JAK inhibitors for the treatment of inflammatory bowel disease

Abstract

Over the past decade, Janus kinase (JAK) inhibitors have been developed for the treatment of several immune-mediated inflammatory diseases, including ulcerative colitis (UC) and Crohn’s disease (CD). The JAK-signal transducer and activator of transcription (STAT) pathway plays an essential role in coordinating the human immune response. Phosphorylation and activation of the JAK family of tyrosine kinases results in subsequent activation of intracytoplasmic STAT pathways with upregulation of inflammatory gene transcription. Blocking this signalling results in broad-spectrum immunosuppression, which is effective in the treatment of rheumatoid arthritis (RA), psoriasis, atopic dermatitis, and inflammatory bowel disease (IBD). To date, three oral, small-molecule JAK inhibitors (tofacitinib, filgotinib, and upadacitinib) have received regulatory approval in various jurisdictions globally for the treatment of moderate-to-severely active UC. It is anticipated that upadacitinib will soon become the first novel, advanced oral small molecule therapy approved for moderate-to-severely active CD. While these agents are highly effective, emerging data has highlighted potentially relevant safety signals associated with JAK inhibitors, and that the therapeutic index of these therapies may be distinct from that of monoclonal antibodies. Therefore, JAK inhibitors have a unique position in the therapeutic armamentarium for IBD. Here, we summarize the evidence supporting the use of JAK inhibitors and provide an overview of their practical applications in clinical care.