Inflammatory skin diseases and stratified medicine

Question 1

What are the aims of stratified medicine

Answer 1

To identify subgroups of patients with distinct:

• Risk of disease
• Mechanisms of disease
• Responses to treatment
• Tailor treatment to each group

Question 2

What does stratified medicine rely upon?

Answer 2

Use of biomarkers

Question 3

Biomarkers are able to…

Answer 3

Predict disease development
Early intervention
Improve diagnosis
Provide prognostic information
Predict and monitor treatment responses and outcomes

Question 4

What are options for psoriasis biomarkers?

Answer 4

Clinical parameters
Cytokine, chemokine levels
Autoantibody profiles
Genetic polymorphisms

Question 5

What are the challenges in clinical practise that drive the need for biomarkers?

Answer 5

Inflammatory diseases have high heterogeneity in clinical features and underlying molecular mechanisms
- Panels of biomarkers likely more relevant for clinical practice. One biomarker does not accurately account for complexity.

Question 6

Biomarkers must be…

Answer 6

Validated 
Reproducible
High sensitivity and specificity
Ideally non-invasive
Cost effective
Fast turnaround time (clinically viable)
Easily understandable

Question 7

What is psoriasis?

How common is psoriasis?

Answer 7

Immune-mediated skin disease

2-4% of population

Question 8

Female are affected more by psoriasis

True or false

Answer 8

False

Males and females equally affected

Question 9

Psoriasis increases morbidity and mortality for what?

Answer 9

Arthritis
Cardiovascular disease
Metabolic syndrome
Psychosocial issues

Question 10

Psoriasis is clinically heterogenous

True or false

Answer 10

True

Question 11

Plaque psoriasis is a…

Answer 11

Common, complex trait

Question 12

What factors lead to plaque psoriasis?

Answer 12

Environment: Trauma, infection, drugs

Genetics: PSORS1-9,
HLA-C*06:02, IL23R

Immunological: Innate and adaptive immunity, keratinocytes

Question 13

How many regions of the genome are associated with plaque psoriasis?

Answer 13

> 60

Question 14

35-50% of plaque psoriasis heritability is due to what?

What is the challenge?

Answer 14

• due to PSORS1, HLA-C*06:02(located in PSORS1) is the most likelyPSORS1gene
• To find causal alleles for other regions

Question 15

What are the 4 steps of Plaque Psoriasis?

Answer 15

1. Trauma/infection/drugs lead to the activation of T17 and Th1 cells by dendritic cells in lymph nodes
2. T cells migrate into skin
3. T cells expand and release inflammatory factors (cytokines) in the skin
4. Blood vessels widen, keratinocytes proliferate, nerves that cause pain/itch are stimulated

Question 16

What are targeted treatments in psoriasis?

Answer 16

IL12B inhibitors:
- Ustekinumab

IL23A inhibitors:

• Risankizumab
• Guselkumab
• Tildrakizumab

JAK inhibitors:
Ruxolitinib

IL-17-A inhibitors:
Ixekizumab
Secukinumab

IL-17R:
Brodalumab

Question 17

Define Pustular psoriasis

Answer 17

Sterile pustules on variably erythematous skin

Question 18

How can Pustular psoriasis be characterised?

Answer 18

Acute generalised
- Generalised pustular psoriasis

Chronic localised

• Acrodermatitis continua of Hallopeau
• Palmoplantar pustulosis

Question 19

How can Pustular psoriasis be characterised?

Answer 19

Acute generalised
- Generalised pustular psoriasis

Chronic localised

• Acrodermatitis continua of Hallopeau
• Palmoplantar pustulosis

Question 20

What factors describe Pustular psoriasis?

Answer 20

Rare, severe

Monogenic trait, with reduced penetrance

Question 21

What factors describe Pustular psoriasis?

Answer 21

Rare, severe

Monogenic trait, with reduced penetrance

Question 22

What are the 3 Pustular psoriasis disease genes?

State the genetic defect that each impose.

Answer 22

IL36RN - Unopposed IL-36R

AP1S3- Defective autophagy

CARD14- Abnormal NF-κB activation

Question 23

How do the 3 Pustular psoriasis disease result in Pustular psoriasis?

Answer 23

Lead to upregulated IL-36 signalling

This results in skin inflammation, peripheral neutrophillia and systemic inflammation

Pustular psoriasis manifestation

Question 24

What are potential biomarkers biomarkers to differentiate between psoriasis and eczema as appear similarly on skin?

Answer 24

IL-36γ staining of skin biopsies - higher in psoriasis

Psoriasis skin specific gene expression
IL-19, IL-20, IL-36A, IL-36G, IL-8, NOS2, CXCL1 (increase ), CCL27 (decrease ) Vs Eczema specific cytokines IL-13, IL-6

Disease classifier
NOS2 (metabolic processes and TH17, TH1 immunity)
CCL27 (chemokine, regulates epidermal development)

Question 25

What are potential biomarkers in psoriasis to determine disease severity?

Answer 25

1. HLA-C*06:02 positive patients More severe, earlier onset disease 2. Lesional expression of keratins Upregulation of keratinocyte proliferation markers: KRT6 and KRT16 Downregulation of keratinocyte differentiation markers: KRT1 and KRT10 ``` 3. Serum cytokines IL-22 IL-20 TGFβ ( downregulation ) Conflicting data on IL-17A, IL-23, IL-36γ ``` 4. MicroRNAs (miRs) miR-143 expression in PBMCs (downregulation) miR-200a expression in CD4+T cells (upregulation) 5. Acute phase response markers (used clinically) CRP

Question 26

What are potential biomarkers to monitor response to psoriasis treatment?

Answer 26

Blockage of IL-17, IL-23 or TNF signalling - Skin-specific markers IL-17 regulated molecules- LL37, beta defensin 2, S100A7, S100A8, CXCL1, LCN2 - Lymphocytic and dendritic cell infiltration - Keratinocyte structural and activation markers

Question 27

What are potential prognostic biomarkers in psoriasis?

Answer 27

1. Peripheral blood - T regulatory cells increasing within 8 weeks of TNF antagonist treatment predicts good response (6 months) - Low expression of cutaneous lymphocyte antigen (CLA) on lymphocytes within 6 weeks of TNF antagonist treatment predicts poor response 2. Genetic variants - Candidate studies mostly, small cohorts/underpowered, small effect sizes, poor reproducibility -Methotrexate response: ABCC1 and ABCG2 (efflux transporters) -TNF antagonist response: TNFA variants (etanercept) Also seen in RA and PsA cohorts, TNFAIP3 -Ustekinumab response: HLA-C*06:02 + patients have a higher clinical response at week 12; sustained at 3 years 3. IL36RN alleles - Generalised pustular psoriasis phenotype: Early onset, high risk of systemic inflammation and low prevalence of plaque disease, Gene dosage effect - Not associated with plaque psoriasis

Question 28

What does PSORT integrate? What are the aims of PSORT?

Answer 28

Large-scale UK-based clinical data with genetic, immune, and transcriptomic data on patients treated with biologics Aim to discover psoriasis biomarkers: Diagnostic Prognostic Drug response Streamline targeted therapies

Question 29

What genetic, clinical and pharmacological biomarkers has PSORT identified? Do the predictors improve disease outcomes in real-world? What is the next challenge?

Answer 29

Genetic- HLA-C positive patients effective response to Ustekinumab Clinical- Patients with concurrent psoratic arthritis with psoriasis are likely to have a better chance of response Pharmacological- adalimumab drug levels predict response Genetic biomarkers not used in everyday practise, clinical biomarkers are and now integrating pharmacological biomarkers integrate biomarkers in routine practise

Question 30

What is the lifetime prevalence in developed countries of Atopic dermatitis? What are symptoms of atopic dermatitis? Atopic dermatitis commonly occurs with..

Answer 30

15-20% Chronic, relapsing, itchy, erythematous patches -Fissuring, scaling, lichenification Asthma, allergic rhinitis, food allergy

Question 31

What are complications relating to Atopic dermatitis?

Answer 31

Infections Poor sleep, school performance Anxiety, depression Cardiovascular disease

Question 32

Atopic dermatitis is clinically heterogenous. What are some examples of this?

Answer 32

``` Flexural Erythroderma Pompholyx (vesicular) Discoid Follicular type Nodular prurigo type ```

Question 33

Pathogenesis of atopic dermatitis involves Epidermal barrier dysfunction. What are the primary and secondary causes of this?

Answer 33

Primary; genetic susceptibility -Deficiency of epidermal structural protein filaggrin: 10% of European/Japanese individuals carry single loss of function mutations in FLG, ~3 fold increase risk of atopic dermatitis Secondary - Itch-scratch cycle - Reduced expression of epidermal structural proteins or lipids in response to Th2 cytokines (IL-4, IL-13)

Question 34

How does atopic dermatitis develop?

Answer 34

Injury to barrier through scratching or filaggrin This alteration in skin barrier causes release of damage to alarmins such as TSLP, this can also be triggers from pathogen or allergen entry through barrier Causes upregulation of localised inflammatory response – Th2 IL4 and IL13 upregulation Drive IgE secretion Positive feedback loops

Question 35

Aside from Epidermal barrier dysfunction, atopic dermatitis pathogenesis includes...

Answer 35

``` 1. Cutaneous inflammation Alarmins activate inflammatory dendritic cells, which initiate Th2 responses- Upregulate IL-4, IL-13, Drive B cell IgE class switching -> antigen specific IgE ``` 2. Dysbiosis/imbalance of commensal skin microbiota - Decreased microbiota diversity in inflamed eczema: Overgrowth of Staphylococcus aureus – produce virulence factors 3. Neuroinflammation Itch (histamine, endothelin 1, TSLP, IL-4, IL-31)

Question 36

What treatment is recommended to treat severe atopic dermatitis?

Answer 36

Dupilumab

Question 37

Psoriasis is revolutionising faster compared eczema in terms of biomarkers True or false

Answer 37

True