Autoimmune and Immune mediated skin diseases 2 Flashcards
Autoimmune, immune mediated, allergy, management of allergic skin disease
Explain the use of tetracyclines in the treatment of CLE/DLE (modes of action)
- Inhibits neutrophil and leukocyte chemotaxis
- Inhibits degranulation and phagocytosis
- Inhibits lymphoblast formation/proliferation/antibody production
- Inhibits activation of complement C3
- Increases prostaglandin synthesis
- Inhibits lipases and collagenases
What are the treatment options for plasma cell pododermatitis?
- Resolution without therapy
- Glucocorticoids
- Gold salts
- Chlorambucil
- Surgery
- Doxycycline
- Ciclosporin, but not documented
How are glucocorticoids used in the treatment of plasma cell pododermatitis?
Prednisolone 4mg/kg/day initially, subject to change
How long until gold salts show an effect in the treatment of plasma cell pododermatitis
Can take up to 12 weeks to full effect
Outline the use of chlorambucil in the treatment of plasma cell pododermatitis
In combination with other drugs, especially steroids
Discuss the role of surgery in the treatment of plasma cell pododermatitis
- Effective in severe cases, esp. where bleeding may be a major problem
- Pad tissue regrows after the srugery
Discuss the use of doxycycline in the treatment of plasma cell pododermatitis (dose, long term use, mode of action)
- 5mg/kg BID for up to 3 weeks
- May have initial improvement allowing pulse therapy or low dose continuous therapy
- Mode of action presumed immune mediate effects
Outline the management of idiopathic symmetric lupoid onychodystrophy when the nails start to lift off
- Sedate/anaesthetise
- Remove all loose nails
- Bandage and antibacterial therapy combined with NSAIDs for pain relief
Describe the long term treatment of ILSO
- Will have recurrent bouts of nail loss
- Pentoxifylline (Trental), or tetracycline and niacinamide
- Severe cases: glucocorticoids, ciclosporin
- Keep nails short to avoid catching and ripping (main management)
Outline the treatment of vasculitis
- Remove underlying cause
- Outcome dependent on organs affected
- Glucocorticoids are mainstay of treatment using immunosuppressive doses
- Alternate therapies: pentoxifylline, sulphasalazine, dapsone
- Sulphasalazine and dapsone not commonly used
What is pentoxifylline?
Methylxanthine derivative and phosphodiesterase inhibitor
What is the key risk owners need to be aware of when usinng pentoxifylline?
Risk of kidney failure
What are the effects of pentoxifylline?
- Immunomodulatory (inhibits pro-inflammatory cytokines, upregulates anti-inflammatory IL-10)
- Stimulates wound healing by stimulating collagenase production
- interferes with adhesion of inflamm. cells to endothelial cells and keratinocytes
- Decreases blood viscosity by inhibition of platelet aggregation
What conditions is pentoxifylline used for?
- Vasculitis
- Contact allergic dermatitis
- Erythema multiforme
- Dermatomyositis
- Ulcerative dermatitis syndrome of rough collies
What are the 3 main groups of conditions that will cause pruritus?
- Infections
- Allergic skin disease
- Ectoparasites
List potential differentials for pruritus/allergic skin disease
- Ectoparasites hypersensitivities
- Environmental atopy
- Cutaneous adverse food reactions (CAFR) (dietary allergens and intolerance)
- Contact allergy
- Drug reactions
Define atopy
Inherited predisposition to develop a type I hypersensitivity reaction to environmental allergens
What is atopy-like dermatitis/intrinsic atopy?
Atopy with no IgE demonstrable (atopy usually associated with IgE)
What 2 defects are required in order for canine atopic dermatitis to develop?
- Epidermal barrier function defect, allowing entry of percutaneous allergens from the environment
- Polarisation of lymphocytes towards Th2, instead of Th1, routes
What steps are involved in the pathogenesis of canine atopic dermatitis?
- Sensitisation and epidermal barrier defect
- Re-exposure to the allergen
- Direct neuronal stimulation
- Chronicity
Explain the sensitisation and epidermal barrier defect step in the pathogenesis of canine atopic dermatitis
- Percutaneous exposure to allergen leads to allergen capture and processing by Langerhans cells -> presented to naiive T lymphocytes, production of Th2 lymphocytes
- Production of IL-4, IL-5, IL-13, activate skin immune system, stim, class switchin gin B cells = prod. of allergen specific IgE
- Tissue mast cells bind IgE, sensitised to allergen
- Additional IgE on basophils, langerhans cells and in circulation
- Period of sensitisation before allergy
What is expressed by mast cells that allows binding to the allergen specific IgE in canine atopic dermatitis?
High-affinity Fc Epsilon receptors
Describe the re-exposure to allergen step in the pathogenesis of canine atopic dermatitis
- Cross linking of mast cell surface IgE by allergen -> degran. of MCs -> released of preformed mediators and new synthesis -> cytokines from keratinocytes, activated T cells
- Recruitment of inflamm. cells to dermis
- Inflamm cells activate and proliferate via Janus Kinase (JAK) pathways on cell surface
- Leads to inflammation, itch and scratch, worsen epidermal barrier, epidermal hyperplasia, worsening of epidermal barrier function
Explain the direct neuronal stimulation step in the pathogenesis of canine atopic dermatitis
- On re-exposure, LC recognises allergen, migrates to dermis, presents allergen to primed Th2 cells
- Pro-inflamm cytokines e.g. IL-31 released, bind to receptors on surface of neurons, trigger activation of JAK enzymes, stimulate nerve
- Leads to itch then scratch
Explain the role of chronicity in the pathogenesis of canine atopic dermatitis
- Scratching, toxins from secondary microbial infections, continued exposure to allergens all lead to progression of atopy
- Activate keratinocytes and other immune cells e.g. macrophages
- IL-12 released
- Polarisation to ?Th1 phenotype => release of IFN-y increases monocyte/macrophage recruitment and activation
- Leads to thickening of epidermis, stratum corneum etc.
- Further worsening of epidermal barrier function
What are the 3 phases of inflammation seen in canine atopic dermatitis?
- Acute phase
- Late phase
- Chronic phase
Describe the acute phase of inflammation in canine atopic dermatitis
- Th2 cytokine profile
- 15-20 mins after initiation
- Inflammatory mediators released from mast cells (e.g. histamine, serotonin, PGs)
- Effect is local vasodilation, tissue oedema, influc of inflammatory cells
- Often pruritus
Describe the late phase of inflammation in canine atopic dermatitis
Eosinophil dominated, seen after 6-12 hours
Describe the chronic phase of inflammation in canine atopic dermatitis
- Subsequent infiltration of lymphocytes
- Th1 dominated or unpolarised cytokine profile
Compare feline and canine atopic dermatitis
- Poorly defined in cats
- Not simple Th2 bias in lesional skin in cats
- Cats referred to as “non-flea, non-food induced hypersensitivity dermatitis” i.e. hypersensitivity proven to not be food or fleas and therefore assume environmental
Describe the typical presentation for feline atopic dermatitis
- Chronic, relapsing disease
- May be seasonal or perennial
- Hypersensitivity proven to not be food or fleas
- May present at young age (6mo-3yr)
- Genetic predilection recognised by some reports, esp. purebreds
What is allergic respiratory and cutaneous disease recognised for in horses?
Culicoides/insect bite hypersensitivity and atopic dermatitis
Give examples of allergens implicated in equine atopic dermatitis
- Dust mites, forage mites (>90%)
- Dust extracts, epidermals, feathers
- Mould spores
- Tree, grassweed pollens
- Concurrent insect-bite hypersensitivity
What is meant by cutaneous adverse food reaction?
Inappropriate reactions to elements of diet
Compare food intolerance and dietary hypersensitivity
- Intolerance: non-immunological mechansism
- Hypersensitivity: immunological mechanisms, not just type I hypersensitivity
What are the potential manifestations of CAFR?
- GI disease
- GI + cutaneous disease
- Cutaneous disease alone
Compare the prevalence of atopic dermatitis and CAFR in dogs and cats
- CAFR uncommon in dogs, whereas AD is common
- CAFR may be as common as AD in cats
Compare the clinical appearance of atopic dermatitis and CAFR
Are clinically indistinguishable
Outline the development of CAFR
- Require sensitisation, generally over long period of time
- Must be exposed to diet before
- Clinical signs generally when diet has been eaten long term
- Allergens poorly characterised and geographical differences likely
- May react more to one protein
Describe the onset of clinical signs of CAFR
- Can be within minutes of exposure
- More often 4-24 hours after ingestion
In what ways may chemicals and biologicals cause cutaneous skin disease on contact?
- Irritant nature of substance: not hypersensitivity, contact irritant dermatitis
- Or true allergy: type IV hypersensitivity reactions, contact hypersensitivity, delayed type
Give examples of substances that may cause allergic contact dermatitis
- Plants: pollen and sap
- topical drugs and shampoos
- Chemicals in furniture, carpet dyes, polishes, cleaners, rubber, plastic, leather, metal
Describe the cutaneous manifestations of drug reactions
- Can manifest as almost any type of cutaneous lesion or reaction pattern
- Variable pruritus
- May involve any hypersensitivity mechanisms
Which drugs most frequently cause cutaneous reactions?
Antibiotics, esp. potentiated sulphonamides
Describe the clinical signs of canine atopic dermatitis
- Chronic relapsing dermatitis
- Seasonal intially, progress to perennial
- Onset young adult, 6mo to 3yr
- Glucocorticoid responsive
- Pruritus
- Otitis externa
- erythema, papules, wheals, alopecia, lichenification, hyperpigmentation
- Secondary pyoderma/Malassezia dermatitis
List breeds that are predisposed to canine atopic dermatitis
- Terriers
- Retrievers
- english setters
- Boxers
- GSDs
- French bulldog
Describe the pruritus that may occur with canine atopic dermatitis
- Face, feet, inguinum, axillae, flexural surfaces of limb, pinnae
- Face rubbing and foot licking
- Acral lick granulomas
- May be the only sign initially
What is the significance for having 5 out of 8 of Favrot’s criteria, and 6 out of 8?
- 5: sensitivity 85%, specificity 79.1% for AD
- 6: sensitivity 58%, specificity 89% for AD
What is unusual about AD in WHWT?
- Usually AD does not cause dorsal pruritus
- But in Westies, AD, Demodex injai and fleas all cause dorsal pruritus
Compare the onset of CAFR and AD
CAFR usually very early or later than expected for AD
Compare the responsiveness to steroids in CAFR and AD
Pruritus less often responsive to steroids in CAFR than AD
Explain the allergic threshold principle
- AD may coexist with other allergic diseases
- Secondary infections common which add to pruritus
- Pruritic threshold below which have no clinical signs
- Need to address all compounding concurrent or secondary pruritic disease to reduce pruritus to below threshold and stop itching and reduce chance of secondary infections
What are the 4 cutaneous reaction patterns of cats?
- Head and neck excoriations
- symmetrical self-induced alopecia
- Miliary dermatitis
- Eosinophilic granuloma complexes (granulomas/ulcers/plaques)
In what conditions do the 4 cutaneous reaction patterns of cats occur?
- Flea bite hypersensitivity
- Non-flea non-food induced hypersensitivity/feline atopy
- Food induced hypersensitivity dermatitis
- Other diseases e.g. parasitic, viral, bacterial, fungal, autoimmunem neoplastic
What are Favrot’s criteria for the diagnosis of non-flea hypersensitivity dermatitis (i.e. food induced and/or non-food induced hypersensitivity dermatitis)?
- At least 2 body sites affected
- At least 2 of the cutaneous reaction patterns
- Presence of symmetrical alopecia
- Presence of any lesions on lips
- Presence of erosions/ulcerations on chin or neck
- Absence of lesions on rump
- Absence of non-symmetrical lesions on rump/tail
- Absnece of nodule or tumours
How many criteria are required to have a 75% sensitivity and 76% specific for the diagnosis of non-flea hypersensitivity dermatitis in cats?
5
Other than Favrot’s criteria, what are the clinical signs of feline AD?
- +/- sneezing, chronic coughing, asthma
- Secondary bacterial and yeast infection less common vs. dog but possible
- +/- blood eosinophilia non-specific finding)
Outline the value of histopathology in the diagnosis of allergic diseases
Are all indistinguishable from one another so not useful
Describe the signalment for equine AD
- Uncertain prevalence
- Onset most commonly 1.5-6yrs
- No sex predilection
- Breed predilection for TB and Arabs
- Signs seasonal and progress to perrenial, or start non-seasonal
Describe the clinical signs of equine AD
- Pruritus and urticaria (urticarial wheal, rugae, angio-oedema)
- Tail flicking, stamping, rubbing, head shaking
- Initially no dermatological signs, but self-inflicted damage leads to alopecia, excoriations, lichenification, thickening, hyperpigmentation, secondary infection
- Rufted papules, may coalesce to form crusts and focal alopecia
- Nodues
- Rarely concurrent respiratory disease e.g. COPD, allergic rhinitis/conjunctivitis
Describe the presentation of CAFR in dogs
- All signs indistinguishable from AD
- Only distinguishable by age of onset (older and younger animals affected, in AD mainly younger animals)
Describe the presentation of CAfR in the cat
Any one or more of the 4 cutaneous reaction patterns in cats
Describe the presentation of CAFR in horses
- RARE
- Foods often suspected by owners, aka “protein bumps” but not supported by elimination diets or challenge
Describe the clinical manifestation of contact hypersensitiity
- Rare, difficult to confirm
- Patch testing difficult
- lesion areas related to exposure
- Often affects more sparsely haired areas
- Variable pruritus
- Erythema, papules, plaques, hypo- or hyperpigmentation
Discuss the difficulties associated with management of allergic skin disease
- Cannot be cured, only controlled
- Allergen avoidance ideally
- Life long therapy required if cannot avoid
What is the effect of stress on the development of AD?
- Stress increases pruritus
- Adds to self trauma and inflammation
- Worsens barrier defect
- Increased entrance of allergens
What aspects are involved in the treatment of AD?
- Allergen avoidance
- Control of secondary infection
- Anti-inflammatory/antipruritic agents
- Address barrier function
- Allergen specific immunotherapy
List examples of products that may support the cutaneous barrier function
- Oral essential fatty acids
- EFA shampoos
- Topical skin lipid complex/essential oils
- Topical moisturisers
List examples of anti-inflammatory/anti-pruritic agents that can be used inn the treatment of atopy
- Glucocorticoids (systemic/topical)
- Ciclosporin
- Oclacitanib
- Lokivetmab
- Antihistamines, Tacrolimus, PEA-UM
Explain the importance of controlling secondary infections in the treatment of atopy
- Will reduce pruritus andminimise self trauma
- Allows healing of barrier function if self trauma is reduced
Outline the method of control of secondary infections associated with atopy
- Assess if pyoderma +/- Malassezia present using clinical presentation, in house cytology, culture and susceptibility if history of recurrent pyoderma
- Treat infections but avoid immunosuppressives
Explain why the use of immunosuppressives should be avoided when treating atopy with concurrent secondary infection
Immunosuppression causes superficial and deep pyoderma, so administration of glucocorticoids or oclacitanib will worsen the disease
Outline the treatment of bacterial pyoderma with concurrent atopy
- Topical: antimicrobial shampoo/wipes.foams, esp/ chlorhexidine 2-4%, use in preference to antibiotics where possible
- Systemic antibiotics if necessary: adequate length of time for superficial or deep
Outline the treatment of Malassezia dermatitis with concurrent atopy
Topical antifungals usually, occasionally systemic
How may allergens be avoided?
- Rarely possible to eliminate
- Can reduce house dust mites by steam cleaning, freezing bedding after washing etc
- Regular shampooing to remove allergens from coat
Outline the role of barrier function in the treatment of AD
- Impaired barrier function allows entry of allergen into the skin
- Need to reduce trans-epidermal water loss
- Important in long term control but slow to take effect
- Use in combination with other therapies
Explain how topical moisturisers aid barrier function
- Restore barrier function and reduce pruritus
- May contain urea, glycerine, linoleic acid, colloidal oatmeal
- Draw moisture into skin by osmosis or act as emolients and trap water
- Cooling effect reduces pruritus
Explain the role of glucocorticoids in the treatment of atopy
- Anti-inflammatory, non-specific action that will also stop itch
- Rapid onset of action, inexpensive
Outline a treatment plan for glucocorticoids in the treatment of AD
- Pred or methylpred (Mpred has no mineralocorticoid action but more expensive)
- Start daily at antiinflamm dose of 0.5-1mg/kg pred SID, then reduce to lowest effective alternate day dose to protect adrenal axis
- Aim for <0.5mg/kg pred EOD
- Taper gradually
- Owner must aware of side effects
Describe the short and long term side effects of glucocorticoids
- Most side effects of all AD treatments
- Short: PUPD, polyphagia, panting
- Long: live problems, bladder infection, diabetes mellitus, muscle wasting, gastric ulcers, pancreatitis, hair loss, skin thinning, pyoderma
When is the use of systemic glucocorticoids int he treatment of AD indicated?
- ONly when necessary
- Short term treatment of severe pruritic flare up
- In early stages of immunotherapy
- Seasonal pruritus requiring only 3-4months treatment/year
- When other treatments are inadequate or financially prohibited
Discuss the use of long acting injectable glucocorticoids in the treatment of AD
- High risk of HPA axis suppression
- Poorer dose control
- Induces diabetes mellitus relatively frequently
- Rarely used except in fractious cats
When are topical glucocorticoids indicated in the treatment of AD?
- Pyotraumatic dermatitis (surface pyoderma), eyes, ears
- Short term flare ups affecting small areas
Discuss the considerations regarding the use of topical glucocorticoids in the treatment of AD
- Must wear gloves
- Some may contain antibiotics and should only be used short term
- Consider potency of glucocorticoid: higher ok short ter,, but lower preferred long term
- Side effects possible, including skin thinning
How does the potentcy of hydrocortisone aceponate compare to that of other glucocorticoids?
- Hydrocortisone usually lower
- Hydrocortisone aceponate is exception, similar potency to betamethasone (i.e. higher)
What is are the main advantages of using hydrocortisone aceponate?
- Similar potency to betamethasone, but less systemic absorption so less effect on HPA suppression
- less skin thining vs other topicals of similar potency
- Spray
- Licensed for 7 day use
Which treatments are licensed in the treatment of atopic dermatitis in dogs and cats?
- Ciclosporin in both
- Glucocorticoids in both
- Oclacitanib only licensed in dogs
- Lokivetmab only in dogs
Describe the mechanism of action of ciclosporin
- Calcineurin inhibitor
- Blocks release of inflammatory mediated molecules e.g. cytokines, ILs
- Inhibit cells of allergic reaction e.g. T lymphocytes, eosinophils, mast cells
- T cell suppression non-specific
What is required prior to use of ciclosporin n cats?
Need to test for FeLV, FIV and toxoplasmosis
How may ciclosporin have drug interactions?
Via cytochrome P450 or P-glycoprotein
Explain how ciclosporin may have drug interactions via CYP450
- CYP450 metabolises ciclosporin to inactive/weakly active metabolites
- Drugs also metabolised by CYP450 may therefore increase ciclosporin bioavailability e.g erythromycin
- Enzyme inducers may reduce ciclosporin bioavailability e.g. phenobarbitone
Explain how ciclosporin may have drug interactions via P-glycoprotein
- Drugs inhibiting efflux pump increase ciclosporin bioavailability, leading to increased brain penetration and potential toxicity
- e.g. ketoconazole
- If giving systemic anti-fungals, halve dose of ciclosporin given
Describe the efficacy of ciclosporin in the treatment of AD
- Effective in ~80% of cases
- Slower to effect vs glucocorticoids
- Changes in 1st month,but 2-3 months to full effect
- Taper to q48h or twice weekly dosing in many
Desribe the side effects of ciclosporin treatment for AD
- Often initial V/D but settles
- In dogs, occasional reversible anorexia, hirsuitism, gingival hyperplasia, papillomatosis
- Some risk of immunosuppression leading to bacterial infection, demodicosis, dermatophytosis
What are the contraindications for ciclosporin use in the treatment of AD?
- Avoid use 2 weeks either side of vaccination
- If gingival hyperplasia occurs
- in dogs <6mo or <2kg body weight
- Breeding, pregnant, lactating animals
- Animals with history of malignant disorders
- Diabetics (may affect circulating insulin, use with caution)
What is the mechanism of action of oclacitanib?
JAK1 inhibitor, prevents direct stimulation of nerves by IL-31 causing pruritus, and also reduces inflammation
What is the indication for use of oclacitanib?
Pruritus associated with allergic skin disease, particularly clinical manifestations of atopic dermatitis
What are the key advantages of oclacitanib over the other treatments for AD?
- Rapid onset (as fast as pred in most)
- Side effects less than pred
- Does not interfere with intradermal testing/IgE serology (corticosteroids do)
- Can vaccinate during treatment
- Minimal interactions with other drugs
- Useful short and long term
- Cheaper than ciclosporin
Describe the typical dosing regime of oclacitanib for the treatment of AD
- Dose 2x daily for 2 weeks
- Then once daily (may get intial increase in pruritus but will settle)
- Must see efficacy at once daily administration to continue use
What are the contraindications for the use of oclacitanib?
- Dogs <1yo, <3kg
- Immunosuppressed (may increase susceptibility to infection)
- Progressive neoplasia
- Pregnancy, lactation, breeding males
