JAK inhibitors for inflammatory bowel disease: recent advances

Abstract

Inflammatory bowel disease (IBD) commonly requires immunosuppressive treatments to induce and maintain durable remission. Janus kinase inhibitors (JAKis) are a novel group of orally administered, small molecule drugs that work by attenuating multiple cytokine signalling pathways to mediate dysregulated immune responses involved in the pathogenesis of IBD. Tofacitinib, filgotinib and upadacitinib have demonstrated efficacy against placebo and are licensed for the treatment of moderate to severe ulcerative colitis; upadacitinib is the only JAKi also currently approved for the treatment of Crohn's disease. Safety concerns stratified by age have led to class-wide regulatory restrictions for JAKi use across all inflammatory diseases. It is important for gastroenterologists managing patients with IBD to be aware of the key pivotal trial outcomes, to identify appropriate patients in whom to commence a JAKi, and to understand the safety considerations and ways to mitigate these risks in the patients they treat. This review provides a contemporaneous overview of this emerging therapeutic class and provides a practical guide for healthcare practitioners for initiating and monitoring JAKi in IBD.

Keywords: CROHN'S DISEASE; IBD CLINICAL; INFLAMMATORY BOWEL DISEASE; ULCERATIVE COLITIS.

Figure 1

The structure of a JAK protein and the mechanism of action of JAK inhibitors. (A) Functional domains of a JAK protein. This schematic displays the four functional domains common to all JAKs. The kinase domain is responsible for enzymatic activity and substrate phosphorylation while the pseudokinase domain lacks enzymatic activity but regulates the active catalytic kinase domain and is also associated with STAT recruitment. The Src-homology-2 (SH2) and FERM domains are involved in associating the JAK with the respective cell membrane receptors. Alternative nomenclature in the literature describes seven JAK homology domains (JH) numbered from the carboxyl terminus to the amino terminus. (B) JAK-STAT signal transduction and the mechanism of action of JAKi in attenuating cytokine signalling. The four members of the JAK family, JAK1, JAK2, JAK3 and Tyk2, are located on the intracellular domain of the cell surface receptor and are essential in mediating signalling downstream of cytokine receptors for a broad range of cellular processes. Numerous cytokines implicated in the pathogenesis of IBD, involved in both innate and adaptive immunity, signal through this pathway. Different cytokine-activated JAK-STAT combinations drive different cellular processes with a high degree of specificity. Extracellular cytokine binding result in conformational receptor changes, which brings the associated JAKs in close proximity and in turn, results in autophosphorylation and transphosphorylation of receptor chains. These forms docking sites for downstream STAT proteins, which after phosphorylation, receptor chains dissociation, and STAT homodimerisation or heterodimerisation, translocate to the nucleus to modulate gene transcription. JAKi reversibly bind onto the ATP site on the catalytic cleft of the kinase domain to prevent JAK phosphorylation and activation and inhibits the ensuing signalling cascade. IBD, inflammatory bowel disease; JAK, Janus kinase inhibitor. Adapted with permission using the Creative Commons Attribution 4.0 International License from Nielsen OH et al, Selective JAK1 inhibitors for the treatment of inflammatory bowel disease, Pharmacol Ther, 2023.

Figure 2

Managing potential adverse events of JAK inhibition. ALC, absolute lymphocyte count; ANC, absolute neutrophil count; CVS, cardiovascular; CVD, cerebrovascular disease; ESRF, end-stage renal failure; IHD, ischaemic heart disease; JAK, Janus kinase; LFTs, liver function tests; MACE, major adverse cardiovascular events; NMSC, non-melanoma skin cancer; VTE, venous thromboembolism.

Figure 3

A checklist for initiating and monitoring therapy. *If no suitable alternative available. BSG, British Society of Gastroenterology; FBC, full blood count; JAKi, Janus kinase inhibitor; LFT, liver function tests; MACE, major adverse cardiovascular events; VTE, venous thromboembolism.