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THERAPEUTIC APPROACH TO AUTOIMMUNE SKIN DISEASES IN VETERINARY DERMATOLOGY

Anthony A. Yu DVM, MS, ACVD Guelph Veterinary Specialty Hospital yuvetpc@gmail.com

Causes of alopecia ¨  Folliculitis

¤  Dermatophytosis ¤  Pyoderma ¤  Demodicosis

¨  Endocrine ¤  Hypothyroidism ¤  Hyperadrenocorticism ¤  Sertoli cell tumour ¤  Ovarian cyst/tumour ¤  Alopecia X

¨  Nutritional ¤  Deficiency - protein, EFA, Vit A

¨  Congenital ¤  Ectodermal defect ¤  Feline alopecia universalis/ hypotrichosis

¨  Hereditary ¤  Colour dilution alopecia ¤  Follicular dysplasias ¤  Dermatomyositis

¨  Immune-mediated

¤  Alopecia areata ¤  DLE/SLE ¤  Pemphigus complex ¤  Sebaceous adenitis

¨  Neoplasia ¤  Epitheliotropic Lymphoma ¤  Mast cell tumor

¨  Psychogenic ¤  Acral lick dermatitis ¤  Feline psychogenic alopecia

¨  Traumatic ¤  Allergic Dermatitis ¤  Traction alopecia ¤  Thermal burn

¨  Miscellaneous ¤  Canine recurrent flank alopecia ¤  Telogen defluxion ¤  Anagen defluxion

They all look alike…

Terra Cotta Museum – Pit 1 – Xian – 2005 5 25

NOT !!

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Alopecias Are Not Alike

¨  Loss of telogenized hairs in frictional areas ¤  dorsal muzzle, tail, back ¤ HypoT4, Cushing’s, sex hormone, Alopecia X

¨  Post-clipping alopecia ¤  telogen phase when hair is shaved ¤  vasoconstriction dt cold temp at shaved area

¨  Hair growth at sites of trauma ¤ Alopecia X – dt PDGF

¨  Hair loss affecting one colour ¤  follicular dysplasia – genetic

¨  Hair loss affecting abnormal colours ¤ Color Dilution Alopecia

Treatment of Alopecia

Knit a Sweater !!!

….Questions??

Cushing’s unusual clinical findings

¤  Loss of muscle mass ¤  Split ends ¤  Coat color change ¤  Collagen breakdown

n  Spay incision n  Poor healing wounds

¤  Anterior cruciate rupture ¤  Reproduction failure

n êFSH – failure to cycle n êLH – testicular atrophy

¤  Secondary hypothyroidism n êTSH – reversible hypothyroidism

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Cushing’s Syndrome ¨  Pituitary Tumor

¤  Lysodren® 25-50mg/kg 1-3X/week ¤  Trilostane 1-2.5 mg/kg BID ¤  Retinoid therapy

¨  Adrenal Tumor ¤  Hi Dose Lysodren® ¤  Trilostane ¤  Surgery

¨  Feline Cushing’s Syndrome ¤  Trilostane

¨  Adjust thyroid dose

Treatment

¨  Trilostane n competitive inhibitor of 3β HSD n competitive inhibitor of 11β HSD??

¤ 2-5mg/kg q24h OR 1-2.5 mg/kg BID ¤ ACTH 4-6h post Trilostane 10d, 4wks, 3mos, 6-12 mos ¤ goal post-ACTH = 50-150 nmol/L 4-6h post Trilostane ¤ post-ACTH>250 nmol/L double the dose ¤ post-ACTH<20 nmol/L, d/c 2d, next lower dose

¨  SE: cost, lethargy, anorexia, V/D, adrenocortical necrosis or hyperplasia, hypoadrenocorticism

Unsusual signs of Hypothyroidism

¨  Muscle atrophy ¨  Facial nerve paralysis ¨  Acral lick granuloma ¨  Ceruminous otitis externa ¨  ACL rupture ¨  Laryngeal paralysis/voice ¨  Megaesophagus ¨  Cardiomyopathy ¨  Peripinnal hyperkeratosis

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Peripinnal hyperkeratosis

Hypothyroidism ¨  Levothyroxine

¤  0.02 mg/kg BID ¤  S.E. = anxiety, panting, PU/PD

¨  Adjust dose if concurrent illness or cardiac compromise

¨  6 hour post-pill Total T4 ¨  Expected responses

¤  7 days – behavior ¤  4-6 wks – hair/scale ¤  3 months - normal

Girlfriend – 3 months post-thyroid

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Before and post-supplementation

“Alopecia X”

¨  Adrenal sex hormone imbalance ¨  Adrenal hyperplasia-like syndrome ¨  Growth hormone-responsive alopecia ¨  Castration-responsive alopecia ¨  Alopecia of plush-coated breeds

¤  Pomeranian, Chow ¤  Poodle, sled breeds ¤  M/F; neutered or intact

¨  Malamute or Husky “Coat Funk” ¨  Biopsy-responsive alopecia ¨  Pseudo-Cushing’s Syndrome

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“Alopecia X”: The presentation

¨  Gradual loss of hair of ventral neck, caudal thighs, trunk

§  Hyperpigmentation

“Alopecia X”: possible pathogenesis

¨  Pathogenesis unknown ¤  Abnormality in adrenal steroid production ¤  Altered adrenal or gonadal sex hormones ¤  Possibly a combination of cortisol and sex

hormones causing arrest of hair cycle ¤  Partial 21-hydroxylase deficiency

¨  Different breeds = different pathomechanisms?? We are just as confused as

Donald Rumsfeld

Adrenal Steroidogenesis

Cholesterol

Progesterone

Aldosterone

17-OHP DHEAS

Androstenedione

Testosterone Estrogen

Cortisol

21-OH 3B-HSD

3B-HSD

3B-HSD

21-OH

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Is treatment VooDoo?

¨  First, spay / neuter if intact ¨  Anticipated response in 3-6 months

Next try: ¨  Melatonin (30-40% success)

¤  1 mg/kg/day divided TID

¨  Knit sweaters OR ¨  Lysodren ¨  Trilostane ¨  Cyclosporine?? ¨  Lupron ¨  Growth Hormone ¨  Methyltestosterone ¨  Allow 3-6 months before moving to next option

only partly

Low dose Lysodren 15-25mg/kg daily 7-14 days, then weekly

¨  Watch Coumpounding RX

¨  One month after starting Lysodren

Trilostane

¨  Orally active steroid analogue ¨  Competitive inhibitor of the 3 B- hydroxysteroid

dehydrogenase enzyme system ¨  Blocks production of several adrenal steroids ¨  Possible side effects

¤  Hypoadrenocorticism – Addisonian crisis: n  Electrolyte abnormalities (hyperkalemia and/or hyponatremia); Shivering;

Weakness; Reduced appetite/anorexia; Vomiting; Diarrhea ¤  Adrenal necrosis

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Adrenal Steroidogenesis

Cholesterol

Progesterone

Aldosterone

17-OHP DHEAS

Androstenedione

Testosterone Estrogen

Cortisol

21-OH 3B-HSD

3B-HSD

3B-HSD

Trilostane block

21-OH

Trilostane

¨  Cerundolo et al, 2004 ¨  16 Poms and 8 Min Poodles with Alopecia X ¨  Hair re-growth: 14/16 (85%) Poms; 100% Min Poodles ¨  Dose:12 mg/kg and 9 mg/kg, respectively ¨  Re-growth occurred most often within 4-8 weeks ¨  In dogs that did not have hair re-growth at that time, the dose

was doubled and re-growth occurred

¨  Cost: Pomeranian (3 kg) $80/mo; Malamute (50 kg) $563/mo

6 Months After Trilostane

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Cyclosporine for Alopecia X?

¨  Cyclosporin prolongs the anagen

phase of the hair cycle

¨  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®

Alopecia is not always a bad condition

The Buddhist Monks of Xian

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Recurrent seasonal flank alopecia

Rhodesian Ridgeback – atypical breed

Recurrent seasonal flank alopecia

¨  Seasonal, recurrent ¨  Breed predisposition

¤  Airedale, Bulldog, Boxer

¨  Bilaterally symmetrical ¤  flanks ¤  hyperpigmentation

¨  Spontaneous regrowth 3-6 mths later ¨  Can become permanent

Seasonal Flank Alopecia

¨  Diagnosis: ¤  R/O endocrinopathies ¤  Trichogram to evaluate for

follicular dysplasia ¤  Clinical impression ¤  +/- Dermatohistopathology ¤  Very distorted hair follicles

filled with keratin ¤  “witches feet”

In a word, classic!

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Seasonal Flank Alopecia

¨  Recurrent annually ¨  Fall and Spring ¨  +/- skip a year ¨  Melatonin imbalance

¤  Fall – insufficient production ¤  Spring – too much of a drop

Minoxidil

¨  Vasodilator used topically in man ¨  androgenic alopecia ¨  Used orally in CRFA

¤ dogs regrew hair – spontaneous???

¨  side effects - weakness, lethargy, collapses ¨  50% of the dogs treated

Oral minoxidil NOT recommended Topical….we have other options

Melatonin More Than a Jet Lag Pill

¨  Pineal gland è L-tryptophan è serotonin è melatonin

¨  Promotes ↑IL-12 èTh-1 response ¨  Enhance IL-2 antitumor/cytotoxic lymphocytes

¨  ↑ pulsatile Hypothalamic LHRH ¨  Controls photoperiod-dependent molting/coat color

¤  via direct effects on hair follicles ¤  via pars tuberalis altered MSH and/or prolactin secretion

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Melatonin Uses

Recurrent Seasonal Flank Alopecia

Alopecia X

Pattern Baldness

Melatonin More Than a Jet Lag Pill ¨  CRFA (50-75%), ¨  Canine Pattern Alopecia (50%+) ¨  Alopecia-X of the Nordic breeds (30-40%)

¨  Oral melatonin ¨  Injectable melatonin ¨  Implantable melatonin

¨  Peach fuzz in 4-6wks ¨  Maximal growth in 3-4 months

¨  +/- Lethargy, aggressiveness, ¨  Insulin resistance (not in DM) ¨  NOT w/neuropathies or breeding dogs

The Oriental Pearl from the Bund – Shanghai – 2005 6 4

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BBBTS Greyhounds

¨  Nonpruritic, noninflammatory alopecia

¨  Affects the caudal aspect of the pelvic limbs

¨  Can be progressive and involve the abdomen.

BBBTS Greyhounds

¨  Pentoxifylline ¤ 10-30mg/kg TID

¨  Melatonin ¤ 1mg/kg divided TID

¨  Thyroxine ¤ 0.1mg/10lbs BID

¨  Cyclosporine ¨  Soft, warm bedding

Non-specific hair growth promoters

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Ischemic folliculopathies Pentoxifylline candidates 10-30mg/kg TID

¤  bald thigh/bald belly syndrome in greyhounds/whippets

¤  post-clipping ¤  traction alopecia ¤  elbow/hock calluses ¤  deep scarring pyoderma/pododermatitis

CDA: Clinical Signs

¨  Normal at birth ¨  Gradual onset of dry, dull coat ¨  Alopecia on dorsum of trunk

¤ Progresses to partial/complete alopecia ¤ Hair regrowth is poor ¤ Poor quality of remaining hairs

¨  Usually most severe on trunk/colour diluted areas ¤ Often spares head, tail, limbs

CDA: Clinical Signs

¨  Secondary superficial pyoderma ¨  May develop comedomes ¨  Skin usually becomes scaly ¨  Usually not pruritic

¤ Only if secondary infection

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Dermatopathology

CDA: Treatment Options

¨  No known specific treatment ¨  Hair growth promotion

¤ Melatonin – 1mg/kg TID

¨  Help with epidermal barrier ¤ Vitamin A/synthetic retinoids ¤ Antiseborrheic/antibacterial shampoos ¤ Epidermal Barrier Repair Products ¤ Systemic antibiotics to treat secondary pyoderma

n Oral/Injectable

Remind owners that hair growth takes time

¨  Maximum 0.7 mm/day

¨  AFTER underlying etiology identified and addressed, it may take 10-12 weeks to see significant response

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Bald is Beautiful.

Questions?

Ashtyn, Alyssa, Anthony, Andrea