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+ Therapeutic Approach to Canine Allergic Skin Diseases in Veterinary Dermatology

Anthony Yu, DVM, MS, Dipl. ACVD

Guelph Veterinary Specialty Hospital

yuvetpc@gmail.com

TOP 10 reasons dogs/cats visit vets VPI 2012

Top 10 Canine Claims Top 10 Feline Claims

1. Ear infections 1. Lower urinary tract diseases

2. Skin allergies 2. Stomach upsets/gastritis

3. Pyoderma (hot spots) 3. Renal failure

4. Stomach upsets 4. IBD/diarrhea

5. IBD/diarrhea 5. Skin allergies

6. Bladder diseases 6. Diabetes

7. Eye infections 7. Colitis/Constipation

8. Arthritis 8. Ear infections

9. Hypothyroidism 9. Upper respiratory virus

10. Sprains 10. Hyperthyroidism

How would I treat this moderately Atopic dog?

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That was then…..

J Am Vet Med Assoc. 2012 Jul 15;241(2):194-207. Current understanding of the pathophysiologic mechanisms of canine atopic dermatitis. Marsella R, Sousa CA, Gonzales AJ, Fadok VA.

This is NOW !

J Am Vet Med Assoc. 2012 Jul 15;241(2):194-207. Current understanding of the pathophysiologic mechanisms of canine atopic dermatitis. Marsella R, Sousa CA, Gonzales AJ, Fadok VA.

The neurogenic role of itch Sonja Ständer, Itch in Atopic Dermatitis – Pathophysiology and Treatment Acta Dermatovenerol Croat 2010;18(4):289-296

¨  Histamine 1 and 4 receptor ¤ H1 = Erythema, wheal and flare ¤ H4 = up-regulation of pruritogenic IL31

¨  Neuropeptides ¤ Sub-P, Vasoactive intestinal peptide, somatostatin, neurotensin

¨  IL31 by Staphylococcal superAG, Malassezia zymosan ¨  Neurotrophin-4 by PGE2 ¨  Eosinophil-derived neurotoxin

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+ TH-1: TH-2 Cell Paradigm

T Helper-2 Humoral IDS ↑ IL4, 5, 13, 31 SP, NT4, EDN èAllergies

T Helper-1 Local IDS ↓ IFN-γ, IL2 2ry Yeast Bacteria Fungal Parasitic Viral

TARC Eotaxin

T-reg, IL-10

Pech Merle Dordogne River France

+Multi-Modal Therapy

Antineuronal therapy

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+ Repairing the Epidermal Barrier In the hands of the primary veterinarian

n Minimize TEWL and allergen penetration

n Topical replacement therapy

n Ceramides, free fatty acids (Allerderm SpotOn®, Virbac) n Phytosphingosine (Douxo®, Sogeval) n Omega 3 and 6 fatty acids (Dermoscent®, LDCA/Aventix)

+ Repairing the Epidermal Barrier In the hands of the primary veterinarian

n Dietary replacement therapy n Pantothenic acid, n Inositol n Nicotinamide n Choline n Histidine n Skin Support® (Royal Canin) n Omega 3/6 fatty acids

n  various diets & supplements

+Cetirizine: my new favorite antihistamine

n H1-antihistamines act as inverse agonists that bind and stabilize the inactive form of H1-receptors

n Classification based on: Chemical Grouping

•  Ethanolamines •  Alkylamines •  Piperazines •  Piperidines •  Phenothiazines •  Ethylenediamines

Generations

•  1st generation = sedating •  2nd generation = non-sedating •  “3rd generation” (derivatives of

2nd gen and this nomenclature should be reserved for next true class of antihistamines to be developed)

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+Piperazines

1st generation n  Antiemetic properties n  hydroxyzine (Atarax®, Vistaril®)

2nd generation n  Active metabolite of hydroxyzine n  Min crossing of BBB n  Canada: Reactine®, USA: Zyrtec®

n  0.5-1.0 mg/kg Q12-24hrs n  1 mg/ml, 5mg, 10mg n  ~ $0.17- 0.60/Tx/10kg pet n  Combine with amitriptyline/doxepin n  Combine with t-butyl carbamate derivatives of aminopyridine (H4 antagonist)

Hydroxyzine

+ Immunotherapy

n Indications: n  Cannot avoid allergens n  Signs present > 4-6 months n  Antipruriticsè side effects or

incomplete control

n Benefits n Not as treatment intensive n Minimal side effects n Weight independent dosing n Eventuate of a ‘cure’

§ Client Education: §  Injections administer sub-Q § Sublingual option twice daily §  Response may take up to 1 year §  Treatment usually lifelong

+ ASIT based on IDT or SAT

n My personal response rates: n  ASIT based on SAT = 40-60%

n  ASIT based on IDT = 60-80%

n  Combined = 75-90%+

n Sublingual immunotherapy (SLIT) n Heska, Bio-Medical

n BID oral drops

n Follow-up and client education paramount to success

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+What drug(s) do I use?

n First time pruritic patient n EFAs, AH, Atopica®

n Acute Flare-up of pruritus (<30d) n Steroids (dexamethasone, Vanectyl-P)

n Pruritus lasting 4-6 months n Atopica® +/- alternating/pulse steroids n Pentoxifylline +/- alternating/pulse steroids

n Pruritus lasting greater than 4-6 months n Immunotherapy +/- Atopica®, pulse steroids

Atopica® (cyclosporine) Update n Anti-inflammatory

n Anti-neurogenic n  Calcineurin inhibition on nerves n  Bind capsaicin receptor TRPV1 è burn è cool

n How to institute n  5mg/kg/day for 30-60 days n  +/-With steroids to start 7-14d n  Multi-modal therapy n  Client expectations

n Recheck in 4 weeks n  25% Decrease to 5 mg/kg q48h

n Recheck in 8 weeks n  50% Decrease to 5 mg/kg q48-72h

Westies – best Atopica® responders

Scruffie Hoch

8 weeks Atopica®

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+GINGIVAL HYPERPLASIA

n Cyclosporin increases intracellular Ca2+

n Collagenase is regulated by Ca2+ influx è Fibroblasts produce an inactive form of collagenase

èIncreased extracellular matrix

Lin et al., 2007

n More often when CSA + KCZ

n Gingival resection n  REVERSIBLE

n  Azithromycin toothpaste or orally

+Hirsutism

n Cyclosporin prolongs the anagen phase of the hair cycle

n Cyclosporin inhibits the expression of Protein kinase C

è stimulating hair follicle growth

and hair fibre production

HARMON et al., 1995

TAKAHASHI AND KAMIMURA, 2001

+Rocky 8 weeks post-Atopica®

Can I give this to my husband?

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Atopica® – 4 week recheck Continue or decrease to every other day?

Next year, start at EOD 1 month prior to allergy season

Preventative therapy for atopy n  Patients with known seasonal allergies

n  Treat atopy BEFORE it becomes a forest fire

n  Start medications at MAINTENANCE dose

n  Start 1 month PRIOR to start of season n  Vanectyl-P – 1 tab/10kg every q48-72h n  Atopica – 5mg/kg q48-72h

n  PREVENT inflammation n  PREVENT secondary infections n  PREVENT side effects

n  Max Pred dose/yr = 30mg X BW in kg

+ Calcinosis Cutis due to Steroids

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+ Iatrogenic effects of steroids

ALTERNARIA MUSCLE ATROPHY/CALCINOSIS

CUTIS

Adult-onset demodicosis iatrogenic steroids = most common cause

What about a severe allergic case like ‘Honey Bear’?

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+ Gray L, et al The effect of ketoconazole on whole blood and skin concentrations of cyclosporine Vet Derm 2012:23 suppl:13

n  N=6 research hounds; randomized cross-over study n  Daily for 7d w/14d washout; D1,4,7 - Blood 1.4h/24h, Skin 4h/24h

n  T1 = 5mg/kg Atopica

n  T2 = 2.5mg/kg CSA

n  T3 = 2.5mg/kg CSA + 5mg/kg KCZ

n  T4 = 2.5 mg/kg CSA + 2.5 mg/kg KCZ

n  Blood: T3 (644ng/ml)>>T4 (417ng/ml), T1 (307ng/ml), T2 (169 ng/ml)

n  Skin: T3 (1.2 ng/mg)>>T4 (0.7ng/mg), T1 (0.6ng/mg)>T2 (0.26ng/mg)

n  5mg/kg CSA = 2.5mg/kg CSA + 2.5 mg/kg KCZ

Honey Bear 8-weeks after

+Directions for the future

n  ID gene markers to breed out Atopic Dermatitis

n  Stimulate the Th1 and Treg arm of immune system n  Medical grade endoparasite n  Re-Poop-ulate n  Bacterial DNA motifs

n  Target specific mediators of inflammation n  Monoclonal antibodies n  Anti-IL-5, anti-TNF-α? anti- CCR4? n  Janus Kinase inhibitors n  Anti-IgE (Xolair® - $10-12K/year)

n  Potentiated ASIT n  CpG motifs, lysosomes, cell wall extracts

Mueller RS et al. The effect of nematode administration on canine atopic dermatitis Vet Parasit 2011;181(2-4):203–209

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+Neurogenic Itch

n  Gabapentin (Neurontin®) n  Dec Ca++ influx è inhibit excitatory neurotransmitters

n  5-10mg/kg TID

n  Avoid oral solution (Neurontin®) - contains 300 mg/mL xylitol.

n  Maropitant citrate (Cerenia®) n  neurokinin-1 receptor antagonist è inhibiting Substance P

n  1-2 mg/kg once daily for 4 days, then 2-3X weekly.

n  Combine both therapies in severe steroid non-responsive itch

+ Janus Kinase Inhibitors Apoquel® (Pfizer) Allerquel for Canada?

MOA: n  inhibiting JAK family of enzymes (JAK1,2,3 or TYK2) n  interfering with the JAK-STAT signaling pathway (receptor, JAK, and STAT (Signal Transducer and Activator of Transcription)

n  Humans: psoriasis, rheumatoid arthritis, neoplasia, polycythemia vera, etc.

n  Blocks IL-31 (pruritogenic) binding and activation of JAK/STAT.

n  0.4mg/kg BID

n  Vet Derm 2012;23 Suppl:38-39 n  Cosgrove S et al. Multicentre clinical trial to evaluate the efficacy and field safety of

oclacitinib – n=341 dogs, placebo matched study, significant improvement 14d, V/D n  Fleck T et al. Comparison of Janus Kinase inhibitor oclacitinib, and prednisolone in canine

models of pruritus – Oclacitinib >> and faster than prednisolone n  Wheeler DW et al. Oclacitinib for the treatment of pruritus and lesions associated with

canine flea-allergi dermatitis – n-36 FAD – sig improvement in VAS 0.4, 0.8mg/kg>>Placebo

Victoria BC – Butchart Gardens Sunken Garden – old lime quarry