Selective JAK1 inhibition using upadacitinib for the management of inflammatory bowel diseases

Abstract

Inflammatory bowel disease (IBD) is a chronic disorder characterized by inflammation of the gastrointestinal tract, with two main subtypes: ulcerative colitis (UC) and Crohn’s disease (CD). The cause of IBD is not fully understood, but it involves a complex interaction between genetics and environmental factors that trigger an abnormal immune response in the gut. The immune system plays a central role in IBD, with an imbalance between pro- and anti-inflammatory mediators leading to an exaggerated immune response and infiltration of immune cells into the mucosa.2 This infiltration triggers the release of cytokines, interleukins and interferons, activating signalling pathways that damage the mucosal barrier. Despite the presence of several treatment choices for individuals with inflammatory bowel diseases (IBDs), there still remain significant challenges. The symptoms associated with the disease have a detrimental impact on individuals’ quality of life, and uncontrolled inflammation can lead to complications of disease requiring surgery, further emphasizing the need for improved treatment to achieve disease control and enhance overall well-being. The involvement of the Janus kinase inhibitor (JAK) family of enzymes in the signalling pathways of several pro-inflammatory cytokines plays an important role in the pathogenesis of IBD, which makes it a potential therapeutic target. Tofacitinib, a nonselective pan-JAK inhibitor, was the first JAK inhibitor treatment approved for moderate-to-severe cases of UC. However, long-term studies on rheumatoid arthritis (RA) patients treated with tofacitinib have highlighted safety concerns including potentially higher risk of major adverse cardiovascular (CV) events and venous thromboembolism. The second generation of JAK inhibitors include selective JAK1 therapies, such as upadacitinib. Upadacitinib is a selective and reversible JAK inhibitor approved for treating UC; RA; psoriatic arthritis; ankylosing spondylitis (AS); and atopic dermatitis, and approval for Crohn’s disease is expected in the near future. This review intends to describe the mechanism of upadacitinib, evaluate the current clinical evidence of its effectiveness in treating IBD, and discuss safety considerations.