacitinib use were older age and participation in the trials in Asia. If possible, vaccination for zoster is suggested prior to initiation of tofacitinib.

Baricitinib — Baricitinib is a small molecule, orally administered, JAK1 and JAK2 inhibitor. It is commercially available for use in both Europe (at a dose of either 2 or 4 mg daily) for csDMARD incomplete responders and the United States for TNF inhibitor incomplete responders at the 2 mg dose. Baricitinib has been effective in patients with RA compared with both placebo and with other active DMARDs and in studies with patients who are naïve to DMARD therapy, as well as patients with inadequate responses to prior therapies [135-140]. Safety issues with baricitinib are similar to those with tofacitinib, but in the United States, baricitinib does have a boxed warning regarding thrombosis (including deep vein thrombosis, pulmonary embolism, and arterial thrombosis) risk based upon findings in the placebo-controlled portion of the randomized trials. The use and efficacy of baricitinib in patients resistant to biologic DMARDs is described separately. As with the other JAK inhibitors, it should not be used in combination with azathioprine or cyclosporine. (See "Treatment of rheumatoid arthritis in adults resistant to initial biologic DMARD therapy", section on 'Baricitinib'.)

Examples of the efficacy of baricitinib in patients with an inadequate response or intolerance to csDMARDs include:

●Compared with placebo – Several trials have shown baricitinib to be more effective than placebo in patients who have had an inadequate response to conventional DMARDs [136-138]. As an example, in a randomized trial involving 684 patients with active RA and an inadequate response to or intolerance of conventional DMARDs, the addition of baricitinib (4 mg daily taken orally) to the background therapy resulted in improved efficacy using ACR20 response criteria compared with those receiving placebo at week 12 (62 versus 39 percent) [138]. A 2 mg daily dose of baricitinib appeared less effective than the higher (4 mg) dose; adverse events were similar in all three groups; and radiographic progression, although quantitatively small, was reduced with baricitinib compared with placebo at week 24.

●Compared with adalimumab and with placebo – In a randomized trial involving 1307 patients with active RA and an inadequate response to MTX, the addition of baricitinib (4 mg daily taken orally) was more effective than ADA (40 mg administered subcutaneously every other week) and placebo at week 12 (ACR20 of 70 versus 61 versus 40 percent) [139]. Baricitinib and ADA both reduced the progression of radiographic damage at week 24.

The relative safety of baricitinib and other JAK inhibitors in the clinical trials and observational studies appear similar. Like the other JAK inhibitors, baricitinib has a boxed warning for thromboembolic events at the 4 mg dose, as in the placebo-controlled RA clinical trials, six VTEs (1.4/100 patient-years) occurred on 4 mg baricitinib with none reported on 2 mg or placebo. Similar to tofacitinib, it is associated with a higher risk of herpes zoster. Studies demonstrated minor increases in serum creatinine and low-density lipoprotein (LDL) cholesterol, and small reductions in blood neutrophil counts. As examples, from week 0 to 52 in one trial, the serum creatinine increased by 0.086 (±0.005) mg/dL; the LDL cholesterol increased by 18 (±1) mg/dL; and the neutrophil count decreased by 1230 (±90) per mm³ [139].

Upadacitinib — Upadacitinib is a small, orally active drug that, in preclinical evaluation, preferentially inhibits JAK-1 over JAK-2, -3, and non-receptor tyrosine-protein kinases, although it is not entirely specific for JAK-1. Upadacitinib (15 mg once daily) can be used in the United States in patients with moderately to severely active RA resistant or intolerant to MTX as monotherapy or in combination with MTX or other csDMARDs (with the exceptions of azathioprine and cyclosporine). Randomized trials comparing it with placebo have demonstrated benefit in patients with RA with inadequate responses to csDMARDs, including MTX [141-143]. The adverse effects of upadacitinib are similar to those with the other JAK inhibitors, and in the United States, the drug carries a boxed warning regarding serious infections, malignancies, and thrombosis, as do the other JAK inhibitors. The use and efficacy of upadacitinib in patients resistant to biologic DMARDs is described separately. (See "Treatment of rheumatoid arthritis in adults resistant to initial biologic DMARD therapy", section on 'Upadacitinib'.)

Trials illustrating the efficacy and relative safety of upadacitinib in patients with an inadequate response or intolerance to csDMARDs include:

●Upadacitinib plus csDMARD in csDMARD inadequate responders (IR) – In a randomized trial involving 661 patients with active RA and an inadequate response to nonbiologic DMARDs (the majority of whom had been receiving MTX as monotherapy or combined with other csDMARDs), the addition of upadacitinib (15 or 30 mg daily) was more likely, compared with placebo, to result in an ACR20 at week 12 (64 and 66 versus 34 percent) [141]. A response was noted by week 1. Low disease activity (DAS28-CRP ≤3.2) was achieved more often with upadacitinib at 12 weeks as well (48 and 48 versus 17 percent). Infections were more frequent in patients receiving either dose of upadacitinib; one case of herpes zoster was reported in each group, including placebo; no deaths were reported during the trial. Stable low-dose glucocorticoids (prednisone ≤10 mg daily or equivalent) were allowed and being taken by approximately half of the patients during the trial.

●Upadacitinib monotherapy in methotrexate-IR – In another randomized trial, involving 648 patients with active RA and an inadequate response to MTX, switching from MTX to upadacitinib (15 or 30 mg daily) was more likely to result in an ACR20 response at week 14 compared with continuing MTX (68 and 71 versus 41 percent) [142]. A DAS28-CRP ≤3.2 was also more frequent with upadacitinib (45 and 53 versus 19 percent). Herpes zoster was reported in patients receiving upadacitinib (15 and 30 mg daily) and MTX in three (1 percent), six (3 percent), and one (<1 percent) patient(s), respectively. A VTE, a pulmonary embolus, was reported in one patient on upadacitinib 15 mg daily (<1 percent) but not in the other groups.

●Upadacitinib versus adalimumab in methotrexate-IR – In a randomized trial involving 1629 patients with active RA and an inadequate response to MTX, the addition to ongoing MTX of upadacitinib (15 mg once daily) or ADA (40 mg every two weeks) was more likely to result at week 12 in an ACR20 response compared with placebo (71 and 63 versus 36 percent, respectively); in an ACR50 (45 and 29 versus 15 percent, respectively); and in a DAS28-CRP <2.6 (29 and 18 versus 6 percent, respectively) [143]. Upadacitinib was superior to ADA in the proportion with an ACR50 and with a DAS28-CRP ≤3.2, and in the degrees of improvement in pain and function. Both upadacitinib and ADA reduced radiographic progression at week 26 compared with placebo. The frequency of adverse events, including serious infections, was similar for the two active agents; herpes zoster was seen in <1 percent of all groups. VTE were reported in six patients (upadacitinib [two patients (0.3 percent)], ADA [three patients (0.9 percent)], and placebo [one patient (0.2 percent)]). Benefits were maintained at 48 weeks, as was the superiority of upadacitinib, and rescue with the alternative agent was effective in a substantial number of patients with insufficient responses to the initially assigned agent at specified time points during the trial [144].

Peficitinib — Peficitinib is a "pan-JAK" inhibitor, with activity against JAK-1, -2, -3, and tyrosine kinase 2, although effects on JAK-2 appear less substantial compared with the other targets. It is available for clinical use in Japan, where the recommended dose is 100 to 150 mg taken orally once daily after meals [145]. Peficitinib is contraindicated in patients with severe liver dysfunction, and the dose should be reduced to 50 mg once daily in those with moderate liver dysfunction.

Most trials, including several phase 2 [146-149] and phase 3 [150,151] randomized trials, have evaluated the efficacy and safety of the drug in patients who have had a prior inadequate response or intolerance to csDMARDs, usually MTX. In these trials, the efficacy and toxicity of this orally administered agent appeared generally similar to other JAK inhibitors, although neither peficitinib nor any of the other JAK inhibitors have been compared directly with each other in clinical trials.

Peficitinib is also under regulatory review in South Korea and Taiwan and is in clinical development in China [145].

Filgotinib — Filgotinib is a selective JAK1 inhibitor that is available in 100 and 200 mg. It has been shown to be efficacious as monotherapy or in combination with MTX in patients with moderate to severe RA [152,153]. Filgotinib is available in Europe and Japan but not in the United States.

A Bayesian network meta-analysis comparing the randomized controlled trials of the five available tsDMARDs concluded that all five were efficacious as monotherapy in active RA. Importantly, there were no differences in their efficacy and safety as monotherapy [119].

Given the benefit seen in these trials in active and difficult-to-treat RA, JAK inhibitors are comparable or superior in efficacy to biologic DMARDs. Overall safety in the clinical trial programs and observational registries have demonstrated comparable safety profiles with biologic DMARDs. However, the safety issues seen with tofacitinib in older patients with cardiovascular risk factors resulted in a class warning from the FDA, which recommended use only in TNF failures. For patients failing an initial biologic DMARD who have cardiovascular/VTE or malignancy risk factors such as smoking, we would not suggest a JAK inhibitor at this time if alternatives exist. For younger patients without risk factors, we consider JAK inhibitors appropriate (see 'Upadacitinib' above). Further trials, including additional comparisons with other biologic DMARDs and comparisons with other JAK inhibitors, will be useful in better determining its place in therapy.

Leflunomide — In patients with an inadequate response to MTX, LEF can be used in place of or in addition to ongoing MTX therapy. The use of LEF alone, without MTX, is preferred in the absence of clinical improvement from prior treatment with the maximally tolerated dose of MTX within the usual therapeutic range, as well as in patients in whom there is a greater degree of concern for the possible increased risk of side effects with the combination of LEF and MTX. Although both drugs are potentially hepatotoxic, the rationale for combined therapy is based upon their differing mechanisms of action. (See "Pharmacology, dosing, and adverse effects of leflunomide in the treatment of rheumatoid arthritis" and "Use of methotrexate in the treatment of rheumatoid arthritis", section on 'Mechanism of action'.)

●Use, dosing, and adverse effects – In patients in whom LEF is used in place of MTX, the usual dose is 20 mg daily. Reduced dosing with either LEF (10 instead of 20 mg daily) or MTX (eg, 15 mg instead of 20 to 25 mg weekly) should be used initially if the drugs are used in combination; the dose is then increased incrementally no more frequently than monthly to usual maximal doses if it is required clinically and there is no evidence of toxicity. Some experts continue to use a loading dose of LEF (100 mg daily for the first three days of therapy) in patients given LEF monotherapy, but other experts avoid the use of a loading dose because of increased risk of diarrhea with this approach. The use and adverse effects of LEF in patients with RA is discussed in detail separately. (See "Pharmacology, dosing, and adverse effects of leflunomide in the treatment of rheumatoid arthritis".)

Patients on both LEF and MTX may require closer monitoring (eg, monthly aminotransferase testing) for hepatotoxicity, given the increased risk of hepatotoxicity in some but not most studies, including reports of fatal liver failure [154-156]. Other adverse effects of LEF include diarrhea, alopecia, myelosuppression, hypertension, and rash. LEF has an unusually long half-life due to its enterohepatic recirculation. In a patient who takes LEF who becomes pregnant or develops a serious infection, chelation with cholestyramine is required to eliminate LEF from the body. (See "Pharmacology, dosing, and adverse effects of leflunomide in the treatment of rheumatoid arthritis", section on 'Adverse effects' and "Pharmacology, dosing, and adverse effects of leflunomide in the treatment of rheumatoid arthritis", section on 'Pregnancy and lactation'.)

●Leflunomide efficacy – The efficacy of LEF was superior to placebo and was comparable to MTX in a systematic review of six randomized trials including comparisons of LEF with placebo and/or MTX, suggesting approximately twice the likelihood compared with placebo of achieving an ACR20 response at 6 or 12 months for either LEF or MTX [157]. In one trial involving 482 patients, for example, an ACR20 at one year was achieved in a similar proportion of patients on LEF or on MTX, and this rate was significantly higher than that seen with placebo (52 and 46 percent versus 26 percent) [158]. 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) [157-159].

The combination of LEF and MTX is effective in patients who have not responded adequately to MTX alone. As an example, in a randomized trial of 263 patients, LEF or placebo was added to existing MTX therapy [160]. At 24 weeks, the proportion of patients who met ACR20 criteria for improvement was significantly higher with LEF compared with placebo (46 versus 20 percent). The combination was well tolerated. The rate of discontinuation and the incidence of adverse events, which were predominantly mild or moderate, were similar in the two groups. Diarrhea and elevation of serum aminotransferases were the only adverse effects seen significantly more often with LEF plus MTX than with placebo plus MTX.

LEF had comparable efficacy to cyclosporine at 12 months of therapy in patients with an inadequate response to MTX (ACR50 of 40 versus 42 percent), and the combination of LEF with cyclosporine is more effective in such patients than either agent as monotherapy [161]; however, LEF has not been compared directly with other agents in such patients. As an example, LEF has not been directly compared with the TNF inhibitors, although the superiority of TNF inhibitors is suggested by the comparability of LEF to sometimes suboptimal doses of MTX and to SSZ, by the more rapid effects and greater overall benefit of TNF inhibitors when they have been directly compared with MTX or SSZ, and by clinical experience. The trial data that support the efficacy of LEF in the treatment of RA, including its use together with MTX, and the adverse effects of LEF are reviewed in detail separately. (See "Initial treatment of rheumatoid arthritis in adults", section on 'Methotrexate versus other DMARDs'.)

In patients with an inadequate response to initial treatment with LEF alone, a TNF inhibitor may be added to LEF [156,162-164]. An analysis of patients with RA in a large population database from Switzerland indicated that the addition of a TNF inhibitor was beneficial in patients with persistent disease activity on LEF alone [162]. However, randomized trials to prospectively evaluate the efficacy and safety of LEF used together with a biologic DMARD have not been performed.

Methotrexate plus rituximab — Rituximab is another alternative that may have similar efficacy to a TNF inhibitor in patients with seropositive RA, but regulatory restrictions may limit its availability before a TNF inhibitor has been tried. However, rituximab is a reasonable alternative for patients with a prior lymphoproliferative malignancy. (See 'Choice of therapy' above and "Treatment of rheumatoid arthritis in adults resistant to initial biologic DMARD therapy".)

●Use, dosing, and adverse effects – We generally administer rituximab as an intravenous infusion of 1000 mg, repeated once two weeks later, together with ongoing weekly MTX. Courses of rituximab can be administered as frequently as every four to six months depending on disease activity, but most patients are treated less frequently due to adequate disease control. Studies have demonstrated that a treat-to-target approach based on an increase in disease activity is more effective than physician preference to treat [165]. Preliminary reports suggest lower doses of rituximab may be as effective as the approved 1000 mg dose [166]. Rituximab biosimilars are available in the clinic with comparable efficacy and safety, and data have demonstrated no significant issues with switch to biosimilar rituximab as far as efficacy, safety, or immunogenicity [167,168].

We generally wait six months after administration of rituximab before switching to an alternative medication for lack of efficacy or for adverse effects because of the duration of its biologic effects. Rituximab is given in combination with ongoing MTX treatment unless MTX is contraindicated. Use either with LEF or as monotherapy are alternatives in patients unable to take MTX. A small open-label trial [169] and observational studies with much larger numbers of patients have shown comparable efficacy and safety of rituximab in combination with either MTX or LEF [170-172]. With rituximab monotherapy, good responses to treatment are often seen [171], but discontinuation is more frequent than when it is used in combination with either MTX or LEF [170].

The use, pretreatment testing, administration, monitoring, and adverse effects of rituximab in RA are described in detail separately. (See "Rituximab: Principles of use and adverse effects in rheumatoid arthritis".)

●Efficacy of rituximab – The benefits of rituximab in patients with RA resistant to MTX and in those resistant to other conventional nonbiologic DMARDs has been documented in several randomized trials. As an example, in one randomized trial of patients resistant to MTX, the ACR20, -50, and -70 responses after six months were all greater in patients who received rituximab plus MTX, compared with continuing MTX alone (73, 43, and 23 versus 38, 13, and 5 percent, respectively) [80]. The efficacy of rituximab in RA was shown initially in uncontrolled studies of rituximab alone or in combination with glucocorticoids and cyclophosphamide [173-175], then further established by randomized trials in patients with active disease despite MTX [80,176], and in patients refractory or intolerant to anti-TNF therapy [177].

In support of using rituximab together with MTX or an alternative such as LEF, observational data from the German Rheumatoid Arthritis: Observation of Biologic Therapy (RABBIT) registry suggest that treatment discontinuation and dropout rates are higher when rituximab is used as monotherapy rather than in combination with either MTX or LEF [170]. Efficacy and safety when rituximab is combined with either MTX or LEF appear similar [169-172]. However, rituximab can also often be effective as monotherapy in patients who are intolerant of MTX or have contraindications to MTX and/or other DMARDs [171].

A 2015 systematic review and meta-analysis of eight trials, involving 2720 patients with active RA despite MTX, has confirmed the benefit of rituximab in such patients [178]. Several reports indicate that positive testing for rheumatoid factor or anti-cyclic citrullinated peptide (CCP) antibodies predicts a greater likelihood of responsiveness to rituximab [179-182]. Data from a large registry suggest that the efficacy of rituximab is reduced in patients over age 75 compared with younger patients at 12, 18, and 24 months, although no differences were seen at six months; whether there were differences between the frequency of retreatment with rituximab or number and/or doses of concomitant DMARDs in the different groups was not described [183].

The efficacy of rituximab was comparable to a TNF inhibitor (ETN or ADA) in patients with an inadequate response to nonbiologic DMARDs in a randomized, open-label trial involving 295 patients with active seropositive RA who had not received a biologic DMARD [184]. In this trial, rituximab (1 g administered intravenously on days 1 and 15, which was repeated after 26 weeks in patients with a partial response to therapy but with persistent disease activity) resulted in a similar response at one year to TNF inhibitor therapy (with either ETN 50 mg weekly or ADA 40 mg every two weeks administered subcutaneously) with respect to the degree of improvement in the DAS28-ESR and other measures. Severe adverse events attributed to the medications occurred at a similar frequency in the two groups. Several issues limited interpretation of the trial [185]. The mean number of conventional nonbiologic DMARDs was only one in both groups, and the specific medications and the number on each were not specified; approximately a quarter of patients were reported to be intolerant of MTX. Radiographic outcomes were not assessed. Recruitment was very slow despite a large number of participating research centers, suggesting that potentially confounding clinician and patient factors may have influenced patient selection for the trial.

The efficacy of rituximab for the treatment of RA resistant to an initial biologic agent is described separately. (See "Treatment of rheumatoid arthritis in adults resistant to initial biologic DMARD therapy", section on 'Choice of therapy' and "Treatment of rheumatoid arthritis in adults resistant to initial biologic DMARD therapy", section on 'Rituximab'.)

REEVALUATION AND MONITORING — Disease activity and the response to therapy should be regularly reassessed, along with monitoring for drug toxicities, every 4 to 12 weeks following a change in the treatment regimen until the patient is stable and until disease is under control [9,186-188]. Subsequently, assessments should not be less frequent than every three to six months. More frequent laboratory monitoring may be required depending upon the medications being used and following increases in dosing; more frequent clinical assessments may be required in patients experiencing a flare of disease or in those undergoing changes in therapy. 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 'Pretreatment evaluation' and "General principles and overview of management of rheumatoid arthritis in adults", section on 'Assessment and monitoring'.)

We periodically reevaluate disease activity using a quantitative composite measure at each assessment (eg, the clinical disease activity index [CDAI] or the disease activity score [DAS] with 28 joint count [DAS28]). (See "Assessment of rheumatoid arthritis disease activity and physical function" and "General principles and overview of management of rheumatoid arthritis in adults", section on 'Structured measures of disease activity and functional status' and "General principles and overview of management of rheumatoid arthritis in adults", section on 'Tight control'.)

Patients who fail to achieve remission or low disease activity within three to six months of initiating therapy or who require more than 5 mg/day of prednisone or equivalent glucocorticoid to maintain a state of remission should generally escalate to a more potent disease-modifying antirheumatic drug (DMARD) or combination of DMARDs. A therapeutic trial of greater than three months is generally used in patients with partial responses showing progressive improvement, particularly in those with low to moderate levels of disease activity and with limited functional impairment.

In patients in whom treatment with both combination nonbiologic DMARDs (eg, triple therapy with methotrexate [MTX], sulfasalazine [SSZ], and hydroxychloroquine [HCQ]) and a combination of a potent nonbiologic therapy (eg, MTX) with a biologic agent (eg, a tumor necrosis factor [TNF] inhibitor) have been inadequate to achieve therapeutic goals, switching to another biologic agent is generally indicated. The approach in such patients is described in detail separately. (See "Treatment of rheumatoid arthritis in adults resistant to initial biologic DMARD therapy".)

SYMPTOMATIC DRUG THERAPY — Antiinflammatory drugs are used as a supplement to disease-modifying antirheumatic drugs (DMARDs) under several conditions, including as bridging therapies until newly instituted DMARD regimens become effective, as adjuncts to DMARDs on a chronic basis, and for the management of disease exacerbations (flares). Analgesic effects of nonsteroidal antiinflammatory drugs (NSAIDs) or acetaminophen may also give additional relief.

Antiinflammatory therapy — We use NSAIDs or systemic and/or intraarticular glucocorticoids when needed for ongoing control of inflammation, while awaiting the response to modifications in DMARD therapy. Glucocorticoids can help to rapidly control inflammation and to improve symptoms. However, they should be used in the lowest dose required once such control is achieved, and they should be tapered and discontinued as soon as feasible. Some patients require ongoing therapy with low doses of glucocorticoids to maintain remission or a low level of disease activity. (See "Initial treatment of rheumatoid arthritis in adults", section on 'NSAIDs' and "Initial treatment of rheumatoid arthritis in adults", section on 'Glucocorticoids' and "Use of glucocorticoids in the treatment of rheumatoid arthritis".)

Drug therapy for 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 by 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. The treatment of such flares is described in detail elsewhere. (See "Clinical manifestations of rheumatoid arthritis" and "General principles and overview of management of rheumatoid arthritis in adults", section on 'Assessment and monitoring' and "Use of glucocorticoids in the treatment of rheumatoid arthritis" and "General principles and overview of management of rheumatoid arthritis in adults", section on 'Drug therapy for flares'.)

Analgesics — In addition to the medications noted above, including NSAIDs, which also have analgesic effects, we use other analgesic medications, such as acetaminophen and/or tramadol, which is an opioid, for additional pain relief, if required. However, we generally avoid the use of opioids, if possible, because pain can be controlled in most patients with RA by effective use of antiinflammatories and DMARDs that control the disease process. For patients in whom structural damage requires significant pharmacologic pain control, we prefer nonopioid pain-management strategies. Patients without evidence of very significant joint inflammation who request potent opioids for pain relief should be evaluated for other comorbid causes of pain.

DURATION OF THERAPY — In the few patients who achieve a sustained clinical remission for greater than one year, we cautiously try to reduce nonbiologic and biologic disease-modifying antirheumatic drug (DMARD) doses while closely monitoring the patient for evidence of disease flare. However, we generally avoid discontinuing all DMARD treatment. Although some patients may tolerate a reduced dose of medications, there are insufficient data to prospectively identify which patients will be able to successfully reduce or discontinue therapy without clinical recurrence or radiographic progression. The decision to discontinue DMARDs in patients in remission remains controversial.

Our approach is based upon the available data and our clinical experience. (See "Initial treatment of rheumatoid arthritis in adults", section on 'Duration of therapy' and "Assessment of rheumatoid arthritis disease activity and physical function", section on 'Criteria for remission'.)

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

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

●Taper biologic DMARD – This may be accomplished either by decreasing the dose or increasing the interval between doses. As examples, we try to reduce etanercept (ETN) by slowly decreasing the dosing frequency (eg, to every 10 to 14 days, then gradually to every three to four weeks, if tolerated). In patients on infliximab, we would try to incrementally reduce the dose to as low as 3 mg/kg and then increase interval between infusions.

●Taper DMARD – For methotrexate (MTX), we decrease the dose in 2.5 mg increments every two to four weeks, but generally no lower than 10 mg/week.

We suggest reducing the prednisone dose first because of the risk of long-term adverse effects of glucocorticoids. If the prednisone can be lowered to a dose no greater than 5 mg/day but cannot be discontinued entirely, we then try to taper the biologic DMARD. If the patient remains in remission without a biologic DMARD for at least one year, we then try to taper the DMARD, without discontinuing the drug entirely.

Continued close monitoring for disease activity is required in patients who discontinue or reduce any of their medications. Any change in medications may increase the risk of disease recurrence, and flares of disease may occur even several years after stopping therapy [189-193]. Additionally, clinical remission can be difficult to achieve upon resumption of DMARD therapy in patients who have discontinued all DMARDs.

Nevertheless, multiple studies suggest that rheumatoid arthritis (RA) patients who have achieved a sustained clinical remission may tolerate a reduction in immunosuppression without a significant increased risk of relapse. In a meta-analysis of randomized trials including 1430 patients with RA who had achieved a prolonged remission after treatment with a biologic or targeted synthetic DMARD plus MTX, stopping MTX did not affect the remission rate [194]. However, withdrawal of methotrexate slightly increased the Disease Activity Score-28 (DAS-28) by 0.20 and slightly decreased the percentage of patients who achieved low disease activity (risk ratio 0.88, 95% CI 0.80-0.97). Similarly, in a cohort study of 437 patients who had been in remission for at least six months, reduction of immunosuppression (including conventional and biologic DMARDs) did not increase the risk of flare (hazard ratio [HR] 0.88) or loss of remission (HR 1.04) when compared with patients who remained on chronic immunosuppression [195].

Factors associated with a drug-free remission include [191,196-198]:

●Short duration of symptoms

●Male sex

●Absence of rheumatoid factor and anti-citrullinated peptide antibodies

●Early intensive therapy

●Complete, prolonged remission, based on composite scores of disease activity

There is relatively limited evidence regarding radiographic outcomes of tapering of DMARDs in patients who are started on DMARDs early in their disease course and those who have been treated with biologic DMARDs [189-193,199-202]. In general, randomized trials have demonstrated that gradual reduction of immunosuppression is associated with some increased risk of flare, but not necessarily progression of radiographic damage. As examples:

●In a trial involving initial therapy of early RA (symptoms less than one year) with ETN (50 mg weekly) and MTX (up to 25 mg weekly administered orally), 193 patients achieving remission after one year of therapy were randomly assigned to receive either ETN 25 mg weekly plus MTX, MTX alone, or placebo in a blinded fashion for the next 39 weeks [203]. None of the patients in remission were assigned to continue the original dosing regimen.

•Low disease activity (disease activity score [DAS] with 28 joint count [DAS28] ≤3.2) or remission was more common in the patients on the combination of ETN plus MTX compared with those receiving only MTX or only placebo (63 versus 40 versus 23 percent).

•Patients with low disease activity or remission then discontinued therapy, and after another 24 weeks (65 weeks following randomization), those from the combination group were more likely to maintain a clinical response (DAS28 ≤3.2; 44 versus 29 versus 23 percent).

•Despite the differences in the clinical response, there was no significant radiographic progression in any group and no difference in radiographic response between the three groups at week 39 of the blinded phase of the study.

●Another trial, involving 1032 patients, suggested that most patients with early RA who respond very well to the combination of MTX and a tumor necrosis factor (TNF) inhibitor may be able to tolerate discontinuation of the TNF inhibitor after six months of combination therapy [204]. In this trial, patients with early RA (disease duration less than one year) were randomly assigned to treatment for the first 26 weeks of the trial with either adalimumab (ADA; 40 mg every two weeks) plus MTX (titrated to 20 mg weekly by week 8) or with placebo plus MTX. Patients who achieved remission or low disease activity were subsequently randomized to either withdrawal or continuation of ADA for another 52 weeks.

•Those continuing ADA had a relatively small but statistically significantly greater likelihood of maintaining remission or low disease activity (DAS28 <3.2) at week 78 compared with those in whom ADA was withdrawn (91 versus 81 percent).

•A small difference in the proportion with radiographic nonprogression did not achieve statistical significance (89 versus 81 percent).

SPECIAL POPULATIONS

Pregnancy — Considerations relevant to the management of rheumatoid arthritis (RA) during pregnancy are reviewed separately. (See "Rheumatoid arthritis and pregnancy" and "Safety of rheumatic disease medication use during pregnancy and lactation".)

Resource-poor settings — Some patients may not have adequate access to healthcare resources. For patients with RA, this can result in limited or no access to biologic therapies, specialist clinicians, and other resources. In such patients, treatment may need to rely upon the available nonbiologic (traditional or conventional) disease-modifying antirheumatic drugs (DMARDs). Initial therapy would not generally differ from patients with greater resources. (See "Alternatives to methotrexate for the initial treatment of rheumatoid arthritis in adults" and "Initial treatment of rheumatoid arthritis in adults".)

In patients resistant to initial therapy we would take the following approach, assuming the availability of the nonbiologic, but not biologic, DMARDs:

●Triple therapy (with methotrexate [MTX], sulfasalazine [SSZ], and hydroxychloroquine [HCQ]) would be used in patients resistant to MTX alone. (See 'Resistant to methotrexate' above and 'DMARD triple therapy' above.)

●Patients resistant to triple therapy can be treated with MTX plus leflunomide (LEF), with very close attention to monitoring of liver function tests. Unblinded studies have reported that the other combinations may also be effective alternatives, including MTX and azathioprine, as well as MTX, azathioprine, and HCQ [205]. Patients intolerant of MTX may be treated with LEF alone. (See 'Leflunomide' above.)

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 treatment (Beyond the Basics)" and "Patient education: Rheumatoid arthritis symptoms and diagnosis (Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS

●Patients with rheumatoid arthritis (RA) benefit from the achievement and maintenance of tight control of disease activity, with the ideal goal of remission. Whenever possible, nonsteroidal antiinflammatory drugs (NSAIDs) and glucocorticoids should be used only as adjunctive agents. Patient education and other nonpharmacologic and preventive therapies, including appropriate immunizations, are needed for all patients with RA. (See 'General principles and approach' above.)

●In patients with RA, resistance to initial therapy with disease-modifying antirheumatic drugs (DMARDs) is defined here as failure to achieve remission or low disease activity within three to six months despite the use of maximally tolerated doses within the usual therapeutic range; a need for excessively high doses of glucocorticoids in addition to DMARDs; or as recurrent flares of disease requiring multiple courses of glucocorticoids with doses in excess of those acceptable for chronic therapy, despite maximally tolerated or acceptable doses of the DMARDs being used. (See 'Definition of resistance to initial therapy with conventional synthetic DMARDs' above.)

●In patients with active RA resistant to initial therapy after three to six months of optimal treatment, we recommend treatment with a different or additional DMARD or with DMARD combinations to achieve control of signs and symptoms of disease, rather than continuing the initial DMARD regimen. The choice of drug combinations in such patients depends upon prior therapy, the level of disease activity, patient preference for route of administration, the presence of adverse prognostic features, and regulatory and cost barriers to drug access. Drug doses are described in the relevant sections on each agent within the topic review. (See 'General approach' above and 'Choice of therapy' above.)

•In patients resistant to initial therapy with hydroxychloroquine (HCQ) or sulfasalazine (SSZ), we suggest adding methotrexate (MTX) and treating with a combination of HCQ, SSZ, and MTX, or switching to MTX, rather than switching to a tumor necrosis factor (TNF) inhibitor or to a TNF inhibitor plus MTX. The choice to add or continue HCQ and/or SSZ depends upon patient tolerance to the prior therapy and willingness to take multiple medications. (See 'Resistant to hydroxychloroquine and/or sulfasalazine' above and "Alternatives to methotrexate for the initial treatment of rheumatoid arthritis in adults", section on 'Monitoring and reevaluation' and "Initial treatment of rheumatoid arthritis in adults".)

•In patients who have not achieved treatment goals after three to six months of MTX at optimal doses, we suggest either the use of DMARD "triple therapy" with MTX plus SSZ and HCQ or the use of the combination of continued MTX plus a TNF inhibitor, rather than monotherapy with another conventional synthetic (cs) nonbiologic or biologic DMARD. In patients with partial responses or showing progressive improvement, we may continue therapy with MTX for greater than three months before switching to one of these approaches, particularly in those with low to moderate levels of disease activity and with limited functional impairment. The available TNF inhibitors, including etanercept, adalimumab (ADA), infliximab, golimumab, and certolizumab pegol, are comparably effective. (See 'Choice of therapy' above and 'DMARD triple therapy' above and 'Methotrexate plus TNF inhibitor' above and 'Alternatives to triple therapy and methotrexate/TNF inhibitor' above and 'Resistant to methotrexate' above.)

We prefer triple therapy in patients for whom personal drug cost, regulatory restrictions on the use of biologic DMARDs, preference for an oral nonbiologic agent rather than an injectable, or particular concern regarding infectious risks are important factors. We prefer combination therapy with MTX plus a TNF inhibitor in patients who would benefit from a more rapid therapeutic response, particularly those with high levels of disease activity and adverse prognostic features. The combination of MTX with a TNF inhibitor is also preferred for patients who do not achieve a satisfactory response within three to six months with nonbiologic triple therapy following an inadequate response to MTX. In such patients, we either discontinue SSZ and HCQ and administer a TNF inhibitor with the MTX, or continue both the HCQ and SSZ (or just one of the agents, usually the HCQ) when adding a TNF inhibitor, particularly in patients who have experienced partial clinical benefit. (See 'Choice of therapy' above and 'Methotrexate plus TNF inhibitor' above and "Tumor necrosis factor-alpha inhibitors: An overview of adverse effects".)

•In patients in whom MTX plus a TNF inhibitor would otherwise be appropriate but who are unable to use a TNF inhibitor, we suggest the combination of MTX plus either abatacept, tocilizumab, sarilumab, tofacitinib, upadacitinib, or baricitinib rather than biologic monotherapy or another DMARD combination. (See 'Alternatives to triple therapy and methotrexate/TNF inhibitor' above and 'Methotrexate plus abatacept' above and 'Methotrexate plus IL-6 inhibitor/IL-6 inhibitor monotherapy' above and 'JAK inhibitor therapy' above.)

•In patients in whom MTX or DMARD triple therapy fails to adequately control disease activity and regulatory or cost considerations preclude use of a biologic agent, we suggest the use of leflunomide (LEF) rather than alternative nonbiologic DMARDs (eg, gold, azathioprine, or cyclosporine). LEF may also be used as an alternative to MTX or in combination with MTX if needed. (See 'Leflunomide' above.)

•Based on recent data, the US Food and Drug Administration (FDA) has issued a warning for the class of Janus kinase (JAK) inhibitors in RA patients at increased risk for cardiovascular disease, venous thromboembolic event (VTE), or malignancy, and if alternatives exist, JAK inhibitors would not be initial choice after csDMARD failures in this population.

●In patients whose treatment regimen has changed, reevaluation may be required up to every 4 to 12 weeks for the effectiveness of therapy and for the monitoring of possible drug toxicity. We assess and monitor disease activity using a quantitative composite measure at each assessment. Further management is dependent upon disease response. In patients who do not respond adequately to triple therapy after three to six months and therapy with an initial TNF inhibitor within three to six months, we further modify the treatment regimen. (See 'Reevaluation and monitoring' above and "Treatment of rheumatoid arthritis in adults resistant to initial biologic DMARD therapy".)

●We continue nonbiologic and biologic DMARD therapy at reduced doses, if possible, for patients in remission, rather than discontinuing treatment with DMARDs. (See 'Duration of therapy' above.)

●In patients experiencing a disease flare that is not controlled with NSAIDs, we suggest treatment with intraarticular or oral glucocorticoids rather than switching or continuing NSAIDs as the only additional agent. We use antiinflammatory drug therapy, including NSAIDs or glucocorticoids, on a temporary basis to quickly achieve control of signs and symptoms of disease, and we then taper and withdraw these medications once a new DMARD regimen has taken effect. Some patients benefit from chronic low-dose glucocorticoid therapy (eg, prednisone to 5 mg daily). (See 'Symptomatic drug therapy' above and 'Antiinflammatory therapy' above and 'Drug therapy for flares' above and "General principles and overview of management of rheumatoid arthritis in adults", section on 'Drug therapy for flares'.)

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