Inflammation Flashcards
What is atopic dermatitis
- Atopic eczema (atopic dermatitis) is the most common form of eczema
- Disease of the skin which is increasing in prevalence
- 20% of children and 10% of adults affected globally
- Characterised as an itch with an inflammatory eruption
What does AD impact?
• It affects quality of life, productivity, and mental health
What physicians try to do to treat AD
- Manage co-morbidities
- Minimise adverse events
- Prevent itching
- Improve quality of life
Current treatment options
• AD is treated by palliative care of the skin barrier and with drugs targeting immune response pathways
Treated with: • Steroids • Phototherapy • Calcineurin inhibitors • Crisaborole
Moderate to severe AD is treated by: • Phototherapy and systemic pharmacotherapy e.g. • Oral steroids • Ciclosporin A • Immunosuppressants e.g., methotrexate
Therapeutic challenges
- ONLY relieves symptoms of AD
- Adults show insensitivity to medicines used topically to manage AD
- PROBLEM with systemic therapy = increased risk of adverse event and limits treatment duration
The challenges presented include:
• Paediatric vs adult usage
• Genetic predispositions in skin barrier
• Safety vs efficacy profiles
Established first line care Is not ideal
• Approved medicines are few and can only be used short term due to side effects
• Other medicines are not formally approved and have limitations
Interventions against single inflammatory mediator struggle to show efficacy due to heterogeneity due to age ethnicity and disease diversity
Are there new treatments? moderate-severe
- Dupilumab
- Tralokinumab
- JAK inhibitors
What is Dupilumab
- Called dupixent
- Used as second line therapy treatment for AD
- A fully humanised Monoclonal antibody
- It targets 2 key mediators of type 2 inflammation IL3 and IL4 – Good because it is targeting more than just one target
Cons of dupilumab
- Significant numbers of primary non-responders
- Only 40% achieve clear skin
- High-cost limits
- injection site tolerability - route of administration
- side effects – head and neck erythema and conjunctivitis
What are Janus kinase inhibitors?
- Small molecules that Inhibit activity of one or more of the janus kinse enzymes
- Interfering with the JAK-STAT pathway which sends responses to IL4 and il3
- Thereby suppressing cytokine signal and action
- Cytokines are responsible for controlling growth and activity of immune system cells
- Already licensed for rheumatoid arthritis = so development path is easy to repurpose
Pros and Cons for janus kinase inhibitors
PROS
selective and low cost of goods
Orally given
Safety profiles are concerning
• Adverse event rates at 55-75% quite common with orally
• Maybe using topical treatment may fix this?
• Multiple players working on target area may restrict commercial dominance
What is tralukinomab
• Anti IL-13 monoclonal antibody
Pros and Cons for tralukinomab
Given subcutaneously
PROS
proven asset in allergic indicationi
short development cycle
CONS
Upper respiratory infection side effects
high cost of goods
• Considered inferior to dupilumab due to restricted mechanism of action
What is nemolizumab
- Monoclonal antibody targeting IL-31 (itch cytokine)
- Not yet approved
- Phase 2b success
What is Omalizumab
- Anti-IgE monoclonal
- Binds to IgE
- Ige are antibodies produced by immune system
- Not approved but used experimentally
What is Crisaborole
- Phosphodiesterase inhibitor
- PDE inhibitor results in anti-inflammatory action
- Licensed for and efficacious in mild AD
- Paediatric use
- Dupilumab is better because it targets severe AD
