Иммунопатогенетические основы кожных парадоксальных реакций при лечении ингибиторами ФНО-α

Длительная терапия генно-инженерными препаратами из группы ингибиторов фактора некроза опухоли-α (иФНО-α), являющаяся стандартом лечения тяжелых иммуновоспалительных заболеваний, может индуцировать развитие парадоксальных реакций (ПР) – возникновение или обострение иммуноопосредованных дерматозов, патогенетически родственных тем, для лечения которых применяется препарат. В основе патогенеза ПР лежит нарушение системного иммунного гомеостаза вследствие блокады цитокина, обладающего широким спектром функций, что приводит к дисрегуляции цитокинового баланса, изменению доминирующего типа иммунного ответа и гиперактивации альтернативных провоспалительных путей. Клинические проявления ПР многообразны и включают псориазиформные, экзематозные, лихеноидные, гранулематозные реакции, а также парадоксальные формы нейтрофильных дерматозов, каждая из которых обладает уникальными эпидемиологическими и клинико-морфологическими особенностями. Развитие ПР детерминировано взаимодействием фармакологического вмешательства с индивидуальным генетическим фоном пациента. Изучение ПР представляет значительный интерес не только в контексте фармакологической безопасности, но и как уникальная модель для исследования иммунного гомеостаза человека in vivo, демонстрирующая высокую степень компенсации и нелинейность цитокиновых коллатералей.

Цель обзора: систематизировать современные представления о патогенезе парадоксальных реакций (ПР), развивающихся на фоне генно-инженерной биологической терапии препаратами из группы ингибиторов ФНО-α.

1. Brown G., Wang E., Leon A., Huynh M., Wehner M. Tumor necrosis factor-α inhibitor-induced psoriasis: systematic review of clinical features, histopathological findings, and management experience. J Am Acad Dermatol. 2017; 76 (2): 334–341. https://doi.org/10.1016/j.jaad.2016.08.012

2. Toussirot É., Aubin F. Paradoxical reactions under TNF-α blocking agents and other biological agents given for chronic immune-mediated diseases: an analytical and comprehensive overview. RMD Open. 2016; 2 (2): e000239. https://doi.org/10.1136/rmdopen-2015–000239

3. Toussirot E., Pertuiset E. TNFα blocking agents and sarcoidosis: an update. Rev Med Interne. 2010; 31 (12): 828–37. https://doi.org/10.1016/j.revmed.2010.02.007

4. Murphy M.J., Cohen J.M., Vesely M.D. Paradoxical eruptions to targeted therapies in dermatology: A systematic review and analysis. J Am Acad Der matol. 2022; 86 (5):1080–91. https://doi.org/10.1016/j.jaad.2020.12.010

5. Eyerich, K., Eyerich, S. Immune response patterns in non-communicable inflammatory skin diseases. J. Eur. Acad. Dermatol. Venereol. 2018; 32 (5): 692–703. https://doi.org/10.1111/jdv.14673

6. Schett G., McInnes I.B., Neurath M.F. Reframing Immune-Mediated Inflammatory Diseases through Signature Cytokine Hubs. N. Engl. J. Med. 2021; 385 (7):628–639. https://doi.org/10.1056/NEJMra1909094

7. Braegelmann C., Niebel D., Wenzel J. Targeted Therapies in Autoimmune Skin Diseases. J. Investig. Dermatol. 2022; 142 (3): 969–975.e7. https://doi.org/10.1016/j.jid.2021.08.439

8. Annunziato F., Romagnani C., Romagnani S. The 3 major types of innate and adaptive cell-mediated effector immunity. J. Allergy Clin. Immunol. 2015; 135 (3): 626–35. https://doi.org/10.1016/j.jaci.2014.11.001

9. Wenzel J., Tuting T. An IFN-associated cytotoxic cellular immune response against viral, self-, or tumor antigens is a common pathogenetic feature in “interface dermatitis”. J. Investig. Dermatol. 2008; 128 (10): 2392–2402. https://doi.org/10.1038/jid.2008.96

10. Jutel M., Agache I., Zemelka-Wiacek M. Nomenclature of allergic diseases and hypersensitivity reactions: Adapted to modern needs: An EAACI position paper. Allergy. 2023; 78 (11): 2851–2874. https://doi.org/10.1111/all.15889

11. Rappl G., Pabst S., Riemann D. Regulatory T cells with reduced repressor capacities are extensively amplified in pulmonary sarcoid lesions and sustain granuloma formation. Clin Immunol. 2011; 140 (1): 71–83. https://doi.org/10.1016/j.clim.2011.03.015

12. Cilfone N.A., Perry C.R., Kirschner D.E. Multi-scale modeling predicts a balance of tumor necrosis factor-alpha and interleukin-10 controls the granuloma environment during Mycobacterium tuberculosis infection. PLoS One. 2013; 8 (7): e68680. https://doi.org/10.1371/journal.pone.0068680

13. Eyerich K., Eyerich S. Immune response patterns in non-communicable inflammatory skin diseases. J Eur Acad Dermatol Venereol. 2018; 32(5): 692–703. https://doi.org/10.1111/jdv.14673.

14. Gonzalez Caldito N. Role of tumor necrosis factor-alpha in the central nervous system: a focus on autoimmune disorders. Front Immunol. 2023; 14: 1213448. https://doi.org/10.3389/fimmu.2023.1213448

15. Молочкова Ю.В., Хлебникова А.Н. Клинико-патоморфологические ассоциации красного плоского лишая. Российский журнал кожных и венерических болезней. 2016; 19 (5): 286–290. https://doi.org/10.18821/1560-9588-2016-19-5-286-290

16. Galli S.J. The mast cell-IgE paradox: from homeostasis to anaphylaxis. Am J Pathol. 2016; 186 (2): 212–224. https://doi.org/10.1016/j.ajpath.2015.07.025

17. Howell M.D., Kim B.E., Gao P. Cytokine modulation of atopic dermatitis filaggrin skin expression. J Allergy Clin Immunol. 2009; 124 (3): R7-R12. https://doi.org/10.1016/j.jaci.2009.07.012

18. Сапунцова С.Г., Лебедько О.А., Обухова Г.Г. Влияние гептапептида Семакс на содержание фактора некроза опухолей-альфа и биогенез свободных радикалов при атопическом дерматите. Дальневосточный медицинский журнал. 2015. (2): 61–64.

19. Zhestkov A.V., Pobezhimova O.O. The main aspects of the immunopathogenesis of atopic dermatitis in children. Allergology and Immunology in Pediatrics. 2021; 3 (66): 27–34. (In Russ.). https://doi.org/10.53529/2500-1175-2021-3-27-34

20. Huang I.H., Chung W.H., Wu P.C., Chen C.B. JAK-STAT signaling pathway in the pathogenesis of atopic dermatitis: An updated review. Front Immunol. 2022; 13: 1068260. https://doi.org/10.3389/fimmu.2022.1068260

21. Eyerich S., Eyerich K., Cavani A., Schmidt-Weber C. IL-17 and IL-22: siblings, not twins. Trends Immunol. 2010; 31 (9): 354–61. https://doi.org/10.1016/j.it.2010.06.004

22. Caruso R., Botti E., Sarra M. Involvement of interleukin-21 in the epidermal hyperplasia of psoriasis. Nat Med. 2009; 15 (9): 1013–5. https://doi.org/10.1038/nm.1995

23. Zheng Y., Danilenko D.M., Valdez P. Interleukin-22, a T(H)17 cytokine, mediates IL-23-induced dermal inflammation and acanthosis. Nature. 2007; 445 (7128): 648–51. https://doi.org/10.1038/nature05505

24. Wolk K., Haugen H.S., Xu W. IL-22 and IL-20 are key mediators of the epidermal alterations in psoriasis while IL-17 and IFN-gamma are not. J Mol Med. 2009; 87 (5): 523–36. https://doi.org/10.1007/s00109-009-0457-0

25. Donetti E., Cornaghi L., Arnaboldi F. Epidermal barrier reaction to an in vitro psoriatic microenvironment. Exp Cell Res. 2017; 360 (2): 180–188. https://doi.org/10.1016/j.yexcr.2017.09.004

26. Терещенко И.В., Каюшев П.Е. Фактор некроза опухоли α и его роль в патологии. РМЖ. Медицинское обозрение. 2022; 6 (9): 523–527. https://doi.org/10.32364/2587-6821-2022-6-9-523-527

27. Kumagai N., Fukuda K., Fujitsu Y., Nishida T. Expression of functional ICAM-1 on cultured human keratocytes induced by tumor necrosis factor-alpha. Jpn J Ophthalmol. 2003; 47 (2): 134–41. https://doi.org/10.1016/s0021–5155(02)00686-x

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

29. Sabat R., Alavi A., Wolk K. Hidradenitis suppurativa. Lancet. 2025; 405 (10476): 420–438. https://doi.org/10.1016/S0140–6736 (24) 02475-9

30. Maverakis E., Marzano A.V., Le S.T. Pyoderma gangrenosum. Nat Rev Dis Primers. 2020; 6 (1): 81. https://doi.org/10.1038/s41572–020–0213-x

31. Gunes P., Goktay F., Mansur A.T., Koker F., Erfan G. Collagen-elastic tissue changes and vascular involvement in granuloma annulare: a review of 35 cases. J Cutan Pathol. 2009; 36 (8): 838–44. https://doi.org/10.1111/j.1600–0560.2008.01169.x

32. Verwoerd A., Hijdra D., Vorselaars A.D. Infliximab therapy balances regulatory T cells, tumour necrosis factor receptor 2 (TNFR2) expression and soluble TNFR2 in sarcoidosis. Clin Exp Immunol. 2016; 185 (2): 263–70. https://doi.org/10.1111/cei.12808

33. Cantaert T., Baeten D., Tak P.P. Type I IFN and TNFA cross-regulation in immune-mediated inflam matory disease: Basic concepts and clinical relevance. Arthritis Res Ther. 2010; 12 (5). https://doi.org/10.1186/ar3150

34. Palucka A.K., Blanck J.P., Bennett L. Cross-regulation of TNF and IFN-a in autoimmune diseases. Proc Natl Acad Sci U S A. 2005; 102 (9): 3372–7. https://doi.org/10.1073/pnas.0408506102

35. Круглова Л.С., Щукина О.Б. Парадоксальная псориазиформная воспалительная реакция на фоне применения блокаторов фактора некроза опухоли-альфа у пациентов с болезнью Крона. Альманах клинической медицины. 2018; 46 (5): 522–530. https://doi.org/10.18786/20720505-2018-46-5-522-530

36. DeGannes G.C., Ghoreishi M., Pope J. Psoriasis and pustular dermatitis triggered by TNF-{alpha} inhibitors in patients with rheumatologic conditions. Arch Dermatol. 2007; 143 (2): 223–31. https://doi.org/10.1001/archderm

37. Conrad C., Di Domizio J., Mylonas A. TNF blockade induces a dysregulated type I interferon response without autoimmunity in paradoxical psoriasis. Nat Commun. 2018; 9 (1): 25. https://doi.org/10.1038/s41467-017-02466-4

38. Fania L., Morelli M., Scarponi C. Paradoxical psoriasis induced by TNF-α blockade shows immunological features typical of the early phase of psoriasis development. J Pathol Clin Res. 2020; 6 (1): 55–68. https://doi.org/10.1002/cjp2.147

39. Collamer A.N., Guerrero K.T., Henning J.S., Battafarano D.F. Psoriatic skin lesions induced by tumor necrosis factor antagonist therapy: a literature review and potential mechanisms of action. Arthritis Rheum. 2008; 59 (7): 996-1001. https://doi.org/10.1002/art.23835.PMID: 18576309.

40. Ursini F., Naty S., Bruno C. CD4+ T-cells lymphocytosis and reduction of neutrophils during treatment with adalimumab: Challenge and dechallenge study. Clin Immunol. 2010; 135 (3): 499–500. https://doi.org/10.1016/j.clim.2010.02.004

41. Frew J. W., Vekic D. A., Woods J. A., Cains G. D. Drug-associated hidradenitis suppurativa: A systematic review of case reports. J Am Acad Dermatol. 2018; 78 (1): 217–219.e2. https://doi.org/10.1016/j.jaad.2017.08.046

42. Ghoreschi K., Thomas P., Breit S. Interleukin-4 therapy of psoriasis induces Th2 responses and improves human autoimmune disease. Nat Med. 2003; 9 (1): 40–6. https://doi.org/10.1038/nm804

43. Zaba L.C., Cardinale I., Gilleaudeau P. Amelioration of epidermal hyperplasia by TNF inhibition is associated with reduced Th17 responses. J Exp Med. 2007; 204 (13): 3183–94. https://doi.org/10.1084/jem.20071094

44. Quaglino P., Bergallo M., Ponti R. Th1, Th2, Th17 and regulatory T cell pattern in psoriatic patients: modulation of cytokines and gene targets induced by etanercept treatment and correlation with clinical response. Dermatology. 2011; 223 (1): 57–67. https://doi.org/10.1159/000330330

45. Malisiewicz B., Murer C., Schmid J.P. Eosinophilia during psoriasis treatment with TNF antagonists. Dermatology. 2011; 223 (4): 311–5. https://doi.org/10.1159/000334805

46. Stoffel E., Maier H., Riedl E. Analysis of anti-tumour necrosis factor-induced skin lesions reveals strong T helper 1 activation with some distinct immunological characteristics. Br.J. Dermatol. 2018; 178 (5): 1151–1162. https://doi.org/10.1111/bjd.16126

47. Ariyasu T., Tanaka T., Fujioka N. Effects of interferon-alpha subtypes on the TH1/TH2 balance in peripheral blood mononuclear cells from patients with hepatitis virus infection-associated liver disorders. In Vitro Cell Dev Biol Anim. 2005; 41 (1): 50–56. https://doi.org/10.1290/0501008.1

48. Esmailzadeh A., Yousefi P., Farhi D. Predictive Factors of Eczema-Like Eruptions among Patients without Cutaneous Psoriasis Receiving Infliximab: A Cohort Study of 92 Patients. Dermatology. 2009; 219 (3): 263–267. https://doi.org/10.1159/000235582

49. De Vries H.J., van Marle J., Teunissen M.B. Lichen planus is associated with human herpesvirus type 7 replication and infiltration of plasmacytoid dendritic cells. Br J Dermatol. 2006; 154(2): 361–364. https://doi.org/10.1111/j.1365–2133.2005.06999.x

50. Santoro A., Majorana A., Roversi L. Recruitment of dendritic cells in oral lichen planus. J Pathol. 2005; 205 (4): 426–434. https://doi.org/10.1002/path.1699.

51. Wenzel J, Scheler M, Proelss J, et al. Type I interferon-associated cytotoxic inflammation in lichen planus. J Cutan Pathol. 2006; 33 (10): 672–678. https://doi.org/10.1111/j.1600–0560.2006.00527.x

52. Karnik P, Tekeste Z, McCormick TS, et al. Hair follicle stem cell-specific PPARγ deletion causes scarring alopecia. J Invest Dermatol. 2009; 129 (5): 1243–1257. https://doi.org/10.1038/jid.2008.369