JAK-STAT Inhibitors: A Game Changer, from Rheumatology to Gastroenterology
Main Article Content
Abstract
Autoimmune diseases represent a growing global health concern, with a rising incidence and prevalence across the globe, and are expected to exponentially rise through 2050. This increase is attributed to factors such as urbanization, lifestyle changes, and improved healthcare access. Historically, the management of autoimmune and immune-mediated diseases has revolved around broad immunosuppression, primarily relying on corticosteroids and other disease-modifying agents. These have limitations such as non-specific immunosuppression, increased risk of infection, and end-organ damage. In subsequent years, the therapeutic armamentarium expanded to include biologic agents that selectively target individual pro-inflammatory cytokines, such as tumor necrosis factor (TNF) alpha inhibitors and anti-integrin or anti-interleukin-12/23 therapies. Although biologics have improved disease outcomes and enabled more targeted intervention, their use is constrained by factors such as immunogenicity, the need for parenteral administration, and a persistent risk of adverse effects, including serious infections and malignancy. These limitations have underscored the need for novel therapeutic modalities with improved efficacy, safety, and patient convenience. The advent of Janus kinase (JAK)-signal transducer and activator of transcription (STAT) inhibitors has transformed the therapeutic landscape of immune-mediated diseases. Tofacitinib, upadacitinib, and filgotinib are orally administered small molecules that inhibit intracellular signaling of pro-inflammatory cytokines, which modulate several pathways simultaneously. In recent years, a therapeutic paradigm shift has emerged in the field of gastroenterology, with JAK inhibitors being increasingly utilized for the management of Inflammatory Bowel Disease (IBD). These have demonstrated efficacy in both induction and maintenance of remission, including among patients refractory to anti-TNF and other biologic therapies. This article will focus on the evolving role and paradigm shift in the use of JAK-STAT inhibitors from rheumatology to gastroenterology.
Article Details
How to Cite
KALRA, Shivam et al.
JAK-STAT Inhibitors: A Game Changer, from Rheumatology to Gastroenterology.
Medical Research Archives, [S.l.], v. 13, n. 9, sep. 2025.
ISSN 2375-1924.
Available at: <https://esmed.org/MRA/mra/article/view/6935>. Date accessed: 05 dec. 2025.
doi: https://doi.org/10.18103/mra.v13i9.6935.
Section
Research Articles
The Medical Research Archives grants authors the right to publish and reproduce the unrevised contribution in whole or in part at any time and in any form for any scholarly non-commercial purpose with the condition that all publications of the contribution include a full citation to the journal as published by the Medical Research Archives.
References
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9. Chen Z, Jiang P, Su D, Zhao Y, Zhang M. Therapeutic inhibition of the JAK-STAT pathway in the treatment of inflammatory bowel disease. Cytokine Growth Factor Rev. 2024 Oct;79:1-15.
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20. McInnes IB, Anderson JK, Magrey M, Merola JF, Liu Y, Kishimoto M, et al. Trial of upadacitinib and adalimumab for psoriatic arthritis. N Engl J Med. 2021 Mar 31;384(13):1227-39.
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23. Danese S, Peyrin-Biroulet L. Selective tyrosine kinase 2 inhibition for treatment of inflammatory bowel disease: New hope on the rise. Inflamm Bowel Dis. 2021 Nov 15;27(12):2023-30.
24. Sandborn WJ, Su C, Sands BE, D’Haens GR, Vermeire S, Schreiber S, et al. Tofacitinib as induction and maintenance therapy for ulcerative colitis. N Engl J Med. 2017 May 4;376(18):1723-36.
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27. Feagan BG, Danese S, Loftus EV, Vermeire S, Schreiber S, Ritter T, et al. Filgotinib as induction and maintenance therapy for ulcerative colitis (SELECTION): A phase 2b/3 double-blind, randomized, placebo-controlled trial. Lancet. 2021 Jun 19;397(10292):2372-84.
28. Rogler G. Efficacy of JAK inhibitors in Crohn’s disease. J Crohns Colitis. 2020 Aug 1;14(Suppl 2):S746-54.
29. Goyal MK. Comments on “Enduring clinical remission in refractory celiac disease type II with tofacitinib: An open-label clinical study.” Clin Gastroenterol Hepatol. 2025 Mar 1;23(4):678-9.
30. Loftus EV, Panés J, Lacerda AP, Peyrin-Biroulet L, D’Haens G, Panaccione R, et al. Upadacitinib induction and maintenance therapy for Crohn’s disease. N Engl J Med. 2023 May 24;388(21):1966-80.
31. Farkas B, Bessissow T, Limdi JK, Sethi-Arora K, Kagramanova A, Knyazev O, et al. Real-world effectiveness and safety of selective JAK inhibitors in ulcerative colitis and Crohn’s disease: A retrospective, multicentre study. J Clin Med. 2024 Dec 20;13(24):7804.
32. Goyal MK, Kalra S, Rao A ,Khubber M, Gupta A,Vuthaluru AR. Beyond the gut: Exploring neurological manifestations in inflammatory bowel disease. Brain & Heart 2024, 2(4), 3486.
33. Elford AT, Bishara M, Plevris N, Gros B, Constantine-Cooke N, Goodhand J, et al. Real-world effectiveness of upadacitinib in Crohn’s disease: A UK multicentre retrospective cohort study. Frontline Gastroenterol. 2024 Jul;15(4):297-304.
34. Vermeire S, Schreiber S, Petryka R, Kuehbacher T, Hebuterne X, Roblin X, et al. Clinical remission in patients with moderate-to-severe Crohn’s disease treated with filgotinib (the FITZROY study): Results from a phase 2, double-blind, randomized, placebo-controlled trial. Lancet. 2017 Jan 21;389 (10066):266-75.
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36. Solitano V, Vuyyuru SK, MacDonald JK, Zayadi A, Parker CE, Narula N, et al. Efficacy and safety of advanced oral small molecules for inflammatory bowel disease: Systematic review and meta-analysis. J Crohns Colitis. 2023 Nov 24;17(11):1800-16.
37. Akiyama S, Shimizu H, Tamura A, Yokoyama K, Sakurai T, Kobayashi M, et al. Comparative efficacy and safety of three Janus kinase inhibitors in ulcerative colitis: A real-world multicentre study in Japan. Aliment Pharmacol Ther. 2025 Feb;61(3): 524-37.
38. Li Y, Yao C, Xiong Q, Xie F, Luo L, Li T, et al. Network meta-analysis on efficacy and safety of different Janus kinase inhibitors for ulcerative colitis. J Clin Pharm Ther. 2022 Jul;47(7):851-9.
39. Burmester GR, Mysler E, Taylor P, Hall S, Wick-Urban B, Garrison A, et al. Benefit–risk analysis of upadacitinib versus adalimumab in patients with rheumatoid arthritis and higher or lower risk of cardiovascular disease. RMD Open. 2025 Jun 3;11 (2):e005371.
40. Yang H, An T, Zhao Y, Shi X, Wang B, Zhang Q. Cardiovascular safety of Janus kinase inhibitors in inflammatory bowel disease: A systematic review and network meta-analysis. Ann Med. 2025 Dec;57 (1):2455536.
41. Bieber T, Feist E, Irvine AD, Harigai M, Haladyj E, Ball S, et al. A review of safety outcomes from clinical trials of baricitinib in rheumatology, dermatology and COVID-19. Adv Ther. 2022;39 (11):4910-60.
42. Fakhouri W, Wang X, de la Torre I, Nicolay C. A network meta-analysis to compare effectiveness of baricitinib and other treatments in rheumatoid arthritis patients with inadequate response to methotrexate. J Health Econ Outcomes Res. 2020 Apr 10;7(1):10-23.
43. Zeng L, Feng S, Yao L, Wang B, Zhang G. Efficacy and safety of upadacitinib for the treatment of moderate-to-severe atopic dermatitis: A meta-analysis of randomized clinical trials. Adv Dermatol Allergol. 2023 Dec;40(6):734-40.
44. Genovese MC, Greenwald MW, Gutierrez-Ureña SR, Cardiel MH, Poiley JE, Zubrzycka-Sienkiewicz A, et al. Two-year safety and effectiveness of peficitinib in moderate-to-severe rheumatoid arthritis: A phase IIb, open-label extension study. Rheumatol Ther. 2019 Dec;6(4):503-20.
45. Lee YH, Song GG. Comparative efficacy and safety of tofacitinib, baricitinib, upadacitinib, filgotinib and peficitinib as monotherapy for active rheumatoid arthritis. J Clin Pharm Ther. 2020 Aug;45(4):674-81.
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2. Hracs L, Windsor JW, Gorospe J, Cummings M, Coward S, Buie MJ, et al. Global evolution of inflammatory bowel disease across epidemiologic stages. Nature. 2025 Jun;642(8067):458-66.
3. Fansiwala K, Sauk JS. Small molecules, big results: How JAK inhibitors have transformed the treatment of patients with inflammatory bowel disease. Dig Dis Sci. 2025 Feb;70(2):469-77.
4. Caballero-Mateos AM, Cañadas-de la Fuente GA. Game changer: How Janus kinase inhibitors are reshaping the landscape of ulcerative colitis management. World J Gastroenterol. 2024 Sep 21;30(35):3942-53.
5. Herrera-de Guise C, Serra-Ruiz X, Lastiri E, Borruel N. JAK inhibitors: A new dawn for oral therapies in inflammatory bowel diseases. Front Med (Lausanne). 2023;10:1089099.
6. Benucci M, Bernardini P, Coccia C, De Luca R, Levani J, Economou A, et al. JAK inhibitors and autoimmune rheumatic diseases. Autoimmun Rev. 2023 Apr;22(4):103276.
7. Cordes F, Foell D, Ding JN, Varga G, Bettenworth D. Differential regulation of JAK/STAT signaling in patients with ulcerative colitis and Crohn’s disease. World J Gastroenterol. 2020 Jul 28;26(28):4055-75.
8. Taylor PC, Choy E, Baraliakos X, Szekanecz Z, Xavier RM, Isaacs JD, et al. Differential properties of Janus kinase inhibitors in the treatment of immune-mediated inflammatory diseases. Rheumatology (Oxford). 2024 Feb 1;63(2):298-308.
9. Chen Z, Jiang P, Su D, Zhao Y, Zhang M. Therapeutic inhibition of the JAK-STAT pathway in the treatment of inflammatory bowel disease. Cytokine Growth Factor Rev. 2024 Oct;79:1-15.
10. Nielsen OH, Boye TL, Gubatan J, Chakravarti D, Jaquith JB, LaCasse EC. Selective JAK1 inhibitors for the treatment of inflammatory bowel disease. Pharmacol Ther. 2023 May;245:108402.
11. Almoallim HM, Omair MA, Ahmed SA, Vidyasagar K, Sawaf B, Yassin MA. Comparative efficacy and safety of JAK inhibitors in the management of rheumatoid arthritis: A network meta-analysis. Pharmaceuticals (Basel). 2025 Jan 28;18(2):178.
12. Lee YH, Song GG. Relative remission and low disease activity rates of tofacitinib, baricitinib, upadacitinib, and filgotinib versus methotrexate in patients with disease-modifying antirheumatic drug-naive rheumatoid arthritis. Pharmacology. 2023;108(6):589-98.
13. Genovese MC, Kalunian K, Gottenberg JE, Mozaffarian N, Bartok B, Matzkies F, et al. Effect of filgotinib vs placebo on clinical response in patients with moderate to severe rheumatoid arthritis refractory to disease-modifying antirheumatic drug therapy: The FINCH 2 randomized clinical trial. JAMA. 2019 Jul 23;322(4):315-25.
14. Liu L, Yan YD, Shi FH, Lin HW, Gu ZC, Li J. Comparative efficacy and safety of JAK inhibitors as monotherapy and in combination with methotrexate in patients with active rheumatoid arthritis: A systematic review and meta-analysis. Front Immunol. 2022;13:977265.
15. Wang F, Tang X, Zhu M, Mao H, Wan H, Luo F. Efficacy and safety of JAK inhibitors for rheumatoid arthritis: A meta-analysis. J Clin Med. 2022 Jul 30;11(15):4459.
16. Tóth L, Juhász MF, Szabó L, Abada A, Kiss F, Hegyi P, et al. Janus kinase inhibitors improve disease activity and patient-reported outcomes in rheumatoid arthritis: A systematic review and meta-analysis of 24,135 patients. Int J Mol Sci. 2022 Jan 23;23(3):1246.
17. Vallez-Valero L, Gasó-Gago I, Marcos-Fendian Á, Garrido-Alejos G, Riera-Magallón A, Plaza Diaz A, et al. Are all JAK inhibitors for the treatment of rheumatoid arthritis equivalent? An adjusted indirect comparison of the efficacy of tofacitinib, baricitinib, upadacitinib, and filgotinib. Clin Rheumatol. 2023 Dec;42(12):3225-35.
18. Lee EB, Fleischmann R, Hall S, Wilkinson B, Bradley JD, Gruben D, et al. Tofacitinib versus methotrexate in rheumatoid arthritis. N Engl J Med. 2014 Jun 19;370(25):2377-86.
19. Klavdianou K, Papagoras C, Baraliakos X. JAK inhibitors for the treatment of axial spondyloarthritis. Mediterr J Rheumatol. 2023 Jun 30;34(2):129-38.
20. McInnes IB, Anderson JK, Magrey M, Merola JF, Liu Y, Kishimoto M, et al. Trial of upadacitinib and adalimumab for psoriatic arthritis. N Engl J Med. 2021 Mar 31;384(13):1227-39.
21. Deodhar A, van der Bosch F, Poddubnyy D, Maksymowych WP, van der Heijde D, Kim TH, et al. Upadacitinib for the treatment of active non-radiographic axial spondyloarthritis (SELECT-AXIS 2): A randomized, double-blind, placebo-controlled, phase 3 trial. Lancet. 2022 Jul 30;400(10349):369-79.
22. Singh A, Goyal MK, Midha V, Mahajan R, Kaur K, Gupta YK, et al. Tofacitinib in acute severe ulcerative colitis (TACOS): A randomized controlled trial. Am J Gastroenterol. 2024 Jul 1;119(7):1365-72.
23. Danese S, Peyrin-Biroulet L. Selective tyrosine kinase 2 inhibition for treatment of inflammatory bowel disease: New hope on the rise. Inflamm Bowel Dis. 2021 Nov 15;27(12):2023-30.
24. Sandborn WJ, Su C, Sands BE, D’Haens GR, Vermeire S, Schreiber S, et al. Tofacitinib as induction and maintenance therapy for ulcerative colitis. N Engl J Med. 2017 May 4;376(18):1723-36.
25. Danese S, Vermeire S, Zhou W, Pangan AL, Siffledeen J, Greenbloom S, et al. Upadacitinib as induction and maintenance therapy for moderately to severely active ulcerative colitis: Results from three phase 3, multicentre, double-blind, randomized trials. Lancet. 2022 Jun 4;399(10341):2113-28.
26. Vermeire S, Danese S, Zhou W, Pangan A, Greenbloom S, D’Haens G, et al. OP23 efficacy and safety of upadacitinib as induction therapy in patients with moderately to severely active ulcerative colitis: Results from phase 3 U-ACCOMPLISH study. J Crohns Colitis. 2021 May 27;15(Suppl 1):S021-2.
27. Feagan BG, Danese S, Loftus EV, Vermeire S, Schreiber S, Ritter T, et al. Filgotinib as induction and maintenance therapy for ulcerative colitis (SELECTION): A phase 2b/3 double-blind, randomized, placebo-controlled trial. Lancet. 2021 Jun 19;397(10292):2372-84.
28. Rogler G. Efficacy of JAK inhibitors in Crohn’s disease. J Crohns Colitis. 2020 Aug 1;14(Suppl 2):S746-54.
29. Goyal MK. Comments on “Enduring clinical remission in refractory celiac disease type II with tofacitinib: An open-label clinical study.” Clin Gastroenterol Hepatol. 2025 Mar 1;23(4):678-9.
30. Loftus EV, Panés J, Lacerda AP, Peyrin-Biroulet L, D’Haens G, Panaccione R, et al. Upadacitinib induction and maintenance therapy for Crohn’s disease. N Engl J Med. 2023 May 24;388(21):1966-80.
31. Farkas B, Bessissow T, Limdi JK, Sethi-Arora K, Kagramanova A, Knyazev O, et al. Real-world effectiveness and safety of selective JAK inhibitors in ulcerative colitis and Crohn’s disease: A retrospective, multicentre study. J Clin Med. 2024 Dec 20;13(24):7804.
32. Goyal MK, Kalra S, Rao A ,Khubber M, Gupta A,Vuthaluru AR. Beyond the gut: Exploring neurological manifestations in inflammatory bowel disease. Brain & Heart 2024, 2(4), 3486.
33. Elford AT, Bishara M, Plevris N, Gros B, Constantine-Cooke N, Goodhand J, et al. Real-world effectiveness of upadacitinib in Crohn’s disease: A UK multicentre retrospective cohort study. Frontline Gastroenterol. 2024 Jul;15(4):297-304.
34. Vermeire S, Schreiber S, Petryka R, Kuehbacher T, Hebuterne X, Roblin X, et al. Clinical remission in patients with moderate-to-severe Crohn’s disease treated with filgotinib (the FITZROY study): Results from a phase 2, double-blind, randomized, placebo-controlled trial. Lancet. 2017 Jan 21;389 (10066):266-75.
35. Vermeire S, Schreiber S, Rubin DT, D’Haens G, Reinisch W, Watanabe M, et al. Efficacy and safety of filgotinib as induction and maintenance therapy for Crohn’s disease (DIVERSITY): A phase 3, double-blind, randomized, placebo-controlled trial. Lancet Gastroenterol Hepatol. 2025 Feb 1;10(2):138-53.
36. Solitano V, Vuyyuru SK, MacDonald JK, Zayadi A, Parker CE, Narula N, et al. Efficacy and safety of advanced oral small molecules for inflammatory bowel disease: Systematic review and meta-analysis. J Crohns Colitis. 2023 Nov 24;17(11):1800-16.
37. Akiyama S, Shimizu H, Tamura A, Yokoyama K, Sakurai T, Kobayashi M, et al. Comparative efficacy and safety of three Janus kinase inhibitors in ulcerative colitis: A real-world multicentre study in Japan. Aliment Pharmacol Ther. 2025 Feb;61(3): 524-37.
38. Li Y, Yao C, Xiong Q, Xie F, Luo L, Li T, et al. Network meta-analysis on efficacy and safety of different Janus kinase inhibitors for ulcerative colitis. J Clin Pharm Ther. 2022 Jul;47(7):851-9.
39. Burmester GR, Mysler E, Taylor P, Hall S, Wick-Urban B, Garrison A, et al. Benefit–risk analysis of upadacitinib versus adalimumab in patients with rheumatoid arthritis and higher or lower risk of cardiovascular disease. RMD Open. 2025 Jun 3;11 (2):e005371.
40. Yang H, An T, Zhao Y, Shi X, Wang B, Zhang Q. Cardiovascular safety of Janus kinase inhibitors in inflammatory bowel disease: A systematic review and network meta-analysis. Ann Med. 2025 Dec;57 (1):2455536.
41. Bieber T, Feist E, Irvine AD, Harigai M, Haladyj E, Ball S, et al. A review of safety outcomes from clinical trials of baricitinib in rheumatology, dermatology and COVID-19. Adv Ther. 2022;39 (11):4910-60.
42. Fakhouri W, Wang X, de la Torre I, Nicolay C. A network meta-analysis to compare effectiveness of baricitinib and other treatments in rheumatoid arthritis patients with inadequate response to methotrexate. J Health Econ Outcomes Res. 2020 Apr 10;7(1):10-23.
43. Zeng L, Feng S, Yao L, Wang B, Zhang G. Efficacy and safety of upadacitinib for the treatment of moderate-to-severe atopic dermatitis: A meta-analysis of randomized clinical trials. Adv Dermatol Allergol. 2023 Dec;40(6):734-40.
44. Genovese MC, Greenwald MW, Gutierrez-Ureña SR, Cardiel MH, Poiley JE, Zubrzycka-Sienkiewicz A, et al. Two-year safety and effectiveness of peficitinib in moderate-to-severe rheumatoid arthritis: A phase IIb, open-label extension study. Rheumatol Ther. 2019 Dec;6(4):503-20.
45. Lee YH, Song GG. Comparative efficacy and safety of tofacitinib, baricitinib, upadacitinib, filgotinib and peficitinib as monotherapy for active rheumatoid arthritis. J Clin Pharm Ther. 2020 Aug;45(4):674-81.
46. Gadina M, Schwartz DM, O’Shea JJ. Decernotinib: A next-generation jakinib. Arthritis Rheumatol. 2016 Jan;68(1):31-4.
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