Sir Alfred Baring Garrod Clinical Trials Unit, Academic Department of Rheumatology, GKT School of Medicine, King's College London, UK
Correspondence to: E. Choy, Sir Alfred Baring Garrod Clinical Trials Unit, Academic Department of Rheumatology, 2nd Floor, Weston Education Centre, King's College London, Cutcombe Road, London SE5 9PJ, UK. E-mail: ernest.choy{at}kcl.ac.uk
Treatment for rheumatoid arthritis (RA) has changed considerably over the last 20 yr. Gone are the days when treatment was based on the pyramid approach. Instead, patients with RA are now started on disease-modifying anti-rheumatic drugs (DMARDs) once the diagnosis is established. Although DMARD monotherapy reduces inflammation, disease remission is uncommon. Consequently they do not arrest joint damage completely, although the rate of progression is reduced. In cross-sectional studies, the percentage of patients with RA in disease remission, as defined by the 1981 American Rheumatology Association preliminary criteria, is less than 10% [1]. In longitudinal studies, 3040% of patients experience remission some time during their disease but persistent remission is uncommon [2]. The limitations of DMARD monotherapy prompted the search for more effective treatment strategies.
Combining two or more DMARDs to treat patients with RA is not a new idea. The first report was published over 40 yr ago, in 1959 [3]. Subsequent case series suggested that disease remission was more common in patients treated with a combination of DMARDs. Despite these encouraging reports, combination therapy was not recommended for routine clinical practice in 1966 [4] because of concerns over toxicity. It was not until 1982 that Dan McCarty and his colleagues rekindled interest in this approach with a report of 17 patients with refractory RA successfully treated with a combination of azathioprine, cyclophosphamide and hydroxychloroquine [5]. In a subsequent study of 31 patients, remission was reported in 30% of those treated and in nine cases recortication of erosions was observed on radiographs [6]. Encouraged by these observations, many randomized control trials were undertaken to evaluate the effect of combination DMARDs in RA. The results of early studies were disappointing. Excessive toxicity and limited efficacy were the main problems. An early meta-analysis concluded that none of these combinations had a favourable efficacy/toxicity ratio [7]. The situation altered when positive results were published from randomized controlled trials of methotrexatecyclosporin [8] and methotrexatesulphasalazinehydroxychloroquine [9]. Subsequently, trials of steroidsmethotrexatesulphasalazine [10], steroidsmethotrexatesulphasalazinehydroxychloroquine [11], methotrexate plus tumour necrosis factor antagonists [1215], methotrexate plus anakinra [16] and methotrexate plus leflunomide [17] have shown that these combinations are superior to monotherapy. The success of these studies has led to a significant increase in the use of combination therapy in routine clinic practice, especially in patients who are partial responders to DMARD monotherapy.
The publication of the Trial of etanercept and methotrexate with radiological patient outcome (TEMPO) by Klareskog et al. [18] offers an opportunity to review combination therapy in RA. In this double-blind, double-dummy, randomized, placebo-controlled trial, 686 patients with active established RA were recruited. Their mean disease duration was 6 yr and the average number of previous DMARDs was 2.3. They were randomized to receive etanercept 25 mg subcutaneously twice a week, oral methotrexate, or a combination of the two for 52 weeks. All the patients were naive to tumour necrosis factor antagonists. At the end of the trial, improvement in disease activity was superior in the combination group when compared with either monotherapy group. The American College of Rheumatology (ACR) 20% response criterion was met in 85% of patients at the end of the trial compared with 75 and 76% in the methotrexate and etanercept monotherapy groups, respectively. The differences were statistically significant. Combination therapy was also more effective than monotherapy in slowing joint damage measured by mean change in the total Sharp score, which was 0.54 in those treated with combination therapy compared with 2.80 in the methotrexate group and 0.52 in the etanercept group. The proportion of patients who achieved remission as defined by a disease activity score of less than 1.6 was 35% in the combination group but only 13 and 16% in the methotrexate and etanercept groups respectively. In addition, 80% of patients in the combination group showed no significant progression of erosion vs 57 and 68% in the methotrexate and etanercept groups respectively. Differences in the percentage of patients who were in disease remission and progression of erosion were statistically significant. Infection and adverse events were similar in all the treatment groups.
Remarkably, the result of the TEMPO trial echoed what was first found by McCarthy et al. in 1982 [6]: disease remission was more common with combination therapy than with monotherapy, and healing of erosions may be tangible. Yet, in the TEMPO trial, toxicity was not a concern while it had been the Achilles heel in early studies of combination therapy. The immediate question arising from the TEMPO trial is whether disease remission is sustained. Many longitudinal studies in RA have shown that while many patients with RA meet the American Rheumatology Association remission criteria some time during their disease, sustained remission is uncommon. However, Molenaar et al. had shown that sustained disease remission is a necessity if joint damage is to be arrested [19]. In this study, the progress of 187 patients with RA who met the American Rheumatology Association remission criteria, with the exception of fatigue, was followed for 1 yr. Patients who experienced exacerbation in disease had significant progression of radiological joint damage, while patients who were in sustained remission did not. Hence, follow-up data on the disease activity status of those patients whose disease remitted in the TEMPO trial are keenly awaited.
Given the convincing efficacy and reassuring adverse event data in a large randomized control trial, the obvious conclusion to draw from the TEMPO trial is that methotrexate plus etanercept is superior to either drug as monotherapy in patients with established RA. Therefore, methotrexate should be coprescribed in all patients initiated on etanercept unless they are intolerant of methotrexate. Similarly, in methotrexate partial responders, etanercept should be added to methotrexate rather than substituted. Logically, methotrexate plus etanercept may be superior to monotherapy in early RA, but this requires confirmation by randomized control trials with evaluation of health economics.
The other interesting observation from the TEMPO trial was the lack of radiological progression in the combination therapy group. The mean change in modified Sharp score was negative, the upper limit of the 95% confidence interval being 0.07. This raises the intriguing possibility that erosion can heal, as was suggested by McCarthy et al. when they reported recortification of erosion [6]. Such an intriguing possibility will need to be confirmed by a long-term study demonstrating that radiological healing translates into meaningful clinical benefit. If so, defining the therapeutic window in which clinically meaningful healing of erosions can be achieved is essential, since healing may not be feasible if joint damage exceeds a certain level.
Perhaps one of most valuable pieces of information provided by the TEMPO trial is that, through its trial design, it has shown conclusively that methotrexate plus etanercept is superior to both methotrexate and etanercept monotherapy. Previously, trials of combination therapy in established RA, a step-up trial design is often used. In these studies, partial responders to methotrexate were recruited and randomized to receive either placebo or active treatment in addition to methotrexate. Pivotal trials of combination therapy including methotrexate plus cyclosporin [8], methotrexate plus etanercept [12], methotrexate plus infliximab [12, 14] and methotrexate plus adalimumab [15] all adopted this trial design. Indeed, both the ATTRACT [14] trial and the ARMADA [15] trial of methotrexate plus infliximab and methotrexate plus adalimumab showed impressive clinical and radiological improvement. The advantage of the step-up trial design is that it mirrors clinical practice but the disadvantage is that it does not provide conclusive evidence that adding a second agent is better than switching to a different agent.
One randomized control trial comparing adding with switching to etanercept in partial responders to sulphasalazine illustrates this limitation particularly well. In this study, 254 patients with RA, who were partial responders to sulphasalazine, were randomized to receive etanercept 25 mg twice weekly (with sulphasalazine discontinued at the trial baseline) or etanercept 25 mg twice per week plus sulphasalazine, or to continue with sulphasalazine alone [20]. At the end of this 24-week trial, the percentage of patients who met the ACR20 response criteria was 74% in the etanercept monotherapy and combination therapy groups. However, side-effects were less common in the etanercept-only group compared with the combination therapy group. Therefore, in sulphasalazine partial responders, switching sulphasalazine to etanercept rather than adding etanercept is more appropriate.
Contrasting the different conclusions drawn from the studies of sulphasalazine plus etanercept and the TEMPO trial raises an intriguing possibility. Perhaps the secret to the success of combination therapy in RA is methotrexate, seemingly the perfect partner to other DMARDs, including the tumour necrosis factor antagonists. This argument is support by the negative experience with combining anakinra and etanercept in patients with RA [21]. In a double-blind study, 244 patients with active RA who were naive to treatment with tumour necrosis factor antagonists or anakinra were randomized to treatment with etanercept 25 mg subcutaneously twice per week alone or anakinra 100 mg/day subcutaneously plus either etanercept 25 mg subcutaneously every week or twice per week. Forty-one per cent of patients treated in the etanercept-alone group achieved an ACR50 response compared with 31% of the patients treated with etanercept plus anakinra. However, serious infectious events occurred in 7% of patients in the combination therapy arm compared with none in the etanercept-alone group. Clearly, the combination of anakinra and etanercept provided no additional benefit for the treatment of RA compared with etanercept alone. But the combination was more toxic than etanercept monotherapy. The negative result of this study surprised many since such a combination was successful when tested in animal models of RA [22].
The results of this study, together with the study of sulphasalazine plus etanercept, serve as an important reminder to all than one cannot assume all combinations of DMARDs are more effective than monotherapy. Indeed, if studies involving methotrexate are excluded from the literature of combination therapy, there is insufficient evidence to justify the use of combination therapy in RA. So why is methotrexate so critical? The sad answer is that we do not know. When combination therapy was first advocated for the treatment of refractory RA, the rationale was based on the poor prognosis of RA, the failure of monotherapy to achieve an optimal therapeutic response in most patients and, pathologically, the similarity between proliferating rheumatoid pannus and an invasive malignant tumour. Our knowledge of the mode of action and immunological effect of DMARDs was limited and insufficient to inform the choice of DMARDs that should be used in combination. The widespread use of methotrexate in the combination DMARDs trial owes more to its popularity as a DMARD rather than to its mode of action. Recent research has suggested some plausible reasons why methotrexate may be such an important ingredient in combination therapy. First, there are convincing data to show that methotrexate reduces the development of neutralizing antibodies to TNF antagonists [23]. In a study in which infliximab was added to methotrexate in the treatment of partial responders to methotrexate, neutralizing antibodies were found in 21% of patients who received 3 mg/kg of infliximab monotherapy but only 7% of those who also received methotrexate. Although the effect of methotrexate in reducing neutralizing antibodies to infliximab is clear, this probably does not explain completely the benefit of combination therapy that was observed in the TEMPO, ATTRACT and ARMARDA trials. Secondly, recent data have shown that there is a pharmacokinetic interaction between cyclosporin and methotrexate, the former increasing the bioavailability of latter by 18% [24]. These studies provide important mechanistic rationales for combination therapy. Much more research on the interaction between second-line agents is needed to help in developing rational combination therapy in RA.
All this is good news for patients who can tolerate methotrexate. For those who cannot tolerate methotrexate, combination therapy has not been of significant benefit. Yet two studies have demonstrated that patients in whom methotrexate has failed have higher mortality and morbidity [25, 26]. The mortality of methotrexate failure patients is 16 times higher that of others [26]. For these patients, the need to find suitable combination DMARDs that are more effective than monotherapy is urgent. Practical trials, such as STAR (Safety Trial of Adalimumab in Rheumatoid Arthritis), in which 636 patients who were partial responders on various DMARDs are given either adalimumab 40 mg every other week or placebo for 24 weeks in addition, is an attempt to address this [27]. However, most of the patients in this study were taking methotrexate and 17% were not taking any DMARDs. Therefore the percentage of patients taking non-methotrexate DMARD monotherapy was small and therefore the trial lacks the necessary statistical power to allow definitive conclusions about specific combinations. A definitive answer can be provided only by large randomized controlled trials assessing the effectiveness and toxicity of combining non-methotrexate DMARDs and biological agents.
The author has served as a consultant on national and international advisory boards of Abbott, Schering Plough and Aventis. He has also received honoraria for speaking at meetings sponsored by Wyeth and Abbott. The Clinical Trials Unit has conducted research funded by Abbott Laboratories.
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