Association of cytokine gene polymorphisms with the effectiveness of various types of therapy in patients with psoriasis

Introduction. The high variability of the cytokine profile in patients with psoriasis and the risk of adverse events (up to 30% of cases) make it difficult to choose the optimal therapy. In this regard, pharmacogenetics, which studies the effect of single- nucleotide polymorphisms of cytokine genes and their receptors on the effectiveness of treatment, is a promising area.

Aim. To evaluate the association of polymorphisms of genes IL-1B (rs16944), IL-2 (rs2069762), IL-4 (rs2243250), IL-6 (rs1800795), IL-10 (rs1800896, rs1800872), IL-12B (rs3212227), IL-15RA (rs2296135), IL-17A (rs2275913), IL-17F (rs612242), IL-23R (rs11209026), TNF (rs1800629) with dynamics of PASI and BSA indices in patients with moderate and severe psoriasis on the background of three therapy regimens: mometasone furoate, methotrexate and IL-17A inhibitor.

Materials and methods. The study included 155 patients (aged over 18 years, duration of the disease from 6 months to 3 years), randomized into 3 groups according to the treatment regimen. The clinical outcome was assessed after 3 months by reducing the PASI index by 50% or more (PASI 50) and the BSA index. Statistical processing was performed in the StatTech v. 4.11.2 program.

Results. The evaluation of the rs2296135 polymorphism of the IL15RA gene in group 1 (THCs) revealed a statistically significant association with the dynamics of both PASI and BSA (p = 0.02). Carriers of the T/T genotype showed the greatest decrease in PASI (19.89 ± 5.77), while homozygotes with C/C had practically no decrease (-0.004 ± 2.23). No significant associations were found in groups 2 and 3, although in group 2 there was a tendency for T/T carriers to be more effective. The remaining polymorphisms showed no significant associations.

Conclusion. The rs2296135 (IL15RA) polymorphism, the T/T genotype, is associated with higher efficacy of topical mometasone furoate therapy in patients with psoriasis, whereas the C/C genotype is associated with treatment resistance.

1. Kubanov AA, Bogdanova EV. Epidemiology of psoriasis in the Russian Federation according to the patient registry Vestnik dermatologii i venerologii. 2022;98(1):33–41. (In Russ.) https://doi.org/10.25208/vdv1268.

2. Benhadou F, Mintoff D, Del Marmol V. Psoriasis: Keratinocytes or Immune Cells – Which Is the Trigger? Dermatology. 2019;235(2):91–100. https://doi.org/10.1159/000495291.

3. Albanesi C, Madonna S, Gisondi P, Girolomoni G. The Interplay Between Keratinocytes and Immune Cells in the Pathogenesis of Psoriasis. Front Immunol. 2018;9:1549. https://doi.org/10.3389/fimmu.2018.01549.

4. Michalek IM, Loring B, John SM. A systematic review of worldwide epidemiology of psoriasis. J Eur Acad Dermatol Venereol. 2017;31(2):205–212. https://doi.org/10.1111/jdv.13854.

5. Rendon A, Schäkel K. Psoriasis Pathogenesis and Treatment. Int J Mol Sci. 2019;20(6):1475. https://doi.org/10.3390/ijms20061475.

6. Hanna N, Yang SB, McPhie ML, Kirchhof MG. Distribution of Cytokines and Their Receptors Targeted by Biologics in the Treatment of Psoriasis. J Cutan Med Surg. 2026:12034754251408380. https://doi.org/10.1177/12034754251408380.

7. Mohd Noor AA, Azlan M, Mohd Redzwan N. Orchestrated Cytokines Mediated by Biologics in Psoriasis and Its Mechanisms of Action. Biomedicines. 2022;10(2):498. https://doi.org/10.3390/biomedicines10020498.

8. Zhou X, Chen Y, Cui L, Shi Y, Guo C. Advances in the pathogenesis of psoriasis: from keratinocyte perspective. Cell Death Dis. 2022;13(1):81. https://doi.org/10.1038/s41419-022-04523-3.

9. Funakoshi A, Tatsuno K, Shimauchi T, Fujiyama T, Ito T, Tokura Y. Cholecystokinin Downregulates Psoriatic Inflammation by Its Possible Self-Regulatory Effect on Epidermal Keratinocytes. J Immunol. 2019;202(9):2609–2615. https://doi.org/10.4049/jimmunol.1801426.

10. Ehst B, Wang Z, Leitenberger J, McClanahan D, De La Torre R, Sawka E et al. Synergistic induction of IL-23 by TNFα, IL-17A, and EGF in keratinocytes. Cytokine. 2021;138:155357. https://doi.org/10.1016/j.cyto.2020.155357.

11. Chakith MRS, Pradeep S, Gangadhar M, Maheshwari NC, Pasha S, Kollur SP et al. Advancements in understanding and treating psoriasis: a comprehensive review of pathophysiology, diagnosis, and therapeutic approaches. PeerJ. 2025;13:e19325. https://doi.org/10.7717/peerj.19325.

12. Tan ES, Chong WS, Tey HL. Nail psoriasis: a review. Am J Clin Dermatol. 2012;13(6):375–388. https://doi.org/10.2165/11597000-000000000-00000.

13. Reynolds G, Vegh P, Fletcher J, Poyner EFM, Stephenson E, Goh I et al. Developmental cell programs are co-opted in inflammatory skin disease. Science. 2021;371(6527):eaba6500. https://doi.org/10.1126/science.aba6500.

14. Mercurio L, Failla CM, Capriotti L, Scarponi C, Facchiano F, Morelli M et al. Interleukin (IL)-17/IL-36 axis participates to the crosstalk between endothelial cells and keratinocytes during inflammatory skin responses. PLoS ONE. 2020;15(4):e0222969. https://doi.org/10.1371/journal.pone.0222969.

15. Warren RB, Smith CH, Yiu ZZN, Ashcroft DM, Barker JNWN, Burden AD et al. Differential Drug Survival of Biologic Therapies for the Treatment of Psoriasis: A Prospective Observational Cohort Study from the British Association of Dermatologists Biologic Interventions Register (BADBIR). J Invest Dermatol. 2015;135(11):2632–2640. https://doi.org/10.1038/jid.2015.208.

16. Gisondi P, Talamonti M, Chiricozzi A, Piaserico S, Amerio P, Balato A et al. Treat-to-Target Approach for the Management of Patients with Moderateto-Severe Plaque Psoriasis: Consensus Recommendations. Dermatol Ther. 2021;11(1):235-252. https://doi.org/10.1007/s13555-020-00475-8.

17. Lu J, Tang S, Xie S, Yi X, Yu N, Gao Y, Ding Y. The potential of IL- 12 in predicting clinical response to etanercept treatment in patients with psoriasis. Int J Clin Exp Med. 2016;9(12):23519–23524. Available at: https://ijcem.com/files/ijcem0037555.pdf.

18. Kubanova AA, Lesnaya IN, Frigo NV, Kaganova NL, Znamenskaya LF, Kubanov AA. Molecular Markers In Forecasting The Clinical Efficacy Of Infliximab In Psoriasis Patients. Vestnik Dermatologii i Venerologii. 2010;86(1):57–66. (In Russ.) https://doi.org/10.25208/vdv827.

19. Shatokhina EA, Egoshina IG, Bridan-Rostovskaya AS, Kruglova LS, Shatokhin MN. Pharmacogenetics of psoriasis: predictors of the efficacy of anticytokine biological therapy. Russian Journal of Allergy. 2024;21(1):167–176. (In Russ.) https://doi.org/10.36691/RJA16929.

20. Sokolik R, Iwaszko M, Świerkot J, Wysoczańska B, Korman L, Wiland P, Bogunia-Kubik K. Relationship Between Interleukin-6 -174G/C Genetic Variant and Efficacy of Methotrexate Treatment in Psoriatic Arthritis Patients. Pharmgenomics Pers Med. 2021;14:157–166. https://doi.org/10.2147/PGPM.S264555.

21. Indhumathi S, Rajappa M, Chandrashekar L, Ananthanarayanan PH, Thappa DM, Negi VS. Pharmacogenetic markers to predict the clinical response to methotrexate in south Indian Tamil patients with psoriasis. Eur J Clin Pharmacol. 2017;73(8):965–971. https://doi.org/10.1007/s00228-017-2255-x.

22. Melnichenko OO, Denisova EV, Zhukova OV, Potekaev NN. Basic genetic and biological markers of psoriasis. Consilium Medicum. 2021;23(8):672–675. (In Russ.) https://doi.org/10.26442/20751753.2021.8.201188.

23. Pandey R, Al-Nuaimi Y, Mishra RK, Spurgeon SK, Goodfellow M. Role of subnetworks mediated by [Formula: see text], IL-23/IL-17 and IL-15 in a network involved in the pathogenesis of psoriasis. Sci Rep. 2021;11(1):2204. https://doi.org/10.1038/s41598-020-80507-7.

24. Smith P, Yao W, Shepard S, Covington M, Lee J, Lofland J et al. Developing a JAK Inhibitor for Targeted Local Delivery: Ruxolitinib Cream. Pharmaceutics. 2021;13(7):1044. https://doi.org/10.3390/pharmaceutics13071044.

25. Mesa RA. Ruxolitinib, a selective JAK1 and JAK2 inhibitor for the treatment of myeloproliferative neoplasms and psoriasis. IDrugs. 2010;13(6):394–403. Available at: https://pubmed.ncbi.nlm.nih.gov/20506062.

26. Wang G, Peng X. A Review of Clinical Applications and Side Effects of Methotrexate in Ophthalmology. J Ophthalmol. 2020;2020:1537689. https://doi.org/10.1155/2020/1537689.

27. El Gayar MA, Atwa D, Girgis G, Marie L. Clinical, dermoscopic, and histopathologic evaluation of topical methotrexate 1% hydrogel versus topical Calcipotriol 0.005% cream in the treatment of plaque psoriasis. J Cosmet Dermatol. 2022;21(11):5779–5789. https://doi.org/10.1111/jocd.15285.

28. Bouchaud G, Gehrke S, Krieg C, Kolios A, Hafner J, Navarini AA et al. Epidermal IL-15Rα acts as an endogenous antagonist of psoriasiform inflammation in mouse and man. J Exp Med. 2013;210(10):2105–2117. https://doi.org/10.1084/jem.20130291.