Inibidores de JAK no tratamento da dermatite atópica
JAK inhibitors in the treatment of atopic dermatitis
Luiza de Bortolli Nogueira; Débora Carla Chong-Silva; Nelson Augusto Rosário Filho; Herberto José Chong-Neto
Resumo
A dermatite atópica é a doença inflamatória cutânea mais prevalente mundialmente. A via JAK/STAT tem papel importante no mecanismo da doença e as pequenas moléculas inibidores de JAK são fármacos com grande potencial de uso na dermatite atópica. Foi realizada uma revisão sistemática da literatura na base de dados PubMed, utilizando os termos “atopic dermatitis” e/ou “JAK inhibitors” e/ou “small molecules” entre 2017 e 2022. Foram incluídos os resultados disponíveis de estudos de fase 3, avaliando o uso de inibidores de JAK em apresentações tópicas e sistêmicas. Entre 646 estudos, foram selecionados 37 em humanos que avaliaram a eficácia e segurança dos inibidores de JAK. Os resultados do uso, quando bem indicados, mostraram-se positivos e em alguns casos superiores a outros tratamentos já preconizados para o controle da dermatite atópica, com um bom perfil de segurança.
Palavras-chave
Abstract
Atopic dermatitis is the most common inflammatory skin disease worldwide. The JAK/STAT pathway plays an important role in the disease mechanism, and small-molecule JAK inhibitors are drugs with great potential for use in atopic dermatitis. We systematically reviewed PubMed using the search terms “atopic dermatitis” AND/OR “JAK inhibitors” AND/OR “small molecules” for studies published between 2017 and 2022. Results from phase III trials evaluating both topical and systemic application of JAK inhibitors were included. Of 646 studies retrieved, 37 evaluating the efficacy and safety of JAK inhibitors in humans were selected for analysis. When properly indicated, the use of JAK inhibitors yielded positive results, some of which were superior to those of recommended treatments for the control of atopic dermatitis, with a good safety profile.
Keywords
References
1. Weidinger S, Beck LA, Bieber T, Kabashima K, Irvine AD. Atopic dermatitis. Nat Rev Dis Primers. 2018;4(1). doi: 10.1038/s41572-018-0001-z.
2. Institute for Health Metrics and Evaluation [Internet]. Atopic dermatitis - Level 4 cause. [Internet]. Disponível em: https://www.healthdata.org/results/gbd_summaries/2019/atopic-dermatitis-level-4-cause. Acessado em: 05/07/2022.
3. Solé D, Wandalsen GF, Camelo-Nunes IC, Naspitz CK, Group IB. Prevalence of symptoms of asthma, rhinitis, and atopic eczema among Brazilian children and adolescents identified by the International Study of Asthma and Allergies in Childhood (ISAAC) - Phase 3. J Pediatr (Rio J). 2006;82(5):341-6. doi:10.2223/ jped.1521.
4. Dubin C, Del Duca E, Guttman-Yassky E. The IL-4, IL-13 and IL-31 pathways in atopic dermatitis. Expert Rev Clin Immunol. 2021;17(8):835-52. doi: 10.1080/1744666x.2021.1940962.
5. Howell MD, Fitzsimons C, Smith PA. JAK/STAT inhibitors and other small molecule cytokine antagonists for the treatment of allergic disease. Ann Allergy Asthma Immunol. 2018;120(4):367-75. doi:10.1016/j.anai.2018.02.012.
6. Klein B, Treudler R, Simon JC. JAKinhibitors in dermatology – small molecules, big impact? Overview of the mechanism of action, previous study results and potential adverse effects. J Dtsch Dermatol Ges. 2022;20(1):19-24. doi: 10.1111/ddg.14668.
7. ANVISA. Agência Nacional de Vigilância Sanitária. Dupixent (dupilumabe): nova indicação [Internet]. Disponível em: https://www.gov.br/anvisa/pt-br/assuntos/medicamentos/novos-medicamentose-indicacoes/dupixent-dupilumabe-nova-indicacao. Acessado em: 10/07/2022.
8. FDA. Dupilumab - Drugs@FDA: FDA-Approved Drugs [Internet]. Disponível em: https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=BasicSearch.process. Acessado em: 10/07/2022.
9. Stölzl D, Weidinger S, Drerup K. A new era has begun: Treatment of atopic dermatitis with biologics. Allergol Select. 2021;5:265-73. doi.org: 10.5414/alx02259e
10. Soeberdt M, Kilic A, Abels C. Small molecule drugs for the treatment of pruritus in patients with atopic dermatitis. Eur J Pharmacol. 2020;881: 73242. doi: 10.1016/j.ejphar.2020.173242
11. Li Q, Kang C. Mechanisms of Action for Small Molecules Revealed by Structural Biology in Drug Discovery. Int J Mol Sci. 2020;21(15):5262. doi: 10.3390/ijms21155262.
12. FDA. Ruloxitinib. Drugs@FDA: FDA-Approved Drugs; [Internet]. Disponível em: https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=overview.process&ApplNo=215309. Acessado em: 10/07/2022.
13. Guttman-Yassky E, Thaçi D, Pangan AL, Hong HC, Papp KA, Reich K, et al. Upadacitinib in adults with moderate to severe atopic dermatitis: 16-week results from a randomized, placebo-controlled trial. J Allergy Clin Immunol. 2020;145(3):877-84. doi: 10.1016/j.jaci.2019.11.025.
14. Mohamed MF, Gopalakrishnan S, Teixeira HD, Othman AA. Exposure-Response Analyses for Upadacitinib Efficacy in Subjects With Atopic Dermatitis-Analyses of Phase 2b Study to Support Selection of Phase 3 Doses. J Clin Pharmacol. 2021;61(5):628-35. doi: 10.1002/jcph.1782.
15. Guttman-Yassky E, Teixeira HD, Simpson EL, Papp KA, Pangan AL, Blauvelt A, et al. Once-daily upadacitinib versus placebo in adolescents and adults with moderate-to-severe atopic dermatitis (Measure Up 1 and Measure Up 2): results from two replicate double-blind, randomised controlled phase 3 trials. Lancet. 2021;397(10290):2151-68. doi: 10.1016/S0140-6736(21)00588-2
16. Reich K, Teixeira HD, de Bruin-Weller M, Bieber T, Soong W, Kabashima K, et al. Safety and efficacy of upadacitinib in combination with topical corticosteroids in adolescents and adults with moderate-to-severe atopic dermatitis (AD Up): results from a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet. 2021;397(10290):2169-81. doi: 10.1016/S0140-6736(21)00589-4.
17. Mendes-Bastos P, Ladizinski B, Guttman-Yassky E, Jiang P, Liu J, Prajapati VH, et al. Characterization of acne associated with upadacitinib treatment in patients with moderate-to-severe atopic dermatitis: A post hoc integrated analysis of 3 phase 3 randomized, double-blind, placebo-controlled trials. J Am Acad Dermatol. 2022. doi: 10.1016/j.jaad.2022.06.012.
18. Simpson EL, Papp KA, Blauvelt A, Chu CY, Hong HC, Katoh N, et al. Efficacy and Safety of Upadacitinib in Patients with Moderate to Severe Atopic Dermatitis: Analysis of Follow-up Data From the Measure Up 1 and Measure Up 2 Randomized Clinical Trials. JAMA Dermatol 2022;158(4):404-13. doi: 10.1001/jamadermatol.2022.0029
19. Silverberg JI, de Bruin-Weller M, Bieber T, Soong W, Kabashima K, Costanzo A, et al. Upadacitinib plus topical corticosteroids in atopic dermatitis: Week 52 AD Up study results. J Allergy Clin Immunol 2022;149(3):977-87.e14. doi: 10.1016/j.jaci.2021.07.036.
20. Blauvelt A, Teixeira HD, Simpson EL, Costanzo A, De Bruin-Weller M, Barbarot S, et al. Efficacy and Safety of Upadacitinib vs Dupilumab in Adults with Moderate-to-Severe Atopic Dermatitis: A Randomized Clinical Trial. JAMA Dermatol 2021;157(9):1047-55. doi: 10.1001/jamadermatol.2021.3023.
21. Katoh N, Ohya Y, Murota H, Ikeda M, Hu X, Ikeda K, et al. A phase 3 randomized, multicenter, double-blind study to evaluate the safety of upadacitinib in combination with topical corticosteroids in adolescent and adult patients with moderate-to-severe atopic dermatitis in Japan (Rising Up): An interim 24-week analysis. JAAD Int. 2021;6:27-36. doi: 10.1016/j.jdin.2021.11.001.
22. Pereyra-Rodriguez JJ, Herranz P, Figueras-Nart I, Perez B, Elosua M, Munera-Campos M, et al. Treatment of severe atopic dermatitis with upadacitinib in real clinical practice. Short-term efficacy and safety results. J Investig Allergol Clin Immunol. 2022. doi: 10.18176/ jiaci.0831.
23. European Medicines Agency [Internet]. Rinvoq - european medicines agency. Disponível em: https://www.ema.europa.eu/en/medicines/human/EPAR/rinvoq. Acessado em: 10/07/2022.
24. FDA. Upadacitinib - Drugs@FDA: FDA-Approved Drugs [Internet]. Disponível em: https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=BasicSearch.process. Acessado em: 15/07/2022.
25. Diário Oficial da União. Ministério da Saúde/Agência Nacional de Vigilância Sanitária/2ª Diretoria/Gerência-Geral de Medicamentos e Produtos. Resolução Re Nº 1.355, de 28 de Abril de 2022; 2022 Disponível em: https://www.in.gov.br/web/dou/-/resolucaore-n-1.355-de-28-de-abril-de-2022-396547245. Acessado em: 15/07/2022.
26. Gooderham MJ, Forman SB, Bissonnette R, Beebe JS, Zhang W, Banfield C, et al. Efficacy and Safety of Oral Janus Kinase 1 Inhibitor Abrocitinib for Patients with Atopic Dermatitis: A Phase 2 Randomized Clinical Trial. JAMA Dermatol. 2019;155(12):1371‑9. doi: 10.1001/jamadermatol.2019.2855.
27. Simpson EL, Wollenberg A, Bissonnette R, Silverberg JI, Papacharalambous J, Zhu L, et al. Patient-Reported Symptoms and disease impacts in adults with Moderate-to-Severe Atopic Dermatitis: results from a Phase 2b study with Abrocitinib. Dermatitis 2021;32:S53-S61. doi: 10.1097/DER.0000000000000725.
28. Silverberg JI, Simpson EL, Thyssen JP, Gooderham M, Chan G, Feeney C, et al. Efficacy and Safety of Abrocitinib in Patients With Moderate-to-Severe Atopic Dermatitis: A Randomized Clinical Trial. JAMA Dermatol. 2020;156(8):863-73. doi: 10.1001/ jamadermatol.2020.1406.
29. Simpson EL, Sinclair R, Forman S, Wollenberg A, Aschoff R, Cork M, et al. Efficacy and safety of abrocitinib in adults and adolescents with moderate-to-severe atopic dermatitis (JADE MONO-1): a multicentre, double-blind, randomised, placebo-controlled, phase 3 trial. Lancet. 2020;396(10246):255-66. doi: 10.1016/S0140-6736(20)30732-7.
30. Blauvelt A, Boguniewicz M, Brunner PM, Luna PC, Biswas P, DiBonaventura M, et al. Abrocitinib monotherapy in Investigator's Global Assessment nonresponders: improvement in signs and symptoms of atopic dermatitis and quality of life. J Dermatolog Treat. 2022;33(5):2605-13. doi: 10.1080/09546634.2022.2059053.
31. Blauvelt A, Silverberg JI, Lynde CW, Bieber T, Eisman S, Zdybski J, et al. Abrocitinib induction, randomized withdrawal, and retreatment in patients with moderate-to-severe atopic dermatitis: Results from the JAK1 Atopic Dermatitis Efficacy and Safety (JADE) REGIMEN phase 3 trial. J Am Acad Dermatol. 2022;86(1):104-12. doi: 10.1016/j.jaad.2021.05.075.
32. Shi VY, Bhutani T, Fonacier L, Deleuran M, Shumack S, Valdez H, et al. Phase 3 efficacy and safety of abrocitinib in adults with moderateto-severe atopic dermatitis after switching from dupilumab (JADE EXTEND). J Am Acad Dermatol. 2022;87(2):351-8. doi: 10.1016/j.jaad.2022.04.009.
33. Thyssen JP, Yosipovitch G, Paul C, Kwatra SG, Chu CY, DiBonaventura M, et al. Patient-reported outcomes from the JADE COMPARE randomized phase 3 study of abrocitinib in adults with moderate-to-severe atopic dermatitis. J Eur Acad Dermatol Venereol. 2022;36(3):434-43. doi: 10.1111/jdv.17813.
34. Alexis A, de Bruin-Weller M, Weidinger S, Soong W, Barbarot S, Ionita I, et al. Rapidity of Improvement in Signs/Symptoms of Moderate-to-Severe Atopic Dermatitis by Body Region with Abrocitinib in the Phase 3 JADE COMPARE Study. Dermatol Ther (Heidelb). 2022;12(3):771-85. doi: 10.1007/s13555-022-00694-1.
35 Eichenfield LF, Flohr C, Sidbury R, Siegfried E, Szalai Z, Galus R, et al. Efficacy and Safety of Abrocitinib in Combination With Topical Therapy in Adolescents With Moderate-to-Severe Atopic Dermatitis: The JADE TEEN Randomized Clinical Trial. JAMA Dermatol. 2021;157(10):1165-73. doi: 10.1001/jamadermatol.2021.2830.
36. Cork MJ, McMichael A, Teng J, Valdez H, Rojo R, Chan G, et al. Impact of oral abrocitinib on signs, symptoms and quality of life among adolescents with moderate-to-severe atopic dermatitis: an analysis of patient-reported outcomes. J Eur Acad Dermatol Venereol. 2022;36(3):422-33. doi: 10.1111/jdv.17792.
37. FDA. Abrocitinib - Drugs@FDA: FDA-Approved Drugs. [Internet]. Disponível em: https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=BasicSearch.process. Acessado em: 12/07/2022.
38. Guttman-Yassky E, Silverberg JI, Nemoto O, Forman SB, Wilke A, Prescilla R, et al. Baricitinib in adult patients with moderateto-severe atopic dermatitis: A phase 2 parallel, double-blinded, randomized placebo-controlled multiple-dose study. J Am Acad Dermatol. 2019;80(4):913-21.e9. doi: 10.1016/j.jaad.2018.01.018
39. Reich K, DeLozier AM, Nunes FP, Thyssen JP, Eichenfield LF, Wollenberg A, et al. Baricitinib improves symptoms in patients with moderate-to-severe atopic dermatitis and inadequate response to topical corticosteroids: patient-reported outcomes from two randomized monotherapy phase III trials. J Dermatolog Treat. 2020;22:1-10. doi: 10.1080/09546634.2020.1839008.
40. Bieber T, Reich K, Paul C, Tsunemi Y, Augustin M, Lacour JP, et al. BREEZE-AD4 study group. Efficacy and safety of baricitinib in combination with topical corticosteroids in patients with moderateto-severe atopic dermatitis with inadequate response, intolerance or contraindication to ciclosporin: results from a randomized, placebocontrolled, phase III clinical trial (BREEZE-AD4). Br J Dermatol. 2022. doi: 10.1111/bjd.21630.
41. Silverberg JI, Boguniewicz M, Waibel J, Weisman J, Strowd L, Sun L et al. Clinical Tailoring of Baricitinib 2 mg in Atopic Dermatitis: Baseline Body Surface Area and Rapid Onset of Action Identifies Response at Week 16. Dermatol Ther (Heidelb). 2022 Jan;12(1):137‑48. doi: 10.1007/s13555-021-00640-7.
42. Simpson EL, Forman S, Silverberg JI, Zirwas M, Maverakis E, Han G, et al. Baricitinib in patients with moderate-to-severe atopic dermatitis: Results from a randomized monotherapy phase 3 trial in the United States and Canada (BREEZE-AD5). J Am Acad Dermatol. 2021;85(1):62-70. doi: 10.1016/j.jaad.2021.02.028.
43. Reich K, Kabashima K, Peris K, Silverberg JI, Eichenfield LF, Bieber T, et al. Efficacy and Safety of Baricitinib Combined With Topical Corticosteroids for Treatment of Moderate to Severe Atopic Dermatitis: A Randomized Clinical Trial. JAMA Dermatol. 2020;156(12):1333-1343. doi: 10.1001/jamadermatol.2020.3260.
44. European Medicines Agency. Olumiant. [Internet] Disponível em: https://www.ema.europa.eu/en/medicines/human/EPAR/olumiant.Acessado em: 22/07/2022.
45. de Bruin-Weller MS, Serra-Baldrich E, Barbarot S, Grond S, Schuster C, Petto H, et al. Indirect Treatment Comparison of Baricitinib versus Dupilumab in Adults with Moderate-to-Severe Atopic Dermatitis. Dermatol Ther (Heidelb). 2022;12(6):1481-91. doi: 10.1007/s13555-022-00734-w.
46. Simpson EL, Bieber T, Guttman-Yassky E, Beck LA, Blauvelt A, Cork MJ, et al.; SOLO 1 and SOLO 2 Investigators. Two Phase 3 Trials of Dupilumab versus Placebo in Atopic Dermatitis. N Engl J Med. 2016;375(24):2335-48. doi: 10.1056/NEJMoa1610020.
47. Kim BS, Howell MD, Sun K, Papp K, Nasir A, Kuligowski ME; INCB 18424-206 Study Investigators. Treatment of atopic dermatitis with ruxolitinib cream (JAK1/JAK2 inhibitor) or triamcinolone cream. J Allergy Clin Immunol 2020;145(2):572-82. doi: 10.1016/j.jaci.2019.08.042.
48. Kim BS, Sun K, Papp K, Venturanza M, Nasir A, Kuligowski ME. Effects of ruxolitinib cream on pruritus and quality of life in atopic dermatitis: Results from a phase 2, randomized, dose-ranging, vehicle- and active-controlled study. J Am Acad Dermatol. 2020;82(6):1305-13. doi: 10.1016/j.jaad.2020.02.009.
49. Papp K, Szepietowski JC, Kircik L, Toth D, Eichenfield LF, Leung DYM, Forman SB, et al. Efficacy and safety of ruxolitinib cream for the treatment of atopic dermatitis: Results from 2 phase 3, randomized, double-blind studies. J Am Acad Dermatol. 2021;85(4):863-72. doi: 10.1016/j.jaad.2021.04.085.
50. Nakagawa H, Nemoto O, Yamada H, Nagata T, Ninomiya N. Phase 1 studies to assess the safety, tolerability and pharmacokinetics of JTE-052 (a novel Janus kinase inhibitor) ointment in Japanese healthy volunteers and patients with atopic dermatitis. J Dermatol. 2018;45(6):701-9. doi: 10.1111/1346-8138.14322.
51. Nakagawa H, Nemoto O, Igarashi A, Nagata T. Efficacy and safety of topical JTE-052, a Janus kinase inhibitor, in Japanese adult patients with moderate-to-severe atopic dermatitis: a phase II, multicentre, randomized, vehicle-controlled clinical study. Br J Dermatol. 2018;178(2):424-32. doi: 10.1111/bjd.16014.
52. Nakagawa H, Nemoto O, Igarashi A, Saeki H, Oda M, Kabashima K, Nagata T. Phase 2 clinical study of delgocitinib ointment in pediatric patients with atopic dermatitis. J Allergy Clin Immunol 2019; 144(6): 1575-83. doi:10.1016/j.jaci.2019.08.004
53. Nakagawa H, Nemoto O, Igarashi A, Saeki H, Kabashima K, Oda M, et al. Delgocitinib ointment in pediatric patients with atopic dermatitis: A phase 3, randomized, double-blind, vehicle-controlled study and a subsequent open-label, long-term study. J Am Acad Dermatol. 2021;85(4):854-62. doi: 10.1016/j.jaad.2021.06.014.
54. Nakagawa H, Nemoto O, Igarashi A, Saeki H, Murata R, Kaino H, Nagata T. Long-term safety and efficacy of delgocitinib ointment, a topical Janus kinase inhibitor, in adult patients with atopic dermatitis. J Dermatol 2020;47(2):114-20. doi: 10.1111/1346-8138.15173.
55. Dhillon S. Delgocitinib: First Approval. Drugs 2020;80(6):609-15. doi: 10.1007/s40265-020-01291-2.
56. Ahn J, Choi Y, Simpson EL. Therapeutic New Era for Atopic Dermatitis: Part 2. Small Molecules. Ann Dermatol 2021;33(2):101-7. doi: 10.5021/ad.2021.33.2.101.
Submitted date:
07/25/2022
Accepted date:
08/01/2022
Facebook
Google+
Twitter
LinkedIn
Mendeley
StumbleUpon
CiteULike
Reddit
Email