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== Treatment ==
== Treatment ==
Flare factors
Ectoparasites
Fleas and Neotrombicula frequently complicate
AD. Atopic dogs can also contract Sarcoptes.
Demodicosis may be associated with immunosuppression
particularly iatrogenic hyperadrenocorticism.
Microbial infections
Secondary infections should be identified and
treated promptly. Topical therapy can reduce microbial populations and recurrence of infections.
Immunosuppression may result in infections
but control of inflammation usually reduces
colonization and infection with Malassezia
and staphylococci. Dogs that are very prone to
pyoderma, however, can benefit from long term
pulse antibiotic therapy.
Stress
Stress can exacerbate human inflammatory dermatoses,
and this may be true in animals. There is
anecdotal evidence that behavioral therapy and
pheromones can help.
Environmental effects
Excesses of temperature and humidity, irritant
surfaces or cleaning solutions etc. can all worsen
skin diseases. Observant owners will often report
associations.
Improving skin barrier function
Diet and the skin
Many atopic animals non-specifically improve
following food trials, probably because high quality,
essential fatty acid (EFA) enriched, single-protein
sensitivity control and hydrolyzed hypoallergenic
diets affect the skin barrier and/or skin immune
system. Nutrients believed to be important include:
•Zinc – decreases inflammation.
•Long chain omega (n-3) EFAs – alter eicosanoids
and decrease inflammation.
•Inositol, choline, histidine, pantothenate,
nicotinamide – improve epidermal lipid barrier
formation.
•Aloe vera and curcumin – up regulate fibroblasts,
proteoglycan synthesis and TGF-β production,
and decrease inflammation.
In the author’s opinion, unpublished data from
randomized cross-over studies have shown that
Eukanuba Dermatosis FP and Royal Canin Skin
Support diets significantly ameliorated clinical
signs in atopic dogs.
Topical therapy
Topical therapy has a number of benefits although
it is time-consuming. Physical removal of allergens
is likely to be helpful. Hydration can be prolonged
by using moisturizing shampoos and conditioners.
These can also improve the skin lipid barrier.
Colloidal oatmeal may also have a direct antipruritic
action. Virbac’s Allermyl® range contains
linoleic acid (improves the skin lipid barrier),
vitamin E and mono-oligosaccharides (may reduce
TNF-α production and prevent microbial adherence)
and piroctone olamine (modulates the skin flora).
Chitosanides and microspherulites help prolong
retention and activity on the skin and coat. Other
topical products that may be helpful in individual
cases include ear cleaners and anti-microbial or
anti-scaling shampoos. The exact balance of
desired effects varies between individuals, so be
prepared to try different products and/or alternate
between antimicrobial and emollient shampoos.
Essential fatty acids (EFA)
Numerous clinical trials and studies have evaluated
EFAs particularly the n-3 EFA eicosapentenoic acid
(EPA) and the n-6 EFA gamma-linolenic acid (GLA).
Supplementation can result in altered plasma levels
and incorporation into cell membranes, which may
lead to production of less inflammatory leucotrienes
and prostaglandins and improved cutaneous lipid
barrier. Recent studies, however, have not found
consistent changes in plasma, subcutaneous fat or
cutaneous EFAs following supplementation in atopic
and healthy dogs, and no correlation with the
clinical response (1-3).
Clinical results have been variable in controlled
trials, and no relationship between efficacy and
ratio of n-3/n-6 EFAs have been proven, although
high doses seem to be more effective. Recent
studies have shown that high quality, EFA enriched
diets are beneficial in canine AD although how
much of this is due to anti-inflammatory activity
or cutaneous barrier improvements is unclear (4).
Allergen specific therapy
Allergen specific therapy will only be appropriate
in animals with identified sensitivities. The aim of
allergen testing is to identify allergens for avoidance
and immunotherapy, not to confirm the diagnosis.
Allergen avoidance
Allergen avoidance measures can result in a significant
reduction in exposure to house dust mite (5).
Whether allergen avoidance results in clinically
significant improvement is controversial, although
one uncontrolled study demonstrated that allergen
avoidance was beneficial in canine AD (6). Allergen specific immunotherapy (ASIT)
ASIT involves the administration of gradually
increasing amounts of allergen by subcutaneous
injection. The mechanism of action is unknown
but it is thought that administering large doses
of allergen in an unusual route (i.e. subcutaneous
instead of epidermal) induces tolerance. Many
studies (albeit mostly open or retrospective)
have shown that 60-80% of dogs have a greater
than 50% improvement following ASIT. The
best results seem to occur with early treatment,
although a 9-12 month trial is necessary to assess
the response in each case. Animals on ASIT
require careful supervision to control microbial
infections and other flare factors, to administer
anti-inflammatory treatment as required and to
adjust the dose and/or frequency according
to the clinical response (Figure 1).
The exact protocol varies widely but usually
involves repeated injections a few days to 1-2
weeks apart. Once the full dose is reached, the
interval between injections can be extended.
A rush protocol, where the initial loading course
is given within a single day, was recently shown
to be as effective as conventional ASIT in a small
number of dogs (7). Recent reports also described
starting with a full dose (monodose therapy).
No adverse effects were seen in either case
although the dogs were pre-medicated with
an anti-histamine.
Alum precipitated vaccines have a depot effect
and require less frequent administration. Alum
adjuvants potentiate IgE responses in experimental
animals but no differences in efficacy between
alum-precipitated and aqueous vaccines have been
demonstrated in dogs. There are anecdotal reports
of improved efficacy with low dose ASIT, but a
controlled study, however, found no difference in
efficacy between low dose and conventional
alum-precipitated ASIT (8).
If ASIT proves successful, the interval between
injections can be extended. Increased pruritus
before the next injection is due indicates that the
interval is too long. The interval may also vary
through the year, especially in pollen sensitive
animals. Some dogs can be weaned off treatment,
but most require maintenance injections every
1-2 months.
Re-testing may reveal new sensitivities in dogs
with initially negative tests, dogs <12 months
old at the time of the original test, if there has
been a poor response to ASIT or where a good
response is not maintained. Re-formulating ASIT
can be beneficial in these dogs.
Adverse effects are uncommon. Injection site
reactions and anaphylactic shock are very rare,
although many dermatologists advise giving the
first 5-6 doses in a veterinary clinic. Increased
pruritus after an injection indicates that the dose is
too high although mild reactions can sometimes be
managed with antihistamines.
Anti-inflammatory therapy
Anti-inflammatory therapy is used as required
to control residual pruritus and inflammation.
Almost all atopics will require treatment in the
short to medium term, but the dose, frequency
and/or potency of drugs can be reduced if other
treatments are successful in the long term.
Cyclosporine
Cyclosporine suppresses T-cells, which have been
implicated in the pathogenesis of canine AD.
I t also inhibits other key cells in allergic inflammatory reactions such as mast cells and
eosinophils. This has profound effects on antigen
presentation, IgE production, mononuclear cell
activity and the development of inflammatory
lesions, although at the doses used in canine AD,
cyclosporine is immuno-modulating rather than
immunosuppressive (Figure 2).
Cyclosporine is rapidly absorbed and distributed.
Bioavailability varies from 15-60% in individual
dogs and is not affected by food. There is little
correlation between trough levels and efficacy, and
dose adjustments are made according to the clinical
response rather than monitoring plasma levels.
Metabolism is via the cytochrome P450 system.
Numerous drugs can decrease metabolism, notably
itraconazole and ketoconazole, which increases
plasma concentrations, efficacy and the likelihood of
adverse effects (Figure 3). Phenobarbital increases
metabolism and decreases plasma levels.
Cyclosporine is administered for canine AD at a
dose of 5 mg/kg once daily. Controlled studies
have shown that it is at least as effective as
prednisolone and methyl-prednisolone (9,10),
although this may take 2-3 weeks to become
apparent. Glucocorticoids can be initially coadministered
to achieve more rapid remission.
Approximately one third of treated dogs require
daily dosing, one third every other day and one
third twice weekly to maintain remission.
Using cyclosporine as part of an integrated
management program can be more cost-effective
than relying on it alone.
The effect on intradermal testing and serology is
thought to be minimal, although the data is sparse.
Anecdotal data suggests that cyclosporine does
not affect the response to ASIT any more than
glucocorticoids although controlled studies have
not yet been performed.
Cyclosporine is well tolerated by the majority of dogs.
Transient anorexia and vomiting are the most likely
problems. Persistent vomiting is uncommon but
may be eased by administering with food, and/or by
using the gastrointestinal protectant sucralfate
or H-2 blocking agents such as ranitidine. Other
uncommon adverse effects include hirsuitism,
increased shedding of hair and transient alopecia,
gingival hyperplasia, papillomatosis, diarrhea,
lameness and muscle tremors, and erythema
and edema of the ears. These are largely dosedependent
and reversible. The nephropathy,
hepatopathy and hypertension seen in humans
have not been recognized in dogs except at doses
>20 mg/kg. Immunosuppression is a potential concern.
Inhibition of cell-mediated immunity in particular
could result in bacterial and protozoal infections,
dermatophytosis and demodicosis. In practice,
however, the risk appears to be very small and most
atopic dogs experience fewer secondary infections
following treatment. Feline and human patients on
long term treatment have a small risk of developing
lymphoma and cutaneous neoplasms. Lymphoplasmatoid
dermatitis has been seen following
doses >20 mg/kg and there is a single case report
of lymphoma in an older dog following treatment
for anal furunculosis. These have, however, not
been reported in atopic dogs (11). Inhibition of
T-helper cell function and β-cell activation could
affect the response to vaccination. Some authors
advocate withdrawing treatment for up to two
weeks either side of vaccination, although this
will lead to worsening of the skin condition. The
pros and cons for each individual case should
be discussed with the owner.
Tacrolimus
Tacrolimus has a similar mechanism of action to
cyclosporine. A 0.1% tacrolimus ointment lead
to a greater than 50% improvement in 70-75% of
atopic dogs with localized lesions in two trials
(12,13). Plasma levels remained low throughout
and no adverse effects apart from minor self
trauma immediately after application were seen.
Phytopica™
Phytopica™, a compound derived from Rehmannia
glutinosa, Paeonia lactiflora and Glycyrrhiza
uralensis improved canine AD in a preliminary
study (14). In a recent randomized, double-blind
and placebo-controlled trial of 120 dogs Phytopica™
(200 mg/kg/day) appeared to be an efficacious,
safe and palatable non-steroidal treatment for
canine AD, although the effect was modest with
most dogs achieving a 20-50% improvement in
clinical signs (15). Responses are typically evident
within four weeks (Figure 4). Adverse effects are
self-limiting gastro-intestinal disturbances such as
diarrhea and vomiting. This is generally a better
safety profile than has been reported for other
anti-inflammatory therapies (16).
Glucocorticoids
Corticosteroids, synthesized in the adrenal cortex,
have glucocorticoid (anti-inflammatory and
gluconeogenic) and mineralocorticoid (salt
and water balance) activity. Glucocorticoids are
simultaneously the most used and abused drugs in veterinary dermatology. They are cheap, easy
to administer and highly efficacious but are
associated with a plethora of side-effects (17,18).
At pharmacological doses they inhibit the expression
of genes encoding a variety of molecules
involved in immunity and inflammation, resulting
in rapid and profound immunosuppression and
decreased inflammation.
Most quoted doses are for prednisolone (Table 1);
the dose for other steroids is calculated according
to the relative potency. Steroids also vary in
their mineralocorticoid activity and duration of
activity, but that suppression of the hypothalamicpituitary-
adrenal (HPA) axis may last longer
than the therapeutic effect. Only prednisolone
and methyl-prednisolone are suitable for long term
alternate day dosing as their duration of activity
should leave at least 12 hours for the HPA axis
to recover. The formulation also has an impact:
soluble esters (such as succinates and phosphates)
have a rapid onset and shorter duration of
action; acetates have a moderate onset and
duration; and acetonides and dipropionates are
long-acting depot preparations.
Glucocorticoids are highly effective in canine
AD, but must be used with care and, ideally,
as a last resort. Exploring alternative approaches
will help minimize the dose and frequency
required. Genuine seasonal AD that requires
3-4 months treatment each year, however, can
usually be managed successfully with minimal
problems. Short courses (0.5-1.0 mg/kg once
daily for 3-5 days) can also be administered to
treat flares of inflammation in dogs otherwise
well controlled on other medication.
Topical treatment directs the steroid to affected skin
and avoids the need for systemic therapy. Topical
glucocorticoids can be used where inflammation is
localized to relatively hairless skin, pyotraumatic
dermatitis (‘hot-spots’) or in the ears and eyes.
More potent products containing betamethasone
etc. can be used once or twice daily initially, but
hydrocortisone is better for long term, alternate day
treatment. Fuciderm® (contains betamethasone) is
a good choice as the gel formulation allows rapid
penetration and drying.
Systemic therapy is necessary with more severe
or widespread lesions. 0.5-1.0 mg/kg prednisolone
is given once daily until remission. You can then
administer the same dose every other day and then
reduce the dose by 50% every 7-14 days until the
lowest maintenance dose is established; or,
gradually wean the alternate day dose off, and
then establish the lowest every other day
maintenance dose. The only suitable systemic
drugs for alternate day dosing are prednisolone
or methyl-prednisolone, but triamcinolone,
betamethasone or dexamethasone can be used
to achieve remission in severe cases. Injectable
preparations should not be used unless absolutely
necessary, as it cannot be withdrawn, the dose
cannot be altered, nor the hypothalamic-pituitaryadrenal
(HPA) axis allowed to recover.
Glucocorticoids will suppress reactions to intradermal
allergen tests, although the effect on serology is believed to be less marked. It is currently
recommended that you withdraw topical glucocorticoids
for at least two weeks, short acting oral
glucocorticoids for at least three weeks and longer
acting injectable glucocorticoids for at least six
weeks before allergy testing. Dogs on long term
treatment or with iatrogenic hyperadrenocorticism
may need considerably longer withdrawal
times (Figure 5). Glucocorticoids are frequently
administered to control inflammation during the
induction phase of immunotherapy. This does not
appear to affect the response rate although there
are no controlled studies.
Adverse effects arise from the glucocorticoid
and mineralocorticoid activity as well as
suppression of the HPA axis and endogenous
steroid production. Common acute side-effects
include polyuria and polydipsia. The risk of
these problems developing can be reduced by
using methyl-prednisolone, which has much less
mineralocorticoid activity. Other acute sideeffects
include polyphagia and weight gain
(which can be managed using a low calorie diet),
panting and behavioral changes (including
dullness and, rarely, aggression). The onset of
iatrogenic hyperadrenocorticism is dose and
duration dependent, but there is a wide
variation in tolerance between individuals.
Immunosuppression and secondary infections
are quite common with long term treatment.
Inhibition of cell-mediated immunity can result
in demodicosis, dermatophytosis and infections
with intracellular organisms. Immunosuppression
and alterations in cutaneous barrier function
commonly result in superficial pyoderma.
Production of dilute urine is a factor that
contributes to cystitis.
Some of these infections may be clinically
inapparent, as steroid therapy may mask some of
the associated inflammation and characteristic
clinical signs such as pruritus or dysuria.
Because humoral immunity is less affected,
animals can develop adequate antibody titers
following vaccination. For this reason, short
term treatment may be used to control the
clinical signs if cyclosporine has to be withdrawn
because of routine vaccination.
Hydrocortisone aceponate
Hydrocortisone aceponate is a novel topical
diester glucocorticoid for the treatment of pruritus
in dogs. Topical diester glucocorticoids overcome
many of the adverse effects traditionally
associated with systemic or topical glucocorticoid
therapy. They are rapidly absorbed and exert
potent anti-inflammatory effects within the
epidermis and superficial dermis. Metabolism
within the dermis, however, ensures that very
little active compound reaches deeper tissues
and the circulation, minimizing skin thinning
and systemic effects. The topical formulation,
furthermore, eases topical administration. The
small dose volume, very small droplet size and
volatile carrier help to ensure quick and easy
application, penetration of even haired skin and
rapid drying with minimal cutaneous after
effects. The spray is formulated such that two
sprays from 10 cm away will penetrate the coat
and treat a 10 x 10 cm (i.e. palm sized area of
skin). Early studies (unpublished) demonstrated good
efficacy and safety in short term treatment of
various pruritic disorders in dogs including
pyotraumatic dermatitis and f lea allergic
dermatitis. An open-label pilot study and
preliminary findings from a randomized, doubleblind,
placebo controlled study found that
Cortavance® was effective and well-tolerated in
managing canine AD. One dog has suffered a
contact reaction, but adverse effects have not
otherwise been noted. Once daily administration
was sufficient to induce remission, after which a
proportion of dogs can be maintained on every
other day therapy. Twice weekly administration,
however, resulted in a relapse in most dogs.
Antihistamines
A large review of clinical trials (16) concluded
that there is no more than fair evidence of
medium efficacy for the first generation antihistamines
clemastine and a combination
of chlorpheniramine and hydroxyzine, and
the second generation (non-sedating) drug
oxatomide. There may however be some synergistic
activity with EFAs and glucocorticoids.
Adverse effects of first generation drugs are
uncommon and are usually linked to drowsiness.
Adverse effects to second generation drugs
are more common and include gastrointestinal
tract upsets and cardiac arrhythmias.
Other therapeutic options
Phosphodiesterase inhibitors improve peripheral
blood flow and oxygenation, and are immunomodulating.
There is fair evidence for medium
efficacy of pentoxifylline (10 mg/kg 2-3 times
daily) and medium to high efficacy of arofylline
(1 mg/kg twice daily) (16). Arofylline caused
frequent vomiting, but no adverse effects were
seen with pentoxifylline.
Misoprostol is a prostaglandin E1 analogue that
inhibits activation of basophils, mast cells and
eosinophils, blunting late-phase inflammatory
reactions. Two studies have provided fair evidence
of medium efficacy in canine AD at 6-10 μg/kg
three times daily (16). Misoprostol was well
tolerated with only minor gastrointestinal tract
signs reported.
==Prognosis==
==Prognosis==