Getting Under Skin of Canine Atopic Dermatitis Treatment

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GETTING UNDER SKIN OF CANINE ATOPIC DERMATITIS TREATMENT

Author : Vanessa Schmidt, Tim Nuttall, Neil Mcewan

Categories : Vets

Date : June 7, 2010

Vanessa Schmidt, Tim Nuttall and Neil Mcewan discuss why long-term treatment plans for this condition need to be individualised, and how controlling flare factors is a key consideration

CANINE atopic dermatitis (CAD) is a multifactorial disease. The best approach to managing this lifelong condition is a multimodal treatment plan that addresses each problem.

The plan must aim to:

• control flare factors;

• improve skin barrier function;

• provide allergen avoidance and allergen-specific immunotherapy (ASIT);

• utilise anti-inflammatory treatment; and

• tailor treatment for the individual patient.

Human and canine atopic skin is not “normal”, even when in clinical remission. Long-term, low- frequency and regular treatment (often with topical glucocorticoids) in human AD ensures flares are less frequent and severe, and more easily managed. This helps prevent chronic AD development. It is likely this approach will also help CAD.

1 / 8 Flare factors

Major flare factors in CAD are infections, ectoparasites, other hypersensitivities and environmental allergens. In humans, stress and environmental factors lower the pruritic threshold, and it is likely these play a role in CAD. Dog-appeasing pheromones, mood-modifying drugs and/or behavioural therapy may, therefore, be helpful in suitable cases. Observant owners may also identify and avoid other environmental triggers.

Infections

Recurrent staphylococcal and Malassezia dermatitis and/or otitis are common complications in CAD. The infections should be diagnosed on the basis of clinical signs, cytology and – where necessary – culture. Routinely using antibiotics to treat non-specific clinical signs is not recommended.

Using topical antimicrobial shampoos, sprays, ear cleaners and/or wipes regularly can be helpful. A contemporary review paper on the treatment of canine Malassezia dermatitis recommended topical treatment using shampoo containing miconazole nitrate and chlorhexidine gluconate. Topical antimicrobials may be drying and irritating, and may be best followed by, or alternated with, emollient products.

Systemic antimicrobial therapy is indicated for more generalised infections, or where topical therapy is not feasible. Chronically relapsing infections that cannot be controlled by treating the underlying AD, and regular topical antimicrobial therapy, may require pulse therapy. Cefalexin or amoxicillin-clavulanate are usually suitable for bacterial infections, but antibiotic sensitivity should be confirmed on culture. The appropriate dose is given every 12 hours on two to three consecutive days each week (in effect, weekend therapy).

Itraconazole or ketoconazole may be similarly used to treat Malassezia dermatitis and/or otitis. Ketoconazole, however, is not licensed in animals and itraconazole is not licensed for dogs. Azoles, particularly ketoconazole, have anti-inflammatory effects, which may complicate the treatment assessment.

Currently, no evidence recommends using serology or intradermal testing for Malassezia or staphylococci, or their inclusion into allergen immunotherapy protocols. However, if significant sensitivities are identified, it is possible that aggressive antimicrobial therapy may help reduce inflammation and pruritus.

Parasites

Canine atopic dermatitis predisposes to the development of flea-allergic dermatitis, and flea bites

2 / 8 can also act as flare factors. Therefore, a thorough flea eradication programme is recommended in all cases. The authors recommend treatment every month, as the relatively high bathing frequency in these patients may limit flea control efficacy.

Neotrombicula autumnalis is a common cause of pedal pruritus during the summer and autumn months in some areas of the UK, and may be mistaken for a seasonal pollen flare.

Sarcoptic mange is a major differential for CAD but can also be superimposed, causing a dramatic pruritus increase. We have also seen demodicosis secondary to chronic treatment of CAD with glucocorticoids.

Concurrent hypersensitivities

Dogs with CAD are also predisposed to adverse food reactions, and food allergens may also exacerbate clinical CAD signs. Therefore, to identify these patients, a strict elimination diet trial is recommended in all dogs with perennial signs.

Improve skin barrier defects

Dogs with AD have a defective cutaneous barrier, which is permeable, thus increasing transepidermal water loss, microbial colonisation and exposure to irritants and allergens. Inflammation and self trauma further degrades the skin barrier.

Two prescription diets enriched with essential fatty acids (EFAs) have been shown to reduce the clinical signs and pruritus associated with CAD in randomised, controlled trials (RCTs), although the diets are mildly to moderately efficacious (improvement in most dogs is limited to 25 to 50 per cent). These diets contain high levels of EFAs, and are also rich in pantothenate, choline, nicotinamide, histidine and inositol, which may improve the skin barrier.

Alternatively, EFA supplements may be added to the normal diet. An RCT has shown that one particular EFA supplement reduced glucocorticoid requirements in atopic dogs by approximately 50 per cent after eight to 12 weeks’ treatment. EFAs may also be synergistic with antihistamines. Proprietary preparations usually contain both omega-6 and omega-3 EFAs, although the optimum ratio is still unclear.

Regular use of emollient shampoos, conditioners and ear cleaners may also help improve the skin barrier, and remove debris, allergens and microbes. Bathing and ear cleaning should be done at least once weekly.

An RCT has shown that bathing with one micro-emulsion, hypo-allergenic, unscented shampoo, especially in whirlpool baths, significantly reduces pruritus, although the efficacy was mild to moderate in most cases. The monosaccharides in the tested product have also been shown to

3 / 8 inhibit the adherence of pathogens to corneocytes, and other ingredients may inhibit inflammatory cytokines.

Allergen avoidance

Most environmental allergens are ubiquitous and, therefore, avoidance strategies may be difficult. It is possible to significantly reduce house dust mites in the environment (especially by vacuuming, environmental flea control and washing dog beds), but little evidence exists to suggest this helps individual dogs. One open study using benzoyl benzoate showed good efficacy in atopic dogs, but meta-analyses of human studies concluded efficacy evidence was insufficient.

Allergen-specific immunotherapy

ASIT is indicated where sensitivities are identified on either intradermal testing or serology. The results’clinical significance should be evaluated using the patient’s history and geographical location.

ASIT has been found to be safe, efficacious and cost effective, resulting in at least a 50 per cent improvement in 60 to 80 per cent of dogs, although the efficacy is reduced in chronic cases. The benefits may not be appreciated for at least nine to 12 months.

Concurrent anti-inflammatory treatment is often required, and has not been proven to affect the response. Despite a lack of consensus on the relative efficacy of tests, the number or type of allergens or the ASIT protocol, it is important to tailor the protocol according to the individual’s response.

Increased pruritus or malaise usually make up the adverse effects. Injection-site reactions and anaphylaxis are rare, although most dermatologists recommend the first five injections are administered at the surgery where the patient can be monitored for 30 minutes after the treatment. If successful, treatment is usually required for life, but some dogs may eventually be weaned off.

Anti-inflammatory pharmacotherapy

• Topical glucocorticoids

Topical glucocorticoids are commonly used with emollients in human AD. Until recently, their use in CAD had been limited to focal lesions, and the potential adverse effects (including skin thinning, comedones, telangiectasia, bruising and secondary infections) limited treatment to short-term use.

Topical diester glucocorticoids avoid many of these problems: they are rapidly absorbed, have potent anti-inflammatory effects and are metabolised within the dermis, thus minimising systemic

4 / 8 and cutaneous adverse effects.

A 0.584 per cent spray formulation of hydrocortisone aceponate is licensed for dogs.

In RCTs, 55 to 75 per cent of dogs improved more than 50 per cent when the spray was used to treat pedal or generalised CAD, and coat length did not affect the outcome. Dogs should be treated once daily for one month to remission, and then the frequency can be gradually reduced for maintenance. It can also be used once daily for up to seven days to manage acute exacerbations. It appears to be safe in CAD, but it is not licensed for long-term use, and dogs should be monitored for adverse affects.

• Systemic glucocorticoids

Systemic glucocorticoids are cheap and highly effective, but due to their adverse affects, they are not ideal for long-term therapy. Ideally, they should be used as “crisis busters” for short, infrequent courses to manage flares in dogs on other treatments (usually 0.5mg/kg to 1.0mg/kg prednisolone once daily for three to five days; use methyl-prednisolone at 80 per cent of the prednisolone dose). However, they can also be used safely to treat dogs suffering from seasonal CAD.

For long-term treatment, administer prednisolone once daily at 0.5mg/kg to 1.0mg/kg to remission, and then gradually reduce the dose to the lowest every-other-day dose for maintenance. Using steroid sparing agents concurrently is recommended where possible.

Acute side effects include polyuria (PU), polydipsia (PD), polyphagia, panting and behavioural changes, and chronic side effects include signs of iatrogenic hyperadrenocorticism. Individual dogs may be more sensitive to these effects than others. Injectable medications are not recommended, as they are not easily removed following adverse effects, and they cannot be reduced to alternateday therapy.

Methylprednisolone has less mineralocorticoid effects than prednisolone, and may be useful to reduce PU/PD in some cases.

Calcineurin inhibitors

Cyclosporin is highly effective, and comparable to systemic glucocorticoids. The full response may take four to six weeks, and dose or frequency adjustments should not be made until the dog is fully in remission. Other antiinflammatory treatment may be required initially to relieve the pruritus.

Approximately onethird of dogs may remain stable on alternate – day therapy and another onethird on twice-weekly treatment. Alternatively, the once-daily dose may be adjusted. It can be effective as a single treatment, but – once again – combination therapy will help to reduce the frequency and/or dose.

5 / 8 Cyclosporin is well tolerated by most dogs. Up to 25 per cent of patients experience transient vomiting, which may be more persistent in some cases. This can be alleviated by gradual introduction, administrating with food or using gut protectants (sucralfate and cimetidine or ranitidine). Other uncommon adverse effects – which respond to reducing to the dose or stopping medication – include hirsutism, increased hair shedding, gingival hyperplasia, papillomatosis, diarrhoea, lameness and muscle tremors.

Nephropathy and hypertension have not been seen, and an association with lymphoma in dogs has not been found.

Cyclosporin metabolism is decreased by ketoconazole, diltiazem and erythromycin, increased by phenobarbitone and rifampin, and may enhance ivermectin’s effects and, therefore, the possibility of adverse effects. Data sheets recommend stopping cyclosporin for two weeks before and after routine vaccinations – during which time dogs may be managed with glucocorticoids.

In human AD, 0.1 per cent tacrolimus is very effective. Two RCTs have shown it is effective for localised CAD on non-haired skin when used twice daily until remission, and then reducing the frequency. Human patients report a mild burning sensation after application, and this may also occur in dogs. Tacrolimus is not licensed for animals.

Chinese herbal therapy

A proprietary blend of standardised plant extracts (Rehmannia glutinosa, Paeonia lactiflora and Glycyrrhiza uralensis) with anti-inflammatory properties is available. It is well tolerated and palatable for most dogs, although diarrhoea may be seen. The efficacy is mild to moderate, but a contemporaneous RCT demonstrated a 50 per cent reduction in methyl-prednisolone requirements in treated dogs after four to eight weeks.

Antihistamines

Antihistamines are better suited to dogs with mild disease, and are best used as daily preventive treatments. There is fair evidence of medium efficacy for cetirizine, a chlorphenamine/hydroxyzine combination or oxatomide. The response is variable, and efficacy may be associated with the sedative properties. Possible synergy with EFAs and/or glucocorticoids may occur.

Miscellaneous drugs

Fair evidence exists for the medium efficacy of pentoxyfyline and misoprostol, although neither is licensed for dogs.

Interferon omega has been used to treat CAD, with promising results. None of these drugs is

6 / 8 licensed for CAD treatment.

Summary

The best treatment programme for a patient suffering from CAD is tailored to the individual, and may include any combination of the following:

• improving the cutaneous barrier function;

• identification, treatment and prevention of potential flare factors;

• allergen avoidance and ASIT; and

• anti-inflammatory pharmacotherapy.

References and further reading

Bensignor E, Morgan D M and Nuttall T (2008). Efficacy of an essential fatty acid-enriched diet in managing canine atopic dermatitis: a randomized, single-blinded, cross-over study, Veterinary Dermatology 19(3): 156-162. Bizikova P, Linder K E, Paps J and 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(1): 71-80. Carlotti D N, Boulet M, Ducret J, Machicote G, Jasmin P, Rème C A and Albou M (2009). The use of recombinant omega interferon therapy in canine atopic dermatitis: a doubleblind controlled study, Veterinary Dermatology 20(5): 405-411. Favrot C, Steffan J, Seewald W and Picco F (2010). A prospective study on the clinical features of chronic canine atopic dermatitis and its diagnosis, Veterinary Dermatology 21(1): 23-31. Ferguson E A, Littlewood J D, Carlotti D N, Grover R and Nuttall T (2006). Management of canine atopic dermatitis using the plant extract PYM00217: a randomized, doubleblind, placebo-controlled clinical study, Veterinary Dermatology 17(4): 236-243. Glos K, Linek M, Loewenstein C, Mayer U and Mueller R S (2008). The efficacy of commercially available veterinary diets recommended for dogs with atopic dermatitis, Veterinary Dermatology 19(5): 280-287. Loewenstein C and Mueller R S (2009). A review of allergen-specific immunotherapy in human and veterinary medicine, Veterinary Dermatology 20(2): 84-98. Löflath A, von Voigts-Rhetz A, Jaeger K, Schmid M, Kuechenhoff H and 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(6): 427-431. McEwan N A, Rème C A, Gatto H and Nuttall T J (2008). Monosaccharide inhibition of

7 / 8 adherence by Pseudomonas aeruginosa to canine corneocytes, Veterinary Dermatology 19(4): 221-225. Negre A, Bensignor E and Guillot J (2009). Evidence-based veterinary dermatology: a systematic review of interventions for Malassezia dermatitis in dogs, Veterinary Dermatology 20(1): 1-12. Nuttall T, Mueller R, Bensignor E, Verde M, Noli C, Schmidt V and Rème C (2009). Efficacy of a 0.0584 per cent hydrocortisone aceponate spray in the management of canine atopic dermatitis: a randomised, double blind, placebo-controlled trial, Veterinary Dermatology 20(3): 191-198. Olivry T, Foster A P, Mueller R S, McEwan N A, Chesney C and Williams H C (2010). Interventions for atopic dermatitis in dogs: a systematic review of randomized controlled trials, Veterinary Dermatology 21(1): 4-22. Olivry T, DeBoer D J, Favrot C, Jackson H A, Mueller R S, Nuttall T and Prélaud P (2010). Treatment of canine atopic dermatitis: 2010 clinical practice guidelines from the International Task Force on Canine Atopic Dermatitis, Veterinary Dermatology 21(3): 233-248. Olivry T and Bizikova P (2010), A systematic review of the evidence of reduced allergenicity and clinical benefit of food hydrolysates in dogs with cutaneous adverse food reactions, Veterinary Dermatology 21(1): 32-41. Saevik B K, Bergvall K, Holm B R, Saijonmaa-Koulumies L E, Hedhammar A, Stig Larsen S and Flemming A (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(3): 137-145. Schmidt V, McEwan N, Volk A, Helps J, Morrell K and Nuttall T (2010). The glucocorticoid sparing efficacy of Phytopica in the management of canine atopic dermatitis, Veterinary Dermatology 21(1): 97-105. Swinnen C and Vroom M (2004). The clinical effect of environmental control of house dust mites in 60 house dust mite-sensitive dogs, Veterinary Dermatology 15(1): 31-36. Yasukawa K, Saito S, Kubo T, Shibasaki Y, Yamaoka K, Hachimura H, Kuyama T, Amimoto A, Kumata T, Kitahara Y, Takenaka M, Matsumura H, Uno T, Uchino T, Takehara K, Nishida K, Kadoya M, Sato M, Kato K, Matsumoto K, Saito S and Shimoda T (2010). Low-dose recombinant canine interferon for treatment of canine atopic dermatitis: an open randomized comparative trial of two doses, Veterinary Dermatology 21(1): 42-49.

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