Clinical trials of combination therapy in persistently active rheumatoid arthritis in adults

Clinical trials of combination therapy in persistently active rheumatoid arthritis in adults

Author
James R O'Dell, MD

Section Editor
Ravinder N Maini, BA, MB BChir, FRCP, FMedSci, FRS

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: Jan 02, 2016.

INTRODUCTION — Patients with rheumatoid arthritis (RA) and persistently active disease despite initial pharmacologic therapies require adjustments in their treatment regimen to achieve effective disease control. The use of combinations of disease-modifying antirheumatic drugs (DMARDs) is typically required in patients with persistently active disease, defined as RA of at least six months’ duration which remains active despite initial treatment with one or several DMARDs [1].
DMARDs are divided into two broad major categories, nonbiologic and biologic, and a third category of drugs with some features of each of the major types.
●The nonbiologic DMARDs are traditional small-molecule or synthetic DMARDs, such as methotrexate, leflunomide, sulfasalazine, and hydroxychloroquine.
●The biologic DMARDs, produced by recombinant deoxyribonucleic acid (DNA) technology, usually target specific cytokines or their receptors, such as tumor necrosis factor (TNF)-alpha, interleukin (IL)-1, or IL-6 receptors. Other types of biologic DMARDs include B-cell depleting agents and T-cell costimulatory blockers. The use of biologic DMARDs has been referred to as “targeted therapy.”
●A third category of DMARDs includes the drug tofacitinib, which shares some features with the nonbiologic DMARDs as an orally active small molecule drug but is an inhibitor of isoforms of the Janus kinases, which are cytoplasmic protein tyrosine kinases that are critical for signal transduction from plasma membrane receptors for a number of different interleukins. Janus kinase inhibition by this agent has biologic and clinical effects similar to the biologic agents.
The results of representative clinical trials in patients with persistently active RA despite prior DMARD therapy will be reviewed here. The principles and strategies for treating such patients, as well as the randomized trials of nonbiologic DMARD combinations and of biologic agents, are presented in more detail separately. (See "Treatment of rheumatoid arthritis in adults resistant to initial nonbiologic DMARD therapy" and "General principles of management of rheumatoid arthritis in adults" and "Randomized clinical trials of combinations of nonbiologic DMARDs in rheumatoid arthritis" and "Randomized clinical trials of tumor necrosis factor inhibitors in rheumatoid arthritis" and "Rituximab and other B cell targeted therapies for rheumatoid arthritis" and "T-cell targeted therapies for rheumatoid arthritis" and "Randomized clinical trials in rheumatoid arthritis of biologic agents that inhibit IL-1, IL-6, and RANKL".)
COMBINATIONS OF NONBIOLOGIC DMARDS — A number of combinations of nonbiologic disease-modifying antirheumatic drugs (DMARDs) are more effective than single agents. The following examples include some commonly prescribed combinations.
Triple therapy with MTX-SSZ-HCQ — Combination nonbiologic DMARDs were evaluated in a randomized trial of 102 patients with established rheumatoid arthritis (RA), disease lasting more than six months, and a poor response to one DMARD or to two or more sequential DMARDs [2]. Triple therapy with methotrexate (MTX; 7.5 to 17.5 mg per week, titrated for response), sulfasalazine (SSZ; 500 mg twice daily), and hydroxychloroquine (HCQ; 200 mg twice daily) was superior to SSZ plus HCQ or to MTX alone in achieving the primary endpoint of at least a 50 percent improvement at nine months (77 percent versus 40 and 33 percent, respectively), with sustained benefit for at least two years without the development of significant drug toxicity.
Additional support for the efficacy of a similar regimen was provided by a randomized trial in DMARD-naïve patients who had RA for less than two years and who had persistent disease activity [3]. The patients were treated with MTX, SSZ, and HCQ or with SSZ with sequential switching (if the clinical responses were inadequate) to MTX and then to azathioprine. The rate of remission was significantly higher in the patients treated with triple therapy at both one year (25 versus 11 percent) and two years (37 versus 18 percent). Triple therapy was also associated with significantly higher rates of at least a 50 percent response at one year (75 versus 60 percent) and with more limited joint damage at two and five years [4]. Although treatment was unrestricted after two years, differences in radiographic damage persisted at five years of follow-up. Further evidence for this approach in patients with active disease despite MTX comes from the patients started on MTX alone in the Treatment of Early Aggressive Rheumatoid Arthritis (TEAR) trial [5], in which 72 percent of such patients required step-up to triple therapy or MTX plus etanercept. The patients who were stepped improved significantly, regardless of which therapy they were given, and had clinical and radiographic results that were similar to those in patients who received initial combination therapy.
At least two major trials have now proven the efficacy of this triple regimen in patients who were selected for the trials based upon having active disease despite therapy with MTX. Both the RACAT trial [6] and the Swefot trial [7] randomized patients with active disease to receive either full triple therapy or MTX plus a biologic. All groups of patients in both trials improved. In TEAR, there was no difference between the triple and the MTX/etanercept groups clinically or radiographically. In Swefot, there was no difference at 6, 9, or 24 months between the groups and, importantly, two-year data revealed no difference between the groups with regard to work productivity [7-9].
MTX-HCQ versus MTX-SSZ versus all three — A two-year trial included 171 patients with disease of more than six months’ duration who had not received DMARD combinations; the patients were randomly assigned to a three-drug combination of methotrexate (MTX; 7.5 to 17.5 mg per week), sulfasalazine (SSZ; 500 mg to 1000 mg twice daily), and hydroxychloroquine (HCQ; 200 mg twice daily) or to two-drug regimens either of MTX plus HCQ or of MTX plus SSZ [10]. The primary endpoint, which was the percent of patients who achieved an American College of Rheumatology (ACR) 20 percent response (ACR20) response at two years, was significantly higher with the three-drug regimen (78 percent versus 60 and 49 percent, respectively). A similar difference was seen for ACR50 responses (55 percent versus 40 and 29 percent, respectively). The likelihood of a response did not appear to differ between patients who were MTX-naive and those who had previously received MTX but had responded inadequately. All treatment regimens were well-tolerated. The most common conventional combination used in practice may be MTX and HCQ.
MTX-leflunomide — Leflunomide (LEF) is usually used as an alternative to MTX, but the two drugs can also be used in combination. 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'.)
The addition of either LEF or placebo to MTX was compared in a randomized trial of 263 patients with persistently active disease despite treatment with MTX for at least six months [11]. The results of this trial are discussed in detail elsewhere but will be briefly reviewed here. (See "Randomized clinical trials of combinations of nonbiologic DMARDs in rheumatoid arthritis", section on 'Leflunomide and MTX'.)
The primary outcome, the proportion of patients achieving an ACR20 after 24 weeks of therapy, was significantly higher in the group receiving LEF plus MTX (46.2 versus 19.5 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. Close monitoring for hepatotoxicity is important.
MTX-cyclosporine — A six-month randomized trial evaluated the combination of MTX with cyclosporine (CSA) in 148 patients with severe RA; the patients were assigned to receive MTX (at the maximal tolerated dose) plus CSA (2.5 to 5 mg/kg per day) or MTX plus placebo [12]. After six months of treatment, the combination of MTX and CSA resulted in a greater reduction in the tender joint count (the primary outcome) compared with MTX plus placebo (-7.5 versus -2.7 joints). The net decrease of -4.8 joints was equal to 25 percent of the initial tender joint count. An ACR20 response was achieved more often in the combination group (48 versus 16 percent). Clinical improvement was maintained when the study was extended for another 24 weeks [13].
There were 17 patients in the CSA group and 12 in the placebo group who withdrew from the study. The threshold for CSA dose reduction was a 30 percent increase in serum creatinine [12]. This combination is infrequently used because of concerns regarding adverse effects including increased blood pressure and reduced renal function.
MTX-gold — Injected gold salts are used infrequently because of significant toxicity, and there are only a small proportion of patients who have long-term efficacy without serious side effects. (See "Use of gold compounds in rheumatic diseases".)
The addition of intramuscular (IM) gold injections to MTX may benefit some patients who are unable to use other potent alternative agents. In the METGO trial, 65 patients with RA and with a partial response to MTX (mean dose of 18.5 mg/week)continued MTX and were randomly assigned to IM gold (aurothioglucose up to 50 mg once weekly as tolerated) or to placebo injections for 48 weeks [14]. Patients who received IM gold were significantly more likely to achieve the primary outcome, an ACR20 response at week 48 (61 versus 30 percent). ACR50 and ACR70 were also achieved more often with gold plus MTX (26 versus 4 percent and 21 versus 0 percent, respectively).
Adverse events were minor. Mucocutaneous side effects were frequent but usually required only temporary suspension of gold therapy. Gold-related adverse events led to permanent discontinuation of therapy in 11 percent of patients receiving gold.
This combination is discussed in more detail elsewhere. (See "Use of gold compounds in rheumatic diseases", section on 'Gold combined with other drugs'.)
NONBIOLOGIC DMARDS PLUS ANTI-TNF THERAPIES — Randomized clinical trials support the efficacy of adding an anti-tumor necrosis factor (TNF)-alpha agent to ongoing methotrexate (MTX) therapy [7,15]. (See "Treatment of rheumatoid arthritis in adults resistant to initial nonbiologic DMARD therapy", section on 'MTX plus TNF inhibitor'.)
Although several of the TNF-alpha inhibitors can be used as the initial disease-modifying antirheumatic drug (DMARD) and as single agents, the combination of a TNF-alpha inhibitor with MTX results in a greater likelihood of a good response to treatment and in better radiographic outcomes than either treatment alone [16,17]. Additionally, MTX and azathioprine have been shown to significantly decrease the incidence of anti-drug antibody formation to the monoclonal anti-TNF agents [18]. The following are examples of such combinations:
MTX-etanercept — Combination therapy with a TNF-alpha receptor fusion protein, etanercept, and MTX was evaluated in a trial of 89 patients with persistent disease despite at least six months of treatment with MTX [19]. Patients were randomly assigned to twice-weekly subcutaneous etanercept (25 mg) or placebo, while continuing to receive MTX. Significantly more patients in the active therapy group than in the placebo group achieved an American College of Rheumatology (ACR) 20 response (the primary outcome measure) and an ACR50 response at 24 weeks of therapy (71 versus 27 percent and 39 versus 3 percent, respectively).
The combination of etanercept and MTX may also be more effective in retarding radiographic joint damage than either agent alone. This was illustrated in the TEMPO trial of 686 patients with active disease of over six months’ duration who had responded inadequately to at least one DMARD but who had not received MTX. Patients were randomly assigned to one of three regimens: a combination of etanercept (25 mg twice weekly) and MTX (up to 20 mg/week), etanercept plus placebo, or MTX plus placebo [20]. Clinical and radiographic assessments were made periodically during one year of study.
Greater improvements with the combination than with either drug alone were evident in symptoms and signs of disease activity, in physical function, in patient-reported outcomes, and in radiographic data. The primary efficacy endpoint was the ACR-N, the numeric index of the ACR response area under the curve (AUC) over the first 24 weeks. The ACR-N AUC was greater for the combination group than for etanercept alone or for MTX alone (18.3 versus 14.7 versus 12.2 percent-years). The difference between etanercept alone and MTX was also significant.
The combination also resulted in reduced radiographic joint injury compared with etanercept alone or with MTX alone according to the primary radiographic endpoint, the change in the modified Sharp score at week 52 (-0.54 versus +0.52 versus +2.80).
Results of the TEMPO trial at two years are available for 503 patients [21]. ACR20, ACR50, and ACR70 responses remained significantly greater, withdrawal rates remained lower, and radiographic progression remained slower in the group receiving combination therapy than in either of the monotherapy groups. Similar proportions of patients had serious infections in each of the three groups (7, 6, and 6 percent).
Doses of etanercept greater than 50 mg weekly, with or without MTX, do not appear to have greater efficacy in patients with rheumatoid arthritis (RA) [22,23]. This combination is discussed in more detail elsewhere. (See "Randomized clinical trials of tumor necrosis factor inhibitors in rheumatoid arthritis", section on 'Etanercept and related agents'.)
MTX-infliximab — Infliximab (an anti-TNF alpha monoclonal antibody) is also effective in patients with persistently active disease and is generally used in combination with MTX [24,25]. In the ATTRACT trial involving 428 patients with disease duration of greater than six months (median 7.2 to 9 years) and with active disease despite receiving MTX for at least three months, infliximab plus MTX was superior to placebo plus MTX in controlling signs and symptoms of disease and in improving physical function [24].
Patients on one of the four infliximab plus MTX regimens were more likely to reach the primary outcome, an ACR20 response at 30 weeks of treatment (50 to 58 percent versus 20 percent). These benefits were maintained for two years [26]. Similar numbers of serious adverse events, including serious infections, were seen in infliximab-treated and placebo-treated patients.
In the ASPIRE trial, combination therapy with MTX and infliximab provided greater clinical, radiographic, and functional benefits than MTX plus placebo for patients with active, early RA (3 to 36 months’ duration, with a mean of 10.4 months) who were not previously exposed to MTX [27]. The primary endpoint for clinical efficacy, the ACR-N, which represents percent improvement in signs and symptoms, was significantly higher in patients on infliximab (3 or 6 mg/kg) plus MTX (38.9 and 46.7 percent versus 26.4 percent). Similarly, the infliximab patients exhibited less radiographic progression of joint damage as measured by the primary radiographic endpoint, the van der Heijde modified Sharp score (vdH-S; 0.4 and 0.5 versus 3.7). There was a higher incidence of serious infections with combination therapy (5 to 5.6 percent versus 2.1 percent) [27].
Patients initially controlled with a given infliximab dosing regimen may subsequently require higher infliximab doses or a decrease in the dosing interval to continue to suppress disease activity [28].
This combination is discussed in more detail elsewhere. (See "Randomized clinical trials of tumor necrosis factor inhibitors in rheumatoid arthritis", section on 'Infliximab and related agents'.)
MTX-infliximab biosimilar — The immunoglobulin (Ig)G1 chimeric human–murine monoclonal antibody, CT-P13 [29,30], was developed as an anti-TNF alpha monoclonal antibody biosimilar to the original (termed “innovator”) infliximab that first became commercially available in 1999 for the treatment of RA. A “biosimilar” is defined by the World Health Organization (WHO) as a “biotherapeutic product which is similar in terms of quality, safety and efficacy to an already licensed reference biotherapeutic product” [31]; “similarity” is defined as the “absence of a relevant difference in the parameter of interest.” CT-P13 has an identical amino acid sequence to infliximab and is produced in the same type of cell line; it exhibits highly similar in vitro and in vivo pharmacodynamics, binding specificities and affinities, and other biologic and pharmacologic characteristics [29,30].
CT-P13 has shown equivalent clinical efficacy to the innovator infliximab in a small number of clinical trials, including the PLANETRA (Programme evaluating the autoimmune disease investigational drug CT-P13 in RA patients) trial, a randomized phase 3 trial in patients with RA [29]. In this trial, which involved 606 patients with active RA despite use of MTX, the combination of MTX plus CT-P13 demonstrated equivalent efficacy to MTX plus infliximab at week 30 (ACR20 of 61 versus 59 percent, difference of 2 percent with 95% CI of -6 to 10 percent) [29], Multiple other response measures were also comparable, and there were no differences detected in immunogenicity or safety. The initial trials of CT-P13 were the first clinical trials comparing a biosimilar to an innovator biologic agent for a rheumatic disease [32]. The worldwide availability of this agent is limited and will depend upon regulatory requirements in different regions and local patent laws and patent expiration dates [32].
MTX-adalimumab — The benefit of the addition of the fully human anti-TNF-alpha monoclonal antibody, adalimumab, to ongoing MTX therapy was demonstrated in the ARMADA trial of 271 patients with active RA despite treatment with MTX for at least six months [33]. In this 52-week randomized trial, the addition to MTX of adalimumab given subcutaneously at a dose of 20, 40, or 80 mg every two weeks was more effective than placebo for achieving the primary efficacy endpoint, the proportion of patients with an ACR20 response (47.8, 67.2, and 65.8 percent versus 14.5 percent). Adverse events were comparable between adalimumab-treated and placebo-treated patients.
Adalimumab exhibited radiographic, clinical, and functional benefits in a trial of 619 patients with active RA despite ongoing treatment with MTX for greater than or equal to three months and with at least one joint erosion on radiographs of the hands and feet [34]. In this study, patients were randomized to receive either adalimumab (40 or 20 mg subcutaneously every two weeks) plus MTX or placebo plus MTX.
The primary efficacy endpoints were radiographic progression of structural joint damage at week 52, assessed by the modified total Sharp score (mTSS); clinical response at week 24, measured by the proportion of patients with an ACR20 response; and physical function at week 52, measured with the disability index of the Health Assessment Questionnaire (HAQ). Adalimumab patients achieved a significantly lower mTSS (0.1 and 0.8 versus 2.7), higher proportions of ACR20 (63 and 61 percent versus 30 percent), and greater decreases in the HAQ score (-0.59 and -0.61 versus -0.25).
The serious and nonserious adverse event rates were comparable in the adalimumab and placebo groups, but serious infections were reported more often with adalimumab (3.8 versus 0.5 percent).
Additional support for this combination is demonstrated by the PREMIER trial of patients with active RA for less than three years (57 percent for less than six months) who were not previously exposed to MTX [35]. Combination therapy with MTX and adalimumab was more effective than either drug alone in improving signs and symptoms of disease, in inhibiting radiographic progression, and in effecting clinical remission.
This combination is discussed in more detail elsewhere. (See "Randomized clinical trials of tumor necrosis factor inhibitors in rheumatoid arthritis".)
MTX-golimumab — Golimumab, a TNF inhibitor that is administered by monthly subcutaneous injection, demonstrated benefit in the GO-FORWARD study when given together with MTX in patients who had not responded adequately to at least three months of treatment with MTX alone [36].
In the GO-FORWARD trial, patients receiving golimumab (100 or 50 mg) plus MTX were more likely to achieve an ACR20 response at week 14, one of two primary outcomes, than were patients on either golimumab (100 mg) or MTX alone (56 and 55 percent versus 44 percent versus 33 percent). The other primary outcome, which was the degree of improvement in physical function measured using the Health Assessment Questionnaire Disability Index (HAQ-DI), showed similar superiority for the golimumab plus MTX combinations (-0.50 and -0.38 versus -0.13 versus -0.13).
In patients treated with golimumab plus MTX, ACR50 and ACR70 responses were also reached more often at week 14 (29 and 35 percent versus 20 percent versus 10 percent for ACR50; 14 and 9 percent versus 8 percent versus 4 percent for ACR70). DAS28 remissions were more common as well (18 and 16 percent versus 8 percent versus 2 percent).
Serious adverse events through week 16 in patients on golimumab (100 or 50 mg) plus MTX, on golimumab plus placebo, or on MTX plus placebo occurred in 9, 5.6, 3.8, and 2.3 percent of patients, respectively. Serious infections occurred in 5.6, 2.2, 0.8, and 0.8 percent of patients, respectively. Latent tuberculosis was detected at screening and was treated in 21 percent of patients. None of these patients developed active tuberculosis during the study, nor were opportunistic infections seen in any of the study patients.
Injection site reactions were uncommon (<5 percent) and mild. The 2.1 percent of patients with antibodies to golimumab at week 24 had all initially received golimumab alone without MTX for the first 16 weeks of the study.
The efficacy and safety of golimumab in patients with active RA despite prior use of at least one TNF inhibitor were described in a preliminary report of a trial of 461 patients who were randomly assigned to receive golimumab (50 or 100 mg every four weeks) or placebo, while continuing baseline nonbiologic DMARDs [37]. Among the patients in whom prior TNF inhibitor therapy was discontinued for lack of efficacy, those treated with golimumab were significantly more likely to achieve an ACR20 at week 14 (36 and 43 percent versus 18 percent). There were no significant differences in serious adverse events or in serious infections between the groups.
This combination is discussed in more detail elsewhere. (See "Randomized clinical trials of tumor necrosis factor inhibitors in rheumatoid arthritis".)
MTX-certolizumab pegol — The combination of MTX and certolizumab pegol (CZP), which is administered by subcutaneous injection every two weeks, improves signs and symptoms of RA in patients with active disease despite at least two months of treatment with MTX (≥10 mg/week) [38]. In the RAPID1 trial, 982 patients on MTX were randomized to receive CZP (400 mg at weeks zero, two, and four, followed by either 200 or 400 mg every two weeks) or placebo.
ACR20 responder rates at week 24, one of the primary outcomes, were greater for patients who received CZP (200 or 400 mg) plus MTX than for those who received placebo plus MTX (59 and 61 percent versus 14 percent). At week 52, mean radiographic progression from baseline (change in mTSS), the other primary outcome, was significantly lower in the CZP-treated patients (+0.4 and +0.2 versus +2.8).
Efficacy was evident at week one, by which time CZP-treated patients were more likely to have achieved an ACR20 response (23 and 22 percent versus 6 percent). At week 24, patients treated with CZP were more likely to achieve an ACR50 (37 and 40 percent versus 8 percent) or ACR70 (21 and 21 percent versus 3 percent).
Improvement in physical function was also evident in the CZP-treated patients at week one (HAQ-DI mean change of -13.5 and -10.9 versus -2.4) and was sustained through week 52 (-0.60 and -0.63 versus -0.18).
The rates of serious adverse events and serious infections in the two groups receiving CZP plus MTX and in the group receiving the placebo plus MTX were 15.2, 14.8, and 12 per 100 patient-years and 7.3, 5.3, and 2.2 per 100 patient-years, respectively. The most common serious infections reported were pneumonia, gastroenteritis, urinary tract infections, and tuberculosis. Tuberculosis was seen in five patients from Eastern Europe but in none from North America. These included three patients with negative chest radiographs and positive tuberculin skin tests who had received past Bacille Calmette-Guérin (BCG) vaccination, as well as one individual who worked in a tuberculosis clinic.
Anti-CZP antibodies were detected in 6.4 percent of patients receiving CZP at week 52.
Leflunomide-TNF inhibitors — Like MTX, LEF has been used in combination with TNF-alpha inhibitors, but this is less well-studied. An observational study using a population-based RA cohort of 1218 patients showed no difference in discontinuation rates, radiographic damage, functional disability, disease activity, or adverse events between patients who received a TNF inhibitor with methotrexate, leflunomide, or another nonbiologic DMARD [39].
TNF inhibitor switching — An inadequate response to one anti-TNF agent is not predictive of resistance to other agents in this class. Observations that provide support for the efficacy of switching and some estimate of its benefit are reviewed elsewhere. (See "Treatment of rheumatoid arthritis in adults resistant to initial biologic DMARD therapy", section on 'Resistant to one TNF inhibitor' and "Treatment of rheumatoid arthritis in adults resistant to initial nonbiologic DMARD therapy".)
MTX PLUS T-CELL COSTIMULATION BLOCKADE — Abatacept inhibits T cell costimulation and is effective in the treatment rheumatoid arthritis (RA) as monotherapy and in combination with methotrexate (MTX). It has also been effective in patients who have not adequately responded to the combination of MTX with a tumor necrosis factor inhibitor. (See "T-cell targeted therapies for rheumatoid arthritis", section on 'Costimulatory molecule inhibition'.)
MTX PLUS IL-1 OR IL-6 INHIBITION
MTX-anakinra — The combination of the recombinant human interleukin (IL)-1 receptor antagonist, anakinra, was effective when added to a stable dose of methotrexate (MTX) in patients with moderate to severe rheumatoid arthritis (RA) in a 24-week trial [40]. Although additional studies have also shown benefit, anakinra is rarely used in RA because it is significantly less potent than tumor necrosis factor (TNF) inhibitors in most patients [16,41]. (See "Randomized clinical trials in rheumatoid arthritis of biologic agents that inhibit IL-1, IL-6, and RANKL", section on 'Anakinra' and "Overview of biologic agents in the rheumatic diseases", section on 'Anakinra'.)
MTX-tocilizumab — Tocilizumab, a humanized anti-IL-6 receptor antibody, is effective when used together with methotrexate in patients who have had an inadequate response to methotrexate (MTX) alone or to MTX used together with a tumor necrosis factor inhibitor. Clinical trials of tocilizumab are discussed in detail elsewhere. (See "Randomized clinical trials in rheumatoid arthritis of biologic agents that inhibit IL-1, IL-6, and RANKL", section on 'Tocilizumab'.)
RITUXIMAB — B lymphocyte depletion using a monoclonal antibody to CD20 (rituximab) has been assessed in various clinical trials. Initial studies that enrolled patients with severe rheumatoid arthritis (RA) that was refractory to disease-modifying antirheumatic drug (DMARD) therapy used rituximab in combination with cyclophosphamide and high doses of glucocorticoids. Less complex regimens without cyclophosphamide and with limited glucocorticoid use were also found to be clinically efficacious. A detailed discussion of clinical trials of rituximab is presented elsewhere. (See "Rituximab and other B cell targeted therapies for rheumatoid arthritis", section on 'Rituximab'.)
MTX-rituximab — B lymphocyte depletion using a combination of rituximab plus methotrexate has been effective in randomized trials of patients resistant to methotrexate (MTX) alone as well as those resistant to tumor necrosis factor (TNF) inhibitors [42,43]. Preliminary data from long-term safety follow-up studies suggest a similar safety profile to other biologics. However, concerns regarding rare reports of progressive multifocal leukoencephalopathy (PML) with rituximab have resulted in use of this combination primarily in patients in whom TNF inhibitors have been inadequate. Further, rituximab was found to be more effective in patients who are seropositive for rheumatoid factor or antineutrophil cytoplasmic antibodies (ANCA). (See "Rituximab and other B cell targeted therapies for rheumatoid arthritis", section on 'Rituximab'.)
SUMMARY
●Patients with rheumatoid arthritis (RA) and persistently active disease despite initial pharmacologic therapies require adjustments in their treatment regimen to achieve effective disease control. The use of combinations of disease-modifying antirheumatic drugs (DMARDs), which may include both nonbiologic (traditional) and biologic DMARDs, is typically required in patients with persistently active disease. (See 'Introduction' above.)
●A number of combinations of nonbiologic DMARDs are more effective than such agents when used alone. Beneficial combinations include methotrexate (MTX), sulfasalazine (SSZ), and hydroxychloroquine (HCQ), also termed “triple therapy;” MTX plus leflunomide (LEF), used with particular caution because of the risk of hepatotoxicity with either drug; and, to a lesser degree than triple therapy, MTX plus either HCQ or SSZ. The addition of cyclosporine (CYS) or parenteral gold to MTX has also been studied, but these combinations are used very infrequently because of potential toxicities of CYS and gold. (See 'Combinations of nonbiologic DMARDs' above and 'Triple therapy with MTX-SSZ-HCQ' above and 'MTX-HCQ versus MTX-SSZ versus all three' above and 'MTX-leflunomide' above and 'MTX-cyclosporine' above and 'MTX-gold' above.)
●Randomized trials support the efficacy of adding an anti-tumor necrosis factor (TNF)-alpha agent (eg, etanercept, infliximab, adalimumab, golimumab, or certolizumab pegol) to ongoing MTX therapy, resulting in a greater likelihood of a good response to treatment, better radiographic outcomes than either treatment alone and a decreased incidence of anti-drug antibodies from the monoclonal anti-TNF agents. Of note, essentially all trials have shown that TNF inhibition works best when given with MTX. A strategy that is less well-studied is the combination of LEF with a TNF inhibitor. Azathioprine has also been shown to decrease anti-drug antibodies and may be a consideration in patients who can’t take MTX. An inadequate response to one anti-TNF agent is not predictive of resistance to other agents in this class. (See 'Nonbiologic DMARDs plus anti-TNF therapies' above and 'MTX-etanercept' above and 'MTX-infliximab' above and 'MTX-adalimumab' above and 'MTX-golimumab' above and 'MTX-certolizumab pegol' above and 'Leflunomide-TNF inhibitors' above and 'TNF inhibitor switching' above.)
●Combinations of MTX with abatacept, a T-cell costimulation blocker, or with tocilizumab, a humanized anti-interleukin (IL)-6 receptor antibody, are also effective in patients with persistent disease activity. Some benefit has been shown with the combination of MTX and anakinra, a recombinant human IL-1 receptor antagonist, but this combination is used very infrequently because of the greater efficacy observed with use of TNF inhibitors compared with anakinra. (See 'MTX plus T-cell costimulation blockade' above and 'MTX plus IL-1 or IL-6 inhibition' above and 'MTX-anakinra' above and 'MTX-tocilizumab' above.)
●B lymphocyte depletion using a monoclonal antibody to CD20 (rituximab) has been assessed in various clinical trials. The combination of rituximab plus MTX has been effective in randomized trials of patients resistant to MTX alone as well as those resistant to TNF inhibitors. (See "Rituximab and other B cell targeted therapies for rheumatoid arthritis", section on 'Rituximab' and 'Rituximab' above and 'MTX-rituximab' above.)