Dupilumab Efficacy and Safety in Severe Atopic Dermatitis in Children under 6 Years of Age: Two Clinical Cases

Background. Atopic dermatitis (AD) manifests during the first year of life in majority of all cases. The early disease onset is associated with the development of comorbid atopic conditions within the «atopic march» phenomenon. The AD pathogenesis is associated with genetic predisposition, epidermal barrier dysfunction, and immune dysregulation. T2-inflammation specifically determines the entire immune cascade of inflammatory reactions, and, thus, dictates the need of early drug intervention to modify the disease course. Clinical case description. This article presents two clinical cases of severe AD in children under 6 years of age. The treatment of both cases included genetically engineered biologic drug dupilumab. Continuous therapy for 4–5 months made it possible to relieve the skin manifestations of the disease.

Conclusion. AD, manifesting in infancy, is associated with high risk of developing other atopic spectrum diseases in older age. The timely onset of biological therapy allows us to affect immune dysregulation, and thereby to prevent the comorbid atopic conditions development.

1. Eichenfield LF, Stripling S, Fung S, et al. Recent Developments and Advances in Atopic Dermatitis: A Focus on Epidemiology, Pathophysiology, and Treatment in the Pediatric Setting. Paediatr Drugs. 2022;24(4):293–305. doi: https://doi.org/10.1007/s40272-022-00499-x

2. Bylund S, von Kobyletzki LB, Svalstedt M, Svensson Å. Prevalence and incidence of atopic dermatitis. A systematic review. Acta Derm Venereol. 2020;100(12):adv00160. doi: https://doi.org/10.2340/00015555-3510

3. Bylund S, Kobyletzki LB, Svalstedt M, Svensson Å. Prevalence and Incidence of Atopic Dermatitis: A Systematic Review. Acta Derm Venereol. 2020;100(12):adv00160. doi: https://doi.org/10.2340/00015555-3510

4. McKenzie C, Silverberg JI. The prevalence and persistence of atopic dermatitis in urban United States children. Ann Allergy Asthma Immunol. 2019;123(2):173–178.e1. doi: https://doi.org/10.1016/j.anai.2019.05.014

5. Cho YT, Chu CY. Advances in systemic treatment for adults with moderate-to-severe atopic dermatitis. Dermatologica Sinica. 2019;37(1):3. doi: https://doi.org/10.4103/ds.ds_48_18

6. Esaki H, Czarnowicki T, Gonzalez J, et al. Accelerated T-cell activation and differentiation of polar subsets characterizes early atopic dermatitis development. J Allergy Clin Immunol. 2016;138(5):1473–1477. doi: https://doi.org/10.1016/j.jaci.2016.04.052

7. Harb H, Irvine J, Amarasekera M, et al. The role of PKCzeta in cord blood T-cell maturation towards Th1 cytokine profile and its epigenetic regulation by fish oil. Biosci Rep. 2017;37(2): BSR20160485. doi: https://doi.org/10.1042/BSR20160485

8. Herberth G, Heinrich J, Roder S, et al. Reduced IFN-gamma- and enhanced IL-4-producing CD4+ cord blood T cells are associated with a higher risk for atopic dermatitis during the first 2 yr of life. Pediatr Allergy Immunol. 2010;21(1 Pt 1):5–13. doi: https://doi.org/10.1111/j.1399-3038.2009.00890.x

9. Chaplin DD. Overview of the immune response. J Allergy Clin Immunol. 2010;125(2 Suppl 2):S3–S23. doi: https://doi.org/10.1067/mai.2003.125

10. Palm NW, Rosenstein RK, Medzhitov R. Allergic host defences. Nature. 2012;484(7395):465–472. doi: https://doi.org/10.1038/nature11047

11. Brandt EB, Sivaprasad U. Th2 Cytokines and Atopic Dermatitis. J Clin Cell Immunol. 2011;2(3):110. doi: https://doi.org/10.4172/2155-9899.1000110

12. Huang YJ, Marsland BJ, Bunyavanich S, et al. The microbiome in allergic disease: Current understanding and future opportunities-2017 PRACTALL document of the American Academy of Allergy, Asthma & Immunology and the European Academy of Allergy and Clinical Immunology. J Allergy Clin Immunol. 2017;139(4):1099–1110. doi: https://doi.org/10.1016/j.jaci.2017.02.007

13. Kouchkovsky DA, Ghosh S, Rothlin CV. Negative regulation of type 2 immunity. Trends Immunol. 2017;38(3):154–167. doi: https://doi.org/10.1016/j.it.2016.12.002

14. Furue M. Regulation of Skin Barrier Function via Competition between AHR Axis versus IL-13/IL-4–JAK–STAT6/STAT3 Axis: Pathogenic and Therapeutic Implications in Atopic Dermatitis. J Clin Med. 2020;9(11):3741. doi: https://doi.org/10.3390/jcm9113741

15. Leung DY, Guttman-Yassky E. Deciphering the com- plexities of atopic dermatitis: shifting paradigms in treatment approaches. J Allergy Clin Immunol. 2014;134(4):769–779. doi: https://doi.org/10.1016/j.jaci.2014.08.008

16. McKenzie AN, Culpepper JA, De Waal Malefyt R, et al. Interleukin 13, a T-cell-derived cytokine that regulates human monocyte and B-cell function. Proc Natl Acad Sci U S A. 1993;90(8): 3735–3739. doi: https://doi.org/10.1073/pnas.90.8.3735

17. Werfel T, Allam JP, Biedermann T, et al. Cellular and molecular immunologic mechanisms in patients with atopic dermatitis. J Allergy Clin Immunol. 2016;138(2):336–349. doi: https://doi.org/10.1016/j.jaci.2016.06.010

18. Seegraäber M, Srour J, Walter A, et al. Dupilumab for treatment of atopic dermatitis. Expert Rev Clin Pharmacol. 2018;11(5): 467–474. doi: https://doi.org/10.1080/17512433.2018.1449642

19. Gooderham MJ, Hong HC, Eshtiaghi P, Papp KA. Dupilumab: A review of its use in the treatment of atopic dermatitis. J Am Acad Dermatol. 2018;78(3 Suppl 1):S28–S36. doi: https://doi.org/10.1016/j.jaad.2017.12.022

20. Kim BE, Leung DY, Boguniewicz M, Howell MD. Loricrin and involucrin expression is down-regulated by Th2 cytokines through STAT-6. Clin Immunol. 2008;126:332–337. doi: https://doi.org/10.1016/j.clim.2007.11.006

21. Ong PY, Ohtake T, Brandt C, et al. Endogenous antimicrobial peptides and skin infections in atopic dermatitis. N Engl J Med. 2002; 347:1151–1160. doi: https://doi.org/10.1056/NEJMoa021481

22. Shi B, Leung DY, Taylor PA, et al. Methicillin-resistant Staphylococcus aureus colonization is associated with decreased skin commensal bacteria in atopic dermatitis. J Invest Dermatol. 2018;138(7): 1668–1671. doi: https://doi.org/10.1016/j.jid.2018.01.022

23. Moriwaki M, Iwamoto K, Niitsu Y, et al. Staphylococcus aureus from atopic dermatitis skin accumulates in the lysosomes of keratinocytes with induction of IL-1α secretion via TLR9. Allergy. 2019;74(3):560–571. doi: https://doi.org/10.1111/all.13622

24. Garcovich S, Maurelli M, Gisondi P, et al. Pruritus as a distinctive feature of type 2 inflammation. Vaccines (Basel). 2021;9(3):303. doi: https://doi.org/10.3390/vaccines9030303

25. Gupta K, Harvima IT. Mast cell-neural interactions contribute to pain and itch. Immunol Rev. 2018;282(1):168–187. doi: https://doi.org/10.1111/imr.12622

26. Wang F, Trier AM, Li F, et al. A basophil-neuronal axis promotes itch. Cell. 2021;184(2):422–440.e17. doi: https://doi.org/10.1016/j.cell.2020.12.033

27. Brunner T, Heusser CH, Dahinden CA. Human peripheral blood basophils primed by interleukin 3 (IL-3) produce IL-4 in response to immunoglobulin E receptor stimulation. J Exp Med. 1993;177(3): 605–611. doi: https://doi.org/10.1084/jem.177.3.605

28. Oetjen LK, Mack MR, Feng J, et al. Sensory neurons co-opt classical immune signaling pathways to mediate chronic itch. Cell. 2017;171(1):217–228.e13. doi: https://doi.org/10.1016/j.cell.2017.08.006

29. Mollanazar NK, Smith PK, Yosipovitch G. Mediators of chronic pruritus in atopic dermatitis: getting the itch out? Clin Rev Allergy Immunol. 2016;51(3):263–292. doi: https://doi.org/10.1007/s12016-015-8488-5

30. Feld M, Garcia R, Buddenkotte J, et al. The pruritus-and TH2-associated cytokine IL-31 promotes growth of sensory nerves. J Allergy Clin Immunol. 2016;138(2):500–508.e24. doi: https://doi.org/10.1016/j.jaci.2016.02.020

31. Furue M, Ulzii D, Vu YH, et al. Pathogenesis of atopic dermatitis: current paradigm. Iran J Immunol. 2019;16(2):97–107. doi: https://doi.org/10.22034/IJI.2019.80253

32. Meng J, Moriyama M, Feld M, et al. New mechanism underlying IL-31-induced atopic dermatitis. J Allergy Clin Immunol. 2018;141(5):1677–1689.e8. doi: https://doi.org/10.1016/j.jaci.2017.12.1002

33. Gutzmer R, Mommert S, Gschwandtner M, et al. The histamine H4 receptor is functionally expressed on T(H)2 cells. J Allergy Clin Immunol. 2009;123(3):619–625. doi: https://doi.org/10.1016/j.jaci.2008.12.1110

34. Campion M, Smith L, Gatault S, et al. Interleukin-4 and interleukin-13 evoke scratching behavior in mice. Exp Dermatol. 2019;28(12):1501–1504. doi: https://doi.org/10.1111/exd.14034

35. Gandhi NA, Bennett BL, Graham NM, et al. Targeting key proximal drivers of type 2 inflammation in disease. Nat Rev Drug Discov. 2016;15(1):35–50. doi: https://doi.org/10.1038/nrd4624

36. Dupixent®: drug label. Registration certificate No. ЛП-005440. Registration date: April 04, 2019. In: State Register of Medicines: Official website. (In Russ).] Доступно по: https://grls.rosminzdrav.ru/Grls_View_v2.aspx?routingGuid=cc2ed2eb-e849-4650-a643cb2715d37bfc. Ссылка активна на 21.08.2023.

37. Silverberg JI, Barbarot S, Gadkari A, et al. Atopic dermatitis in the pediatric population: A cross-sectional, international epidemiologic study. Ann Allergy Asthma Immunol. 2021;126(4):417–428.e2. doi: https://doi.org/10.1016/j.anai.2020.12.020

38. Czarnowicki T, He H, Canter T, et al. Evolution of pathologic T-cell subsets in patients with atopic dermatitis from infancy to adulthood. J Allergy Clin Immunol. 2020;145(1):215–228. doi: https://doi.org/10.1016/j.jaci.2019.09.031

39. Paller AS, Spergel JM, Mina-Osorio P, Irvine AD. The atopic march and atopic multimorbidity: Many trajectories, many pathways. J Allergy Clin Immunol. 2019;143(1):46–55. doi: https://doi.org/10.1016/j.jaci.2018.11.006

40. Illi S, von Mutius E, Lau S, et al. Multicenter Allergy Study Group. The natural course of atopic dermatitis from birth to age 7 years and the association with asthma. J Allergy Clin Immunol. 2004;113(5):925–931. doi: https://doi.org/10.1016/j.jaci.2004.01.778

41. Kim JP, Chao LX, Simpson EL, Silverberg JI. Persistence of atopic dermatitis (AD): A systematic review and meta-analysis. J Am Acad Dermatol. 2016;75(4):681–687.e11. doi: https://doi.org/10.1016/j.jaad.2016.05.028

42. Ricci G, Patrizi A, Giannetti A, et al. Does improvement management of atopic dermatitis influence the appearance of respiratory allergic diseases? A follow-up study. Clin Mol Allergy. 2010;8:8. doi: https://doi.org/10.1186/1476-7961-8-8

43. Irvine AD, Mina-Osorio P. Disease trajectories in childhood atopic dermatitis: an update and practitioner’s guide. Br J Dermatol. 2019;181(5):895–906. doi: https://doi.org/10.1111/bjd.17766 44.

44. Beck L, Thaci D, Hamilton JD, et al. Dupilumab treatment in adults with moderate-to-severe atopic dermatitis. N Engl J Med. 2014; 371(2):130–139. doi: https://doi.org/10.1056/NEJMoa1314768

45. Andrews R, Rosa L, Daines M, et al. Reconstitution of a functional human type II IL-4/IL-13 receptor in mouse B cells: demonstration of species specificity. J Immunol. 2001;166(3):1716–1722. doi: https://doi.org/10.4049/jimmunol.166.3.1716

46. Bao L, Zhang H, Chan LS. The involvement of the JAK-STAT signaling pathway in chronic inflammatory skin disease atopic dermatitis. JAKSTAT. 2013;2(3):e24137. doi: https://doi.org/10.4161/jkst.24137

47. Hendricks AJ, Yosipovitch G, Shi VY. Dupilumabuse in dermatologic conditions beyond atopic dermatitis — a systematic review. J Dermatolog Treat. 2019;32(1):19–28. doi: https://doi.org/10.1080/09546634.2019.1689227

48. Paller AS, Simpson EL, Siegfried EC, et al. Dupilumab in children aged 6 months to younger than 6 years with uncontrolled atopic dermatitis: a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet. 2022;400(10356):908–919. doi: https://doi.org/10.1016/S0140-6736(22)01539-2

49. Igelman S, Kurta AO, Sheikh U, et al. Off-label use of dupilumab for pediatric patients with atopic dermatitis: A multicenter retrospective review. J Am Acad Dermatol. 2020;82(2):407–411. doi: https://doi.org/10.1016/j.jaad.2019.10.010