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

INTRODUCTION — 

The treatment of rheumatoid arthritis (RA) is directed toward control of synovitis, prevention of joint damage, maintenance of musculoskeletal function, and relief of pain. Joint damage begins early in the disease course, and tight control of disease activity leads to improved outcomes and reduced disability [1-9]. The longer disease activity persists, the less likely the patient is to respond to therapy [10].

In patients whose condition is resistant to an initial course of treatment with a conventional synthetic (also termed nonbiologic 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 'Definition of resistance to initial therapy' below.)

The treatment of active RA in adults who are resistant to initial therapy with a csDMARD (eg, MTX monotherapy) will be reviewed here. An overview of the management of RA, the use of nonpharmacologic therapies for patients with RA, the initial treatment of RA, and the treatment of RA resistant to initial biologic therapy are presented elsewhere:

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

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

●(See "Initial pharmacologic management of rheumatoid arthritis in adults".)

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

DEFINITION OF RESISTANCE TO INITIAL THERAPY — 

Resistance to initial conventional synthetic disease-modifying antirheumatic drug (csDMARD) therapy is defined as any of the following:

●Failure to achieve remission – Failure to achieve remission or low disease activity within three to four months of initiating methotrexate (MTX) or other csDMARD therapy in maximally tolerated doses within the usual therapeutic range. A therapeutic trial of up to six 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. (See "Initial pharmacologic management of rheumatoid arthritis in adults", section on 'DMARD therapy'.)

●Chronic glucocorticoid therapy – A need for chronic glucocorticoids to remain in remission, despite concurrent DMARD therapy. Studies have suggested that even lower dose prednisone is associated with increase in comorbidities [11].

●Recurrent disease flares – Multiple relapses (ie, >2) annually.

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

Joint symptoms may also be caused by prior joint damage and disability, as well as a concomitant illness such as fibromyalgia. Symptoms due to these other noninflammatory diagnoses do not benefit from DMARD therapy. (See "Assessment of rheumatoid arthritis disease activity and physical function" and "Overview of the management of rheumatoid arthritis in adults", section on 'Assessment and monitoring during treatment'.)

PRETREATMENT INTERVENTIONS — 

A number of interventions are required before using disease-modifying antirheumatic drugs (DMARDs); these include screening for viral hepatitis, interventions to reduce the risk of cardiovascular disease and osteoporosis, immunizations, and nonpharmacologic interventions.

Some patients may require additional pretreatment interventions, depending on the specific DMARDs used. These issues are discussed in detail elsewhere. (See "Overview of the management of rheumatoid arthritis in adults", section on 'Pretreatment assessments and interventions'.)

APPROACH TO PHARMACOTHERAPY — 

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 (see 'Definition of resistance to initial therapy' above). The choices include both conventional synthetic DMARDs (csDMARDs) and biologic DMARDs.

The choice of DMARDs is influenced by the treatments the patient has already received and the level of disease activity. Drug choice should also take into account the patient's comorbid conditions, fertility considerations, preference for the route of administration (ie, oral versus parenteral), regulatory or insurance limitations, and cost to the patient.

Resistant to hydroxychloroquine and/or sulfasalazine — In patients with initially mild active disease who are resistant to three to four months of therapy with hydroxychloroquine (HCQ), we suggest one of the following approaches (algorithm 1):

●Switch to methotrexate (MTX) monotherapy

●Add MTX while continuing either HCQ or sulfasalazine (SSZ)

A therapeutic trial of up to six months can be used in patients with partial responses showing progressive improvement, particularly in patients with low levels of disease activity and limited functional impairment. However, in most cases, if there has not been a significant response after four months on a particular regimen, then a change in the therapeutic regimen is required.

The use of MTX for rheumatoid arthritis (RA; including precautions, dosing, and administration), and the rationale supporting the use of MTX and triple therapy, are discussed in detail elsewhere:

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

●(See "Initial pharmacologic management of rheumatoid arthritis in adults", section on 'Methotrexate for most patients'.)

●(See 'DMARD triple therapy' below.)

Resistant to methotrexate

Choice of therapy — In patients resistant to MTX after three to four months of treatment at optimal doses (usually 25 mg/week), we use one of the following approaches (algorithm 2):

●Add a TNF inhibitor to MTX – We use MTX plus a tumor necrosis factor (TNF) inhibitor in patients with high disease activity with adverse prognostic features (eg, high-titer rheumatoid factor or anti-citrullinated peptide antibody, elevated C-reactive protein [CRP], and/or baseline erosive disease) and in patients who have had an inadequate response to triple therapy. (See 'TNF inhibitor plus methotrexate' below.)

●Add HCQ and SSZ to MTX (triple therapy) – We use triple therapy with MTX, SSZ, and HCQ in patients who are unable to use TNF inhibitors (either due to medical contraindications or cost). We also use triple therapy in patients who prefer an oral nonbiologic agent. (See 'DMARD triple therapy' below.)

●Other considerations – In patients with partial responses or showing progressive improvement, we may continue therapy with MTX for up to six months before switching to one of these approaches, particularly in those with low to moderate levels of disease activity and with limited functional impairment.

Guidelines favor the addition of TNF inhibitors for patients who fail to have an adequate response to MTX monotherapy. However, choosing between these options often depends on multiple factors (eg disease activity, patient preference) and must be individualized.

Some patients cannot be treated with either a TNF inhibitor or triple therapy (due to contraindications, cost, patient or provider preferences, or other issues). Alternative treatment regimens for such patients are discussed below. (See 'Alternatives to triple therapy and methotrexate/TNF inhibitor' below.)

TNF inhibitor plus methotrexate

Selection of TNF inhibitor — The choice of tumor necrosis factor (TNF) inhibitor depends upon patient factors such as comorbidities and patient preferences (eg, the route of administration and dosing frequency), regulatory or insurance restrictions on drug choice, and safety issues (eg, drug half-life); there is no convincing evidence that any one of the TNF inhibitors (including biosimilars) has greater efficacy than the others [12]. We use the following approach:

●Subcutaneous etanercept or adalimumab for most patients – We usually use etanercept (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.

For select patients with an inadequate response to adalimumab, the dose may be increased to 40 mg every week. However, we would consider this only for patients who strongly wish to remain on adalimumab and/or have limited options for other reasons.

●Intravenous TNF inhibitors – 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).

●Other subcutaneous TNF inhibitors – 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 (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). A subcutaneous version of a biosimilar infliximab is available for rheumatoid arthritis as maintenance therapy (120 mg once every two weeks beginning four weeks following intravenous induction therapy) [13].

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

Cotreatment with methotrexate — We use TNF inhibitors in combination with continued MTX therapy, without further dose adjustment, even for patients who have failed to respond adequately to MTX monotherapy.

In patients who have contraindications to continued treatment with MTX, TNF inhibitors may be used in combination with leflunomide (LEF) or used as monotherapy. However, TNF inhibitor monotherapy is associated with a higher risk of antidrug antibodies, which may cause allergic reactions and loss of drug efficacy. This risk seems to be highest for infliximab and adalimumab, which should not be used as monotherapy. (See "Tumor necrosis factor-alpha inhibitors: Induction of antibodies, autoantibodies, and autoimmune diseases", section on 'Anti-drug antibodies'.)

In patients transitioning from triple therapy to a TNF inhibitor who have developed contraindications to MTX, we will continue both HCQ and SSZ.

The use of MTX for the treatment of RA is discussed in detail elsewhere. (See "Use of methotrexate in the treatment of rheumatoid arthritis", section on 'Dosing and administration'.)

Precautions — TNF inhibitor therapy is generally well tolerated. However, 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. TNF inhibitors may be associated with an increased risk of nonmelanoma skin cancer but not leukemia, lymphoma, or solid tumor malignancy. TNF inhibitors can induce autoimmunity, but this rarely leads to clinical disease.

Specific considerations include the following:

●Lymphoproliferative disorder – In patients with a history of a lymphoproliferative disorder, we use rituximab or triple therapy. However, the majority of observational studies have not confirmed an increased risk of malignancy associated with TNF inhibitors, with the possible exception of nonmelanoma skin cancer. (See 'Rituximab' below and 'DMARD triple therapy' below and "Tumor necrosis factor-alpha inhibitors: Risk of malignancy".)

●Pregnancy – For patients contemplating pregnancy (or who are already pregnant), we suggest using the TNF inhibitor certolizumab as monotherapy.

Certolizumab does not cross the placenta and is safe to use throughout pregnancy. However, MTX should be discontinued prior to conception and avoided during pregnancy.

Issues pertaining to rheumatoid arthritis and pregnancy, and the use of specific DMARDs during pregnancy and lactation, are discussed elsewhere. (See "Rheumatoid arthritis and pregnancy" and "Safety of rheumatic disease medication use during pregnancy and lactation".)

The adverse effects of TNF inhibitor therapy, and their association with infection, malignancy, and autoimmunity, are discussed in detail elsewhere:

●(See "Tumor necrosis factor-alpha inhibitors: An overview of adverse effects".)

●(See "Tumor necrosis factor-alpha inhibitors: Bacterial, viral, and fungal infections".)

●(See "Tumor necrosis factor-alpha inhibitors: Risk of malignancy".)

●(See "Tumor necrosis factor-alpha inhibitors: Induction of antibodies, autoantibodies, and autoimmune diseases", section on 'Autoimmune diseases'.)

Efficacy of this approach — In patients with an inadequate response to MTX and other conventional DMARDs, the use of a TNF inhibitor plus MTX is supported by a number of meta-analyses [14-17] and multiple randomized trials of all five agents (ie, etanercept [18-20], infliximab [21,22], adalimumab [23,24], golimumab [25-27], and certolizumab pegol [28,29]) which demonstrate the superiority of this approach, compared with continuing MTX alone.

●MTX plus TNF inhibitor versus MTX 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 (table 1) [30].

●MTX plus TNF inhibitor versus biologic DMARD monotherapy – Meta-analyses and randomized trials have also shown that combination therapy of MTX with a TNF inhibitor is superior to biologic DMARD monotherapy in patients who are naïve to biologic DMARDs [14,16,31-33].

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 [25,26,34-40]. Indirect comparisons of the biologic agents in meta-analyses of randomized trials involving patients with an inadequate response to MTX have suggested 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) [41]. (See "Assessment of rheumatoid arthritis disease activity and physical function", section on 'ACR response criteria'.)

Additionally, MTX has been shown to significantly decrease the incidence of antidrug antibody formation to the monoclonal anti-TNF agents [42]. (See 'Cotreatment with methotrexate' above.)

●Comparison of specific TNF inhibitors

•Adalimumab versus certolizumab pegol – Only one trial has directly compared the combination of MTX with either of two TNF inhibitors (adalimumab and certolizumab pegol) and found neither combination superior to the other [43]. 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 Disease Activity Score in 28 joints using erythrocyte sedimentation rate (DAS28-ESR) at week 104, or other major clinical outcome measures. Adverse effects were similar as well.

•Infliximab versus other TNF inhibitors – Infliximab may be associated with a higher rate of adverse events than the other TNF inhibitors, including etanercept and adalimumab [15,44,45]. Indirect comparisons of randomized trials in a 2011 meta-analysis suggested that patients receiving etanercept, 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) [45].

DMARD triple therapy

Dosing and administration — Triple therapy uses oral MTX, SSZ, and HCQ simultaneously. Each component is administered as follows:

●MTX – MTX is continued at the maximum tolerated dose achieved, up to 25 mg once weekly. MTX may also be administered subcutaneously or intramuscularly.

The use of MTX in RA and the adverse effects of MTX are described in detail separately. (See "Use of methotrexate in the treatment of rheumatoid arthritis" and "Major adverse effects of low-dose methotrexate" and "Initial pharmacologic management of rheumatoid arthritis in adults".)

●SSX – 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".)

●HCQ – HCQ is used at a dose of 400 mg daily in most patients but should not exceed 5 mg/kg daily calculated using 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".)

Treatment with the triple-therapy regimen is usually well tolerated, with adverse effects comparable to MTX alone [46].

Efficacy of triple therapy

●Triple therapy versus MTX plus TNF inhibitor – The triple-therapy regimen (MTX plus SSZ plus HCQ) has been found to have 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 "Overview of the management of rheumatoid arthritis in adults", section on 'Prognosis'.)

As examples, three randomized trials (discussed in detail below) have compared the combination of MTX plus a TNF inhibitor with triple therapy [46-49]; two trials found no significant differences in clinical efficacy using composite measures of disease activity (ie, ACR20 responses of approximately 35 to 60 percent after one or two years) [46,49], while one trial showed a significant difference at 12 months but not at 6, 9, or 24 months [47,48]. Radiographic outcomes slightly favored TNF inhibitor use, but whether these differences are clinically significant is less clear.

•Swefot trial – The Swedish Pharmacotherapy (Swefot) trial compared the efficacy of MTX plus infliximab with that of triple therapy (ie, MTX plus SSZ plus HCQ) [47,48,50]. 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).

-Clinical outcomes – 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 (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).

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) [51].

-Radiographic outcomes – Radiographic outcomes at two years favored the infliximab group, but the treatment differences were of uncertain clinical significance [48]. 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 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 [52].

-Adverse events – There was no difference in the frequency of overall adverse effects or serious adverse effects between the treatment groups.

-Limitations – 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.

•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 four treatment strategies over two years [49]. Previous treatment with 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 etanercept; immediate treatment with DMARD triple therapy (MTX plus SSZ plus HCQ); step-up from MTX to MTX plus etanercept at week 24, if the DAS28-ESR was ≥3.2 (ie, moderate or greater disease activity); and step-up from MTX to triple therapy at week 24, if the DAS28-ESR was ≥3.2 (figure 1).

-Clinical outcomes – 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 etanercept 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 either MTX plus etanercept or 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).

-Radiographic outcomes – At two years, the immediate combination groups did not differ radiographically from the step-up combination groups, as confirmed in a post hoc analysis of the data [53]. However, radiographic outcomes at week 102 slightly but statistically significantly favored those who received MTX plus etanercept (increased van der Heijde-modified Sharp score of 0.64 versus 1.69 on a scale of 0 to 448).

-Adverse events – There was no difference in the frequency of overall adverse effects or serious adverse effects between the treatment groups.

•RACAT trial – The RA Comparison of Active Therapies (RACAT) trial was a blinded 48-week trial involving 353 patients with moderate to severely active RA (despite the use of MTX) who were randomly assigned to receive triple therapy (MTX plus SSZ plus HCQ) or the combination of MTX and etanercept [46].

-Clinical outcomes – 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. Patients did equally well after switching from triple therapy to MTX plus etanercept and vice versa.

At week 24, a lower proportion of patients receiving triple therapy had achieved an ACR70 response (5 versus 16 percent), suggesting a more rapid response to MTX plus etanercept. However, by week 48, differences between the triple therapy group and the MTX plus etanercept 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.

At week 48, the strategy of initial assignment to triple therapy was clinically and statistically noninferior to the initial assignment to MTX plus etanercept with respect to the degree of improvement in disease activity (change in DAS28 of -2.12 and -2.29).

-Radiographic outcomes – 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.

-Adverse events – There were four serious infections in patients receiving triple therapy and 12 serious infections in those receiving MTX plus etanercept. 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 etanercept (four of five).

•Triple therapy versus nonbiologic DMARDs – 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 [54]; the two-drug regimens of MTX plus HCQ and MTX plus SSZ [55]; and sequential DMARD monotherapy with different agents [56]. In the last trial, triple therapy was also associated with more limited joint damage at two and five years than sequential monotherapy [56].

Alternatives to triple therapy and methotrexate/TNF inhibitor

Indications for alternative therapies — Some patients cannot be treated with either a TNF inhibitor or triple therapy (due to contraindications, cost, patient or provider preferences, or other issues). Several reasonable treatment options may serve as alternatives for patients in whom MTX fails to control disease activity adequately:

●Unable to use TNF inhibitor – In patients in whom MTX plus a TNF inhibitor would otherwise be appropriate (see 'TNF inhibitor plus methotrexate' above), particularly those who have a high level of disease activity, we use the combinations of MTX plus abatacept, tocilizumab, or sarilumab as alternatives to a TNF inhibitor, rather than biologic monotherapy or other csDMARD or biologic DMARD combinations. (See 'Abatacept' below and 'Interleukin 6 inhibitor therapies' below.)

In patients who are unable to use biologic agents, we use leflunomide. (See 'Leflunomide' below.)

However, other alternatives exist, including rituximab and targeted synthetic DMARDs. Additionally, a second nonbiologic DMARD to continued MTX therapy may be an option for patients who cannot use LEF. Conventional nonbiologic DMARDs that have been evaluated in combination with MTX include LEF, SSZ [57-59], HCQ [55], cyclosporine [60-64], tacrolimus [65], and doxycycline [66].

Choosing between these agents is based upon comorbidities and adverse event risk in individual patients; regulatory, insurance, and patient cost concerns; and patient and clinician preference. (See 'Less common alternatives' below.)

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 [67,68].

●Dosing and precautions – Abatacept can be administered intravenously (750 mg per dose for patients 60 to 100 kg, adjusted for lower or higher weight to 500 or 1000 mg, respectively). It is administered every two weeks for three doses, then every four weeks after that.

Alternatively, it can be administered subcutaneously (125 mg once weekly).

The overall safety of abatacept appears comparable to slightly better than that of the TNF inhibitors. However, in patients with chronic obstructive pulmonary disease (COPD), abatacept may be associated with an increase in COPD exacerbations.

Other issues regarding the use of abatacept for RA, including precautions for its use, are discussed in greater detail elsewhere. (See "Treatment of rheumatoid arthritis in adults resistant to initial biologic DMARD therapy", section on 'Abatacept'.)

●Cotreatment with MTX – We use abatacept in combination with continued MTX therapy, without further dose adjustment, even for patients who have failed to respond adequately to MTX monotherapy. However, in patients who have contraindications to continued treatment with MTX, abatacept may be used as monotherapy. Additionally, patients who achieve low disease activity or remission frequently discontinue MTX with persistence of response [69]. The use of MTX for the treatment of RA is discussed in detail elsewhere. (See "Use of methotrexate in the treatment of rheumatoid arthritis", section on 'Dosing and administration'.)

●Efficacy – 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 [45,70-72]. 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 plus MTX was significantly more effective than MTX alone (ACR50 at 24 weeks of 32 versus 12 percent) and was as effective as other biologic agents (eg, TNF inhibitors, rituximab, tocilizumab) [70].

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 versus TNF inhibitor therapy when either was combined with continued MTX, with 60 to 70 percent of patients achieving an ACR20 response [73,74]:

•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 who had an inadequate response to MTX were randomly assigned to receive abatacept (500, 750, or 1000 mg in patients weighing <60, 60 to 100, 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 [73].

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). However, 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.

Patients receiving abatacept had numerically fewer serious adverse events (10 versus 18 percent) and serious infections (2 versus 9 percent) compared with those receiving infliximab. This study did not examine differences in radiologic outcomes between the two groups.

•AMPLE trial – The Abatacept versus Adalimumab Comparison in Biologic-Naïve RA Subjects with Background Methotrexate (AMPLE) trial enrolled 646 patients with active RA and with an inadequate response to MTX, who were randomized to receive either abatacept or adalimumab, in addition to background MTX [75]. There were comparable clinical and radiologic responses to abatacept plus MTX (125 mg administered subcutaneously weekly) and to adalimumab plus MTX (40 mg administered subcutaneously every two weeks) at one year (ACR20 of 65 and 63 percent, respectively). Rates of adverse effects, including infections, were similar between the two groups.

Interleukin 6 inhibitor therapies — There are two interleukin 6 (IL-6) receptor inhibitors, tocilizumab and sarilumab, available for use together with MTX or as monotherapy, which have shown efficacy in patients resistant to other biologic DMARDs, including TNF inhibitors. Both agents are anti-IL-6 receptor antibodies.

●Tocilizumab – Tocilizumab is a humanized IgG1 anti-human IL-6 receptor antibody.

•Dosing and precautions – Tocilizumab can be administered either by intravenous infusion (4 to 8 mg/kg every four weeks) or by subcutaneous injection (162 mg every other week in patients <100 kg; weekly dosing in patients >100 kg).

A dose adjustment or drug discontinuation may be required in patients with significant liver enzyme (aminotransferase) elevations, neutropenia, or thrombocytopenia. Tocilizumab may also cause dyslipidemia, which may require treatment. Diverticulitis is a contraindication to the use of tocilizumab because it has been associated with intestinal perforations, especially in older patients.

Treatment should not be initiated in patients with an absolute neutrophil count <2000/mm³ or platelets <150,000/mm³, or if alanine aminotransferase (ALT) or aspartate aminotransferase (AST) are >1.5 times the upper limit of normal.

Other issues regarding the use of tocilizumab for RA, including precautions, are discussed in greater detail elsewhere. (See "Treatment of rheumatoid arthritis in adults resistant to initial biologic DMARD therapy", section on 'Tocilizumab'.)

•Cotreatment with MTX – We initially use tocilizumab in combination with continued MTX therapy, without further dose adjustment, even for patients who have failed to respond adequately to MTX monotherapy. However, in patients who have contraindications to continued treatment with MTX, tocilizumab may be used as monotherapy. Additionally, in patients in low disease activity or remission, MTX is often discontinued with maintenance of benefit. The use of MTX for the treatment of RA is discussed in detail elsewhere. (See "Use of methotrexate in the treatment of rheumatoid arthritis", section on 'Dosing and administration'.)

•Efficacy – The efficacy of tocilizumab in RA has been characterized in multiple randomized trials [34,76-81] and in meta-analyses of randomized trials of the drug as monotherapy or together with MTX compared with placebo [82,83].

-CHARISMA trial – 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 and 8 mg/kg of tocilizumab as monotherapy, respectively, and by 63 and 74 percent of patients receiving those doses of tocilizumab plus MTX [34]. By contrast, only 41 percent of patients receiving MTX plus placebo achieved ACR20 responses.

-OPTION trial – In a six-month trial of patients resistant to MTX monotherapy, ACR20 responses were achieved more often by patients receiving tocilizumab 4 8 mg/kg, respectively, compared with placebo (48 and 59 versus 26 percent) [76].

-ADACTA trial – 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 adalimumab (40 mg administered subcutaneously every two weeks plus intravenous placebo every four weeks) for patients with active RA who were intolerant to MTX or who were considered inappropriate candidates for continued treatment with MTX [84].

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. (See "Assessment of rheumatoid arthritis disease activity and physical function", section on 'Composites involving clinician assessment'.)

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 (ie, increased low-density lipoprotein cholesterol, increased ALT concentrations, and reduced platelet and neutrophil counts) 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'.)

●Sarilumab – Sarilumab is a human monoclonal antibody directed against the membrane-bound and soluble IL-6R. The efficacy and safety of sarilumab is similar to tocilizumab, and the indications for utilization are the same.

•Dosing and precautions – Sarilumab is administered at 200 mg subcutaneously once every two weeks, although the dose can be reduced to 150 mg every two weeks for issues with toxicity.

As with tocilizumab and other biologics, there is a moderately 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 has been reported, and sarilumab is relatively contraindicated in patients with a history of diverticulitis.

Treatment should not be initiated in patients with an absolute neutrophil count <2000/mm³ or platelets <150,000/mm³, or if ALT or AST are >1.5 times the upper limit of normal.

•Cotreatment with MTX – We use sarilumab in combination with continued MTX therapy, without further dose adjustment, even for patients who have failed to respond adequately to MTX monotherapy. However, in patients who have contraindications to continued treatment with MTX, sarilumab may be used as monotherapy. Additionally, in patients in low disease activity or remission, MTX is often discontinued with maintenance of benefit. The use of MTX for the treatment of RA is discussed in detail elsewhere. (See "Use of methotrexate in the treatment of rheumatoid arthritis", section on 'Dosing and administration'.)

•Efficacy

-RA-MOBILITY trial – 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) [85]. Improvements in physical functioning at week 16 and decreased progression of radiographic damage were also seen.

-MONARCH trial – 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 [86]. 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, ACR50, and ACR70 responses (72, 46, and 23 versus 58, 30, and 12 percent).

Leflunomide — LEF is an orally administered csDMARD. In patients with an inadequate response to MTX, LEF can be used in place of or in addition to ongoing MTX therapy.

●Dosing and precautions – In patients in whom LEF is used in place of MTX, the usual dose is 20 mg orally daily. If used together, the dose of either LEF (10 instead of 20 mg daily) or MTX (eg, 15 mg instead of 20 to 25 mg weekly) should be reduced initially; 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.

A range of potential adverse effects may occur in patients using LEF, including hypertension, diarrhea, nausea, hepatotoxicity, fetal and neonatal toxicity.

The use of LEF for the treatment of RA, including dosing, adverse effects, monitoring, and precautions regarding its use, is discussed in greater detail elsewhere. (See "Pharmacology, dosing, and adverse effects of leflunomide in the treatment of rheumatoid arthritis".)

●Use without MTX – We prefer to use LEF alone, without MTX, in patients who have failed to improve 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.

We use LEF with MTX in patients who have failed to respond to triple therapy and do not have access to biologic DMARD therapy. (See 'Resource limited settings' below.)

●Efficacy

•LEF monotherapy – 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 [87]. 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) [87-89].

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) [90]. LEF has not been compared directly with other agents in this patient population; however, in our clinical experience, TNF inhibitors are more efficacious than LEF monotherapy.

•LEF plus other DMARDs

-LEF plus MTX – 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 [91]. 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 plus TNF inhibitor – In patients with an inadequate response to initial treatment with LEF alone, a TNF inhibitor may be added to LEF [92-95]. 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 [93]. However, randomized trials to prospectively evaluate the efficacy and safety of LEF used together with a biologic DMARD have not been performed.

Less common alternatives — MTX plus rituximab or a Janus kinase (JAK) inhibitor are reasonable options in select patients, but regulatory restrictions may limit their availability for patients who have not previously been treated with a TNF inhibitor.

Janus kinase inhibitor — There are several JAK inhibitors marketed for inflammatory arthritis (including RA), including tofacitinib, baricitinib, upadacitinib, filgotinib, and peficitinib, which are all available as oral agents.

However, JAK inhibitors have been associated with an increased risk of malignancy, venous thromboembolic events, and cardiovascular events, particularly in patients older than 65 years.

Evidence supporting the use of specific JAK inhibitors in patients with RA resistant to initial nonbiologic DMARDs is reviewed below. The mechanism of JAK inhibitors, pretreatment screening and precautions, contraindications, monitoring, and adverse effects are discussed in detail separately. (See "Overview of the Janus kinase inhibitors for rheumatologic and other inflammatory disorders" and "Treatment of rheumatoid arthritis in adults resistant to initial biologic DMARD therapy", section on 'Janus kinase inhibitors'.)

●Tofacitinib – Tofacitinib is a small-molecule, orally administered JAK1 and JAK3 inhibitor.

•Dosing – It is taken as 5 mg twice daily (immediate-release form) or 11 mg once daily (extended-release form) [96].

•Cotreatment with MTX – We initially use tofacitinib in combination with continued MTX therapy, without further dose adjustment, even in patients who have failed to respond adequately to MTX monotherapy. The use of MTX for the treatment of RA is discussed in detail elsewhere. (See "Use of methotrexate in the treatment of rheumatoid arthritis", section on 'Dosing and administration'.)

However, in patients who have contraindications to continued treatment with MTX, tofacitinib may be used as monotherapy. Additionally, we discontinue MTX in patients who have achieved sustained low disease activity or remission [97,98].

•Efficacy – The efficacy of tofacitinib in RA has been evaluated in a series of randomized trials in patients with an inadequate response to MTX or another conventional DMARD [99-104]. It has also been compared as monotherapy with MTX in patients who are naïve to this agent [105].

Examples of studies examining the use of tofacitinib in patients with an inadequate response to MTX and/or other csDMARDs include:

-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) [99].

-Tofacitinib plus MTX – Tofacitinib plus MTX is effective in patients who have not had an adequate response to MTX alone [100-102,104]. For example, a trial involving 797 patients with active RA and inadequate responses to MTX showed significantly greater benefit at six months associated with 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) [101]. At six months, those treated with tofacitinib plus MTX demonstrated improved HAQ disability indices (HAQ-DI -0.4 and -0.54 versus -0.15). Among patients treated with tofacitinib 5 mg twice daily, there was a reduction in radiographic damage that was not statistically significant.

The combination of MTX with either tofacitinib or a TNF inhibitor is comparably effective in patients resistant to MTX [100,104]. For example, the combination of tofacitinib (5 mg twice daily) with MTX (15 to 25 mg per week) was compared with adalimumab (40 mg every two weeks) plus MTX and tofacitinib monotherapy in a randomized trial involving 1146 patients with active RA despite MTX therapy [104]. The combination of tofacitinib plus MTX was comparable to adalimumab 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 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'.)

●Baricitinib – Baricitinib is a small-molecule, orally administered JAK1 and JAK2 inhibitor.

•Dosing – In the United States, it is administered as 2 mg orally once daily; in Europe, it may also be administered as 4 mg orally once daily.

•Cotreatment with MTX – We initially use baricitinib in combination with continued MTX therapy, without further dose adjustment, even for patients who have failed to respond adequately to MTX monotherapy. The use of MTX for the treatment of RA is discussed in detail elsewhere. (See "Use of methotrexate in the treatment of rheumatoid arthritis", section on 'Dosing and administration'.)

However, in patients who have contraindications to continued treatment with MTX, baricitinib may be used as monotherapy. Additionally, we discontinue MTX in patients who have achieved sustained low disease activity or remission [106-108].

•Efficacy – 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 [106,109-113]. Examples of the efficacy of baricitinib plus csDMARD (generally MTX) in patients with an inadequate response or intolerance to csDMARDs include:

-Baricitinib versus placebo – Several trials have shown baricitinib to be more effective than placebo in patients who have had an inadequate response to conventional DMARDs [109-111].

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 background therapy with csDMARDs resulted in improved efficacy using ACR20 response criteria compared with those receiving placebo at week 12 (62 versus 39 percent) [111]. 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.

-Baricitinib versus adalimumab – 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 adalimumab (40 mg administered subcutaneously every other week) and placebo at week 12 (ACR20 of 70 versus 61 versus 40 percent) [112]. Baricitinib and adalimumab both reduced the progression of radiographic damage at week 24.

The use and efficacy of baricitinib in patients resistant to biologic DMARDs is described separately. (See "Treatment of rheumatoid arthritis in adults resistant to initial biologic DMARD therapy", section on 'Baricitinib'.)

●Upadacitinib – Upadacitinib is a small-molecule, orally administered drug that preferentially inhibits JAK-1 over JAK-2, -3, and non-receptor tyrosine-protein kinases.

•Dosing – Upadacitinib is administered as 15 mg orally once daily.

•Cotreatment with MTX – We use upadacitinib initially in combination with continued MTX therapy, without further dose adjustment, even for patients who have failed to respond adequately to MTX monotherapy. The use of MTX for the treatment of RA is discussed in detail elsewhere. (See "Use of methotrexate in the treatment of rheumatoid arthritis", section on 'Dosing and administration'.)

However, in patients who have contraindications to continued treatment with MTX, upadacitinib may be used as monotherapy. Additionally, we discontinue MTX in patients who have achieved sustained low disease activity or remission [114]

•Efficacy – Randomized trials comparing upadacitinib with placebo have demonstrated benefit in patients with RA with inadequate responses to csDMARDs, including MTX [115-117].

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

-Upadacitinib monotherapy – In a 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) [116]. A Disease Activity Score in 28 joints using CRP (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 venous thromboembolism, a pulmonary embolus, was reported in one patient on upadacitinib 15 mg daily (<1 percent) but not in the other groups.

-Upadacitinib plus MTX – 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 adalimumab (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) [117].

Upadacitinib was superior to adalimumab in the proportion with an ACR50 and DAS28-CRP ≤3.2 and in the degrees of improvement in pain and function. Both upadacitinib and adalimumab reduced radiographic progression at week 26 compared with placebo.

Upadacitinib remained superior to adalimumab at 48 weeks. Rescue by treating the patient 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 [118].

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. Venous thromboembolisms were reported in six patients (upadacitinib [two patients (0.3 percent)], adalimumab [three patients (0.9 percent)], and placebo [one patient (0.2 percent)]).

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'.)

●Other JAK inhibitors – Other JAK inhibitors (ie, peficitinib [119-124] and filgotinib [125,126]) are also effective for the treatment of RA (either as monotherapy or in combination with MTX) in patients with RA who have had a prior inadequate response or intolerance to csDMARDs such as MTX.

In these trials, the efficacy and toxicity of these agents appeared generally similar to other JAK inhibitors.

However, peficitinib and filgotinib are not available for use in the United States.

Rituximab — Rituximab is a monoclonal antibody that depletes B cells by targeting the CD20 antigen. We use rituximab for patients with RA who have a history of a lymphoproliferative disorder, since it is unlikely to induce recurrence [127]. (See 'Choice of therapy' above.)

●Dosing – We generally administer rituximab as an intravenous infusion of 1000 mg, repeated once two weeks later. Courses of rituximab can be administered as frequently as every six months, depending on disease activity. However, most patients are treated less frequently due to adequate disease control.

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 rheumatologic disease".)

●Cotreatment with MTX – We use rituximab in combination with continued MTX therapy, even for patients who have failed to respond adequately to MTX monotherapy, without further dose adjustment. However, in patients who have contraindications to continued treatment with MTX, rituximab may be used as monotherapy.

A small open-label trial [128] and observational studies with much larger numbers of patients have shown comparable efficacy and safety of rituximab in combination with either MTX or LEF [129-131]. With rituximab monotherapy, good responses to treatment are often seen [130], but discontinuation is more frequent than when it is used in combination with either MTX or LEF [129].

The use of MTX for the treatment of RA is discussed in detail elsewhere. (See "Use of methotrexate in the treatment of rheumatoid arthritis", section on 'Dosing and administration'.)

●Efficacy of rituximab – The benefits of rituximab in patients with RA resistant to MTX and in those resistant to other csDMARDs have been documented in several randomized trials.

•A 2015 systematic review and meta-analysis of eight trials, involving 2720 patients with active RA despite MTX, has confirmed that rituximab (two 1000 mg doses) in combination with MTX is effective for improving the symptoms of RA and preventing disease progression. [132].

•The efficacy of rituximab was comparable to a TNF inhibitor (etanercept or adalimumab) in patients with an inadequate response to nonbiologic DMARDs in a randomized, open-label trial involving 295 patients with active seropositive RA who were naïve to biologic DMARDs [133]. 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 etanercept 50 mg weekly or adalimumab 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.

However, several issues limited the interpretation of the trial [134]. Patients failed to respond to a median of only one csDMARD prior to trial entry. The specific csDMARDs that had been used previously were not specified, although 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 'Rituximab'.)

OTHER MANAGEMENT ISSUES

Reevaluation and monitoring — Disease activity and the response to therapy should be regularly reassessed, along with monitoring for drug toxicities, every three months following a change in the treatment regimen until the patient is stable and until the disease is under control [8,135-137]. The approach to monitoring patients with rheumatoid arthritis (RA) is discussed in detail elsewhere. (See "Overview of the management of rheumatoid arthritis in adults", section on 'Assessment and monitoring during treatment'.)

Patients who fail to achieve remission or low disease activity within three to four months of initiating therapy or who require chronic glucocorticoid therapy (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 up to six months is usually used in patients with partial responses showing progressive improvement, particularly in those with low to moderate levels of disease activity and limited functional impairment. (See "Treatment of rheumatoid arthritis in adults resistant to initial biologic DMARD therapy", section on 'Definition of resistance to DMARDs'.).

Patients who have failed to achieve remission or low disease activity either using combination nonbiologic DMARDs (eg, triple therapy with methotrexate [MTX], sulfasalazine [SSZ], and hydroxychloroquine [HCQ]) or a tumor necrosis factor (TNF) inhibitor may be crossed over to the alternate strategy or transitioned to another biologic agent using another mechanism of action.

The approach in such patients is described in detail separately. (See "Treatment of rheumatoid arthritis in adults resistant to initial biologic DMARD therapy", section on 'Approach to pharmacotherapy'.)

Symptomatic drug therapy — Antiinflammatory drugs (including nonsteroidal antiinflammatory drugs [NSAIDs] and glucocorticoids) are used as a supplement to 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 (ie, flares). The use of symptomatic drug therapy is discussed in detail elsewhere. (See "Initial pharmacologic management of rheumatoid arthritis in adults", section on 'Adjunctive symptomatic treatment'.)

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

Resource limited settings — Some patients may not have adequate access to health care 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 conventional synthetic DMARDs (csDMARDs). Initial therapy would not generally differ from patients with greater resources. (See "Initial pharmacologic management 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 – Triple therapy (with MTX, SSZ, and HCQ) would be used in patients resistant to MTX alone. (See 'Resistant to methotrexate' above and 'DMARD triple therapy' above.)

●MTX plus LEF – Patients resistant to triple therapy can be treated with MTX plus leflunomide (LEF), with very close attention to monitoring liver function tests. Unblinded studies have reported that the other combinations may also be effective alternatives, including MTX and azathioprine, as well as MTX with azathioprine and HCQ [138]. Patients intolerant of MTX may be treated with LEF alone. (See 'Leflunomide' above and "Pharmacology, dosing, and adverse effects of leflunomide in the treatment of rheumatoid arthritis", section on 'Monitoring'.)

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

●Definition of DMARD resistance – In patients with rheumatoid arthritis (RA), resistance to initial therapy with disease-modifying antirheumatic drugs (DMARDs) is defined here as one of the following (see 'Definition of resistance to initial therapy' above):

•Failure to achieve remission or low disease activity within three to four months of initiating therapy

•A need for chronic glucocorticoids in addition to DMARDs

•Recurrent flares (ie, >2 annually) despite appropriate DMARD therapy

●Selection of an alternative regimen – In patients with active RA resistant to initial therapy after three to four months of optimal treatment, we treat with a different or additional DMARD or with DMARD combinations to achieve control of signs and symptoms of disease. 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.

•HCQ and/or SSZ resistance – In patients resistant to initial therapy with hydroxychloroquine (HCQ) or sulfasalazine (SSZ), we suggest either switching to methotrexate (MTX) monotherapy or adding MTX to either HCQ or SSZ rather than switching to a biologic DMARD (eg, tumor necrosis factor [TNF] inhibitor) (Grade 2B). 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.)

•MTX resistance – In patients who have not achieved treatment goals after three to six months of MTX at optimal doses, we suggest either the use of the combination of continued MTX plus a TNF inhibitor, or the use of DMARD triple therapy with MTX plus SSZ and HCQ, rather than monotherapy with another conventional synthetic (nonbiologic) DMARD (csDMARD) or biologic DMARD (Grade 2C). (See 'Resistant to methotrexate' above.)

-TNF inhibitor plus MTX – We use combination therapy with MTX plus a TNF inhibitor in patients with high levels of disease activity and adverse prognostic features as well as patients who have had an inadequate response to triple therapy. (See 'TNF inhibitor plus methotrexate' above.)

-Triple therapy – We use 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. (See 'DMARD triple therapy' above.)

In patients with partial responses or showing progressive improvement, we may continue therapy with MTX for up to six 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.)

•Alternate treatment approaches – In patients in whom MTX plus a TNF inhibitor would otherwise be appropriate but who are unable to use a TNF inhibitor, we use the combination of MTX plus either abatacept, tocilizumab, or sarilumab.

In patients who cannot use a biologic agent, we use leflunomide (LEF). In patients with a history of lymphoproliferative disorder, we use either rituximab or triple therapy. In patients who are pregnant or contemplating pregnancy, we use certolizumab pegol monotherapy. (See 'Alternatives to triple therapy and methotrexate/TNF inhibitor' above and 'Less common alternatives' above.)

●Monitoring – In patients whose treatment regimen has changed, reevaluation may be required up to every three months for the effectiveness of therapy and for the monitoring of possible drug toxicity. Patients who fail to achieve remission or low disease activity within three to six months of initiating therapy or who require chronic glucocorticoid therapy to maintain a state of remission should generally escalate to a more potent DMARD or combination of DMARDs. (See 'Reevaluation and monitoring' above and "Treatment of rheumatoid arthritis in adults resistant to initial biologic DMARD therapy".)

●Symptomatic drug therapy – We use antiinflammatory drug therapy, including nonsteroidal antiinflammatory drugs (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. (See "Initial pharmacologic management of rheumatoid arthritis in adults", section on 'Adjunctive symptomatic treatment'.)

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

ACKNOWLEDGMENT — 

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