Elsevier

The Lancet

Volume 353, Issue 9164, 8 May 1999, Pages 1568-1573
The Lancet

Articles
Comparison of combination therapy with single-drug therapy in early rheumatoid arthritis: a randomised trial

https://doi.org/10.1016/S0140-6736(98)08513-4Get rights and content

Summary

Background

The treatment of rheumatoid arthritis should aim at clinical remission. This multicentre, randomised trial with 2-year follow-up sought evidence on the efficacy and tolerability of combination therapy (sulphasalazine, methotrexate, hydroxychloroquine, and prednisolone) compared with treatment with a single disease-modifying antirheumatic drug, with or without prednisolone, in the treatment of early rheumatoid arthritis.

Methods

199 patients were randomly assigned to two treatment groups. 195 started the treatment (97 received combination and 98 single drug therapy). Single-drug therapy in all patients started with sulphasalazine; in 51 patients methotrexate was later substituted. Oral prednisolone was required by 63 patients. The primary outcome measure was induction of remission. Analyses were intention to treat.

Findings

87 patients in the combination group and 91 in the single-therapy group completed the trial. After a year, remission was achieved in 24 of 97 patients with combination therapy, and 11 of 98 with single-drug therapy (p=0·011). The remission frequencies at 2 years were 36 of 97 and 18 of 98 (p=0·003). Clinical improvement (American College of Rheumatology criteria of 50% clinical response) was achieved after 1 year in 68 (75%) patients with combination therapy, and in 56 (60%) using single-drug therapy (p=0·028), while at the 2-year visit 69 and 57 respectively (71% vs 58%, p=0·058) had clinically improved. The frequencies of adverse events were similar in both treatment groups.

Interpretation

Combination therapy was better and not more hazardous than single treatment in induction of remission in early rheumatoid arthritis. The combination strategy as an initial therapy seems to increase the efficacy of the treatment in at least a proportion of patients with early rheumatoid arthritis.

Introduction

Rheumatoid arthritis is a chronic inflammatory disease with varying course.1 Despite the best therapeutic efforts, in a great number of cases the disease shows a resistant course with progressive joint destruction and physical disability.2, 3, 4, 5, 6, 7

There is increasing evidence from randomised clinical trials and longitudinal observational studies that conventional single-drug therapy with disease-modifying antirheumatic drugs (DMARDs) and glucocorticoids can alter the clinical course of rheumatoid arthritis, but in most patients the benefits are insufficient.7, 8, 9, 10, 11, 12, 13, 14 Therefore, more powerful therapies are needed, such as the use of more than one DMARD simultaneously in the hope of additive efficacy.15 Most clinical trials using various combination therapies have not, however, shown increased efficacy.16, 17 In two short-term controlled clinical trials of patients with advanced disease, the combinaton of DMARDs seemed to improve the outcome for patients in comparison with single-drug treatment.18, 19 By contrast, in two randomised combination studies of patients with very early rheumatoid arthritis, neither a combination of high-dose prednisolone (for 28 weeks), methotrexate (for 40 weeks), and sulphasalazine, nor methotrexate with sulphasalazine, showed any benefit on disease activity over single-drug treatment at 1 year.20, 21

In our study we compared the efficacy and tolerability of a DMARD combination including sulphasalazine, methotrexate, hydroxychloroquine, and low-dose prednisolone with the same DMARDs as single treatment with or without oral prednisolone in patients with early, active rheumatoid arthritis. The primary aim of both the treatment regimens was the induction of remission. As other endpoints we used the number of patients achieving clinical improvement (American College of Rheumatology [ACR] criteria of 50% clinical response), and the extent of radiological joint damage.

Section snippets

Patients

Patients were recruited between April, 1993, and May, 1995. Inclusion requirements were: the criteria of the American Rheumatism Association for rheumatoid arthritis;22 age between 18 and 65 years; duration of symptoms of less than 2 years; active disease with three or more swollen joints and at least three of the following: erythrocyte sedimentation rate (ESR), at least 28 mm/h or C-reactive protein (CRP) concentration above 19 mg/L; morning stiffness of 29 min or more; more than five swollen

Results

The 199 eligible patients were randomised (figure 1). There were no substantial differences between the groups in baseline characteristics of patients (table 1).

87 (90%) combination-group and 91 (93%) single-treatment-group patients completed the treatment according to the protocol. No patient discontinued the study because of toxic effects of drugs, but one did so because of lack of efficacy (figure 1).

At the end of the study, 36 (37%) and 18 (18%), respectively, of the patients originally

Discussion

Most rheumatologists agree that DMARD treatment should be introduced early in the course of rheumatoid arthritis and that the ultimate target of treatment should be the induction of remission.27 More aggressive use of DMARDs, for example, in combination, should be favoured.19 Most previous studies have investigated this issue in patients with advanced disease. In one study of patients with early rheumatoid arthritis, the rapid clinical response and high remission rate disappeared after the

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