P135 BIOLOGICAL EVIDENCE OF TOFACITINIB EFFICACY IN CROHN'S DISEASE. (18th January 2018)

• Record Type: Journal Article
• Authors: Theodorou, Evangelos; Cao, Peirang; Karagiannis, Fotios; Park, Eden; Cheifetz, Adam; Moss, Alan C; Kokkotou, Efi
• Is Part Of: Inflammatory bowel diseases. Volume 24(2018)Supplement 1
• Page Start: S48
• Page End: S49
• Publication Date: 2018-01-18
• Subjects: Inflammatory bowel diseases -- Periodicals; Colitis, Ulcerative -- Periodicals; Crohn Disease -- Periodicals; Inflammatory Bowel Diseases -- Periodicals; 616.344
• DOI: 10.1093/ibd/izy037.003
• Languages: English
• ISSNs: 1078-0998

Abstract

Abstract: Background: While phase II-III trials clearly demonstrated efficacy of tofacitinib, an oral small molecule pan-JAK inhibitor, in patients with UC, in CD tofacitinib did not differ from placebo, raising questions about the design of those trials but also about tofacitinb elicited biological mechanisms that can be beneficial for only UC. Subsequently, second generation JAK-1 selective inhibitors such as filgotinib were found efficacious in CD, underscoring lack of understanding how JAK inhibitors work in IBD and which patients are more likely to benefit from their use. To overcome the limitations of current drug evaluation approaches using primarily mouse models of experimental colitis, we have developed a Therapeutic Response Predictor Assay-TheRPA, which is based on treatment of patient-derived tissue explants and has been validated using anti-TNF (45% patient response rate and 87% test accuracy). Methods: Punch biopsies obtained from the inflamed mucosa of 12 patients with CD were cultured with 100uM tofacitinib or vehicle. Culture supernatants were collected for multiplex cytokine analysis (16-plex) and tissues for RNA extraction followed by RNAseq analysis. Results: TheRPA-based response rates to tofacitinib (ie inhibition of >2 cytokines) were comparable in CD (8/12) and UC (6/9) patients. TNFa, GM-CSF, MCP-1, IL-8 and IL-6 were inhibited more frequently, consistent with reports from the field of rheumatoid arthritis. IL-10 was also downregulated, which is in contrast to previous findings in mice, but in agreement with the effects of treatment of human IBD explants with anti-TNF. Conclusion: Our study provides biological evidence that tofacitinib treatment might be beneficial in patients with CD. TheRPA can be used to select patients with IBD more likely to respond to tofacitinib and guide tailored therapies in IBD. Finally, it represents a suitable platform to evaluate newly developed JAK selective inhibitors and uncover their specific mechanisms of actions.