Translating research to clinical application: The utilization of JAK inhibitors in scleroderma

Abstract

The clinical characteristics and prognosis of scleroderma (SSc), an uncommon autoimmune disease, can vary widely. There is no specific treatment for SSc. Medications used for the treatment of SSc, such as tocilizumab, cyclophosphamide, mycophenolate mofetil, and nintedanib, have a range of potential side effects. More than 50 ligands have been shown to activate the JAK/STAT signalling pathway, which plays a role in cell signal transmission through an evolutionarily conserved mechanism. The pathway of JAK/STAT signalling contributes to autoimmune. JAK inhibitors are tiny compounds with various molecular configurations. Patient illness development is only slightly slowed down or stabilised when these medications are used. In animal models of SSc, JAK inhibitors decreased pulmonary and cutaneous fibrosis. There are only few clinical studies on the effectiveness and safety of JAK inhibitors in individuals with SSc. In particular, tofacitinib and baricitinib are used for treating SSc. The reduction in the modified rodnan skin score after treatment initiation was more significant in patients with previously untreated SSc. JAK inhibitors may be a safe and effective treatment option for skin fibrosis and interstitial lung disease in SSc. This review examines the application of JAK inhibitors in scleroderma, encompassing both fundamental research and clinical investigations. In the future, JAK inhibitors may serve as a prospective treatment for SSc; nonetheless, the paramount consideration remains the patient’s well-being and quality of life. The realization of this part will be contingent upon the completion of clinical trials.

Keywords

• SSc
• JAK inhibitors
• Treatment

References

1. Aittomaki, S., & Pesu, M. (2014). Therapeutic targeting of the Jak/STAT pathway. Basic & clinical pharmacology & toxicology, 114(1), 18-23. google scholar
2. Aung, W. W., Wang, C., Xibei, J., Horii, M., Mizumaki, K., Kano, M., Okamura, A., ... Matsushita, T. (2021). Immunomodulating role of the JAKs inhibitor tofacitinib in a mouse model of bleomycin-induced scleroderma. Journal of dermatological science, 101(3), 174-184. google scholar
3. Cao, X. Y., Zhao, J. L., Hou, Y., Wang, F. D., & Lu, Z. H. (2020). Janus kinase inhibitor tofacitinib is a potential therapeutic op-tion for refractory eosinophilic fasciitis. Clinical and experimental rheumatology, 38(3), 567-568. google scholar
4. Chen, C., Yin, Y., Shi, G., Zhou, Y., Shao, S., Wei, Y., Wu, L., Zhang, D., Sun, L., & Zhang, T. (2022). A highly selective JAK3 in-hibitor is developed for treating rheumatoid arthritis by suppress-ing c cytokine-related JAK-STAT signal. Science advances, 8(33), eabo4363. google scholar
5. Damsky, W., Patel, D., Garelli, C. J., Garg, M., Wang, A., Dresser, K., ... King, B. (2020). Jak Inhibition Prevents Bleomycin-Induced Fibrosis in Mice and Is Effective in Patients with Morphea. The Journal of investigative dermatology, 140(7), 1446-1449.e4. google scholar
6. Darnell, J. E., Jr, Kerr, I. M., & Stark, G. R. (1994). Jak-STAT pathways and transcriptional activation in response to IFNs and other extra-cellular signaling proteins. Science (New York, N.Y.), 264(5164), 1415-1421. google scholar
7. Dees, C., Tomcik, M., Palumbo-Zerr, K., Distler, A., Beyer, C., Lang, V., ... Distler, J. H. (2012). JAK-2 as a novel mediator of the profibrotic effects of transforming growth factor 0 in systemic sclerosis. Arthritis and rheumatism, 64(9), 3006-3015. google scholar
8. Delany, A. M., & Brinckerhoff, C. E. (1993). The synthetic retinoid (4-hydroxyphenyl)retinamide decreases collagen expression in vitro and in the tight-skin mouse. Arthritis and rheumatism, 36(7), 983-993. google scholar

9. Distler, O., Highland, K. B., Gahlemann, M., Azuma, A., Fischer, A., Mayes, M. D., ... SENSCIS Trial Investigators (2019). Nintedanib for Systemic Sclerosis-Associated Interstitial Lung Disease. The New England journal of medicine, 380(26), 2518-2528. google scholar
10. Gadina, M., Chisolm, D. A., Philips, R. L., McInness, I. B., Changelian, P. S., & O’Shea, J. J. (2020). Translating JAKs to Jakinibs. Journal of immunology (Baltimore, Md. : 1950), 204(8), 2011-2020. google scholar
11. Gulle S., Çelik A., Lebe B., Ulukus C., Barış M., et al. (2023). pos0628 Baricitinib ameliorates bleomycin-induced pulmonary and skin fibrosis via Jak 1/2 inhibition. Annals of Rheumatology, 82:588-589. google scholar
12. Harrison, D. A. (2012). The jak/stat pathway. Cold Spring Harbor perspectives in biology, 4(3), a011205. google scholar
13. Hu, X., Li, J., Fu, M., Zhao, X., & Wang, W. (2021). The JAK/STAT signaling pathway: from bench to clinic. Signal transduction and targeted therapy, 6(1), 402. google scholar
14. Hurabielle, C., Sicre de Fontbrune, F., Moins-Teisserenc, H., Robin, M., Jachiet, M., Coman, T., ... Bouaziz, J. D. (2017). Efficacy and tolerance of ruxolitinib in refractory sclerodermatous chronic graft-versus-host disease. The British journal of dermatology, 177(5), e206-e208. google scholar
15. Hou, Z., Su, X., Han, G., Xue, R., Chen, Y., Chen, Y., ... Ji, S. (2022). JAK1/2 Inhibitor Baricitinib Improves Skin Fibrosis and Digital Ulcers in Systemic Sclerosis. Frontiers in medicine, 9, 859330. google scholar
16. Khanna, D., Padilla, C., Tsoi, L. C., Nagaraja, V., Khanna, P. P., Tabib, T., ... Lafyatis, R. (2022). Tofacitinib blocks IFN-regulated biomarker genes in skin fibroblasts and keratinocytes in a systemic sclerosis trial. JCI insight, 7(17), e159566. google scholar
17. Khoury, H. J., Langston, A. A., Kota, V. K., Wilkinson, J. A., Pusic, I., Jillella, A., ... DiPersio, J. F. (2018). Ruxolitinib: a steroid sparing agent in chronic graft-versus-host disease. Bone marrow transplantation, 53(7), 826-831. google scholar
18. Kim, S. R., Charos, A., Damsky, W., Heald, P., Girardi, M., & King, B. A. (2018). Treatment of generalized deep morphea and eosinophilic fasciitis with the Janus kinase inhibitor tofacitinib. JAAD case reports, 4(5), 443-445. google scholar
19. Kitanaga, Y., Imamura, E., Nakahara, Y., Fukahori, H., Fujii, Y., Kubo, S., Nakayamada, S., & Tanaka, Y. (2019). In vitro pharmacological effects of peficitinib on lymphocyte activation: a potential treat-ment for systemic sclerosis with JAK inhibitors. Rheumatology (Oxford, England), 59, 1957 - 1968. google scholar
20. Leonard, W. J., & O’Shea, J. J. (1998). Jaks and STATs: biological implications. Annual review of immunology, 16, 293-322. google scholar
21. Lescoat, A., Lelong, M., Jeljeli, M., Piquet-Pellorce, C., Morzadec, C., Ballerie, A., ... Lecureur, V.(2020). Combined anti-fibrotic and anti-inflammatory properties of JAK-inhibitors on macrophages in vitro and in vivo: Perspectives for scleroderma-associated inter-stitial lung disease. Biochemical pharmacology, 178, 114103. google scholar
22. Mendoza, F. A., Piera-Velazquez, S., & Jimenez, S.A. (2021). Tyrosine kinases in the pathogenesis of tissue fibrosis in systemic sclerosis and potential therapeutic role of their inhibition. Translational research : the journal of laboratory and clinical medicine, 231, 139-158. google scholar
23. Moriana, C., Moulinet, T., Jaussaud, R., & Decker, P. (2022). JAK inhibitors and systemic sclerosis: A systematic review of the liter-ature. Autoimmunity reviews, 21(10), 103168. google scholar
24. Okiyama, N., Furumoto, Y., Villarroel, V. A., Linton, J. T., Tsai,W. L., Gutermuth, J., ... Katz, S. I. (2014). Reversal of CD8 T-cell-mediated mucocutaneous graft-versus-host-like disease by the JAK inhibitor tofacitinib. The Journal of investigative dermatol-ogy, 134(4), 992-1000. google scholar
25. Perelas, A., Silver, R. M., Arrossi, A. V., & Highland, K. B. (2020). Systemic sclerosis-associated interstitial lung disease. The Lancet. Respiratory medicine, 8(3), 304-320. google scholar
26. Pokeerbux, M. R., Giovannelli, J., Dauchet, L., Mouthon, L., Agard, C., Lega, J. C., ... Launay, D. (2019). Survival and prognosis factors in systemic sclerosis: data of a French multicenter cohort, systematic review, and meta-analysis of the literature. Arthritis research & therapy, 21(1), 86. google scholar
27. Jerjen, R., Nikpour, M., Krieg, T., Denton, C. P., & Saracino, A. M. (2022). Systemic sclerosis in adults. Part II: management and therapeutics. Journal of the American Academy of Dermatology, 87(5), 957-978. google scholar
28. Seif, F., Khoshmirsafa, M., Aazami, H., Mohsenzadegan, M., Sedighi, G., & Bahar, M. (2017). The role of JAK-STAT signaling pathway and its regulators in the fate of T helper cells. Cell communication and signaling : CCS, 15(1), 23. google scholar
29. Shawky, A. M., Almalki, F. A., Abdalla, A. N., Abdelazeem, A. H., & Gouda, A. M. (2022). A Comprehensive Overview of Globally Approved JAK Inhibitors. Pharmaceutics, 14(5), 1001. google scholar
30. Sobanski, V., Giovannelli, J., Allanore, Y., Riemekasten, G., Airo, P., Vettori, S., ... EUSTAR Collaborators (2019). Phenotypes Deter-mined by Cluster Analysis and Their Survival in the Prospective European Scleroderma Trials and Research Cohort of Patients With Systemic Sclerosis. Arthritis & rheumatology (Hoboken, N.J.), 71(9), 1553-1570. google scholar
31. Tashkin, D. P., Elashoff, R., Clements, P. J., Goldin, J., Roth, M. D., Furst, D. E., ... Scleroderma Lung Study Research Group (2006). Cyclophosphamide versus placebo in scleroderma lung disease. The New England journal of medicine, 354(25), 2655-2666. google scholar
32. Tashkin, D. P., Roth, M. D., Clements, P. J., Furst, D. E., Khanna, D., Kleerup, E. C., ... Sclerodema Lung Study II Investigator (2016). Mycophenolate mofetil versus oral cyclophosphamide in scleroderma-related interstitial lung disease (SLS II): a ran-domised controlled, double-blind, parallel group trial. The Lancet. Respiratory medicine, 4(9), 708-719. google scholar
33. Taylor, P. C. (2019). Clinical efficacy of launched JAK inhibitors in rheumatoid arthritis. Rheumatology, 58(Supplement_1), i17-i26. google scholar
34. Xiao, R., Kanekura, T., Yoshida, N., Higashi, Y., Yan, K. L., Fukushige, T., & Kanzaki, T. (2008). 9-Cis-retinoic acid exhibits antifibrotic activity via the induction of cyclooxygenase-2 expression and prostaglandin E2 production in scleroderma fibroblasts. Clinical and experimental dermatology, 33(4), 484-490. google scholar