Elsevier

The Lancet

Volume 374, Issue 9688, 8–14 August 2009, Pages 459-466
The Lancet

Articles
Addition of infliximab compared with addition of sulfasalazine and hydroxychloroquine to methotrexate in patients with early rheumatoid arthritis (Swefot trial): 1-year results of a randomised trial

https://doi.org/10.1016/S0140-6736(09)60944-2Get rights and content

Summary

Background

New treatment strategies for early rheumatoid arthritis are evolving rapidly. We aimed to compare addition of conventional disease-modifying antirheumatic drugs (sulfasalazine and hydroxychloroquine) with addition of a tumour necrosis factor antagonist (infliximab) to methotrexate in patients with early rheumatoid arthritis.

Methods

We undertook a randomised trial in 15 rheumatology units in Sweden. We enrolled patients with early rheumatoid arthritis (symptom duration <1 year) and administered methotrexate (up to 20 mg per week). After 3–4 months, those who had not achieved low disease activity but who could tolerate methotrexate were randomly allocated by computer addition of either sulfasalazine and hydroxychloroquine or infliximab. Primary outcome was achievement of a good response according to European League Against Rheumatism (EULAR) criteria at 12 months. Patients were followed up to 24 months; here, we present findings at 12 months. Analysis was by intention to treat and we used non-responder imputation. The Swefot (Swedish Pharmacotherapy) study is registered in the WHO database at the Karolinska University Hospital, number CT20080004.

Findings

487 patients were initially enrolled. Of 258 who had not achieved low disease activity with methotrexate, 130 were allocated sulfasalazine and hydroxychloroquine and 128 were assigned infliximab. 32 of 130 (25%) patients allocated sulfasalazine and hydroxychloroquine achieved the primary outcome compared with 50 of 128 (39%) assigned infliximab (risk ratio 1·59 [95% CI 1·10–2·30], p=0·0160). Adverse events were balanced fairly well between the two groups and accorded with known adverse events of the drugs used. No deaths occurred in either group.

Interpretation

In patients with early rheumatoid arthritis in whom methotrexate treatment failed, addition of a tumour necrosis factor antagonist to methotrexate monotherapy is clinically superior to addition of conventional disease-modifying antirheumatic drugs.

Funding

Swedish Rheumatism Association, Schering-Plough.

Introduction

New treatment options have resulted in remarkable changes in the therapeutic approach to newly diagnosed rheumatoid arthritis. Specifically, findings of randomised clinical trials show that the tumour necrosis factor antagonists adalimumab,1 etanercept,2 and infliximab,3 given in combination with methotrexate, provide superior results compared with methotrexate alone. However, data of these three trials also indicate that a sizeable subset of patients (20–40%) have a good clinical response to methotrexate monotherapy. Some researchers have suggested that this subgroup could be identified prospectively with specific baseline characteristics.4 However, in practice, doctors could opt to treat patients with methotrexate monotherapy for a short period, thus enabling them to identify individuals who do not need an intensive therapeutic strategy while not losing too much ground with those who do.

For patients who have an incomplete or no response to methotrexate, will addition of an antagonist to tumour necrosis factor, which is more effective than placebo,5, 6, 7 be superior to addition of conventional disease-modifying antirheumatic drugs? Data show combinations of methotrexate with sulfasalazine and hydroxychloroquine8, 9 and with ciclosporin A10 are better than methotrexate alone. We designed the Swedish Pharmacotherapy (Swefot) study—an investigator-initiated, multicentre, randomised, active-controlled, clinical trial—with the aim to assess two aggressive treatment options in patients with early rheumatoid arthritis who did not respond well to methotrexate monotherapy after 3–4 months. We compared addition of sulfasalazine and hydroxychloroquine with addition of the tumour necrosis factor antagonist infliximab. Here, we report 1-year clinical results.

Section snippets

Patients

15 rheumatology units in Sweden collaborated in this trial. We invited adults (age ≥18 years) diagnosed with rheumatoid arthritis and with symptom duration of less than 1 year to participate in the trial. Key inclusion criteria were: rheumatoid arthritis diagnosed according to revised American College of Rheumatology (ACR) criteria; no previous treatment with disease-modifying antirheumatic drugs; either no oral glucocorticoid or stable glucocorticoid therapy for at least 4 weeks of, at most,

Results

Between October, 2002, and December, 2005, a total of 493 patients were screened for inclusion in the Swefot trial. Figure 2 shows how participants progressed through the trial. Six patients failed screening mostly because of abnormal liver function tests. Of the 487 people who received methotrexate monotherapy, 229 did not undergo random allocation after 3–4 months. Of these, 145 had responded well to methotrexate monotherapy, 27 were intolerant to methotrexate, nine developed another illness

Discussion

1-year findings of the Swefot study show that for patients who do not respond sufficiently to methotrexate monotherapy, addition of a tumour necrosis factor antagonist (eg, infliximab) is superior to addition of conventional disease-modifying antirheumatic drugs (eg, sulfasalazine and hydroxychloroquine), with respect to achievement of a good response according to EULAR criteria. This finding was robust statistically and because the primary outcome was supported by most secondary clinical

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