Efficacy, Safety and Future Perspectives of JAK Inhibitors in the IBD Treatment

Abstract

Although development of biologics has importantly improved the effectiveness in inducing and maintaining remission in inflammatory bowel disease (IBD), biologic therapies still have several limitations. Effective, low-cost drug therapy with good safety profile and compliance is therefore a substantial unmet medical need. A promising target for IBD treatment strategies are Janus kinase (JAK) inhibitors, which are small molecules that interact with cytokines implicated in pathogenesis of IBD. In contrast to monoclonal antibodies, which are able to block a single cytokine, JAK inhibitors have the potential to affect multiple cytokine-dependent immune pathways, which may improve the therapeutic response in some IBD patients. Tofacitinib, inhibiting signaling via different types of JAKs, has been already approved for ulcerative colitis, and several other small-molecule are still under investigation. However, one of the main concerns about using JAK inhibitors is the risk of thromboembolic events. Moreover, patients with COVID-19 appear to have an increased susceptibility for immunothrombosis. Therefore, thrombotic complications may become a serious limitation in the use of JAK inhibitors in the SARS-CoV-2 pandemic. As many questions about safety and efficacy of small molecules still remain unclear, in our review we present the current data regarding approved JAK inhibitors, as well as those in clinical development for the treatment of IBD.

Mechanism of Sishen-Pill-Regulated Special Memory T and mTfh Cell via Involving JAK/STAT5 Pathway in Colitis Mice

“…After acute infection or antigen clearance, the differentiation of memory T cells no longer relies on the classical antigen-recognition MHC-II pathway but mainly on intracellular signals (such as JAK/STAT and PI3K/Akt signaling pathways) and inflammatory mediators [ 6 ]. Previous studies have shown that the overactivation of the JAK/STAT signaling pathway is closely related to the pathogenesis of colitis, which seems to be involved in the regulation of physiological processes such as proliferation, apoptosis, and differentiation of various immune cells [ 19 , 20 ]. The JAK/STAT signaling pathway has an important role in the cellular immune response [ 21 ].…”

Selective Forms of Therapy in the Treatment of Inflammatory Bowel Diseases

“…Similar results were obtained in the U-ACHIEVE study evaluating the efficacy of Upadacitinib in patients with moderately or severely active UC compared to the placebo in induction of clinical remission (p = 0.002 for the 45 mg dose) and endoscopic remission (p < 0.05 regardless of dose). However, there is a need for further, more detailed studies on a large population of patients to confirm these observations [38]. Another selective JAK1 inhibitor is filgotinib.…”

Targeting pathophysiological changes using biomaterials-based drug delivery systems: A key to managing inflammatory bowel disease

“…The management of this disease engages the utilization of anti-inflammatory drugs which can considerably decrease the symptoms of disease and help preserve its remission. Drugs employed to treat the signs of IBD consist of aminosalicylates (like sulfasalazine and Mesalamine), corticosteroids, immunomodulators (such as azathioprine and methotrexate), Tofacitinib (a Janus kinase inhibitor), TNF-α blocking biological agents (like infliximab and adalimumab), and anti-integrin biological factors (such as natalizumab) ( Fakhoury et al, 2014 ; Al-Bawardy et al, 2021 ; Battat and Sandborn, 2021 ; Burr et al, 2021 ; Dudek et al, 2021 ; Hanzel et al, 2022 ). For the patients who do not respond to less aggressive treatment like sulfasalazine and azathioprine, biological drugs such as infliximab, adalimumab, and natalizumab are utilized.…”