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Psoriasis (3) Flashcards

1
Q

What is psoriasis

A

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

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2
Q

Psoriasis etiology

A

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

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3
Q

Which medications can cause exacerbation of psoriasis? (5)

A

Lithium
NSAIDs
Anti-malarials
Beta blockers
Corticosteroid withdrawal

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4
Q

Psoriasis clinical presentation

A

-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)

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5
Q

Koebner phenomenon

A

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)

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6
Q

Auspitz sign

A

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)

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7
Q

How is severity of psoriasis assessed?

A

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

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8
Q

General psoriasis management approach

A

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

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9
Q

Mild/moderate psoriasis treatment approach

A

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

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10
Q

Moderate/severe psoriasis treatment approach

A

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

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11
Q

How is response to therapy assessed?

A

Primary marker of improvement is the clearance of skin lesions
-this may take weeks to months to achieve

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12
Q

2 phases of treatment

A

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

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13
Q

Immune response pathophysiology

A

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

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14
Q

How does the immune response cause the presenting damage? How does this apply to how we treat psoriasis?

A

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

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15
Q

TNF alpha inhibitors

A

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

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16
Q

Ustekinumab (Stelara) MOA

A

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

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17
Q

IL-17A inhibitors

A

Selectively binds to IL-17A cytokines, inhibiting its interaction with its receptor

Drugs:
Secukinumab
Vunakizumab
Perakizumab

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18
Q

IL-17 receptor inhibitor

A

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)

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19
Q

IL-23 inhibitors

A

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

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20
Q

JAK (janus kinase) Inhibitor

A

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)

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21
Q

Tyrosine Kinase 2 (TYK2) inhibitor

A

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)

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22
Q

Phosphodiesterase 4 inhibitors (PDE 4)

A

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

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23
Q

Corticosteroid MOA

A

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

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24
Q

Calcineurin inhibitors

A

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)

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25
6 topical drug classes used for psoriasis
1. Corticosteroids 2. Vitamin D3 analogs 3. Retinoids 4. Anthralin 5. Coal Tar 6. Calcineurin inhibitors
26
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
27
What are the class 1 topical corticosteroid agents (3)
Class 1 = super potent Betamethasone dipropionate 0.05% ointment (note - salt form matters - dipropionate is more potent than valerate, and formulation matters - ointment is the most potent) Clobetasol propionate 0.05% cream, lotion, gel, ointment Halobetasol propionate 0.05% cream, lotion, ointment
28
What are the class 2 topical corticosteroid agents (2)
Class 2 = potent Betamethasone dipropionate 0.05% cream, gel (note - salt form matters - dipropionate is more potent than valerate, and formulation matters - ointment is the most potent) Fluocinonide 0.05% cream, gel, ointment
29
What are the class 7 topical corticosteroid agents?
Class 7 = least potent Hydrocortisone 0.5%, 1%, 2%, 2.5% - cream, lotion, spray, and ointment
30
Topical corticosteroid (TCS) selection and considerations
The higher the potency, the higher the risk of ADRs - risk v benefit decision Salt forms make a difference -Betamethasone dipropionate is more potent compared to betamethasone valerate Vehicle formulations make a difference -Ointments are most occlusive and potent -Creams/lotions may be less greasy, and preferred for daytime use Agents can be combined with other topical agents - this can be helpful in providing a steroid sparing effect
31
Class 1 and 2 TCS use considerations
Super potent (class 1) and high potency (class 2) TCS should be limited to 2-4 weeks of use should not be used on large areas of the body (should be targeted areas of the body) avoid in infants avoid on the face or intertriginous areas
32
TCS adverse effects
Cutaneous ADEs thinning of skin, spider veins, stretch marks dermatitis acne Systemic ADEs - can occur if applying over large areas of body HPA axis suppression Cushing's syndrome Osteonecrosis Cataracts/glaucoma Tachyphylaxis - decreased effectiveness over chronic use can occur with topical corticosteroids - if this happens taper down to least potent most effective dose, or use pulse dosing - stop and then start again for week or 2
33
Vitamin D3 analog MOA
Binds to vitamin D receptors, inhibiting keratinocyte proliferation and enhancement of differentiation
34
2 vitamin D3 analog agents
calcipotriol & calcitriol
35
Vitamin D3 analog place in therapy
Safest long term topical therapy Comparable efficacy to class 3 TCS ointments Can be used in combination with TCS
36
Vitamin D3 analog ADRs
Irritant contact dermatitis, localized burning, pruritus, edema, dryness Systemic adverse effects are rare if dosed appropriately (avoid overuse)
37
Retinoids MOA
Normalizes abnormal keratinocyte differentiation and diminishes hyperproliferation of keratinocytes
38
Which retinoid agent can be used for psoriasis
Tazarotene
39
Retinoid place in therapy/considerations
Similar efficacy to Vitamin D3 analogs Can be used in combination with TCS More ADRs than Vitamin D3 analogs though... Skin irritation is common but dose dependent (can lower concentration/frequency of application if occurs or use cream formulation instead of ointment) CONTRAINDICATED IN PREGNANCY
40
Anthralin MOA
Direct antiproliferative effect on epidermal keratinocytes, by inhibiting synthesis of DNA to affected areas
41
Anthralin administration
Commonly causes skin irritation - to the point where we want to use short contact anthralin therapy (SCAT) -Apply only to thick plaque lesions for 2 hours or less, then wipe off -Start by applying for 5-10 minutes daily, then titrate up to 20-30 minutes as tolerated Use skin protectant (zinc oxide) on skin surrounding psoriasis plaques before application and wear gloves to avoid contact with normal skin
42
Coal tarr mechanism
Loosens and softens scales/crusts on skin
43
Coal Tarr place in therapy/considerations
one of the earliest agents used for psoriasis, not used as much today because it takes longer to work Not cosmetically appealing because of unpleasant odor and ability to stain clothing
44
Coal Tarr ADRs
Folliculitis Acne Local irritation Phototoxicity
45
Calcineurin inhibitor topical agents for psoriasis
Used off label Pimecrolimus cream Tacrolimus cream
46
Topical calcineurin inhibitor place in therapy / considerations
Not typically first line but can be used as alternative - not as effective as other agents but is nicer on the skin - less adrs compared to other agents -good for face or intertriginous areas So, good if patient has very sensitive skin and can not tolerate other agents May cause some burning and pruritus but improves with continued use Does have a BBW for theoretical malignancy (but this is just theoretical no studies have shown that this actually occurs)
47
Phototherapy
This is a non-pharm therapy widely used and FDA approved for psoriasis can be used adjunct to pharm therapy 15-30 minute sessions 3 times a week Can be targeted phototherapy or full body There are 2 types - UVA and UVB -UVB is used more often -UVA needs to be given with an oral photosensitizer (oral psoralens) to enhance efficacy ADRs: erythema, pruritus, xerosis, blistering Consider DDIs- do not use with photosensitizing medications Theoretical risk of photocarcinogenesis (skin cancer) with increased use
48
Acitretin MOA
oral retinoid like agent binds to retinoic acid receptors to inhibit expression of proinflammatory cytokines
49
Acitretin place in therapy
Less effective than methotrexate or cyclosporine, but useful for combination therapy with topical calcipotriol or phototherapy
50
Acitretin ADRs/safety considerations/counseling points
Hypertriglyceridemia, dry eyes, dry lips, epistaxis, xerosis, brittle nails Contraindicated in pregnancy -Women of childbearing age must use effective birth control during and for 3 years after discontinuing therapy -Women of childbearing age must avoid ethanol consumption during and for 2 months after discontinuing therapy (ethanol with acitretin causes synthesis of teratogenic molecules)
51
Cyclosporine place in therapy / administration
Reserved for moderate/severe plaque psoriasis Generally should not be used chronically, should be limited to <12 week short course therapy -Stopping abruptly can cause rebound of symptoms - important to titrate down slowly
52
Methotrexate place in therapy
Generally safer alternative than cyclosporine and can be used for chronic therapy -but less effective than biologics
53
Methotrexate dosing for psoriasis
Once weekly dosing -start at 7.5-15 and titrated up slowly to 20-25 mg once weekly Note - if using in combination with biologic agent, stay at low dose (7.5-10 mg weekly)
54
Methotrexate safety consideration/counseling point
Teratogenic *Due to teratogenicity, men should continue effective birth control for 3 months following discontinuation of therapy and women should continue effective birth control for at least 1 ovulatory cycle
55
JAK inhibitor BBWs (3)
-Increased risk of developing serious infections, especially when used in combination with immunosuppressants -Increased risk of mortality in high doses (not recommended to use 10mg twice daily or XR 22mg once daily) for psoriasis -Increased risk of thrombosis, PE, and/or DVT when used to treat inflammatory conditions. Avoid in patients at high risk, and discontinue in patients with signs of thrombosis
56
JAK inhibitor formulations
Tofacitinib is available as oral and topical formulation
57
TY2K inhibitor warnings
this was recently approved, warnings are not boxed yet -May increase risk of cardiac events in patients with RA -May increase elevations of CPK and risk of rhabdomyolysis -Increased risk of thrombosis, PE, and/or DVT when used to treat inflammatory conditions -Increased risk of infections, tuberculosis - avoid live vaccines during use
58
PDE inhibitor ADRs
Drug - Apremilast Mainly GI adrs - diarrhea/nausea -occur in good majority of patients, should be titrated up slowly for several days to avoid this Weight loss with chronic use may occur Small risk of depression/suicidal thoughts in 1% of patients
59
Biologics place in therapy
In general we wait until patient present with moderate/severe psoriasis to start systemic biologic agent this is mainly because efficacy decreases over several years of use (except for if they have psoriatic arthritis, then we may start a biologic earlier) Efficacy may not be sustainable for more than about 3 years and data suggests failure of one biologic may negatively impact efficacy of the next (so continued decrease in efficacy even if switching agents)
60
Which TNF alpha inhibitor has the most data for long term effectiveness for psoriasis treatment?
Adalimumab - demonstrates effectiveness maintained for 3 years
61
What is the disadvantage of etanercept (over the other TNF alpha inhibitors)
Most frequent dosing - twice weekly
62
What are 2 disadvantages of infliximab for psoriasis?
IV only (need to go to clinic) Clinical response to infliximab was shown to decrease by week 50 (may be combined with MTX for increased response)
63
Which 4 tnf alpha inhibitors are used for psoriasis
Adalimumab Etanercept Certalizumab Infliximab
64
Ustekinumab class and clinical pearl
IL-12/23 inhibitor Longer duration of efficacy compared to TNF alpha inhibitors and onset of efficacy in as little as 2 weeks
65
Which drugs are IL-23 inhibitors
Guselkumab (Tremfya®) Tildrakizumab (Ilumya®) Risankizumab (Skyrizi®)
66
Which IL-23 inhibitor can only be administered by a HCP?
Tildrakizumab
67
Which drugs are IL-17 (or IL-17A inhibitors)
Secukinumab (Cosentyx®) (IL-17A) Ixekizumab (Taltz®) (IL-17A) Brodalumab (Siliq®) (IL-17)

Imm/Musculoskel/Skin (16 decks)

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