Top-down infliximab superior to step-up in children with Moderate-to-Severe Crohn's disease: A multicentre randomised controlled trial

Abstract Background In newly diagnosed paediatric Crohn’s disease (CD) patients current guidelines instruct to start exclusive enteral nutrition (EEN) or oral prednisolone in combination with immunomodulators to achieve remission. Infliximab (IFX) is proven to be highly effective in paediatric CD patients, but mostly used once patients are refractory, the so-called step-up (SU) treatment strategy. However, evidence is emerging IFX is more effective if initiated earlier in the disease course. We investigated whether initiation of IFX directly after diagnosis of moderate-to-severe CD, i.e. top-down (TD) treatment, results in a higher long-term remission rate compared with SU treatment. Methods For this international randomised controlled trial (RCT) patients aged 3–17 years, with new-onset, untreated CD with weighted paediatric CD activity index (wPCDAI) >40 were included. TD treatment consisted of 5 IFX (CT-P13) infusions of 5 mg/kg (0, 2, 6, 14, 22 weeks) combined with azathioprine (AZA). After 5 infusions, IFX was stopped while continuing AZA. SU treatment consisted of induction therapy with EEN or oral prednisolone combined with AZA as a maintenance treatment. In both groups, IFX could be (re)started on predefined conditions. The primary endpoint of this study was sustained clinical remission (wPCDAI <12.5) at week 52 without the need for additional therapy or surgery. Secondary endpoints included patient rate using IFX at week 52, mucosal healing (SES-CD <3) and low faecal calprotectin levels (<250 μg/g) at week 10. Results 100 patients were included in 12 centres. Three out of 100 patients did not start with the study after randomisation (n = 97; 49 TD vs. 48 SU). At 52 weeks, 21/48 (44%) of TD patients were in clinical remission without a need for treatment intensification or surgery, while in the SU group this number was significantly lower (8/48, p = 0.004). After induction therapy, IFX was (re)started in 19/49 (39%) TD patients compared with 30/48 (62%) SU patients within 52 weeks (p = 0.019). At week 10, significantly more TD (27/44, 61%) than SU treated patients (17/44, 39%) were in clinical remission (p = 0.033). Fifty-seven of 97 consented to endoscopy at week 10. Endoscopic remission rates were higher in TD (16/27 [59%], median SES-CD 1 [IQR 0–5]) than SU treated patients (5/30 [17%], median SES-CD 6 [IQR 3–16], p = 0.001). Similarly, low faecal calprotectin levels were more frequent in the TD group (n = 75; TD 21/40 [53%] vs. SU 9/35 [26%], p = 0.027). Conclusion We are the first to compare TD IFX to SU treatment in an RCT of paediatric CD patients. TD treatment was superior to SU in achieving sustained clinical remission. Therefore, we advise to start IFX directly after diagnosis in moderate-to-severe paediatric Crohn’s disease patients.