The Future of Janus Kinase Inhibitors in Inflammatory Bowel Disease.
Inflammatory bowel diseases, such as ulcerative colitis and Crohn's disease, are disabling conditions characterised by chronic, relapsing inflammation of the gastrointestinal tract. Current treatments are not universally effective or, in the case of therapeutic antibodies, are hampered by immune responses. Janus kinase inhibitors are orally delivered small molecules that target cytokine signalling by preventing phosphorylation of Janus kinases associated with the cytokine receptor. Subsequently, phosphorylation of signal transducers and activators of transcription that relay Janus kinase signalling and transcription of cytokines in the nucleus will be diminished. Key cytokines in the pathogenesis of inflammatory bowel diseases are targeted by Janus kinase inhibitors. Several Janus kinase inhibitors are in development for the treatment of inflammatory bowel diseases. Tofacitinib, inhibiting signalling via all Janus kinase family members, was effective in phase 2 and 3 trials in moderate-severe ulcerative colitis. GSK2586184, a Janus kinase 1 selective inhibitor, induced clinical and endoscopic response in ulcerative colitis; however, the study was discontinued at an early stage due to liver toxicity observed in systemic lupus patients receiving the drug. Filgotinib, a Janus kinase 1 selective inhibitor investigated in treatment of Crohn's disease, was superior to placebo. As adverse events associated with the broad immunological effect of these agents have been reported, the future application of these drugs is potentially limited. We will discuss the treatment efficacy of Janus kinase inhibition in inflammatory bowel diseases, how current Janus kinase inhibitors available target immune responses relevant in inflammatory bowel disease, and whether more specific kinase inhibition could be effective.
Tytgat Institute for Liver and Intestinal Research, Academic Medical Center, Amsterdam, The Netherlands.|Department of Gastroenterology and Hepatology, Academic Medical Center, Amsterdam, The Netherlands.
L C S
LCS
De Vries
Tytgat Institute for Liver and Intestinal Research, Academic Medical Center, Amsterdam, The Netherlands.|Department of Gastroenterology and Hepatology, Academic Medical Center, Amsterdam, The Netherlands.
M E
ME
Wildenberg
Tytgat Institute for Liver and Intestinal Research, Academic Medical Center, Amsterdam, The Netherlands.
W J
WJ
De Jonge
Department of Gastroenterology and Hepatology, Academic Medical Center, Amsterdam, The Netherlands.
G R
GR
D'Haens
D000818:Animals; D016207:Cytokines / Q000378:metabolism; D006801:Humans; D015212:Inflammatory Bowel Diseases / Q000188:drug therapy* / Q000378:metabolism*; D000075242:Janus Kinase Inhibitors / Q000009:adverse effects / Q000627:therapeutic use*; D053612:Janus Kinases / Q000235:genetics / Q000378:metabolism*; D009154:Mutation; D010880:Piperidines / Q000009:adverse effects / Q000627:therapeutic use*; D011743:Pyrimidines / Q000009:adverse effects / Q000627:therapeutic use*; D011758:Pyrroles / Q000009:adverse effects / Q000627:therapeutic use*; D050791:STAT Transcription Factors / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction
D016207:Cytokines; D000075242:Janus Kinase Inhibitors; D010880:Piperidines; D011743:Pyrimidines; D011758:Pyrroles; D050791:STAT Transcription Factors; C479163:tofacitinib; D053612:Janus Kinases
Crohn’s disease; Kinase inhibitors; filgotinib; tofacitinib; ulcerative colitis