The survival rate of biological therapy in immunosuppressive diseases in children

Genetically engineered biological preparations (GEBP) are successfully used in various immunosuppressive diseases. Despite the effectiveness of GEBP, some patients experience primary non-response, as well as loss of effect from therapy. There is a need to objectively assess the effect of the therapy for its timely correction. The aim of the work was to determine the survival rate of GIBP depending on the form of pathology, drug, age, and immune indices in children with Crohn’s disease (CD), ulcerative colitis (UC), psoriasis (PS), multiple sclerosis (MS).

Materials and methods. Three hundred eighty three children (1394 observations) were examined in dynamics: 117 children with BC (treated by infliximab (IFX)/adalimumab (ADA), 83 children with UC (IFX/ADA), 87 children with PS (ADA), 96 children with PC (IFNβ1α) during the maintenance course therapy. Lymphocytes were immunophenotyped by flow cytometry with the determination of Treg (CD4⁺CD25highCD127low), Th17 lymphocytes (CD4⁺CD161⁺CD3⁺), succinate dehydrogenase (SDH) activity in Treg. Data processing was carried out using Statistica 16.0 application. Kaplan–Mayer survival curves are constructed. The significance of the differences between the groups was assessed using the Gehan–Wilcoxon criterion (p < 0.05).

Results. The survival rate of biological therapy in CD patients on IFX therapy is significantly higher than in children with UC — 161 weeks versus 135 weeks. There was no difference in CBT on ADA therapy between patients with CD and UC. The IBT index depends on the age of the patients: on IFX therapy (159 weeks) the best indices were in CD patients over 12 years. Combination therapy improves the survival of TNF blockers in patients with IBD (azathioprine) and PS (methotrexate). The survival of GIBP is influenced by the ratio of effector and regulatory cells (Th17|Treg) and the functional activity of Treg (SDH activity). A decrease in IBD was revealed in patients with IBD, PS, and MS with an increase in the Th17/Treg index above the age norm and a decrease in the activity of SDH in Treg below the norm.

Conclusion. The survival rate of biological therapy for immunosuppressive diseases in children depends on the form of pathology, the drug, the age of patients, previous therapy, combination therapy, as well as immune indices during the maintenance course. Monitoring of Th17/Treg and SDH activity in Treg may be an important laboratory criterion for the effectiveness of GIBP.

Contribution:
Radygina T.V., Petrichuk S.V. — research concept and design of the study;
Radygina T.V., Petrichuk S.V., Kuptsova D.G., Kurbatova O.V., Abdullaeva L.M., Freydlin E.V., Potapov A.S., Kuzenkova L.M. — collection and proces­sing of material;
Radygina T.V. — writing the text;
Radygina T.V., Petrichuk S.V., Fisenko A.P., Kuptsova D.G., Kurbatova O.V., Potapov A.S., Murashkin N.N., Kuzenkova L.M., Semikina E.L. — editing the text.
All co-authors — approval of the final version of the article, responsibility for the integrity of all parts of the article.

Acknowledgment. The study had no sponsorship.

Conflict of interest. The authors declare no conflict of interest.

Received: September 05, 2024
Accepted: October 08, 2024
Published: November 12, 2024

1. Abdulganieva D.I., Bakulev A.L., Belousova E.A., Veselov A.V., Korotaeva T.V., Lila A.M., et al. Early administration of genetically engineered biological agents for immune-mediated inflammatory diseases: opportunities and prospects. An experts’ opinion. Almanakh klinicheskoy meditsiny. 2020; 48(6): 422–36. https://doi.org/10.18786/2072-0505-2020-48-050 https://elibrary.ru/nqfftp (in Russian)

2. Olisova O.Yu., Anpilogova E.M. Systemic treatment of psoriasis: from methotrexate to biologics. Vestnik dermatologii i venereologii. 2020; 96(3): 7–26. https://doi.org/10.25208/vdv1162 https://elibrary.ru/oruvzi (in Russian)

3. Lu Q., Yang M.F., Liang Y.J., Xu J., Xu H.M., Nie Y.Q., et al. Immunology of inflammatory bowel disease: molecular mechanisms and therapeutics. J. Inflamm Res. 2022; 15: 1825–44. https://doi.org/10.2147/JIR.S353038

4. Sieminska I., Pieniawska M., Grzywa T.M. The immunology of psoriasis-current concepts in pathogenesis. Clin. Rev. Allergy Immunol. 2024; 66(2): 164–91. https://doi.org/10.1007/s12016-024-08991-7

5. Baecher-Allan C., Kaskow B.J., Weiner H.L. Multiple sclerosis: mechanisms and immunotherapy. Neuron. 2018; 97(4): 742–68. https://doi.org/10.1016/j.neuron.2018.01.021

6. Pucino V., Guma M. Editorial: The role of immunometabolism in autoimmune mediated and autoinflammatory disorders. Front. Immunol. 2022; 13: 969939. https://doi.org/10.3389/fimmu.2022.969939

7. Qin Y., Gao C., Luo J. Metabolism characteristics of Th17 and regulatory T cells in autoimmune diseases. Front. Immunol. 2022; 13: 828191. https://doi.org/10.3389/fimmu.2022.828191

8. Moosavi B., Zhu X.L., Yang W.C., Yang G.F. Genetic, epigenetic and biochemical regulation of succinate dehydrogenase function. Biol. Chem. 2020; 401(3): 319–30. https://doi.org/10.1515/hsz-2019-0264

9. Nakase H., Sato N., Mizuno N., Ikawa Y. The influence of cytokines on the complex pathology of ulcerative colitis. Autoimmun. Rev. 2022; 21(3): 103017. https://doi.org/10.1016/j.autrev.2021.103017

10. Mohd Noor A.A., 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

11. Selinger C.P., Rosiou K., Lenti M.V. Biological therapy for inflammatory bowel disease: cyclical rather than lifelong treatment? BMJ Open Gastroenterol. 2024; 11(1): e001225. https://doi.org/10.1136/bmjgast-2023-001225

12. Zettl U.K., Hecker M., Aktas O., Wagner T., Rommer P.S. Interferon β-1a and β-1b for patients with multiple sclerosis: updates to current knowledge. Expert. Rev. Clin. Immunol. 2018; 14(2): 137–53. https://doi.org/10.1080/1744666X.2018.1426462

13. Kapizioni C., Desoki R., Lam D., Balendran K., Al-Sulais E., Subramanian S., et al. Biologic therapy for inflammatory bowel disease: real-world comparative effectiveness and impact of drug sequencing in 13 222 patients within the UK IBD BioResource. J. Crohns Colitis. 2024; 18(6): 790–800. https://doi.org/10.1093/ecco-jcc/jjad203

14. Chanchlani N., Lin S., Bewshea C., Hamilton B., Thomas A., Smith R., et al. Mechanisms and management of loss of response to anti-TNF therapy for patients with Crohn’s disease: 3-year data from the prospective, multicentre PANTS cohort study. Lancet Gastroenterol. Hepatol. 2024; 9(6): 521–38. https://doi.org/10.1016/S2468-1253(24)00044-X

15. Phan C., Beauchet A., Burztejn A.C. Biological treatments for paediatric psoriasis: a retrospective observational study on biological drug survival in daily practice in childhood psoriasis. J. Eur. Acad. Dermatol. Venereol. 2019; 33(10): 1984–92. https://doi.org/10.1111/jdv.15579

16. Lytkina K.A., Lukina G.V., Koltsova E.N., Schmidt E.I., Zhilyaev E.V. Biologic therapy survival in patients with psoriatic arthritis. RMJ. Meditsinskoe obozrenie. 2019; 3(11-2): 86–9. https://elibrary.ru/aidlms (in Russian)

17. Ivanov R.A., Murashkin N.N. Biological therapy survivability in children with psoriasis: cohort study. Voprosy sovremennoy pediatrii. 2021; 20(5): 451–8. https://doi.org/10.15690/vsp.v20i5.2323 https://elibrary.ru/gorfcq (in Russian)

18. Petrichuk C.V., Izmailova T.D., Radygina T.V. Method for measuring mitochondrial lymphocyte activity. Patent RF № 2302635; 2007. https://elibrary.ru/zheslh (in Russian)

19. Kurbatova O.V., Petrichuk S.V., Movsesian G.B., Kuptsova D.G., Radygina T.V., Anishchenko A.O., et al. The role of small populations of lymphocytes in the formation of liver fibrosis in children with glycogen disease. Rossiskiy immunologicheskiy zhurnal. 2023; 26(3): 337–44. https://doi.org/10.46235/1028-7221-10013-ROM https://elibrary.ru/fklrml (in Russian)

20. Kurbatova O.V., Kuptsova D.G., Zakirov R.Sh., Radygina T.V., Movsisyan G.B., Freidlin E.V., et al. Prospects for studying immunometabolism in clinical practice. Vestnik Tashkentskoy meditsinskoy akademii. 2023; 3(1): 98. (in Russian)

21. Clinical recommendations. Crohn’s disease. Moscow; 2021. Available at: https://cr.minzdrav.gov.ru/schema/682_1 (in Russian)

22. Clinical recommendations. Ulcerative colitis. Moscow; 2021. Available at: https://cr.minzdrav.gov.ru/recomend/391_2 (in Russian)

23. van Rhenen P.F., Aloi M., Assa A., Bronsky J., Escher J.C., Fagerberg U.L., et al. The medical management of paediatric Crohn”s disease: an ECCO-ESPGHAN guideline update. J. Crohns Colitis. 2020; jjaa161. https://doi.org/10.1093/ecco-jcc/jjaa161

24. Abdullayeva L.M., Bursagova B.I., Kurenkov A.L., Kuzenkova L.M. Treatment of multiple sclerosis in children: review of clinical trials. Nevrologicheskiy zhurnal imeni L.O. Badalyana. 2023; 4(1): 43–51. https://doi.org/10.46563/2686-8997-2023-4-1-43-51 https://elibrary.ru/yjkpuy (in Russian)

25. Clinical recommendations. Psoriasis. Moscow; 2023. Available at: https://cr.minzdrav.gov.ru/recomend/234_226 (in Russian)

26. Blesl A., Binder L., Högenauer C. Limited long-term treatment persistence of first anti-TNF therapy in 538 patients with inflammatory bowel diseases: a 20-year real-world study. Aliment. Pharmacol. Ther. 2021; 54: 667–77. https://doi.org/10.1111/apt.16478

27. Gisbert J.P., Chaparro M. Primary failure to an anti-TNF agent in inflammatory bowel Disease: switch (to a second Anti-TNF agent) or swap (for another mechanism of action)? J. Clin. Med. 2021; 10(22): 5318. https://doi.org/10.3390/jcm10225318

28. Gisbert J.P., Marin A.C., McNicholl A.G., Chaparro M. Systematic review with meta-analysis: The efficacy of a second anti-TNF in patients with inflammatory bowel disease whose previous anti-TNF treatment has failed. Aliment. Pharmacol. Ther. 2015; 41(7): 613–23. https://doi.org/10.1111/apt.13083

29. Dai C., Huang Y.H., Jiang M. Combination therapy in inflammatory bowel disease: Current evidence and perspectives. Int. Immunopharmacol. 2023; 114: 109545. https://doi.org/10.1016/j.intimp.2022.109545

30. Kim J., Moreno A., Krueger J.G. The imbalance between Type 17 T-cells and regulatory immune cell subsets in psoriasis vulgaris. Front. Immunol. 2022; 13: 1005115. https://doi.org/10.3389/fimmu.2022.1005115

31. Yan J.B., Luo M.M., Chen Z.Y., He B.H. The function and role of the Th17/Treg cell balance in inflammatory bowel disease. J. Immunol. Res. 2020; 2020: 8813558. https://https://doi.org/10.1155/2020/8813558

32. Mo C., Zeng Z., Deng Q., Ding Y., Xiao R. Imbalance between T helper 17 and regulatory T cell subsets plays a significant role in the pathogenesis of systemic sclerosis. Biomed. Pharmacother. 2018; 108: 177–83. https://doi.org/10.1016/j.biopha.2018.09.037

33. Antony I.R., Wong B.H.S., Kelleher D., Verma N.K. Maladaptive T-cell metabolic fitness in autoimmune diseases. Cells. 2023; 12(21): 2541. https://doi.org/10.3390/cells1221254

34. Pucino V., Guma M. Editorial: The role of immunometabolism in autoimmune mediated and autoinflammatory disorders. Front. Immunol. 2022; 13: 969939. https://doi.org/10.3389/fimmu.2022.969939