Maarten Cozijnsen

121 Chapter 6 Benefits and risks of combination therapy in children with IBD Endpoints Result** a) ACCENT I: clinical response b) ACCENT I: clinical remission c) ACCENT II: fistula response d) ACCENT II: complete fistula response e) ACCENT I: ATI presence f) ACCENT II: ATI presence g) Median IFX concentration a) [1] 27/54 (50%) vs. [2] 69/170 (41%), P≈0.3 b) [1] 20/54 (37%) vs. [2] 55/171 (32%), P≈0.5 c) [1] 12/28 (43%) vs. [2] 30/63 (48%), P≈0.8 d) [1] 9/28 (32%) vs. [2] 24/63 (38%), P≈0.6 e) [1] 5/90 (6%) vs. [2] 24/245 (10%), P≈0.2 f) [1] 1/42 (2%) vs. [2] 15/83 (18%), P≈0.01 g) No differences between group [1] and [2] in all studies (numbers to comprehensive to disclose) a) Remission wk 26 b) Remission wk 56 a) [1] 53/136 (39%) vs. [2] 15/36 (42%), P≈0.8 b) [1] 50/136 (37%) vs. [2] 12/36 (33%), P≈0.8 ATIs=antibodies-to-infliximab; MH=mucosal healing; OR=odds ratio. * Treatment of the two sub- groups is displayed, not of the randomization arms ** When the P-value is followed by the “≈” symbol, no P-value is provided in the original article; we estimated the P-value using the Fisher Exact Test Lastly, six retrospective observational cohort studies compared combination therapy with anti-TNF monotherapy in treating adult CD. Most of these studies compared sustained clinical benefit rates or therapy failure rates of patients with and without concomitant IMs. Some found combination therapy to be more beneficial than monotherapy (28-30) whereas others did not (10, 31, 32). Although approximately half of the studies show similar response, loss of response or remission rates, it is clear from the vast majority of studies that combined therapy is associated with higher IFX trough levels and decreased ATI rates.(11, 13, 14, 25) These two findings have been consistently associated with better clinical outcome.(33-35) The lack of this finding in some of the aforementioned studies might be explained by a small effect size, or by confounding-by-indication. Moreover, the results of one small (n=5) retrospective study even suggest that concomitant IMs may be used to treat patients who have lost response to anti-TNF agents due to anti-drug antibodies.(36) On the other hand, combination therapy may be less effective in IM refractory that in IM naïve patients. Fewer studies have compared ADA combination therapy with monotherapy and no RCT has done so.(26-28, 30, 37) Furthermore, only one adult study compared ADA concentrations in patients treated with combination vs. monotherapy, which found similar concentrations.(38)