psoriasis pathology

1. Psoriasis (Part 2)
Fouad El Sayed, MD,MScMed
Professor of Dermatology, Lebanese University

2. Pathogenesis PsO
• Complex genetic disease with many enviromental factors
• Hyperproliferative state resulting in thick skin and excess scale
• Skin proliferation is caused by cytokines released by immune cells
• Systemic treatments of psoriasis will target these cytokines and
immune cells

3. In patients with psoriasis, the immune response is uncontrolled, resulting in a chronic
production of pro-inflammatory cytokines. Multiple cytokine pathways are involved
Th1, Tc1
Th17
IL-23
Keratinocyte
Th22, Tc22
Neutrophils
Mature dermal DCs
Inflammatory
myeloid DCs
IL-17A/F
IL-21
TNF-
IFN-
TNF-
IL-22
TNF-
Chemokines
AMPs
IL-12
Amplification of
psoriatic inflammation
IL-12
Pathogenic pathways in psoriasis

4. Pathogenesis PsO
Effector cells expressing chemokine
receptors re-circulate and migrate
into skin tissue stimulated by
chemokines
Key processes take place during disease maintenance:
Key processes take place during disease maintenance:
Presentation of putative autoantigens
to T cells
Release of IL-23 by dermal dendritic
cells and production
of pro-inflammatory mediators, such
as TNF- and nitric oxide,
by dendritic cells
Release of IL-23 by dermal dendritic
cells and production
of pro-inflammatory mediators, such
as TNF- and nitric oxide,
by dendritic cells

5. Disclaimer: The licensed dose of Taltz in moderate-to-severe plaque psoriasis is a loading dose of 160 mg, followed by 80 mg every 2 weeks between Week 2 and Week 12. After 12 weeks, the dose is 80 mg every 4 weeks.
Lilly Speaker Workshop Forum Singapore June 2018
Psoriasis Therapy Developments Since 1960
1960 1970 1980 1990 2000 2010 2020
1959
Fumarates
1961
Methotextrate
1970
Retinoids
1972
PUVA
1991
Anti-CD4
1987
Vitamin D3
and Derivatives
1992
Tacrolimus
1979
CSA
1996
IL-10
1999
IL-11
2000
Etanercept
2000
Infliximab
2002
Efalizumab
2004
Adalimumab
2004
Pimecrolimus
2008
PKC Inhibitor
2009
Anti-IL-
12/23p40
Ustekinumab
2015
Anti-IL-17
Secukinumab
20??
Anti-IL-23p19s
2001
Alefacept
Progress reflects better understanding of the immune system and
pathophysiology of psoriasis, leading to development of more targeted therapies
2016
Anti-IL-17
Ixekizumab
2017
Anti-IL-23p19
Guselkumab
2017
Anti-IL-17R
Brodalumab
2014
PDE4i
Apremilast

6. • Psoriasis therapy has changed dramatically in the past decade with
the introduction of biologic therapy
• Overall approaches to treatment are discussed along with special
circumstances where individual therapies have advantage

7. Cytokines, immune cells and extracellular pathways in psoriasis which are targets for treatment
DC
IL-12
IL-23
Th1
Th17
T
IL-12
(p35/40)
IL-1
TGF-β
IL-6
IFN-γ
IL-23
(p40/p19)
Anti-p40
Anti-p19
IL-2
IFN-γ
TNF
TNF
IL-17A
IL-17F
IL-21
IL-22
IL-6
IL-23
IL-21
Anti-TNF
TNFR-Fc
Anti-IL-17A
Anti-IL-17RA
Target Current targeted
therapies
Targeted
therapies in
development
TNF-α Etanercept
Adalimumab
Infliximab
IL-12/23p-40 Ustekinumab
IL-17 Secukinumab
Brodalumab
Ixekizumab
RG76242
IL-23p-192 Guselkumab
Tildrakizumab
T cells AbGn-168H3
tregalizumab4
Sphingosine-1-
phosphate (S1P)
receptor5
Ponesimod
1. Belge K, et al. F1000Prime Reports. 2014;6:4; 2. Gaspari A and Tyring S. Dermatologic Therapy. 2015;28:179–193;
2. 3. AbGn-168H. National Psoriasis Foundation. Accessed 14.09.16; 4. König M, et al. Front Immunol. 2016;7:11;
5. Kunkel T, et al. Nature Reviews Drug Discov. 2013;12:688–702.
DC, dendritic cell; IL, interleukin; T, naïve T;
Th, T helper; TNF, tumour necrosis factor.

8. Potential interactions between disease mechanisms in inflammatory skin disorders
and major comorbidities
CRP, C-reactive protein; CV, cardiovascular; OCP, osteoclast
precursor; SNP, single-nucleotide polymorphism.
Adapted from Guttman-Yassky E, et al. Systemic immune
mechanisms in atopic dermatitis and psoriasis with
implications for treatment. Exp Dermatol 2017. [Epub]
Metabolic/CV disorders
• Visceral adipocytes
• TNF
• IL-8
• IL-12
• IL-17
• IFN-γ
• CRP
• Leptin
• Resistin
• Chemerin
• Omentin
• Adiponectin
Systemic
Inflammation
Psoriasis
• Th17/Th22
• TNF
• IL-23
• IFN-γ
• IL-29
Skin
Inflammation
Psoriatic arthritis
• TNF
• Circulating OCPs
• IL-23/IL-17
• IL-22
• Pro-inflammatory
microRNAs and SNPs
Chronic
inflammatory
feedback
Environmental factors
…smoking, alcohol, behaviour
Genetic predisposition
…in genes of innate and adaptive
immunity

10. Baseline investigations
• As with any systemic agent, moderate to severe disease (BSA
>10%, or PASI>10) or disease with high functional or cosmetic
impact, could justify biological therapy.
• Prior to commencing biological therapy a full history, examination
and set of baseline investigations are required:
-PASI / BSA
-Life Quality Index (DLQI)
-Full blood count (FBC)
-Renal profile
-Liver function test
-ANA
-Hepatitis B & C , HIV
-Urine analysis
-Chest X ray
-Assessment for tuberculosis++

11. Summary
• Psoriasis is a chronic systemic inflammatory disease involving the skin
resulting from a dysregulated immune response
• The dysregulated immune response in psoriasis results in a chronic
imbalance in the production of pro- and anti-inflammatory cytokines
• Chronic inflammation of the skin drives many of the signs and
symptoms of psoriasis, including epidermal thickening, increased
vascularity of the skin, pruritus, and nail disease
• Specific pro-inflammatory cytokines are associated with different bothersome
symptoms of psoriasis
• Because dysregulated inflammation has systemic effects, psoriasis is
associated with a number of serious comorbidities beyond the skin