Elsevier

The Lancet

Volume 371, Issue 9613, 23–29 February 2008, Pages 660-667
The Lancet

Articles
Early combined immunosuppression or conventional management in patients with newly diagnosed Crohn's disease: an open randomised trial

https://doi.org/10.1016/S0140-6736(08)60304-9Get rights and content

Summary

Background

Most patients who have active Crohn's disease are treated initially with corticosteroids. Although this approach usually controls symptoms, many patients become resistant to or dependent on corticosteroids, and long exposure is associated with an increased risk of mortality. We aimed to compare the effectiveness of early use of combined immunosuppression with conventional management in patients with active Crohn's disease who had not previously received glucocorticoids, antimetabolites, or infliximab.

Methods

We did a 2-year open-label randomised trial at 18 centres in Belgium, Holland, and Germany between May, 2001, and January, 2004. We randomly assigned 133 patients to either early combined immunosuppression or conventional treatment. The 67 patients assigned to combined immunosuppression received three infusions of infliximab (5 mg/kg of bodyweight) at weeks 0, 2, and 6, with azathioprine. We gave additional treatment with infliximab and, if necessary, corticosteroids, to control disease activity. 66 patients assigned to conventional management received corticosteroids, followed, in sequence, by azathioprine and infliximab. The primary outcome measures were remission without corticosteroids and without bowel resection at weeks 26 and 52. Analysis was by modified intention to treat. This trial was registered with ClinicalTrials.gov, number NCT00554710.

Findings

Four patients (two in each group) did not receive treatment as per protocol. At week 26, 39 (60·0%) of 65 patients in the combined immunosuppression group were in remission without corticosteroids and without surgical resection, compared with 23 (35·9%) of 64 controls, for an absolute difference of 24·1% (95% CI 7·3–40·8, p=0·0062). Corresponding rates at week 52 were 40/65 (61·5%) and 27/64 (42·2%) (absolute difference 19·3%, 95% CI 2·4–36·3, p=0·0278). 20 of the 65 patients (30·8%) in the early combined immunosuppression group had serious adverse events, compared with 19 of 64 (25·3%) controls (p=1·0).

Interpretation

Combined immunosuppression was more effective than conventional management for induction of remission and reduction of corticosteroid use in patients who had been recently diagnosed with Crohn's disease. Initiation of more intensive treatment early in the course of the disease could result in better outcomes.

Introduction

Crohn's disease is a chronic inflammatory disorder of the gastrointestinal tract. Current practice guidelines recommend that most patients with active disease should be treated initially with corticosteroids.1, 2 Although this approach is usually effective for control of symptoms, many patients become resistant to, or dependent on, these drugs.3 Long exposure to corticosteroids is also associated with the complications of Cushing's syndrome, and therefore with an increased risk of mortality.1, 2, 4, 5, 6 For this reason, most clinicians initiate treatment with corticosteroid-sparing drugs such as azathioprine, mercaptopurine, or methotrexate once corticosteroid-resistance or dependence develops, but initiation of these immunosuppressive drugs earlier in the course of the disease is not recommended.7, 8, 9, 10 However, since these antimetabolites are only moderately effective,1, 7, 10, 11, 12 repeated or long courses of corticosteroids are frequently given.

Treatment directed towards tumour-necrosis factor (TNF) has improved the management of refractory Crohn's disease.13, 14, 15 TNF antagonists, such as infliximab, are conventionally reserved for patients who have failed, in sequence, both corticosteroids and antimetabolites. In rheumatoid arthritis, however, which has many pathophysiological similarities to Crohn's disease, the early introduction of TNF antagonists in combination with methotrexate has been shown to treat early disease better than does monotherapy with either agent.16, 17, 18

Moreover, one randomised controlled trial has suggested that the combination of azathioprine and infliximab in corticosteroid-dependent Crohn's disease was more effective than azathioprine alone.19 On the basis of these observations, we did a randomised trial of early combined immunosuppression in patients with recently diagnosed Crohn's disease. We aimed to investigate the effectiveness of short-term infliximab combined with azathioprine or 6-mercaptopurine in patients with active Crohn's disease who were receiving induction therapy with corticosteroids.

Section snippets

Study design and participants

We did an investigator-initiated trial at 18 centres in Belgium, Holland, and Germany between May, 2001, and January, 2004. The investigational review board at each of these centres approved the protocol. All patients gave written informed consent before random assignment.

We defined eligible patients as those who were aged 16–75 years; who had been diagnosed with Crohn's disease within the past 4 years; and who had not previously received corticosteroids, antimetabolites, or biological agents.

Results

Figure 1 shows the trial profile. Of the 133 patients who were randomly assigned, four did not receive treatment as per protocol. One patient in the early combined intervention group had a gastric carcinoma, and one in the conventional management group had ulcerative colitis. One patient in each group was not willing to accept the treatment to which they had been assigned. 65 patients had combined immunosuppression and 64 had conventional management. Baseline characteristics of the two groups

Discussion

Treatment algorithms in early Crohn's disease and their effect on long-term outcomes have not been studied in randomised trials. We have shown that in patients with Crohn's disease who had not previously received corticosteroids, antimetabolites, or biologicals, use of early combined immunosuppression resulted in remission more quickly than did treatment according to existing consensus guidelines.25, 26, 27, 28 Although conventional guidelines support the use of corticosteroids as first-line

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