Slide 1: Alopecia Areata Mechanism of Disease
Alopecia Areata Mechanism of Disease VV-MED-118223 © 2022 Lilly, USA, LLC. All rights reserved.
Slide 2: Introduction & Unmet Needs in Alopecia Areata
Chapter 1 Chapter 1 Introduction Introduction & & Unmet Needs Unmet Needs inin Alopecia Areata Alopecia Areata VV-MED-118223 © 2022 Lilly, USA, LLC. All rights reserved.
Slide 3: Defining AA
Defining AA • Alopecia areata, or AA, is an autoimmune hair loss disorder1 • AA causes well-defined coin- shaped patches of nonscarring hair loss1 1. Pratt CH, et al. Nat Rev Dis Primers. 2017;3:17011. VV-MED-118223 © 2022 Lilly, USA, LLC. All rights reserved. 3
Slide 4: Presentation and Prevalence
Presentation and Prevalence Hair loss in AA is varied and can include1: • Single well-defined patches AA affects nearly 2% of • Multiple discrete or overlapping patches the population2 • Loss of hair in all hair-bearing sites, known as alopecia universalis 1. Pratt CH, et al. Nat Rev Dis Primers. 20
Slide 5: Comorbidities
Comorbidities Common comorbid disorders associated with AA include1-3: Atopic dermatitis3 Thyroid disease1 Allergic rhinitis1 Vitiligo3 1. Chu SY, et al. J Am Acad Dermatol. 2011;65(5):949-956; 2. Lee NR, et al. Ann Dermatol. 2014;26(6):722-726; 3. Drucker AM, et al. Allergy. 2017;72(5):831-834. VV-
Slide 6: Psychiatric Comorbidities
Psychiatric Comorbidities • Alopecia areata is also associated with psychiatric comorbidities such as anxiety and depression, affecting patients’ quality of life1 1. Lee S, et al. J Am Acad Dermatol. 2019;80:466-477. VV-MED-118223 © 2022 Lilly, USA, LLC. All rights reserved. 6
Slide 7: Complex Etiology
Complex Etiology • AA has a complex etiology with an unpredictable disease course, making management difficult1 1. Pratt CH, et al. Nat Rev Dis Primers. 2017;3:17011. VV-MED-118223 © 2022 Lilly, USA, LLC. All rights reserved. 7
Slide 8: Mechanism of Disease in Alopecia Areata
Chapter 2 Chapter 1 Mechanism Introduction &of Disease of in Unmet Needs Alopecia Areata Alopecia Areata VV-MED-118223 © 2022 Lilly, USA, LLC. All rights reserved.
Slide 9: The Human Hair Cycle
The Human Hair Cycle • The human hair cycle has four distinct phases1,2: • Anagen is the growth phase • Catagen is the transitional phase • Telogen is the resting phase, where hair is shed towards the end • Exogen is the phase where the follicle remains empty until the onset of the next anagen phase
Slide 10: AA Disrupts the Hair Cycle
AA Disrupts the Hair Cycle • In AA, the cyclical nature of hair growth is disrupted1 • Hair prematurely leaves the anagen phase and transitions through the catagen, telogen, and exogen phases2 • It then enters the kenogen phase, where the hair follicle remains empty and does not re-enter the growth
Slide 11: Loss of Hair Follicle Immune Privilege
Loss of Hair Follicle Immune Privilege • The pathogenesis of AA and the interference of the hair growth cycle are believed to be phenomena resulting from loss of hair follicle immune privilege1 1. Ito T. Clin Dev Immunol. 2013;2013:348546. VV-MED-118223 © 2022 Lilly, USA, LLC. All rights reserved. 1
Slide 12: Immune Privilege
Immune Privilege • Immune privilege is a complex mechanism that suppresses inflammation and promotes immune tolerance in the hair follicle1,2 1. Paus R, et al. J Investig Dermatol Symp Proc. 2018;19(1):S12-S17; 2. Azzawi S, et al. Skin Appendage Disord. 2018;4(4):236-244. VV-MED-118223 © 2022 Lilly,
Slide 13: Immune Privilege
Immune Privilege • Immune privilege protects the follicle from autoimmune attack1 • This process may be triggered by immunogenic alloantigen generated during anagen and exposed as a result of the apoptosis and necrosis associated with cyclical hair growth1-4 1. Pratt CH, et al. Nat Rev Dis Primers.
Slide 14: Immune Cell Infiltration
Immune Cell Infiltration • Loss of immune privilege allows immune cells to Hair bulb with immune privilege infiltrate the hair follicle, leading to an inflammatory swarm around the anagen hair bulb1,2 Hair bulb with loss of immune privilege and inflammatory cytokine swarm 1. Azzawi S, et al. Skin Ap
Slide 15: The JAK-STAT Pathway
Chapter 3 Chapter 1 The JAK-STAT Introduction & Pathway Unmet Needsin in Alopecia Areata Alopecia Areata VV-MED-118223 © 2022 Lilly, USA, LLC. All rights reserved.
Slide 16: The JAK-STAT Pathway
The JAK-STAT Pathway • The JAK-STAT pathway is a proinflammatory signaling pathway utilized by cytokines in AA1,2 1. Wang EHC, et al. J Invest Dermatol. 2018;138:1911-1916; 2. O'Shea JJ, et al. Annu Rev Med. 2015;66:311-328. VV-MED-118223 © 2022 Lilly, USA, LLC. All rights reserved. 16
Slide 17: The JAK-STAT Pathway
The JAK-STAT Pathway • The effects of cytokines such as IFN-𝛾 and IL-15 are mediated by JAK kinases of the JAK-STAT pathway1,2 1. O'Shea JJ, et al. Annu Rev Med. 2015;66:311-328; 2. Wang EHC, et al. J Invest Dermatol. 2018;138:1911-1916. VV-MED-118223 © 2022 Lilly, USA, LLC. All rights reserved. 17
Slide 18: The JAK-STAT Pathway
The JAK-STAT Pathway • The pathway is activated when ligand binding induces the dimerization of receptor subunits1,2 1. O'Shea JJ, et al. Annu Rev Med. 2015;66:311-328; 2. Wang EHC, et al. J Invest Dermatol. 2018;138:1911-1916. VV-MED-118223 © 2022 Lilly, USA, LLC. All rights reserved. 18
Slide 19: The JAK-STAT Pathway
The JAK-STAT Pathway • Receptor-associated JAKs then bind ATP and become active1 1. O'Shea JJ, et al. Annu Rev Med. 2015;66:311-328. VV-MED-118223 © 2022 Lilly, USA, LLC. All rights reserved. 19
Slide 20: The JAK-STAT Pathway
The JAK-STAT Pathway • Subsequent activation of STAT transcription factors, which translocate to the nucleus, regulate the transcription of genes involved in the production of proinflammatory cytokines responsible for disease maintenance in AA1,2 1. Wang EHC, et al. J Invest Dermatol. 2018;138:1911-
Slide 21: References
References • Azzawi S, Penzi LR, Senna MM. Immune privilege collapse and alopecia development: is 2015;66:311-328. doi:10.1146/annurev-med-051113-024537 stress a factor? Skin Appendage Disord. 2018;4(4):236-244. doi:10.1159/000485080 • Paus R, Bulfone-Paus S, Bertolini M. Hair follicle immune privil