Atopic Dermatitis Flashcards
What is atopic dermatitis?
- Genetically predisposed inflammatory and pruritic skin disease
- Tendency to develop IgE-mediated allergy against environmental allergens
Risk factors for atopic dermatitis?
- Strong hereditary tendencies
What factors work into the pathophysiology of atopic dermatitis?
- Genetic
- Barrier function
- Immunologic factors
- Allergens
What type of hypersensitivity is atopic dermatitis?
- Type I
What is the second most common hypersensitivity disorder in dogs?
- Atopic dermatitis
Role of cutaneous itch-selective neurons in atopic dermatitis?
- Skin held quite tightly together
- If you have allergens that penetrate through cracks in the skin
- Langerhans process them and present them to T helper cells –> release of cytokines
- More inflammatory substances and mast cell degranulation (vicious cycle)
- Cytokines go to afferent nerve pathways and dorsal root ganglion, then perceived in the brain to start itching
What are genetic factors in humans that are implicated in atopic dermatitis?
- Filaggrin gene mutations
- Abnormal epidermal differentiation
- Defective defense mechanisms predispose to AD
- In veterinary studies, nothing has been shown like this
What are the major lipids of the stratum corneum, and which are the most important?
- Cholesterol
- FFAs
- Ceramides
How does transepidermal water loss play a role in atopic dermatitis?
- Cracks allow moisture to evaporate through
- Allergens can get in
What is the major entry route in dogs for atopic dermatitis?
- Percutaneous absorption (PRIMARY)
- Also Inhalation
Which cytokine do individuals with atopy produce greater amounts of?
- IL-4
IL-4 cascade
- IL-4 pushes the immune system into a T-lymphocyte helper 2 (Th2) direction
- Th2 is associated with allergic diseases and release of more IL-4, as well as IL-5, IL-13, and IL-31
- IL-31 recently identified as a major cause of pruritus
- Th2 response results in a significant increase in production of IgE antibody
- Other antibody classes may be involved in the pathogenesis of atopy (short term sensitizing IgG or IgD)
What type of allergens can contribute to or exacerbate atopic dermatitis?
- Environmental allergens***
- Food allergens (triggers AD)
- Bacterial antigens (Staph pseudintermedius)
- Yeast antigens (Malassezia pachydermatis)
Which bacterial antigens contribute to AD?
- Staphylococcus pseudintermedius
Which yeast antigens contribute to AD?
- Malassezia pachydermatis
Signalment of dogs with AD
- 1-3 years of age (not younger than 6-9 months usually and uncommon in middle age to older animals)
- Breeds: Terriers, boxers, labs
Seasonality of AD?
- Seasonal but can be year round
- Often spring and summer
- Chronic disease, and continued sensitization can lead to more progressive, year-round symptoms
Which sites are affected with AD?
- Ventral hairless areas
- Face
- Feet
- Peri-anal
Atopy and sensitization
- Requires prior sensitization wherein IgE and IgGd antibody then fix to tissue mast cells and basophils
When do clinical signs develop with atopy?
- Secondary challenge
- Allergen cross-links cell-fixed IgE results in degranulation of mast cells releasing pharmacologically active substances
How does abnormal barrier function contribute to atopic dermatitis/
- Ceramides are an important lipid component
- Abnormal barrier function leads to increased trans-epidermal water loss, dry and itchy skin, and allows for penetration of allergens and pathogens
Secondary infections with AD
- Atopic patients have higher rates of colonization of normal microflora (e.g. staph and malassezia)
- Can be induced from scratching/pruritus and excoriations
- Pyoderma
- Yeast dermatitis
- Otitis externa
Diagnosis of atopic dermatitis?
- No definitive test
- Signalment and seasonality
- Distribution of pruritus
- History
- Clinical signs
- Exclusion of other pruritic disease (ectoparasites, infections, and allergies)
- Look for and address all secondary infections (Cytology! Skin, ear, and feet)
Lesions associated with AD
- Typically secondary from self-trauma
- Erythema (ear/pinnae, interdigital, axillae)
- Excoriations
- Crust and scale (rule out pyoderma)
- Alopecia
- Hyperpigmentation
- Lichenification
- Salivary staining
Breeds with AD association
- Any breed!
- Terriers
- Labs
- Setters
- Boxers
- Lhasa apso
Differential diagnoses for Atopic Dermatitis?
- Ectoparasites (Scabies, otodectes, fleas)
- Seasonal pruritus (consider or rule out flea allergy)
- None-seasonal (year-round) pruritus: rule out food allergy
- Not all itchy dogs are atopic!
What are three important concepts for treatment of atopic dermatitis?
- Threshold phenomenon
- Summation effect
- Avoidance
Threshold phenomenon
- A certain allergen load can be tolerated by individuals without manifesting in disease, but a small increase in that load may push them over that threshold and result in clinical signs
Summation effect
- A subclinical hypersensitivity in combination with pyoderma or yeast dermatitis may lead to severe pruritus
Avoidance
- Not always possible
- Decrease in overall contributing antigen load may be helpful (e.g. flea allergy)
- This is why flea control is very important in atopic patients
Antihistamine MOA
- Prevent release of histamine but do nothing for the cytokines or TH2 associated with atopic dermatitis
How useful are antihistamines?
- Can be useful or helpful in mild, non-acute pruritus
- Tend to be mediocre for more severely pruritic patients
- Sedative effects may be a reason they can be helpful
- Clinical trials show no significant benefits
Where are antihistamines metabolized?
- Liver
Drug examples of antihistamines
- Hydroxyzine (1st gen)
- Diphenhydramine
- Cetirizine (2nd gen)
How are antihistamines most useful?
- Given as a preventative
Glucocorticoids - how effective?
- VERY useful short term
How selective are glucocorticoids?
- Not, they act at multiple sites
How do glucocorticoids work?
- Prevent release of inflammatory mediators from TH2 cells
- Impact mast cells
- neutrophils and eosinophils with extravasation which causes the cascade
Side effects of corticosteroids
- PU/PD
- Polyphagia
- Panting
- Behavioral changes/aggression
Examples of oral glucocorticoids
- Prednisone
- Prednisolone
- Methylprednisolone
- Temaril P (combined with antihistamine)
Long-acting formulations of glucocorticoids - recommended?
- Solumedrol
- Vetalog
- Few RCTs proving efficacy
- Greater potency
- Greater risk of adverse effects
What are life-threatening side effects of steroids used inappropriately?
- Diabetes mellitus
- Calcinosis cutis
- Exacerbate kidney disease and proteinuria
- Lead to CHF
- Iatrogenic Cushing’s disease
- Steroid hepatopathy
- Pancreatitis
- Predispose to infections (Skin, UTIs)
- Muscle wasting/atrophy
Free fatty acids for atopic dermatitis
- Many formulations including topical, diets, and supplements
How are topical free fatty acids thought to help AD?
- Thought that they restore barrier function
- May prevent release of hsitamine from mast cells and prevent neutrophils from extravasating
- He doesn’t like
- Inhibits production of pro-inflammatory mediators of prostaglandin PG2 and leukotriene (LT4 series)
Topical therapy for AD
- Shampoos bathing 1-3x a week (shouldn’t dry them too much)
- Regular sprays and wipes
- Avoid potent glucocorticoids
What does dermal atrophy or miliary dermatitis in dogs suggest?
- excessive corticosteroid use
Dose of steroids used for AD
- Anti-inflammatory induction dose (0.5-1 mg/kg/day for 3-7 days) then taper
- If necessary for long-term use: find the lowest effective anti-inflammatory dose and only use EVERY OTHER DAY or less frequently even
What active ingredients are drying?
- Benzoyl peroxide or dawn dish detergent
What focal pruritus sprays/wipes, or mousses should you use?
- Avoid potent steroids sprays like triamcinolone or betamethasone
- Use hydrocortisone based products
What is it important to do before testing for allergen-specific desensitization?
- Important to have made clinical diagnosis or ruled out other causes (e.g. flea allergy, food allergy, and/or ectoparasites) before testing
What is allergy testing technically testing for?
- What the patient is reactive too
- Based on intradermal testing and serum blood testing
What is the gold standard for allergy diagnosis?
- Intradermal testing
How does the intradermal test work?
- Inject into skin and see immediate reaction
- Results in mast cell degranulation
Causes of false negatives for intradermal skin testing?
- Medications (steroids)
- Diseases
- Timing (peak season)
- Technique
In vitro serum test
- What is it measuring?
- IgE
In vitro serum test
- How good of an indicator of allergic disease is it?
- Poor
- Never completely sensitive nor specific
Correlation of serum testing with IDT?
- Poor
Reproducibility of serum testing?
Poor
Is serum testing affected by medications?
No
What drugs can alter IDT?
- Antihistamines
- Corticosteroids
What are the significance of the reactions with IDT?
- Important to interpret in light of patient’s clinical signs (e.g. year round pruritus and only 1-2 reactions??)
- Tells you animal has allergen specific IgE but does NOT tell you allergen is CAUSING clinical signs
What should results from in vitro serum testing correlate with?
- sesaonality
Seasonal allergens
- Grasses
- Trees
- Weeds
Year round allergens
- Dust mites
Mechanism of allergen immunotherapy
- Maybe blunts T helper and reduces mast cells as well as eosinophils?
- Unknown exactly how it works
Response to desensitization therapy - rate and timeline?
- Can be effective in up to 75% of patients
- Response can be seen within 4 months to 1 year
How is desensitization therapy administered?
- Shots every 7-21 days and should be tailored to patient’s response
- Sublingual drops 1-2x a day
Sublingual immunotherapy - response rate?
- Novel therapy
- 60% response rate
Where are allergy drops giveN?
- Under the tongue
- Absorbed by oral mucosa
- q12-24hrs EVERY day
Allergy drops for shot failures - how many of those respond?
- 50% response
Reactions to allergy drops
- 3% may develop mild to moderate pruritus, hives, and GI signs
How long should you continue with desensitization therapy?
- If effective, continue long-term (if possible)
- UP to 1 year; if no improvement, consider discontinuing
- May need to consider use of anti-pruritic treatments during desensitization process
- Attempt to taper/reduce dependency of anti-pruritic meds to determine efficacy of desensitization therapy
Shots vs drops - how to decide one over the other?
- No clear advantage (similar cost)
- Drops are novel
- Client schedule and convenience (Aversion to needles?)
- Shot failure?
- Adverse effects are rare
Mechanism of atopica
- Cyclosporine binds cyclophilin, which inhibits calcineurin
- Inhibition works upstream, blocking pro-inflammatory cytokines such as IL-2
- Targets T cells
- Prevents T cell activation and release of pro-inflammatory cytokines (IL-2, IL-4, IL-5)
- Inhibits histamine release (blocks degranulation of mast cells)
Other uses of cyclosporine
- IMmune mediated diseases
- Organ transplant rejection therapy in humans
Downstream pathways of calcineurin (i.e. the pathways inhibited by cyclosporine)
- NFAT (Nuclear factor of activated T-cells) dephosphorylated
- Goes into the cell leading to RNA polymerase transcription of DNA
- Translation of mRNA produces proteins
- Function of the cell is changed
What enzyme metabolizes cyclosporine, and where is it metabolized?
- Cytochrome P450
- Liver
- Small intestine
How can you utilize drug interactions to reduce the amount of cyclosporine you use?
- They can increase bioavailability
- Ketoconazole inhibits Cytochrome P450
- Fluconazole inhibits CYP3a in vitro
How quickly does cyclosporine work?
- Slow onset
- Takes about 2-4 weeks
- Treatment may be refractory
Is skin testing affected by Cyclosporine?
- No
Treatment trial for cyclosporine
- Try for 30-60 days
- Taper to every other day
- SHould work for the first 30 days or not
- Should work for patients with true environmental allergens
Side effects of cyclosporine (+ what’s the big one)?
- Most are GI related (up to 25%)
- Gingival hyperplasia (more likely with daily dosing)
- Cutaneous papillomatosis
- Hypertrichosis
- Susceptibility to opportunistic infections (e.g. systemic fungal infections
- POSSIBLE risk of neoplasia
Oclacitinib labeled use
- Control of allergic dermatitis and cAD
- Dogs at least 12 months of age
- Not for cats
What diseases may oclacitinib predispose to?
- Demodicosis
- Infections
- Neoplasia
Jak-Stat - how many members in each?
- JAK has 4 members
- STAT has 7 members
Which JAK proteins does apoquel target?
- JAK 1 and 2
- JAK-1 (IL-31 and pruritus)
- JAK2: Polycythemia vera; myelofibrosis; rheumatoid arthritis?; neutropenia, thrombocytopenia; anemias)
What is JAK1 responsiblefor?
- Pruritus
JAK2 responsible for what?
Hematopoiesis
JAK3 responsible for what?
- Expressed in lymphocytes and regulates the immune system
Tyrosine kinase 2 responsible for what?
- Regulates immune system
JAK-STAT signaling
- Cytokines convey information by binding to specific receptors (JAK) on the cell membrane that induce biological responses
- Cytokine bninds its receptor to activate JAK
- JAK activates the intracellular proteins called STAT
- STATs go to the nucleus and activate gene transcription (of IL-31 and inflammation)
- Apoquel blocks the JAK protein from activating intracellular STAT proteins
How quickly should dogs stop itching with oclacitinib, and how long should it last?
- Stop itching in 2-3 hours
- Last for about 24 hours
Mechanism of action of Lokivetmab (Cytopoint)?
- 90% caninized monoclonal antibody
- Neutralizes IL-31
- Inhibits binding to IL-31 receptors
Why doesn’t lokivetmab work on cats?
- It’s a primarily caninized antibody
- Murine portions added
Side effects of oclacitinib
- GI upset (rare)
- Susceptibility to opportunistic infections (demodicosis, dermatophytosis)
- Possible risk of neoplasia
- Bone marrow supression?
- Immune-suppression?
Route of cytopoint?
- Subcutaneous injection
How long does lokivetmab work?
- 4-8 weeks, but approximately 30 days for most patients
Metabolism of lokivetmab?
- Does not depend on normal liver and kidney function
Primary effect of lokivetmab?
- Anti-pruritic
- No known anti-inflammatory or immune-suppression
Safety for lokivetmab - what age of patient can use it?
- All ages (vs apoquel which is over 12 months
Side effects of lokivetmab?
- Pain/discomfort when administering
- Possible recurring skin/ear infections
