Management of Recent Onset Crohn’s Disease: A Controlled, Randomized Trial Comparing Step-up and Top-down Therapy

Abstract

Introduction: Current management of moderate/severe CD patients failing 5-ASA consists of glucocorticosteroids (GCS), resulting in a 1-year remission rate of 26%, steroid dependency, and significant toxicity. This study examined whether more aggressive induction therapy with infliximab (IFX) and azathioprine (AZA) would lead to higher remission rates, lower toxicity, and superior mucosal healing. Methods: One hundred thirty CD patients with a CDAI > 220, diagnosed within 4 years and never treated with GCS/immunomodulators/IFX, were randomized to receive either (1) top-down (TD) treatment with 3 infusions of IFX (at week 0, 2, and 6) and AZA 2 to 2.5 mg/kg per day or (2) step-up (SU) treatment with topical (budesonide 9 mg/day) or systemic (prednisone 40 mg/day) GCS, to be repeated as clinically necessary. In the TD group, relapsing patients were given repeated IFX and GCS when they failed to respond to IFX. In the SU group, AZA was added in case of repeated need for GCS or dependency and IFX was given only after failure of immunosuppression. The primary endpoints were remission (CDAI <150, no GCS) at month 6 and 12. Secondary endpoints included mean CDAI scores, mucosal healing 2 years after randomization and safety. Results: Baseline patient characteristics were similar in both groups (mean CDAI 331 TD [n = 65] vs 306 SU [n = 65]). Remission was attained in 74.5% (TD) vs 48.1% (SU) (P = .006) at 6 months and in 76.9% (TD) vs 63.8 % (SU) at 12 months (P = .15). At 6 months, 32.7% of SU patients were still receiving GCS (median dose 26 mg/day) compared with 0% for the TD group. At 12 months, 18.8% of SU patients remained on GCS (median dose 24 mg) compared with 0% in the TD group (P < .001). At 6 and 12 months 86.8% and 94.2% of patients were using immunomodulators in the TD group, compared with 40.4% and 62.5% in the SU group (P < .001). Ten of 65 (15 %) SU patients needed IFX to induce remission whereas 25/65 (38%) of patients in the TD group needed repeat IFX. Fistulas developed in 2/45 SU patients and no patients in TD. Endoscopic healing was significantly more pronounced in TD patients than in SU patients (at 2 years, ulcers were absent in 15/20 TD patients versus 3/14 SU patients, P = .002). The occurrence of serious adverse events was comparable in both groups. Conclusion: Induction therapy with IFX + AZA is superior to sequential SU therapy for reducing exposure to GCS. One third of patients treated with GCS induction therapy still require GCS at month 6, and 18.8% at 12 months. Using the TD induction strategy, long-lasting remission was achieved in 77% of patients without GCS. Our results strongly suggest that GCS therapy is not necessary for induction of remission in moderate to severely active CD.