The Cat’s MeowDiagnosis and Management of the allergic cat

What is an allergy? An abnormal reaction to a normal

substance

Classic allergic reactions are Type I hypersensitivities or IgE mediated hypersensitivity

What is an allergen? Substance which upon exposure elicits an

immunologic reaction Almost always proteins Must be of sufficient size to stimulate the

immune system (>10kda) Hapten phenomenon- small proteins that

link to larger proteins and together induce an immune response

Hypersensitivity Reactions Type I IgE mediated Immediate type Crosslinking of allergen specific IgE on

mast cells following exposure and recognition to the allergen

Degranulation of mast cells results in release of pro-inflammatory mediators

Hypersensitivity Reactions Type II Antibody mediated Cytotoxic hypersensitivity Antibody attaches to cell membrane

resulting in cell lysis Usually endogenous though can be

exogenous e.g. pemphigus, IMHA

Hypersensitivity Reactions Type III Antigen-Antibody complexes Mostly IgG though can be IgM e.g. vasculitis

Hypersensitivity Reactions Type IV Delayed type hypersensitivity Also known as cell mediated

hypersensitivity T lymphoyctes, monocytes, macrophages

mediate cell damage

When mast cells attack

It’s what’s on the inside that counts!

Stranger Danger! Classic view of immunology based on self vs

non-self Immune system triggered by ‘foreign-ness’ Does not well explain for tolerance of body

changes (e.g. puberty, pregnancy, lactation, metamorphosis, neoplasia)

Does not well explain the rarity of adverse reactions to vaccines

Does not well explain why most of us have auto reactive lymphocytes but so few of us have autoimmune disease

Danger Model Proposed by Polly Matzinger Represents a major paradigm shift Immune system is stimulated by damage Immune system responds to cellular signals

indicative of tissue health Cells dying of programmed cell death are

usually scavenged before they release their contents

Release of any intracellular substance can be a potential ‘danger’ signal

Danger Model and Atopic Dermatitis Exposure to allergens, bacteria, fungi,

proteases Mechanical damage from scratching May induce IL-33 which stimulate Th2 cells

and mast cells Th2 cells activate B cells which produce

IgE

Atopic Dermatitis Type I hypersensitivity Pruritic dermatosis Triggered by exposure to environmental

or aeroallergens In dogs and cats cutaneous absorption is

believed to be the primary source of exposure

Food allergy

Pruritic dermatosis Can be Type I, Type II, Type III or Type IV

hypersensitivity Exposure to a food item(s) induces an

immune response NOT the same as intolerance which is a

non-immunologic reaction May or may not be associated with

gastrointestinal signs

Diagnosis Food allergies and atopic dermatitis are

clinical diagnoses Based on compatible history and physical

exam Laboratory tests sometimes helpful

Presentation Atopic dermatitis Strong genetic predisposition Most common age of onset 1-3 years May be seasonal or year round

Atopic dermatitis Associated with elevated serum levels of

total and allergen specific IgE IgE synthesis is stimulated by T cell derived

cytokines Production of IgE is enhanced by IL-4 and

IL-13 High numbers of IL-4 producing Th2 (CD4+) cells are found in lesional skin

and peripheral blood mononuclear cells

Atopic dermatitis IgE mediated allergen presentation can

lead to enhanced activation of the immune system

Leads to expansion of Th2 population and increased IgE

Lesional skin shows increased numbers of T cells and high CD4+/CD8+ ratio

Atopic dermatitis Biopsy features No pathognomonic changes Epidermal hyperplasia Mixed perivascular inflammation including

mast cells, eosinophils, neutrophils, lymphocytes,

Presentation Food allergies May or may not have a genetic

predisposition No specific age Year round but may wax and wane

Flea allergy dermatitis Most common allergic skin disease in dogs

and cats Lack of recent publications re-evaluating

its prevalence Significance of FAD probably

underestimated in pampered pets Use of flea control does not rule out flea

exposure

Presentation Four commonly recognized reaction

patterns in the cat1) Non-lesional pruritus2) Symmetric alopecia3) Miliary dermatitis4) Eosinophilic granuloma complex

Non lesional pruritus Cats in a dog suit Primary complaint from owner will be

itching Exam will show hair loss, excoriations,

erythema, etc. May or may not be complicated by

secondary infection

Non lesional pruritus

Symmetric Alopecia ‘Fur mowers’ Presenting complaint may be excessive

grooming or hair loss Owners may believe hair loss is

spontaneous Clinical exam shows regional hypotrichosis

to alopecia Skin may be visually normal or mildly

inflamed

Is my cat crazy? Or is it just me? Previously known as psychogenic

alopecia Believed that cats literally pulled their own

hair out from stress or anxiety Behavior modifying drugs were commonly

recommended but often ineffective Many psychotropic drugs such as SSRIs,

TCAs often are potent anti-histamines

It’s probably just you… 2006 JAVMA study (Waisglass et al) n=21 Adult cats with a previous diagnosis of

psychogenic alopecia Extensive work ups on all cats including:

cbc/chem/t4, cytology, fungal cultures, diet trial, skin biopsy

Response to Depo injections where symptoms were otherwise unexplained

It’s probably just you… 76% (16 cats) were found to have a

medical reason for their hair loss 10% (2 cats) were found to have true

psychogenic alopecia 14% (3 cats) were found to have a

combination of psychogenic and medical factors

>90% of cats had some medical reason for hair loss

Food allergies vs atopic dermatitis 57% (12 cats) were confirmed to have a

food allergy Food allergies suspected but not

confirmed in an additional 2 cats (10%)

Histopathology 70% of cats had evidence of

inflammation of their skin biopsies 6 cats had ‘normal’ skin biopsies 2/3 cats with normal skin biopsies were

diagnosed with an allergic skin condition based on clinical response to therapy

Feline symmetric alopecia

Miliary dermatitis So named because these lesions feel like

millet seeds Characteristic lesion is a papule

surmounted by crust May be felt more easily than they are

seen May or may not be pruritic

Miliary dermatitis Not pathognomonic for allergic dermatitis Most common differentials include FAD,

atopy, food allergy Consider infectious causes such as

dermatophytosis and bacterial folliculitis Consider parasitic causes such as

demodicosis, otodectes, trombiculosis, lice, cheyletiella intestinal parasite hypersensitivity

Military dermatitisThe good, the bad and the crusty!

Miliary dermatitisThe good, the bad and the crusty!

Eosinophilic Granuloma Complex Umbrella term including: Rodent ulcer (indolent or lip ulcer) Eosinophilic plaque Linear granuloma (Eosinophilic

granuloma)

Eosinophilic Granuloma Complex Multiple forms may co-exist at the same

time May change pattern from season to

season or year to year

Eosinophilic Granuloma Complex Often associated with allergic skin disease One study (n=88) found 31% of allergic

cats to have one or more lesions of EGC May be heritable in some cases EGC lesions have occurred in SPF cats These cats typically ‘outgrow’ the disease

by 2-3 years of age Oral lesions could result from imbedded,

swallowed insect parts

Rodent ulcer Well circumscribed red-brown, alopecic

lesions May have a raised border Most often unilateral Most often on the upper lip Pruritus and pain are rare Rarely may undergo malignant

transformation to squamous cell carcinoma

Rodent ulcer Differentials: Infectious (bacterial, fungal, viral) Trauma Neoplasia (SCC, MCT, lymphoma)

Rodent ulcer

Eosinophilic plaque Most often occur on the abdomen or

medial thighs Well circumscribed, raised, round to oval,

oozing, often ulcerated Often severely pruritic

Eosinophilic plaque Differentials: Infectious (bacterial, fungal) Neoplasia (MCT, lymphoma)

Eosinophilic plaque

Eosinophilic Granuloma Most often occur on the caudal thighs, face,

and oral cavity (esp tongue and palate) When on the thigh lesions are usually well

defined, raised, firm, yellowish to pink plaques with a distinctive linear configuration

Lesions on the face and oral cavity have a papular to nodular configuration

Usually discovered incidentally

Eosinophilic Granuloma Most common cause of lower lip swelling

and nodules (pouting cats) Most common cause of asymptomatic

swollen chins May resolve spontaneously in cats

younger than 1 year

Eosinophilic Granuloma Differentials Infectious (bacterial or fungal) Insect bite reactions Neoplasia

Eosinophilic Granuloma

Eosinophilic Granuloma

Head/Neck Pruritus Controversial designation Itching is confined to the head and neck Food allergic cats may be over-

represented

Diagnosis Physical Exam History Cytology Skin scrape Tape prep Trichogram Fungal culture

Diagnosis CBC/Chem/T4 Skin biopsy Diet trial Allergy testing

To biopsy or not to biopsy? Rarely helpful Biopsy will identify a reaction pattern but

will not provide clues as to the underlying cause

Allergy testing Who? What? When? Where? Why?

Allergy testing Who? Patients who you have clinically

diagnosed with atopic dermatitis Other causes of skin lesions or pruritus

have been ruled out

Allergy testing What? Intradermal skin testing remains the gold

standard Results are more difficult to interpret Results may be enhanced with

intravenous fluorescein Serology is a reasonable alternative

Allergy testing What? Intradermal skin testing (IDST) involves the

injection of an allergen into the dermis A positive reaction involves the

development of a wheal Wheal is a result of mast cell

degranulation secondary to cross-linking of allergen specific IgE within the skin

Allergy testing What? Serologic allergy testing involves

screening the serum for allergen specific IgE

Based on the premise that tolerance induces production of IgG and hypersensitivity induces the production of IgE

Allergy testing When? After other causes of pruritus and/or skin

lesions have been ruled out

Allergy testing Where? Don’t try this at home?

Allergy testing Why? NOT TO MAKE A DIAGNOSIS To select allergens for inclusion in

immunotherapy

Food allergy Consider in any case where symptoms

occur year round Consider in any case where symptoms do

not respond to steroids

Food allergy The only accurate test for food allergies

remains a strict elimination diet trial Minimum of 4-6 weeks No other food item crosses the pets lips

during this time

Food allergy ELISA and RAST tests are exceptionally

poor diagnostic tools for diagnosing food allergies

Patch testing shows promise but is logistically difficult and expensive

Cooking for cats Basic principles Feed a novel protein Eliminate all access to other food items

until the diet trial is complete All or nothing

Cooking for cats No protein is inherently hypoallergenic Look for a food your patient has not

eaten before

Cooking for cats Hydrolyzed diets Based on the principle that an enzymatically

degraded protein will be below the molecular threshold to be recognized as an allergen

There is a lack of research in veterinary medicine to know what this molecular threshold is

These are all commercial diets and therefore have preservatives, additives and ‘other’ ingredients

Approximately 20% of dogs who have an allergy to a food item cannot tolerate a hydrolyzed version of that food

Cooking for cats Approximately 15-20% of dogs cannot

tolerate any commercial diet No specific studies on this in cats A home cooked diet may be the only

means of diagnosis and managing a food allergic cat

Proceed cautiously given risks of nutritional HCM and hepatic lipidosis

Treatment Every pruritic cat needs strict flea control Many great options Topicals (Frontline, Advantage, etc) Comfortis Seresto collars Some cases may require off label use of

products for optimal results

Treatment Screen each patient for infectious and

parasitic diseases Treat as appropriate

Atopic Dermatitis Treatment Corticosteroids Antihistamines Atopica Immunotherapy Interferon Mast cell inhibitors Ovaban

Atopic dermatitis Steroids Highly effective Cats may be more tolerant to adverse

effects of glucocorticoids Still have risks of cutaneous atrophy,

hepatopathy, kidney disease, diabetes Oral and injectable forms available

Atopic dermatitis Glucocorticoids work by altering gene

transcription Bind to intracellular glucocorticoid

receptor Leads to increase of lipocortin-1 Reduces activity of phospholipase A2 on

cell membranes which inhibits arachidonic acid cascade

Atopic dermatitis Glucocorticoids Some cats may not be able to efficiently

convert prednisone (pro-drug) to prednisolone

For chronic oral use wean to alternate day administration

For injectable repositol steroids no more than 1 injection every 6-8 weeks

Administer injectable steroids IM or IV

Atopic dermatitis Atopica (Cyclosporine) Fat soluble cyclic polypeptide metabolite of

fungus Tolypocladium inflatum gams Used to treat a variety of different conditions Microemulsified or modified form is absorbed

better and produces more stable blood levels For skin disease blood levels do not appear to

correlate to clinical efficacy

Atopic dermatitis Atopica (cyclosporine) Blocks IL-2 transcription and T cell responsiveness

to IL-2 Diminishes amplification signals for macrophage

and monocyte activation Production of other cytokines such as IL-3, IL-4, IL-5,

TNF-alpha and IFN-gamma may also be impaired Inhibits mononuclear cell function, antigen

presentation, neutrophil adherence, natural killer cell activity, growth and differentiation of B cells

May inhibit mast cell degranulation by affecting the interaction between mast cells and nerves

Atopic dermatitis Atopica (Cyclosporine) Safety Humans experience high incidence of

nephrotoxicity and hepatoxicity Hepatic lipidosis and jaundice were reported

in less than 2% of cats Increased ALT reported in less than 2% of cats Increased BUN/Cre reported in less than 2% of

cats

Atopic dermatitis Atopica Most common adverse effect is vomiting

and/or decreased appetite Reported in approximately 30% of cases Palatibility and difficulty of administration

can be a problem for many owners May be able to reduce to alternate day

or twice weekly use in some cases

Atopic dermatitis

Atopica (Cyclosporine) Potential increased susceptibility to

infectious diseases Reports of fatal toxoplasmosis Recommend cats be kept indoors

Atopic dermatitis Interferon-omega Interferon-gamma Extensive use in Europe, Australia, Asia Not approved for use in U.S.

Atopic dermatitis Interferon Family of regulatory proteins with anti-

viral, anti-tumor and immunmodulatory effects

Type I (alpha, beta, omega, delta, tau) Type II (gamma) Interferon gamma shown to be effective

in managing atopic dermatitis in humans

Atopic dermatitis Mechanism of action not well understood Humans with AD have low levels of IFN-

gamma and high levels of IL-4 Also shown to be true in dogs (not studied

in cats) May restore ‘normal’ Th1/Th2 balance Dogs who respond well to

immunotherapy show significant increase in IFN-gamma:IL-4 ratio

Atopic dermatitis Canine studies show similar success rates

to Atopica Well tolerated therapy Concern about immunologic reactions

when used parenterally Improvement may take months Not approved for use in U.S. VERY expensive

Atopic dermatitis Allergen specific immunotherapy Allergens selected based on serologic or

intradermal skin testing Mechanism of action is not well understood Old theory was induction of blocking

antibodies (IgG) Newer theory is that it may increase

concentration of Th1 vs Th2 cytokines Keppel et al. study (2008) showed responders

to immunotherapy had increased levels of IFN-gamma, IL-10, T-reg cells

Atopic dermatitis Kinavet (Masitinab) Palladia (Toceranib phosphate) “Mast cell stabilizers” Oral tyrosine kinase inhibitors Target key kinases involved in various cancers

(KIT, PDGFR, Lyn) Main target is the mast cell which release a

number of pro-inflammatory cytokines capable of initiating and sustaining an allergic response

Atopic dermatitis Palladia v Kinavet Major difference is in their degree of

selectivity Kinavet is more selective Theoretical benefit is lower toxicity Theoretical trade off is lower anti-cancer

potency

Atopic dermatitis Kinavet carries FDA approval for treatment of

atopic dermatitis in dogs 2011 study Cadot et al. 61% of treated dogs showed significant reduction

in CADESI scores vs 35% of control dogs 60% of dogs reported to be refractory to

cyclosporine or steroids showed significant reduction in CADESI scores

46% of dogs showed a significant reduction in pruritus

65% of owners reported good to excellent control with masitinab

Atopic dermatitis Monitoring CBC (leukopenia, neutropenia, anemia) Chemistry (hypoproteinemia, elevated

liver and kidney enzymes) Baseline At 14d of therapy At 30d of therapy

Atopic dermatitis Extremely expensive Pills can be difficult for many cat owners

to administer Can be compounded but little data

available and a large volume is recommended

Atopic dermatitis One pilot study assessing the safety of Kinavet

in cats N= 20 healthy spf research colony cats 10 received 50 mg po 24h and 10 received 50

mg po q48h x 4 weeks 2/10 developed proteinuria 3/10 developed proteinuria Increased creatinine was noted in some cats GI side effects noted in some cats

Atopic dermatitis Apoquel (oclacitinab) JAK-STAT inhibitor IL-31 antagonist Approved for treatment atopic dermatitis

in dogs >1 year of age

Atopic dermatitis Apoquel Studies show reduced pruritus in 79% of

dogs Response is usually within 2-3 days Does not interfere with allergy testing Unknown if it affects response to

immunotherapy Not recommended to be combined with

other immunosuppressive agents

Atopic dermatitis Apoquel No routine monitoring recommended Similar drugs in humans warn or

liver/kidney toxicity, and blood dyscrasias Label warnings of increased susceptibility

to infection, neoplasia, demodicosis

Atopic dermatitis No published data on use of Apoquel in

cats Limited data suggests a very short half life

which could make dosing difficult

Case Studies Alex P Kitten 1 year old male, neutered DSH Severe facial pruritus since adopted No seasonal variability

Case Studies Lord Tubbington 12 year old male, neutered DSH 3-4 year history of warm weather miliary

dermatitis

Case Studies J. Lo 4 year old female, spayed Maine Coon 2 year history of eosinophilic granuloma

complex that exists in various forms through all four seasons

PPhx: asthma