Treatment of rheumatoid arthritis in adults resistant to initial nonbiologic DMARD therapy

Treatment of rheumatoid arthritis in adults resistant to initial nonbiologic DMARD therapy

Authors
Stanley Cohen, MD
Amy Cannella, MD, MS, RhMSUS

Section Editor
James R O'Dell, MD

Deputy Editor
Paul L Romain, MD

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

Literature review current through: May 2016. &#124 This topic last updated: Apr 18, 2016.

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 (traditional) disease-modifying antirheumatic drug (DMARD), such as methotrexate (MTX), timely adjustments in the treatment regimen are required to achieve effective disease control and prevent damage to the joints. (See "General principles of management of rheumatoid arthritis in adults", section on 'Tight control' and "General principles of management of rheumatoid arthritis in adults", section on 'Early use of DMARDs'.)
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 nonbiologic (traditional) 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 nonbiologic DMARD (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 of management of rheumatoid arthritis in adults" and "Initial treatment of mildly active rheumatoid arthritis in adults" and "Initial treatment of moderately to severely active rheumatoid arthritis in adults", section on 'Monitoring and reevaluation' and "Treatment of rheumatoid arthritis in adults resistant to initial biologic DMARD therapy" and "Evaluation and medical management of end-stage rheumatoid arthritis" and "Total joint replacement for severe rheumatoid arthritis".)
GENERAL PRINCIPLES AND APPROACH
Principles of management — There are several general principles that are important in the management of all patients with rheumatoid arthritis (RA). 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
These principles are discussed in detail elsewhere. (See "General principles of management of rheumatoid arthritis in adults".)
It is important to determine whether joint symptoms in patients with persistently symptomatic RA are due to active inflammatory arthritis or are the result of structural damage that is unlikely to respond to antiinflammatory drugs and nonbiologic or biologic DMARDs. (See "Assessment of rheumatoid arthritis activity in clinical trials and clinical practice" and "General principles of management of rheumatoid arthritis in adults", section on 'Assessment of disease activity'.)
Definition of resistance to initial therapy with nonbiologic DMARDs — Resistance to initial nonbiologic (traditional) 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 DMARD therapy in maximally tolerated doses within the usual therapeutic range (see "Assessment of rheumatoid arthritis activity in clinical trials and clinical practice", section on 'Remission' and "Initial treatment of moderately to severely active rheumatoid arthritis in adults")
●A requirement, in addition to DMARDs, for chronic glucocorticoid therapy in a dose of greater than about 5 to 7.5 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 mechanical destabilization of the joints
Resistance or an inadequate response to subsequent DMARD therapy may be defined similarly, depending upon the treatment goals in an individual patient. (See "General principles of management of rheumatoid arthritis in adults", section on 'Tight control' and "General principles of management of rheumatoid arthritis in adults", section on 'Other considerations in RA management'.)
Nonpharmacologic and preventive therapies — A number of nonpharmacologic measures and other medical interventions are important in the comprehensive management of RA, in addition to antiinflammatory and antirheumatic drug therapies. These interventions, including patient education, vaccinations, and others, are discussed in detail elsewhere. (See "Nonpharmacologic therapies and preventive measures for patients with rheumatoid arthritis".)
Pharmacotherapy — In patients resistant to initial 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. The choice of the DMARD regimen in patients resistant to initial DMARD treatment depends largely upon the responses to the specific medications that have been used previously. It 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. The choice among available agents is dependent upon the initial DMARD therapy and upon disease activity. (See 'Approach to treatment with DMARDs' below and 'Symptomatic drug therapy' below.)
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. A chest radiograph should be obtained prior to initiating treatment with methotrexate (MTX). These issues are discussed in detail elsewhere. (See "Nonpharmacologic therapies and preventive measures for patients with rheumatoid arthritis", section on 'Vaccinations' and "Hepatitis B virus reactivation associated with immunosuppressive therapy" and "Tumor necrosis factor-alpha inhibitors and mycobacterial infections" and "Diagnosis of latent tuberculosis infection (tuberculosis screening) in HIV-uninfected adults" and "Major side effects of low-dose methotrexate", section on 'Pulmonary toxicity' and "General principles of management of rheumatoid arthritis in adults", section on 'Pretreatment evaluation'.)
APPROACH TO TREATMENT WITH DMARDS — The approach for patients resistant to initial disease-modifying antirheumatic drug (DMARD) therapy depends upon the treatment the patient has already been given. 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. In patients who have already been treated with MTX without achieving therapeutic goals, treatment combining MTX with other nonbiologic DMARDs or with a biologic DMARD is the next step. (See 'Resistant to HCQ and/or SSZ' below and 'Resistant to MTX' below and 'Choice of therapy' below.)
Resistant to HCQ and/or SSZ — In patients resistant to three to six months of therapy with HCQ or SSZ for initially mildly active disease, we suggest adding an alternative DMARD, usually MTX; the approach in these patients is generally similar to that for patients with moderately to severely active disease presenting for initial DMARD therapy. An acceptable alternative would be treatment with a combination of HCQ, SSZ, and MTX, termed “triple therapy” (see 'DMARD triple therapy' below). A therapeutic trial of greater than three months is generally used in patients with partial responses showing progressive improvement, particularly in those in this group with low levels of disease activity and with limited functional impairment. (See "Initial treatment of mildly active rheumatoid arthritis in adults", section on 'Monitoring and reevaluation' and "Initial treatment of moderately to severely active rheumatoid arthritis in adults", section on 'Initial therapy with methotrexate'.)
We prefer MTX over alternative nonbiologic 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 nonbiologic DMARD monotherapy [16,17]. Direct comparisons of MTX with tumor necrosis factor (TNF) inhibitor monotherapy have also shown similar clinical benefit [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 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, and the efficacy of such “triple therapy” with this DMARD combination is discussed in further detail below. (See "Initial treatment of moderately to severely active rheumatoid arthritis in adults", section on 'Initial therapy with methotrexate' and "Initial treatment of moderately to severely active rheumatoid arthritis in adults", section on 'MTX versus other DMARDs' and "Initial treatment of moderately to severely active rheumatoid arthritis in adults", section on 'MTX versus initial combination therapy' and 'Efficacy of triple therapy versus MTX/TNF inhibitor' below.)
Resistant to MTX — In patients resistant to MTX after three to six months of treatment at optimal doses (usually 25mg/week), we suggest either the use of DMARD “triple therapy” with MTX plus SSZ and HCQ, or the combination of continued MTX plus a TNF inhibitor, rather than monotherapy with another nonbiologic or biologic DMARD. Optimization of MTX dosing is described in more detail separately (see "Use of methotrexate in the treatment of rheumatoid arthritis", section on 'Dosing of MTX'). 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. (See 'Choice of therapy' below and 'DMARD triple therapy' below and 'MTX plus TNF inhibitor' below and 'Alternatives to triple therapy and MTX/TNF inhibitor' below.)
In patients begun on a biologic DMARD, we generally continue MTX, unless contraindicated, to improve the degree of clinical and radiographic benefit and to inhibit the development of antibodies directed at the biologic agent that can reduce efficacy.
Leflunomide 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. It may also be used in combination with MTX as an alternative to adding a TNF inhibitor, which may be of particular use in patients unable to obtain or with contraindications to use of a TNF inhibitor or other biologic agents. (See 'Choice of therapy' below and 'Leflunomide' below and "Initial treatment of moderately to severely active rheumatoid arthritis in adults" and "Initial treatment of mildly active rheumatoid arthritis in adults".)
Abatacept, the T-cell costimulation blocker, and tocilizumab, the interleukin (IL)-6 inhibitor, are alternatives to TNF inhibitors for use in combination with MTX in patients with an inadequate response to MTX, but their use in this setting is supported by a smaller body of evidence than that for TNF inhibitor use. Either can be administered intravenously or subcutaneously. 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. However, both of these biologic agents are available for use in the United States for patients who have not responded adequately to MTX alone. (See 'MTX plus abatacept' below and "Randomized clinical trials in rheumatoid arthritis of biologic agents that inhibit IL-1, IL-6, and RANKL", section on 'Tocilizumab'.)
Choice of therapy — A number of treatment options are reasonable in patients with an inadequate response to MTX therapy. The choice of drug combinations 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 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 'Efficacy of triple therapy versus MTX/TNF inhibitor' below and "General principles of management of rheumatoid arthritis in adults", section on 'Prognosis'.)
●We prefer triple therapy with MTX, SSZ, and HCQ in patients for whom personal drug cost, regulatory restrictions on the use of biologic DMARDs, or preference for an oral nonbiologic agent, rather than an injectable, is an important factor. In addition, concern regarding the risk of serious infections, the uncertain long-term increased risk of malignancy, and other possible adverse effects may influence clinician or patient preference for nonbiologic agents [24-27]. (See 'DMARD triple therapy' below.)
●We prefer combination therapy with MTX plus a TNF inhibitor, particularly in patients with high levels of disease activity and adverse prognostic features who would benefit from a more rapid therapeutic response. All of the available TNF inhibitors appear to provide comparable benefit. These regimens may have a faster onset of action compared with DMARD triple therapy. However, use of a TNF inhibitor or other biologic requires subcutaneous injections or intravenous infusions, and regulatory or cost considerations may limit access. (See 'MTX plus TNF inhibitor' below.)
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. However, this latter practice has not been formally evaluated or compared with other approaches, and patient tolerance or preferences regarding concerns about adverse effects, as well as clinician preference, also affect the choice of drug combinations (see 'MTX plus TNF inhibitor' below and "Tumor necrosis factor-alpha inhibitors: An overview of adverse effects").
●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 methotrexate is contraindicated, or for whom MTX is inadequate, particularly in 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.
●Abatacept or tocilizumab may be used as an alternative 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. (See 'MTX plus abatacept' below and 'MTX plus tocilizumab' below.)
●In patients with latent tuberculosis (TB) who are unable to complete anti-tuberculous therapy we prefer to use nonbiologic DMARDs as monotherapy or in combinations. In patients with persistent disease activity despite such intervention, it may be necessary to use a biologic DMARD, in which case we prefer agents other than TNF inhibitors. We also review the risks of such intervention in detail with the patient when deciding upon therapy and consult with a specialist in infectious disease for additional assistance in management. (See "Treatment of latent tuberculosis infection in HIV-uninfected adults".)
DMARD triple therapy — 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 moderately to severely active 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 in the treatment of rheumatoid arthritis" and "Initial treatment of mildly active rheumatoid arthritis in adults", section on 'Patients with mild activity and poor prognostic signs'.)
●HCQ is used at a dose of 400 mg daily in most patients but does not exceed 6.5 mg/kg/day calculated on the basis of lean body weight. The use of HCQ in rheumatic disease, including RA, as well as the dosing, adverse effects, and monitoring of HCQ, is discussed in detail separately. (See "Antimalarial drugs in the treatment of rheumatic disease" and "Initial treatment of mildly active rheumatoid arthritis in adults" and "Initial treatment of mildly active rheumatoid arthritis in adults", section on 'Patients who lack poor prognostic features'.)
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 having started a biologic agent sooner [28]. The evidence describing the efficacy of triple therapy in patients who have had an inadequate response to MTX and comparing triple therapy with the combination of MTX plus a TNF inhibitor are described below (see 'Efficacy of triple therapy versus MTX/TNF inhibitor' below); the efficacy and safety of DMARD triple therapy compared with other nonbiologic DMARDs used singly or in combination are described separately. (See "Randomized clinical trials of combinations of nonbiologic DMARDs in rheumatoid arthritis" and "Clinical trials of combination therapy in persistently active rheumatoid arthritis in adults".)
MTX plus TNF inhibitor — There is no convincing evidence that any one of the TNF inhibitors has greater efficacy than the others [29]; thus, the choice of 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. We usually use etanercept (ETN; 50 mg administered subcutaneously once weekly) or adalimumab (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. (See 'Nonpharmacologic and preventive therapies' above and 'Pretreatment interventions' above.)
An alternative TNF inhibitor in patients who prefer therapy by intravenous infusions is infliximab (usually 3 to 5 mg/kg every four to eight weeks after an initial loading schedule at zero, two, and six weeks). Other alternative TNF inhibitors that are effective in patients with ongoing disease activity despite MTX include golimumab (50 mg administered subcutaneously once monthly) and certolizumab pegol (initial dose of 400 mg [given as two subcutaneous 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).
In patients with an inadequate response to MTX, the use of combination therapy with the addition of a TNF inhibitor is supported by multiple randomized trials and meta-analyses that demonstrate the superiority of this approach compared with adding placebo while continuing the MTX [24,30-33]. The American College of Rheumatology (ACR) 20 percent response (ACR20), ACR50, and ACR70 are composite measures reflecting at least 20, 50, and 70 percent improvement in several defined measurements of disease activity [34]. 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 about 60, 40, and 20 percent, respectively [31]. 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) [35]. (See "Assessment of rheumatoid arthritis activity in clinical trials and clinical practice", section on 'ACR response criteria'.)
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 [19,24,32,36,37]. 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 [38-45]. Trials of biologic DMARDs and data supporting their use in patients with active RA are described in detail separately. (See "Clinical trials of combination therapy in persistently active rheumatoid arthritis in adults" and "Randomized clinical trials of tumor necrosis factor inhibitors in rheumatoid arthritis".)
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 detail below. (See 'Efficacy of triple therapy versus MTX/TNF inhibitor' below and 'Efficacy of MTX/TNF inhibitor versus MTX/abatacept' below.)
ETN and adalimumab might be safer than infliximab [25,30,46]. However, comparisons between these agents are largely indirect [25,30]; additionally, a case control study suggesting greater safety with ETN, compared with infliximab or adalimumab, only addressed the risk of reactivation of latent TB in patients who had not received adequate chemoprophylaxis prior to therapy [46]. Indirect comparisons of randomized trial results in a 2011 meta-analysis suggested that patients receiving ETN, adalimumab, 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) [25].
TNF inhibitor therapy is generally well-tolerated, but these medications pose increased risk of reactivation of latent TB 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 may not be initiated on anti-TNF therapy [47-49]. TNF inhibitors should not be administered to patients with active infections, and they are relatively contraindicated in patients with multiple sclerosis or 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 "Tumor necrosis factor-alpha inhibitors and mycobacterial infections" and "Tumor necrosis factor-alpha inhibitors: Risk of malignancy" and "Tumor necrosis factor-alpha inhibitors: Induction of antibodies, autoantibodies, and autoimmune diseases".)
Alternatives to triple therapy and MTX/TNF inhibitor — We suggest the combinations of MTX plus either abatacept or tocilizumab, which may be administered by intravenous infusion or subcutaneous injection, as alternatives to a TNF inhibitor in patients in whom MTX plus a TNF inhibitor would otherwise be appropriate (see 'MTX plus TNF inhibitor' above), particularly in patients who are unable to use a TNF inhibitor and who have a high level of disease activity (see 'MTX plus abatacept' below and 'MTX plus tocilizumab' below). In patients in whom MTX fails to adequately control disease activity and who are unable to use a biologic agent because of regulatory or cost considerations or other factors, we suggest either switching from MTX to leflunomide (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.
The efficacy of abatacept and tocilizumab together with MTX in patients with an inadequate response to MTX alone is supported by evidence from randomized trials, including trials in which each were compared with a TNF inhibitor, which are described separately. (See 'MTX plus abatacept' below and "Treatment of rheumatoid arthritis in adults resistant to initial biologic DMARD therapy", section on 'Abatacept' and "Treatment of rheumatoid arthritis in adults resistant to initial biologic DMARD therapy", section on 'Tocilizumab'.)
MTX plus abatacept — Abatacept may be used as an alternative to a TNF inhibitor. 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. 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. (See "T-cell targeted therapies for rheumatoid arthritis", section on '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 [25,50,51]. 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) [50]. 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 described above, which have suggested comparable benefit of abatacept to TNF inhibitor therapy when either is used in combination with continued MTX in patients with an inadequate response to MTX therapy [52,53]. (See 'Efficacy of MTX/TNF inhibitor versus MTX/abatacept' below.)
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 [54]. The efficacy of abatacept subcutaneously (125 mg subcutaneously on days 1 and 8, then weekly, plus an intravenous loading dose on day one of approximately 10 mg/kg) was comparable to abatacept intravenously (approximately 10 mg/kg IV 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).
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 also 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 TB has not been shown, although screening for latent TB prior to treatment is recommended. 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 [25]. Additional evidence supporting the use and safety of abatacept in RA is reviewed in detail separately. (See "T-cell targeted therapies for rheumatoid arthritis", section on 'Abatacept'.)
MTX plus tocilizumab — Tocilizumab, a humanized 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) [55]. We use tocilizumab in combination with MTX, unless MTX is contraindicated.
Tocilizumab is available for use in RA patients with active disease despite treatment with MTX, but we use it primarily in patients with RA who have not responded adequately to TNF inhibitors. The efficacy and safety of tocilizumab in RA have been characterized in meta-analyses of randomized trials of the drug as monotherapy or together with MTX compared with placebo. Evidence supporting the use of tocilizumab is described in detail separately. (See "Treatment of rheumatoid arthritis in adults resistant to initial biologic DMARD therapy", section on 'Tocilizumab' and "Randomized clinical trials in rheumatoid arthritis of biologic agents that inhibit IL-1, IL-6, and RANKL", section on 'Tocilizumab'.)
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. The risk of adverse effects is greater in patients on concomitant immunosuppressive therapy. Hyperlipidemia may occur and should be managed according to available guidelines. 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 "Treatment of lipids (including hypercholesterolemia) in primary prevention" and "Treatment of lipids (including hypercholesterolemia) in secondary prevention".)
Leflunomide — In patients with an inadequate response to MTX, some, but not all, experts advocate either switching to LEF or adding LEF 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 "Leflunomide in the treatment of rheumatoid arthritis" and "Use of methotrexate in the treatment of rheumatoid arthritis", section on 'Mechanism of action'.)
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 of LEF in patients with RA is discussed in detail separately. (See "Leflunomide in the treatment of rheumatoid arthritis".)
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 [56]. 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) [57]. However, these trials have been criticized for using lower maximum doses of MTX (up to 15 mg/week) than those that have subsequently been commonly employed (up to 25 mg/week) [56-58]. 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) [59]; however, LEF has not been compared directly with other agents in such patients. LEF has not been directly compared with the TNF inhibitors, but 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 moderately to severely active rheumatoid arthritis in adults", section on 'MTX versus other DMARDs' and "Clinical trials of combination therapy in persistently active rheumatoid arthritis in adults", section on 'MTX-leflunomide' and "Leflunomide in the treatment of rheumatoid arthritis".)
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 [60]. 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. (See "Randomized clinical trials of combinations of nonbiologic DMARDs in rheumatoid arthritis", section on 'Leflunomide and MTX'.)
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 [61-63]. 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 "Leflunomide in the treatment of rheumatoid arthritis", section on 'Adverse effects' and "Leflunomide in the treatment of rheumatoid arthritis", section on 'Pregnancy'.)
In patients with an inadequate response to initial treatment with LEF alone, a TNF inhibitor may be added to LEF. 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 [64]. However, randomized trials to prospectively evaluate the efficacy and safety of LEF used together with a biologic DMARD have not been performed. (See "Clinical trials of combination therapy in persistently active rheumatoid arthritis in adults", section on 'Leflunomide-TNF inhibitors'.)
REEVALUATION AND MONITORING — Disease activity and the response to therapy should be regularly reassessed, along with monitoring for drug toxicities, every four to eight weeks following a change in the treatment regimen until the patient is stable and until disease is under control [9,65-67]. 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 of management of rheumatoid arthritis in adults", section on 'Pretreatment evaluation' and "General principles 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 activity in clinical trials and clinical practice" and "General principles of management of rheumatoid arthritis in adults", section on 'Tight control' and "General principles of management of rheumatoid arthritis in adults", section on 'Assessment of disease activity'.)
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 a second TNF inhibitor or 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 moderately to severely active rheumatoid arthritis in adults", section on 'NSAIDs' and "Initial treatment of moderately to severely active 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 "Use of glucocorticoids in the treatment of rheumatoid arthritis" and "General principles of management of rheumatoid arthritis in adults", section on 'Assessment of disease activity' and "General principles 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, for additional pain relief, if required. We generally avoid the use of potent opioids because pain can be controlled in most patients with RA by effective use of antiinflammatories and DMARDs that control the disease process. 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 — Most patients with early, severely active rheumatoid arthritis (RA) require sustained therapy and adjustments in their treatment regimen over months to years to achieve treatment goals. In the minority of patients who achieve a sustained clinical remission of greater than one year, we cautiously try to reduce nonbiologic and biologic disease-modifying antirheumatic drug (DMARD) doses while maintaining close monitoring to facilitate recognition of any recurrence of disease activity. However, we generally avoid discontinuing all DMARD treatment, and there are insufficient data to prospectively identify which patients will be able to successfully reduce or discontinue therapy without clinical recurrence or radiographic progression. Although some patients may tolerate a reduced dose of medications, 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 moderately to severely active rheumatoid arthritis in adults", section on 'Duration of therapy' and "Assessment of rheumatoid arthritis activity in clinical trials and clinical practice", section on 'Remission'.)
As an example of our approach, in a patient in clinical remission being treated with prednisone (7 mg/day), methotrexate (MTX; 20 mg/week), and etanercept (ETN; 50 mg/week), we would first try to reduce prednisone because of the risk of long-term adverse effects with glucocorticoids. In such a patient, we would lower the glucocorticoid dose slowly (no faster than 1 mg every two to four weeks), as long as there was no recurrence of disease activity.
If prednisone can be discontinued or if it cannot be completely eliminated but can be lowered to a dose no greater than 5mg/day, we would then reduce the dosing of the tumor necrosis factor (TNF) inhibitor, based upon our clinical experience. As examples, we try to reduce ETN by slowly decreasing the dosing frequency (eg, to every 10 to 14 days, then gradually to every three to four weeks if dose reduction is tolerated). In patients on infliximab, in whom dose adjustment is more feasible compared with ETN or adalimumab, we would try to incrementally reduce the dose to as low as 3 mg/kg and to increase the interval between infusions to every eight weeks.
In patients who are able to discontinue a biologic and who then remain in remission for at least a year, we next decrease MTX. We reduce the MTX dose in 2.5 mg increments every two to three months as tolerated but generally to no lower than 10mg/week. In patients who are tolerating MTX more poorly, reduction in the MTX dose can be implemented before reduction in the dose of the TNF antagonist.
Continued close monitoring is required in patients who discontinue or reduce any of their medications. The risk of disease recurrence in such patients is high, and flares of disease may occur even several years after stopping therapy [68-72]. Additionally, clinical remission can be difficult to achieve upon resumption of DMARD therapy in patients who have discontinued all DMARDs. The best candidates for achieving a drug-free remission appear to be patients who have a short duration of symptoms when treatment is started, are of the male sex, have an absence of rheumatoid factor and anti-citrullinated peptide antibodies, have received early intensive therapy, and have achieved a deep remission based upon composite scores of disease activity [70,73-75]. The effects on the progression of joint injury of less frequent dosing (eg, based upon symptomatic need only) have not been evaluated.
There is relatively limited evidence regarding the clinical and 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 [68-72,76-79]. As examples:
●One randomized trial involving 604 patients evaluated the consequences of discontinuation of ETN in patients who had previously achieved a reduction from moderate to (at most) low disease activity at week 36 after the addition of ETN (50 mg weekly) to ongoing use of MTX [77]. Patients with low disease activity randomly assigned to continue ETN (50 or 25 mg weekly) plus MTX were significantly more likely to maintain low disease activity after one additional year of therapy compared with patients assigned to MTX plus placebo injections (83 and 79 percent versus 43 percent).

In another 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 (Disease Activity Score [DAS] with 28 joint count [DAS28] <2.6) 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 [80]. None of the patients in remission were assigned to continue the original dosing regimen. Low disease activity (DAS28 ≤3.2) or remission was significantly 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). Therapy in patients with low disease activity or remission was then withdrawn, and after another 24 weeks (65 weeks following randomization) a clinical response (DAS28 ≤3.2) was maintained significantly more often in the patients from the combination group (44 versus 29 versus 23 percent). Despite the differences in the clinical response, there was no significant radiographic progression in any group or a difference between the three groups at week 39 of the blinded phase of the study. Limitations of the study included the absence of control group continuing the original therapy or on ETN alone, and the lack of long-term radiographic follow-up.
●Another trial, involving 1032 patients, suggested that most patients with early RA who respond very well to the combination of MTX and a TNF inhibitor may be able to tolerate discontinuation of the TNF inhibitor after six months of combination therapy [81]. 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 (40 mg every two weeks) plus MTX (titrated to 20 mg weekly by week eight) or with placebo plus MTX, followed by further randomization of the 207 patients receiving adalimumab who had achieved remission or low disease activity to either withdrawal or continuation of adalimumab for another 52 weeks. Those continuing adalimumab 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 adalimumab was withdrawn (91 versus 81 percent); a small difference in the proportion with radiographic non-progression 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 "Use of antiinflammatory and immunosuppressive drugs in rheumatic diseases during pregnancy and lactation".)
Resource-poor settings — In patients for whom the cost or availability of biologic therapies precludes the use of these medications choices may be limited to traditional nonbiologic disease-modifying antirheumatic drugs (DMARDs) that are regularly used even when biologics may be available (eg, methotrexate [MTX], leflunomide [LEF], sulfasalazine [SSZ], and hydroxychloroquine [HCQ]), as well as other nonbiologic DMARDs that have been much less frequently employed since the biologic agents and kinase inhibitor therapy became available (eg, azathioprine, gold, cyclosporine, and minocycline). These agents may also be employed in patients resistant to standard therapies and their use is described separately. (See "Treatment of rheumatoid arthritis in adults resistant to initial biologic DMARD therapy", section on 'Resistant to standard therapies'.)
EFFICACY OF MAJOR INTERVENTIONS
Efficacy of triple therapy versus MTX/TNF inhibitor — Three randomized trials have compared the combination of methotrexate (MTX) plus a tumor necrosis factor (TNF) inhibitor with disease-modifying antirheumatic drug (DMARD) triple therapy combining MTX plus sulfasalazine (SSZ) and hydroxychloroquine (HCQ) [28,82-84]; two of the trials found no significant differences in clinical efficacy using composite measures of disease activity (eg, American College of Rheumatology [ACR] 20 percent responses [ACR20] of approximately 35 to 60 percent after one or two years) [28,84], while one of the trials showed a significant difference at 12 months but not at 6, 9, or 24 months [82,83]. 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 [82-84]; 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 [28]:
●Swefot trial – The Swedish Pharmacotherapy (Swefot) trial compared the efficacy of MTX plus infliximab with that of triple therapy using MTX, SSZ, and HCQ [82,83]. This randomized but non-blinded 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 League Against Rheumatism [EULAR] 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 reduced, 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 [83]. 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 [85]. Moreover, despite these radiographic differences, at 21 months after randomization both the infliximab and the triple therapy groups experienced similar reductions 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) [86].
●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 [84]. 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 28 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 [87]. 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 [28]. 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 non-inferior 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 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.
Efficacy of MTX/TNF inhibitor versus MTX/abatacept — Two randomized trials have compared abatacept with a TNF inhibitor for use in combination with continued MTX therapy in patients with an inadequate response to MTX, suggesting comparable benefit and safety of the two regimens, with 60 to 70 percent of patients achieving an ACR20 response [52,53]:
●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 [52]. 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 adalimumab in patients on background MTX suggests comparable efficacy and safety [88]. 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 adalimumab (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 therapy versus MTX/TNF inhibitor' above.)
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 information: Rheumatoid arthritis (The Basics)" and "Patient information: Disease modifying antirheumatic drugs (DMARDs) (The Basics)")
●Beyond the Basics topics (see "Patient information: Rheumatoid arthritis treatment (Beyond the Basics)" and "Patient information: 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, antiinflammatory agents, including 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 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 nonbiologic DMARDs' above.)
●In patients with active RA resistant to initial therapy after three to six months of 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 (Grade 1B). 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. (See 'Approach to treatment with DMARDs' above and 'Choice of therapy' above.)
•In patients resistant to initial therapy with hydroxychloroquine (HCQ) or sulfasalazine (SSZ), we suggest adding methotrexate (MTX) or treating with a combination of HCQ, SSZ, and MTX, rather than switching to a tumor necrosis factor (TNF) inhibitor or to a TNF inhibitor plus MTX (Grade 2B). Usual doses of these medications are MTX (up to 25 mg once weekly administered orally or parenterally), HCQ (400 mg daily taken orally), and SSZ (1000 to 1500 mg twice daily taken orally). (See 'Resistant to HCQ and/or SSZ' above and "Initial treatment of mildly active rheumatoid arthritis in adults", section on 'Monitoring and reevaluation' and "Initial treatment of moderately to severely active rheumatoid arthritis in adults".)
•In patients resistant to MTX after three to six months of treatment at optimal doses (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 a TNF inhibitor, rather than monotherapy with another 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. (See 'Choice of therapy' above and 'DMARD triple therapy' above and 'MTX plus TNF inhibitor' above and 'Alternatives to triple therapy and MTX/TNF inhibitor' above.)
•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 nonbiologic or biologic DMARD (Grade 2A). The available TNF inhibitors are comparably effective. Usual doses are: etanercept (ETN), 50 mg subcutaneously once weekly; adalimumab, 40 mg subcutaneously every two weeks; infliximab, 3 to 5 mg/kg every four to eight weeks after an initial loading schedule at zero, two, and six weeks; golimumab, 50 mg administered subcutaneously once monthly; and certolizumab pegol, initial dose of 400 mg (given as two subcutaneous injections) and repeat doses two and four weeks after the initial dose, and a maintenance dose of 200 mg every other week or 400 mg every four weeks. (See 'Resistant to MTX' above and 'Choice of therapy' above and 'DMARD triple therapy' above and 'MTX plus TNF inhibitor' 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, particularly in patients with high levels of disease activity and adverse prognostic features who would benefit from a more rapid therapeutic response. 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, particularly those with a partial response to triple therapy, we either continue HCQ and SSZ (or just one of these agents, typically HCQ) or administer a TNF inhibitor with MTX as the only concurrent nonbiologic DMARD. (See 'Choice of therapy' above and 'MTX 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 or tocilizumab, rather than biologic monotherapy or another DMARD combination (Grade 2B). Abatacept may be administered either intravenously (usually 750 mg once every four weeks) or subcutaneously (125 mg once weekly). Tocilizumab may be administered intravenously (4 to 8 mg/kg) or subcutaneously 162 mg every 7 to 14 days. (See 'Alternatives to triple therapy and MTX/TNF inhibitor' above and 'MTX plus abatacept' above and 'MTX plus tocilizumab' 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; 20 mg orally once daily) rather than alternative nonbiologic DMARDs (eg, gold, azathioprine, or cyclosporine) (Grade 2B). LEF may also be used as an alternative to MTX or in combination with MTX if needed.
●In patients whose treatment regimen has changed, reevaluation may be required up to every four to eight 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 nonsteroidal antiinflammatory drugs (NSAIDs), we suggest treatment with intraarticular or oral glucocorticoids rather than switching or continuing NSAIDs as the only additional agent (Grade 2A). 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 to 7.5 mg daily). (See 'Symptomatic drug therapy' above and 'Antiinflammatory therapy' above and 'Drug therapy for flares' above and "General principles of management of rheumatoid arthritis in adults", section on 'Drug therapy for flares'.)