February 26, 2008 — Combined immunosuppression was more effective than conventional management for induction of remission and reduction of corticosteroid use in patients newly diagnosed with Crohn's disease, according to the results of a 2-year, open-label, randomized trial reported in the February 23 issue of The Lancet.

"Most patients who have active Crohn's disease are treated initially with corticosteroids," write Geert D'Haens, MD, PhD, from the Imelda Gastrointestinal Clinical Research Centre in Bonheiden, Belgium, and colleagues from the Belgian Inflammatory Bowel Disease Research Group and the North-Holland Gut Club. "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."

At 18 centers in Belgium, Holland, and Germany between May 2001 and January 2004, a total of 133 patients were randomized to receive either early combined immunosuppression (n = 67) or conventional treatment (n = 66). In the combined immunosuppression group, patients received 3 infusions of infliximab (Remicade; Centocor) in doses of 5 mg/kg of body weight at weeks 0, 2, and 6, with azathioprine. For control of disease activity, patients received additional treatment with infliximab and corticosteroids if needed.

In the conventional management group, patients received corticosteroids, followed, in sequence, by azathioprine and infliximab. The main endpoints were remission without corticosteroid use and without bowel resection at weeks 26 and 52. Analysis was by modified intent-to-treat; 4 patients (2 in each group) did not receive assigned treatment as per protocol.

Remission without corticosteroids and without surgical resection at week 26 occurred in 39 (60.0%) of 65 patients in the combined immunosuppression group and in 23 (35.9%) of 64 patients in the control group (absolute difference, 24.1%; 95% confidence interval [CI], 7.3 - 40.8; P = .0062). At week 52, the corresponding rates were 40 (61.5%) of 65 patients and 27 (42.2%) of 64 patients (absolute difference, 19.3%; 95% CI, 2.4 - 36.3; P =.0278).

Serious adverse events occurred in 20 (30.8%) of the 65 patients in the early combined immunosuppression group vs 19 (25.3%) of 64 patients in the control group (P = 1.0).

"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," the study authors write. "Initiation of more intensive treatment early in the course of the disease could result in better outcomes."

Limitations of the study included lack of blinding to treatment assignment. Although remission was faster for patients in the early combined immunosuppression group vs the conventional treatment group, simultaneous initiation of antimetabolites and corticosteroids could potentially have produced similar results.

Some of the study authors have disclosed various financial relationships with Centocor (maker of infliximab [Remicade] used in the study), Schering Plough, UCB, AstraZeneca (maker of budesonide [Entocort], a corticosteroid used in the study), Ferring, Shire, Essex-Germany, Abbott, Boston Scientific, AGA, the Initiative on Crohn's and Colitis, Independent Dutch Academic Non-profit Organisation for IBD Research, Altana, Roche, Novartis Fund for Scientific Research Flanders, Special Research Fund University Ghent, Tillotts, Elan, Tramedico, ISIS, Elan, Synta, Millennium, Celltech, Elan/Biogen, Berlex, Ortho-Biotech, Protein Design Labs, Santarus, Celgene, Napo Pharma, BMS, Otsuka, Proctor and Gamble, GeneLogic, Cerimon Pharmaceuticals, Tioga Pharmaceuticals, Serono, Teva, Genentech, and CombinatoRx.

In an accompanying editorial, William J. Sandborn, MD, from the Mayo Clinic in Rochester, Minnesota, notes that this trial may have underestimated the benefit of combination therapy and that the findings are insufficient to change clinical practice.

"A definitive trial should compare azathioprine, a tumour necrosis-factor antagonist such as infliximab, and the combination of the two, continued for at least 1 year in enough patients to assess safety, typical clinical endpoints (eg, clinical response and remission, and steroid sparing), endoscopic healing, and hospitalisation and surgery rates," Dr. Sandborn writes. "If the preliminary data on initial combination therapy in early Crohn's disease reported by D'Haens and colleagues are confirmed, the treatment algorithm for patients with Crohn's disease will change."

Dr. Sandborn has disclosed various financial relationships with many relevant manufacturers, and he is co-principal investigator of the Study of Biologic and Immunomodulator Naive Patients in Crohn's Disease trial sponsored by Centocor and Schering Plough.

Lancet. 2008;371:635-636, 660-667.

Clinical Context

Study Highlights

• In this 2-year, open-label, multicenter, randomized trial, 133 patients were assigned to receive either early combined immunosuppression or conventional treatment between May 2001 and January 2004.
• Eligible patients were those aged 16 to 75 years who had been diagnosed with Crohn's disease within the past 4 years and who had not previously received corticosteroids, antimetabolites, or biologic agents.
• The 67 patients assigned to combined immunosuppression received 3 infusions of infliximab (5 mg/kg of body weight) at weeks 0, 2, and 6, with azathioprine. Additional treatment with infliximab and, if necessary, corticosteroids, were given to control disease activity.
• 66 patients assigned to conventional management received corticosteroids, followed, in sequence, by azathioprine and infliximab to control disease activity.
• The primary outcome measures were a Crohn's disease activity index (CDAI) score of less than 150 points and remission without corticosteroids and without bowel resection at weeks 26 and 52. Analysis was by modified intent-to-treat.
• 4 patients (2 in each group) did not receive treatment as per protocol.
• Baseline characteristics of the 2 groups were similar, although patients assigned to conventional treatment had better quality-of-life scores.
• By week 14, a greater proportion of patients in the combined immunosuppression group were in remission vs patients given conventional treatment (P = .0001).
• At week 26, 39 (60.0%) of 65 patients in the combined immunosuppression group were in remission without corticosteroids and without surgical resection vs 23 (35.9%) of 64 patients in the control group for an absolute difference of 24.1% (95% CI, 7.3 - 40.8;
  P = .0062).
• Corresponding rates at week 52 were 40 (61.5%) of 65 patients and 27 (42.2%) of 64 patients (absolute difference, 19.3%; 95% CI, 2.4 - 36.3; P = .0278).
• After week 52, the proportion of patients in remission did not differ between the 2 groups.
• The median time to relapse after successful induction therapy at week 14 was longer for patients assigned to early immunosuppression vs patients in the control group (329.0 vs 174.5 days; P = .031).
• At week 10, patients assigned to combined immunosuppression showed a more rapid drop in CDAI scores; however, after week 10, mean scores in both groups were similar and consistently less than 150 points.
• 20 (30.8%) of the 65 patients in the early combined immunosuppression group had serious adverse events vs 19 (25.3%) of 64 patients in the control group (P = 1.0).
• Limitations to this study were that investigators and patients were aware of the treatment assignment, which could have biased their assessment of its efficacy, and simultaneous initiation of antimetabolites and corticosteroids could potentially have produced similar remission rates between the 2 groups.

Pearls for Practice

• Conventional guidelines supports the use of corticosteroids as first-line treatment for no longer than 6 months. Initiation of treatment with corticosteroid-sparing drugs such as azathioprine, mercaptopurine, or methotrexate is considered once patients become resistant to or dependent on corticosteroids.
• 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.

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