Randomized clinical trials of combinations of nonbiologic DMARDs in rheumatoid arthritis

Randomized clinical trials of combinations of nonbiologic DMARDs in rheumatoid arthritis

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, 2014.

INTRODUCTION — More than a dozen traditional disease-modifying antirheumatic drugs (DMARDs) and biologic agents, respectively termed nonbiologic and biologic DMARDs, are currently available; thus, there are more than 100 and 1000 potential combinations of two and three DMARDs, respectively. Of these, only a few have been directly compared in randomized clinical trials. Some well-designed studies have demonstrated clinically significant efficacy with a generally acceptable risk of toxicity.
Representative clinical trials of various combinations of nonbiologic DMARDs in early and established rheumatoid arthritis (RA) will be reviewed here. The general approach to management of RA and randomized controlled trials of biologic agents in this disease are discussed separately. (See "General principles of management of rheumatoid arthritis in adults" 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".)
METHOTREXATE-BASED COMBINATIONS
Gold and MTX — The clinical effectiveness of the combination of intramuscular gold when added to ongoing methotrexate (MTX) was best illustrated in a study in which 65 patients with rheumatoid arthritis (RA) and a partial response to MTX (mean dose of 18.5 mg per week) continued MTX therapy and were randomly assigned to receive gold sodium thioglucose (initial dose of 10 mg, followed by 25 mg at week one and 50 mg per week thereafter) or placebo injections for 48 weeks [1]. At the end of the trial, those who received gold injections did significantly better than the placebo group:
●American College of Rheumatology (ACR) 20 percent improvement (ACR20 responses) occurred in a significantly greater proportion of gold plus MTX-treated subjects (61 versus 30 percent).
●ACR50 responses also occurred more often in those receiving gold (26 versus 4 percent).
●ACR70 responses were only seen in those receiving gold (21 versus 0 percent).
●Fewer withdrawals in the gold plus MTX group than in the placebo group were due to lack of efficacy (3 of 9 versus 10 of 14, respectively).
●Withdrawals due to adverse events were not significantly more frequent in the gold plus MTX group (10 versus 3 percent).
Mucocutaneous side effects occurred in 17 of 38 gold/MTX-treated patients, leading to temporary suspension of therapy with gold. However, in 15 of 17 patients, gold was reintroduced (at one-half the dose at which the adverse effect occurred, followed by a gradual increase by 5 mg per week to the maximum tolerated dose or 50 mg per week) without recurrent rash or mucositis.
Intramuscular gold is rarely used in the treatment of RA because of its slow onset of action and difficulty of administration compared with many newer therapies.
SSZ and MTX — There are conflicting data on the efficacy of the two-drug combination of sulfasalazine (SSZ) and MTX.
●Forty patients with RA unresponsive to sulfasalazine alone were randomized to combination therapy consisting of SSZ and MTX or to MTX alone [2]. At 24 weeks, combination therapy resulted in a significant decrease in disease activity compared with MTX alone. No difference in toxicity was observed between the two treatment groups.
●A multicenter study in Europe enrolled 205 patients with RA who had not previously been treated with any disease-modifying antirheumatic drug(s) (DMARD[s]) and randomly assigned them to SSZ, MTX, or a combination of the two agents [3]. After one year of concealed treatment, 146 were followed for an additional four years in an unblinded fashion and with whatever treatment was chosen by the clinicians managing their care. Five years after initial enrollment, disease activity, functional status, and radiographic scores were assessed [4]. These outcomes were not significantly different among the three groups at the one- or five-year points.
●A molecular rationale for the failure of SSZ and MTX given in combination to be more efficacious than either drug given alone was provided in a Dutch study [5]. SSZ was found to be a potent inhibitor of the principal cell membrane transporter for folates as well as MTX, along with inducing cellular folate depletion. These observations led to recommendations that the drugs should not be given in combination and that folate supplementation should be administered to patients on either drug.
SSZ, HCQ, and MTX — Several trials have documented the benefits of the three drug combination of MTX, SSZ, and hydroxychloroquine (HCQ). A well-controlled, prospective randomized trial of 102 patients with established RA found that triple therapy with MTX (7.5 to 17.5 mg per week, titrated for response), SSZ (500 mg twice daily), and HCQ (200 mg twice daily) was superior to MTX alone or to SSZ plus HCQ [6]. The primary endpoint was at least 50 percent improvement at nine months, a benefit which had to be sustained for two years without the development of significant drug toxicity. Response was realized in 77, 40, and 33 percent of patients randomized to triple-, double-, or single-agent therapy, respectively (p = 0.003 for comparisons with the triple agent group).
Subsequent trials have documented in patients with an inadequate response to MTX monotherapy that the addition of SSZ and HCQ can result in clinical benefit that is comparable to the addition of a tumor necrosis factor inhibitor. (See "Treatment of rheumatoid arthritis in adults resistant to initial nonbiologic DMARD therapy", section on 'Efficacy of triple therapy versus MTX/TNF inhibitor'.)
HCQ/MTX versus SSZ/MTX versus HCQ/SSZ/MTX — The question of whether a two- or three-drug combination that included MTX was more efficacious for patients with RA who had an inadequate response to MTX alone was addressed in a study that randomized 171 patients to one of three groups: a three-drug combination of MTX, HCQ, and SSZ; a two-drug regimen of MTX plus HCQ (plus placebo); or MTX plus SSZ (plus placebo) [7].
Patients all had active disease and were followed for two years. The MTX dose was escalated from 7.5 mg per week to a maximum of 17.5 mg per week. SSZ was initially given at a dose of 500 mg twice daily and increased to 1 gram twice daily. The HCQ dose was 200 mg twice daily.
Patients on the three-drug combination had a significantly greater proportion of ACR 20 and 50 responses than those on either of the two-drug plus placebo combinations (ACR20 responses of 78 percent, 60 percent, and 49 percent for those receiving three drugs, MTX plus HCQ, and MTX plus SSZ, respectively; ACR50 responses of 55, 40, and 29 percent, respectively). There was no significant difference in toxicity among the three groups.
SSZ, prednisolone, and MTX — A double-blind study randomized 155 patients with early-onset RA to combination therapy consisting of SSZ (2 g per day), MTX (7.5 mg per week), and prednisolone (initial dose of 60 mg per day which was lowered over six weeks to 7.5 mg per day) or to SSZ alone [8,9]. Prednisolone and MTX were withdrawn at weeks 28 and 40, respectively. Evaluation of therapeutic efficacy was assessed via a pooled index of five disease activity measures and via radiographic outcomes. At week 28, combination therapy resulted in significant clinical benefits as determined by the pooled index when compared with SSZ alone (p<0.0001). In addition, 72 and 49 percent of patients treated with combination therapy and SSZ alone had improved, respectively. These benefits were not statistically significant once prednisolone was withdrawn, and the clinical differences between the groups were unchanged after MTX was stopped. Nevertheless, radiographic benefits due to combination therapy were statistically significant at multiple time periods (weeks 28, 56, and 80).
SSZ, HCQ, prednisolone, and MTX — In a multicenter trial (FIN-RACo), 199 patients were randomly assigned either to combination therapy consisting of MTX, SSZ, HCQ, and prednisolone, or to single-agent therapy [10]. Patients randomized to single-agent therapy were initially treated with SSZ, but MTX was later substituted for SSZ in 51 patients. In addition, prednisolone was required in 63 individuals. After two years, remission was realized in 36 and 18 percent of the combination and single-agent therapy group, respectively (p = 0.003). In addition, 7 percent of those assigned to single-agent therapy, but none who received combination therapy developed radiographically apparent atlantoaxial subluxation (p = 0.029) [11].
Calcineurin inhibitor plus MTX — The calcineurin inhibitors (CNI) cyclosporine and tacrolimus have each been studied in RA in combination with MTX. These drugs are rarely used in RA because of the availability of effective medications that lack the degree of renal risk associated with the CNIs.
Cyclosporine and MTX — The combination of cyclosporine and MTX has generally been more effective than either agent used individually [12-15]. The following studies are illustrative:
●A six-month study evaluated the clinical response of 148 patients with severe RA randomized to MTX (at the maximal tolerated dose) plus cyclosporine (2.5 to 5 mg/kg per day) or to methotrexate plus placebo [16]. Compared with MTX alone, combination therapy resulted in fewer tender joints (average decrease of 4.8 joints, p = 0.02), fewer swollen joints (average decrease of 3.8 joints, p = 0.005), and improvement in disease activity as determined by both the clinician and patient. Clinical improvement was maintained when this study was extended for another 24 weeks [12].
●Another study that randomly assigned 120 patients with active RA either to the combination of cyclosporine (2.5 mg/kgincreased to 5 mg/kg per day, if tolerated) and MTX (7.5 mg per week, increased to 15 mg per week, if tolerated) or to cyclosporine and placebo [13]. The combination of cyclosporine and MTX tended to produce better clinical responses. In those followed for 48 weeks, significantly less radiographic damage occurred in the combination group than in the group on cyclosporine alone (median Larsen scores of 10 and 4, respectively, p = 0.004) [13]. Remissions were uncommon in both groups (four versus six patients, respectively).
●In another study, 61 patients with active RA of less than two years’ duration who had not received DMARDs or prednisone in a dose of more than 10 mg per day were randomly assigned to receive cyclosporine (3 mg/kg per day initially with an increase to 4 mg/kg per day) plus MTX (10 to 15 mg intramuscularly weekly with an increase to 20 mg per week, if necessary) or MTX and placebo [14]. ACR 20, ACR 50, and ACR 70 response rates in the combination and MTX alone groups were 53 versus 61 percent, 50 versus 42 percent, and 47 versus 19 percent, respectively. There was significantly less progression in radiographic joint damage during one year of treatment in the combination than in the MTX-only groups (change in joint damage score 1.9 versus 7.5, respectively). There were more withdrawals from the combination group due to adverse effects (seven patients, 23 percent) than the MTX-only group (two patients, 6 percent). Although patients were aware of their assigned treatment, the scoring of radiographs was performed by an investigator who was unaware of this factor.
However, another study comparing MTX and cyclosporine with sulfasalazine alone found no significant difference at 48 weeks in clinical and radiographic outcome with the two regimens [17].
Tacrolimus and MTX — The combination of tacrolimus (3 mg per day) and MTX (mean of 15 mg per week) may have some benefit, as suggested by the results of an uncontrolled multicenter trial in 80 patients with RA that was still active despite ongoing MTX therapy [18]. ACR20 responses were noted in 52.5 percent of those receiving the combination at the end of six months of treatment. Increases in serum creatinine of ≥30 percent were seen in 29 percent of patients. Withdrawals from the study were predominantly due to possible or probable adverse effects from tacrolimus and lack of efficacy (12.5 and 5 percent, respectively).
Careful monitoring of renal function is required if this combination is utilized, as the renal dysfunction that is a common adverse effect of tacrolimus may lead to a prolongation of the half-life of MTX and could increase the risk of myelosuppression. (See "Pharmacology and side effects of cyclosporine and tacrolimus" and "Cyclosporine and tacrolimus nephrotoxicity".)
Leflunomide and MTX — The administration of leflunomide (LEF) in combination with MTX is based upon the premise that it may be useful to combine an agent whose mode of action is different from that of MTX (see "Leflunomide in the treatment of rheumatoid arthritis"). An initial open-label study of 30 patients with active RA suggested benefit from this combination and provided the rationale for further studies [19].
A subsequent trial randomly assigned 263 patients with persistent disease activity despite use of MTX (mean 17 mg per week) to groups that received either leflunomide (100 mg per day for two days, followed by 10 mg per day with titration upward to 20 mg per day or down to 10 mg every other day as indicated by clinical response or adverse effects) or placebo [20]. More than three-quarters of the subjects were women, the mean age was approximately 56 years, and disease duration averaged 10 to 12 years. Eighty to 90 percent of the patients were rheumatoid factor-positive. Blood counts, serum aminotransferase enzyme levels, and serum albumin were followed carefully, and the dose of leflunomide adjusted accordingly.
After six months, an ACR20 response was noted in significantly more patients in the LEF plus MTX group than in the placebo plus MTX group (46 versus 19 percent, respectively). LEF plus MTX-treated patients also had more frequent ACR 50 (26 versus 6 percent) and ACR 70 (10 versus 2 percent) responses than did those who received MTX and placebo.
At the end of the study, a majority of patients in the LEF plus MTX group were receiving 20 mg per day of LEF (55 percent), while a minority were on 10 mg per day or every other day (39 and 6 percent, respectively). Adverse events were common in both groups, but only diarrhea was more common in the LEF plus MTX group (25 versus 13 percent).
●There were fewer infections in the combination group, and there were no opportunistic infections in either group of patients.
●There were more discontinuations of treatment due to adverse events in the combination group and more withdrawals due to lack of efficacy in the MTX plus placebo group. The proportion of withdrawals from the study was similar in the two groups (23 and 25 percent, respectively).
●Elevation of serum aminotransferase enzyme levels (more than 1.2-fold greater than the upper limit of normal) was more frequent in the combination group than in the MTX plus placebo group (31 versus 7 percent).
●Mild or moderate decreases in leukocyte and/or neutrophil counts were more frequently noted in those receiving the MTX-LEF combination, but none of the patients experienced severe leukopenia or neutropenia.
At the conclusion of the double-blind portion of this study, an open-label extension was conducted for an additional 24 weeks [21]. Responses noted in 96 patients who initially received MTX plus LEF were generally maintained, while 96 others who had received placebo plus MTX for 24 weeks experienced a gradual improvement after LEF was substituted for placebo. Among the latter group, those who did not receive a loading dose of LEF had less nausea and diarrhea and less often had elevations of serum aminotransferases than those who did receive a loading dose.
Overall, addition of LEF to MTX therapy had moderate efficacy. However, scrupulous monitoring of serum aminotransferase levels and adjustment of the LEF or MTX dose are necessary, since the combination of these two agents frequently led to enzyme elevations.
Doxycycline and MTX — Clinical trials of doxycycline have not demonstrated efficacy of this agent for signs and symptoms of arthritis when used alone in patients with RA. It is rarely used in the treatment of RA because of the availability of more effective therapies.
However, doxycycline may enhance the effectiveness of MTX when used early in the course of disease. This was illustrated in a trial that enrolled 66 patients with early seropositive RA, each of whom received escalating doses of MTX (initial dose 7.5 mg per week, mean final dose approximately 15 mg per week) [22]. Patients were randomly assigned to one of three groups: placebo, low-dose doxycycline (20 mg twice daily), or high-dose doxycycline (100 mg twice daily). After two years of treatment, the ACR50 response rates in the placebo, low-dose doxycycline, and high-dose doxycycline groups were 12.5, 39, and 41.6 percent, respectively, a statistically and clinically significant difference.
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.)
●Beyond the Basics topics (see "Patient information: Rheumatoid arthritis symptoms and diagnosis (Beyond the Basics)" and "Patient information: Rheumatoid arthritis treatment (Beyond the Basics)" and "Patient information: Disease-modifying antirheumatic drugs (DMARDs) (Beyond the Basics)" and "Patient information: Complementary and alternative therapies for rheumatoid arthritis (Beyond the Basics)")
SUMMARY AND RECOMMENDATIONS
●In patients with a partial response to methotrexate (MTX) alone, the addition of intramuscular gold resulted in greater benefit than placebo, although mucocutaneous side effects were common and required adjustments in dosing. Gold therapy is rarely used because of its disadvantages compared with other available therapies. (See 'Gold and MTX' above.)
●The drug combination of MTX, sulfasalazine (SSZ), and hydroxychloroquine (HCQ) results in greater clinical benefit than MTX alone, MTX plus HCQ, or MTX plus SSZ in patients with an inadequate response to MTX or another disease-modifying antirheumatic drug (DMARD) alone. The efficacy of SSZ plus MTX is uncertain compared with either drug alone. (See 'SSZ and MTX' above and 'SSZ, HCQ, and MTX' above and 'HCQ/MTX versus SSZ/MTX versus HCQ/SSZ/MTX' above.)
●Treatment with combinations of DMARDs plus glucocorticoids provides greater benefit clinically and results in less radiographic progression compared with DMARD monotherapy. (See 'SSZ, prednisolone, and MTX' above and 'SSZ, HCQ, prednisolone, and MTX' above.)
●Combination therapy with MTX plus cyclosporine, a calcineurin inhibitor (CNI), generally results in greater clinical and radiographic benefit compared with either therapy alone. Limited data suggest that the combination of MTX with another CNI, tacrolimus, may also be of benefit. CNIs are rarely used in rheumatoid arthritis (RA) because of their greater risks compared with other available therapies. (See 'Cyclosporine and MTX' above and 'Tacrolimus and MTX' above.)
●In patients who have not responded adequately to MTX alone, the addition of leflunomide (LEF) resulted in greater benefit compared with placebo. Diarrhea was the only adverse event that was more common in the combination therapy group, although scrupulous monitoring of serum aminotransferase levels and adjustment of the LEF or MTX dose are necessary in patients receiving both drugs, since the combination frequently led to liver enzyme elevations. (See 'Leflunomide and MTX' above.)
●Doxycycline may enhance the effectiveness of MTX when used early in the course of seropositive disease, but it is rarely used because of the greater efficacy of other available therapies. (See 'Doxycycline and MTX' above.)