Pediatric inflammatory bowel disease : clinical and immunological aspects on remission treatment

Sammanfattning: Background - Inflammatory bowel disease (IBD), including Crohn’s disease (CD) and ulcerative colitis (UC), are lifelong conditions characterized by abdominal pain, bloody diarrhea and fatigue. The incidence and prevalence are increasing worldwide, with approximately 10-20% of all IBD cases diagnosed during childhood. The etiology is considered multifactorial but is not completely understood. However, genetic susceptibility, environmental factors and disturbed immunological function appear to contribute to the development of IBD. The treatments of pediatric CD and UC are only in part the same. Unfortunately, we still frequently use high dosage of corticosteroids, and we do not practice personalized medicine because of a lack of knowledge about which treatment best suits the individual patient. In our ambition to better understand the pathophysiology of IBD and the mode of action of established therapies, as well as to determine new therapy strategies, we studied the clinical effect of Infliximab (IFX) in children on maintenance treatment and the therapeutic effect of granulocyte and monocyte apheresis (GMA) in children with newly onset IBD. In addition, children with CD were treated with exclusive enteral nutrition (EEN) as induction of remission therapy. Finally, we studied the immunological profile in blood at onset and in intestinal mucosa at onset and after GMA and EEN treatment. Methods and results - We investigated the association between s-IFX trough levels and antibodies to IFX (measured with ELISA, enzyme-linked immunosorbent assay) to clinical indices and CRP, ESR, albumin and F-calprotectin in 45 children om maintenance IFX treatment. The mean s-IFX trough levels were significantly higher during remission than in active disease, correlating to the clinical indices, ESR, CRP and albumin. The development of antibodies to IFX strongly correlated to undetectable s-IFX and active disease (Paper 1). In paper II (pilot study), 12 children with newly IBD colitis received 10 sessions with GMA together with a low to moderate dose of mesalazine as induction of remission. A control colonoscopy (CC) was performed 12 to 16 weeks post-treatment, in which the endoscopic Mayo score showed significant improvement in 9/12 children (8/12 were in clinical remission). In seven of these children (paper V), the expressions of 14 cytokines were investigated (by real time polymerase chain reaction, PCR) in the intestinal mucosa at onset and after the combination therapy of GMA and mesalazine. Significant decreases were seen in CSF-2, TNF-α, IL-23α, IL-1β, IL-36γ, IL-10 and TGFβ1 after treatment while significant decreases were observed in the clinical index and Mayo endoscopic score. Compared with the IBD patients, significantly lower levels of IL-12β and IL- 23α were found in the six non-IBD controls at onset. In paper III, we characterized the chemokine receptor landscape in 45 children (UC: n=16, CD: n=12 and healthy controls: n=17) using flow cytometry. By defining a diagnostic algorithm based on these markers, we could distinguish UC from CD in >92% of the studied children with newly onset IBD. In paper IV, 12 children with newly onset IBD were treated with six weeks of EEN as induction of remission therapy. Eleven of the 12 patients successfully completed the treatment. A CC after completion of EEN showed significant decreases in endoscopic scoring (SES-CD) and 83% of the patients were in clinical remission. Additionally, in six of the children mucosal cytokines were measured by real time PCR at diagnosis and at CC. An overall decrease (though not statistically significant) in pro-inflammatory cytokines, as well as both decreases and increases in the regulatory cytokines, were seen after EEN therapy. Conclusions - We conclude that an active approach is needed in the care of children with IBD to achieve and maintain remission. Our findings reveal that the children on IFX maintenance treatment were only in remission in 28% of the visits. The combination of GMA and mesalazine was found to be a safe and effective treatment in children with newly onset IBD. It seems plausible to speculate that the decreases in mucosal cytokines after the induction of remission may explain the good clinical result. Moreover, a change in the mucosal cytokine profile after induction of remission with EEN was observed. By investigating the chemokine receptors, we found a possible prognostic IBD marker, and by analyzing the cytokine profiles in mucosal biopsies, we have extended the knowledge of immunological phenotypes in children with IBD. Suggestions for the future - Corticosteroid-free treatment alternatives must be explored and those currently in use must be optimized. To conclude, more and bigger studies are needed to explore the pathogenesis of IBD to determine new treatment alternatives.