Clinical and Mechanistic Characteristics of Current JAK Inhibitors in IBD

Abstract

Crohn's disease (CD) and ulcerative colitis (UC) are chronic, immune-mediated diseases of the gastrointestinal (GI) tract. Their etiology is complex and involves immune (eg, cytokines) and nonimmune (eg, environment) mediated contributions, causing inflammatory damage to the GI tract. Though cytokines contribute a major role in the inflammatory process of both CD and UC, there are some key differences in which cytokines are involved in the pathobiology of CD and UC. Over the past several years, new biologic-directed therapies have focused on controlling specific aspects of inflammation associated with both conditions. Although these treatments have benefited patients overall, approximately 30% of patients still do not respond to induction (initial) therapy, and up to 50% of patients lose response to treatment over a year. Many of these therapies are administered parenterally and have been associated with adverse events such as serious infections or malignancy. Therefore, there is a significant unmet medical need for these patients to minimize symptoms and promote GI healing. There are several therapeutic agents in the pipeline, including oral, small molecules, which hold much promise. One group of small molecules known as Janus kinase (JAK) inhibitors offers an additional option for treatment of chronic inflammatory conditions, based on currently available data. The article will focus on the potential benefits of JAK inhibitors as oral, small molecules, such as the potential role of selectivity, and potential risks.

Keywords: Crohn’s disease; JAK; biologic drugs; inflammatory bowel disease treatment; ulcerative colitis.

FIGURE 1.

Figure shows the interaction between different cytokines and JAK pairings and resultant physiologic effects in both healthy and disease states. Normal cytokine signaling through JAK pairs is essential for bodily functions such as providing immunity against pathogens and hematopoiesis. In inflammatory bowel disease, an exaggerated immune response leads to excessive signaling through the JAK-STAT pathway, resulting in overexpression of proinflammatory cytokines and a cycle of chronic, relapsing gastrointestinal inflammation and potential damage.

FIGURE 2.

Figure illustrates the steps involved in the JAK-STAT pathway.

FIGURE 3.

Figure provides the chemical structures of JAK inhibitors currently under investigation for Crohn’s disease and/or ulcerative colitis.