Elsevier

The Lancet

Volume 379, Issue 9827, 5–11 May 2012, Pages 1712-1720
The Lancet

Articles
Conventional combination treatment versus biological treatment in methotrexate-refractory early rheumatoid arthritis: 2 year follow-up of the randomised, non-blinded, parallel-group Swefot trial

https://doi.org/10.1016/S0140-6736(12)60027-0Get rights and content

Summary

Background

Analysis of the Swedish Farmacotherapy (Swefot) trial at 12 months showed that the addition of an anti-tumour-necrosis-factor agent gave an improved clinical outcome compared with the addition of conventional disease-modifying antirheumatic drugs in patients with methotrexate-refractory early rheumatoid arthritis. Here we report the 2 year follow-up assessment.

Methods

In this randomised, non-blinded, parallel-group trial, we enrolled adult patients older than 18 years with rheumatoid arthritis and a symptom duration of less than 1 year from 15 rheumatology units in Sweden between December, 2002 and December, 2006. All patients were started on methotrexate. After 3–4 months, those who failed treatment were randomly assigned (1:1) to group A (conventional treatment; additional sulfasalazine and hydroxychloroquine) or group B (biological treatment; additional infliximab). Randomisation was done with a computer-generated sequence. We analysed clinical outcomes at months 18 and 24 by the response criteria of the American College of Rheumatology and the European League Against Rheumatism, and radiographs of patients' hands and feet at months 12 and 24 using the Van der Heijde modification of the Sharp score. Analysis was by intention to treat. This trial is registered with www.ClinicalTrials.gov, number NCT00764725.

Findings

Of 493 screened individuals, we enrolled 487, of whom 258 were randomly allocated to treatment. The proportion of patients in group B who received a EULAR-defined good response was non-significantly greater than it was in group A at 18 months (49 of 128 [38%] vs 38 of 130 [29%]) and at 24 months (49 of 128 [38%] vs 40 of 130 [31%]; p=0·204). After 24 months, radiological disease progression was greater in patients in group A than it was in those in group B (mean 7·23 [SD 12·72] vs 4·00 [10·0]; p=0·009). We recorded three serious adverse events: an extended generalised illness in group A, an extended febrile episode in group B, and a generalised illness in group B.

Interpretation

Additional biological treatment is a valid option for patients who fail initial methotrexate treatment. However, improved clinical outcomes after 12 months and better radiographical results after 24 months should be weighed against the absence of a convincing clinical difference at 24 months and substantially higher costs. Therefore, for many patients who fail initial methotrexate treatment, add-on treatment with disease-modifying antirheumatic drugs is an appropriate treatment option.

Funding

Swedish Rheumatism Association, Stockholm County, and Schering-Plough/Merck Sharp and Dohme.

Introduction

New treatment options and a focus on the achievement of the best possible control of disease have resulted in substantial changes in the approach to the treatment of newly diagnosed rheumatoid arthritis. Specifically, randomised clinical trials have shown that tumour necrosis factor (TNF)-antagonists1, 2, 3 with methotrexate give better results than does methotrexate alone. However, these trials also showed that a subset of patients (20–40%) have an excellent clinical response to methotrexate monotherapy. Because even the best model based on baseline characteristics provides only restricted predictability of a good response to methotrexate,4 physicians can opt to treat with methotrexate monotherapy for a given period to identify patients who do not need more intensive treatment, retaining the ability to switch those that do to a more appropriate treatment. For patients who have an incomplete response or no response to methotrexate, an important question is whether the addition to methotrexate of an anti-TNF agent, which is better than placebo,5, 6, 7 is also better than the addition of conventional disease-modifying antirheumatic drugs (DMARDs) in clinical or radiological outcomes. The combination of methotrexate with sulfasalazine plus hydroxychloroquine has well-established benefits compared with methotrexate monotherapy,8, 9 as does the combination of methotrexate plus cyclosporin A.10 Therefore, the Swedish Farmacotherapy (Swefot) trial, an investigator-initiated, multicentre, randomised, active-controlled clinical trial compared the addition of an anti-TNF agent versus the addition of sulfasalazine plus hydroxychloroquine in patients who failed initial methotrexate.

We previously reported the primary clinical outcome of the trial, a comparison between the proportions of patients in each group who had achieved the European League Against Rheumatism (EULAR) good response11 after 1 year.12 In that analysis, the addition of an anti-TNF agent was better than the addition of conventional DMARDs. However, this finding does not completely answer the main therapeutic questions for two reasons. First, the clinical response to conventional DMARDs occurs slowly, but with more than 1 year of follow-up the treatment effect of DMARDs might be similar to that of biological treatments. Second, treatments for rheumatoid arthritis should not only control the clinical disease activity, but also prevent the progression of structural damage to the joints, which can be assessed radiologically. These two considerations made analysis of both the longer-term clinical and the radiological results with these two treatment strategies crucial, and were the specific objectives of this study. Thus, here we report the 2-year clinical and radiological results of the Swefot randomised clinical trial in early rheumatoid arthritis.

Section snippets

Participants and study design

We did a randomised, non-blinded, parallel-group trial. 15 rheumatology units in Sweden collaborated in this trial. Recruitment began in December, 2002 and was completed in December, 2006. Adult patients older than 18 years diagnosed with rheumatoid arthritis and with a symptom duration of less than 1 year were invited to participate in the trial.

Key inclusion criteria were as follows: rheumatoid arthritis according to the revised American College of Rheumatology (ACR) (formerly American

Results

We screened 493 patients and enrolled 487, of whom 258 were randomly allocated to treatment (figure 1). Patients' baseline characteristics were much the same between the two groups (table 1). Most patients completed the 2 year follow-up, but more patients withdrew because of a lack of efficacy in group A than they did in group B (figure 1). A larger proportion of patients in group B stayed on treatment as per protocol compared with group A, and the difference was explained mostly by those

Discussion

In patients with early rheumatoid arthritis who do not respond to methotrexate, the addition of infliximab provided clinical improvements compared with the addition of sulfasalazine and hydroxychloroquine at 12 months. However, we recoded no difference in clinical efficacy after 18 months or 24 months. The biological treatment gave better radiological outcomes compared with the conventional alternative through 24 months.

We believe that our descision to include patients only after they had

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