Vet Dermatology. A for Apoquel

1. What’s New in Vet Dermatology?
Small Animal Specialist Hospital
Linda Vogelnest BVSc (Hons)
MANZCVSc (Feline Medicine)
FANZCVSc (Veterinary Dermatology)
Specialist Veterinary Dermatologist

2. What’s new?
• New Meds
– Apoquel® – when and why?, compared to Atopica®
– Bravecto® & Nexgard®- demodicosis
• Update on tricky infections
– MRSP dermatitis/otitis – diagnosis & treatment options
– Malassezia dermatitis/otitis – treatments

3. Apoquel
• Oclacitinib
– New drug and class
• Janus Kinase inhibitor
– Enzymes vital to signaling & cell activation
– Found in many cell types
» Suppressing activation (i.e. immunosuppressant!)
» Lymphocytes (cell-mediated immunity)
• “allergy” cytokines e.g. IL-2/4/7/9/21
• “itch” cytokine – IL-31
• “anti-viral/anti-tumour” cytokines e.g. IL-10, IFN-γ
» Innate immunity – macrophages, neutrophils etc – IL-12/23

4. Apoquel
• Oclacitinib
– Immunosuppressant
• No metabolic effects
• No drug interactions
– Indications
• Control of pruritus from allergic dermatitis
• Control of atopic dermatitis
• In dogs ≥ 12 months old

5. IL-31
• Injected into 11 dogs (expt AD)  pruritus (lasted 4-24 hours)*
– 2 dogs – placebo; 10 dogs - itch increased 2-10 fold; 1 dog – no itch
• Detected in serum*
– in 57% of dogs with ‘natural’ AD(127/223)
– in 0% of dogs with expt AD (no itch; 0/24), normal dogs (no itch; 0/87)
– in 0% of dogs with flea allergy (itchy; 0/30)
• Detected in human AD; levels correlate with severity of AD
Gonzales et al(2013)*
Interleukin-31: its role in
canine pruritus and
naturally occurring
canine atopic dermatitis."
Vet Dermatol 24(1): 48-
53

6. • 299 dogs client-owned dogs with AD
• Enrolled at 19 Dermatology Specialty Practices in USA

7. 0
1
2
3
4
5
6
7
8
9
10
0 7 14 21 28 35 42 49 56 63 70 77 84 91 98 105 112
OwnerVASScore(cm)
Day of Study
OWNER VAS SCORE
Placebo (P) Oclacitinib (O) Open Label (OL)
0
10
20
30
40
50
60
70
80
90
100
0 7 14 21 28 35 42 49 56 63 70 77 84 91 98 105 112
MeanCADESI-02Score
Day of Study
DERMATOLOGIST CADESI-02 SCORE
Placebo (P) Oclacitinib (O) Open Label (OL)
After time 0 Oclacitinib is significantly different from Placebo
As much as (p < 0.0001)

8. More Controlled Studies - AUS
• Gadeyne C, Little PR, King VL, et al (2014)
– Efficacy of oclacitinib (Apoquel®) compared with prednisolone for the control
of pruritus and clinical signs associated with allergic dermatitis in client-owned
dogs in Australia. Vet Dermatol 25(6), 512-e586
• single-masked, randomized controlled clinical trial
• 123 client-owned dogs with allergic dermatitis in GP
0
10
20
30
40
50
60
70
80
90
100
0 7 14 21 28
MeanVASScore(mm)
Day of Study
Delta-Cortef (prednisolone)
APOQUEL (oclacitinib)
DOSE:
Pred – 0.5-1mg/kg SID up to
Day 6, then EOD to Day 28
Apoquel – 0.4-0.6mg/kg BID
up to Day 14, then SID

9. More Controlled Studies - AUS
• Little PR, King VL, Davis KR, et al (2015)
– A blinded, randomized clinical trial comparing the efficacy and safety of
oclacitinib and ciclosporin for the control of atopic dermatitis in client-owned
dogs. Vet Dermatol, 26(1), 23-e28
• blinded, randomized clinical trial, non-inferiority test at day 28
• 226 client-owned dogs with AD from eight specialty derm practices
DOSE:
Atopica – 5mg/kg SID
Apoquel – 0.4-
0.6mg/kg BID up to
Day 14, then SID
0
10
20
30
40
50
60
70
80
90
100
0 7 14 21 28 35 42 49 56 63 70 77 84
MeanVASScore(mm)
Day of Study
Owner VAS Pruritus Score
Atopica APOQUEL
Extremely severe
itching
Severe itching
Moderate itching
Mild itching
Very mild itching
Normal dog
*
*
*
*

10. Apoquel in Sydney
• Compassionate use
– 5 dogs severe AD – 1-2 years
• Not readily controlled variety other tx
– 4 dogs x 2 years (JRT, Staffie, Sharpei X, Lab)
• Owners extremely happy
• Mild intermittent dermatitis – erythema, alopecia
• Minimal pruritus
• Worsening when daily dose due/if dose late (1 dog)
• Weight gain (mild, 2 dogs)
– 1 dog (Lab) – moved to Canberra (AD signs resolved)

11. Apoquel in
Sydney
• Compassionate use
– 1 dog (choc lab)
– severe AD
• Partially controlled - pred 0.5mg/kg EOD, azathioprine, shampoo
– Couldn’t afford cyclosporin
• Responded brilliantly in trial on Apoquel (within one day)
• Severe secondary infections – yeast, bacterial
• Poor response 1yr later restarting under compassionate use
– severe infections, continued pruritus, ultimately euthenasia

12. When To Use Apoquel?
• Indicated for Atopic dermatitis
• Also FAD, Food allergy, Contact (?)

13. 13
1. Atopic Dermatitis
Multi-modal treatment plans
1. Acute flare plan
2. Long-term management plan
Strategies:
1. Minimise allergen &/or irritant exposure
2. Immunotherapy
3. Symptomatic therapy
OLIVRY, DE BOER (2010). Treatment of canine atopic dermatitis: 2010 clinical practice
guidelines from the International Task Force on Canine Atopic Dermatitis. Veterinary
Dermatology 21: 3; 233-248.

14. 14
1. Atopic Dermatitis
Multimodal Treatment
• Allergen-specific Immunotherapy (“allergy vaccines”)
– May reduce need for life-long symptomatic therapy
• Safe symptomatic options
– Antihistamines, Fatty acids
– Topicals – cleansing, soothing, potent steroids
– Manage secondary infections
• More potent options
– Glucocorticoids
– Cyclosporin
– Oclacitinib

15. 15
1. Atopic Dermatitis
Multimodal Treatment
• Allergen-specific Immunotherapy (“allergy vaccines”)
• Safe symptomatic options
• More potent options
– Glucocorticoids – flares & long-term (low regular dose e.g. 1-2X wkly)
– Cyclosporin – slow onset: long-term (2-6wks; wean gradually)
– Oclacitinib – quick onset: flares & long-term (daily for life)
• ADVANTAGES
– small, easily divided tablets
– rare, mild side effects – GIT
– quick response
– no interference with allergy testing
• DISADVANTAGES
– Flare secondary infections/otitis?
– Cost

16. 16
2. Food Allergy?
• Diagnosis
– Elimination diet x 6-8 weeks
• Novel protein – fresh (ideal) or commercial
• Hydrolysed commercial
– Rechallenge phase x 2wks (smorgasbord)
• Role for Apoquel?
– During diagnostic trial - initial relief
– Discontinue last week of diet
• Stabilise if flare before progress to rechallenge

17. 17
3. Flea Allergy?
• Diagnosis
– Flea treatment trial x 4wks
• Adulticidal: quick flea kill
• Consider environment: consider IGR
• Role for Apoquel?
– During diagnostic trial - initial relief
– Discontinue last week of trial

18. When Not To Use Apoquel
• For pruritus due to infectious causes
– Bacterial pyoderma
– Malassezia dermatitis
– Bacterial &/or malassezia otitis
– Sarcoptes, Demodicosis, Dermatophytosis etc.

19. When Not To Use Apoquel
• For pruritus due to infectious causes
• For AD with effective, safe, affordable control plans
– Allergen-specific immunotherapy
– Safer symptomatic treatment plans
– Cyclosporin (EOD or less)
• For FAD, Food allergy in long-term
– Diagnose and avoid allergens
• In dogs under one year age
• In dogs with history of demodicosis?

20. Using Apoquel
Dose:
• 0.4-0.6mg/kg BID x 2wks, then SID long term
• Poor response – reconsider infections/diagnosis

21. Expectations:
• Quick response
• Pruritus flares common when reduce to SID
– Not severe
– Usually settle over next ~2-4 weeks
• What if SID not sufficiently effective?
– Consider timing of administration – AM vs PM
– Can dose be raised?
– Remember the dose range
– Consider off-label BID dosing (low dose)
Using Apoquel

22. 22
Vet Dermatol 2015; 26: 235–e52
5/12 Cats - AD

23. What’s new?
• New Meds
– Apoquel® – when and why?, compared to Atopica®
–Bravecto® & Nexgard®- demodicosis
• Update on tricky infections
– MRSP dermatitis/otitis – diagnosis & treatment options
– Malassezia dermatitis/otitis – treatments

24. Squeeze Tape Impression
for Demodicosis

25.  30 dogs – demodicosis
 21 generalised; 9 localised
 27 positive deep scrape (single)
 30 positive tape squeeze (one squeeze)
 Advantages
 Simple, less invasive
 Sensitivity comparable
(greater?) than deep scraping

26. 26
40 dogs – demodicosis
 23 generalised; 17 localised
 40 positive deep scrape
 30 positive tape squeeze (one
squeeze per site)
 29 positive trichogram
Advantage
 Simple, less invasive first test
Disadvantage
 Deep skin scraping more sensitive

27. 16 dogs Demodicosis
15 dogs – normal skin
15 dogs – inflamed skin
- Multiple squeezes per site
100% specificity – no mites
in normal/inflamed skin
(120 samples)
100% sensitivity – mites in
each lesional sample 16
dogs (16 samples)
Deep skin scraping – 90%
sensitivity
Mites in 14/16 samples

29. Squeeze Tape Impression
• Simple, minimally invasive test
– Less patient discomfort
– No skin trauma
– Readily sample multiple sites
• High specificity
• Apparent high sensitivity

30. Isoxazolines
• Bravecto® - fluralaner
– 8 dogs generalised
demodicosis
– No mites Days 56, 84

31. Isoxazolines
• Nexgard® - afoxolaner
– Twice monthly
– 8 dogs generalised
demodicosis; no mites day 84
– Anecdotal: monthly very
effective

32. Isoxazolines
• Simparica® - sarolaner
– Zoetis
– Monthly flea/tick control

33. What’s new?
• New Meds
– Apoquel® – when and why?, compared to Atopica®
– Bravecto® & Nexgard®- demodicosis
• Update on tricky infections
– MRSP dermatitis/otitis – diagnosis & treatment options
– Malassezia dermatitis/otitis – treatments

34. • Superficial - pyoderma, folliculitis, impetigo, mucocutaneous pyoderma
• Deep
• 2° to
– 1° Skin disease/defects
– Systemic immune suppression
34
Bacterial Pyoderma

35. 35
Bacterial Pyoderma
• Causal Bacteria
– Staphylococcus pseudintermedius
• Normal flora – esp. moist sites: nares, mouth, perianal
• Virulence factors
– Staphylococcus aureus
– Staphylococcus schleiferi schleiferi
• Other normal flora – many
– Gram +ve - coagulase negative Staph, α-haem. Streptococci,
Propionibacterium acnes
– Gram –ve - Clostridium spp., Acinetobacter spp.
• Transients – many
– Proteus mirabilis, Pseudomonas spp., Corynebacterium spp.

36. • Historically – predictable antibiotic sensitivity
– ~98% isolates sensitive to β-lactams
• cephalexin, amoxyclav
• Methicillin-resistance (MRSP, MRSA)
– Small mobile gene (mecA), transferred amongst Staph spp.; alters PBP
– MRSP - first report France – mid 1980’s; first dz USA – 1999
– Alarming  MRSP since 2006 – clonal spread of small number isolates
• ST71 (Europe, Japan), ST68 (USA)
• ST45 (Israel, Thailand)
36
Staphylococcus pseudintermedius

37. • Colonisation/transient carriage (dogs, cats)
– 0-10% worldwide; 30% in Japan (2006)
• Pyoderma (dogs)
– 15-17% (USA 2001-4); 0.8% (Germany 2007); 10% (Spain 2009)
– ~30% (USA 2008); 55-67% (Japan 2007-9)
– Australia – Sydney, Brisbane, Melbourne, Adelaide, Perth
• Perth - 12 isolates/19 dogs 2011/12: some potentially related ST45
(Thailand); some new lineage Canada
• Sydney – 1/29 dogs 2010/12
– 55 dogs 2013 - ~ 20%
37
MRSP
Siak M, Burrows AK, Coombs GW et al. Journal of Medical Microbiology 2014; 63 (9): 1228-1233
Ravens PA, Vogelnest LJ, Ewen E et al.
AVJ 2014; 92(5): 149-155.

38. • Concurrent transfer of resistance to multiple antibiotics: MDR
• Resistance to
– Β-lactams: cephalexin, amoxyclav, cefovecin
– Macrolides: clindamycin
– Fluoroquinolones: enro, marbo
– Tetracyclines: doxy
– TMS
– Chloramphenicol (European isolates)
• Sensitive to
– Rifampicin, amikacin
– Topicals: fusicid acid, mupirocin
– Restricted: vancomycin, linezolid, teicoplanin
38
MRSP Challenges

39. • Dissemination
–  risk MRSP infections – hospitalisation, prior antibiotic therapy
– Positive cultures hospital environment/staff
– Hospital outbreaks
• Zoonosis
– Rare
–  concern – hospital staff, pet owners
• Survival 6mnth (environ)
• Ready transmission household pets
39
MRSP Challenges

40. • Dogs, Cats, (Horses)
• Skin/ears
– Pyoderma – superficial, deep
– Otitis
– Surgical wound infections
• Urinary tract infections
• Septicaemia
40
MRSP Infections

41. • Clinical clues?
– None – looks like ‘normal’ pyoderma
• Historical clues?
– Poorly responsive to antibiotics
• Inadequate antibiotics dose/duration/poor owner compliance
• Concurrent GC therapy
• Active underlying disease (rare)
• MRSP
41
MRSP Pyoderma

42. • Diagnosis?
– Cytology
• Neutrophils, i/c bacterial cocci
– Exclude other causes for poor response to empirical ab’s
– Bacterial C&S (cytologically confirmed pyoderma sites)
• Pustule - puncture sterile 25g needle, culture swab
• Other lesions - dry swab rubbed vigorously 5 sec
• Avoid moist sites/cytology confirms mixed microbes
42
MRSP Pyoderma

43. • Skin cytology
– Adhesive tape impression (all lesions)
• Diff-Quik stain (no fixative)
43
Diagnosis

44. • Skin cytology
– Adhesive tape impression (all lesions)
– Glass slide impression/FNA (moist/nodular lesions)
44
Diagnosis

45. 45
Tape Impression - Normal skin - 4X lens (40x magnification)
 Keratinocytes dominate; normal flora very sparse

46. 46
Tape Impression – Pyoderma 4X lens (40x magnification)
 Clumped keratinocytes; Neutrophil rims/clusters

47. 47
4X lens (40x magnification)

48. 48
Neutrophils with intracellular & colonising cocci
1000X (oil)
200X (20X lens)

49. 49
Degenerate neutrophils with intracellular cocci – oif (1000x)

50. 50
Neutrophils with intracellular & colonising cocci – oif (1000x)

51. 51
Neutrophils with intracellular & colonising cocci
1000X (oil)
40X (4X lens)

52. 52
Neutrophils, colonising bacterial rods –
oif (1000x)
Yeast, and colonising cocci, rods
– oif (1000x)

53. 53
Deep Pyoderma: neutrophils with intracellular cocci (often sparse)
1000X (oil)

54. 1. Address 1° disease/cause
– Reduce immunosuppression
– Atopic Dermatitis – cyclosporin
2. Antibiotic susceptibility unpredictable
– Susceptibility testing important, in light of cytology findings!
– Methicillin (oxacillin) resistance = resistant to all β lactams
54
MRSP Pyoderma - Treatment

55. 1. Systemic Options
– Possibly doxycycline – 10mg/kg SID
– Possibly TMS – 30mg/kg BID
– Rifampicin – 5-10mg/kg SID
• Hepatotoxicity (25% dogs)
• Drug interactions – many
• Orange discolouration body fluids
• Combine with 2nd antibiotic?
55
MRSP Pyoderma - Treatment

56. 1. Systemic Options – doxy?, enro?, TMS? – based on C/S
2. Topical Options
– Antibiotics - resistance documented; colonisation MRSA (people)
• Mupirocin oint/cream (Bactroban®)
• Fusidic acid oint (Conoptal®, Fucidin® - tablet also)
– Antiseptics - act rapidly at bacterial cell walls; less susceptible to resistance?
• Chlorhexidine (more effective; less irritating/staining vs iodine)
– Effective as sole tx MRSP in dogs; daily chlorhex baths reduce MRSA (people)
– 3-4% faster antibacterial effect; leave-on solution/cream; shampoos/scrubs
– Resistance documented
• Other: acetic/boric acid; benzoyl peroxide
• Low irritant: silver sulfadiazine (Flamazine®); medical honey
• Sodium hypochlorite (household bleach) ~ 1ml per litre water
56
MRSP Pyoderma - Treatment

57. • Aggressive individual patient treatment plan
1. Minimum 3-wk treatment course
• Topicals - chlorhexidine; bleach +/- antibiotics
• Cleaning - frequent swimming (salt water), gentle shampooing
2. NO CONCURRENT GLUCOCORTICOIDS!
• Incomplete/delayed resolution of infections
• Encourages antimicrobial resistance
• Pruritus markedly reduced in 24-48 hours without steroids in most cases
57
MRSP Pyoderma – Tx Summary

58. • Aggressive individual patient treatment plan
1. Minimum 3-wk treatment course
• Topicals - chlorhexidine; bleach +/- antibiotics
• Cleaning - frequent swimming (salt water), gentle shampooing
2. NO CONCURRENT GLUCOCORTICOIDS!
3. Address underlying disease
• Atopic Dermatitis/On-going immunosuppression – active prevention plan
1. Topical antiseptics/cleaning
58
MRSP Pyoderma – Tx Summary

59. 59
Diagnosis uncertain?
• Options
1. Antibiotic (or antifungal) treatment trial (3wks; no steroids)
• Pruritic: pruritus & lesions should improve by 5-7d
• Non-pruritic: lesions should resolve by 2-3wks
2. Steroid-treatment trial (2-7 days; no antibiotics/antifungals)
• Pruritic: pruritus and lesions should improve notably by 7d
• Non-pruritic: not indicated!
3. Referral?
DON’T use pred & 5-10 days antibiotics !!
Pyoderma (& MD) - Treatment

60. 1. Prudent Antibiotic Use
1. Pruritic presentations
1. DO NOT USE pred/dex + 5-10d course cephalexin/cefovecin inj
2. Identify pyoderma (cytology or tx trial)
– 3wk cephalexin/amoxyclav AND NO concurrent GC
– Only use 2nd line drugs e.g. fluoroquinolones, clindamycin, cefovecin IF
supported by C&S
60
MRSP – Limiting Spread

61. 1. Sensitivity testing SP isolates Sydney
– 27 dogs; 227 isolates - dry swab, saline-moistened swab, skin scraping
– Cephalexin, amoxyclav, TMS (96%)
– Enrofloxacin, chloramphenicol (96%)
– Less to cefovecin (90%) , clindamycin (88%), doxycycline (78%)
61
Staph Pseudintermedius - Sydney
Ravens PA, Vogelnest LJ, Ewen E et al. Canine superficial bacterial pyoderma: evaluation of skin
surface sampling methods and antimicrobial susceptibility of casual Staphylococcus isolates.
AVJ 2014; 92(5): 149-155.

62. 1. Prudent Antibiotic Use
– When clearly indicated, wise choices, complete courses (3wks), no GC
2. Adequate staff and patient hygiene
– Strict hand hygiene
• Remove gross contamination – soap/water
• Alcohol hand gel
– Patient barrier nursing – if MRSP infection confirmed
3. Hospital disinfection/maintenance
– Regular decontamination – two-step process
• Remove organic debris
• Disinfection
– Alcohol (70-90% ethanol, isopropanol) – fastest action
– Bleach 0.5% (1:10 dilution) – 10-min contact time
– Chlorhexidine 0.15% - 10-min contact time
– Quarternary ammonium compounds e.g. Trigene® – less effective
62
MRSP – Limiting Spread

63. 1. Treat the infection first
 Topicals essential
 Fusidic Acid - Canaural®
 Miconazole/Polymixin B - Surolan®/Dermotic®
2. Reduce any chronic inflammatory changes
3. Treat the underlying disease
63
Treatment – MRSP Otitis

64. What’s new?
• New Meds
– Apoquel® – when and why?, compared to Atopica®
– Bravecto® & Nexgard®- demodicosis
• Update on tricky infections
– MRSP dermatitis/otitis – diagnosis & treatment options
– Malassezia dermatitis/otitis – treatments

65. • 2° to
– Allergies – AD (can markedly  pruritus)
– Systemic immune suppression
• Immuno-suppressive therapies (e.g. pred)
• Disease (e.g. neoplasia, FIV)
– Hormonal – hypoT, hyperA (can cause pruritus)
– Keratinisation defects - primary seborrhoea, sebaceous adenitis
65
Malassezia dermatitis

66. • Skin cytology
– Adhesive tape impression (all lesions)
• Diff-Quik stain (no fixative)
66
Diagnosis

67. 67
MD – oil lens (1000X)
Dx = >1 yeast per oif

68. • Surface cytology
– Most important
– Not 100% sensitive (esp. pyoderma)
• Clinical appearance
– Rarely reliable
– Odour – variable
• Consider treatment trial
– Antifungals alone (3wks min - superficial)
68
Diagnosis

69. 1. Treat the infection first (underlying dz 2nd)
 Systemic most reliable (min. 3wk course)
 Itraconazole 5-10mg/kg SID
 Pulse tx: 2 consecutive days/wk?
69
Treatment – Malassezia Dermatitis

70. 1. Treat the infection first (underlying dz 2nd)
 Systemic most reliable (min. 3wk course)
 Topicals can be useful
 Enilconazole rinse (twice wkly), miconazole cream (BID)
 Chlorhexidine solution (2-3%) sid-bid
 Shampoos – adjunctive only (limited residual effect)
 Chlorhexidine, miconazole
 Piroctone olamine, econazole
70
Treatment – Malassezia Dermatitis

71. 1. Treat the infection first (underlying dz 2nd)
 Topicals essential
 ‘azoles’ - BID seems most effective
 Miconazole - Surolan®/Dermotic®
 Clotrimazone - Otomax®
 Nystatin – BID
 Canaural®, Topigen®
 Systemics – may be helpful, especially if otitis media?
71
Treatment - Otitis

72. 72
Questions?