P582. Remission induction therapy with infliximab in patients with ulcerative colitis: Does tumour necrosis factor-α blockade per se explain its multiple actions?
M. Kawai1, Y. Yokoyama1, K. Kamikozuru1, K. Nagase1, M. Iimuro1, H. Miwa2, S. Nakamura1, 1Hyogo College of Medicine, Internal Medicine, Lower Gastroenterology, Nishinomiya, Japan, 2Hyogo College of Medicine, Internal Medicine, Upper gastroenterology, Nishinomiya, Japan
Inflammatory bowel disease (IBD) including ulcerative colitis (UC) and Crohn's disease are perpetuated and exacerbated by inflammatory cytokines like tumour necrosis factor (TNF)-α, interleukin (IL)-1, IL-4, IL-6 and the IL-12, IL-17, IL-23 cascade. Based on this knowledge, anti-cytokine antibodies, notably infliximab (IFX) against TNF-α have been developed and used to treat patients with IBD. Indeed, the efficacy of IFX has validated the role of TNF-α in the immunopathogenesis of IBD. In this study, we were interested to see the impact of IFX on inflammatory cytokine and chemokine profiles in patients with UC.
In a single centre, and retrospective setting, 33 consecutive patients with active UC, Lichtiger's clinical activity index 11.2±4.0, range 5–14, and average UC duration 5.0±5.2 yr who had received IFX were reviewed. All included patients had received their first IFX remission induction therapy with 3 infusion sessions (5 mg/kg) at weeks 0, 2 and 6. Further, among the 33 patients, 31 (93.9%) had received prednisolone with or without azathioprine prior to IFX therapy. Clinical remission was defined as CAI ≤3. Blood samples were taken at baseline, 12 hours post first IFX infusion and then at week 14. Blood concentrations of 19 known cytokines and chemokines were measured by processing test samples for suspension array assays.
At week 10, sixteen of 33 patients (48.5%) achieved remission (CAI <3), and at 12 hours after the first IFX infusion, the concentration of interferon (IFN)-γ-inducible protein (IP)-10 was very markedly decreased (P < 0.001). Likewise, at week 14 after the first IFX infusion, the concentration of IL-4, IFN-γ, IL-6, granulocyte colony-stimulating factor (G-CSF) and macrophage inflammatory protein (MIP)-1α were significantly decreased (P < 0.05). However, these effects were not exclusive to responders, indicating that the blockade of TNF-α receptors per se does not fully explain all actions of IFX.
This is the first study that has looked at a broad range of cytokines and chemokines in UC patients receiving IFX remission induction therapy. Most notably in this study, we found that the concentration of IP-10, which is known to be elevated in the mucosa of patients with UC and is suspected to be a significant factor in mucosal injury was markedly decreased after the first IFX infusion. This could suggest that protection from further mucosal injury is likely by depletion of IP10. Additionally, IFX therapy reduced the generation of IL-4, IL-6, IFN-γ, G-CSF and MIP-1α. The clinical significance of these actions remains to be evaluated.