An update on the treatment of canine atopic dermatitis

Accepted Manuscript Title: An update on the treatment of canine atopic dermatitis Author: Manolis N. Saridomichelakis, Thierry Olivry PII: DOI: Reference:

S1090-0233(15)00386-X http://dx.doi.org/doi: 10.1016/j.tvjl.2015.09.016 YTVJL 4627

To appear in:

The Veterinary Journal

Accepted date:

11-9-2015

Please cite this article as: Manolis N. Saridomichelakis, Thierry Olivry, An update on the treatment of canine atopic dermatitis, The Veterinary Journal (2015), http://dx.doi.org/doi: 10.1016/j.tvjl.2015.09.016. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23

Review An update on the treatment of canine atopic dermatitis Manolis N. Saridomichelakis a,*, Thierry Olivry b

a

Clinic of Medicine, Faculty of Veterinary Science, University of Thessaly, Trikalon Str. 224, GR-43100, Karditsa, Greece b

Department of Clinical Sciences, College of Veterinary Medicine, North Carolina State University, 1060 William Moore Drive, Raleigh, NC, 27607, USA and Center for Comparative Medicine and Translational Research, North Carolina State University, Raleigh, NC, 27606, USA

* Corresponding author. Tel.: +30 244 106 6053. E-mail address: [email protected] (M.N. Saridomichelakis).

Page 1 of 41

24

Highlights

25



Treatment of canine atopic dermatitis must be individualized for each patient

26



Control and prevention of secondary bacterial and yeast infections is essential

27



Food allergies should be investigated in all cases with non-seasonal signs

28



Glucocorticoids, cyclosporine and oclacitinib are the most effective systemic drugs

29



Multiple treatment modalities may have to be combined for optimal results

30 31

Graphical Abstract Clinical diagnosis of atopic dermatitis Flea prevention

Systemic and/or topical treatment of Restriction-provocation dietary trial bacterial and yeast infections Avoidance of responsible foods Topical treatment to prevent recurrences

Etiologic treatment (environmental allergy)

Symptomatic treatmenthighly effective

Symptomatic treatmentlower or unknown efficacy

Allergen avoidance Allergen-specific immunotherapy

Systemic Glucocorticoids Cyclosporine Oclacitinib

Systemic Antihistamines Dextromethorphan Fatty acids Feline interferon-omega Misoprostol Pentoxifylline Serotonin reuptake inhibitors Tricyclic antidepressants Topical Fatty acids Various

Topical Glucocorticoids Tacrolimus

32 33 34

Abstract

35

Canine atopic dermatitis is a common skin disease seen in veterinary clinical practice.

36

Several factors appear to contribute to the cutaneous inflammation and pruritus. The

37

therapeutic strategy should focus on control of those factors that can be identified and for

38

which interventional measures are feasible; these include ectoparasites, bacterial/fungal

39

infection and dietary hypersensitivity. Ectoparasites, particularly fleas, are not the cause of

Page 2 of 41

40

atopic dermatitis, but they are a confounding factor, which can exacerbate pruritus, and

41

preventative measures are therefore indicated. Bacterial and yeast infections are frequently

42

associated with atopic dermatitis and initial systemic and/or topical therapy should be

43

considered, followed by regular topical treatment for preventing relapse. Concurrent dietary

44

hypersensitivity should be investigated by undertaking an elimination/provocation trial,

45

followed by feeding of a hypoallergenic diet where appropriate.

46 47

Depending on the severity of the clinical signs of atopic dermatitis and the willingness

48

and expectations of owners, symptomatic treatment and/or specific interventional therapy for

49

environmental allergy (allergen avoidance, allergen-specific immunotherapy) may be

50

implemented. Symptomatic treatment includes use of glucocorticoids (systemically or

51

topically), ciclosporin and oclacitinib. Other treatment modalities of lower or less proven

52

efficacy include antihistamines, dextromethorphan, fatty acids, feline interferon-omega,

53

misoprostol,

54

antidepressant drugs. The therapeutic approach should be reviewed at regular intervals and

55

tailored to the individual’s needs. A successful long-term outcome can usually be achieved by

56

combining the various treatment approaches in a way that maximises their benefits and

57

minimises their drawbacks.

pentoxifylline,

specific

serotonin

re-uptake

inhibitors

and

tricyclic

58 59

Keywords: Atopic dermatitis; Dog; Ciclosporin; Glucocorticoids, Oclacitinib

60

Page 3 of 41

61

Introduction

62

Canine atopic dermatitis (AD) has been defined as a ‘genetically predisposed

63

inflammatory and pruritic allergic skin disease with characteristic clinical features,

64

associated with IgE antibodies most commonly directed against environmental allergens’

65

(Halliwell, 2006). AD is one of the most common skin diseases of dogs, with a prevalence of

66

3–15% in the general dog population and representing between 3% and 58% of dogs affected

67

with skin disease presented to veterinarians (Hillier and Griffin, 2001a; Hill et al., 2006;

68

Nødtvedt et al., 2006). The diagnosis of canine AD is based on the characteristic clinical

69

features, with exclusion of other diseases with a similar clinical presentation. Therefore, a

70

clinical diagnosis can be made without necessarily employing further diagnostic procedures,

71

such as intradermal skin testing or IgE serology, although these can contribute to clinical

72

decision making in terms of targeted therapy. Rational clinical management of canine AD is

73

required, since AD is usually a life-long disease that can be controlled but rarely cured.

74 75

The age of onset of canine AD is typically between 6 months and 3 years and the

76

most important clinical features include the presence of pruritus, associated with skin lesions

77

of a characteristic distribution around the mouth, eyes (especially in the presence of

78

conjunctivitis), ears, flexor aspects of elbow, carpal and tarsal joints, digits and interdigital

79

skin, ventral abdomen, perineum and ventral aspect of the proximal tail (see Appendix:

80

Supplementary Figs. 1–4). Clinical signs are either seasonal or, most commonly, non-

81

seasonal, or non-seasonal with seasonal exacerbation (Lourenço-Martins et al., 2011;

82

Marsella, 2013a).

83 84

The pathogenesis of canine AD is complex and not particularly well understood, with

85

genetic and environmental factors involved in determining susceptibility to clinical disease.

Page 4 of 41

86

Sensitisation to environmental allergens and/or allergens from food, microbial or insect

87

sources can lead to infiltration of the skin by inflammatory cells, activation of resident cells

88

and local production of inflammatory mediators. Contributory factors include epidermal

89

barrier dysfunction, cutaneous bacterial (usually by Staphylococcus pseudintermedius) and

90

yeast (i.e. Malassezia pachydermatis) infections, psychogenic factors, and concurrent skin

91

diseases (Nuttall, 2012; Marsella, 2013a). These factors are inter-related (Fig. 1) and, for

92

most, it is unclear whether they represent a primary cause or a secondary phenomenon. Thus,

93

a rational approach to treatment is required for each individual dog affected with AD, to

94

manage those factors amenable to specific interventional measures and to institute

95

symptomatic treatment, customised to the needs of each patient and to the expectations and

96

financial circumstances of the owner.

97 98

Sensitisation to environmental allergens and targeted therapy

99

IgE antibodies, generated against environmental allergens, are demonstrable in ~80%

100

of dogs affected with AD, and there is a temporal association between clinical signs of skin

101

disease and the level of exposure to these allergens (Marsella, 2013a). The current hypothesis

102

is that there is a genetic predisposition in some dogs to becoming sensitised to such

103

environmental allergens, mainly via cutaneous exposure (Olivry and Hill, 2001; Marsella et

104

al., 2006a; Marsella et al., 2006b; Pucheu-Haston et al., 2008). Environmental allergens can

105

be captured by Langerhans cells (immature dendritic cells) that migrate to the lymph nodes

106

and present these, in the context of peptide epitopes bound to major histocompatibility

107

complex (MHC) class II molecules, to CD4+ T lymphocytes. Differentiation of naïve CD4+

108

T cells to the T-helper type 2 phenotype enhances maturation of allergen-specific B cells and

109

production of allergen-specific IgE. The IgE circulates and will bind specifically to the

110

surface of mast cells, through their expression of the high affinity IgE receptor (FcεRI)

Page 5 of 41

111

(Olivry et al., 1997; Hill and Olivry, 2001; Marsella et al., 2006b; Pucheu-Haston et al.,

112

2008). Upon subsequent exposure, allergens may penetrate the epidermis and cross-link IgE

113

on the surface of the dermal mast cells, leading to degranulation and immediate release of

114

inflammatory mediators including histamine, followed by a late phase reaction that involves

115

de novo synthesis of inflammatory mediators including leukotrienes (LT), prostaglandins

116

(PG) and various cytokines that recruit inflammatory cells into the skin (Hill and Olivry,

117

2001).

118 119

Sensitisation to environmental allergens can be demonstrated, and the specificity of

120

the hypersensitivity reaction elucidated, by performing the intradermal skin test and/or

121

assessing circulating IgE by serology (Table 1). Anti-inflammatory drugs such as

122

corticosteroids and antihistamines can be employed to provide symptomatic treatment of

123

clinical signs (Table 2). Targeted therapy includes allergen avoidance and use of allergen-

124

specific immunotherapy (ASIT).

125 126

Depending upon the source of allergen, various strategies have been suggested to

127

reduce exposure to environmental allergens, such as a change in household environment,

128

lifestyle and daily routine of the dog, mechanical and/or thermal removal of allergens, use of

129

impermeable barriers, and, for house-dust mites, use of acaricides, growth regulators or

130

chemicals that denature their allergens (Olivry and Sousa, 2001a; Scott et al., 2001; Swinnen

131

and Vroom, 2004). However, there is limited published evidence in favour of this approach.

132

In an open study, ‘excellent’ or ‘partial’ responses were reported in domestic mite-sensitive

133

dogs affected with AD after benzyl benzoate treatment of their households (Swinnen and

134

Vroom, 2004). In another study, there was improvement in clinical signs of house dust mite-

135

associated AD upon a change to a mite-deficient environment (Fujimura, 2011). Since

Page 6 of 41

136

allergen avoidance is often difficult to achieve under most circumstances, it could be argued

137

that there is little benefit in undertaking intradermal skin testing and/or IgE serology for this

138

purpose. However, if a reduction in exposure to offending allergens seems possible, this

139

should be discussed with the owner, since this approach will only benefit and not harm the

140

patient (Scott et al., 2001).

141 142

ASIT involves injecting increasing amounts of a bespoke combination of allergens,

143

following identification of those against which they have been sensitised. Although this

144

immunotherapeutic approach has been shown to ameliorate the clinical signs of AD in many

145

cases, its mechanism of action it is still unclear (Shida et al., 2004; Hou et al., 2008; Keppel

146

et al., 2008). In the ‘traditional’ form of ASIT, an aqueous or alum-precipitated mixture of

147

allergens is injected subcutaneously, at increasing doses and time intervals (Griffin and

148

Hillier, 2001). Alternative dosing schedules (e.g. low-dose ASIT, rush ASIT, omission of the

149

induction phase) (Mueller and Bettenay, 2001; Colombo et al., 2005; Mueller et al., 2005),

150

routes of administration (intradermal, oral, sublingual, intra-lymphatic) (Marsella, 2010) and

151

addition of adjuvants (e.g. oligodeoxynucleotides rich in cytosine-phosphate-guanine motifs)

152

(Rostaher Prélaud et al., 2013) have also been investigated, although there is little evidence

153

that they have any greater benefit, compared with that of the traditional protocol.

154 155

Several open observational studies have shown that ASIT is effective (usually at least

156

50% ‘improvement’ observed) with response rates varying between 50% and 100% of treated

157

dogs. Unfortunately, there are relatively few controlled or long-term trials (Park et al., 2000;

158

Zur et al., 2002b; Colombo et al., 2005; Schnabl et al., 2006; Keppel et al., 2008; Dell et al.,

159

2012) and only one published placebo-controlled trial (Willemse et al., 1984) has shown that

Page 7 of 41

160

ASIT is of benefit in dogs affected with AD, associated with sensitisation to environmental

161

allergens.

162 163

The main advantages of ASIT are its relative safety and its potential to modify the

164

course of the disease. Its drawbacks include a relatively high cost, compared with

165

symptomatic medical treatments (particularly in small breed dogs) and a delay before

166

improvement is usually evident (typically around 3 to 9 months) (Griffin and Hillier, 2001;

167

Saevik et al., 2002; Colombo et al., 2007; Dell et al., 2012; Griffin et al., 2014). ASIT should

168

be considered to be part of an integrated treatment approach for dogs affected with AD,

169

whose disease is associated with those environmental allergens that cannot be avoided, or

170

where symptomatic therapy is not effective (Griffin and Hillier, 2001; Olivry and Sousa,

171

2001a; Olivry et al., 2010b).

172 173

ASIT is an individualised treatment, based on the results of intradermal skin testing

174

and/or IgE serology (there is no indication of superiority of intradermal testing over serology

175

or vice versa, but their combination may give the best results). To be effective, ASIT requires

176

identification of relevant allergens to inform decision making and selection of those

177

components to be included in the individualised ‘vaccine’ and customisation of the dosing

178

regimen, based on the clinical response of each dog (Park et al., 2000; Griffin and Hillier,

179

2001; Zur et al., 2002b; Rosser, 2005; Schnabl et al., 2006). When effective, ASIT is usually

180

a life-long treatment, although in some cases it can be discontinued after a minimum of 2

181

years, without deterioration of the clinical signs (Park et al., 2000; Griffin and Hillier, 2001;

182

Zur et al., 2002b).

183 184

Sensitisation to food allergens and targeted therapy

Page 8 of 41

185

The most common dermatological manifestation of food allergy is a pruritic

186

dermatitis, which is clinically indistinguishable from AD. Sensitisation to dietary allergens is

187

seen in up to 40% of dogs with AD (see Appendix: Supplementary Fig. S5) (Hillier and

188

Griffin, 2001b; Tarpataki et al., 2006; Olivry et al., 2007; Picco et al., 2008; Proverbio et al.,

189

2010; Marsella, 2013b). Based on a rather limited number of research studies, food-induced

190

AD can probably be considered to be a hypersensitivity reaction, rather than a non-

191

immunological food intolerance (Halliwell et al., 2005; Fujimura et al., 2011; Bethlehem et

192

al., 2012).

193 194

The recommended approach for identifying food-induced AD, is to perform a

195

restriction dietary trial (typically for 6–8 weeks), followed by provocation with the previous

196

food for up to 2 weeks (Olivry and Sousa, 2001a). Investigation for food allergies should be

197

undertaken in all dogs with non-seasonal clinical signs of AD. Furthermore, the diagnosis of

198

food-induced AD should be based not only on a response to the restriction diet phase, but

199

also relapse during the provocation phase (Marsella, 2013b). Long-term treatment of food-

200

induced AD is based on allergen avoidance, through the use of food that lacks those dietary

201

components that trigger an allergic response, or by feeding a generic hypoallergenic diet,

202

several of which are now commercially available.

203 204

Therapies aimed at inflammatory cells, cell activation and mediators of inflammation

205

Degranulation of IgE-sensitised mast cells is a major contributor to a type 1

206

hypersensitivity reaction. Antihistamines (H1 receptor antagonists) interfere with the effector

207

responses following histamine release, although some of these drugs might also inhibit mast

208

cell degranulation (DeBoer and Griffin, 2001). Thus, these drugs represent a specific

209

treatment against allergic inflammation (Table 2). Type I antihistamines are fast acting,

Page 9 of 41

210

usually inexpensive and have a relatively good safety profile, but their efficacy in canine AD

211

is somewhat limited (DeBoer and Griffin, 2001). The lack of efficacy of antihistamines in

212

dogs affected with AD probably relates to histamine not being a major mediator for

213

cutaneous inflammation and pruritus in this disease, and because antihistamines cannot exert

214

their action once histamine has already bound to its receptors (DeBoer and Griffin, 2001;

215

Olivry et al., 2003b, 2010b). For these reasons, antihistamines are not usually recommended

216

for treating acute disease, but may be used as part of a combination therapy approach for

217

long-term management of AD, in an attempt to reduce the dose of other drugs, such as

218

corticosteroids (DeBoer and Griffin, 2001; Dell et al., 2012). Those antihistamines with

219

existing pharmacological data in dogs include hydroxyzine (2 mg/kg twice daily orally) and

220

its active metabolite cetirizine (1 mg/kg once daily orally) (Bizikova et al., 2008). One

221

strategy for combination therapy is to establish the minimum dosage of glucocorticoids that

222

controls the clinical signs by sequential dose reduction, then reducing this dose by 50% and

223

adding in an antihistamine.

224 225

In addition to mast cells, many other cell types (keratinocytes, epidermal Langerhans

226

cells, dermal dendritic cells, T lymphocytes, macrophages, eosinophils, neutrophils) can

227

participate in the inflammatory reaction associated with AD (Olivry et al., 1997; Hill and

228

Olivry, 2001; Jassies-van der Lee et al., 2014). These cells can become activated and produce

229

or down-regulate secretion of various cytokines, chemokines and arachidonic acid derivatives

230

(Nuttall et al., 2005; Klukowska-Rötzler et al., 2013; Jassies-van der Lee et al., 2014).

231

Pharmacological modulation of these mediators can be achieved through use of highly

232

effective

233

calcineurin inhibitors such as ciclosporin or Janus kinase inhibitors such as oclacitinib) and

anti-inflammatory/immune

modulatory

drugs

(including

glucocorticoids,

Page 10 of 41

234

perhaps with some drugs of lower efficacy (misoprostol, pentoxifylline) or with recombinant

235

interferon (Tables 2 and 3).

236 237

Glucocorticoids bind to cytoplasmic glucocorticoid receptors, then translocate to the

238

nucleus, where they influence gene expression (Olivry and Sousa, 2001b). Systemic

239

glucocorticoid therapy in AD results in decreased numbers of inflammatory cells and reduced

240

production of inflammatory mediators that effectively controls both acute and chronic

241

cutaneous inflammation and pruritus (Olivry and Sousa, 2001b; Pucheu-Haston et al., 2005).

242

The additional advantages of glucocorticoids include their fast action and low cost, whereas

243

adverse-effects, including polyuria, polydipsia, polyphagia, obesity, muscle atrophy,

244

behavioural changes, bacterial and fungal infections, demodicosis, skin atrophy and

245

iatrogenic hyperadrenocorticism, are a major disadvantage (Olivry et al., 2003b, 2010a,b;

246

Steffan et al., 2003; Olivry and Bizikova, 2013; Gadeyne et al., 2014).

247 248

Since adverse effects are more commonly seen with higher doses, daily administration

249

and long-term use of glucocorticoids, their main indication is for control of acute AD or for

250

episodic flares of clinical signs. Glucocorticoids are better suited for treatment of seasonal

251

AD and for use as a short term palliative treatment, while other therapeutic options are

252

identified and implemented (i.e. during the first months of ASIT or during the first weeks of

253

ciclosporin treatment) (Colombo et al., 2007; Olivry et al., 2010a; Dip et al., 2013). However,

254

in practice, systemic glucocorticoids are often used on a long-term basis, when alternative

255

treatments are not effective or when there are financial constraints on treatment options.

256 257

Short-acting oral glucocorticoids (prednisone, prednisolone, methylprednisolone) can

258

be used long term in dogs affected with AD with reasonable safety (Olivry and Sousa,

Page 11 of 41

259

2001b).

In

the

short-term,

prednisone,

prednisolone

(0.5–1

mg/kg

orally)

or

260

methylprednisolone (0.4–0.8 mg/kg orally) can be administered either once daily or divided

261

into two doses for the first week, followed by a reduction of dosage and frequency that

262

should be tailored to each patient (Olivry and Sousa, 2001b; Olivry et al., 2010a). After 2

263

weeks of treatment, resolution of clinical signs is expected, although if this is not the case,

264

other causes of the clinical signs, such as skin infections and food-induced AD, should be

265

suspected. If long-term treatment is planned, a typical regimen involves tapering the last daily

266

dose to alternate days (administered in the mornings) followed by gradual tapering until the

267

lowest effective dose is established. Dogs receiving long-term treatment should be monitored

268

(including physical examination and urine culture) every 12 months, as well as each time an

269

adverse effect is suspected (Torres et al., 2005).

270 271

Use of topical glucocorticoids can replace systemic therapy for long-term

272

management of AD, if the inflammation and pruritus are restricted to localised areas of the

273

skin (DeBoer et al., 2002; Olivry et al., 2003b, 2010b; Nuttall et al., 2009; Nuttall et al.,

274

2012; Olivry and Bizikova, 2013). Although topical treatment is relatively labour-intensive

275

and more expensive for the owner, compared with oral administration, it is considered to be

276

much safer (Olivry et al., 2003b). However, local (e.g. skin atrophy) and even generalised

277

adverse-effects can still occur and therefore the least potent molecule given at the longest

278

effective dosing interval should be considered (Olivry and Sousa, 2001b; Nuttall et al., 2009;

279

Olivry et al., 2010a).

280 281

More recently, use of diester topical glucocorticoids, such as hydrocortisone

282

aceponate, which are metabolised in situ into inactive molecules, has been reported that

283

combines high potency with lower propensity for systemic adverse-effects (Nuttall et al.,

Page 12 of 41

284

2009; Olivry and Bizikova, 2013). However, even with these drugs, development of skin

285

atrophy should be monitored (Bizikova et al., 2010), although this is unlikely with

286

intermittent application (Nuttall et al., 2009). Once in remission, following daily

287

hydrocortisone aceponate treatment, topical treatment (once daily for two consecutive days

288

per week) has been proposed in an effort to delay recurrence of clinical signs and to reduce

289

the need for systemic anti-inflammatory medication (Lourenco-Martins et al., 2012).

290 291

Ciclosporin is a calcineurin inhibitor that binds to cyclophilin in the cytoplasm of

292

lymphocytes, inhibiting translocation of the nuclear factor of activated T cells (NF-AT) to the

293

nucleus, thereby resulting in down-regulation of synthesis of numerous cytokines, including

294

interleukin (IL)-2 and interferon (IFN)-γ (Nuttall et al., 2002, 2005; Kobayashi et al., 2007;

295

Forsythe and Paterson, 2014). Compared with glucocorticoids, ciclosporin is similarly

296

effective, shows less frequent and less severe adverse effects, but has a slower onset of action

297

(usually 2–3 weeks) and is more expensive (Olivry et al., 2002, 2003b; 2010b; Steffan et al.,

298

2003; Olivry and Bizikova, 2013). Therefore, it is not indicated for the treatment of acute

299

episodes of clinical signs, but it is one of the drugs recommended for long term symptomatic

300

treatment of canine AD.

301 302

After a 4–6 week period and effective control of clinical signs, the initial dosing

303

regimen of microemulsified (modified) ciclosporin (5 mg/kg, once daily orally) can be

304

reduced, in more than half of dogs, to either the same dose administered on alternate

305

(sometimes every third) days or by gradual reduction of the daily dose by 25% every 4 weeks

306

(Steffan et al., 2003; Nuttall et al., 2010; Forsythe and Paterson, 2014). Also, the dose and

307

therefore the cost of the treatment can be reduced by approximately 50% with concurrent

308

administration of ketoconazole (2.5 mg/kg, once daily orally), which inhibits ciclosporin

Page 13 of 41

309

metabolism, resulting in a prolonged half-life (Hillier et al., 2012; Palmeiro, 2013; Forsythe

310

and Paterson, 2014; Nuttall et al., 2014), although this practice should be considered against

311

the increased likelihood of adverse effects, such as hepatotoxicity.

312 313

Although ciclosporin is generally considered safe for long-term administration,

314

adverse effects, including nausea, vomiting and diarrhoea (Marsella and Olivry, 2001; Steffan

315

et al., 2003; Palmeiro, 2013; Nuttall et al., 2014) can occur, most commonly during the initial

316

phase of treatment and which usually resolve thereafter. Other adverse-effects include

317

anorexia, weight loss, aggression, hypertrichosis, cutaneous papillomatosis, gingival

318

hyperplasia (see Appendix: Supplementary Fig. S6), and, rarely, opportunistic infections

319

(Steffan et al., 2006; Palmeiro, 2013; Nuttall et al., 2014). These adverse-effects typically

320

depend on the dose, duration of treatment and co-administration of other immunosuppressive

321

agents or drugs that interfere with ciclosporin metabolism, and can lead to treatment

322

discontinuation in ~5% of cases (Forsythe and Paterson, 2014; Nuttall et al., 2014).

323 324

Tacrolimus is a topical calcineurin inhibitor that can be used instead of systemic

325

immunosuppressive therapy to treat localised inflammation and pruritus (Marsella and

326

Olivry, 2001; Bensignor and Olivry, 2005). It is effective and relatively safe, but its high cost

327

and difficulty associated with application of the ointment to small areas of the skin are major

328

disadvantages (Olivry et al., 2003b, 2010b). The use of tacrolimus ointment can also cause

329

transient signs suggestive of topical irritation (Bensignor and Olivry, 2005).

330 331

Oclacitinib is a Janus kinase inhibitor that blocks signalling after binding of several

332

pruritogenic and pro-inflammatory cytokines to their receptors (Gonzales et al., 2013, 2014).

333

It is effective, fast-acting and has a good safety profile, but is relatively more expensive than

Page 14 of 41

334

systemic glucocorticoids. It has been recommended for management of both acute flares of

335

clinical signs and long-term treatment of AD (Cosgrove et al., 2013a,b, 2015; Collard et al.,

336

2014; Gadeyne et al., 2014; Little et al., 2015). The initial dosage of 0.4–0.6 mg/kg orally

337

twice daily can be reduced to once daily after the first 2 weeks (Cosgrove et al., 2013a,b;

338

Gadeyne et al., 2014). Adverse-effects seem to be uncommon, but include anorexia, vomiting

339

and diarrhoea (Cosgrove et al., 2013a,b, 2015; Little et al., 2015). Further independent and

340

long-term studies are needed to fully appreciate the effectiveness and safety of this drug for

341

treatment of canine AD.

342 343

Misoprostol is a synthetic analogue of prostaglandin E1 that reduces production of IL-

344

1, tumour necrosis factor (TNF)-α and leukotriene B4 (Marsella and Olivry, 2001; Olivry et

345

al., 2003a). This drug is of moderate efficacy, but due to its relative safety and moderate cost

346

it has been suggested at 3–6 μg/kg three times daily (off license) in an effort to reduce the

347

dose of glucocorticoids required (Marsella and Olivry, 2001; Olivry et al., 2003a,b).

348 349

Pentoxifylline is a phosphodiesterase inhibitor that down-regulates activation of

350

inflammatory cells and TNF-α production (Marsella and Olivry, 2001). Its efficacy is

351

somewhat moderate, but it appears to be relatively safe and has been suggested at 10–20

352

mg/kg two or three times daily, to reduce glucocorticoid use (Olivry et al., 2003b; Singh et

353

al., 2010). Pentoxifylline has a lag phase of 1 to 2 months and it may be particularly useful in

354

dogs with concurrent allergic contact dermatitis, although it is not formally approved for use

355

in dogs with AD (Singh et al., 2010).

356 357

Recombinant feline interferon-omega has been shown in one study to be equally as

358

effective as ciclosporin (Carlotti et al., 2009). However, indications for the use of this drug

Page 15 of 41

359

are unclear, since its mechanism of action is not known, the dosing regimen and the route of

360

administration have not been standardised, its efficacy is inconsistent among studies and

361

long-term safety has not been thoroughly evaluated (Carlotti et al., 2009; Litzlbauer et al.,

362

2012).

363 364

Additional medications such as tepoxalin (Horvath-Ungerboeck et al., 2009) and

365

alternative routes of administration of anti-inflammatory drugs (i.e. topical ciclosporin

366

nanoemulsion) (Puigdemont et al., 2013), have shown some efficacy in controlled trials, but

367

there is a need for more extensive evaluation before they can be recommended for the

368

treatment of canine AD.

369 370

Epidermal barrier dysfunction and therapeutic options

371

Defective skin barrier function has been consistently shown in both lesional and, to a

372

lesser extent, non-lesional skin of dogs affected with AD (Inman et al., 2001; Shimada et al.,

373

2009; Marsella et al., 2010, 2011; Popa et al., 2011; Cornegliani et al., 2012). A primary

374

barrier defect has not been proven, but the research literature shows that it can occur

375

secondary to inflammation and self-trauma (Hightower et al., 2010; Cornegliani et al., 2012;

376

Schamber et al., 2014). Epidermal barrier dysfunction has been associated with perturbation

377

of lipid metabolism (e.g. reduced or defective ceramide synthesis) and with altered synthesis

378

or dysfunction of proteins such as filaggrin, keratins and intercellular adhesion molecules

379

(Marsella et al., 2011; Stahl et al., 2012; Theerawatanasirikul et al., 2012; Santoro et al.,

380

2013b; Schamber et al., 2014; Olivry and Dunston, 2015). Such epidermal barrier defects can

381

result in dry skin (Shimada et al., 2009), which may aggravate pruritus and lead to increased

382

penetration and sensitisation to environmental (Olivry et al., 2011) and perhaps bacterial or

383

fungal, allergens as well as to increased penetration of irritants.

Page 16 of 41

384 385

Demonstration of epidermal barrier dysfunction can be achieved through

386

measurement of trans-epidermal water loss, although this procedure is neither standardised

387

nor widely used in veterinary clinical practice (Table 1). Therefore, epidermal barrier

388

dysfunction should be assumed in dogs affected with AD and efforts made to restore the

389

epidermal barrier with fatty acids (oral supplements either in the diet or applied topically) and

390

various topical treatments (Table 2) should be included as part of an integrated therapeutic

391

approach.

392 393

Oral supplementation with n-3 and n-6 fatty acids (either in the form of specific

394

dietary supplements or a commercially-available fatty acid-enriched diet) has been used for

395

many years in dogs affected with AD, with the aims of down-regulating pro-inflammatory

396

eicosanoid production, inhibiting inflammatory cell activation and cytokine secretion,

397

restoring perturbations in lipid metabolism and, ultimately, normalising the stratum corneum

398

(Olivry et al., 2001; Stehle et al., 2010; Popa et al., 2011). However, the ideal fatty acid

399

composition of these supplements and the dosage regimen required to achieve these goals

400

remain unclear. n-6 fatty acids, such as linoleic acid, are naturally present in the epidermis,

401

where they are incorporated into ceramides. Since the latter are important for epidermal

402

barrier function, n-6 fatty acid supplementation may be preferable at least for the restoration

403

of barrier function (Abba et al., 2005). Essential fatty acid supplementation is generally

404

considered to be safe, but clinical efficacy is slow to become apparent, and it can take several

405

weeks to appreciate any benefit (Mueller et al., 2004; Saevik et al., 2004). For these reasons,

406

fatty acid supplementation is only indicated for long-term management of AD as an adjunct

407

to other treatment modalities (Saevik et al., 2004; Olivry et al., 2010b; Dell et al., 2012)

408

(Table 3).

Page 17 of 41

409 410

In recent years, some topical (spot-on, spray, shampoo, emulsion) formulations

411

containing fatty acids, other lipids (such as ceramides) and non-lipid ingredients have been

412

advocated for dogs affected with AD (Marsella et al., 2012; Blaskovic et al., 2014). Although

413

they can increase epidermal lipid lamellae (Piekutowska et al., 2008) and normalise skin

414

lipids (Popa et al., 2011), their efficacy in terms of reduction of pruritus and improvement in

415

skin lesions is inconsistent and their clinical benefit is somewhat modest (Table 3).

416

Veterinarians should weigh the benefit and cost of these supplements before deciding

417

whether fatty acid supplementation should be given orally or topically.

418 419

Various other topical ingredients (capsaicin, colloidal oatmeal, pramoxine, rhamnose)

420

and modalities (bathing with ultrapure soft water, whirlpool hydrotherapy) have been

421

suggested as options for dogs affected with AD (Marsella et al., 2002; Loflath et al., 2007;

422

Ohmori et al., 2010). The mode of action of such therapies is not always clear, but they may

423

normalise the defective epidermal barrier, remove allergens and irritants from the skin

424

surface and reduce inflammation and/or pruritus (Marsella et al., 2002; Olivry et al., 2003b;

425

Ohmori et al., 2010). Although generalisations are not possible and most of these treatment

426

options have not been evaluated extensively, they are usually safe and they might be of

427

benefit as an adjunct therapy, at least in some patients (Marsella et al., 2002; Olivry et al.,

428

2010b).

429 430

Bacterial infections and the therapeutic approach

431

In cross-sectional studies, up to 66% of dogs affected with AD showed evidence of

432

bacterial skin infection (Favrot et al., 2010) and these figures might even be higher if more

433

longitudinal studies had been performed (Colombo et al., 2007). Many explanations for the

Page 18 of 41

434

predisposition to pyoderma in dogs affected with AD have been proposed, including

435

increased expression of skin adhesion molecules, decreased production or dysfunction of

436

antimicrobial peptides, epidermal barrier dysfunction, chronic inflammation and self-trauma

437

(Simou et al., 2005; McEwan et al., 2006; Fazakerley et al., 2009; van Damme et al., 2009;

438

Lancto et al., 2013; Santoro et al., 2013a). Infection can induce or exacerbate cutaneous

439

inflammation (Nesbitt et al., 2004) and there is evidence that dogs affected with AD might

440

become sensitised to bacterial antigens, or that they may be exposed to microbial components

441

such as staphylococcal superantigens (DeBoer and Marsella, 2001; Bexley et al., 2013).

442 443

In most cases, dogs affected with AD present with superficial infection, in the form of

444

bacterial folliculitis, bacterial overgrowth or exfoliative pyoderma (see Appendix:

445

Supplementary Fig. S7) (Griffin and DeBoer, 2001), usually identified from clinical features

446

and cutaneous cytology. Systemic and topical treatment of canine pyoderma (Table 2) has

447

been reviewed elsewhere (Mueller et al., 2012; Beco et al., 2013a, b; Hillier et al., 2014).

448

Bacterial skin infections in dogs affected with AD tend to be recurrent, and repeated systemic

449

administration of antimicrobial drugs carries the risk of contributing to emergence of

450

antimicrobial resistance. For this reason, systemic antimicrobial drugs should only be used

451

when deemed absolutely necessary and selected based on in vitro susceptibility testing,

452

particularly when the dog has been treated with antibiotics previously. Topical antiseptics

453

should always be recommended, either alone or in combination with systemic antimicrobial

454

drugs, for the treatment of pyoderma and their long-term use is a good strategy for the

455

prevention of recurrent pyoderma.

456 457

Malassezia dermatitis and the therapeutic approach

Page 19 of 41

458

Malassezia dermatitis has been reported in up to 38% of dogs affected with AD in

459

cross-sectional studies (Zur et al., 2002a) and it is frequently a recurrent problem. Malassezia

460

dermatitis by itself will exacerbate cutaneous inflammation (Nesbitt et al., 2004) and, in

461

comparison with infection by Staphylococcus pseudintermedius, there is more robust

462

evidence for development of hypersensitivity to yeast antigens in dogs affected with AD

463

(Nuttall and Halliwell, 2001; Bond et al., 2002; Chen et al., 2002; Morris et al., 2002; Farver

464

et al., 2005; Oldenhoff et al., 2014).

465 466

The clinical signs of infection are typically non-specific and may be caused by

467

Malassezia spp., bacteria or of mixed organisms, therefore cytology is the diagnostic test of

468

choice (Table 1). Systemic and/or topical antifungal treatment (Table 2) can be beneficial for

469

the treatment and prevention of yeast infections in dogs affected with AD (Table 3) (Nuttall

470

and Halliwell, 2001; Negre et al., 2009; Dell et al., 2012; Mueller et al., 2012).

471 472

A specific consideration in dogs affected with AD is allergic otitis externa, which may

473

lead in some cases to otitis media (Zur et al., 2002a; Saridomichelakis et al., 2007; Picco et

474

al., 2008; Favrot et al., 2010). Treatment of bacterial and yeast infections of the ear follows

475

the same principles as previously described for skin infections, with treatment usually

476

administered topically for otitis externa and systemically for otitis media. Symptomatic

477

treatment of allergic inflammation, if needed, is usually based on use of topical

478

glucocorticoids, which may also be of benefit as a preventative treatment after resolution of

479

infection and acute inflammation (Bensignor, 2008; Bensignor et al., 2012).

480 481

Psychogenic factors

Page 20 of 41

482

Psychogenic factors (including environmental stress) may also contribute to some

483

dogs demonstrating clinical signs of AD (Virga, 2003; Moriello, 2005). In such patients,

484

anxiolytic agents, such as tricyclic antidepressants (TCA) and specific serotonin re-uptake

485

inhibitors (SSRI), as well as N-methyl-D-aspartate, may prove to be beneficial (Table 2). Use

486

of various TCA, such as doxepin (1–2 mg/kg, orally twice daily) and amitriptyline (1–2

487

mg/kg, orally twice daily) have been reported in dogs with AD (Virga, 2003). Their primary

488

mode of action is to increase serotonin and noradrenaline concentrations in the central

489

nervous system, but they also have antihistamine (H1 receptor antagonist) and analgesic

490

(NMDA receptor antagonist) properties (Virga, 2003). However, their efficacy is

491

questionable and quite variable (Olivry et al., 2003b) and adverse effects can occur. Of the

492

SSRIs, use of fluoxetine (1 mg/kg, orally once or twice daily) has been reported, but its

493

efficacy has not been clearly demonstrated (Marsella and Olivry, 2001; Virga, 2003).

494 495

Dextromethorphan is a NMDA receptor antagonist with some non-specific serotonin

496

re-uptake inhibition properties (Dodman et al., 2004). When administered at 2 mg/kg orally

497

twice daily, it has been shown to result in a mild to moderate improvement in clinical signs

498

and it has been recommended for dogs with AD when a strong behavioural component is

499

suspected (Dodman et al., 2004; Moriello, 2005), although further studies are required to

500

fully appreciate its effectiveness and long-term safety (Moriello, 2005).

501 502

Concurrent skin diseases

503

Canine AD can co-exist with several other skin diseases, due to mere chance, due to

504

similar predisposition (e.g. flea allergic dermatitis, allergic contact dermatitis) or due to the

505

immunosuppressive effects of therapy (e.g. demodicosis, canine leishmaniosis) (Sousa and

506

Halliwell, 2001; Olivry et al., 2010a; Miller et al., 2013; Saridomichelakis and Koutinas,

Page 21 of 41

507

2014). The presence of comorbidities can change the clinical features of AD and need to be

508

considered, diagnosed and treated as complicating factors in individual cases. In flea-endemic

509

areas, clinicians should implement preventative measures against flea infestation, using

510

highly effective long-lasting ectoparasiticides (Olivry and Sousa, 2001a; Bruet et al., 2012).

511 512

Conclusions

513

Multiple pathogenetic factors are responsible for cutaneous inflammation and pruritus

514

in dogs affected with AD. The initial steps of a rational diagnostic and therapeutic plan

515

should include preventative measures against ectoparasites and treatment of existing skin

516

infections. This should be followed by proactive topical treatment to prevent or delay clinical

517

relapses when they tend to be recurrent and implementation of a food elimination/provocation

518

trial, followed by feeding a well-tolerated diet in cases with adverse food reactions.

519

Thereafter, depending on the severity of clinical signs of AD and the owner expectations,

520

symptomatic treatment and/or etiologic treatment for environmental allergy (allergen

521

avoidance, ASIT) can be implemented. Symptomatic treatment should be tailored to the

522

individual needs of the patient and owner, taking into consideration efficacy, safety, cost and

523

the owner’s personal preferences. The treatment approach should be re-evaluated regularly

524

and routinely, particularly with every flare of clinical signs of AD, and modified when

525

needed. The key to a successful long-term outcome is often to combine treatments to

526

maximise benefits and minimise adverse effects.

527 528

Conflict of interest statement

529

The first author (MNS) has received lecture honoraria and research grants from the

530

following companies (or their local representatives) whose products are discussed in this

531

article: Bayer, Elanco, Hill’s, ICF, Merial, MSD, Novartis Animal Health, Royal Canin,

Page 22 of 41

532

Virbac, and Zoetis. The second author (TO) has consulted or received lecture honoraria from

533

Aratana Therapeutics, Ceva, Novartis Animal Health, Royal Canin, Vétoquinol, Virbac and

534

Zoetis. None of these companies had any influence on the decision of the authors to prepare

535

this article or on its contents.

536 537 538 539

Acknowledgements The authors express their gratitude to Dr Patricia Gray for her help in proof reading the article.

540 541 542 543

Appendix: Supplementary material Supplementary material, associated with this article, can be found in the online version, at doi: ...setters please insert doi number

544 545

References

546 547 548 549 550 551 552 553 554 555 556 557 558 559 560 561 562 563 564 565 566 567

Abba, C., Mussa, P.P., Vercelli, A., Raviri, G., 2005. Essential fatty acids supplementation in different-stage atopic dogs fed on a controlled diet. Journal of Animal Physiology and Animal Nutrition 89, 203-207. Beco, L., Guaguère, E., Lorente Méndez, C., Noli, C., Nuttall, T., Vroom, M., 2013a. Suggested guidelines for using systemic antimicrobials in bacterial skin infections (1): diagnosis based on clinical presentation, cytology and culture. Veterinary Record 172, 72-78. Beco, L., Guaguère, E., Lorente Méndez, C., Noli, C., Nuttall, T., Vroom, M., 2013b. Suggested guidelines for using systemic antimicrobials in bacterial skin infections: part 2-- antimicrobial choice, treatment regimens and compliance. Veterinary Record 172, 156-160. Bensignor, E., 2008. Evaluation of intermittent topical therapy in the control of recurrent allergic otitis externa in dogs: a randomized, double-blinded, placebo controlled study. Veterinary Dermatology 19 (Suppl. 1), 71. Bensignor, E., Olivry, T., 2005. Treatment of localized lesions of canine atopic dermatitis with tacrolimus ointment: a blinded randomized controlled trial. Veterinary Dermatology 16, 52-60.

Page 23 of 41

568 569 570 571 572 573 574 575 576 577 578 579 580 581 582 583 584 585 586 587 588 589 590 591 592 593 594 595 596 597 598 599 600 601 602 603 604 605 606 607 608 609 610 611 612 613 614 615 616 617

Bensignor, E., Pattyn, J., Reme, C., 2012. Preduction of relapses of recurrent otitis externa in atopic dogs with twice-weekly topical application of hydrocortisone aceponate in the ear canal: a randomized, blinded, controlled study. Veterinary Dermatology 23 (Suppl. 1), 92. Bethlehem, S., Bexley, J., Mueller, R.S., 2012. Patch testing and allergen-specific serum IgE and IgG antibodies in the diagnosis of canine adverse food reactions. Veterinary Immunology and Immunopathology 145, 582-589. Bexley, J., Nuttall, T.J., Hammerberg, B., Fitzgerald, J.R., Halliwell, R.E., 2013. Serum antiStaphylococcus pseudintermedius IgE and IgG antibodies in dogs with atopic dermatitis and nonatopic dogs. Veterinary Dermatology 24, 19-e6 Bizikova, P., Papich, M.G., Olivry, T., 2008. Hydroxyzine and cetirizine pharmacokinetics and pharmacodynamics after oral and intravenous administration of hydroxyzine to healthy dogs. Veterinary Dermatology 19, 348-357. Bizikova, P., Linder, K.E., Paps, J., Olivry, T., 2010. Effect of a novel topical diester glucocorticoid spray on immediate- and late-phase cutaneous allergic reactions in Maltese-beagle atopic dogs: a placebo-controlled study. Veterinary Dermatology 21, 71-80. Blaskovic, M., Rosenkrantz, W., Neuber, A., Sauter-Louis, C., Mueller, R.S., 2014. The effect of a spot-on formulation containing polyunsaturated fatty acids and essential oils on dogs with atopic dermatitis. The Veterinary Journal 199, 39-43. Bond, R., Curtis, C.F., Hendricks, A., Ferguson, E.A., Lloyd, D.H., 2002. Intradermal test reactivity to Malassezia pachydermatis in atopic dogs. Veterinary Record 150, 448449. Bruet, V., Bourdeau, P.J., Roussel, A., Imparato, L., Desfontis, J.C., 2012. Characterization of pruritus in canine atopic dermatitis, flea bite hypersensitivity and flea infestation and its role in diagnosis. Veterinary Dermatology 23, 487-e93. Carlotti, D.N., Boulet, M., Ducret, J., Machicote, G., Jasmin, P., Reme, C.A., Albouy, M., 2009. The use of recombinant omega interferon therapy in canine atopic dermatitis: a double-blind controlled study. Veterinary Dermatology 20, 405-411. Chen, T.A., Halliwell, R.E., Pemberton, A.D., Hill, P.B., 2002. Identification of major allergens of Malassezia pachydermatis in dogs with atopic dermatitis and Malassezia overgrowth. Veterinary Dermatology 13, 141-150. Collard, W.T., Hummel, B.D., Fielder, A.F., King, V.L., Boucher, J.F., Mullins, M.A., Malpas, P.B., Stegemann, M.R., 2014. The pharmacokinetics of oclacitinib maleate, a Janus kinase inhibitor, in the dog. Journal of Veterinary Pharmacology and Therapeutics 37, 279-285. Colombo, S., Hill, P.B., Shaw, D.J., Thoday, K.L., 2005. Effectiveness of low dose immunotherapy in the treatment of canine atopic dermatitis: a prospective, doubleblinded, clinical study. Veterinary Dermatology 16, 162-170.

Page 24 of 41

618 619 620 621 622 623 624 625 626 627 628 629 630 631 632 633 634 635 636 637 638 639 640 641 642 643 644 645 646 647 648 649 650 651 652 653 654 655 656 657 658 659 660 661 662 663 664 665 666

Colombo, S., Hill, P.B., Shaw, D.J., Thoday, K.L., 2007. Requirement for additional treatment for dogs with atopic dermatitis undergoing allergen-specific immunotherapy. Veterinary Record 160, 861-864. Cornegliani, L., Vercelli, A., Sala, E., Marsella, R., 2012. Transepidermal water loss in healthy and atopic dogs, treated and untreated: a comparative preliminary study. Veterinary Dermatology 23, 41-e10. Cosgrove, S.B., Cleaver, D.M., King, V.L., Gilmer, A.R., Daniels, A.E., Wren, J.A., Stegemann, M.R., 2015. Long-term compassionate use of oclacitinib in dogs with atopic and allergic skin disease: safety, efficacy and quality of life. Veterinary Dermatology 26, 171-e35. Cosgrove, S.B., Wren, J.A., Cleaver, D.M., Martin, D.D., Walsh, K.F., Harfst, J.A., Follis, S.L., King, V.L., Boucher, J.F., Stegemann, M.R., 2013a. Efficacy and safety of oclacitinib for the control of pruritus and associated skin lesions in dogs with canine allergic dermatitis. Veterinary Dermatology 24, 479-e114. Cosgrove, S.B., Wren, J.A., Cleaver, D.M., Walsh, K.F., Follis, S.L., King, V.L., Tena, J.S., Stegemann, M.R., 2013b. A blinded, randomized, placebo-controlled trial of the efficacy and safety of the Janus kinase inhibitor oclacitinib (Apoquel ®) in client-owned dogs with atopic dermatitis. Veterinary Dermatology 24, 587-e142. DeBoer, D.J., Griffin, C.E., 2001. The ACVD task force on canine atopic dermatitis (XXI): antihistamine pharmacotherapy. Veterinary Immunology and Immunopathology 81, 323-329. DeBoer, D.J., Marsella, R., 2001. The ACVD task force on canine atopic dermatitis (XII): the relationship of cutaneous infections to the pathogenesis and clinical course of canine atopic dermatitis. Veterinary Immunology and Immunopathology 81, 239-249. DeBoer, D.J., Schafer, J.H., Salsbury, C.S., Blum, J.R., Beale, K.M., Vitale, C.B., Muse, R., Moriello, K.A., Garfield, R.A., Keefe, T.J., McArthur, T.R., 2002. Multiple-center study of reduced-concentration triamcinolone topical solution for the treatment of dogs with known or suspected allergic pruritus. American Journal of Veterinary Research 63, 408-413. Dell, D.L., Griffin, C.E., Thompson, L.A., Griffies, J.D., 2012. Owner assessment of therapeutic interventions for canine atopic dermatitis: a long-term retrospective analysis. Veterinary Dermatology 23, 228-e47. Dip, R., Carmichael, J., Letellier, I., Strehlau, G., Roberts, E., Bensignor, E., Rosenkrantz, W., 2013. Concurrent short-term use of prednisolone with cyclosporine A accelerates pruritus reduction and improvement in clinical scoring in dogs with atopic dermatitis. BMC Veterinary Research 9, 173. Dodman, N.H., Shuster, L., Nesbitt, G., Weissman, A., Lo, W.Y., Chang, W.W., Cottam, N., 2004. The use of dextromethorphan to treat repetitive self-directed scratching, biting, or

Page 25 of 41

667 668 669 670 671 672 673 674 675 676 677 678 679 680 681 682 683 684 685 686 687 688 689 690 691 692 693 694 695 696 697 698 699 700 701 702 703 704 705 706 707 708 709 710 711 712 713 714

chewing in dogs with allergic dermatitis. Journal of Veterinary Pharmacology and Therapeutics 27, 99-104. Farver, K., Morris, D.O., Shofer, F., Esch, B., 2005. Humoral measurement of type-1 hypersensitivity reactions to a commercial Malassezia allergen. Veterinary Dermatology 16, 261-268. Favrot, C., Steffan, J., Seewald, W., Picco, F., 2010. A prospective study on the clinical features of chronic canine atopic dermatitis and its diagnosis. Veterinary Dermatology 21, 23-31. Fazakerley, J., Nuttall, T., Sales, D., Schmidt, V., Carter, S.D., Hart, C.A., McEwan, N.A., 2009. Staphylococcal colonization of mucosal and lesional skin sites in atopic and healthy dogs. Veterinary Dermatology 20, 179-184. Forsythe, P., Paterson, S., 2014. Ciclosporin 10 years on: indications and efficacy. Veterinary Record 174 (Suppl. 2), 13-21. Fujimura, M., 2011. The study of canine atopic dermatitis involving the isolation of dogs. Polish Journal of Veterinary Sciences 14, 273-277. Fujimura, M., Masuda, K., Hayashiya, M., Okayama, T., 2011. Flow cytometric analysis of lymphocyte proliferative responses to food allergens in dogs with food allergy. Journal of Veterinary Medical Science 73, 1309-1317. Gadeyne, C., Little, P., King, V.L., Edwards, N., Davis, K., Stegemann, M.R., 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. Veterinary Dermatology 25, 512-e586. Gonzales, A.J., Humphrey, W.R., Messamore, J.E., Fleck, T.J., Fici, G.J., Shelly, J.A., Teel, J.F., Bammert, G.F., Dunham, S.A., Fuller, T.E., McCall, R.B., 2013. Interleukin-31: its role in canine pruritus and naturally occurring canine atopic dermatitis. Veterinary Dermatology 24, 48-e12. Gonzales, A.J., Bowman, J.W., Fici, G.J., Zhang, M., Mann, D.W., Mitton-Fry, M., 2014. Oclacitinib (APOQUEL®) is a novel Janus kinase inhibitor with activity against cytokines involved in allergy. Journal of Veterinary Pharmacology and Therapeutics 37, 317-324. Griffin, C.E., DeBoer, D.J., 2001. The ACVD task force on canine atopic dermatitis (XIV): clinical manifestations of canine atopic dermatitis. Veterinary Immunology and Immunopathology 81, 255-269. Griffin, C.E., Hillier, A., 2001. The ACVD task force on canine atopic dermatitis (XXIV): allergen-specific immunotherapy. Veterinary Immunology and Immunopathology 81, 363-383.

Page 26 of 41

715 716 717 718 719 720 721 722 723 724 725 726 727 728 729 730 731 732 733 734 735 736 737 738 739 740 741 742 743 744 745 746 747 748 749 750 751 752 753 754 755 756 757 758 759 760 761 762 763 764

Griffin, C.E., Rosenkrantz, W.S., Thompson, P., 2014. Prospective survey of reported reactions to allergen-specific immunotherapy injections. Veterinary Dermatology 25, 250. Halliwell, R., 2006. Revised nomenclature for veterinary allergy. Veterinary Immunology and Immunopathology 114, 207-208. Halliwell, R.E.W., Gordon, C.M., Horvath, C., Wagner, R., 2005. IgE and IgG antibodies to food antigens in sera from normal dogs, dogs with atopic dermatitis and dogs with adverse food reactions. In: Hillier, A., Foster, A.P., Kwochka, K.W. (Eds.), Advances in Veteinary Dermatology, Vol. 5. Blackwell Publishing, Oxford, U.K., pp. 28-35. Hightower, K., Marsella, R., Flynn-Lurie, A., 2010. Effects of age and allergen exposure on transepidermal water loss in a house dust mite-sensitized beagle model of atopic dermatitis. Veterinary Dermatology 21, 89-96. Hill, P.B., Olivry, T., 2001. The ACVD task force on canine atopic dermatitis (V): biology and role of inflammatory cells in cutaneous allergic reactions. Veterinary Immunology and Immunopathology 81, 187-198. Hill, P.B., Lo, A., Eden, C.A., Huntley, S., Morey, V., Ramsey, S., Richardson, C., Smith, D.J., Sutton, C., Taylor, M.D., Thorpe, E., Tidmarsh, R., Williams, V., 2006. Survey of the prevalence, diagnosis and treatment of dermatological conditions in small animals in general practice. Veterinary Record 158, 533-539. Hillier, A., Griffin, C.E., 2001a. The ACVD task force on canine atopic dermatitis (I): incidence and prevalence. Veterinary Immunology and Immunopathology 81, 147-151. Hillier, A., Griffin, C.E., 2001b. The ACVD task force on canine atopic dermatitis (X): is there a relationship between canine atopic dermatitis and cutaneous adverse food reactions? Veterinary Immunology and Immunopathology 81, 227-231. Hillier, A., Moning, K.E., Gray, L.L., 2012. Factors affecting ciclosporin concentrations in canine skin. Veterinary Dermatology 23 (Suppl. 1), 63. Hillier, A., Lloyd, D.H., Weese, J.S., Blondeau, J.M., Boothe, D., Breitschwerd, E., Guardabassi, L., Papich, M.G., Rankin, S., Turnidge, J.D., et al., 2014. Guidelines for the diagnosis and antimicrobial therapy of canine superficial bacterial folliculitis (Antimicrobial Guidelines Working Group of the International Society for Companion Animal Infectious Diseases). Veterinary Dermatology 25, 163-e43. Horvath-Ungerboeck, C., Thoday, K.L., Shaw, D.J., van den Broek, A.H., 2009. Tepoxalin reduces pruritus and modified CADESI-01 scores in dogs with atopic dermatitis: a prospective, randomized, double-blinded, placebo-controlled, cross-over study. Veterinary Dermatology 20, 233-242. Hou, C.C., Griffin, C.E., Hill, P.B., 2008. Dermatophagoides farinae-specific IgG responses in atopic dogs undergoing allergen-specific immunotherapy with aqueous vaccines. Veterinary Dermatology 19, 215-220.

Page 27 of 41

765 766 767 768 769 770 771 772 773 774 775 776 777 778 779 780 781 782 783 784 785 786 787 788 789 790 791 792 793 794 795 796 797 798 799 800 801 802 803 804 805 806 807 808 809 810 811 812 813 814

Inman, A.O., Olivry, T., Dunston, S.M., Monteiro-Riviere, N.A., Gatto, H., 2001. Electron microscopic observations of stratum corneum intercellular lipids in normal and atopic dogs. Veterinary Pathology 38, 720-723. Jassies-van der Lee, A., Rutten, V.P., Bruijn, J., Willemse, T., Broere, F., 2014. CD4+ and CD8+ skin-associated T lymphocytes in canine atopic dermatitis produce interleukin13, interleukin-22 and interferon-γ and contain a CD25+ FoxP3+ subset. Veterinary Dermatology 25, 456-e472. Keppel, K.E., Campbell, K.L., Zuckermann, F.A., Greeley, E.A., Schaeffer, D.J., Husmann, R.J., 2008. Quantitation of canine regulatory T cell populations, serum interleukin-10 and allergen-specific IgE concentrations in healthy control dogs and canine atopic dermatitis patients receiving allergen-specific immunotherapy. Veterinary Immunology and Immunopathology 123, 337-344. Klukowska-Rötzler, J., Chervet, L., Müller, E.J., Roosje, P., Marti, E., Janda, J., 2013. Expression of thymic stromal lymphopoietin in canine atopic dermatitis. Veterinary Dermatology 24, 54-e14. Kobayashi, T., Momoi, Y., Iwasaki, T., 2007. Cyclosporine A inhibits the mRNA expressions of IL-2, IL-4 and IFN-gamma, but not TNF-alpha, in canine mononuclear cells. Journal of Veterinary Medical Science 69, 887-892. Lancto, C.A., Torres, S.M., Hendrickson, J.A., Martins, K.V., Rutherford, M.S., 2013. Altered expression of antimicrobial peptide genes in the skin of dogs with atopic dermatitis and other inflammatory skin conditions. Veterinary Dermatology 24, 414e490. Little, P.R., King, V.L., Davis, K.R., Cosgrove, S.B., Stegemann, M.R., 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. Veterinary Dermatology 26, 23-e8. Litzlbauer, P., Weber, K., Mueller, R., S.,, 2012. Recombinant feline interferon-ω as oral or subcutaneous treatment of canine atopic dermatitis. Veterinary Dermatology 23 (Suppl. 1), 38. Loflath, A., von Voigts-Rhetz, A., Jaeger, K., Schmidt, M., Kuechenhoff, H., Mueller, R.S., 2007. The efficacy of a commercial shampoo and whirlpooling in the treatment of canine pruritus-a double-blinded, randomized, placebo-controlled study Veterinary Dermatology 18, 427-431. Lourenço-Martins, A.M., Delgado, E., Neto, I., Peleteiro, M.C., Morais-Almeida, M., Correia, J.H., 2011. Allergic conjunctivitis and conjunctival provocation tests in atopic dogs. Veterinary Ophthalmology 14, 248-256. Lourenco-Martins, A.M., Sao-Braz, B., Schmidt, V.M., Reme, C.A., Nuttall, T., 2012. Longterm maintenance therapy of canine atopic dermatitis with a 0.0584% hydrocortisone aceponate spray (Cortadvance) used on two consecutive days each week. Veterinary Dermatology 23 (Suppl. 1), 38.

Page 28 of 41

815 816 817 818 819 820 821 822 823 824 825 826 827 828 829 830 831 832 833 834 835 836 837 838 839 840 841 842 843 844 845 846 847 848 849 850 851 852 853 854 855 856 857 858 859 860 861 862 863

Marsella, R., 2010. Tolerability and clinical efficacy of oral immunotherapy with house dust mites in a model of canine atopic dermatitis: a pilot study. Veterinary Dermatology 21, 566-571. Marsella, R., 2013a. Atopic disease. In: Miller, W.H.J., Griffin, C.E., Campbell, K.L. (Eds.), Muller & Kirk's Small Animal Dermatology, 7th edn. Elsevier Mosby, St. Louis, Missouri, pp. 365-388. Marsella, R., 2013b. Food hypersensitivity. In: Miller, W.H.J., Griffin, C.E., Campbell, K.L. (Eds.), Muller & Kirk's Small Animal Dermatology, 7th edn. Elsevier Mosby, St. Louis, Missouri, pp. 397-405. Marsella, R., Olivry, T., 2001. The ACVD task force on canine atopic dermatitis (XXII): nonsteroidal anti-inflammatory pharmacotherapy. Veterinary Immunology and Immunopathology 81, 331-345. Marsella, R., Nicklin, C.F., Melloy, C., 2002. The effects of capsaicin topical therapy in dogs with atopic dermatitis: a randomized, double-blinded, placebo-controlled, cross-over clinical trial. Veterinary Dermatology 13, 131-139. Marsella, R., Nicklin, C., Lopez, J., 2006a. Studies on the role of routes of allergen exposure in high IgE-producing beagle dogs sensitized to house dust mites. Veterinary Dermatology 17, 306-312. Marsella, R., Olivry, T., Nicklin, C.F., Lopez, J., 2006b. Pilot investigation of a model of canine atopic dermatitis: environmental house dust mite challenge of high-IgEproducing beagles, mite hypersensitive dogs with atopic dermatitis and normal dogs. Veterinary Dermatology 17, 24-35. Marsella, R., Genovese, D., Gilmer, L., Ahrens, K., 2012. Investigations on the effects of a topical ceramide and free fatty acid solution (Allederm Spot-On) on clinical signs and skin barrier function in dogs with atopic dermatitis: a double-blinded, randomized, controlled study. Veterinary Dermatology 23 (Suppl. 1), 66-67. Marsella, R., Samuelson, D., Doerr, K., 2010. Transmission electron microscopy studies in an experimental model of canine atopic dermatitis. Veterinary Dermatology 21, 81-88. Marsella, R., Olivry, T., Carlotti, D.N., for the International Task Force on Canine Atopic Dermatitis., 2011. Current evidence of skin barrier dysfunction in human and canine atopic dermatitis. Veterinary Dermatology 22, 239-248. McEwan, N.A., Mellor, D., Kalna, G., 2006. Adherence by Staphylococcus intermedius to canine corneocytes: a preliminary study comparing noninflamed and inflamed atopic canine skin. Veterinary Dermatology 17, 151-154. Miller, W.H.J., Griffin, C.E., Campbell, K.L., 2013. Muller & Kirk's Small Animal Dermatology, 7th edn. Elsevier Mosby, St. Louis, Missouri.

Page 29 of 41

864 865 866 867 868 869 870 871 872 873 874 875 876 877 878 879 880 881 882 883 884 885 886 887 888 889 890 891 892 893 894 895 896 897 898 899 900 901 902 903 904 905 906 907 908 909 910 911 912 913

Moriello, K.A., 2005. Can dextromethorphan be used to treat repetitive itching and scratching in atopic dogs? Veterinary Medicine 52, 20-23. Morris, D.O., Clayton, D.J., Drobatz, K.J., Felsburg, P.J., 2002. Response to Malassezia pachydermatis by peripheral blood mononuclear cells from clinically normal and atopic dogs. American Journal of Veterinary Research 63, 358-362. Mueller, R.S., Bettenay, S.V., 2001. Evaluation of the safety of an abbreviated course of injections of allergen extracts (rush immunotherapy) for the treatment of dogs with atopic dermatitis. American Journal of Veterinary Research 62, 307-310. Mueller, R.S., Fieseler, K.V., Fettman, M.J., Zabel, S., Rosychuk, R.A., Ogilvie, G.K., Greenwalt, T.L., 2004. Effect of omega-3 fatty acids on canine atopic dermatitis. Journal of Small Animal Practice 45, 293-297. Mueller, R.S., Fieseler, K.V., Zabel, S., Rosychuk, R.A.W., 2005. Conventional and rush allergen-specific immunotherapy in the treatment of canine atopic dermatitis. In: Hillier, A., Foster, A.P., Kwochka, K.W. (Eds.), Advances in Veteinary Dermatology, Vol. 5. Blackwell Publishing, Oxford, U.K., pp. 60-69. Mueller, R.S., Bergvall, K., Bensignor, E., Bond, R., 2012. A review of topical therapy for skin infections with bacteria and yeast. Veterinary Dermatology 23, 330-e62. Negre, A., Bensignor, E., Guillot, J., 2009. Evidence-based veterinary dermatology: a systematic review of interventions for Malassezia dermatitis in dogs. Veterinary Dermatology 20, 1-12. Nesbitt, G.H., Freeman, L.M., Hannah, S.S., 2004. Correlations of fatty acid supplementation, aeroallergens, shampoo, and ear cleanser with multiple parameters in pruritic dogs. Journal of the American Animal Hospital Association 40, 270-284. Nødtvedt, A., Egenvall, A., Bergvall, K., Hedhammar, A., 2006. Incidence of and risk factors for atopic dermatitis in a Swedish population of insured dogs. Veterinary Record 159, 241-246. Nuttall, T., 2012. Update on the immunopathogenesis of canine atopic dermatitis. In: Proceedings of the Continuing Education Programme of the 7th World Congress of Veterinary Dermatology, Vancouver, Canada, pp. 277-284. Nuttall, T.J., Halliwell, R.E., 2001. Serum antibodies to Malassezia yeasts in canine atopic dermatitis. Veterinary Dermatology 12, 327-332. Nuttall, T.J., Knight, P.A., McAleese, S.M., Lamb, J.R., Hill, P.B., 2002. T-helper 1, Thelper 2 and immunosuppressive cytokines in canine atopic dermatitis. Veterinary Immunology and Immunopathology 87, 379-384. Nuttall, T.J., Knight, P.A., McAleese, S.M., Brown, J., Lamb, J.R., Hill, P.B., 2005. Expression of Th1-cytokine mRNA in canine atopic dermatitis correlates with severity of clinical lesions. In: Hillier, A., Foster, A.P., Kwochka, K.W. (Eds.), Advances in Veteinary Dermatology, Vol. 5. Blackwell Publishing, Oxford, U.K., pp. 17-27.

Page 30 of 41

914 915 916 917 918 919 920 921 922 923 924 925 926 927 928 929 930 931 932 933 934 935 936 937 938 939 940 941 942 943 944 945 946 947 948 949 950 951 952 953 954 955 956 957 958 959 960 961 962 963

Nuttall, T., Mueller, R., Bensignor, E., Verde, M., Noli, C., Schmidt, V., Rème, C., 2009. Efficacy of a 0.0584% hydrocortisone aceponate spray in the management of canine atopic dermatitis: a randomised, double blind, placebo-controlled trial. Veterinary Dermatology 20, 191-198. Nuttall, T., McEwan, N.A., Bensignor, E., Cornegliani, L., Lowerstein, C., Reme, C.A., 2010. Equal efficacy of 0.0548% hydrocortisone aceponate spray and ciclosporin in treating canine atopic dermatitis. Veterinary Dermatology 21, 534. Nuttall, T.J., McEwan, N.A., Bensignor, E., Cornegliani, L., Löwenstein, C., Rème, C.A., 2012. Comparable efficacy of a topical 0.0584% hydrocortisone aceponate spray and oral ciclosporin in treating canine atopic dermatitis. Veterinary Dermatology 23, 4-e2. Nuttall, T., Reece, D., Roberts, E., 2014. Life-long diseases need life-long treatment: longterm safety of ciclosporin in canine atopic dermatitis. Veterinary Record 174 (Suppl. 2), 3-12. Ohmori, K., Tanaka, A., Makita, Y., Takai, M., Yoshinari, Y., Matsuda, H., 2010. Pilot evaluation of the efficacy of shampoo treatment with ultrapure soft water for canine pruritus. Veterinary Dermatology 21, 477-483. Oldenhoff, W.E., Frank, G.R., DeBoer, D.J., 2014. Comparison of the results of intradermal test reactivity and serum allergen-specific IgE measurement for Malassezia pachydermatis in atopic dogs. Veterinary Dermatology 25, 507-e85. Olivry, T., Hill, P.B., 2001. The ACVD task force on canine atopic dermatitis (IX): the controversy surrounding the route of allergen challenge in canine atopic dermatitis. Veterinary Immunology and Immunopathology 81, 219-225. Olivry, T., Sousa, C.A., 2001a. The ACVD task force on canine atopic dermatitis (XIX): general principles of therapy. Veterinary Immunology and Immunopathology 81, 311316. Olivry, T., Sousa, C.A., 2001b. The ACVD task force on canine atopic dermatitis (XX): glucocorticoid pharmacotherapy. Veterinary Immunology and Immunopathology 81, 317-322. Olivry, T., Bizikova, P., 2013. A systematic review of randomized controlled trials for prevention or treatment of atopic dermatitis in dogs: 2008-2011 update. Veterinary Dermatology 24, 97-e26. Olivry, T., Dunston, S.M., 2015. Expression patterns of superficial epidermal adhesion molecules in an experimental dog model of acute atopic dermatitis skin lesions. Veterinary Dermatology 26, 53-e18. Olivry, T., Naydan, D.K., Moore, P.F., 1997. Characterization of the cutaneous inflammatory infiltrate in canine atopic dermatitis. The American Journal of Dermatopathology 19, 477-486.

Page 31 of 41

964 965 966 967 968 969 970 971 972 973 974 975 976 977 978 979 980 981 982 983 984 985 986 987 988 989 990 991 992 993 994 995 996 997 998 999 1000 1001 1002 1003 1004 1005 1006 1007 1008 1009 1010 1011 1012 1013

Olivry, T., Marsella, R., Hillier, A., 2001. The ACVD task force on canine atopic dermatitis (XXIII): are essential fatty acids effective? Veterinary Immunology and Immunopathology 81, 347-362. Olivry, T., Steffan, J., Fisch, R.D., Prélaud, P., Guaguère, E., Fontaine, J., Carlotti, D.N., European Veterinary Dermatology Ciclosporin Group, 2002. Randomized controlled trial of the efficacy of cyclosporine in the treatment of atopic dermatitis in dogs. Journal of the American Veterinary Medical Association 221, 370-377. Olivry, T., Dunston, S.M., Rivierre, C., Jackson, H.A., Murphy, K.M., Peters, E., Dean, G.A., 2003a. A randomized controlled trial of misoprostol monotherapy for canine atopic dermatitis: effects on dermal cellularity and cutaneous tumour necrosis factor-alpha. Veterinary Dermatology 14, 37-46. Olivry, T., Mueller, R.S., for the International Task Force on Canine Atopic Dermatitis, 2003b. Evidence-based veterinary dermatology: a systematic review of the pharmacotherapy of canine atopic dermatitis. Veterinary Dermatology 14, 121-146. Olivry, T., DeBoer, D.J., Prelaud, P., Bensignor, E., 2007. Food for thought: pondering the relationship between canine atopic dermatitis and cutaneous adverse food reactions. Veterinary Dermatology 18, 390-391. Olivry, T., DeBoer, D.J., Favrot, C., Jackson, H.A., Mueller, R.S., Nuttall, T., Prélaud, P., for the International Task Force on Canine Atopic Dermatitis, 2010a. Treatment of canine atopic dermatitis: 2010 clinical practice guidelines from the International Task Force on Canine Atopic Dermatitis. Veterinary Dermatology 21, 233-248. Olivry, T., Foster, A.P., Mueller, R.S., McEwan, N.A., Chesney, C., Williams, H.C., 2010b. Interventions for atopic dermatitis in dogs: a systematic review of randomized controlled trials. Veterinary Dermatology 21, 4-22. Olivry, T., Wofford, J., Paps, J.S., Dunston, S.M., 2011. Stratum corneum removal facilitates experimental sensitization to mite allergens in atopic dogs. Veterinary Dermatology 22, 188-196. Palmeiro, B.S., 2013. Cyclosporine in veterinary dermatology. Veterinary Clinics of North America-Small Animal Practice 43, 153-171. Park, S.J., Ohya, F., Yamashita, K., Nishifuji, K., Iwasaki, T., 2000. Comparison of response to immunotherapy by intradermal skin test and antigen-specific IgE in canine atopy. Journal of Veterinary Medical Science 62, 983-988. Picco, F., Zini, E., Nett, C., Naegeli, C., Bigler, B., Rüfenacht, S., Roosje, P., Gutzwiller, M.E., Wilhelm, S., Pfister, J., Meng, E., Favrot, C., 2008. A prospective study on canine atopic dermatitis and food-induced allergic dermatitis in Switzerland. Veterinary Dermatology 19, 150-155. Piekutowska, A., Pin, D., Rème, C.A., Gatto, H., Haftek, M., 2008. Effects of a topically applied preparation of epidermal lipids on the stratum corneum barrier of atopic dogs. Journal of Comparative Pathology 138, 197-203.

Page 32 of 41

1014 1015 1016 1017 1018 1019 1020 1021 1022 1023 1024 1025 1026 1027 1028 1029 1030 1031 1032 1033 1034 1035 1036 1037 1038 1039 1040 1041 1042 1043 1044 1045 1046 1047 1048 1049 1050 1051 1052 1053 1054 1055 1056 1057 1058 1059 1060 1061 1062 1063

Popa, I., Pin, D., Remoué, N., Osta, B., Callejon, S., Videmont, E., Gatto, H., Portoukalian, J., Haftek, M., 2011. Analysis of epidermal lipids in normal and atopic dogs, before and after administration of an oral omega-6/omega-3 fatty acid feed supplement. A pilot study. Veterinary Research Communications 35, 501-509. Proverbio, D., Perego, R., Spada, E., Ferro, E., 2010. Prevalence of adverse food reactions in 130 dogs in Italy with dermatological signs: a retrospective study. Journal of Small Animal Practice 51, 370-374. Pucheu-Haston, C.M., Shuster, D., Olivry , T., Brianceau, P., Lockwood, P., McClanahan, T., Malefyt, R.W., Mattson, J.D., Hammemberg, B., 2005. A canine model of cutaneous late-phase reactions: prednisolone inhibition of cellular and cytokine responses. Immunology 117, 177-187. Pucheu-Haston, C.M., Jackson, H.A., Olivry, T., Dunston, S.M., Hammerberg, B., 2008. Epicutaneous sensitization with Dermatophagoides farinae induces generalized allergic dermatitis and elevated mite-specific immunoglobulin E levels in a canine model of atopic dermatitis. Clinical and Experimental Allergy 38, 667-679. Puigdemont, A., Brazís, P., Ordeix, L., Dalmau, A., Fuertes, E., Olivar, A., Pérez, C., Ravera, I., 2013. Efficacy of a new topical cyclosporine A formulation in the treatment of atopic dermatitis in dogs. The Veterinary Journal 197, 280-285. Rosser, E.J.J., 2005. Comparison of intradermal testing and allergen-specific IgE serum testing in dogs with warm weather, seasonal atopic dermatitis. In: Hillier, A., Foster, A.P., Kwochka, K.W. (Eds.), Advances in Veteinary Dermatology, Vol. 5. Blackwell Publishing, Oxford, U.K., pp. 42-48. Rostaher Prélaud, A., Fuchs, S., Weber, K., Winter, G., Coester, C., Mueller, R.S., 2013. In vitro effects of CpG oligodeoxynucleotides delivered by gelatin nanoparticles on canine peripheral blood mononuclear cells of atopic and healthy dogs-a pilot study. Veterinary Dermatology 24, 494-e117. Saevik, B.K., Thoresen, S.I., Kristensen, F., 2002. A retrospective study of hyposensitization in canine atopy based on a polyclonal ELISA test. Veterinary Research Communications 26, 613-624. Saevik, B.K., Bergvall, K., Holm, B.R., Saijonmaa-Koulumies, L.E., Hedhammar, A., Larsen, S., Kristensen, F., 2004. A randomized, controlled study to evaluate the steroid sparing effect of essential fatty acid supplementation in the treatment of canine atopic dermatitis. Veterinary Dermatology 15, 137-145. Santoro, D., Bunick, D., Graves, T.K., Segre, M., 2013a. Evaluation of canine antimicrobial peptides in infected and noninfected chronic atopic skin. Veterinary Dermatology 24, 39-e10. Santoro, D., Marsella, R., Ahrens, K., Graves, T.K., Bunick, D., 2013b. Altered mRNA and protein expression of filaggrin in the skin of a canine animal model for atopic dermatitis. Veterinary Dermatology 24, 329-e73.

Page 33 of 41

1064 1065 1066 1067 1068 1069 1070 1071 1072 1073 1074 1075 1076 1077 1078 1079 1080 1081 1082 1083 1084 1085 1086 1087 1088 1089 1090 1091 1092 1093 1094 1095 1096 1097 1098 1099 1100 1101 1102 1103 1104 1105 1106 1107 1108 1109 1110 1111 1112 1113

Saridomichelakis, M.N., Koutinas, A.F., 2014. Cutaneous involvement in canine leishmaniosis due to Leishmania infantum (syn. L. chagasi). Veterinary Dermatology 25, 61-e22. Saridomichelakis, M.N., Farmaki, R., Leontides, L.S., Koutinas, A.F., 2007. Aetiology of canine otitis externa: a retrospective study of 100 cases. Veterinary Dermatology 18, 341-347. Schamber, P., Schwab-Richards, R., Bauersachs, S., Mueller, R.S., 2014. Gene expression in the skin of dogs sensitized to the house dust mite Dermatophagoides farinae. G3 (Bethesda, Md.) 4, 1787-1795. Schnabl, B., Bettenay, S.V., Dow, K., Mueller, R.S., 2006. Results of allergen-specific immunotherapy in 117 dogs with atopic dermatitis. Veterinary Record 158, 81-85. Scott, D.W., Miller, W.H., Griffin, C.E., 2001. Canine atopic disease. In, Muller & Kirk's Small Animal Dermatology, 6th edn. W.B. Saunders, Philadelphia, pp. 574-601. Shida, M., Kadoya, M., Park, S.J., Nishifuji, K., Momoi, Y., Iwasaki, T., 2004. Allergenspecific immunotherapy induces Th1 shift in dogs with atopic dermatitis. Veterinary Immunology and Immunopathology 102, 19-31. Shimada, K., Yoon, J.S., Yoshihara, T., Iwasaki, T., Nishifuji, K., 2009. Increased transepidermal water loss and decreased ceramide content in lesional and non-lesional skin of dogs with atopic dermatitis. Veterinary Dermatology 20, 541-546. Simou, C., Thoday, K.L., Forsythe, P.J., Hill, P.B., 2005. Adherence of Staphylococcus intermedius to corneocytes of healthy and atopic dogs: effect of pyoderma, pruritus score, treatment and gender. Veterinary Dermatology 16, 385-391. Singh, S.K., Dimri, U., Saxena, S.K., Jadhav, R.K., 2010. Therapeutic management of canine atopic dermatitis by combination of pentoxifylline and PUFAs. Journal of Veterinary Pharmacology and Therapeutics 33, 495-498. Sousa, C.A., Halliwell, R.E., 2001. The ACVD task force on canine atopic dermatitis (XI): the relationship between arthropod hypersensitivity and atopic dermatitis in the dog. Veterinary Immunology and Immunopathology 81, 233-237. Stahl, J., Paps, J., Bäumer, W., Olivry, T., 2012. Dermatophagoides farinae house dust mite allergen challenges reduce stratum corneum ceramides in an experimental dog model of acute atopic dermatitis. Veterinary Dermatology 23, 497-e97. Steffan, J., Alexander, D., Brovedani, F., Fisch, R.D., 2003. Comparison of cyclosporine A with methylprednisolone for treatment of canine atopic dermatitis: a parallel, blinded, randomized controlled trial. Veterinary Dermatology 14, 11-22. Steffan, J., Favrot, C., Mueller, R., 2006. A systematic review and meta-analysis of the efficacy and safety of cyclosporin for the treatment of atopic dermatitis in dogs. Veterinary Dermatology 17, 3-16.

Page 34 of 41

1114 1115 1116 1117 1118 1119 1120 1121 1122 1123 1124 1125 1126 1127 1128 1129 1130 1131 1132 1133 1134 1135 1136 1137 1138 1139 1140 1141 1142 1143 1144 1145 1146 1147 1148 1149 1150 1151 1152 1153 1154

Stehle, M.E., Hanczaruk, M., Schwarz, S.C., Göbel, T.W., Mueller, R.S., 2010. Effects of polyunsaturated fatty acids on isolated canine peripheral blood mononuclear cells and cytokine expression (IL-4, IFN-gamma, TGF-beta) in healthy and atopic dogs. Veterinary Dermatology 21, 112-117. Swinnen, C., Vroom, M., 2004. The clinical effect of environmental control of house dust mites in 60 house dust mite-sensitive dogs. Veterinary Dermatology 15, 31-36. Tarpataki, N., Papa, K., Reiczigel, J., Vajdovich, P., Voros, K., 2006. Prevalence and features of canine atopic dermatitis in Hungary. Acta Veterinaria Hungarica 54, 353-366. Theerawatanasirikul, S., Sailasuta, A., Thanawongnuwech, R., Suriyaphol, G., 2012. Alterations of keratins, involucrin and filaggrin gene expression in canine atopic dermatitis. Research in Veterinary Science 93, 1287-1292. Torres, S.M., Diaz, S.F., Nogueira, S.A., Jessen, C., Polzin, D.J., Gilbert, S.M., Horne, K.L., 2005. Frequency of urinary tract infection among dogs with pruritic disorders receiving long-term glucocorticoid treatment. Journal of the American Veterinary Medical Association 227, 239-243. van Damme, C.M., Willemse, T., van Dijk, A., Haagsman, H.P., Veldhuizen, E.J., 2009. Altered cutaneous expression of beta-defensins in dogs with atopic dermatitis. Molecular Immunology 46, 2449-2455. Virga, V., 2003. Behavioral dermatology. Veterinary Clinics of North America-Small Animal Practice 33, 231-251. Willemse, A., Van den Brom, W.E., Rijnberk, A., 1984. Effect of hyposensitization on atopic dermatitis in dogs. Journal of the American Veterinary Medical Association 184, 12771280. Zur, G., Ihrke, P.J., White, S.D., Kass, P.H., 2002a. Canine atopic dermatitis: a retrospective study of 266 cases examined at the University of California, Davies, 1992-1998. Part I. Clinical features and allergy testing results. Veterinary Dermatology 13, 89-102. Zur, G., White, S.D., Ihrke, P.J., Kass, P.H., Toebe, N., 2002b. Canine atopic dermatitis: a retrospective study of 169 cases examined at the University of California, Davis, 19921998. Part II. Response to hyposensitization. Veterinary Dermatology 13, 103-111.

Page 35 of 41

1155

Appendix:

1156 1157

Supplementary Fig. S1. Alopecia-hypotrichosis, erythema, lichenification and excoriations on

1158

the lips, periocular skin and medial aspect of ear pinnae in a 2-year old Jack Russell terrier

1159

with atopic dermatitis and secondary bacterial and yeast infections

1160 1161

Supplementary Fig. S2a. Alopecia-hypotrichosis and mild erythema on the flexor (anterior)

1162

aspect of the elbow joint in a 3-year-old Bichon Frisé with atopic dermatitis; b. Alopecia-

1163

hypotrichosis, erythema, lichenification and crusting on the flexor (posterior) aspect of the

1164

carpal joint and the interdigital skin of the same dog as in Fig. 1

1165 1166

Supplementary Fig. S3. Alopecia-hypotrichosis and erythema on the digits of a 3-year old

1167

Jack Russell terrier with atopic dermatitis

1168 1169

Supplementary Fig. S4. Alopecia-hypotrichosis, erythema, hyperpigmentation, lichenification

1170

and thickening of the skin on the ventral abdomen, inguinal areas, inner thighs, perineum and

1171

ventral aspect of the tail base in a 8.5-year old West Highland White terrier with chronic

1172

atopic dermatitis and secondary bacterial and yeast infections

1173 1174

Supplementary Fig. S5. Food-induced atopic dermatitis in a 3-year old Rhodesian ridgeback

1175

presenting erythema, hyperpigmentation and excoriations in the medial aspect of ear pinnae

1176

and the interdigital skin (a, b). The same dog showing complete remission of dermatitis after

1177

6 weeks on an elimination diet (c, d)

1178

Page 36 of 41

1179

Supplementary Fig. S6. Gingival hyperplasia and papillomatosis of the perioral skin of a Pit

1180

bull terrier after 3.5 months of ciclosporin administration

1181 1182

Supplementary Fig. S7. Exfoliative superficial pyoderma in a 8-year old Poodle-cross with

1183

atopic dermatitis

1184 1185 1186

Figure legends

1187 1188

Fig. 1. Pathogenetic factors responsible for cutaneous inflammation and pruritus in dogs with

1189

atopic dermatitis and their interrelationships.

1190 1191 1192 1193 1194 1195 1196

Table 1. Diagnostic investigation for the various factors which are associated with cutaneous inflammation and pruritus in canine atopic dermatitis Factor Genetic background Sensitisation to environmental allergens Sensitisation to food allergens Inflammatory cells, cell activation, mediators Epidermal barrier dysfunction Bacterial infections Malassezia dermatitis Psychogenic factors Concurrent pruritic skin diseases

1197 1198 1199 1200

Tests available NA Intradermal test, serology for allergen-specific IgE Restriction-provocation food trial NA NA Clinical examination, cytology Clinical examination, cytology History, clinical examination Dermatologic examination, various tests

NA, non-applicable in the clinical setting

Page 37 of 41

1201 Table 2. Etiologic and symptomatic treatment modalities for the various factors which are 1202 associated with cutaneous inflammation and pruritus in canine atopic dermatitis 1203 Factor Treatment Genetic background Sensitization to environmental Etiologic: avoidance, ASIT allergens Symptomatic: antihistamines Sensitization to food allergens Etiologic: avoidance Inflammatory cells, cell Symptomatic: glucocorticoids (systemic, topical), ciclosporin, tacrolimus, activation, mediators oclacitinib, misoprostol, pentoxifylline, feline interferon-omega Epidermal barrier dysfunction Symptomatic: fatty acids (oral supplements, in the diet, topical), various topical treatments Bacterial infections Etiologic: antimicrobials (systemic, topical) Malassezia dermatitis Etiologic: antifungals (systemic, topical) Psychogenic factors Symptomatic: tricyclic antidepressants, SSRI, NMDA receptor antagonists 1204 1205 ASIT, allergen-specific immunotherapy; SSRI, specific serotonin re-uptake inhibitors; NMDA, N-methyl-D-aspartate 1206 1207 1208

Page 38 of 41

1209 1210 1211

Table 3. Efficacy of the various treatment modalities used in dogs with atopic dermatitis (in alphabetical order) Treatment Antifungals (systemic) Antifungals (topical) Antihistamines Antimicrobials (systemic) Antimicrobials (topical) Allergen-specific immunotherapy (ASIT) Avoidance of environmental allergens Avoidance of responsible foods Ciclosporin Fatty acids (in the diet) Fatty acids (oral supplements) Fatty acids (topical) Feline interferon-omega Glucocorticoids (systemic) Glucocorticoids (topical) Misoprostol N-methyl-D-aspartate receptor antagonists Oclacitinib Pentoxifylline Specific serotonin reuptake inhibitors Tacrolimus Tricyclic antidepressants Various topical treatment

Efficacy Probably high (in dogs with Malassezia dermatitis) Probably high (in dogs with Malassezia dermatitis) Nil to moderate Probably high (in dogs with pyoderma) Probably high (in dogs with pyoderma) Probably moderate to high Probably low High (in food-induced atopic dermatitis) High Unknown Low Probably low Unknown High High Moderate Probably mild to moderate High Moderate Probably low High Nil to low Variable depending on the product

1212 1213 1214

Page 39 of 41

1215

Page 40 of 41

1216

Page 41 of 41