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Dermatitis por malassezia en el perro

CANINE ATOPY
AN UPDATE ON PATHOGENESIS, DIAGNOSIS AND TREATMENT
Didier-Noël CARLOTTI, Dip ECVD


Introduction
A revised nomenclature for veterinary allergy has been proposed by Halliwell and the
members of the International Task Force on Canine Atopic Dermatitis in 2006 [Veterinary
Immunology and Immunopathology 114: 207-208].
1. Hypersensitivity: Objectively reproducible clinical signs initiated by exposure to a defined
stimulus at a dose tolerated by normal dogs 2. Allergy (allergic hypersensitivity): A hypersensitivity reaction initiated by a specific immunologic response to an allergen and mediated either by antibodies or cells 3. Non-allergic hypersensitivity: A hypersensitivity reaction initiated by non-immunologic 4. IgE-mediated allergy: A reaction involving IgE responses to allergens resulting in clinical 5. Lymphocyte mediated allergy: A reaction involving allergen-specific lymphocytes resulting in clinical signs 6. Canine atopic dermatitis: A genetically predisposed inflammatory and pruritic allergic
skin disease with characteristic clinical features associated with IgE antibodies most commonly directed against environmental allergens 7. Canine atopic-like dermatitis: An inflammatory and pruritic skin disease with clinical features identical to those seen in canine atopic dermatitis in which an IgE response to environmental or other allergens cannot be documented
The prevalence of Canine Atopic Dermatitis (CAD) is around 10 % and its incidence is
increasing, as in humans. It is likely that CAD represents around 20 % of dermatology cases
in the dog.
Aetiology and pathogenesis of CAD
The aetiology and pathogenesis of CAD are complex and combine intrinsic and extrinsic
factors.
1 – Intrinsic factors
- Genetic factors are strongly suspected because of strong breed predispositions (Sousa and
Marsella 2001). Also, it has been demonstrated that Beagle dogs can have a hereditary predisposition to produce high levels of IgE with a dominant autosomal determinism (Marsella et al, 2006). Furthermore a British study has demonstrated a high heritability of CAD in Labrador and golden retrievers (Shaw et al, 2004). - IgE play an important role (Halliwell and DeBoer, 2001): the interaction allergen-IgE can amplify the immunological response (antigen capture and attachment to Langerhans cells) and initiate inflammation by combination of IgE to allergens on mast cells and basophil surface. - Also, certain cells play a key role (including in a late phase reaction) (Hill and Olivry,  Langerhans cells and dermal dendritic cells (capture and presentation of antigens)  T helper cells, activated by these dendritic cells, particularly CD4+ Th2 cells, including Th2 cells producing cytokines i. e. interleukines (IL-4, IL-5, IL-9, IL-13). It has been shown recently that both TH1- and Th2-type as well as T regulatory cells are present in non-lesional and chronic lesional skin of atopic dogs (Schlotter et al, 2011)  B cells producing allergen-specific reaginic antibodies (IgE) when induced by  Eosinophils recruited in presence of these cytokines  Mast cells producing inflammation mediators by degranulation after IgE-mediated cross-linking, playing a key role in the early stage of the disease  Infiltration of eosinophils and neutrophils occurs between 4 an 6 hours after intradermal skin testing (IDST) and infiltration of T cells and dermal dendritic cells occurs between 6 and 24 hours (late phase reaction) (Olivry, Dunston et al, 2001; Hill, Hillier et al, 2001). Therefore patch testing could be useful in dogs. - Numerous mediators of inflammation play a role in the pathogenesis of CAD: histamine, serotonin, leukotrienes and cytokines. It is not known which mediator is the most clinically relevant and it is likely that a combination of them is responsible for the clinical signs. It is also likely that, as in its human counterpart, the paradigm Th2/Th1 (cells that counter regulate) exists in CAD: IL-4 and IL-5 (Th2 cytokines) are produced in excess in lesional skin of atopic dogs whereas IL 2 (Th1 cytokine) is more commonly found in normal skin (Olivry et al, 1999). Also, overproduction of IL-4 mRNA in lesional infiltrated lymphocytes is a Th2 response. - The relevance of epidermal dysfunction has been emphasized in human AD. There is increasing, albeit preliminary, evidence that alterations to the skin barrier play a role in CAD, be it primary or secondary to underlying inflammation (Marsella, Olivry and Carlotti, 2011).  Transepidermal water loss (TEWL) is higher in human atopic patients. This is likely to occur similarly in dogs, even in atopic skin that appears clinically unaffected. Whether this is due to a primary defect or is secondary to subclinical inflammation is unknown.  Lipid deficiency, especially of ceramides is considered an important component of atopic disease in humans and topical preparations of lipids ameliorate clinical signs. Levels of ceramides in lesional and clinically unaffected skin of atopic dogs are significantly lower than in healthy dogs, but there are no differences in cholesterol and free fatty acids (Shimada et al, 2009). A recent study (Popa et al, 2011) showed differences in the lipid composition of the stratum corneum of normal and atopic dogs, a heterogeneous distribution of lipids and large amounts of glucosylceramides in the stratum corneum of atopic dogs (which are absent in the stratum corneum of normal dogs). Recently also an alteration of stratum corneum ceramide profiles has been shown in spontaneous canine model of atopic dermatitis (Yoon et al, 2011).  Mutations in the gene encoding for filaggrin, an important protein in the epidermal differentiation/cornification process, are thought to be a major factor for AD in humans. Filaggrin can also be reduced by Th2 cytokines. Several studies suggest a similar role of filaggrin deficiency in dogs.  In human AD there is evidence of mutations in the genes encoding for proteases and protease inhibitors, leading to increased desquamation and an impaired skin barrier. This could also occur in dogs, although identified abnormalities could reflect a primary defect or be secondary to skin inflammation.  Ultrastructural evaluation has documented abnormalities in lipid lamellae of the stratum corneum in human AD. It has been demonstrated that the stratum corneum lipid lamellae are altered in dogs (Inman et al, 2001; Piekutowska et al, 2008; Marsella et al, 2010).
Inflammation and lesions could worsen some of these defects being primary and not
secondary to CAD. The dysfunction of the skin barrier could increase allergen penetration
and increase risk for allergic sensitization, in a vicious circle. Marsella (2009) has
proposed that the paradigm of CAD as primarily due to immunologic aberration
("inside/outside") should be shifted to include a primary defect in barrier function
("outside/inside"). However, it is ultimately the demonstration of meaningful clinical
improvement in well-conducted trials that will confirm whether or not the approach of
correcting the barrier dysfunction, if present, is valid.

2 – Extrinsic factors
- Numerous environmental allergens are considered to be responsible for CAD: seasonal
allergens (grass, weed or tree pollens) and non seasonal allergens (house dust mites, storage mites, danders, moulds and even fabrics or insects other than flea). Many studies have been performed but comparisons are difficult. House dust mites and epidermal antigens seem to be important in both North America and Europe whereas pollen and mould antigens appear to be of major importance in North America but of minor importance in Europe (Carlotti and Costargent, 1994, Hill and DeBoer, 2001). Amongst house dust mites, Dermatophagoides farinae is much more important than Dermatophagoides pteronyssinus despite of certain cross-reactivity. About 50 to 80% of atopic dogs are sensitized to D. farinae. In fact atopic dogs do not recognize allergens which are important for man (Der f 1, Der f 2 and Der p 1, Der p 2, respectively) but a 98/109 kDa polypeptide, a chitinase, Der f 15 (Noli et al, 1996; Mc Call et al, 2000; Nuttal et al, 2001; Nuttal et al, 2002). Recently a new major allergen has been identified: Der f 18 (Weber et al, 2003). Dogs with CAD can be sensitized to storage mites but this could be due to cross-reactivity with house dust mites, since exclusive sensitization to storage mites is rare (Bensignor and Carlotti, 2002). Studies on pollen major allergens for dogs have been done only with the Japanese cedar, Cryptomeria japonica: dogs recognize EP-5 of Cry j 1, whereas man recognizes EP-1 (Sakaguchi 2001). The allergens penetrate the organism percutaneously as well as via the respiratory and digestive routes. The percutaneous route predominates (Marsella et al, 2006). House dust mites and their allergens can be found around dogs and on their skin and hair as well (Glass et al, 2003; Jackson et al, 2005). - In dogs as in human beings, atopic dermatitis promotes the development of staphylococcal or Malassezia infections via several mechanisms (DeBoer and Marsella, 2001). Staphylococci, particularly Staphylococcus [pseud]intermedius, colonize easily the skin of atopic dogs where they are more numerous and more adherent (Mason and Lloyd, 1989; McEwan, 2000; McEwan et al, 2006), particularly in those that display a high level of pruritus (Simou et al, 2005). Atopic dogs, as human atopics, could be lacking of antimicrobial peptides or AMP (cathelicidins, beta-defensins) and this could contribute to microbial colonization. Recent results provide evidence for a possible defect in the innate immune response of dogs with CAD (van Damme et al, 2009) (although more recent preliminary results do not suggest this – Torres S et al, Comparative expression of antimicrobial peptides in lesional and non-lesional skin of dogs with atopic dermatitis – abstract in Vet Dermatol 2011; 22: 289). Atopic dogs are commonly affected with staphylococcal Staphylococcus [pseud]intermedius and Malassezia pachydermatis), which contribute to inflammation and pruritus. The pathogenesis of bacterial overgrowth or BOG (action of the bacteria) is in fact poorly known. Low levels of anti-staphylococcal IgE exclude a hypersensitivity process but high levels of IgG suggest that the affected animals have experienced a staphylococcal infection (Pin et al, 2006). There is evidence from an experimental model of canine cutaneous type I hypersensitivity that injection of a mast cell degranulator or histamine intradermally renders the overlying epidermis more permeable to bacterial antigens (Mason and Lloyd, 1990). Bacterial toxins can have an allergic role and can act as superantigens triggering non-specific inflammatory reactions. An important phenomenon to be considered in BOG is quorum sensing: when a certain density level of staphylococci is exceeded, they express particular characteristics and switch their metabolism from cell proliferation to toxin production. Malassezia pachydermatitis can contribute to the inflammatory process via non-specific mechanisms (e.g. alteration in mediator release) but also by specific hypersensitivity reactions (Morris et al, 1998). Some major allergens of Malassezia pachydermatis have been identified (Chen et al, 2002). Indeed, microbial infections can trigger and perpetuate clinical signs of CAD and also promote immunological reactions triggering the allergic process. - Several studies demonstrate clearly that CAD predispose to flea allergy dermatitis (FAD), a common disease in developed countries (but the opposite is not true) (Sousa and Halliwell, 2001). One third of atopic dogs will become sensitive to flea bites in their life and develop FAD and 4 out of 5 dogs suffering from FAD are atopic. Also, dogs with CAD are almost four times more likely to suffer from FAD than dogs not affected with CAD (Carlotti and Costargent, 1994). - Around 40% of atopic children are simultaneously affected with food allergy (Sampson, 1999). There is obviously a clinical overlap in dogs: some cases of clinically defined CAD will respond to an elimination diet whereas there are pruritic dermatoses other than CAD which will do the same. Clinicians will say that food allergy can mimic CAD (linked to aeroallergens) or that food allergy can be a cause of CAD. The International Task Force on Canine Atopic Dermatitis supports the concept that cutaneous adverse food reactions (food allergies) might manifest as atopic dermatitis in some canine patients, or, in other words, that food components might trigger flares of atopic dermatitis in dogs hypersensitive to such allergens (Olivry et al, 2007). In other words, CAD being a clinical diagnosis, there are cases of food-induced CAD and cases of non-food-induced CAD, which include CAD sensu stricto and atopic-like dermatitis (Favrot et al, 2010). In clinical practice every dog diagnosed with nonseasonal (i.e. perennial) atopic dermatitis should undergo one or more dietary restriction-provocation challenges (i.e. "elimination diets") (Olivry et al, 2007).  According to Loeffler et al (2006) 40% of adverse food reaction cases have a CAD  According to Picco et al (2008), amongst cases of allergic skin disease, 71% are CAD sensu stricto, 25% are adverse food reactions and 4% are complex.  According to Favrot et al (2010) 23% of CAD cases are food-induced.
Threshold phenomenon and summation of effects (Marsella and Sousa, 2001)
1 – Threshold phenomenon: a certain allergic load may be tolerated by an individual without
any disease manifestations, but a small increase in that load may push the individual over the
threshold and initiate clinical signs (PJ Ihrke – dermatology course – School of veterinary
medicine, UC Davis, 1982).

2 – Summation of effects: Concomitant diseases fostering pruritus may raise an animal
above its pruritic threshold. Therefore, all factors contributing to pruritus must be
investigated: i. e., a subclinical allergy in combination with a flea infestation or a mild
pyoderma may produce marked discomfort while either condition on its own might be
asymptomatic (PJ Ihrke – dermatology course – School of veterinary medicine, UC Davis,
1982).
Epidemiology of CAD (Hillier and Griffin, 2001; Zur et al, 2002; Picco et al, 2008; Jaeger et
al, 2010, Wilhem et al, 2011)
There is no sexual predisposition.
CAD can start in puppies but the diagnosis is most often established in the young adult.
French bulldogs and shar peis can be affected very early in life.
Many studies have been published on breed predisposition for CAD, in various regions of the
world. Comparisons with populations of healthy dogs in the same areas are obviously
mandatory. There are variations depending on the time of the study. A few breeds seem to be
highly predisposed: boxer, Labrador retriever, golden retriever, West Highland white terrier
and German shepherd in some areas. We believe nowadays that some brachycephalic breeds
(e.g. French bulldog, shih tzus) and the shar pei are also commonly affected. Variations of
clinical presentation may also vary in function of breeds. For instance, Beagle, Jack Russel
terriers and French bulldog are prone to develop otitis externa, and dorso-lumbar involvement
occurs in French bulldogs and shar peis.
Clinical signs and diagnosis of CAD
Griffin and DeBoer wrote in 2001: "because there is no definitive, certain way to diagnose
CAD, the true spectrum of clinical signs of atopy and CAD is better viewed as not known
with certainty". This is obviously in contradiction with the definition of CAD (see
introduction above)… and with the following criteria!
The criteria set out by T. Willemse (1986) have been unanimously accepted to establish the
diagnosis of canine atopic dermatitis. They have been revised in 1997. A revision has also
been proposed by Prélaud in 1998. C. Griffin (1993) and other authors in the early 90's,
thought that the demonstration of in vivo or in vitro sensitization is an important criterion for
the diagnosis and treatment of CAD even if the diagnosis is mainly clinical. They argued that
this is not the case for man, but if the two diseases have common points, they are not
identical. In 2010, Favrot et al published new criteria, considered nowadays as the best ones
by the ITFCAD (International Task Force on Canine Atopic Dermatitis).
1 – GRIFFIN's criteria (1993)
Suggestive:
- History and physical examination findings
- Pruritus should be present in areas other than the dorsolumbar region
Compatible:
- Pruritus in one or more of the following regions : face, paw, extensor tarsus, flexor carpus,
flexor elbow, axilla, pinna
- Effective antibiotic therapy markedly improves the lesions so that involved areas show only
secondary evidence of pruritus
Tentative:
- Compatible plus
- Exclusion of the major differentials : flea allergy dermatitis, food allergy, scabies, pruritic
pyoderma, insect hypersensitivity, keratinization disorder
Definitive:
- Tentative plus
- A positive intradermal test to one or more noninsect aeroallergens (however, by this
criterion atopic disease cannot be confirmed in 10% to 18% of dogs with a tentative
diagnosis)
2 - WILLEMSE's revised criteria (1986 and REEDY, MILLER and WILLEMSE, 1997)
Dogs are considered to be atopic if they meet at least three of the major and three of the minor
features.
Major features:
- Pruritus
- Facial or digital involvement
- Lichenification of the flexor surface of the tarsal joint or the extensor surface of the carpal
joint
- A chronic or chronically-relapsing dermatitis
- An individual or family history of atopy
- A breed predisposition.
Minor features:
- Onset of symptoms before the age of three years
- Immediate skin test reactivity to inhalant allergens
- Elevated serum concentrations of allergen-specific IgGd
- Elevated serum concentrations of allergen-specific IgE
- Xerosis
- Recurrent superficial staphyloccocal pyoderma
- Recurrent Malassezia infection
- Recurrent bilateral otitis externa
- Bilateral recurrent conjunctivitis
- Facial erythema and cheilitis
- Sweating.
3 - PRELAUD et al' criteria (1998)
At least 3 of the following major criteria should be present:
- Onset of first clinical signs between 6 months and 3 years of age
- Corticosteroid responsive pruritus
- Anterior interdigital erythematous bilateral pododermatitis
- Erythema of the concave aspect of the ear pinnae
- Cheilitis
Minor criteria (non-validated, suggestive) :
- Breed predilection or familial predisposition
- Chronic or recurrent dermatitis lasting for more than 2 years
- Dull coat
- Lesions of the fold of the stifle
- Acral lick dermatitis
- Hyperhidrosis
- History of urticaria or angioedema
- Seasonal worsening of symptoms
- Worsening when the dog walks in grass
4 - Favrot et al' criteria (2010)
The authors propose the following criteria as a screening test in practice:
- Age at onset < 3 years
- Mostly indoor
- Pruritus sine material at onset
- Affected front feet
- Affected ear pinnae
- Non-affected ear margins
- Non-affected dorso-lumber area
Five positive criteria are sufficient to get a sensitivity of 77% and a specifity of 83% (with 6
positive criteria, sensitivity decreases to 42% but specificity increases to 94 %). The authors
emphasize that this set of criteria should be used after exclusion of ectoparasites (appropriate
test and/or treatment), bacterial and fungal diseases.
The use of these criteria has been recommended by the ITFCAD (Olivry, 2010).

Treatment of CAD
Treatment of dermatoses which are related or secondary to atopic dermatitis (Olivry,
DeBoer et al, 2010)
1 – Treatment of microbial infections: an adequate antibacterial treatment regimen of
secondary pyoderma, based upon systemic antibiotics and appropriate antibacterial topicals,
may return the animal to a quasi-normal state. Such a case of CAD will only be treated in
cases of regular reoccurrence of pyoderma and/or if the clinical signs of CAD itself become a
concern. Also, some atopic dogs will respond to a well carried out antibiotic treatment, even
without visible signs of secondary pyoderma (Mueller and Bettenay, 1996). A true bacterial
overgrowth (BOG) syndrome is plausible in such cases and the author treats with antibiotics
patients showing an abundant cocoid surface flora after cytological tests, as an empiric
therapeutic test.
The same reasoning is undoubtedly applicable as well to cases of Malassezia dermatitis.
Systemic (ketoconazole) and topical therapy are required with a careful follow-up.

2 – Treatment of FAD: A well conducted flea control regimen can eliminate the FAD and
therefore, in certain cases can enable the animal to fall under its pruritic threshold. In such a
case, atopic dermatitis treatment is not necessary if the clinical signs are not obvious. If this
not the case, the atopic dermatitis should be treated while maintaining absolute antiparasitic
treatment.

3 – Management of food reactions: As discussed above, food intolerance may resemble
CAD and a food elimination diet and the eviction of an offending food are relatively easy to
perform.

4 – Treatment of keratoseborrhoeic skin disease: A keratoseborrhoeic disorder can occur in
CAD particularly in ancient cases. Treatment is mainly topical although systemic Essential
Fatty Acids, used in the treatment of CAD may have an effect on seborrhoea. Shampoos and
moisturizing agents are valuable supporting therapy in keratoseborrhoeic skin disorders.

5 – Treatment of otitis externa: Otitis externa is a major feature of canine atopic dermatitis
which causes inflammation of the external ear canal and ear pinnae. Secondary infections
occur (bacterial and fungal) and perpetuating factors such as hyperplasia of epidermis and
both sebaceous and apocrine glands lead to chronicity. It is typically erythemato-ceruminous
at the beginning of the disease and it becomes eventually suppurative. The associated lesions
of the ear pinnae (lichenification, alopecia, crusting) require therapy. Ear cleansing must be
repeated regularly (eg twice or three times a week). Numerous commercial otic preparations
are available which are usually easy to use and effective. They contain active substances such
as antibiotic, antifungal and corticosteroid agents. Selection must be made after performing a
smear and bacterial culture and sensitivity testing if the smear shows rods and/or if the otitis is
suppurative. Corticosteroids included in otic preparations reduce pruritus, pain and
proliferative reactions. They also decrease cerumen secretion. Systemic antibiotic therapy is
often useful in otitis externa due to CAD, particularly if it is suppurative, because of
associated otitis media. Surgical therapy can be avoided in many circumstances with
appropriate medical therapy. Surgical failure is often due to failure to recognise and control
CAD.

6 – Treatment of pyotraumatic dermatitis: Lesions of pyotraumatic dermatitis are common
in CAD. They are poorly understood. They should be differentiated from pyotraumatic
folliculitis. Although there may be a spontaneous healing in a few days, treatment is
beneficial. Clipping and cleansing with antiseptic shampoos can be followed by the
application of creams containing antibiotics and corticosteroids. If pruritus or above all pain is
important, a short systemic glucocorticoid treatment is useful.

Specific treatment
1 – Allergenic eviction (Olivry, DeBoer et al, 2010): Allergenic eviction is "theoretically" the
ideal treatment for all cases of allergic dermatitis. Totally avoiding the allergen may enable
the animal to fall beneath its pruritic threshold, identical in this instance to the allergic
threshold. This avoidance is illusive in the case of pollens. However, it is possible to eliminate
environmental feathers and fabrics, and moulds can be destroyed by antiseptic or antifungal
sprays or even anti-mould paint. However, the role of these allergens in dogs' atopic
dermatitis is minimal and moreover feathers and fabrics are mostly sources of house dust mite
allergen.
Various methods exist to fight against house dust mites and these may be tried around atopic
dogs : elimination of furnishing fabrics, carpets, curtains, cushions etc, frequent vacuuming
with a High Efficiency Particle Air filter vacuum cleaner which will not leave mites' particles
suspended in the air, use of air dehydration and purification devices, use of acaricide sprays
and foggers (some of which contain an Insect Growth Regulator [IGR] and a denaturing agent
such as tannic acid which is very efficient for both mites' faeces and fungal spores), use of
anti-mite mural paints (also anti-insect and anti-mould), use of cushions and covers which can
be washed at high temperatures as beds for dogs, and use of protection covers produced for
asthmatics if necessary (e.g. made of teflon, though these are expensive). The elimination of
house dust mites may be effective in human atopic dermatitis but only one preliminary study
has been published in canine dermatology, showing good efficacy (Swinnen and Vroom,
2004).
2 – Allergen Specific Immunotherapy (Griffin and Hillier, 2001; Olivry, Foster et al, 2010,
Olivry, DeBoer et al, 2010): specific immunotherapy (hyposensitisation, desensitisation) has
been used in humans, since the beginning of the 20th century, to treat asthma and allergic
rhinitis but never in dermatology (it is also used in cases of hypersensitivity to hymenoptera
bites). It first was reported in dogs in the 40s, expanded in North America in the 60s and in
Europe in the 1980s. The first explanation for desensitisation efficacy in man was in the
production of blocking antibodies (lgG), which combine with allergens before they combine
with the IgE. Later, many mechanisms have been proposed. In brief, the intervention of other
anti IgE anti-bodies (IgG anti IgE, anti-idiotype anti-bodies) has been proposed as well as
allergen-specific IgG immune complex which regulate the immune response. In the same
way, acting on Th2-Th1 substitution will lead to a reduction in the IL4 production and an
increase in the INF-gamma production. The IL4 offers potential for the IgE synthesis,
increases the number of weak affinity IgE receptors or their CD23 soluble form. The INF-
gamma inhibits IgE synthesis. Late phase reaction inhibition in desensitized subjects is
accompanied by the apparition of T-lymphocytes with a Th1 profile (Shida et al, 2004).
Finally, desensitization may be accompanied by a cellular and tissue hyposensitisation by
reducing the basophilic reactivity, blocking the eosinophilic migration, reducing the
neutrophils' chemotactic activity and abolishing the cytotoxic activity of platelets, among
others. Recently, the role of blocking antibodies has been confirmed (Hou et al, 2008). Also,
immunotherapy has been shown to decrease significantly serum IgE levels over a 1-year
treatment period for specific allergens and increasing Treg populations likely play a
significant role in the success of this particular type of therapy (Keppel et al, 2008). These
mechanisms can sequentially intervene and differ between the induction and maintenance
phases. It is reasonable to think that no single mechanism can explain the dog's
immunotherapy efficacy.
The choice of allergens mainly depends on the in vivo or in vitro test results. Skin tests
represent the reference to identify the responsible allergens if they are correctly carried out.
Skin-tests must be performed in the fall if pruritus is seasonal or anytime if it is non seasonal. The patient must withdraw from antihistamines for 10 days and from oral steroids for at least 3 weeks. Long acting steroid injections contra-indicate skin-testing for at least 6 weeks. The patient is restrained in lateral recumbancy (rarely, a non-histamine releasing anaesthesia is needed and acceptable). Gentle clipping is performed on the thorax. Then 0.02 to 0.05 ml of each allergen and control is injected intradermally. Selection of allergens is essential. The allergens used by the author are listed in table 1. There could be a cross reactivity between storage mites extracts and Dermatophagoides sp. extracts. As grasses have a strong antigenic relationship, the use of a mixture of grass pollen extracts is acceptable (the only possible exception being Agropyrum sp., i.e. couch-grass). Table 1 : Control solutions and allergenic extracts used by the author Positive control Histamine phosphate monohydrate (1/10000 = 0.01% w/v of histamine base) to confirm that the animal reacts normally to a mediator of inflammation. Negative control The allergen solvent Non-seasonal allergens moulds (mixture) Alternaria alternata Cladosporium cladosporoides Dermatophagoides farinae house dust mites Dermatophagoides pteronyssinus Acarus siro Tyrophagus putrescentiae storage mites Lepidoglyphus destructor Euroglyphus maynei dog dander cat dander mixed feathers (chicken, goose, duck) cockroach whole flea extract (Ctenocephalides felis) Malassezia pachydermatis Seasonal allergens Grasses : Agrostis stolonifera (marsh bent-grass) Anthoxanthum odoratum (sweet vernal-grass) Lolium perenne (perennial rye-grass) Dactylis glomerata (cock's-foot) Festuca rubra (red fescue) Poa pratensis (smooth meadow grass) Holcus lanatus (Yorshire fog or velvet grass) Arrhenaterum elatius (common false oat) Phleum pratense (thimothy) Cynodon dactylon (bermuda grass)
Agropyrum repens (couch-grass)
Grass pollen mixture (Anthoxanthum, Cynodon, Dactylis, Holcus and Phleum)
Mixed cereal pollens (oat, wheat, barley, rye)
Trees :
Corylus avellana (hazel)
Ulmus americana (elm)
Populus alba (poplar)
Salix viminalis (willow)
Robina pseudoacacia (false acacia)
Quercus robur (common oak)
Fagus silvatica (beech)
Fraxinus sp. (ash)
Alnus glutinosa (alder)
Betula sp. (birch)
Pinus nigra (the Austrian black pine, in default of Pinus maritima, the maritime pine, or
Landes pine)
Weeds :
Solidago virgaurea (goldenrod)
Chenopodium album (lamb's quarter)
Ambrosia sp. (ragweed)
Parietaria officinalis (pellitory)
Taraxacum officinale (dandelion)
Artemisia vulgaris (mugwort)
Chrysanthemum leucanthemum (white ox-eye)
Rumex acetosella (sheep sorrel)
Urtica dioica (nettle)
Plantago lanceolata (English plantain)
Presentation, preservation and standardisation of allergenic extracts are explained in table 2.
Presentation: The allergens are sold commercially as concentrates to be diluted or ready for
use which is more convenient but a little more expensive as the shelf-life is shorter.
Preservation: The allergens are preserved by the addition of glycerine or phenol. The
concentration of glycerine in the injected extract must not exceed 0.5% to avoid skin irritation
and false-positive reactions (in man, the concentration used is higher and causes no problem).
The concentration of phenol in a ready-to-use extract is 0.5%.
Standardisation: Standardisation of allergenic extracts is an area in which there is some
confusion. The principal units used are as follows:
- PNU (Protein Nitrogen Unit) per ml: a measure of the amount of protein nitrogen in the
extract (6-8 g protein nitrogen = 100,000 PNU) (American laboratories, e.g. Greer).
- Weight/volume or w/v.
- Noon units (NU) per ml.
These two units are measures of the quantity of extract found in a given volume of liquid (e.g.
ARTU Laboratories, The Netherlands).
- Biological Activity Units: units derived only by biological standardisation in vivo or in vitro
(in man), and variable depending on the laboratories.
- Index of Reactivity (IR) per ml measured using the prick test and by default, Index of
Concentration (IC) per ml which is a calibration index defined by comparison to IR
(Stallergènes Laboratories, France)
- Allergenic Units (AU) per ml, based on nasal provocation tests and U per ml based on
therapeutical efficacy/safety ratio.
North American veterinary dermatologists principally use extracts standardised in PNU/ml
(generally 1000 PNU/ml but allergens believed to be irritant, such as house dust and wool, are
diluted further) and in w/v (generally at 0.1 to 10%).
In Europe, veterinary dermatologists use extracts standardised in w/v (generally 0.1 to 1.0%),
in NU/ml (generally 1000 NU/ml), in IR or IC/ml (10 IR or IC/ml) or in AU or U/ml (1000
AU or U/ml).
Reactions are read after 15 to 20 minutes and graded from + 1 (5 mm) to + 4 (20 mm) based
on size and thickness of the wheal plus degree of erythema (which must be visible). A
positive reaction is determined as follows:
A ≥ H+C
2
A = diameter of reaction to the allergenic extract
H = diameter of the positive control
C = diameter of the negative control
The reaction to flea extract at 48h appears in dogs as a thickening of the skin or a papule,
sometimes covered with crusts.
It is important to realize that a positive intradermal skin test is only an indication that an
animal has skin-sensitizing antibodies and does not necessarily imply that the dermatological
problem is due to atopic disease. Skin tests should always be interpreted in the light of the
animal's history and clinical signs.
False negative and false positive reactions can occur with skin-testing.
False negative results can be due to:
- injection of air - too small volume injected - subcutaneous injection - too late reading (later than 20 minutes) - use of antihistamines or glucocorticoids (or even progestational compounds) - outdated extracts - nonpotent allergenic extracts (too diluted or inappropriate mixture) - off-season testing. False positive results can be due to: - too large volume injected - irritant allergenic extracts (e.g. improper dilution) - contaminated extracts - improper interpretation - sensitisation as a result of repeated skin-tests - scabies - dermographism A large number of in vitro tests is available in commercial laboratories. Valid tests are proposed for the diagnosis of flea allergy dermatitis and identification of offending aeroallergens in atopic dogs but tests for food allergy, staphylococcal or Malassezia "hypersensitivity" are invalid and unreliable. The ELISA (Enzyme-Linked Immuno-Sorbent Assay) serological diagnosis is attractive due to its simplicity. It is used to assay the allergen-specific IgE in a patient's serum, using anti-IgE antibodies. The monoclonal and polyclonal anti-bodies' respective interest has still to be determined. Polyclonal antibodies can have superior values but if several monoclonal anti-bodies are used grouped, good results can be achieved (Lee et al, 2009). In fact, some dogs' anti-IgE sera recognise both IgE and IgG. An innovative technique using human specific IgE receptors (FcR1), instead of anti-IgE serum, has been proposed. This test detects only IgE, without cross-reactions with IgG. It is applicable to flea saliva allergens and aeroallergens, with also good overall correlation with skin test which allows good sensitivity, specifity, positive and negative predictive values. There is a moderate intra and interlaboratory variability of this test (Thom et al, 2010). However, in a recent study done in West Highland white terriers, positive ELISA results in nonatopic dogs were statistically significantly higher than those in atopic dogs for a large majority of allergens, including D. farinae and D. pteronyssinus. The authors concluded that positive allergen-specific IgE ELISAs were not specific for CAD, and high allergen-specific IgE levels were seen in nonatopic dogs. The significance of this and whether it characterizes a protective phenotype is unclear (Roque et al, 2011). Correlation with skin-testing, considered arbitrarily as the gold standard has been evaluated in several studies. Specificity (rare false positives) and sensitivity (rare false negatives) are very variable. Each laboratory gives results which are based on arbitrary threshold of positivity. This threshold has been carefully established by reliable companies, but in contrast if it is too low, sensitivity is so high that specificity and positive predictive value are very low, which renders the test void. So the reliability of many tests is doubtful as demonstrated in several studies. However some laboratories using monoclonal antibodies or mixed monoclonal antibodies report good overall correlation with skin tests. In the recent studies in West Highland white terriers, there was poor agreement between the allergen-specific serology and the intradermal tests. There is also controversy about the ability to reproduce the tests. However, is complete correlation necessary? The tests evaluate reaginic antibodies in the skin in one case and in the serum in the other (correlation perhaps does not always exist). Also, there may be different types of IgE and eventually different sensitivities for different allergens. In-practice screening tests to differentiate allergic from non-allergic dogs are controversial. They are useless in dogs with clear clinical signs, do not replace a complete testing and add an extra cost. However they might be helpful in doubtful cases and could also convince some reluctant owners to go further in the allergic diagnosis, when positive. Contrary to skin-testing, conventional and FcR1-based ELISA testing can be performed in animal with severe cutaneous lesions and in animals previously treated with antihistamines or above all glucocorticoids, at least for short-term treatment. Test results are to be interpreted in an anamnesis and clinical light in each of the cases. A (good) test means ONLY that the animal has developped specific IgE towards allergens. It does not mean that the clinical signs are linked to this sensitization. Indeed the clinical signs must be compatible with Flea Allergy Dermatitis and/or Atopic Dermatitis to take in account positive tests. In addition, in case of positive reactions, allergens should be included in an immunotherapy protocol only if they are present in the environment (however cat dander can in fact be transported through the air or by people). No standardisation exists for the ASIT methods used. Only aqueous extracts are used in North America, whereas in Europe, mainly alum precipitated extracts are available. It seems that the combination of moulds and pollen extracts alters their quality (due to the presence of protease in the mould extracts) and that different types of vials are necessary. Immunotherapy is efficient in man as testified in the results obtained in allergic rhinitis. The results are more or less difficult to evaluate in dogs. In fact, they depend on the animals (age and especially diagnostic criteria), evaluation criteria (telephone follow-up, clinical score), follow-up duration, and recognition or not of "loss of follow-up" as setbacks. Presently, it is considered that 50 to 80 % of animals respond to immunotherapy in open studies (Griffin and Hillier, 2001; Zur et al, 2002). T. Willemse demonstrated in 1984 the method's efficacy through a double blind placebo controlled study. The 9-month evaluation seems important: it is usual that improvement at this stage is followed by success. The result variation factors are (apart from the diagnostic value and the clinical criteria of each one) the allergen identification method, specificity, allergens nature (Dermatophagoides spp), number of allergens, breed, age and patients' follow-up. Specificity of ASIT has been recently confirmed (Willemse et al, 2008). The use of highly purified allergens (Der f 15 and Der f 18?) could improve results. No study has yet proven that the use of corticosteroids during desensitisation would have a very harmful effect on its efficacy. It is of course impossible to confirm for all in vitro tests the same success rates in immunotherapy as the one obtained after skin-tests (i. e. 60 to 80 % of improvement). However it is likely that the best in vitro tests will give a high percentage of good results, comparable to skin testing. In addition, it is also felt that some dogs with negative skin tests or poor results to immunotherapy based on skin tests may respond well to immunotherapy based on in vitro testing. It is also possible that the combination of in vivo and in vitro tests increase success rates. Rare cases of secondary effects have been mentioned in an anecdotal manner (urticaria, angioedema, anaphylaxis). An exacerbation of clinical signs' is often noticed in the hours following injections. Limited local reactions which are spontaneously reversible often appear with alum precipitated extracts. A majority of veterinary dermatologists believe that the efficacy and absence of secondary effects justifies ad vitam eternam hyposensitization. They empirically remarked that the clinical signs reappear in a period of months to years after the treatment has been stopped. Rush immunotherapy could be effective but secondary effects occur in a fourth of the cases (Mueller and Bettenay, 2001). Oral or sublingual immunotherapy is likely to be safe and preliminary data suggest that this technique should be evaluated in dogs with CAD (Marsella,
2010; DeBoer et al, Changes in mite-specific IgE and IgG levels during sublingual
immunotherapy (SLIT) in dust mite-sensitive dogs with atopic dermatitis, abstract in Vet
Dermatol 2010; 21: 531-2).
Symptomatic treatment (Olivry et al, 2003; Olivry, Foster et al, 2010, Olivry, DeBoer et al,
2010)
This is useful at the beginning of immunotherapy (within the first year in successful cases) or
on a long-term basis in failed cases (total or partial), or even in cases where immunotherapy is
not required (aged animal, owner's hesitation or even, clinically slightly worrying cases apart
from a few signs). Symptomatic therapy is also indicated for canine atopic-like dermatitis.
1 – Glucocorticoids
Corticosteroids are the most effective medications amongst the symptomatic treatment of
allergic dermatitis. They have anti-inflammatory and antipruritic properties as well as
antiproliferative and immunosuppressive effects. They act at almost all inflammation and
immunologic response stages. Their activity, however, varies tremendously. There is no
consistency in the individual reaction not only in relation to the corticosteroid used but also
for the same corticosteroid. The effect is reduced over time, and the doses required are
increased. They are used topically or systemically.
Topical glucocorticoid ointments, creams and gels are useful in veterinary dermatology and perhaps have been neglected. These formulations are useful for localised lesions (e. g. cheilitis, blepharitis, pododermatitis, nasal lesions, excoriations and pyotraumatic dermatitis). Many molecules are available in human dermatology, classified from class I (the least potent) to class IV (the most potent). Some potent human formulations can be used in the dog (e.g. clobetasol propionate); most of the traditional veterinary formulations are in fact combined with antimicrobials and contain less potent agents. Tachyphylaxis, atrophy and microbial infections can occur in case of overuse. Glucocorticoids are also available in lotions, rinses, sprays and even shampoos. Small spray containers are used to treat localized lesions, as creams and ointments. Several glucocorticoids are available, usually not the most potent. Large spray containers (e.g. triamcinolone) can be very useful to treat generalized conditions. Shampoos containing 1% hydrocortisone or 0.01% fluocinolone are available in North America. A new class of glucocorticoids, the diesters, is used in human dermatology and one of them, hydrocortisone aceponate, is now available as a medium-sized spray in canine dermatology. Diesters are lipophilic compounds that quickly penetrate the stratum corneum and are stored and metabolised within the skin after topical application. They are first activated in the epidermis by skin esterases, producing high anti-inflammatory activity. Further ester group removal inside the skin structures deactivates them to produce simple hydrocortisone, eliminated by systemic route in the same way as natural endogenous cortisol at low dose with a negligible bioavailability (reduced systemic secondary effects). They have consequently a high therapeutic index. Cortavance® has been demonstrated to be effective in the treatment of CAD (Nuttal et al, 2009) and recently was found as effective as systemic cyclosporine (Nuttal et al, 2011). Systemic glucocorticoid therapy should be limited to the oral administration of prednisolone or methyl-prednisolone (0.5 to 1 mg/kg/day during 5 to 7 days followed by 1 mg/kg every other day, as shortly as possible). Systemic corticosteroids have significant side effects including polyuria-polydipsia, polyphagia, hepatomegaly, inhibition of the hypothalamo-hypophyso-adrenal axis, dryness of the skin and the hair coat, and even iatrogenic Cushing's syndrome with alopecia. Secondary infections (pyoderma, demodicosis, dermatophytosis) can occur. The following rules must be respected: use them as little as possible (during flares), use the lowest dose possible, only if alternative anti-pruritic medications have been deemed inefficient, and on mid-term in association with other treatment with a sparing effect. 2 - Non steroidal topicals
Various non-steroidal topicals can be used. Non-steroidal antipruritic sprays or rinses, e.g.
containing pramoxine, colloidal oatmeal or aloe vera can be useful. A spray containing
Hamamelis extract and menthol has become popular to treat localized lesions and has been
shown to kill Malassezia. Two micro-emulsion lotions/sprays have been developed to
complement shampoos specifically designed for canine atopic dermatitis (see below). One
contains mono and oligosaccharides (free and in Spherulites®), vitamin E and linoleic acid,
the other (available also in concentrate) contains phytosphingosine (see below), hinokitiol (=
β-thujaplicin, antimicrobial and anti-inflammatory) and essential fatty acids from raspberry
seed oil. Tacrolimus, a calcineurin inhibitor with immunomodulatory properties has been
shown to be effective in the treatment of localized lesions of canine atopic dermatitis.
All shampoos are likely to remove allergens from the skin, which is believed to be helpful in
canine atopic dermatitis. They also help to rehydrate dry skin. Anti-seborrhoeic shampoos and
humectant sprays may be used to treat xerosis. All shampoos containing fatty acids can help
in allergic skin disorders. Shampoos with an antipruritic effect (2% diphenhydramine,
colloidal oatmeal) can be good adjunctive treatments. A micro-emulsion shampoo specifically
designed for canine atopic dermatitis contains linoleic acid and gamma linolenic acid, mono
and oligosaccharides, vitamin E, and piroctone olamine and has been shown to be useful. In
fact, exogenous monosaccharides inhibit the lectin activities of cytokines by combining to
and masking the cell membrane antigens/receptors and so downregulating the cell-to-cell
alarm cascade in the skin. This inhibits the secretion of pro-inflammatory cytokines by
activated keratinocytes and suppresses the manifestations of cellular immunity in vivo. They
downregulate the inflammatory response to allergen challenge. This is why they are used in
topical products for atopic/reactive skin patients in humans and are beneficial in animal with
allergic skin disease. In a published double-blinded, randomized, placebo-controlled study in
22 dogs, the short term efficacy of Allermyl® shampoo and whirlpooling was demonstrated
in the treatment of canine pruritus (Löflath et al, 2077). Another shampoo containing
phytosphingosine, hinokitiol and raspberry seed oil in an hydrating formulation has also been
shown to be beneficial in atopic dermatitis, in association with the corresponding spray (see
above), in a comparative study with the previous one.
As stated above, it is ultimately the demonstration of meaningful clinical improvement in
well-conducted trials that will confirm whether or not the approach of correcting the barrier
dysfunction, if present, is valid. In the study by Piekutowska et al (2008), the topical
application of a skin lipid complex containing ceramides, free fatty acids and cholesterol in
atopic dogs stimulated the production and secretion of stratum corneum lamellar lipids. This
could contribute to the formation of an improved epidermal barrier. A recent open preliminary
clinical study confirmed that such a lipid complex could decrease significantly the CADESI
score in 8 atopic dogs (Fujimura et al, 2011). In another open preliminary study (Tretter et al,
2011), lesional improvement was seen in dogs affected with mild to moderate CAD after the
application of a spot-on (7 dogs) or a spray (7 dogs) containing essential oils and unsatured
fatty acids, while pruritus and TEWL were also significantly decreased by the spray.

3 - Antihistamines
AntiH1 antihistamines, which block H1 receptors, may be useful (antiH2 are inefficient),
although they are not effective in human atopic dermatitis. Many studies have been performed in dogs but there is insufficient evidence to conclude for or against the efficacy of antihistamines for treatment of CAD (15 to 25 % good results, close to a placebo effect). In the 2003 ITFCAD evidence-based review, the following agents were considered as having: - no or low efficacy: chlorpheniramine, pheniramine, diphenhydramine, hydroxyzine, promethazine, trimeprazine (first generation), astemizole and loratadine (second generation) - conflicting evidence of efficacy: terfenadine (second generation) - medium efficacy: clemastine, chlorpheniramine-hydroxyzine combination (first generation), oxatomide (second generation).
Perhaps the dosage of clemastine should be increased in the dog. More recently, cetirizine has
been shown to be ineffective. Moreover, some frequently used products such as ketotifene or
rupatidine have not been evaluated at all.
The relatively low success rates of these antiH1 justify successive tests during at least one
week at a time, until a satisfactory result is obtained.
Trimeprazine, which alone is inefficient, has proven to be able to clearly reduce the need for
prednisone. There is a synergic effect between the essential fatty acids and antihistamines.
Perhaps in the future the antagonists of H4 receptors could be useful. However a recent study
showed that hydroxyzine, cetirizine and two selective type-4 antihistamines were unable to
prevent the development of Dermatophagoides farinae-induced skin lesions in mite-
sensitized dogs (Bäumer et al, 2011).
4 - Essential Fatty Acids
Essential fatty acids (EFA) have been the subject of many clinical studies in dogs, although
there are not used in human atopic dermatitis. The fatty acids that have been studied are
polyunsaturated, administered by oral route, especially omega-3 series eicosapentanoic acid
(EPA) and omega-6 series gamma linolenic acid (GLA). These fatty acids compete with the
arachidonic acid in the cascade of eicosanoids synthesis where leukotrienes and
prostaglandins are formed having an anti-inflammatory activity or at least a pro-inflammatory
activity which is much less significant than that observed with the metabolites emitted from
arachidonic acid. Oral fatty acids could also reinforce the defective cutaneous barrier of atopic
dogs.
Doses were variable and empirical in the first clinical studies (up to 2001) (Olivry, Marsella and Hillier, 2001). Amongst them there are only eight double blind placebo controlled studies, including three in cross-over. Perhaps high doses could be necessary to get a result but studies using high doses of omega-6 or omega-3 give variable results, with duration of treatment from 6 to 16 weeks. Supplementation in EFA does not take in account the intake from the diet in these studies, that can be important and only the three cross-over studies overcome this drawback but their results are variable. The omega-6/omega-3 ratio could be important according to an in vitro study and should be 5 to 10. Recent in vitro studies show that addition of omega-3 and GLA decrease the production of mediators of inflammation by mast cells. More recently (since 2001), clinical studies have been performed with specific diets or with supplements added to standard diets that show the beneficial effect of omega-3 with or without GLA. A 50 % glucocorticoid sparing effect has also been shown by one product (Saevik et al, 2004). The mechanism of action remains obscure since there is no correlation between the EFA concentrations in the skin and plasma and the clinical improvement. A sub-population of non-responsive atopic dogs is likely. In summary, the reaction of atopic dogs to fatty acids varies and there is no supplement or diet that is appropriate to all. Several tests can be made as for antihistamines. There are still doubts, on the real efficacy of EFA in CAD especially since various elements have not yet been made clear: the dosage (varying from 2 to 10 times the advised doses), minimal duration of the therapeutic test to predict efficacy (1 to 12 weeks), optimal ratio between omega-3 and omega-6 (between 5 and 10), the function of co-factors, criteria to select responder dogs, responder breeds, synergy with other anti-inflammatory agents. They are to be principally used with other anti-pruritic treatments. They have few side effects. Their action could be explained by an action on the lamellar lipids of the stratum corneum. In effect, a recent semi-quantitative electron microscopy study revealed that a 2 month treatment of atopic dogs by food supplementation with a mixture of essential fatty acids resulted in a significantly improved organization of the lamellar lipids in the lower stratum corneum, comparable to that of the healthy dogs. Again and as discussed above, whether or not such an effect would be associated with any relevant clinical benefit has not yet been proven with certainty (Popa, Pin at al, 2011). A dietary approach, based on a high quantity of omega-3 and a high ratio omega-3/omega-6 may be helpful. Diets containing increased and balanced levels of EFAs have been shown in blinded randomized studies to be effective in the management of CAD, acting on pruritus and/or CADESI, depending on the diet (Bensignor et al, 2008, Glos et al, 2008). It is likely, however, that most cases will require other forms of therapy, changing the diet being a useful adjunctive therapeutic measure. It is worth noting that some dietary constituents (a combination of pantothenate, choline, nicotinamide, histidine and inositol) could upregulate epidermal lipid synthesis, as shown in an in vitro study (Watson et al, 2006). It was also shown in this study that this combination used in vivo in healthy Labrador retrievers, when fed at supplemented concentrations, was able to significantly reduce TEWL after 9 weeks. Whether or not such an effect would be associated with any relevant clinical benefit in atopic dogs is unknown. 5 – Cyclosporine
Cyclosporine (Atopica®), an orally administered calcineurin inhibitor, is an effective drug for
the treatment of CAD, as shown in four controlled studies including two placebo controlled
double-blind studies and two showing a similar effect as prednisolone and
methylprednisolone.
In another study relapses were more common during 2 months in dogs treated with
methylprednisolone than in dogs treated with cyclosporine and lesions were less severe in the
latter (pruritus was identical). After 4 weeks of daily administration it is possible to
administer the drug only every other day in 39 % of the cases and after 12 weeks every other
day or twice a week in 22 % and 36 % of the cases respectively. In a recent study therapy was
discontinued in 6 to 24 months in 45 % of the cases because of failures (22 %) or success (24
%) without relapses over a period of 3 to 22 months. So a long-term treatment (several
months) is justified and then the treatment is stopped.
This molecule has become, despite its high cost, a very effective symptomatic treatment of
CAD, particularly in severe forms. Its efficacy is dose-dependent but the assay of its blood
level has no value since it cannot predict the clinical response. Secondary effects are limited
and are mainly gastro-intestinal, with more rarely gingival hyperplasia, verrucous lesions or
hypertrichosis. The long-term secondary effects known in man (renal insufficiency,
hypertension) have not been reported in dogs. Last but not least cyclosporine does not
enhance the risk of secondary infections.
6 – Other non steroidal systemic anti-inflammatory/antipruritic agents
- Anti-depressor and psychotropic drugs: Fluoxetine, an anti-depressive agent which inhibits serotonin uptake, doxepin and amitriptyline, tricyclic anti-depressive agents with a antiH1 activity, appear to be moderately efficient giving good results comparable to the "best" antihistamines (20 to 30 %). Dextromethorphan has no effect. - Leukotriene inhibitors have been tried in a few clinical trials and are not very effective. Zileuton and Zafirlukast, for instance, were not very effective in placebo controlled studies. - Misoprostol, a prostaglandin E analog, has shown a moderate effect, including in a randomized controlled study. - Phosphodiesterase inhibitors have shown a moderate efficacy in comparative (arophylline) or double blind placebo controlled cross-over (pentoxyfilline) studies. Arophylline is poorly tolerated. Papaverin is ineffective. - Interferons: interferons gamma and omega have shown promising effects. Various agents: an injectable formulation of fatty acid copolymers, a phytotherapy preparation of Chinese herbs (which could have a steroid-sparing affect), MS-antigen (a peptide extracted from urine of allergic humans), aminopterine (an antifolate), pentoxifylline and PUFAs and masitinib have given interesting results. Other treatments were considered as ineffective: erythromycin, doxycycline, tetracycline-niacinamide, cyproheptadine, ascorbic acid, tranilast, an homeopathic preparation, azathioprine and proanthozone, even infestation with the nematode Trichuris vulpis (Mueller et al, 2011)!
Conclusion: combination therapy case management
A complete dermatology and allergy workup is necessary to establish the diagnosis of CAD,
mainly based on clinical signs.
Long-term management of CAD is difficult. Therapy of dermatoses which are related or
secondary is essential. The hygienic and clinical value of topicals designed for canine
dermatology should be underlined, as in human dermatology.
The treatment, as for all allergic dermatoses, shall act on the pruritic threshold, by specific
immunotherapy and symptomatic treatments and can also include allergen eviction. It should
be remembered that placebo effect exists in canine medicine and is around 9 % in pruritus due
to CAD (less for lesions). This effect must be taken in account in clinical studies.
Each case is different and deserves a "combination therapy", which associates treatment of
complications, eventual allergen eviction measures, allergen-specific immunotherapy and
symptomatic therapy. It is the key to success, both to manage acute flares and chronic
symptoms. The quality of life of both the patient with CAD and the owners can be
significantly improved through an appropriate and thorough therapeutic management.
The author recommends a careful reading of the clinical practice guidelines from the
International Task Force on Canine Atopic Dermatitis (see reference below – Article free on:

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