Brainscape's Knowledge GenomeTM

Browse over 1 million classes created by top students, professors, publishers, and experts.


See full index

Pharmacogenetics > Inflammatory skin diseases and stratified medicine > Flashcards

Inflammatory skin diseases and stratified medicine Flashcards

1
Q

What are the aims of stratified medicine

A

To identify subgroups of patients with distinct:

  • Risk of disease
  • Mechanisms of disease
  • Responses to treatment
  • Tailor treatment to each group
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
2
Q

What does stratified medicine rely upon?

A

Use of biomarkers

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
3
Q

Biomarkers are able to…

A 
Predict disease development
Early intervention
Improve diagnosis
Provide prognostic information
Predict and monitor treatment responses and outcomes
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
4
Q

What are options for psoriasis biomarkers?

A

Clinical parameters
Cytokine, chemokine levels
Autoantibody profiles
Genetic polymorphisms

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
5
Q

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

A

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.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
6
Q

Biomarkers must be…

A 
Validated 
Reproducible
High sensitivity and specificity
Ideally non-invasive
Cost effective
Fast turnaround time (clinically viable)
Easily understandable
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
7
Q

What is psoriasis?

How common is psoriasis?

A

Immune-mediated skin disease

2-4% of population

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
8
Q

Female are affected more by psoriasis

True or false

A

False

Males and females equally affected

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
9
Q

Psoriasis increases morbidity and mortality for what?

A

Arthritis
Cardiovascular disease
Metabolic syndrome
Psychosocial issues

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
10
Q

Psoriasis is clinically heterogenous

True or false

A

True

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
11
Q

Plaque psoriasis is a…

A

Common, complex trait

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
12
Q

What factors lead to plaque psoriasis?

A

Environment: Trauma, infection, drugs

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

Immunological: Innate and adaptive immunity, keratinocytes

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
13
Q

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

A

> 60

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
14
Q

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

What is the challenge?

A
  • due to PSORS1, HLA-C*06:02(located in PSORS1) is the most likelyPSORS1gene
  • To find causal alleles for other regions
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
15
Q

What are the 4 steps of Plaque Psoriasis?

A
  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
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
16
Q

What are targeted treatments in psoriasis?

A

IL12B inhibitors:
- Ustekinumab

IL23A inhibitors:

  • Risankizumab
  • Guselkumab
  • Tildrakizumab

JAK inhibitors:
Ruxolitinib

IL-17-A inhibitors:
Ixekizumab
Secukinumab

IL-17R:
Brodalumab

17
Q

Define Pustular psoriasis

A

Sterile pustules on variably erythematous skin

18
Q

How can Pustular psoriasis be characterised?

A

Acute generalised
- Generalised pustular psoriasis

Chronic localised

  • Acrodermatitis continua of Hallopeau
  • Palmoplantar pustulosis
19
Q

How can Pustular psoriasis be characterised?

A

Acute generalised
- Generalised pustular psoriasis

Chronic localised

  • Acrodermatitis continua of Hallopeau
  • Palmoplantar pustulosis
20
Q

What factors describe Pustular psoriasis?

A

Rare, severe

Monogenic trait, with reduced penetrance

21
Q

What factors describe Pustular psoriasis?

A

Rare, severe

Monogenic trait, with reduced penetrance

22
Q

What are the 3 Pustular psoriasis disease genes?

State the genetic defect that each impose.

A

IL36RN - Unopposed IL-36R

AP1S3- Defective autophagy

CARD14- Abnormal NF-κB activation

23
Q

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

A

Lead to upregulated IL-36 signalling

This results in skin inflammation, peripheral neutrophillia and systemic inflammation

Pustular psoriasis manifestation

24
Q

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

A

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)

25
Q

What are potential biomarkers in psoriasis to determine disease severity?

A
  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
  1. MicroRNAs (miRs)
    miR-143 expression in PBMCs (downregulation)
    miR-200a expression in CD4+T cells (upregulation)
  2. Acute phase response markers (used clinically)
    CRP
26
Q

What are potential biomarkers to monitor response to psoriasis treatment?

A

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
27
Q

What are potential prognostic biomarkers in psoriasis?

A
  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

  1. 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
28
Q

What does PSORT integrate?

What are the aims of PSORT?

A

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

29
Q

What genetic, clinical and pharmacological biomarkers has PSORT identified?

Do the predictors improve disease outcomes in real-world?

What is the next challenge?

A

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

30
Q

What is the lifetime prevalence in developed countries of Atopic dermatitis?

What are symptoms of atopic dermatitis?

Atopic dermatitis commonly occurs with..

A

15-20%

Chronic, relapsing, itchy, erythematous patches
-Fissuring, scaling, lichenification

Asthma, allergic rhinitis, food allergy

31
Q

What are complications relating to Atopic dermatitis?

A

Infections
Poor sleep, school performance
Anxiety, depression
Cardiovascular disease

32
Q

Atopic dermatitis is clinically heterogenous.

What are some examples of this?

A 
Flexural
Erythroderma
Pompholyx (vesicular)
Discoid
Follicular type
Nodular prurigo type
33
Q

Pathogenesis of atopic dermatitis involves Epidermal barrier dysfunction.

What are the primary and secondary causes of this?

A

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)
34
Q

How does atopic dermatitis develop?

A

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

35
Q

Aside from Epidermal barrier dysfunction, atopic dermatitis pathogenesis includes…

A 
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
  1. Dysbiosis/imbalance of commensal skin microbiota
    - Decreased microbiota diversity in inflamed eczema: Overgrowth of Staphylococcus aureus – produce virulence factors
  2. Neuroinflammation
    Itch (histamine, endothelin 1, TSLP, IL-4, IL-31)
36
Q

What treatment is recommended to treat severe atopic dermatitis?

A

Dupilumab

37
Q

Psoriasis is revolutionising faster compared eczema in terms of biomarkers

True or false

A

True

Pharmacogenetics (16 decks)

Brainscape helps you reach your goals faster, through stronger study habits.
© 2024 Bold Learning Solutions. Terms and Conditions