This document discusses the use of Janus kinase (JAK) inhibitors in the treatment of atopic dermatitis (AD). It describes the pathogenesis of AD involving overactivation of the JAK-STAT pathway. Several oral and topical JAK inhibitors are presented that have shown efficacy in clinical trials in reducing AD symptoms and improving quality of life. Meta-analyses of the clinical trials demonstrate that JAK inhibitors are effective and generally safe options for moderate-to-severe AD, with topical treatments having fewer side effects than oral treatments.

1. Os Inibidores da
Janus Cinase na
Terapia da
Dermatite
Atópica
Ramon Antonio Florez Acuna
ULisboa
13 Novembro 2023 Inibidores JAK na DA 1

2. Dermatite
Atópica (DA)
• Condição inflamatória crónica na pele.
• Etiologia multifatorial: genética, disfunção
barreira cutânea, alt. microbioma,
desregulação imune e fatores extrínsecos.
• Prevalência mundial 20% crianças e 10%
adultos.
• Impacto negativo Qualidade vida: prurigo e
recidivas.
• Pobre controlo da doença com tratamento
convencional (casos moderados-severos).
• Scores: EASI, IGA, Prurido
13 Novembro 2023 Inibidores JAK na DA 2

3. Patogénese
DA
• Diversas vias inflamatórias…
• Ativação Th2  IL-4, IL-5, IL-13, IL-31 e IL-22 (Th22)
na fase aguda.
• Ativação Th1  IFN-γ, TNFα e IL-17 na fase crônica.
• As citocinas usam o transdutor do sinal JAK (Janus
cinase)  ativam proteínas STAT (Signal Transducer
and Activator of Transcription) para o sinal de
transdução intracelular.
• Além da regulação imune, a via JAK-STAT está
envolvida em múltiplos processos biológicos, como
hematopoiese, proliferação celular, diferenciação e
apoptose.
13 Novembro 2023 Inibidores JAK na DA 3

4. Via JAK-STAT…
Alberts et al.
2017
Inibidores JAK na DA 13 Novembro 2023 4

5. 13 Novembro 2023 Inibidores JAK na DA 5
Targeting the Janus Kinase Family in Autoimmune Skin Diseases. (Howel et al 2019)

6. Via JAK-STAT na DA
• Over-regulation respostas imunitárias
Th2
• Células Th1 e Th17
• Queratinócitos
• Células T reguladoras
• Eosinófilos e Mastócitos
13 Novembro 2023 Inibidores JAK na DA 6

7. 13 Novembro 2023 Inibidores JAK na DA 7
Targeting the Janus Kinase Family in Autoimmune Skin Diseases. (Howel et al 2019)

8. The involvement of the JAK-STAT
signaling pathway in chronic
inflammatory skin disease atopic
dermatitis
(Proposed mechanism of JAK-
STAT involvement in atopic
dermatitis (AD) development,
part I.)
Bao, Zhang, e Chan 2013
13 Novembro 2023 Inibidores JAK na DA 8

9. Inibidores JAK
Orais
• Baricitinib – Inibidor JAK1 e JAK2.
• Upadacitinid – Inibidor JAK1.
• Abrocitinib – Inibidor JAK1.
13 Novembro 2023 Inibidores JAK na DA 9

10. Long-term Efficacy of Baricitinib
in Adults With Moderate to
Severe Atopic Dermatitis Who
Were Treatment Responders or
Partial Responders
Silverberg et al. 2021
Inibidores
JAK
na
DA
13 Novembro 2023 10

11. Baricitinib in combination
with topical corticosteroids in
patients with moderate-to-
severe atopic dermatitis with
inadequate response,
intolerance or
contraindication to
ciclosporin (BREEZE-AD4)
Tomas Bieber et al. 2022
Inibidores
JAK
na
DA
13 Novembro 2023 11

12. Upadacitinib in
adults with
moderate to severe
atopic dermatitis
Guttman-Yassky et
al. 2020
Inibidores
JAK
na
DA
13 Novembro 2023 12

13. Efficacy and Safety of Upadacitinib in Patients With Moderate to
Severe Atopic Dermatitis
(Simpson et al. 2022)
Inibidores
JAK
na
DA
13 Novembro 2023 13

14. Upadacitinib plus topical
corticosteroids in atopic
dermatitis: Week 52 AD Up
study results
(Silverberg et al. 2022)
Inibidores
JAK
na
DA
13 Novembro 2023 14

15. Efficacy and Safety of
Upadacitinib vs Dupilumab in
Adults With Moderate-to-
Severe Atopic Dermatitis
(Blauvelt et al. 2021)
Inibidores
JAK
na
DA
13 Novembro 2023 15

16. Efficacy and Safety of Oral
Janus Kinase 1 Inhibitor
Abrocitinib for Patients With
Atopic Dermatitis
(Gooderham et al. 2019)
Inibidores
JAK
na
DA
13 Novembro 2023 16

17. Efficacy and Safety of Abrocitinib in Patients
With Moderate-to-Severe Atopic Dermatitis
Silverberg et al. 2020
Inibidores
JAK
na
DA
13 Novembro 2023 17

18. Efficacy and Safety of Abrocitinib in Combination With
Topical Therapy in Adolescents With Moderate-to-
Severe Atopic Dermatitis
Eichenfield et al. 2021
Inibidores
JAK
na
DA
13 Novembro 2023 18

19. Abrocitinib versus
Placebo or
Dupilumab for
Atopic Dermatitis
Thomas Bieber et al. 2021
Inibidores
JAK
na
DA
13 Novembro 2023 19

20. Abrocitinib versus
Placebo or
Dupilumab for
Atopic Dermatitis
Thomas Bieber et al. 2021
Inibidores
JAK
na
DA
13 Novembro 2023 20

21. Inibidores JAK
Tópicos
• Delgocitinib, inhibidor pan-JAK.
• Tofacitinib, inibidor JAK1 e JAK3.
• Ruxolitinib, inibidor JAK1 e JAK2.
13 Novembro 2023 Inibidores JAK na DA 21

22. Delgocitinib
ointment, a topical
Janus kinase
inhibitor, in adult
patients with
moderate to severe
atopic dermatitis
Nakagawa et al. 2020
Inibidores
JAK
na
DA
13 Novembro 2023 22

23. Delgocitinib
ointment in pediatric
patients with atopic
dermatitis
Nakagawa et al. 2021
Inibidores
JAK
na
DA
13 Novembro 2023 23

24. Topical tofacitinib for
atopic dermatitis: a
phase IIa
randomized trial
Bissonnette et al. 2016
Inibidores
JAK
na
DA
13 Novembro 2023 24

25. Efficacy and safety of
ruxolitinib cream for
the treatment of
atopic dermatitis
Papp et al. 2021
Inibidores
JAK
na
DA
13 Novembro 2023 25

26. META-ANALISIS
NA EFICACIA
13 Novembro 2023 Inibidores JAK na DA 26

27. Comparative efficacy and safety of abrocitinib,
baricitinib, and upadacitinib for moderate-to-severe
atopic dermatitis: A network meta-analysis
Want et al. 2022
Inibidores
JAK
na
DA
13 Novembro 2023 27

28. Efficacy and Safety of
Janus Kinase
Inhibitors for
the Treatment of
Atopic Dermatitis (Li
et al. 2022)
IGA

29. • IGA (Li et al. 2022)
13 Novembro 2023 Inibidores JAK na DA 29

30. Efficacy and Safety of
Janus Kinase
Inhibitors for
the Treatment of
Atopic Dermatitis (Li
et al. 2022)
EASI

31. • EASI (Li et al. 2022)
13 Novembro 2023 Inibidores JAK na DA 31

32. 13 Novembro 2023 Inibidores JAK na DA 32
Tópica > Oral

33. META-ANALISIS
NA
SEGURANÇA
13 Novembro 2023 Inibidores JAK na DA 33

34. Eventos Adversos
(EAs)
• Sem diferenças significativas EAs entre os inibidores de JAK
e placebo/veículo que levaram à descontinuação: eczema,
DA, dor de cabeça e dor abdominal (RR 0,79, IC 95% 0,57–
1,10, p = 0,16). (Li et al. 2022)
• EAs emergentes: nasofaringite, dor de cabeça, infeção do
trato respiratório superior e náusea (RR 1,08, 95% CI 1,01–
1,17, p = 0,03): abrocitinib maior incidência (RR 1,25, IC
95% 1,10–1,42, p = 0,001). (Li et al. 2022)
• Risco Tromboembolismo Venoso (VTE) sem associação
significativa (HR, 0.95; 95% CI 0.62-1.45; incidence rate of
VTE, 0.23 events/100 patient-years). (Chen et al 2022)
13 Novembro 2023 Inibidores JAK na DA 34

35. Comparative efficacy and safety of abrocitinib, baricitinib, and
upadacitinib for moderate-to-severe atopic dermatitis: A
network meta-analysis.
Inibidores
JAK
na
DA
13 Novembro 2023 35
Wan et al. 2022
(C) TEAEs: treatment-emergent adverse events.

36. Conclusão
13 Novembro 2023 Inibidores JAK na DA 36
O alvo seletivo da via JAK-STAT permite o controle de múltiplas citocinas envolvidas na
patogénese da DA, como IL4, 13, 31, 22 e TSLP, em vez de bloquear uma única interleucina
inflamatória, como acontece com os anticorpos monoclonais. Além disso, evita-se o uso de
imunossupressores de amplo espectro.
O modo de ação conjuntamente com a farmacocinética dos inibidores da JAK,
provavelmente são responsáveis da excelente eficácia, início rápido e controlo a longo
prazo das lesões eczematosas e prurido na DA, combinado com um perfil de segurança
aceitável sem descuidar o rastreio de eventos adversos.
A informação disponível tanto para a via JAK-STAT quanto para o bloqueio de IL,
juntamente com a investigação de outras vias envolvidas na patogénese da DA, resulta em
novos conhecimentos sobre os componentes imunológicos do distúrbio, assim como uma
nova era de opções de tratamento para os pacientes com DA.

37. Bibliografia
• Abreu, Damien, e Brian S. Kim. 2021. «Innate Immune Regulation of Dermatitis». Immunology and Allergy Clinics of North
America 41 (3): 347–59. https://doi.org/10.1016/j.iac.2021.04.011.
• Agrawal, Rachana, Julia A. Wisniewski, e Judith A. Woodfolk. 2011. «The Role of Regulatory T Cells in Atopic Dermatitis».
Em Current Problems in Dermatology, editado por T. Shiohara, 41:112–24. S. Karger AG.
https://doi.org/10.1159/000323305.
• Albanesi, Cristina, Heather R. Fairchild, Stefania Madonna, Claudia Scarponi, Ornella De Pità, Donald Y. M. Leung, e
Michael D. Howell. 2007. «IL-4 and IL-13 Negatively Regulate TNF-α- and IFN-γ-Induced β-Defensin Expression through
STAT-6, Suppressor of Cytokine Signaling (SOCS)-1, and SOCS-3». The Journal of Immunology 179 (2): 984–92.
https://doi.org/10.4049/jimmunol.179.2.984.
• Alberts, Bruce, Alexander Johnson, Julian Lewis, David Morgan, Martin Raff, Keith Roberts, e Peter Walter. 2017.
Molecular Biology of the Cell. Editado por John Wilson e Tim Hunt. 6.a ed. W.W. Norton & Company.
https://doi.org/10.1201/9781315735368.
• Bao, Lei, Huayi Zhang, e Lawrence S Chan. 2013. «The Involvement of the JAK-STAT Signaling Pathway in Chronic
Inflammatory Skin Disease Atopic Dermatitis». JAK-STAT 2 (3): e24137. https://doi.org/10.4161/jkst.24137.
• Bieber, T., J.P. Thyssen, K. Reich, E.L. Simpson, N. Katoh, A. Torrelo, M. De Bruin‐Weller, et al. 2021. «Pooled Safety
Analysis of Baricitinib in Adult Patients with Atopic Dermatitis from 8 Randomized Clinical Trials». Journal of the European
Academy of Dermatology and Venereology 35 (2): 476–85. https://doi.org/10.1111/jdv.16948.
• Bieber, Thomas, Kristian Reich, Carle Paul, Yuichiro Tsunemi, Matthias Augustin, Jean-Philippe Lacour, Pierre-Dominique
Ghislain, et al. 2022. «Efficacy and Safety of Baricitinib in Combination with Topical Corticosteroids in Patients with
Moderate-to-Severe Atopic Dermatitis with Inadequate Response, Intolerance or Contraindication to Ciclosporin: Results
from a Randomized, Placebo-Controlled, Phase III Clinical Trial (BREEZE-AD4)». British Journal of Dermatology 187 (3):
338–52. https://doi.org/10.1111/bjd.21630.
• Bieber, Thomas, Eric L. Simpson, Jonathan I. Silverberg, Diamant Thaçi, Carle Paul, Andrew E. Pink, Yoko Kataoka, et al.
2021. «Abrocitinib versus Placebo or Dupilumab for Atopic Dermatitis». New England Journal of Medicine 384 (12): 1101–
12. https://doi.org/10.1056/NEJMoa2019380.
• Bissonnette, R., K.A. Papp, Y. Poulin, M. Gooderham, M. Raman, L. Mallbris, C. Wang, et al. 2016. «Topical Tofacitinib for
Atopic Dermatitis: A Phase II a Randomized Trial». British Journal of Dermatology 175 (5): 902–11.
https://doi.org/10.1111/bjd.14871.
• Blauvelt, Andrew, Jonathan I. Silverberg, Charles W. Lynde, Thomas Bieber, Samantha Eisman, Jacek Zdybski, Walter
Gubelin, et al. 2022. «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».
Journal of the American Academy of Dermatology 86 (1): 104–12. https://doi.org/10.1016/j.jaad.2021.05.075.
• Blauvelt, Andrew, Henrique D. Teixeira, Eric L. Simpson, Antonio Costanzo, Marjolein De Bruin-Weller, Sebastien
Barbarot, Vimal H. Prajapati, et al. 2021. «Efficacy and Safety of Upadacitinib vs Dupilumab in Adults With Moderate-to-
Severe Atopic Dermatitis: A Randomized Clinical Trial». JAMA Dermatology 157 (9): 1047.
https://doi.org/10.1001/jamadermatol.2021.3023.
• Boniface, Katia, François-Xavier Bernard, Martine Garcia, Austin L. Gurney, Jean-Claude Lecron, e Franck Morel. 2005. «IL-
22 Inhibits Epidermal Differentiation and Induces Proinflammatory Gene Expression and Migration of Human
Keratinocytes». The Journal of Immunology 174 (6): 3695–3702. https://doi.org/10.4049/jimmunol.174.6.3695.
• Brauweiler, Anne M., Elena Goleva, e Donald Y.M. Leung. 2014. «Th2 Cytokines Increase Staphylococcus Aureus Alpha
Toxin–Induced Keratinocyte Death through the Signal Transducer and Activator of Transcription 6 (STAT6)». Journal of
Investigative Dermatology 134 (8): 2114–21. https://doi.org/10.1038/jid.2014.43.
• Chapoval, Svetlana, Preeta Dasgupta, Nicolas J Dorsey, e Achsah D Keegan. 2010. «Regulation of the T Helper Cell Type 2
(Th2)/T Regulatory Cell (Treg) Balance by IL-4 and STAT6». Journal of Leukocyte Biology 87 (6): 1011–18.
https://doi.org/10.1189/jlb.1209772.
• Chen, Tai-Li, Ling-Ling Lee, Huei-Kai Huang, Li-Yu Chen, Ching-Hui Loh, e Ching-Chi Chi. 2022. «Association of Risk of
Incident Venous Thromboembolism With Atopic Dermatitis and Treatment With Janus Kinase Inhibitors: A Systematic
Review and Meta-Analysis». JAMA Dermatology 158 (11): 1254. https://doi.org/10.1001/jamadermatol.2022.3516.
• Cheung, P. F.-Y., C.-K. Wong, A. W.-Y. Ho, S. Hu, D.-P. Chen, e C. W.-K. Lam. 2010. «Activation of Human Eosinophils and
Epidermal Keratinocytes by Th2 Cytokine IL-31: Implication for the Immunopathogenesis of Atopic Dermatitis».
International Immunology 22 (6): 453–67. https://doi.org/10.1093/intimm/dxq027.
• Chopra, R., P.P. Vakharia, R. Sacotte, N. Patel, S. Immaneni, T. White, R. Kantor, D.Y. Hsu, e J.I. Silverberg. 2017. «Severity
Strata for Eczema Area and Severity Index ( EASI ), Modified EASI , Scoring Atopic Dermatitis ( SCORAD ), Objective
SCORAD , Atopic Dermatitis Severity Index and Body Surface Area in Adolescents and Adults with Atopic Dermatitis».
British Journal of Dermatology 177 (5): 1316–21. https://doi.org/10.1111/bjd.15641.
• Eichenfield, Lawrence F., Carsten Flohr, Robert Sidbury, Elaine Siegfried, Zsuzsanna Szalai, Ryszard Galus, Zhirong Yao, et
al. 2021. «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 Dermatology 157 (10): 1165.
https://doi.org/10.1001/jamadermatol.2021.2830.
• Eyerich, Kilian, Valentina Dimartino, e Andrea Cavani. 2017. «IL-17 and IL-22 in Immunity: Driving Protection and
Pathology». European Journal of Immunology 47 (4): 607–14. https://doi.org/10.1002/eji.201646723.
• Furue, Masutaka. 2020. «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». Journal of Clinical Medicine 9
(11): 3741. https://doi.org/10.3390/jcm9113741.
• Fyhrquist, Nanna, Sari Lehtimäki, Katharina Lahl, Terhi Savinko, Anna-Mari Lappeteläinen, Tim Sparwasser, Henrik Wolff,
Antti Lauerma, e Harri Alenius. 2012. «Foxp3+ Cells Control Th2 Responses in a Murine Model of Atopic Dermatitis».
Journal of Investigative Dermatology 132 (6): 1672–80. https://doi.org/10.1038/jid.2012.40.
• García-Melendo, C., X. Cubiró, e L. Puig. 2021. «Inhibidores de JAK: usos en dermatología. Parte 2: aplicaciones en
psoriasis, dermatitis atópica y otras dermatosis». Actas Dermo-Sifiliográficas 112 (7): 586–600.
https://doi.org/10.1016/j.ad.2020.12.006.
• Goldstein, Jérémie D., Aude Burlion, Bruno Zaragoza, Kélhia Sendeyo, Julia K. Polansky, Jochen Huehn, Eliane Piaggio,
Benoit L. Salomon, e Gilles Marodon. 2016. «Inhibition of the JAK/STAT Signaling Pathway in Regulatory T Cells Reveals a
Very Dynamic Regulation of Foxp3 Expression». Editado por Derya Unutmaz. PLOS ONE 11 (4): e0153682.
https://doi.org/10.1371/journal.pone.0153682.
• Gooderham, Melinda J., Seth B. Forman, Robert Bissonnette, Jean S. Beebe, Weidong Zhang, Chris Banfield, Linda Zhu,
Jocelyne Papacharalambous, Michael S. Vincent, e Elena Peeva. 2019. «Efficacy and Safety of Oral Janus Kinase 1 Inhibitor
Abrocitinib for Patients With Atopic Dermatitis: A Phase 2 Randomized Clinical Trial». JAMA Dermatology 155 (12): 1371.
https://doi.org/10.1001/jamadermatol.2019.2855.
• Guttman-Yassky, Emma, Michelle A. Lowes, Judilyn Fuentes-Duculan, Lisa C. Zaba, Irma Cardinale, Kristine E. Nograles,
Artemis Khatcherian, et al. 2008. «Low Expression of the IL-23/Th17 Pathway in Atopic Dermatitis Compared to
Psoriasis». Journal of Immunology (Baltimore, Md.: 1950) 181 (10): 7420–27.
https://doi.org/10.4049/jimmunol.181.10.7420.
• Guttman-Yassky, Emma, Kristine E. Nograles, e James G. Krueger. 2011. «Contrasting Pathogenesis of Atopic Dermatitis
and Psoriasis—Part I: Clinical and Pathologic Concepts». Journal of Allergy and Clinical Immunology 127 (5): 1110–18.
https://doi.org/10.1016/j.jaci.2011.01.053.
• Guttman-Yassky, Emma, Diamant Thaçi, Aileen L. Pangan, H. Chih-ho Hong, Kim A. Papp, Kristian Reich, Lisa A. Beck, et al.
2020. «Upadacitinib in Adults with Moderate to Severe Atopic Dermatitis: 16-Week Results from a Randomized, Placebo-
Controlled Trial». Journal of Allergy and Clinical Immunology 145 (3): 877–84. https://doi.org/10.1016/j.jaci.2019.11.025.
• Hirahara, Kiyoshi, Kamran Ghoreschi, Arian Laurence, Xiang-Ping Yang, Yuka Kanno, e John J. O’Shea. 2010. «Signal
Transduction Pathways and Transcriptional Regulation in Th17 Cell Differentiation». Cytokine & Growth Factor Reviews 21
(6): 425–34. https://doi.org/10.1016/j.cytogfr.2010.10.006.
• Honda, Tetsuya, Yoshiki Miyachi, e Kenji Kabashima. 2011. «Regulatory T Cells in Cutaneous Immune Responses». Journal
of Dermatological Science 63 (2): 75–82. https://doi.org/10.1016/j.jdermsci.2011.06.004.
• Howell, Michael D., Byung Eui Kim, Peisong Gao, Audrey V. Grant, Mark Boguniewicz, Anna DeBenedetto, Lynda
Schneider, Lisa A. Beck, Kathleen C. Barnes, e Donald Y.M. Leung. 2007. «Cytokine Modulation of Atopic Dermatitis
Filaggrin Skin Expression». Journal of Allergy and Clinical Immunology 120 (1): 150–55.
https://doi.org/10.1016/j.jaci.2007.04.031.
• Howell, Michael D., Fiona I. Kuo, e Paul A. Smith. 2019. «Targeting the Janus Kinase Family in Autoimmune Skin Diseases».
Frontiers in Immunology 10 (outubro): 2342. https://doi.org/10.3389/fimmu.2019.02342.
• Karpathiou, Georgia, Alexandra Papoudou-Bai, Elise Ferrand, Jean Marc Dumollard, e Michel Peoc’h. 2021. «STAT6: A
Review of a Signaling Pathway Implicated in Various Diseases with a Special Emphasis in Its Usefulness in Pathology».
Pathology - Research and Practice 223 (julho): 153477. https://doi.org/10.1016/j.prp.2021.153477.
13 Novembro 2023 Inibidores JAK na DA 37

38. • Abreu, Damien, e Brian S. Kim. 2021. «Innate Immune Regulationof Dermatitis». Immunology and Allergy Clinics of North America 41 (3): 347–59.
https://doi.org/10.1016/j.iac.2021.04.011.
• Agrawal, Rachana, Julia A. Wisniewski, e Judith A. Woodfolk. 2011. «The Role of Regulatory T Cells in Atopic Dermatitis». Em Current Problems in
Dermatology, editado por T. Shiohara, 41:112–24. S. Karger AG. https://doi.org/10.1159/000323305.
• Albanesi, Cristina, Heather R. Fairchild,Stefania Madonna, Claudia Scarponi, OrnellaDe Pità, Donald Y. M. Leung, e Michael D. Howell. 2007. «IL-4
and IL-13 NegativelyRegulate TNF-α- and IFN-γ-Inducedβ-Defensin Expression through STAT-6, Suppressor of Cytokine Signaling(SOCS)-1, and
SOCS-3».The Journal of Immunology 179 (2): 984–92. https://doi.org/10.4049/jimmunol.179.2.984.
• Alberts, Bruce, Alexander Johnson, Julian Lewis, David Morgan, Martin Raff, Keith Roberts, e Peter Walter. 2017. Molecular Biology of the Cell.
Editado por John Wilson e Tim Hunt. 6.a ed. W.W. Norton & Company. https://doi.org/10.1201/9781315735368.
• Bao, Lei, Huayi Zhang, e Lawrence S Chan. 2013. «The Involvementof the JAK-STAT Signaling Pathway in Chronic Inflammatory Skin Disease Atopic
Dermatitis». JAK-STAT 2 (3): e24137. https://doi.org/10.4161/jkst.24137.
• Bieber, T., J.P. Thyssen, K. Reich, E.L. Simpson, N. Katoh, A. Torrelo, M. De Bruin‐Weller, et al. 2021. «Pooled Safety Analysis of Baricitinib in Adult
Patients with Atopic Dermatitis from 8 Randomized ClinicalTrials». Journal of the European Academy of Dermatology and Venereology 35 (2):
476–85. https://doi.org/10.1111/jdv.16948.
• Bieber, Thomas, Kristian Reich, Carle Paul, Yuichiro Tsunemi, Matthias Augustin, Jean-Philippe Lacour, Pierre-DominiqueGhislain, et al. 2022.
«Efficacyand Safety of Baricitinib in Combinationwith Topical Corticosteroids in Patients with Moderate-to-Severe Atopic Dermatitis with
Inadequate Response, Intoleranceor Contraindicationto Ciclosporin: Results from a Randomized, Placebo-Controlled, Phase III ClinicalTrial
(BREEZE-AD4)». British Journal of Dermatology 187 (3): 338–52. https://doi.org/10.1111/bjd.21630.
• Bieber, Thomas, Eric L. Simpson, Jonathan I. Silverberg, Diamant Thaçi, Carle Paul, Andrew E. Pink, Yoko Kataoka, et al. 2021. «Abrocitinibversus
Placebo or Dupilumabfor Atopic Dermatitis». New England Journal of Medicine 384 (12): 1101–12. https://doi.org/10.1056/NEJMoa2019380.
• Bissonnette, R., K.A. Papp, Y. Poulin, M. Gooderham, M. Raman, L. Mallbris, C. Wang, et al. 2016. «TopicalTofacitinibfor Atopic Dermatitis: A
Phase II a Randomized Trial». British Journal of Dermatology 175 (5): 902–11. https://doi.org/10.1111/bjd.14871.
• Blauvelt, Andrew, Jonathan I. Silverberg, Charles W. Lynde, Thomas Bieber, Samantha Eisman, Jacek Zdybski, Walter Gubelin, et al. 2022.
«Abrocitinib Induction, Randomized Withdrawal, and Retreatmentin Patients with Moderate-to-SevereAtopic Dermatitis: Results from the JAK1
Atopic Dermatitis Efficacy and Safety (JADE) REGIMEN Phase 3 Trial». Journal of the American Academy of Dermatology 86 (1): 104–12.
https://doi.org/10.1016/j.jaad.2021.05.075.
• Blauvelt, Andrew, Henrique D. Teixeira, Eric L. Simpson, Antonio Costanzo, Marjolein De Bruin-Weller, Sebastien Barbarot, Vimal H. Prajapati, et al.
2021. «Efficacyand Safety of Upadacitinib vs Dupilumab in Adults With Moderate-to-SevereAtopic Dermatitis: A Randomized ClinicalTrial». JAMA
Dermatology 157 (9): 1047. https://doi.org/10.1001/jamadermatol.2021.3023.
• Boniface, Katia, François-Xavier Bernard, Martine Garcia, Austin L. Gurney, Jean-Claude Lecron, e Franck Morel. 2005. «IL-22Inhibits Epidermal
Differentiationand Induces ProinflammatoryGene Expression and Migrationof Human Keratinocytes». The Journal of Immunology 174 (6): 3695–
3702. https://doi.org/10.4049/jimmunol.174.6.3695.
• Brauweiler, Anne M., Elena Goleva, e Donald Y.M. Leung. 2014. «Th2 Cytokines Increase Staphylococcus Aureus Alpha Toxin–InducedKeratinocyte
Death through the Signal Transducer and Activator of Transcription 6 (STAT6)». Journal of InvestigativeDermatology 134 (8): 2114–21.
https://doi.org/10.1038/jid.2014.43.
• Chapoval, Svetlana, Preeta Dasgupta, Nicolas J Dorsey, e Achsah D Keegan. 2010. «Regulationof the T Helper Cell Type 2 (Th2)/T Regulatory Cell
(Treg) Balance by IL-4 and STAT6». Journal of Leukocyte Biology 87 (6): 1011–18. https://doi.org/10.1189/jlb.1209772.
Marodon. 2016. «Inhibitionof the JAK/STAT SignalingPathway in Regulatory T Cells Reveals a Very Dynamic Regulation of Foxp3 Expression».
Editado por Derya Unutmaz. PLOS ONE 11 (4): e0153682. https://doi.org/10.1371/journal.pone.0153682.
• Gooderham, Melinda J., Seth B. Forman, Robert Bissonnette, Jean S. Beebe, Weidong Zhang, Chris Banfield, Linda Zhu, Jocelyne
Papacharalambous, MichaelS. Vincent, e Elena Peeva. 2019. «Efficacy and Safety of Oral Janus Kinase 1 Inhibitor Abrocitinibfor Patients With
Atopic Dermatitis: A Phase 2 RandomizedClinicalTrial». JAMA Dermatology 155 (12): 1371. https://doi.org/10.1001/jamadermatol.2019.2855.
• Guttman-Yassky, Emma, MichelleA. Lowes, Judilyn Fuentes-Duculan, Lisa C. Zaba, Irma Cardinale, Kristine E. Nograles, Artemis Khatcherian, et al.
2008. «Low Expression of the IL-23/Th17 Pathway in Atopic Dermatitis Compared to Psoriasis». Journal of Immunology (Baltimore, Md.: 1950) 181
(10): 7420–27. https://doi.org/10.4049/jimmunol.181.10.7420.
• Guttman-Yassky, Emma, Kristine E. Nograles, e James G. Krueger. 2011. «Contrasting Pathogenesis of Atopic Dermatitis and Psoriasis—Part I:
Clinicaland PathologicConcepts». Journal of Allergy and Clinical Immunology 127 (5): 1110–18. https://doi.org/10.1016/j.jaci.2011.01.053.
• Guttman-Yassky, Emma, Diamant Thaçi, Aileen L. Pangan, H. Chih-ho Hong, Kim A. Papp, Kristian Reich, Lisa A. Beck, et al. 2020. «Upadacitinibin
Adults with Moderate to Severe Atopic Dermatitis: 16-Week Results from a Randomized, Placebo-Controlled Trial». Journal of Allergy and Clinical
Immunology 145 (3): 877–84. https://doi.org/10.1016/j.jaci.2019.11.025.
• Hirahara, Kiyoshi, Kamran Ghoreschi, Arian Laurence, Xiang-Ping Yang, Yuka Kanno, e John J. O’Shea. 2010. «Signal Transduction Pathways and
TranscriptionalRegulation in Th17 Cell Differentiation». Cytokine & Growth Factor Reviews 21 (6): 425–34.
https://doi.org/10.1016/j.cytogfr.2010.10.006.
• Honda, Tetsuya, Yoshiki Miyachi, e Kenji Kabashima. 2011. «RegulatoryT Cells in Cutaneous Immune Responses». Journal of Dermatological
Science 63 (2): 75–82. https://doi.org/10.1016/j.jdermsci.2011.06.004.
• Howell, Michael D., Byung Eui Kim, Peisong Gao, Audrey V. Grant, Mark Boguniewicz, Anna DeBenedetto, Lynda Schneider, Lisa A. Beck, Kathleen
C. Barnes, e Donald Y.M. Leung. 2007. «CytokineModulationof Atopic Dermatitis FilaggrinSkin Expression». Journal of Allergy and Clinical
Immunology 120 (1): 150–55. https://doi.org/10.1016/j.jaci.2007.04.031.
• Howell, Michael D., Fiona I. Kuo, e Paul A. Smith. 2019. «Targetingthe Janus Kinase Family in AutoimmuneSkin Diseases». Frontiers in
Immunology 10 (outubro): 2342. https://doi.org/10.3389/fimmu.2019.02342.
• Karpathiou, Georgia, Alexandra Papoudou-Bai, Elise Ferrand, Jean Marc Dumollard, e Michel Peoc’h. 2021. «STAT6: A Review of a Signaling
Pathway Implicated in Various Diseases with a Special Emphasis in Its Usefulness in Pathology». Pathology - Research and Practice 223 (julho):
153477. https://doi.org/10.1016/j.prp.2021.153477.
• Katoh, Norito, Yukihiro Ohya, Hiroyuki Murota, Masanori Ikeda, Xiaofei Hu, Kimitoshi Ikeda, John Liu, et al. 2022. «A Phase 3 Randomized,
Multicenter, Double-BlindStudy to Evaluate the Safety of Upadacitinibin Combination with Topical Corticosteroids in Adolescent and Adult
Patients with Moderate-to-SevereAtopic Dermatitis in Japan (Rising Up): An Interim 24-Week Analysis». JAAD International 6 (março): 27–36.
https://doi.org/10.1016/j.jdin.2021.11.001.
• Kim, Byung Eui, Donald Y.M. Leung, Mark Boguniewicz, e Michael D. Howell. 2008. «Loricrinand InvolucrinExpression Is Down-Regulated by Th2
Cytokines through STAT-6». Clinical Immunology 126 (3): 332–37. https://doi.org/10.1016/j.clim.2007.11.006.
• Koga, Chizuko, Kenji Kabashima, Noriko Shiraishi, Miwa Kobayashi, e Yoshiki Tokura. 2008. «Possible Pathogenic Role of Th17 Cells for Atopic
Dermatitis». Journal of InvestigativeDermatology 128 (11): 2625–30. https://doi.org/10.1038/jid.2008.111.
• Li, Chenyang, Xun Sun, Kun Zhao, Fanxiang Meng, Lin Li, Zhenzhen Mu, e Xiuping Han. 2022. «Efficacyand Safety of Janus Kinase Inhibitors for the
Treatmentof Atopic Dermatitis: A Systematic Review and Meta-Analysis». Dermatology 238 (4): 725–35. https://doi.org/10.1159/000518541.
https://doi.org/10.1046/j.1365-2249.1999.01068.x.
• Ong, Peck Y., Takaaki Ohtake, Corinne Brandt, Ian Strickland, Mark Boguniewicz, Tomas Ganz, Richard L. Gallo, e Donald Y.M. Leung. 2002.
«Endogenous AntimicrobialPeptides and Skin Infections in Atopic Dermatitis». New England Journal of Medicine 347 (15): 1151–60.
https://doi.org/10.1056/NEJMoa021481.
• Papp, Kim, Jacek C. Szepietowski, Leon Kircik, Darryl Toth, Lawrence F. Eichenfield, Donald Y.M. Leung, Seth B. Forman, et al. 2021. «Efficacyand
Safety of RuxolitinibCream for the Treatmentof Atopic Dermatitis: Results from 2 Phase 3, Randomized, Double-BlindStudies». Journal of the
American Academy of Dermatology 85 (4): 863–72. https://doi.org/10.1016/j.jaad.2021.04.085.
• Pernis, Alessandra B., e Paul B. Rothman. 2002. «JAK-STAT Signalingin Asthma». Journal of Clinical Investigation 109 (10): 1279–83.
https://doi.org/10.1172/JCI0215786.
• Rawlings, Jason S., Kristin M. Rosler, e Douglas A. Harrison. 2004. «The JAK/STAT SignalingPathway». Journal of Cell Science 117 (8): 1281–83.
https://doi.org/10.1242/jcs.00963.
• Reich, Kristian, Kenji Kabashima, Ketty Peris, Jonathan I. Silverberg, Lawrence F. Eichenfield,Thomas Bieber, Aleksandra Kaszuba, et al. 2020.
«Efficacyand Safety of Baricitinib Combined With Topical Corticosteroids for Treatmentof Moderate to Severe Atopic Dermatitis: A Randomized
ClinicalTrial». JAMA Dermatology 156 (12): 1333. https://doi.org/10.1001/jamadermatol.2020.3260.
• Rochman, Yrina, Mohit Kashyap, Gertraud W. Robinson, Kazuhito Sakamoto, Julio Gomez-Rodriguez, Kay-Uwe Wagner, e Warren J. Leonard. 2010.
«ThymicStromal Lymphopoietin-MediatedSTAT5 Phosphorylationvia Kinases JAK1 and JAK2 Reveals a Key Differencefrom IL-7–Induced
Signaling». Proceedings of the National Academy of Sciences 107 (45): 19455–60. https://doi.org/10.1073/pnas.1008271107.
• Seif, Farhad, Majid Khoshmirsafa, Hossein Aazami, Monireh Mohsenzadegan, GholamrezaSedighi, e Mohammadali Bahar. 2017. «The Role of JAK-
STAT SignalingPathway and Its Regulators in the Fate of T Helper Cells». Cell Communication and Signaling 15 (1): 23.
https://doi.org/10.1186/s12964-017-0177-y.
• Shi, Vivian Y., Tina Bhutani, Luz Fonacier, Mette Deleuran, Stephen Shumack, Hernan Valdez, Fan Zhang, Gary L. Chan, Michael C. Cameron, e
Natalie C. Yin. 2022. «Phase 3 Efficacy and Safety of Abrocitinibin Adults with Moderate-to-Severe Atopic Dermatitis after Switching from
Dupilumab (JADE EXTEND)». Journal of the American Academy of Dermatology 87 (2): 351–58. https://doi.org/10.1016/j.jaad.2022.04.009.
• Silverberg, Jonathan I., Marjolein De Bruin-Weller, Thomas Bieber, Weily Soong, Kenji Kabashima, Antonio Costanzo, David Rosmarin, et al. 2022.
«Upadacitinib plus Topical Corticosteroids in Atopic Dermatitis: Week 52 AD Up Study Results». Journal of Allergy and Clinical Immunology 149
(3): 977-987.e14. https://doi.org/10.1016/j.jaci.2021.07.036.
• Silverberg, Jonathan I., Eric L. Simpson, Jacob P. Thyssen, Melinda Gooderham, Gary Chan, Claire Feeney, Pinaki Biswas, et al. 2020. «Efficacyand
Safety of Abrocitinibin Patients With Moderate-to-SevereAtopic Dermatitis: A Randomized ClinicalTrial». JAMA Dermatology 156 (8): 863.
https://doi.org/10.1001/jamadermatol.2020.1406.
• Silverberg, Jonathan I., Eric L. Simpson, Andreas Wollenberg, Robert Bissonnette, Kenji Kabashima, Amy M. DeLozier, Luna Sun, Tracy Cardillo,
Fabio P. Nunes, e Kristian Reich. 2021. «Long-Term Efficacyof Baricitinibin Adults With Moderate to Severe Atopic Dermatitis Who Were
TreatmentResponders or PartialResponders: An Extension Study of 2 RandomizedClinicalTrials». JAMA Dermatology 157 (6): 691.
https://doi.org/10.1001/jamadermatol.2021.1273.
• Simpson, Eric L., Kim A. Papp, Andrew Blauvelt, Chia-Yu Chu, H. Chih-ho Hong, Norito Katoh, Brian M. Calimlim, et al. 2022. «Efficacyand Safety of
Upadacitinibin Patients With Moderate to Severe Atopic Dermatitis: Analysis of Follow-up Data From the Measure Up 1 and Measure Up 2
Randomized ClinicalTrials». JAMA Dermatology 158 (4): 404. https://doi.org/10.1001/jamadermatol.2022.0029.
• Simpson, Eric L, Rodney Sinclair, Seth Forman, Andreas Wollenberg, Roland Aschoff, Michael Cork, Thomas Bieber, et al. 2020. «Efficacyand Safety
of Abrocitinib in Adults and Adolescents with Moderate-to-SevereAtopic Dermatitis (JADE MONO-1): A Multicentre, Double-Blind, Randomised,
Placebo-Controlled, Phase 3 Trial». The Lancet 396 (10246): 255–66. https://doi.org/10.1016/S0140-6736(20)30732-7.
13 Novembro 2023 Inibidores JAK na DA 38

39. Obrigado
13 Novembro 2023 Inibidores JAK na DA 39