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Selected Publication:
Hoefel, T.
JAK inhibitors and their role in the treatment of inflammatory bowel diseases
Humanmedizin; [ Diplomarbeit ] Medizinische Universität Graz; 2021. pp. 84
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- Authors Med Uni Graz:
- Advisor:
- Böhm Eva
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- Abstract:
- Janus kinases are small molecules, essential for phosphorylation and activation of cytokine receptors after binding of their respective cytokine. After phosphorylating itself and the receptor, STAT molecules are activated, dimerize and translocate into the nucleus to act as transcriptional factors and thereby contributing to the inflammatory process. By investigating patients with JAK deficiencies, the true extent of JAK-dependent signaling was uncovered and a promising new treatment option for inflammatory diseases opened up. Inflammatory bowel diseases, ulcerative colitis (UC) and Crohn’s disease (CD) in particular, are challenging to treat, due to complex pathophysiology, loss of response to therapeutics, or non-responders to drugs. Recently developed JAK inhibitors represent a promising novel class of “targeted” anti-inflammatory drugs. Currently available JAK inhibitors block the ATP binding site of JAKs, hindering phosphorylation and thereby activation of the JAK/STAT-pathway is not possible. One of the first developed and approved JAK inhibitors is tofacitinib, a pan-JAK inhibitor, mainly targeting JAK1, -2, -3, and to a lesser extent TYK2. Tofacitinib is currently approved for rheumatoid arthritis, psoriasis arthritis, and ulcerative colitis. Further JAKinibs with potential therapeutic use in the treatment of inflammatory bowel diseases (IBDs) are upadacitinib, filgotinib, and peficitinib. In the trials reviewed in this thesis, all JAKinibs showed at least minor effectivity in the treatment of UC and CD with acceptable safety profiles. However, most of the analyzed studies were phase-II dose finding trials and showed limitations in endoscopic response, safety profiles, and long-term adverse events (AE), or due to small study-population, a lack of trial duration and follow-up periods, and no standardized enrolling criteria and endpoint surveillance. In conclusion, JAKinibs show promising results in phase-II and- III trials, with acceptable safety-profiles, as far as an interpretation is possible due to limitations of the trials. Tofacitinib is already approved for UC, while further JAKinibs need more research especially addressing AE and side-to-side comparisons with already approved biologics.