Maarten Cozijnsen

56 of patients responded to infliximab after 10 weeks of therapy, of whom the majority achieved and maintained remission on IFX throughout week 54. Subsequent research showed that IFX efficacy can be improved through individualized dose optimization to ensure therapeutic levels and by combination therapy with AZA or MTX to avoid immunogenicity. (11-14) Notably, IFX was also demonstrated to be more effective the sooner it is initiated after diagnosis. Three retrospective trials, assessing the efficacy of IFX, demonstrated that patients receiving IFX ‘ early’ after diagnose (either directly after diagnosis or less than 1 or 2 years afterwards) had longer remission duration and increased fistula closing rates than those receiving IFX ‘ late’ .(15-17) Postponing IFX could thus reduce its efficacy. IFX has also shown to induce mucosal healing in a large proportion of patients: In the ACCENT 1 trial in adult CD patients, 31% (10/32) of the patients receiving IFX maintenance treatment had mucosal healing (absence of ulcers) at week 10 and 50% (13/26) had mucosal healing at week 54 – a post-hoc analysis of week 2 IFX responders who had mucosal ulcerations at baseline.(18) Giving IFX early as part of the top-down strategy may thus optimize IFX efficacy and may offer a good chance for restoration of the gut’s mucosa, which in turn can reduce risks of disease relapse, hospitalization and need for surgery. Evidence on the efficacy of top-down treatment as compared to step-up treatment is however limited. Currently, two prospective trials compared both strategies in adult CD patients. In the first trial(19), 133 adult CD patients were randomized to start with either step- up treatment (steroids only) or top-down therapy (three IFX infusions and AZA maintenance therapy). Top-down therapy resulted in higher remission rates (week 26: 39/65 [60%] vs 23/64 [36%]; week 52: 40/65 [62%] vs 27/64 [42%]), and led more often to mucosal healing (absence of ulcers at week 104: 19/26 [73%] vs 7/23 [30%]). In the second trial(20), 77 patients were randomized to receive either 6 IFX infusions and AZA or prednisone and AZA. At week 30, top-down treatment resulted in higher remission rates (26/38 [68%] vs 17/39 [44%]) and mucosal healing rates (17/38 [45%] vs 7/39 [18%]). There are no prospective randomized controlled trials in pediatric CD patients, only several retrospective, observational studies. The first retrospective study found that patients who – by either patient’s or physician’s choice – had started top-down treatment had lower relapse rates at 1 year than those who had started with step-up treatment (3/13 [23%] vs 8/13 [62%]).(21) A second cohort demonstrated that IFX is more effective in therapy naïve than refractory patients (relapse-free rates at 3 years: 36% vs 15% [survival curve, no absolute numbers]).(15, 22, 23) Results from a third retrospective cohort, using propensity scores analysis to correct for baseline differences, showed that early IFX monotherapy resulted in higher remission rates at 1 year than early immunomodulator monotherapy (thiopurine or methotrexate) (58/68 [85%] vs 152/248 [55%]).(24) The available literature thus suggests that starting IFX therapy early is more effective in pediatric CD patients, but this needs to