Abstract:
:The two major forms of inflammatory bowel disease (IBD), encompassing Crohn's disease (CD) and ulcerative colitis (UC), are chronic immune-mediated conditions characterised by an increased production of pro-inflammatory cytokines that act as critical drivers of intestinal inflammation. Anti-cytokine therapy has been shown to improve clinical outcomes in IBD. Janus kinases (JAKs) are tyrosine kinases that bind different intracellular cytokine receptors, leading to phosphorylation of signal transducer and activation of transcription molecules implicated on targeted gene transcription. Four isoforms of JAKs have been described: JAK1, JAK2, JAK3 and TYK2. Oral JAK inhibitors (JAKi) have been developed as synergic anti-cytokine therapy in IBD, showing different selectivity towards JAK isoforms. Tofacitinib, a pan-JAK inhibitor, has been recently approved for the treatment of moderate-to-severe UC. With the aim of improving the benefit: risk ratio of this drug class, several second-generation subtype-selective JAKi are under development. However, whether selective inhibition of JAK isoforms is associated with an increased clinical efficacy and/or a better safety profile remains debatable. The aim of this review is to critically review the preclinical and clinical data for the differential selectivity of JAK inhibitors and to summarise the potential clinical implications of the selective JAK inhibitors under development for UC and CD.
journal_name
Gutjournal_title
Gutauthors
Danese S,Argollo M,Le Berre C,Peyrin-Biroulet Ldoi
10.1136/gutjnl-2019-318448subject
Has Abstractpub_date
2019-10-01 00:00:00pages
1893-1899issue
10eissn
0017-5749issn
1468-3288pii
gutjnl-2019-318448journal_volume
68pub_type
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