Superior Efficacy of Combination Therapy for Rheumatoid Arthritis

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1 ARTHRITIS & RHEUMATISM Vol. 52, No. 10, October 2005, pp DOI /art , American College of Rheumatology REVIEW Superior Efficacy of Combination Therapy for Rheumatoid Arthritis Fact or Fiction? Josef S. Smolen, 1 Daniel Aletaha, 2 and Edward Keystone 3 1 Josef S. Smolen, MD: Medical University of Vienna and Lainz Hospital, Vienna, Austria; 2 Daniel Aletaha, MD: Medical University of Vienna, Vienna, Austria, and National Institute of Arthritis and Musculoskeletal and Skin Diseases, NIH, Bethesda, Maryland; 3 Edward Keystone, MD: Mount Sinai Hospital, University of Toronto, Toronto, Ontario, Canada. Dr. Smolen has received consulting fees or honoraria (less than $10,000 per year) from Centocor, Bristol-Myers Squibb, Aventis, Roche, Wyeth, Amgen, Schering-Plough, and Abbot. Dr. Keystone has received consulting fees or honoraria (less than $10,000 per year) from Roche, Genentech, Amgen, Wyeth, Centocor, Schering-Plough, Bristol-Myers Squibb, and Abbott. Address correspondence and reprint requests to Edward Keystone, MD, The Rebecca MacDonald Centre for Arthritis and Autoimmunity, Mount Sinai Hospital, 60 Murray Street, Room 2-006, Toronto, Ontario M5G 1X5, Canada. edkeystone@ mtsinai.on.ca. Submitted for publication March 30, 2005; accepted in revised form June 17, Introduction In the last 25 years, there has been a substantial shift in the therapeutic algorithm for rheumatoid arthritis (RA) toward early intensive therapy. The shift has been driven by the recent demonstration of rapid functional decline, early progressive joint destruction, and premature mortality in patients with RA (1,2). The milestones in the course of this evolution were the recognition of the excellent efficacy of methotrexate (MTX), especially when dosing was rapidly increased to mg/week, and the introduction of biologic agents, especially the tumor necrosis factor (TNF) blockers (3 5). An additional cornerstone for optimizing treatment in RA has been combination therapy with diseasemodifying antirheumatic drugs (DMARDs). This strategy used the experience of oncologists in combining drugs with different mechanisms of action with a view to achieving an additive or synergistic effect of the drug combinations without increased toxicity. During the last decade, the combination of traditional DMARDs has been an important addition to the therapeutic armamentarium for RA. In this review, we discuss 5 main points of concern. First, many clinical trials of combination therapy using nonbiologic, traditional DMARDs do not prove the superiority of combination therapy over monotherapy. Second, in the vast majority of trials with traditional DMARDs reporting a superiority of combination therapy compared with monotherapy, there were confounding factors, including differences in the use of glucocorticoids in the treatment arms, and thus, the steroids, rather than the combination of traditional DMARDs, might have been responsible for the results obtained. Third, the concomitant use of glucocorticoids appears to confer greater benefits for DMARD therapy. Fourth, with all caveats regarding comparisons of different trials, the addition of a second DMARD in a step-up strategy usually results in similar response rates on the American College of Rheumatology (ACR) improvement criteria as monotherapy with the same DMARDs. Fifth, combinations of biologic agents with DMARDs have been shown to be superior to monotherapy with either agent. Thus, well-designed trials controlling for confounding factors are needed in order to resolve the controversies concerning DMARD combinations. What is combination therapy? When investigating combination therapy, rheumatologists initially focused on the use of 2 or more DMARDs (6 10). Concomitant treatment with NSAIDs or low-dose glucocorticoids was not generally considered a combination strategy, since these medications were usually also used as adjuncts to DMARD monotherapy. In more recent years, 3 types of combination therapies have been studied: combinations of 2 or more traditional 2975

2 2976 SMOLEN ET AL (small-molecule) DMARDs, combinations of 2 or more traditional DMARDs plus glucocorticoids at low or higher dosages, and combinations of traditional DMARDs (usually MTX) with biologic agents, especially TNF blockers. For the purpose of this review, combination therapy means combinations of 2 or more traditional (nonbiologic) DMARDs. The effects of glucocorticoids or biologic DMARDs will be dealt with separately. Since in many studies of combination therapies incorporating glucocorticoids as part of the treatment strategy, the focus was on combinations of the DMARDs rather than the steroids, we will discuss the effects of glucocorticoids in the context of interpreting the efficacy of the traditional DMARD combinations. With such an approach, we try to address the complexity of combination therapy in RA in order to understand the benefits of this therapeutic strategy. Strategies used in studies of combination therapies and reviews of the subject Combination therapy has been performed using 3 strategies: a parallel strategy in which DMARDs have been initiated simultaneously, a step-up strategy in which one DMARD is added to the background of another DMARD that may have been partially effective, and a step-down strategy in which DMARDs are initiated simultaneously and subsequently withdrawn sequentially once a preset clinical benefit has been achieved. Prior to the mid-1990s, all trials of combination DMARD therapy were of the parallel design. In the 1990s, the first step-up study using cyclosporine on the background of MTX was performed (11). Since then, the step-up strategy has predominated in clinical trials of therapeutics in RA, especially in the context of studying biologic agents on the background of DMARDs (primarily MTX). Most recently, parallel designs have been used again, especially in the context of trials involving biologic agents. Before detailing our analyses of the issue, it should be mentioned that combination therapies have been the subject of several reviews in the last decade. Thus, a number of studies of combination therapy performed in the 1980s and early 1990s were the focus of a meta-analysis by Felson et al (12), which failed to support the concept of their benefit, suggesting that combination therapy not be recommended. However, the studies were small nonrandomized trials of agents of modest benefit or with significant toxicity. The studies of combination DMARDs evaluated by Felson et al included chloroquine/d-penicillamine, sulfasalazine/dpenicillamine, parenteral gold/hydroxychloroquine, parenteral gold/auranofin, and methotrexate/azathioprine. More recently, a systematic review of trials of combinations of conventional DMARDs published between 1992 and 1997 was performed. Although demonstrating that most combinations of DMARDs then in use did not exhibit substantial efficacy (13), notable exceptions included the studies by Tugwell et al (11), who used a step-up strategy with MTX and cyclosporin A (CSA) versus MTX alone; Ferraz et al (14), who used the parallel strategy of hydroxychloroquine (HCQ) plus MTX versus MTX alone; O Dell et al (15,16), who used the parallel strategy of triple therapy with MTX plus sulfasalazine (SSZ) plus HCQ versus SSZ plus HCQ versus MTX alone; and Boers at al (17), who used a step-down strategy comparing MTX, SSZ, and prednisone with SSZ. A review by Goekoop et al (18) of clinical trials of currently used combination therapies with traditional DMARDs that were performed between 1999 and 2000 revealed that only 2 studies of traditional DMARD combinations appeared to demonstrate efficacy: the study by Möttönen et al (19), who used the parallel initiation of MTX plus SSZ plus HCQ plus prednisone versus MTX or other DMARDs (with or without prednisone), and the trial by Calguneri et al (20), who evaluated triple DMARD therapy (MTX plus SSZ plus HCQ) versus double therapy (MTX plus SSZ or MTX plus HCQ) versus monotherapy (MTX or SSZ or HCQ). Since 2000, studies of step-up therapy with leflunomide plus MTX have demonstrated significant efficacy (21). With few exceptions, all trials referred to thus far have involved combinations of traditional, nonbiologic DMARDs. Such trials constitute the major focus of this review. However, the role of steroids has been insufficiently addressed in the trials and therefore merits special consideration in a separate section of this review. As well, the use of biologic agents in combination with traditional DMARDs (a major therapeutic strategy) differs from the use of combinations of traditional DMARDs and will therefore also be discussed separately. Although several trials of combinations of DMARDs have found greater efficacy than with monotherapy, a number of potential study design flaws affect the interpretation of the results. The question raised in this review is, what strategies have used a study design that unequivocally demonstrates the utility of combination therapy with traditional DMARDs over monotherapy? In this context, we will focus on the various

3 EFFICACY OF COMBINATION THERAPY FOR RA 2977 study designs as well as on the questions of whether DMARDs used in comparator arms are comparable and whether differences in the concomitant use of glucocorticoids might have significantly contributed to the results. Study design issues Parallel combination strategy. Despite numerous studies using the parallel combination strategy, flaws in study design mar the interpretation of the findings of many of the early studies. A significant problem in studies of combination therapy versus monotherapy is the inclusion of a DMARD in the monotherapy arm that is less efficacious than one of the DMARDs in the combination arm. The study by Trnavsky et al (22), which demonstrated the superiority of HCQ plus MTX over HCQ monotherapy, illustrates this point. The superiority of the DMARD combination over HCQ likely reflects the inclusion of MTX in the combination arm, a notion supported by the significant inferiority of HCQ, which was also seen in other studies (23). In contrast, the study by Ferraz et al (14), which demonstrated superiority of the combination of HCQ and MTX over MTX alone, is far more clinically relevant. However, as the authors themselves concluded, the study demonstrated that the combination was only marginally more efficacious than MTX monotherapy and had higher levels of toxicity, and taken together, the findings do not support a benefit of the combination for the patient. A critical design flaw in the majority of the parallel strategy trials is the lack of blinding (19,20,24). The use of double or triple combination open-label trials provides a strong placebo bias on the part of the patient as well as an expectation bias on the part of the physician. This concept was dramatically illustrated by the early open-label data obtained in studies of anti-cd4 therapy (25). It is worth pointing out, however, that studies using blinded radiographic outcomes may provide support for open-label studies of signs and symptoms. Nevertheless, confounding factors need to be sorted out. The study by Calguneri et al (20), for example, suggests radiographic benefit of combination triple therapy with MTX, HCQ, and SSZ or dual therapy with MTX plus HCQ or SSZ compared with monotherapy with MTX, HCQ, or SSZ; radiographs were evaluated by readers who were blinded to the clinical outcome. However, the monotherapy arm consisted of 3 different DMARDs, with only one-third of the patients receiving MTX but another one-third receiving HCQ, which does not have significant radiographic benefit (23). The study was therefore biased in favor of a DMARD combination consisting of more effective disease-modifying agents versus a monotherapy arm with little expected radiographic benefit. Like the study by Calguneri, the study by Proudman et al (24) failed to show any clinical superiority of a different combination, namely, MTX plus CSA plus intraarticular glucocorticoids, as compared with SSZ monotherapy. The study by Möttönen et al (19) also deserves special mention. In general, this is a therapeutic approach involving an open-label, real-life type of trial. The authors reported that remission frequencies at 1 and 2 years were significantly higher in the combination arm compared with the SSZ monotherapy arm and that there was also a radiographic benefit. Of significance, the improvement in all of the ACR core set of improvement measures (including joint counts) was very similar between the groups and did not differ statistically. It is also important to mention that all these variables tended to have higher baseline values in the single therapy group compared with the combination therapy group. This was even more true for radiographic abnormalities. Not only did patients in the monotherapy group have more erosions at baseline, but the upper quartile of the Larsen score was twice as high in the monotherapy group than in the combination group, indicating that the former group had worse disease and faster progression of destruction. Importantly, the observed differences between the 2 groups may have to be accounted for by the differential use of glucocorticoids (19,26). The addition of glucocorticoids from the start was mandatory in the combination arm, but was not required in the monotherapy arm. In fact, only 27% of the control patients received glucocorticoids from the start of their monotherapy, and steroids were added for the first time up to 93 weeks from baseline (26). This highly delayed initiation of steroids, which suggests inefficacy earlier in the course of the study, resulted in even more cumulative steroid use in the monotherapy group, although the median dose was the same as that in the combination group. More than one-third of the patients receiving monotherapy never received steroids. Thus, this study does not allow a conclusion that the combination of traditional DMARDs was decisive for the benefit observed. It cannot be ruled out that patients receiving SSZ monotherapy would have achieved a similar frequency of remissions and similar radiographic benefit had all of them, rather than only 1 in 4, received steroids from baseline. In fact, several combination regimens involving

4 2978 SMOLEN ET AL SSZ failed to demonstrate efficacy in well-designed controlled studies that included combinations of MTX plus SSZ (27,28), as well as MTX plus azathioprine (29). Moreover, recent data have indicated that the combination of MTX and SSZ should produce little benefit, given their biologic interactions (30). The study by O Dell et al (15) demonstrating the benefits of combination triple therapy (MTX, HCQ, and SSZ) in a double-blind study provides support for the initiation of a triple regimen in RA. The combination was clearly superior to one of the comparator arms, namely, MTX plus HCQ, although in the other comparator arm, namely, SSZ plus HCQ, SSZ was given at a low dose of 1 gm/day (15). The disease activity in the patient population was numerically milder (usually by 10% or more versus the comparator arms) for all of the ACR core set of variables in the combination arm, and radiographic progression was not analyzed. Thus, the issue of superiority of the combination of MTX and SSZ remains controversial, and unequivocal evidence of clinical or radiographic benefit of this combination over monotherapy is still lacking. A double-blind randomized controlled trial by Gerards et al (31) compared CSA plus MTX against CSA alone (plus placebo) in a parallel design. Although the combination had somewhat better efficacy clinically (ACR 50% improvement, but not ACR 20% and ACR 70% improvement) and radiographically than monotherapy, it is not clear if this was due to the effect of MTX rather than the combination, since a third arm (MTX alone) was lacking. Step-up strategy. Clinical trial data. Although the step-up strategy has become the standard trial design for demonstrating the efficacy of combination therapy and has been used in most trials with biologics, the design does not provide definitive proof that the effect observed relates to the DMARD combination, since the control arm, in reality, constitutes a placebo arm in patients who have very active disease despite therapy with MTX. Only the inclusion of a monotherapy arm of the add-on DMARD will address this issue. It is unclear, for example, from step-up studies of cyclosporine whether the efficacy observed with the combination with MTX relates to the combined effect of the 2 agents or to the effect of cyclosporine alone. In fact, when comparing the results of the study by Tugwell et al (CSA added to preexisting MTX treatment in a step-up design) (11) with those of the study by Gerards et al (CSA monotherapy compared with CSA plus MTX in a parallel design) (31), the clinical response to CSA monotherapy and to CSA step-up treatment were virtually identical (Table 1). Rheumatologists (in contrast to other subspecialists, such as oncologists) tend to avoid comparing arms from different trials and miss important information that is possible to obtain relatively objectively (32). Thus, with all the limitations of such between-trials comparisons, the data reviewed above imply that the combination of these agents may not be superior to monotherapy. The same concerns relate to the combination of leflunomide with MTX, where the increased toxicity associated with that combination makes this issue particularly relevant (21). In fact, when reviewing results from the various leflunomide clinical trials, ACR response rates of patients receiving leflunomide monotherapy were similar, if not superior, compared with the addition of leflunomide to MTX therapy (33 35) (Table 1). Again, comparing clinical trials has its limitations, but the results are clearly consistent with this interpretation. In fact, the results of a trial comparing the addition of SSZ to leflunomide, with switching from leflunomide to SSZ, also failed to show a significant advantage of the combination (36). There was a marginal, but insignificant, numerical benefit in favor of the combination, Table 1. Clinical responses in selected studies using combination therapy or monotherapy* Author, year (ref.), therapy ACR 20% criteria % of patients meeting ACR improvement criteria ACR 50% criteria ACR 70% criteria Tugwell et al, 1995 (11) (MTX ) CSA 48 (MTX ) placebo 16 Gerards et al, 2003 (31) CSA placebo CSA MTX Kremer et al, 2002 (21) (MTX ) LEF (MTX ) placebo Smolen et al, 1999 (33) LEF SSZ Strand et al, 1999 (34) LEF MTX Emery et al, 2000 (35) LEF 51 MTX 65 * Note the similarities of the responses. ACR American College of Rheumatology; MTX methotrexate; CSA cyclosporin A; LEF leflunomide; SSZ sulfasalazine. (MTX ) indicates that the patients had active disease despite MTX therapy and received an add-on disease-modifying antirheumatic drug (step-up design) or an add-on placebo. The other studies had a parallel design.

5 EFFICACY OF COMBINATION THERAPY FOR RA 2979 indicating that the benefit obtained in the combination came mainly from the add-on SSZ rather than the fact that it was combined with leflunomide. In addition, there was higher toxicity observed in the add-on arm. Because of the risk of flares upon discontinuation of MTX, it may be difficult to perform clinical trials in patients who have active disease despite MTX therapy when comparing step-up therapy against monotherapy with the new DMARD when there is a concomitant withdrawal of MTX. However, an effective agent should exert its efficacy before flares from discontinuation of MTX become apparent. Another approach to addressing the need for MTX in the combination would be to gradually withdraw the MTX in a blinded manner once an optimal response of the DMARD combination has been achieved. Unfortunately, no studies of MTX withdrawal have been published to date, with the exception of a trial with a biologic agent (37). Taken together, the efficacy of the combination of cyclosporine or leflunomide with MTX or with SSZ may reflect the efficacy of the DMARD add-on alone, as supported by the remarkably similar efficacy of monotherapy and combination strategies with cyclosporine or leflunomide (Table 1). Further studies are needed to address the question. One of the key issues that remain to be addressed in the therapeutic algorithms for RA is the efficacy of the addition of conventional DMARDs such as SSZ or HCQ to MTX in patients who are partially responsive to high-dose MTX. Only 1 small open-label controlled trial involving 30 patients per group has investigated this (38). The results suggest substantial improvement with the addition of both SSZ and HCQ to MTX. Less impressive results were observed if either SSZ or HCQ alone was added. An arm in which MTX therapy was switched to SSZ, HCQ, or both was not investigated. Studies to address the role of combination therapy with SSZ or HCQ in partial responders to MTX are in progress. Observational studies. Step-up therapy is frequently used in clinical practice, but there are few data on the effectiveness of such therapy. Retention rates for DMARD therapies obtained from retrospectively analyzed long-term observational studies (39) have been shown to be useful outcome measures in these settings, integrating issues of effectiveness, safety, and practicability of the treatment regimens. The results of such long-term observational studies are realistic, since they are derived from a setting and patient population that is familiar and important to the practicing rheumatologist (40), and they have been pivotal in marking MTX as the most effective traditional DMARD (40 42). Figure 1. Cumulative survival for different disease-modifying antirheumatic drug (DMARD) regimens. The y-axis shows the proportions of DMARD courses still on methotrexate (MTX) monotherapy (n 1,030), MTX combination (comb.) therapy (n 258), and combination therapy without (w/o) MTX (n 57). The broken line at 50% indicates the median survival, which was 32 months (quartiles 83 and 11 months) for MTX monotherapy, 21 months (quartiles 44 and 6 months) for MTX combinations, and 11 months (quartiles 42 and 5 months) for combinations without MTX. Pairwise log rank test for monotherapy versus combination therapy was significant (P 0.001). Figure 1 depicts a hitherto unpublished subanalysis of data on treatment retention rates obtained in a typical observational cohort of patients with RA (n 1,479), most of which have been previously presented (42,43). It can be seen that in this cohort, MTX monotherapy had better overall retention rates (n 1,030 courses, with a median survival of 32 months [quartiles 83 and 11 months]) than either combination therapies with MTX (n 258 courses, with a median survival of 21 months [quartiles 44 and 6 months]) or combination therapies without MTX (n 57 courses, with a median survival of 11 months [quartiles 42 and 5 months] (P for monotherapy versus combination therapies with MTX and those without MTX, by log-rank test). This superiority of MTX monotherapy was still significant after adjustment for the number of previous DMARDs, which allowed for the fact that combinations

6 2980 SMOLEN ET AL tended to be used in patients with more refractory RA. Although this adjusted analysis cannot ensure a complete absence of residual bias by indication between MTX and combination groups, it is at least unlikely that a superiority of combination therapies would be seen if perfect adjustments were possible. For a similar analysis, we identified all patients whose DMARD regimens were modified by the treating rheumatologists because of insufficient effectiveness. For their subsequent regimens, we found no difference in drug retention rates whether they were switched to MTX or received MTX as an add-on to their partially effective DMARD (data not shown). Thus, these observational data are consistent with and support our interpretation of the trial results with combination therapy. Step-down strategy. Several DMARDs have been evaluated with the step-down strategy. The classic stepdown therapeutic algorithm is illustrated by the COBRA (Combinatietherapie Bij Reumatoïde Artritis) trial conducted by Boers et al (17), who showed that low-dose MTX plus SSZ in combination with high-dose corticosteroids was superior to SSZ alone in reducing joint damage, despite similar reductions in symptoms and signs at the end point (i.e., after steroid withdrawal). Given the low dose of MTX used in the combination arm (7.5 mg/week), it is likely that the short-duration high-dose corticosteroids played the major role in improving both clinical and radiographic outcomes. In a review of combination therapy in RA, Verhoeven et al (13) also noted that, except for corticosteroids, there was no trend toward an overall beneficial effect of a particular drug in combination therapy. In other studies, step-down therapy cointervention with corticosteroids also appears to account for the efficacy of combination DMARD therapy (44 46). The utility of strategies using a combination of conventional DMARDs with glucocorticoids can also be seen in the BeSt (Behandelstrategieën voor reumatoide artritis) trial (47). This study demonstrated better efficacy, especially with regard to remission rates and radiographic progression, of a COBRA-type therapeutic approach over step-up and sequential therapy strategies. On the other hand, while there may have been a marginal numerical clinical superiority of the step-up approach compared with switching monotherapy, radiographic progression was virtually identical in the sequential monotherapy arm compared with the step-up combination therapy arm, supporting the notion that switching DMARDs may not be less effective than a DMARD step-up approach. Taken together, the studies suggest that the cointervention with corticosteroids likely accounts for the reported benefit of combination therapies. These data also suggest that glucocorticoids are an important addition to our therapeutic algorithm for achieving better efficacy with DMARD therapy. Glucocorticoids. As mentioned above, the addition of glucocorticoids to DMARDs appears to convey superior efficacy compared with DMARDs alone. Since glucocorticoids have rapid antiinflammatory effects (in addition to disease-modifying effects), these results may be similar to those of biologics combined with DMARDs. In fact, in the BeSt study, the combination of a biologic with MTX and the combination of a brief course of intermediate-dose glucocorticoids with MTX and SSZ (COBRA design) led to similar clinical and radiographic results (47). As discussed previously, other trials provide indirect evidence that the superiority of combination therapies over monotherapy may primarily rest upon differential use of glucocorticoids. Thus, further studies, especially trials comparing combinations of biologics plus MTX with a brief course of intermediatedose glucocorticoids plus MTX, are needed to fully appreciate the similarities or differences of these 2 treatment strategies. Combinations of DMARDs with biologic agents. In recent years, TNF inhibitors were evaluated using, for the most part, the step-up design in patients with active disease despite MTX therapy who received the TNF blocker or placebo (for review, see refs. 48 and 49). As mentioned above, although the results have uniformly demonstrated substantial benefit of the combination arm, the failure of most trials to include an arm with the biologic alone calls into question the utility of the combination. In a trial of infliximab in patients with active disease despite MTX therapy, in which MTX was partly withdrawn, there was a clear trend toward better efficacy of the combination compared with the biologic monotherapy, which was partly interpreted as being due to increased immunogenicity of the biologic in the absence of MTX (37). The effect of MTX in combination with monoclonal anti-tnf antibodies has been interpreted as a reduction in the immunogenicity of the monoclonal agent. The mechanism(s) by which MTX reduces the human antichimeric or anti-human antibody response remains to be more completely elucidated. However, the TEMPO (Trial of Etanercept and Methotrexate with Radiographic Patient Outcomes) study (see below), in which even the combination of etanercept with MTX was superior to etanercept alone, suggests that MTX may have other (or additional) effects beyond its effects on immunogenicity (50). Further data indicate that the combination of biologic agents with

7 EFFICACY OF COMBINATION THERAPY FOR RA 2981 DMARDs other than MTX may likewise increase efficacy (51). Most recently, several combination trials of MTX with a TNF antagonist have been examined in parallel 2-arm and 3-arm blinded studies (50,52,53). The results of the TEMPO study, using etanercept in patients with established RA who had previously received many DMARDs, and the PREMIER (Prospective, Multi- Centre, Randomized, Double-Blind, Active Comparator Controlled, Parallel-Groups Study Comparing the Fully Human Monoclonal Anti-TNF Antibody D2E7 Given Every Second Week with Methotrexate Given Weekly and the Combination of D2E7 and Methotrexate Administered Over 2 Years in Patients with Early Rheumatoid Arthritis) trial, using adalimumab in patients with early RA, have provided the strongest evidence for improved efficacy of combination therapy with MTX compared with either agent as monotherapy (50,52). Similar evidence has been provided by the ASPIRE (Active-Controlled Study of Patients Receiving Infliximab for the Treatment of Rheumatoid Arthritis of Early Onset) trial using infliximab (53). If one considers all studies of TNF blockers together, being aware that each agent has only been investigated in 1 trial, these studies, by virtue of their design, the number of patients studied, and the conformity of the results across the 3 different trials of different TNF blockers, constitute the best and only unequivocal results supporting a superiority of combination therapy over monotherapy (not including steroids). Conclusion The available data on the superiority of combinations of DMARDs are controversial. Numerous studies have failed to show any superiority of combination therapy with traditional, small-molecule DMARDs over monotherapy, especially in conjunction with the use of MTX. Nevertheless, a few studies support the concept that DMARD combinations may be superior. However, issues of study design impede the ability to draw unequivocal conclusions. There is much less controversy about the conclusion that the combination of a brief course of intermediate-dose glucocorticoids with DMARDs such as MTX (or MTX plus SSZ) is highly effective. However, glucocorticoids have mostly been added to combinations of traditional DMARDs rather than to the monotherapy control arm. Studies investigating whether DMARD monotherapy in combination with steroids is more effective than the DMARD alone are nonexistent. In any case, the strategy of tight control, with rapid switching of therapeutic regimens, in patients who have active disease despite receiving such regimens will lead to further improvements in therapeutic success (47,54,55). 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