Elsevier

The Lancet

Volume 350, Issue 9074, 2 August 1997, Pages 309-318
The Lancet

Articles
Randomised comparison of combined step-down prednisolone, methotrexate and sulphasalazine with sulphasalazine alone in early rheumatoid arthritis

https://doi.org/10.1016/S0140-6736(97)01300-7Get rights and content

Summary

Background

The value of intensive combination therapy in early rheumatoid arthritis is unproven. In a multicentre, double-blind, randomised trial (COBRA), we compared the combination of sulphasalazine (2 g/day), methotrexate (7·5 mg/week), and prednisolone (initially 60 mg/day, tapered in 6 weekly steps to 7·5 mg/day) with sulphasalazine alone.

Methods

155 patients with early rheumatoid arthritis (median duration 4 months) were randomly assigned combined treatment (76) or sulphasalazine alone (79). Prednisolone and methotrexate were tapered and stopped after 28 and 40 weeks, respectively. The main outcomes were the pooled index (a weighted change score of five disease activity measures) and the Sharp/Van der Heijde radiographic damage score in hands and feet. Independent health-care professionals assessed the main outcomes without knowledge of treatment allocation.

Findings

At week 28, the mean pooled index was 1–4 (95% CI 1·2–1·6) in the combined treatment group and 0·8 (0·6–1·0) in the sulphasalazine group (p<0·0001). At this time, 55 (72%) and 39 (49%) patients, respectively, were improved according to American College of Rheumatology criteria. The clinical difference between the groups decreased and was no longer significant after prednisolone was stopped, and there were no further changes after methotrexate was stopped. At 28 weeks, the radiographic damage score had increased by a median of 1 (range 0–28) in the combined-therapy group and 4 (0–44) in the sulphasalazine group (p<0·0001). The increases at week 56 (2 [0–43] vs6 [0–54], p=0·004), and at week 80 (4 [0–80] vs 12 [0–72], p=0·01) were also significant. Further analysis suggests that combined therapy immediately suppressed damage progression, whereas sulphasalazine did so less effectively and with a lag of 6 to 12 months. There were fewer withdrawals in the combined therapy than the sulphasalazine group (6 [8%] vs 23 [29%]), and they occurred later.

Interpretation

This combined-therapy regimen offers additional disease control over and above that of sulphasalazine alone that persists for up to a year after corticosteroids are stopped. Although confirmatory studies and long-term follow-up are needed, this approach may prove useful in the treatment of early rheumatoid arthritis.

Introduction

The treatment of rheumatoid arthritis is traditionally characterised by escalation. The first step is non-steroidal anti-inflammatory drugs (NSAIDs), and then if necessary a sequence of progressively toxic second-line drugs (disease-modifying antirheumatic drugs) is introduced.1 There is evidence that some of these disease-modifying drugs provide a degree of disease control2 -ie, decrease disease activity but also maintain or improve physical function and retard radiographic joint damag3 However, both patients and physicians are dissatisfied with the long-term results of traditional therapy. A 1996 study suggested that early introduction of disease-modifying antirheumatic drugs may be more beneficial than delayed introduction for patients with recently diagnosed rheumatoid arthritis.4 Research is focused towards finding new, more effective drugs, reassessment and earlier use of existing drugs (such as corticosteroids5), and treatment with drug combinations.6

The COBRA trial (Combinatietherapie Bij Reumatoide Artritis) is an adaptation of the latter two optionsstep-down bridge therapy with corticosteroids in early rheumatoid arthritis.1 Our intention was to control disease rapidly at a very early stage, with agents that have overlapping windows of efficacy onset; and then, after 6 months to taper and stop the more toxic components while retaining disease control. We devised a regimen comprising a short period of high-dose oral prednisolone, rapidly tapered to a low maintenance dose. As the other components we chose methotrexate, commonly used as the disease-modifying drug of first choice in the USA, and sulphasalazine as the anchor drug to remain after the other two drugs were withdrawn. In Europe, sulphasalazine is commonly used as the disease-modifying drug of first choice.

We carried out a 56-week multicentre, randomised controlled trial among patients with early, active rheumatoid arthritis to study the degree of disease control afforded by a combination of sulphasalazine, methotrexate, and high/low oral prednisolone given in the first 28 weeks, compared with that achieved with sulphasalazine alone; and to find out whether control could be maintained on sulphasalazine alone, after sequential tapering and withdrawal of prednisolone and methotrexate in the second 28 weeks.

Section snippets

Patients

We recruited patients between May, 1993, and May, 1995, in ten centres (nine in the Netherlands, one in Belgium). To optimise the benefit/risk ratio in line with the study purpose, we applied strict eligibility criteria to include patients with early rheumatoid arthritis who had very active disease and were most likely to benefit from this intensive treatment, in whom effects could be easily measured, and in whom we believed adverse effects would be least likely. The inclusion criteria were: a

Results

The trial included 156 patients (figure 1). In one patient the protocol medication was stopped within 1 week because his disease was in spontaneous remission at baseline. Data for this patient are not reported. 76 patients received combination treatment, 79 sulphasalazine only. Five patients (3%, all in the sulphasalazine group) were lost to follow-up before week 56. In six patients (all withdrawn) the treatment assignment had to be revealed before week 56 for medical reasons.

The two treatment

Discussion

The combination of an extended oral pulse or corticosteroids, methotrexate, and sulphasalazine led to an immediate, substantial, and highly significant improvement of disease activity and physical function in most patients with severe, early rheumatoid arthritis. On a low daily maintenance dose of 7–5 mg prednisolone from week 7 onwards, this improvement continued ata slower pace up to week 28, and was almost double that of conventional treatment with sulphasalazine alone in all clinical

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