Psoriasis (3) Flashcards
What is psoriasis
Immune mediated condition caused by inappropriate activation of T cells and release of inflammatory cytokines
Hyperinflammatory state can cause chronic inflammation and effect multiple organs resulting in…
-metabolic syndrome
-cardiovascular disease
-inflammatory bowel disease
-malignancies (T cell lymphoma)
-psoriatic arthritis
There is no cure for this disease - patients experience remissions/exacerbations
-because there is no cure psychiatric conditions may develop - depression, anxiety, suicidal ideation, poor self esteem
Psoriasis etiology
Genetics
-first degree relative with psoriasis increases risk
PSORS1 - increases risk
Precipitating factors can lead to exacerbation of disease:
injury to skin
infection
smoking
alcohol consumption
psychogenic stress
medications
Which medications can cause exacerbation of psoriasis? (5)
Lithium
NSAIDs
Anti-malarials
Beta blockers
Corticosteroid withdrawal
Psoriasis clinical presentation
-Lesions on skin usually on knees, elbows and scalp (but can effect other areas as well)
-flakey lesions with silver scales with redness underneath
-large lesions with prominent borders
-severe itchiness at site of lesions
Comorbidities can develop as disease progresses over time (psoriatic arthritis, depression, HTN, obesity, DM, IBD, anxiety)
Koebner phenomenon
Happens when patients with psoriasis has trauma/injury to skin - causes exacerbation of inflammatory process and flare up of disease … swelling, skin becomes raised, may start to look like psoriatic lesions
Can occur after any type of mild injury (including piercings and tattoos)
Auspitz sign
appearance of small pinpoint bleeding after scraping off scales from psoriatic lesions
Can be done during physical exam
but this is not a sensitive test (doesn’t occur in all patients with psoriasis)
How is severity of psoriasis assessed?
Through BSA involvement
-mild is 3%, moderate is 3-10%, severe is > 10%
-1 palm is about 1% BSA (this is a way to estimate)
This is very subjective …
The Psoriasis Area Severity Index (PASI) also exists - this is a more extensive questionnaire but is time consuming and not often used in practice
General psoriasis management approach
always combine nondrug with drug therapy
-Stress reduction
-Moisturizers
-Oatmeal baths
-Sun protection - use at least SPF 30 daily
Comorbidity management
-Diet management
-Increased physical activity
-Smoking cessation
-Decreased alcohol consumption
Mild/moderate psoriasis treatment approach
Start with topical therapy
-then add on phototherapy as second line
-then add on systemic therapy as third line
Note - most patients fall within this category of mild/moderate disease
Moderate/severe psoriasis treatment approach
Start with systemic therapy
-typically start with oral systemic agent (can consider starting with biologic if they have psoriatic arthritis)
-multiple systemic agents can be used if severe psoriasis (but never multiple biologics!)
The goal is to reach remission - then we taper down to the least potent/toxic agent and dose to maintain control
Sequential therapy may be done by some physicians - switching agents every couple of months to avoid long term side effects
How is response to therapy assessed?
Primary marker of improvement is the clearance of skin lesions
-this may take weeks to months to achieve
2 phases of treatment
Induction phase
-first 3 months of therapy
-goal here is to induce remission
-monitor for reduction of PASI or BSA involvement of 75% or more
Maintenance phase
-chronic (remission) phase
-goal is to maintain affected BSA at 1% of less
-follow up every 6 months
Immune response pathophysiology
Innate and adaptive immunity involved in psoriasis
Antigens activate innate immune cells (neutrophils, macrophages, dendritic cells) leading to production of cytokines - interferon, TNF, IL-23 and IL-12
Activated innate immune response leads to attraction, activation, and differentiation of t cells - T helper 1 cells, T helper 17 cells, and cytotoxic T cells - these produce cytokines which lead to epidermal hyperplasia (keratinocyte activation and proliferation) and they also recruit more neutrophils (inflammatory cells) - which results in an positive feedback loop mechanism that maintains the pathological process
How does the immune response cause the presenting damage? How does this apply to how we treat psoriasis?
The inflammatory mediators (IL 17, IL 22, INF-gamma, TNF-alpha) act on keratinocytes and cause the production of peptides which stimulate proliferation and growth of keratinocytes
(causing rapid cell turnover)
So we can disrupt the action of these cytokines on their receptors in order to prevent the progression of psoriasis
TNF alpha inhibitors
These are biologic molecules that bind to TNF-alpha , preventing it from acting on its receptor
There are 5 fda approved drugs:
3 monoclonal antibodies: adalimumab, golimumab, and infliximab
Etanercept - fusion protein (extracellular domain of tnf alpha receptor fused to a fc region of human IgG fragment)
Certolizumab - fragment of antibody bound to tnf alpha conjugated with PEG to increase size and half life of drug
Ustekinumab (Stelara) MOA
This is an IL-12 and IL-23 antagonist
- it binds to the p40 protein subunit which is a common subunit of both IL-12 and IL-23, binding there prevents them from binding to their receptors
IL-12 and 23 help activate T helper cell 1 and 17, so this drug prevents the formation of these proinflammatory cells
IL-17A inhibitors
Selectively binds to IL-17A cytokines, inhibiting its interaction with its receptor
Drugs:
Secukinumab
Vunakizumab
Perakizumab
IL-17 receptor inhibitor
Drug: Brodalumab
Binds to the IL-17 receptor on the cell surface - preventing a variety of IL-17 cytokines from binding to this receptor (not selective for 17A)
IL-23 inhibitors
Bind to the p19 subunit of IL-23 - preventing it from binding to its receptor
-binding to its receptor leads to maintenance/expansion of TH17 cells as well as recruitment of Janus kinase and tyrosine kinases
Drugs:
-Guselkumab
-Tildrakizumab
-Risankizumab
JAK (janus kinase) Inhibitor
When IL-12 or IL-23 binds to its receptor, intracellularly JAK responds by inducing a signaling pathway and causes transcription of a variety of proinflammatory cytokines
A JAK inhibitor, inhibits this intracellular signal transduction and therefore the transcription of cytokines
Drug: Tofacitinib
(inhibits all members of Janus kinase family)
Tyrosine Kinase 2 (TYK2) inhibitor
TYK2 is a member of the JAK family
Deucravacitinib is a drug that is highly selective for TYK2 (has little effect on the other JAKs)
It binds to an allosteric site (rather than an active site) inhibiting TYK2
The selective allosteric TYK2 inhibition reduces its side effects (compared to tofacitinib which is a non selective JAK inhibitor)
Phosphodiesterase 4 inhibitors (PDE 4)
Once cytokines bind to receptors, cAMP will be synthesized intracellularly (this is a messenger that regulates a variety of intracellular events)
PDE4 degrades cAMP
PDE4 inhibitors therefore cause an accumulation of cAMP - causing decreased expression of inflammatory cytokines (TNF-alpha and IL-12), and increased expression of anti-inflammatory cytokines (like IL-10)
Drug: Apremilast
Corticosteroid MOA
Biologics target specific cytokines, whereas corticosteroids are general immunosuppressants (they don’t have a specific target)
They bind to receptors, move into the nucleus, and induce transcription of anti-inflammatory genes and decrease transcription of pro inflammatory proteins
At the cellular level corticosteroids also inhibit the proliferation of t lymphocytes and may induce cytotoxicity to certain t cells
Long term steroid therapy can decrease IgG levels by increasing catabolic rate
Calcineurin inhibitors
Calcineurin is a cytoplasmic phosphatase - it is an essential protein involved in t cell activation
T cell receives the costimulatory signal - calcineurin is activated, it will then activate NFAT, which will go to nucleus and induce transcription of various cytokines involved in t cell activation - particularly IL-2
So, inhibiting calcineurin, inhibits this part of t cell activation by inhibiting the production of these cytokines
These drugs are aka immunophilin inhibitors - because they don’t bind directly to the calcineurin, they bind to immunophilins and form a complex inhibiting calcineurin’s activity
Drugs: cyclosporine (binds to cyclophilin), tacrolimus (binds to FK506)
6 topical drug classes used for psoriasis
- Corticosteroids
- Vitamin D3 analogs
- Retinoids
- Anthralin
- Coal Tar
- Calcineurin inhibitors
How should topical therapies be dosed? (how do we counsel patients and calculate days supply)
1 fingertip unit (FTU) = approximately 0.5 grams
(this is what we use to calculate days supply)
(1 FTU is the length of the finger tip to the first knuckle crease)
1 FTU is enough to cover…
-1 hand front and back (including fingers)
-both elbows
-both knees
