IL-31 and IL-33 in rheumatoid arthritis patients

Objective – to investigate clinical and diagnostic significance of IL-31 and IL-33 determination in patients with rheumatoid arthritis (RA).

Material and methods. 154 patients with a reliable diagnosis of RA were examined. Serum levels of IL-31 and IL-33 were studied using multiplex xMAP technology on Bio-PlexTM 200 System analyzer (BIO-RAD, USA). The upper limit of the norm in the study of 20 healthy donor sera was (M+3σ): IL-31 – 15.08 pg/ml, IL-33 – 3.40 pg/ml.

Results. IL-31 (Me (25th; 75th percentile) – 13.75 (5.63; 308.52) and 6.10 (2.87; 8.62) pg/ml (p<0.001), IL-33 – 18.86 (7.45; 65.95) and 0.52 (0.17; 0.78) pg/ml (p><0.001) levels were observed in RA patients in comparison with the control group. An increase in IL-33 concentration (more than 3.40 pg/ml) was observed in 87.0% of patients, and IL-31 (more than 15.08 pg/ml) in 48.1% of patients with RA. An increase in IL-33 alone was observed in 42.2% (65 of 154 patients) with RA, while an isolated increase in IL-31 concentration was observed in only 2 (1.3%) patients. Simultaneous hyperproduction of IL-33 and IL-31 occurred in 69 (44.9%) patients. We revealed positive correlation of clinical and laboratory parameters of RA with cytokine concentration: SDAI correlated with IL-33 (r=0.36; p><0.05); CRP – with IL-31 (r=0.49; p><0,05) and IL-33 (r=0.40; p><0.05). Conclusion. Concentrations of IL-31 and IL-33 are elevated in RA patients and correlate with the indices of inflammatory activity of the disease.>< 0.001), IL-33 – 18.86 (7.45; 65.95) and 0.52 (0.17; 0.78) pg/ml (p<0.001) levels were observed in RA patients in comparison with the control group. An increase in IL-33 concentration (more than 3.40 pg/ml) was observed in 87.0% of patients, and IL-31 (more than 15.08 pg/ml) in 48.1% of patients with RA. An increase in IL-33 alone was observed in 42.2% (65 of 154 patients) with RA, while an isolated increase in IL-31 concentration was observed in only 2 (1.3%) patients. Simultaneous hyperproduction of IL-33 and IL-31 occurred in 69 (44.9%) patients. We revealed positive correlation of clinical and laboratory parameters of RA with cytokine concentration: SDAI correlated with IL-33 (r=0.36; p><0.05); CRP – with IL-31 (r=0.49; p><0,05) and IL-33 (r=0.40; p><0.05). Conclusion. Concentrations of IL-31 and IL-33 are elevated in RA patients and correlate with the indices of inflammatory activity of the disease.>< 0.001) levels were observed in RA patients in comparison with the control group. An increase in IL-33 concentration (more than 3.40 pg/ml) was observed in 87.0% of patients, and IL-31 (more than 15.08 pg/ml) in 48.1% of patients with RA. An increase in IL-33 alone was observed in 42.2% (65 of 154 patients) with RA, while an isolated increase in IL-31 concentration was observed in only 2 (1.3%) patients. Simultaneous hyperproduction of IL-33 and IL-31 occurred in 69 (44.9%) patients. We revealed positive correlation of clinical and laboratory parameters of RA with cytokine concentration: SDAI correlated with IL-33 (r=0.36; p<0.05); CRP – with IL-31 (r=0.49; p><0,05) and IL-33 (r=0.40; p><0.05). Conclusion. Concentrations of IL-31 and IL-33 are elevated in RA patients and correlate with the indices of inflammatory activity of the disease.>< 0.05); CRP – with IL-31 (r=0.49; p< ,05) and IL-33 (r=0.40; p<0.05)

Conclusion. Concentrations of IL-31 and IL-33 are elevated in RA patients and correlate with the indices of inflammatory activity of the disease.

1. Smolen JS, Aletaha D, McInnes IB. Rheumatoid arthritis. Lancet. 2016;388(10055):2023–2038. doi: 10.1016/S0140-6736(16)30173-8

2. McInnes IB, Buckley CD, Isaacs JD. Cytokines in rheumatoid arthritis – Shaping the immunological landscape. Nat Rev Rheumatol. 2016;12(1):63–68. doi: 10.1038/nrrheum.2015.171

3. 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

4. Alunno A, Carubbi F, Giacomelli R, Gerli R. Cytokines in the pathogenesis of rheumatoid arthritis: New players and therapeutic targets. BMC Rheumatol. 2017;1:3. doi: 10.1186/s41927-017-0001-8

5. Chen Z, Bozec A, Ramming A, Schett G. Anti-inflammatory and immune-regulatory cytokines in rheumatoid arthritis. Nat Rev Rheumatol. 2019;15(1):9–17. doi: 10.1038/s41584-

6. 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

7. Kany S, Vollrath JT, Relja B. Cytokines in inflammatory disease. Int J Mol Sci. 2019;20(23):6008. doi: 10.3390/ijms20236008

8. Dong Y, Zhong J, Dong L. IL-33 in rheumatic diseases. Front Med (Lausanne). 2021;8:739489. doi: 10.3389/fmed.2021.739489

9. Akdis M, Aab A, Altunbulakli C, Azkur K, Costa RA, Crameri R, et al. Interleukins (from IL-1 to IL-38), interferons, transforming growth factor β, and TNF-α: Receptors, functions, and roles in diseases. J Allergy Clin Immunol. 2016;138(4):984–1010. doi: 10.1016/j.jaci.2016.06.033.

10. Murdaca G, Greco M, Tonacci A, Negrini S, Borro M, Puppo F, et al. IL-33/IL-31 axis in immune-mediated and allergic diseases. Int J Mol Sci. 2019;20(23):5856. doi: 10.3390/ijms20235856

11. Cayrol C. IL-33, an alarmin of the IL-1 family involved in allergic and non allergic inflammation: Focus on the mechanisms of regulation of its activity. Cells. 2021;11(1):107. doi: 10.3390/ cells11010107

12. Borgia F, Custurone P, Li Pomi F, Cordiano R, Alessandrello C, Gangemi S. IL-31: State of the art for an inflammation-oriented interleukin. Int J Mol Sci. 2022;23(12):6507. doi: 10.3390/ ijms23126507

13. Pelaia C, Pelaia G, Longhini F, Crimi C, Calabrese C, Gallelli L, et al. Monoclonal antibodies targeting alarmins: A new perspective for biological therapies of severe asthma. Biomedicines. 2021;9(9):1108. doi: 10.3390/biomedicines9091108

14. 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

15. England BR, Tiong BK, Bergman MJ, Curtis JR, Kazi S, Mikuls TR, et al. 2019 update of the American College of Rheumatology recommended rheumatoid arthritis disease activity measures. Arthritis Care Res (Hoboken). 2019;71(12):1540–1555. doi: 10.1002/acr.24042

16. 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. Nauchno-Prakticheskaya Revmatologia = Rheumatology Science and Practice. 2015;53(6):591–595 (In Russ.). doi: 10.14412/1995-4484-2015-591-595

17. 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

18. 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

19. 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

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

21. Palmer G, Talabot-Ayer D, Lamacchia C, Toy D, Seemayer CA, Viatte S, et al. Inhibition of interleukin-33 signaling attenuates the severity of experimental arthritis. Arthritis Rheum. 2009;60(3): 738–749. doi: 10.1002/art.24305

22. Li Y, Fu Y, Chen H, Liu X, Li M. Blocking interleukin-33 alleviates the joint inflammation and inhibits the development of collagen-induced arthritis in mice. J Immunol Res. 2020;2020:4297354. doi: 10.1155/2020/4297354

23. Xu D, Jiang HR, Kewin P, Li Y, Mu R, Fraser AR, et al. IL-33 exacerbates antigen-induced arthritis by activating mast cells. Proc Natl Acad Sci U S A. 2008;105(31):10913–10918. doi: 10.1073/ pnas.0801898105

24. Xu D, Jiang HR, Li Y, Pushparaj PN, Kurowska-Stolarska M, Leung BP, et al. IL-33 exacerbates autoantibody-induced arthritis. J Immunol. 2010;184(5):2620–2626. doi: 10.4049/jimmunol.0902685

25. Kunisch E, Chakilam S, Gandesiri M, Kinne RW. IL-33 regulates TNF-α dependent effects in synovial fibroblasts. Int J Mol Med. 2012;29(4):530–540. doi: 10.3892/ijmm.2012.883

26. Biton J, Khaleghparast Athari S, Thiolat A, Santinon F, Lemeiter D, Hervé R, et al. In vivo expansion of activated Foxp3+ regulatory T cells and establishment of a type 2 immune response upon IL-33 treatment protect against experimental arthritis. J Immunol. 2016;197(5):1708–1719. doi: 10.4049/jimmunol.1502124

27. Rivellese F, Suurmond J, Habets K, Dorjée AL, Ramamoorthi N, Townsend MJ, et al. Ability of interleukin-33- and immune complex-triggered activation of human mast cells to down-regulate monocyte-mediated immune responses. Arthritis Rheumatol. 2015;67(9):2343–2353. doi: 10.1002/art.39192

28. Lee EJ, So MW, Hong S, Kim YG, Yoo B, Lee CK. Interleukin-33 acts as a transcriptional repressor and extracellular cytokine in fibroblast-like synoviocytes in patients with rheumatoid arthritis. Cytokine. 2016;77:35–43. doi: 10.1016/j.cyto.2015.10.005

29. Ahmed A, Koma MK. Interleukin-33 triggers B1 cell expansion and its release of monocyte/macrophage chemoattractants and growth factors. Scand J Immunol. 2015;82(2):118–124. doi: 10.1111/sji.12312

30. Sattler S, Ling GS, Xu D, Hussaarts L, Romaine A, Zhao H, et al. IL-10-producing regulatory B cells induced by IL-33 (Breg(IL-33)) effectively attenuate mucosal inflammatory responses in the gut. J Autoimmun. 2014;50(100):107–122. doi: 10.1016/j.jaut.2014.01.032

31. Hong YS, Moon SJ, Joo YB, Jeon CH, Cho ML, Ju JH, et al. Measurement of interleukin-33 (IL-33) and IL-33 receptors (sST2 and ST2L) in patients with rheumatoid arthritis. J Korean Med Sci. 2011;26(9):1132–1139. doi: 10.3346/jkms.2011.26.9.1132

32. Erfurt S, Hoffmeister M, Oess S, Asmus K, Ritter O, Patschan S, et al. Serum IL-33 as a biomarker in different diseases: Useful parameter or much need for clarification? J Circ Biomark. 2021;10:20–25. doi: 10.33393/jcb.2021.2327

33. Mu R, Huang HQ, Li YH, Li C, Ye H, Li ZG. Elevated serum interleukin 33 is associated with autoantibody production in patients with rheumatoid arthritis. J Rheumatol. 2010; 37(10):2006–2013. doi: 10.3899/jrheum.100184

34. Tang S, Huang H, Hu F, Zhou W, Guo J, Jiang H, et al. Increased IL-33 in synovial fluid and paired serum is associated with disease activity and autoantibodies in rheumatoid arthritis. Clin Dev Immunol. 2013;2013:985301. doi: 10.1155/2013/985301

35. Choi IA, Lee SJ, Park W, Park SH, Shim SC, Baek HJ, et al. Effects of tocilizumab therapy on serum interleukin-33 and interleukin-6 levels in patients with rheumatoid arthritis. Arch Rheumatol. 2018;33(4):389–394. doi: 10.5606/ArchRheumatol.2018.6753

36. Xiangyang Z, Lutian Y, Lin Z, Liping X, Hui S, Jing L. Increased levels of interleukin-33 associated with bone erosion and interstitial lung diseases in patients with rheumatoid arthritis. Cytokine. 2012;58(1):6–9. doi: 10.1016/j.cyto.2011.12.010

37. Kageyama Y, Torikai E, Tsujimura K, Kobayashi M. Involvement of IL-33 in the pathogenesis of rheumatoid arthritis: the effect of etanercept on the serum levels of IL-33. Mod Rheumatol. 2012;22(1):89–93. doi: 10.1007/s10165-011-0480-1

38. Shen J, Shang Q, Wong CK, Li EK, Wang S, Li RJ, et al. IL-33 and soluble ST2 levels as novel predictors for remission and progression of carotid plaque in early rheumatoid arthritis: A prospective study. Semin Arthritis Rheum. 2015;45(1):18–27. doi: 10.1016/j.semarthrit.2015.02.001

39. Shi LJ, Liu C, Li JH, Zhu XY, Li YN, Li JT. Elevated levels of soluble ST2 were associated with rheumatoid arthritis disease activity and ameliorated inflammation in synovial fibroblasts. Chin Med J (Engl). 2018;131(3):316–322. doi: 10.4103/0366- 6999.223847

40. Matsuyama Y, Okazaki H, Hoshino M, Onishi S, Kamata Y, Nagatani K, et al. Sustained elevation of interleukin-33 in sera and synovial fluids from patients with rheumatoid arthritis non-responsive to anti-tumor necrosis factor: Possible association with persistent IL-1β signaling and a poor clinical response. Rheumatol Int. 2012;32(5):1397–1401. doi: 10.1007/s00296-011-1854-6

41. Sellam J, Rivière E, Courties A, Rouzaire PO, Tolusso B, Vital EM, et al. Serum IL-33, a new marker predicting response to rituximab in rheumatoid arthritis. Arthritis Res Ther. 2016; 18(1):294. doi: 10.1186/s13075-016-1190-z

42. Rivière E, Sellam J, Pascaud J, Ravaud P, Gottenberg JE, Mariette X. Serum IL-33 level is associated with auto-antibodies but not with clinical response to biologic agents in rheumatoid arthritis. Arthritis Res Ther. 2018;20(1):122. doi: 10.1186/s13075-018- 1628-6