Dynamics of clinical manifestations and cytokine concentrations in rheumatoid arthritis patients on tofacitinib therapy

Objective - to study the dynamics of clinical and laboratory parameters of inflammatory activity of the disease and cytokines in rheumatoid arthritis (RA) patients on a background of tofacitinib (TOFA) treatment.

Material and methods. Ten patients with a reliable diagnosis of RA have been examined: patients' age was 51.0 (48.0; 62.0) years, duration of disease was 7.0 (3.0; 20.0) years. All patients had high disease activity: DAS28 -5.88 (5.53; 5.94), CDAI - 33.0 (29.0; 36.0), SDAI - 33.72 (30.75; 36.85). All patients were treated with TOFA at a dose of 5 mg 2 times a day on a background of methotrexate therapy, non-steroidal anti-inflammatory drugs, and glucocorticoids. Observations were performed before treatment and after 3 and 6 months of therapy. Serum levels of 15 cytokines (IL-1β, IL-4, IL-6, TNF-α, INF-γ, IL-10, IL-17A, IL-17F, IL-21, IL-22, IL-23, IL-25, IL-31, IL-33, sCD40L) were examined using multiplex xMAP technology.

After 3 and 6 months of TOFA therapy, there was a significant decrease in DAS28 of 4.55 (3.47; 5.16) and 3.92 (3.80; 4.60); CDAI - 16.5 (11.0; 23.0) and 18.0 (15.0; 19.0); SDAI - 16.6 (11.23; 23.06) and 18.07 (15.06; 19.10); ESR - 19.0 (11.0; 26.0) and 7.0 (4.0; 18.0); CRP - 0.56 (0.50; 1.99) and 0.71 (0.51; 1.1) respectively. IL-6 levels decreased after 3 and 6 months of therapy (p<0.05). The concentration of INF-γ significantly decreased after 3 months (p<0.05), but remained unchanged thereafter. Concentrations of IL-25 and IL-31 decreased after 3 months (p<0.05), and by the 6th month of treatment there was an increase, however, not reaching the initial values.

Conclusion. The results of the study show the efficacy of TOFA in RA and create prerequisites for further study of the cytokine-dependent mechanisms of inflammation in this disease.

1. Nasonov EL, Karateev DE. Rheumatoid arthritis. Rheumatology. Russian Clinical Guidelines. Moscow:GEOTAR-Media;2020:17-57 (In Russ.).

2. Smolen JS, Aletaha D, Barton A, Burmester GR, Emery P, Firestein GS, et al. Rheumatoid arthritis. Nat Rev Dis Primers. 2018;4:18001. doi: 10.1038/nrdp.2018.1

3. McInnes IB, Schett G. The pathogenesis of rheumatoid arthritis. N Engl J Med. 2011;365(23):2205-2219. doi: 10.1056/NEJMra1004965

4. Smolen JS, Aletaha D, Bijlsma JW, Breedveld FC, Boumpas D, Burmester G, et al.; T2T Expert Committee. Treating rheumatoid arthritis to target: Recommendations of an international task force. Ann Rheum Dis. 2010;69(4):631-637. doi: 10.1136/ard.2009.123919

5. Smolen JS, Landewc RBM, Bijlsma JWJ, Burmester GR, Dougados M, Kerschbaumer A, et al. EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs: 2019 update. Ann Rheum Dis. 2020;79(6):685-699. doi: 10.1136/annrheumdis-2019-216655

6. Fraenkel L, Bathon JM, England BR, StClair EW, Arayssi T, Carandang K, et al. 2021 American College of Rheumatology guideline for the treatment of rheumatoid arthritis. Arthritis Rheumatol. 2021;73(7):1108-1123. doi: 10.1002/art.41752

7. Nasonov EL (ed.). Rheumatology. Russian Clinical Guidelines. Moscow:GEOTAR-Media;2017 (In Russ.).

8. Schwartz DM, Kanno Y, Villarino A, Ward M, Gadina M, O'Shea JJ. JAK inhibition as a therapeutic strategy for immune and inflammatory diseases. Nat Rev Drug Discov. 2017;16(12):843-862. doi: 10.1038/nrd.2017.201

9. Nasonov EL, Lila AM. Janus kinase inhibitors in immuno-inflammatory rheumatic diseases: New opportunities and prospects. Nauchcno-Prakticheskaya Revmatologia = Rheumatology Science and Practice. 2019;57(1):8-16 (In Russ.). doi: 10.14412/1995-4484-2019-8-16

10. Nasonov EL. New approaches to pharmacotherapy of rheumatoid arthritis: Tofacitinib. Nauchcno-Prakticheskaya Revmatologia = Rheumatology Science and Practice. 2014;52(2):209-221 (In Russ.). doi: 10.14412/1995-4484-2014-209-221

11. Nasonov EL, Avdeeva AS, Lila AM. Efficacy and safety of tofacitinib for immune-mediated inflammatory rheumatic diseases (Part I). Nauchcno-Prakticheskaya Revmatologia = Rheumatology Science and Practice. 2020;58(1):62-79 (In Russ.). doi: 10.14412/1995-4484-2020-62-79

12. Nash P, Kerschbaumer A, Dorner T, Dougados M, Fleischmann RM, Geissler K, et al. Points to consider for the treatment of immune-mediated inflammatory diseases with Janus kinase inhibitors: A consensus statement. Ann Rheum Dis. 2021;80(1):71-87. doi: 10.1136/annrheumdis-2020-218398

13. Dhillon S. Tofacitinib: A review in rheumatoid arthritis. Drugs. 2017;77(18):1987-2001. doi: 10.1007/s40265-017-0835-9

14. Avdeeva AS, Misiyuk AS, Satybaldyev AM, Lukina GV, Sorotskaya VN, Zhilyaev EV, et al. Analysis of the results of tofaci-tinib therapy in real clinical practice according to the all-Russian arthritis registry (OREL). Nauchcno-Prakticheskaya Revmatologia = Rheumatology Science and Practice. 2020;58(3):262-267 (In Russ.). doi: 10.14412/1995-4484-2020262-267

15. Karateev DE, Abdulganieva DE, Babaeva AR, Baranov AA, Evstigneeva LP, Ivanova ON, et al. The effect of tofacitinib on function and quality of life indicators in patients with rheumatoid arthritis resistant to synthetic and biological disease-modifying antirheumatic drugs in real clinical practice: Results of a multicenter observational study. Modern Rheumatology Journal. 2017;11(1):12-18 (In Russ.). doi: 10.14412/1996-7012-2017-1-12-18

16. Luchikhina EL, Karateev DE, Demidova NV, Musiyuk AS, Aleksandrova EN, Novikov AA, et al. Efficacy and safety of Tofacitinib in patients with active rheumatoid arthritis resistant to conventional therapy: Preliminary results of an open-label clinical trial. Modern Rheumatology Journal. 2016;10(2):17-23 (In Russ.). doi: 10.14412/1996-7012-2016-2-17-23

17. Caporali R, Zavaglia D. Real-world experience with tofacitinib for the treatment of rheumatoid arthritis. Clin Exp Rheumatol. 2019;37(3):485-495.

18. Migita K, Izumi Y, Jiuchi Y, Kozuru H, Kawahara C, Izumi M, et al. Effects of Janus kinase inhibitor tofacitinib on circulating serum amyloid A and interleukin-6 during treatment for rheumatoid arthritis. Clin Exp Immunol. 2014;175(2):208-214. doi: 10.1111/cei.12234

19. Li Y, Jie Y, Wang X, Lu J. Serum IL-35 is decreased in overweight patients with rheumatoid arthritis: Its correlation with Th1/Th2/Th17-related cytokines. BMC Immunol. 2021;22(1):42. doi: 10.1186/s12865-021-00431-x

20. Aletaha D, Neogi T, Silman AJ, Funovits J, Felson DT, Bingham CO 3rd, et al. 2010 rheumatoid arthritis classification criteria: An American College of Rheumatology/European League Against Rheumatism collaborative initiative. Arthritis Rheum. 2010;62(9):2569-2581. doi: 10.1002/art.27584

21. Novikov AA, Aleksandrova EN, Gerasimov AN, Karateev DE, Popkova TV, Luchikhina EL, et al. Use of multiparameter analysis of laboratory biomarkers to assess rheumatoid arthritis activity. Nauchcno-Prakticheskaya Revmatologia = Rheumatology Science and Practice. 2015;53(6):591-595 (In Russ.). doi: 10.14412/1995-4484-2015591-595

22. Eastman PS, Manning WC, Qureshi F, Haney D, Cavet G, Alexander C, et al. Characterization of a multiplex, 12-biomarker test for rheumatoid arthritis. J Pharm Biomed Anal. 2012;70:415-424. doi: 10.1016/j.jpba.2012.06.003

23. Centola M, Cavet G, Shen Y, Ramanujan S, Knowlton N, Swan KA, et al. Development of a multi-biomarker disease activity test for rheumatoid arthritis. PLoS One. 2013;8(4):e60635. doi: 10.1371/journal.pone.0060635

24. Laborde CM, Castro-Santos P, Díaz-Peña R. Contribution of multiplex immunoassays to rheumatoid arthritis management: From biomarker discovery to personalized medicine. J Pers Med. 2020;10(4):202. doi: 10.3390/jpm10040202

25. Liu C, Chu D, Kalantar-Zadeh K, George J, Young HA, Liu G. Cytokines: From clinical significance to quantification. Adv Sci (Weinh). 2021;8(15):e2004433. doi: 10.1002/advs.202004433

26. Burska A, Boissinot M, Ponchel F. Cytokines as biomarkers in rheumatoid arthritis. Mediators Inflamm. 2014;2014:545493. doi: 10.1155/2014/545493

27. Ridgley LA, Anderson AE, Pratt AG. What are the dominant cytokines in early rheumatoid arthritis? Curr Opin Rheumatol. 2018;30(2):207-214. doi: 10.1097/BOR.0000000000000470

28. McInnes IB, Byers NL, Higgs RE, Lee J, Macias WL, Na S, et al. Comparison of baricitinib, upadacitinib, and tofacitinib mediated regulation of cytokine signaling in human leukocyte subpopulations. Arthritis Res Ther. 2019;21(1):183. doi: 10.1186/s13075-019-1964-1

29. Dowty ME, Lin TH, Jesson MI, Hegen M, Martin DA, Katkade V, et al. Janus kinase inhibitors for the treatment of rheumatoid arthritis demonstrate similar profiles of in vitro cytokine receptor inhibition. Pharmacol Res Perspect. 2019;7(6):e00537. doi: 10.1002/prp2.537