AD, atopic dermatitis.
For US Healthcare Professionals
AD, atopic dermatitis.
T-cell imbalance is a source of the heterogenous clinical symptoms and chronicity of AD1
1
Excessive co-stimulation dysregulates T cells, making them pathogenic1,3
2
Increased number and/or activity of multiple pathogenic T-cell subsets promote T-cell-mediated inflammation1
3
Effector T cells release multiple proinflammatory cytokines (including IL-4 and IL-13)1
4
T-cell imbalance--an increase in OX40 receptor-positive pathogenic T cells--drives multiple inflammatory pathways, resulting in clinical heterogeneity and disease chronicity1
Pruritus1,4
Diverse lesion
morphology4,5
Lesion
distribution4
Disease presentation
across skin tones5
Disease
severity6
Disease
recurrence7
OX40 receptor-expressing pathogenic T cells drive multiple inflammatory pathways in AD1
References: 1. Kaech S, Cui W. Nat Rev Immunol. 2012;12(11):749–761. 2. Chen L, Shen Z. Cell Mol Immunol. 2020;17(1):64-75. 3. De Bruyn Carlier T, Badloe FMS, Ring J, Gutermuth J, Krohn IK. J Autoimmun. 2021;120:102634. 4. Sadrolashrafi K, Guo L, Kikucha R, et al. Cells. 2024;13(7):587. 5. Croft M, So T, Duan W, Soroosh P. Immunol Rev. 2009;229(1):173–191.
IFN-γ, interferon-gamma; IgE, immunoglobulin E; IL-2, interleukin-2; IL-4, interleukin-4; IL-4Ra, interleukin-4Ra; IL-5, interleukin-5; IL-13, interleukin-13; IL-17, interleukin-17; IL-22, interleukin-22; IL-31, interleukin-31; JAK-STAT, Janus kinase-signal transducer(s) and activator(s) of transcription; Th1, Type 1 T helper; Th2, Type 2 T helper; Th17, Type 17 T helper; Th22, Type 22 T helper; TNF-𝛼, tumor necrosis factor alpha.
Atopic dermatitis, or AD, is a chronic, heterogeneous inflammatory disease1 characterized by skin itchiness1, redness, and pain.1
AD occurs most frequently in children1-3, but may continue into adolescence and adulthood.1,2
Skin barrier disruption,4 along with T-cell mediated inflammation in the skin and blood, are key drivers of AD pathophysiology.4,5
While type 2 inflammation driven by TH2 cells is central to AD4,5, other pathogenic T-cell subsets and their associated cytokines also contribute to disease pathogenesis and clinical heterogeneity.4-7
T cells require multiple activation steps to achieve full effector function.8 An initial signal through the TCR promotes activation of the naïve T cell8,9, resulting in OX40 expression on the activated T cell, which is further enhanced by the presence of proinflammatory cytokines.8,10
OX40, expressed on activated T cells, binds to OX40 ligand, which stimulates the OX40 pathway10, resulting in T-cell proliferation10-13, survival, differentiation10-12, and migration to the skin10,13,14 where they release proinflammatory cytokines that10,13,14 contribute to key aspects of AD pathogenesis10,15,16, including promotion of skin inflammation, itch, and skin pain.10,15-17
Importantly, OX40 signaling also promotes development and reactivation of memory T cells, which contribute to the chronic nature of AD.10,17,18
Taken together, the OX40 pathway plays a central role in pathogenic T-cell expansion10,14,17, effector function development, and subsequent memory T cell formation, which drive local and systemic inflammation10,14,17 critical for AD pathogenesis10,14,17 and clinical burden in patients with AD.14
References: 1. Silverberg JI. Clinical Management of Atopic Dermatitis. 1st ed. West Islip, NY: Professional Communications, Inc: 2018. 2. Margolis JS, et al. JAMA Dermatol. 2014;150:593-600. 3. Lee HH, et al. J Am Acad Dermatol. 2019;80:1526-1532.e7. 4. Weidinger S, et al. Nat Rev Dis Primers. 2018;4:1. 5. De Bruyn Carlier T, et al. J Autoimmun. 2021;120:102634. 6. Beck LA, et al. JID Innov. 2022;2:100131. 7. Czarnowicki T, et al. J Allergy Clin Immunol. 2019;143:1-11. 8. Chen L, et al. Nat Rev Immunol. 2013;13:227-242. 9. Hwang J-R, et al. Exp Mol Med. 2020;52:750-761. 10. Furue M, et al. J Clin Med. 2021;10:2578. 11. Mascarelli DE, et al. Front Cell Dev Biol. 2021;9:692982. 12. Goronzy JJ, et al. Arthritis Res Ther. 2008;10(Suppl1):S3. 13. Croft M, et al. Immunol Rev. 2009;229:173-191. 14. Elsner JSH, et al. Acta Derm Venereol. 2020; 100:adv00099. 15. Guttman-Yassky E, et al. Exp Dermatol. 2018;27:409-417. 16. Fu Y, et al. Acta Pharm Sin B. 2020;10:414-433. 17. Guttman-Yassky E, et al. J Allergy Clin Immunol. 2019;144:482-493.e7. 18. Chen L, et al. Cell Mol Immunol. 2020;17:64-75.
OX40 receptor-expressing pathogenic T cells drive multiple inflammatory pathways in AD1,19
1
2
Promotes T-cell imbalance, including pathogenic T-cell expansion, differentiation, and migration to skin1,3,19
Enhances the release of proinflammatory cytokines by multiple subsets of T cells, which promote skin inflammation, itch, and skin pain1
Promotes the differentiation of pathogenic effector T cells into pathogenic memory T cells, driving long-term immune responses and immunologic memory1,6,7,12
Reactivates resident memory T cells that reside in the skin, which are thought to contribute to the recurrence and location of AD lesions8,9,21
The OX40 pathway may present an opportunity to target pathogenic T cells instead of blocking individual cytokines or downstream pathways1,15
Listen to Dr Jonathan Silverberg discuss OX40 in:
From Heterogeneity Comes New Insights: Exploring the Role of T Cells and OX40 Signaling in Atopic Dermatitis
Listen to Dr Jonathan Silverberg discuss OX40 in:
From Heterogeneity Comes New Insights: Exploring the Role of T Cells and OX40 Signaling in Atopic Dermatitis
Dr Turk and Dr Silverberg were compensated for their time.
[Announcer Intro]
You’re listening to ReachMD. This medical industry feature, titled “From Heterogeneity Comes New Insights: Exploring the Role of T Cells and OX40 Signaling in Atopic Dermatitis,” is sponsored by Amgen and Kyowa Kirin.
Your host is Dr Charles Turk.
[Dr Turk]
This is ReachMD, and I’m Dr Charles Turk.
Joining me today is Dr Jonathan Silverberg, who’s a Professor and Director of Clinical Research and the Director of Patch Testing at George Washington University School of Medicine and Health Sciences. Dr Silverberg, welcome.
[Dr Silverberg]
Thanks for having me.
[Dr Turk]
To start us off, Dr Silverberg, can you tell us a little bit about atopic dermatitis, or AD, and your experience in the clinic managing patients with this disease?
[Dr Silverberg]
Sure. Many patients with AD experience chronic symptoms intensified by unpredictable flares, which can result in significant clinical burden that impact the patient’s overall quality of life.2-4 In fact, AD is the skin disorder with the highest disease burden. This is particularly true for the patients I see in my clinic with moderate-to-severe disease, who may experience skin symptoms, including redness, dryness, and skin thickening, five to seven days per week.5,6 Itch and skin pain also have a significant impact on these patients, with over 40 percent of them reporting skin pain within the past week and about a third experiencing itching five to six days a week.7-9 In many patients these skin symptoms can result in sleep disturbances or loss of sleep, which further increase the burden of disease.7,10 As you can imagine, over the course of the disease these sorts of symptoms negatively impact multiple aspects of patients’ daily lives.
[Dr Turk]
Do your patients experience burden beyond the skin symptoms you described?
[Dr Silverberg]
Unfortunately, yes. The burden of AD can be far reaching, and I have certainly seen this in my patients.1,11-13
In addition to their clinical symptoms, many patients also experience negative emotional or social impacts of the disease.7,14,15 This is further substantiated by a systematic review published by the American Academy of Dermatology in 2022 that showed clinically diagnosed depression and anxiety are associated with atopic dermatitis.16 Many of my patients also tend to feel embarrassed or self-conscious about their skin and so they avoid social interactions altogether.15 Over half of my patients are also limited in their ability to complete common, daily activities, such as household chores.15
All in all, you can start to see how the overall burden in AD extends beyond the skin and can significantly impact a patient’s overall well-being and quality of life.
[Dr Turk]
Hearing a little more about the impact that this disease has on your patients, I can understand why keeping the symptoms of the disease under control would be an important goal for both patients and clinicians. Can you briefly comment on topical and systemic therapies that are currently used in AD? And, based on your experience, what are the remaining challenges regarding management of moderate-to-severe AD?
[Dr Silverberg]
So, topical therapies have been a mainstay of AD treatment for decades.17 While they continue to have a place in the treatment paradigm, especially for patients with mild disease, our understanding of AD pathophysiology and treatment options has evolved over time, providing more options for patients with moderate-to-severe disease.18 We now know that the inflammation that drives many of the skin symptoms associated with AD, including lesion development, itch, and pain, also has an impact outside of the skin.18,19 The systemic nature of the underlying inflammation, coupled with the potentially large body surface area involved, are two reasons why patients with moderate-to-severe disease often have inadequate disease control despite the standard use of topical therapies.20,21 It is recommended that these patients be evaluated for systemic therapy to help better control their disease.20
Current systemic therapies in moderate-to-severe AD target individual cytokines, such as IL-4, IL-13, or IL-31, or broadly inhibit the activity of molecules required for downstream signaling of multiple cytokines.18,22 While these therapies have provided significant benefit to patients with moderate-to-severe AD, some patients still fail to reach and/or maintain adequate control of their disease with systemic therapies.11,23 This could be due to a lack of efficacy, loss of response, or safety and tolerability issues.20 Considering these challenges, additional research is underway seeking to identify distinct inflammatory pathways and cell types that contribute to the heterogeneity of AD pathogenesis.11,24
[Dr Turk]
How can what we know about AD pathophysiology inform research into novel inflammatory pathways?
[Dr Silverberg]
That’s a great question. When thinking about novel inflammatory pathways, we must also keep in mind what we already know about AD pathophysiology. AD is a complex and heterogeneous disease.11 In the clinic, we see AD patients who have skin lesions with different characteristics and variable distribution throughout the body.6 What we cannot see is that these diverse clinical manifestations are driven by multiple inflammatory pathways that are the underlying cause of these clinical symptoms.6,25
T cells appear to play a central role in many of the inflammatory pathways that drive AD pathogenesis.12 One clear indication of their importance is that T cells are the most abundant infiltrate in AD lesions.13,26 This T-cell influx and expansion within the skin, as well as the release of various proinflammatory cytokines, drives multiple aspects of AD pathogenesis, including inflammation, flares, epidermal hyperplasia, itch, and skin pain.3,12,13,19,27,28
[Dr Turk]
So, Dr Silverberg, how does one cell type—the T cell—contribute to so many different activities in AD?
[Dr Silverberg]
There are actually many different types of T cells, each with a specific set of functions that drive inflammation.29 Included in this mix are both effector and memory T cells, which contribute to acute and chronic inflammation, respectively.12,13,28
TH2 cells, one type of effector T cell, play a key role in AD pathogenesis, and are best known for the release of the proinflammatory cytokines IL-4 and IL-13.13,29 However, it’s important to appreciate that TH2 cells also release other cytokines—IL-5 and IL-31 for example—that exert their own effects on the inflammatory response.27,29,30 While pathogenic TH2 cells are dominant in AD, other pathogenic T-cell subsets and their associated cytokines may also contribute to disease pathophysiology.12,27 The relative contribution of each T-cell–mediated inflammatory pathway may evolve over the course of the disease or vary by age and ethnicity, and this drives the complex variations of disease presentation in AD.6,12
As mentioned, memory T cells represent another cell type with an important role in AD. They are long-lived, poised for reactivation, can contribute to inflammation even in the absence of visible lesions, and can drive disease persistence and chronic symptoms.13,31
Taken together, this idea of a T-cell inflammatory network in AD highlights the unique role of T cells upstream of the individual cytokines that they produce.12
[Dr Turk]
And these T cells that you described as critical to the AD disease process, what exactly makes them pathogenic?
[Dr Silverberg]
In order to address this question, let’s first think about T-cell activation in a normal immune response. To form a productive response, T cells need to expand, survive, and mature into robust effector T cells in response to an infectious threat, such as a bacteria or virus.12,32 After the threat is cleared, the effector T cells contract, and a small subset develops into long-lived memory T cells that can quickly become reactivated if the bacteria or virus is reintroduced.12,33 All of these activities require a specific and well-orchestrated set of signals to be delivered to the T cells throughout their development.32
In patients with AD, T cells become pathogenic when they receive signals to expand and mature into effector and memory T cells in the absence of an infectious threat.25,34 One important activation signal for T cells occurs through the OX40 pathway.35
OX40 is expressed on the surface of activated effector and memory T cells—these are the cells that are more likely to be pathogenic in AD.25,35 The OX40 pathway is activated when OX40 expressed on T cells binds to the OX40 ligand, which is expressed on a number of cell types, including antigen-presenting cells.25,36 Activation of the OX40 pathway promotes T-cell proliferation, survival, differentiation, and migration to the skin, where they release proinflammatory cytokines that contribute to key aspects of AD pathogenesis, including promotion of skin inflammation, itch, and skin pain.19,33,37,38 Importantly, these effects of OX40 signaling are seen across multiple pathogenic T-cell subsets, including memory T cells.13,39
[Dr Turk]
So it seems that the OX40 pathway plays a key role in T-cell activation and effector function development. What is known about OX40 specifically in patients with AD?
[Dr Silverberg]
There are some interesting data coming out from multiple groups showing that the OX40 pathway has direct relevance to T-cell–driven inflammation in AD. I think one of the strongest indications that the OX40 pathway plays a role in AD is the increase in expression of OX40 on T cells in AD patients compared to healthy controls.38 We have also seen the expression of OX40 and OX40 ligands in cells co-localizing specifically in lesional skin of AD patients, suggesting that this pathway is actively playing a role in the inflammatory process in the skin.38 In fact, we have also seen that OX40-positive T cells are better able to home to the skin, which may allow these activated pathogenic T cells to drive inflammation directly in the skin.38
[Dr Turk]
Now we’ve talked a lot about the role of OX40 signaling on multiple effector T cells, Dr Silverberg, so I’m wondering if OX40 activation also occurs on memory T cells.
[Dr Silverberg]
Absolutely. OX40 signaling plays a key role in promoting both the development and reactivation of memory T cells residing in the skin.39 These memory T cells develop and persist long after the initial immune response, and can be quickly reactivated, providing the basis for immunologic memory.31,33,34
What does the concept of immunologic memory mean clinically for patients with AD? Well, there is emerging research that memory T cells in the skin contribute to the chronic and persistent nature of AD.25,28,34,40 For example, for many patients, AD lesions may recur in the same body location—this may be due in part to memory T cells residing in the skin at these specific locations.13,34 The severity and persistence of disease symptoms may also be influenced by the long-lived potential of these memory T cells.31,34 In a nutshell, in order to understand and appreciate AD as a chronic disease, we need to also understand and appreciate the key role of memory T cells in disease pathogenesis.
[Dr Turk]
And before we close, Dr Silverberg, are there any final thoughts on our rapidly evolving understanding of AD pathophysiology and implications for future research that you would like to leave with our audience today?
[Dr Silverberg]
Yes. When seeing patients in the clinic, it’s important to keep in mind that AD is more than a disease of the skin. It’s a complex and heterogeneous inflammatory disease mediated by multiple T-cell–driven inflammatory pathways leading to chronic and persistent symptoms and significant burden.1,11-13 Some of our patients, particularly those with moderate-to-severe disease, may require systemic therapy in addition to topical treatment to adequately control their symptoms.11 Moreover, for some patients, treatment with currently available systemic therapies may still not be sufficient to reach their treatment goals.11,41,42
In the future, focusing on pathogenic T cells directly, rather than individual T cell cytokines or downstream pathways, could provide new insights into our understanding of the pathogenesis of AD.
[Dr Turk]
Well, with those final thoughts in mind, I would like to thank my guest, Dr Jonathan Silverberg, for sharing his insights on the heterogeneity of AD and the importance of OX40 signaling in disease pathogenesis. Dr Silverberg, it was a pleasure having you on the program.
[Dr Silverberg]
Thank you very much.
[Announcer Close]
This program was sponsored by Amgen and Kyowa Kirin. If you missed any part of this discussion, visit ReachMD dot com slash medical industry feature. This is ReachMD. Be Part of the Knowledge.
References:
1. Silverberg JI. Clinical Management of Atopic Dermatitis. 1st ed. 2018.
2. Ständer S. N Engl J Med. 2021;384:1136-1143.
3. Girolomoni G, et al. Ther Adv Chronic Dis. 2022;13:20406223211066728.
4. Simpson EL, et al. J Am Acad Dermatol. 2016;74:491-498.
5. Eichenfield LF, et al. Semin Cutan Med Surg. 2017;36:S92-S94.
6. Czarnowicki T, et al. J Allergy Clin Immunol. 2019;143:1-11.
7. Simpson EL, et al. JAMA Dermatol. 2018;154:903-912.
8. Silverberg JI, et al. Ann Allergy Asthma Immunol. 2018;121:340-347.
9. Vakharia PP, et al. Ann Allergy Asthma Immunol. 2017;119:548-552.e3.
10. Chang Y-S, et al. J Allergy Clin Immunol. 2018;142:1033-1040.
11. Ratchataswan T, et al. J Allergy Clin Immunol Pract. 2021;9:1053-1065.
12. Weidinger S, et al. Nat Rev Dis Primers. 2018;4:1.
13. De Bruyn Carlier T, et al. J Autoimmun. 2021;120:102634.
14. Silverberg Jl, et al. Br J Dermatol. 2019;181:554-565.
15. Grant L, et al. Dermatitis. 2019;30:247-254.
16. Davis DMR. J Am Acad Dermatol. 2022;86:1335-1336.e18.
17. Kleinman E, et al. Am J Clin Dermatol. 2022;23:595-603.
18. Bieber T. Nat Rev Drug Discov. 2022;21:21-40.
19. Kwatra SG, et al. Clin Transl Immunology. 2022;11:e1390.
20. Boguniewicz M, et al. J Allergy Clin Immunol Pract. 2017;5:1519-1531.
21. Chovatiya R, et al. J Am Acad Dermatol. 2022;87:541-550.
22. Eichenfield LF, et al. Paediatr Drugs. 2022;24:293-305.
23. Rodriguez-Le Roy Y, et al. Front Med (Lausanne). 2022;9:1079323.
24. Cabanillas B, et al. Curr Opin Allergy Clin Immunol. 2017;17:309-315.
25. Furue M, et al. J Clin Med. 2021;10:2578.
26. Akdis CA, et al. Allergy. 2006;61:969-987.
27. Guttman-Yassky E, et al. Semin Cutan Med Surg. 2017;36:100-103.
28. Czarnowicki T, et al. Allergy. 2017;72:366-372.
29. Krohn IK, et al. Allergy. 2022;77:827-842.
30. Burkett PR, et al. The Autoimmune Diseases. 6th ed. Elsevier; 2020:91-116.
31. Kaech SM, et al. Nat Rev Immunol. 2012;12:749-761.
32. Ho AW, et al. Nat Rev Immunol. 2019;19:490-502.
33. Croft M, et al. Immunol Rev. 2009;229:173-191.
34. Chen L, et al. Cell Mol Immunol. 2020;17:64-75.
35. Guttman-Yassky E, et al. Lancet. 2023;401:204-214.
36. Mascarelli DE, et al. Front Cell Dev Biol. 2021;9:692982.
37. Guttman-Yassky E, et al. J Allergy Clin Immunol. 2019;144:482-493.e7.
38. Elsner JSH, et al. Acta Derm Venereol. 2020;100:adv00099.
39. Fu Y, et al. Acta Pharm Sin B. 2020;10:414-433.
40. Chu K-L, et al. J Immunol. 2020;204:477-485.
41. Newsom M, et al. Drugs. 2020;80:1041-1052.
42. Wang C, et al. Int J Dermatol. 2020;59:253-256.
MID: USA-451-80023
APC, antigen-presenting cell; OX40L, OX40 ligand.
Patients continue to grapple with recurring flares and disease chronicity1
of patients with moderate-to-severe AD experienced at least 1 flare within the past month22,*
AD flare-ups can last 6 weeks or more23
*Based on a longitudinal, prospective, observational study of adult patients (≥18 years of age) with a diagnosis of AD by a dermatologist or allergist. A total of 801 patients with moderate-to-severe AD were surveyed. Among 801 patients, n=149 (18.70%) reported 0 flares, n=186 (23.34%) of patients reported 1 flare, n=157 (19.70%) reported 2 flares, n=305 (38.27%) reported >2 flares, and n=4 had missing data in the past month.22
Many patients with moderate-to-severe AD continue to experience an impact to
their disease-related QoL24
Based on a 2021 cross-sectional survey in the US (N=1931):
Even patients who were considered adequately controlled did not meet the optimal DLQI score of 1 or less24,25
DLQI, Dermatology Life Quality Index; IQR, interquartile range; QoL, quality of life.
Hypothetical patient
Hypothetical patient
Though AD presents differently in each patient, all experience a considerable disease burden1,4,23
References: 1. Croft M, Esfandiari E, Chong C, et al. Am J Clin Dermatol. 2024;25(3):447-461. 2. Chiricozzi A, Maurelli M, Calabrese L, Peris K, Girolomoni G. J Clin Mol. 2023;12(7):2701. 3. Yew YW, Thyssen JP, Silverberg JI. J Am Acad Dermatol. 2019;80(2):390-401. 4. Davis DMR, Drucker AM, Alikhan A, et al. J Am Acad Dermatol. 2023:e1-e14. 5. Sadrolashrafi K, Guo L, Kikuchi R, et al. Cells. 2024;13(7):587.
Investigational OX40–targeted Therapies:* Targeting pathogenic T-cells via the OX40 receptor could provide an alternative approach for the management of moderate-to-severe AD1,2
*Therapeutic classes under investigation have not been approved for use by any regulatory authority and therefore do not have an established efficacy and safety profile.
References: 1. Bieber T. Nat Rev Drug Discov. 2022;21(1):21-40. 2. Croft M, Esfandiari E, Chong C, et al. Am J Clin Dermatol. 2024;25:447-461. 3. Guttman-Yassky E, Krueger JG, Lebwohl MG. Exp Dermatol. 2018;27(4):409-417. 4. Pavel AB, Song T, Kim HJ, et al. J Allergy Clin Immunol. 2019;144(4):1011-1024. 5. Wollenberg A, Christen-Zäch S, Taieb A, et al. J Eur Acad Dermatol Venererol. 2020;34(12):2717-2744. 6. Kamata M, Tada Y. JID Innov. 2023;3(3):100195. 7. Huang I-H, Chung W-H, Wu P-C, Chen C-B. Front Immunol. 2022;13:1068260.
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References
1. Croft M, Esfandiari E, Chong C, et al. Am J Clin Dermatol. 2024;25(3):447-461.
2. Simpson E, Guttman-Yassky E, Margolis D, et al. JAMA Dermatol. 2018;154(8):903-912.
3. Zhang Q, Vignali DAA. Immunity. 2016;44:1034-1051.
4. Yew Y, Thyssen J, Silverberg J. J Am Acad Dermatol. 2019;80(2):390-401.
5. Bissonnette R, Jankicevic J, Saint-Cyr Proulx E, Maari C. J Clin Med. 2023;12(11):3805.
6. Czarnowicki T, Santamaria-Babí L, Guttman-Yassky E. Allergy. 2017;72(3):366–372.
7. De Bruyn Carlier T, Badloe FMS, Ring J, Gutermuth J, Krohn IK. J Autoimmun. 2021;120:102634.
8. Furue M, Furue M. J Clin Med. 2021;10:2578.
9. Chen L, Shen Z. Cell Mol Immunol. 2020;17(1):64-75.
10. Sadrolashrafi K, Guo L, Kikucha R, et al. Cells. 2024;13(7):587.
11. Kaech S, Cui W. Nat Rev Immunol. 2012;12(11):749–761.
12. Fania L, Moretta G, Antonelli F, et al. Int J Mol Sci. 2022;23(5):2684.
13. Kwatra SG, Misery L, Clibborn C, Steinhoff M. Clin Transl Immunol. 2022;11(5):e1390.
14. Guttman-Yassky E, Krueger J, Lebwohl M. Exp Dermatol. 2018;27(4):409-417.
15. Bieber T. Nat Rev Drug Discov. 2022;21(1):21-40.
16. Tominaga M, Takamori K. Allergol Int. 2022;71(3):265-277.
17. Akdis CA, Arkwright PD, Brüggen M-C, et al. Allergy. 2020;75(7):1582-1605.
18. Guttman-Yassky E, Waldman A, Ahluwalia J, Ong PY, Eichenfield LF. Semin Cutan Med Surg. 2017;36(3):100-103.
19. Zheng C, Shi Y, Zou Y. Front Immunol. 2023;14:1081999.
20. Elsner JS, Carlsson M, Stougaard JK, et al. Acta Derm Venereol. 2020;100(6):adv00099.
21. Croft M, So T, Duan W, Soroosh P. Immunol Rev. 2009;229(1):173–191.
22. Wei W, Ghorayeb E, Andria M, et al. Ann Allergy Asthma Immunol. 2019;123(4):381-388.e2.
23. Augustin M, Misery L, von Kobyletzki L, Armario-Hita JC, Mealing S, Redding M. J Eur Acad Dermatol Venereol. 2022;36(Suppl. 7):3-16.
24. Lio P, Mackie D, Bates D, et al. J Drugs Derm. 2023;22(2):119-127.
25. Silverberg J, Gooderham M, Katoh N, et al. J Eur Acad Dermatol Venereol. 2024;00:1-10.
26. Chovatiya R, Silverberg JI. J Drugs Dermatol. 2022;21(2):172-176.
27. Czarnowicki T, He H, Krueger JG, Guttman-Yassky E. J Allergy Clin Immunol. 2019;143(1):1-11.
