Maarten Cozijnsen

71 Chapter 4 Infliximab impacts leukocyte RNA expression and serum inflammatory proteins Background It is widely accepted among clinicians that infliximab treatment for Crohn’s disease (CD) results in higher endoscopic remission rates than prednisolone treatment does. However, scientific support for this assumption remains limited as a prospective head- to-head comparative trial remains to be published. 1 Endoscopic remission has become increasingly important over clinical remission, since it reduces the need for steroids, the risk of complications, of hospitalization and need for surgery. 2 Still, the underlying immune mechanisms by which infliximab treatment restores homeostasis remain largely unknown. Mechanisms by which infliximab restores homeostasis can be studied among others by comparing tissue from patients before and after infliximab treatment initiation using whole genome RNA analyses. Several cohort studies used this approach and identified genes differentially expressed in intestinal mucosal tissue of CD (and UC) patients with versus without endoscopic remission after infliximab treatment initiation. 3–10 The patients included in these trials had lost response to their previous treatments and subsequent started with infliximab treatment. Because these patients were not treatment naïve at baseline and because of the high sensitivity of whole genome RNA analyses, the results of these trials could have been affected by the effects that previous treatments have had on the gene expression of the included patients. Our study is the first to compare gene expression before and after infliximab treatment in treatment naïve patients. Furthermore, it is the first to do so in pediatric CD patients. Since CD dominantly manifests itself in intestinal mucosal tissue, mucosal biopsies are mostly used to study the effect of infliximab on patients’ immune system. 3–10 However, one of the downsides of using mucosal tissue is that to obtain it, patients need to undergo endoscopic examination, which is invasive and potentially harmful for patients, especially for pediatric patients that require anesthesia. In comparison, obtaining peripheral blood is less invasive and thus allows for more frequent sampling to perform longitudinal follow-up. One other study in adult CD patients identified differentially expressed genes upon infliximab initiation by whole genome RNA analyses of peripheral blood instead of mucosal tissue. 11 The investigator-initiated randomized controlled trial (RCT) titled ‘ Infliximab Top-down versus Step-up in Kids with CD’ (ITSKids) offered us the unique opportunity to compare the immune responses following infliximab and prednisolone treatment in pediatric CD. In ITSKids newly diagnosed pediatric CD patients were randomized to infliximab plus azathioprine or prednisolone plus azathioprine. Because these patients were