Exam 2- Autoimmune

Define Atopic dermatitis

Chronic, Itchy, inflammation skin disorder

Atopic means that there is a higher level of IgE

What is the most common atopic dermatitis disorder

eczema

What are the immune cells of epidermis

DC (langerhans cells)

Intraepithelial lymphocytes

What are the immune cells of dermis

(the connective tissues)

Dermal DC

Mast cells

T cells

Stratum corneum

keratin

In atopic dermatitis (AD), this forms a weak outer barrier as keratin is decreased

status granulosum

ceramides that form flaggerns

In atopic dermatitis (AD), this impaired lipid motor, meaning there is more transpidemal water loss, and allergy penetration

Describe atopic dermatitis (AD)

• Th2 oveeractivation (increase IL-5,IL-5, and IL-13)

  • Th2 triggers B cells, leading to IgE production (which forms hypersensitivity reactions)

• Cytokines cause itchiness, spongious (fluid builds up between the cells in epidermis, forming blisters)

How do you diagnose atopic dermatitis (AD)

IgE tst

or

patching test (test for delayed hypersensitivity of T cell involvement)

How do langerhans cells function in the skin

They surround the epidermis, protecting it.

What happens in chronic phase of atopic dermatitis (AD)

• Other T cells join, like Th1, Th22, and Th17

• Inflammation becomes self-substatining if not treated

When the skin barrier is breached, how does the innate immune respond at first

• Fibroblasts are activated

• cytokines triggerd

• Recruitment of immune cells

• epithelial cells trigger “danger!”

• up regulation of ICAM & E-selectin

• Presentation of antigen by langerhans & dermal DCs

When the skin barrier is breached, how does the adaptive immune system respond

• APCs present antigen to baby T cells in lymph nodes

  • Th1 = bacterial/virusus

  • Th2 = allergens & parasites

  • Th17 = fungi & extracullar bacteria

  • Treg = regulate/stop response

• activated Th cells migrate to skin

• Cytokines from APCs, fibroblasts, and keratinocytes express

  • ICAM = helps T cells stick to vessles

  • E-selectin = helps them roll into tissue

• activated dendric cells secrete excess of IL-12 & IL-23

what does IL-12 do

induces differentiation of native T cells to T helper cell 1

(T helper cell 1 thens secretes TNFa & IFN-g)

what does IL-23 do

central to survival & proliferation of T helper cell to T helper cell 17 & T helper cell 22

(T helper 17 —> secrets IL-17)

(T helper 22 secrets IL-22)

Psoriasis in pregnancy:

First line: emoluments & topical steroids

2nd: phototherapy

last: TNF inhibitors, cyclosporine, systemic steroids (steroids only 2nd or 3rd trimester)

What is the MOA for calcinurin inhibitors

• Bind to immunophilins (proteins that affect phosphate activity of calcineurin) —> this then inhibits IL-2 production —> inhibits T cell activation

Tacrolmus binds to

FK506

Pimercrolmus

FKBP-12

PDE4 inhibitors MOA

degreases cMAP to AMP, which reduces inflammatory cytokines

(remember that PDE-4 is overactive in AD)

JAK inhibitors

Inhibits JAK (JAK is the singling pathway in proinflammaotry cytokines)

Topical JAK

ruxolitinib

(non selective JAK inhibitors)

Oral JAK inhibitors

bronstein & upadacitinab

(selective JAK 1)

what is the difference between biological drugs used for atopic dermatitis (AD)

IL-13

• inhibits inflammation

• Tralokinumab

IL-31

• Inhibit itching, inflammation, headache

• Nemulovio

IL-4/IL-13

• inhibits development Th2 cells, inhibits inflmmation

• conjunctivitis arthalgia

• Humplimab

What are the genetic & environmental factors in AD

Genetic: mutation in flaggrin (FLG) which impairs the skin barrier

Environment: allergens, pollutants, dry air

Describe the pathophsyology of atopic dermatitis (AD)

• dominated by Th2 cell overreaction

• Th2 cells please Il-4 & Il-13 which stimulate IgE production

• APC like langerhans cells imitate the response

• innate immune cells: DCs, mast cells, eosinophils, keratinocytes

what happens in chronic stage of atopic dermatitis (AD)

• persistent itch-scratch cycle further damages skin

• leads to skin thickening (linchenification) & atrophy

• additional T cells, like Th1, 17, 22, join

• inflammation is self-perpetuating (more you scratch, the more allergens let in, ect)

What are the pharmacological interventions for AD?

• Target T cell proliferation (calcineurin inhibitors like tacrolimus)

• Block IL-4 & IL-13 with biologics like dupilumab

• topical cortisteroids reduce general inflammatino

• moisturizers

what T cells get activated in chronic atopic dermatitis (AD)

Th1, Th17, Th22

First line treatment for atopic dermatitis (AD) if MILD TO MODERATE

1. emoluments (moisturizers)

2. tropical corticosteroids to reduce flares

3. ADD ON: topical calcinurin inhibitors like tacrolimus, pimecrolmus) which help reduce steroids; antihistamines for itching; avoid triggers

What topical cortiseroids are used in face vs body

Face/kids = hydrocortisone

body = triamcinolone & betamethasone

Dumlimab is used for

• IL-4/IL-13 biologic inhibitor

• used for moderate-severe AD not controlled by tropicals

• reduces Th2 cytokines

Calcineurin inhibitor is only used for

sensitive areas

used to be steroid sparing (helps reduce amount of cortosteroids)

what is the LAST resort for atopic dermatitis (AD)

cyclosporine

Systemic immunosuppressants

what type of hypersensitivity is atopic dermatitis (AD)

type 1 hypersenstiivity mediated by IgE antibodies, causing an allergic response.

what is the KEY KEY KEY facts of atopic dermatitis (AD)

• IgE is elevated

• Th2 = acute

• Th1/Th17 = chronic

• Type 1 hypersenstivity

• Sponginess

• Il-4 & Il-13 are therapeutic targets

What is the typical onset of AD

3-6 months old

What is the atopic triad?

Other atopic diseases state associated with atopic dermatitis

Remember atopic = igE

So atopic treat is also allergies & asthma

So the triad is atopic dermatitis, asthma, and allergic rhinitis

What gene is most commonly seen in AD

Flaggrin gene (FLG)

Non pharmacist treatment for AD

Apply scent free and dye free moisturizer frequently especially immediately after bathing

use neutral to low pH

humidity at or above 50%

Rank these emoluments from the thinnest to thickest

(less greasy: more easily absorbed into skin)

lotion

cream

gel

ointment

(works longer; more effective)

T/F

lotions have a high water to oil ratio

True

What is a fingertip unit (FTU)

the amount squeezed from a 5 mm diameter tube nozzle & measured from the tip of the index finger to the 1st joint

What scoring system is used to determine disease severity

SCORAD (severity scoring of atopic dermatitis)

Reactive vs proactive therapy for AD

Reactive therapy:

• for mild disease

• only treatment when there is a flare-up or pain/inflammation present

proactive therapy

• moderate-severe

• preventing flair ups & actually modifying the disease

(for moderate-severe, use both therapies

If a patient does not respond to second line topical agents, such as topical calcinurin inhibitors , PDE4 inhibitors, what do you use?

phototherapy

If you don’t respond to phototherapy, what is the next step?

Systemic medications, like biologics

How often should topical corticosteroids be used for an active flare? vs maintenance

once or twice daily for active flare

once or twice WEEKLY for maintenance

From highest to lowest potency, rank the topical steroid vehicles?

Ointment, cream, lotion, solution, gel, spray

“ ONLY CALM LIGHT SKIN GETS SOOTHED”

what is intertriginous mean

skin folds

where should you avoid potent fluorinated corticosterods

Face, genitalia, infants, and intertiriginous areas (skin folds)

For the topical corticosteroids, what class has the highest potency? And what class has the lowest potency?

Highest = 1

Lowest = 7

What topical steroid is OTC

Hydrocortisone 0.5-1%

This is low potency, and can be used as maintenance

When do you follow-up with the patient after initiating a topical corticosteroid? Then, when can you fully evaluate the therapy?

1-2 weeks to monitor efficacy and ADs

Then 2-4 weeks after, you can fully evaluate a topical corticosteroid therapy?

when can you stop corticosteroid therapy

Continue until inflammation and lesions are improved, then you can start tapering it off

If a AD flare is resolved with topical steroids, what is the next step?

Proactive maintenance therapy (1-2 times per week) at sites that typically flare to prevent any relapses

What are local effects of topical steroids

Facial rosacea like disease with persistent erythemia

Burning

stinging

skin atrophy

(systemic adverse effects are NOT common with topical steroids)

What are systemic effects of topical steorids

Remember, systemic AEs are NOT common!

• HPA axis supression

• infections

• hyperglycemia

• cataracts

• glaucoma

• growth retardation in children (RARE)

what are the potential effects of topical steroids in infants

Granuloma gluteal infant or iatrogenic Cushing’s disease

What are the topical calcineurin inhibitors

Tacrolimus ointment (Protopic)

Pimecrolimus cream (Elidel)

What is the MOA of calcineurin inhibitors

inhibits the activation of T cell & mast cells, blocking the production of proinflmmatory cytokines & mediators

Where do you use topical calcineurin inhibitors?

• More sensitive areas, like face & skin folds

• places where you wouldn’t want to use steroid long term

• can be used if steroids cause skin atrophy or if long term use of corticosteroids are ineffective

T/F

Topical calcineurin inhibitors cause skin atrophy with long term use

FALSE

boxed warning for topical calcineurin inhibitors

potential cancer risk

when do you follow up with a patient after they start topical calcineurin inhibitors

Initial: after 1-2 weeks

( they usually treat within the first few days of treatment)

What are the topical PDE-4 inhibitors

Crisaborole (Eucrisa)

Roflumilast (Zoryve)

Use on sensitive areas of the skin

What is the MOA for PDE-4 inhibitor?

Inhibits PDE-4 which breaks down cAMP and cGMP into inactive metabolites

this reduces the stimulation of Th2 cells & inflammatory mediators

When should Roflumilast cream be avoided?

In patients with severe liver impairment (like Child-Pugh B or C )

what is the topical JAK inhibitor

Ruxolitinib cream (Opzelura

(also use on more sensitive areas of the skin)

Boxed warning for JAK inhibitors

Increased risk of serious infections, major CV events, malignancy, and mortality

What is Tapinarof (Vtama)

Aryl hydrocarbon receptor agonist

Used in AD in adults and pediatric patients 2 years and older

Used in adults for psoriasis

What are the ADrs for phototherapy

1. Skin redness (erythema)

2. itching

3. pigmentation

4. premature aging of the skin (sunburn)

5. photosensitive eruptions

6. follicultitis

7. HSV re-activation

8. Photo-onycholysis (nail plate detaches from nail bed)

9. skin cancer

10. cataract formation

11. facial hypertrichosis ( excessive hair growth on face)

When are systemic therapies used in AD

Only when patients do not have an adequate response to topical agents and/or phototherapy OR when QoL is substantially affected

What are the most common systemic therapies in AD

JAK inhibitors & biologic agents

(but biologics are preferred)

Most common & strongly recommended systemic biologic agent in AD

Dupilumab (Dupixent)

Tralokinumab (Adbry)

How are all systemic biologics admintered

SubQ

How are systemic JAK inhibitors admisntered

Orally

When should ORAL JAK inhibitors be considered for AD

Patients refractory to topical therapy AND a monoclonal antibody

very very last line

What patient population can you NOT use JAK inhibitor with

patients with anemia, lymphopenia, and neutropenia

T/F

You can give live vaccines to someone on a biologic therapy

FALSE

What are the most common ADRs for biologics

• injection site actions (Obvi)

• Conjunctivitis (Pink eye)

what age is dupixent approved for

6 months and older

What agents are NOT recommended for AD?

Topical antiseptics and antimicrobials if there is NOT an infection

topical antihistamines

oral antihistmaines

transitional biologics

Define Psoriasis

• T-lymphocyte mediated systemic inflammatory disease with NO cute

• plaque psoriasis is the most common

• involves keratinocyte proliferation

• Silvery scales on the skin

• peaks in 30 and 60

What is the most common type of psoriasis

plaque psoriasis

Signs & symptoms of psoriasis

• unbalanced Th1 > Th2 & Tregs

• autoimmunity against kerinocytes

• inflmmation

• skin hyperplasia

• also affects CVD, joints, endocrine system

What is PASI

Psoriasis area & severity index

• measures psoriasis severity

• measured BSA, induration, scaling, ertymeia

• scale of 0-72 (max = 72)

Pre-dispotion & triggers for psoriasis

Pre-disposition

• skin barrier dysfunction (flag grins)

• immune system having mutations in TNFa, IL-23, MHC-HLC type C variant

Environmental triggers

• infections, sunlight, smoking, lithium, NSAIDs, beta blockers, and antimalarials

Pathoohysiology of psoriasis

1. environmental or genetic trigger activates dendritic cells, which secrete IL-12 & IL-23

   1. IL-12 = promotes Th1 cell differntitation

   2. IL-23 = supports Th17 & Th22 cells (which are the key drivers of psoriasis)

2. Cytokines create kerinocytes in the skin (hard skin) which then produce more cytokines, leading to neutrophil infiltration, inflammation, hard skin.

What do these T helper cells do?

Th1

Th17

Th22

Th1 —> releases TNF-a & INF-y cytokines; create infmmation

Th17 = IL-17 cytokine released; neutrophil recruitment & kerinocyte activation

Th22 = Il-22 cytokine released; thick skin created

Non-pharmacist for psoriasis

oatmeal baths

tempted water

soft & lose clothing

psoriasis is pregnancy treatment plan

1st = emoluments & topical sterois

2nd = phototherapy

3rd = TNF inhibitors, cyclosporine, or systemic steroids (steroids only 2nd & 3rd trimester)

T/F

Corticossteroids are vitamin D3 analogs

True

use for cortisteroids for psoriasis

• use once or twice daily for 2-4 weeks

• Recommened ultra high potency for thick skin (class 1 + 2_)

• recommended low potency for face, groin, breasts, axilla (class 6+7)

topical vitamin D3 analogs for psoriasis

• Calcipotroil (calcipotriene ) = inactivated by UVA light

• Calcitrol

  • active metabolite of vitamin D

  • ointment only

MOA for topical vitamin D3 analogs (calcipotrolol)

bind to vitamin D receptors to inhibit keratinocyte proliferation & enhance keratinocyte differentiation and immunosupression

(inhibit cytokine production & t-lymphocyte activation)

Taclenox is __

Enstilar is _

Taclonex is an ointment

Enstilar is a foam

what is the safest long term topical treatmnet

calcitinol

What are the topical calcineurin inhibitors

Tacrolimus ointment (Protopic) and pimercolimus cream (elidel)

consider use for psoriasis in areas of thin skin

steroid sparing

long term use does not cause skin atrophy

boxed warning: potential cancer risk

Tapinarof (vtama)

MOA: aryl hydrocarbon receptor agonist

FDA approved for plaque psoriasis in adults

Topical roflumilast (PDE4 inhibitor)

Roflumilast (Zorreve) cream

may be useful of asteroid sparing and in sensitive areas

ADEs: Rapplication site pain