Another chronic itchy dog, now what? (Proceedings)
It is common for more than one primary disease to be present, at least in the referral population seen at my practice. Multiple or changing secondary etiologies are also common. The most optimum management of a case requires that we recognize which primary diseases, secondary etiologies as well as modulating factors are present.
Most chronic itchy dogs will present with the common causes of pruritus listed in table 1.
Table 1 Common Causes of Canine Pruritus
However many cases may have multiple causes from table one. It is even common for more than one primary disease to be present, at least in the referral population seen at my practice. Multiple or changing secondary etiologies are also common. The most optimum management of a case requires that we recognize which primary diseases, secondary etiologies as well as modulating factors are present. It is also important to realize in chronic cases these often change over time and when secondary etiologies are present they often make control of pruritus more difficult especially with treatments for allergic diseases. Two principles that need to be considered are the threshold effect and summation of effect. The threshold is the level of stimuli needed to activate a physiologic response. The summation of effect is that all the stimuli that may activate a process are additive or even synergistic in activating the process. These two principles apply to both pruritus and allergic disease which though related are separate physiologic reactions.
Considering these principles and the role microbes may play in the itchy dog the first step is to make sure there is no microbial related disease or determining what role microbes play in the pruritus. This is done by doing cytology from a variety of lesions and treating infections that may be present. This is a critical point in managing the chronic itchy dog and each flare up the possibility of microbial disease needs to be considered. A common reason for successful allergy treatments to stop working is microbial disease.
Fleas can also be a confounding factor in the chronic itchy dog therefore making sure fleas are not in the home environment as well as keeping the dog on rapid adulticides in flea season is critical.
The treatment of pyoderma, yeast and fleas has been effective but has not eliminated the pruritus. At this point either it is again wise to consider if scabies is possible. Make sure scabies is not compatible with the signs and symptoms, if it is rule it out with trial therapy with selamectin. Now you are left with the probability the dog is food reactive (allergic) or has atopic dermatitis. At this point one may institute an elimination diet trial or start to pursue treatment for atopic dermatitis if the signs are compatible with that diagnosis. In either case it is time to consider treatments for alleviating the pruritic sensation while doing a diet or starting an approach to the atopic dermatitis case as the best long term treatments are not immediately effective. These will be discussed after reviewing how to do an elimination diet trial.
Elimination Diet Trials
Diet trials with provocation testing are what allow the recognition of what foods cause a adverse reaction and often what type of symptoms are related to the food allergy. Doing diet trials correctly is not as an easy task. Several points are important to completing a successful diet trial. These need to be understood and explained to owners if a trial is going to be successful.
First it is critical to establish a baseline for symptom scores prior to starting the diet that are related to the allergy and not from secondary infections. We do know cross reacting allergens can greatly impact responses to diet trials and in some cases multiple diets including one vegetarian may be tried to be effective. Not only do we change the food but owners must realize they cannot allow anything else to be ingested. In some cases very little food needs to be ingested to cause symptoms. Completing diet trials is not easy and even when owners intend to do a diet trial one study showed a high failure rate of 36% for completing a home cooked diet trial properly. Another study 27% failed to correctly complete a commercial diet trial with 13% for known exposure to other food. A complete diet trial is not just changing foods to see if a pet gets better. A diet trial performed correctly will have multiple phases, all of which need to be completed. Putting the pet on a new diet, referred to as the elimination diet, is the first step. During this phase clients observe for changes, generally the resolution or reduction in signs and symptoms. Once changes are noted or at the end of the specified time that the elimination diet is maintained then the pet is again fed the diet it was on prior to the elimination diet. This is the initial challenge phase. If there is no change then the next phase is making sure the pet is ingesting all the things it used to ingest, the complete challenge. This means all supplements, treats and access to other outdoor or indoor items the pet used to ingest. Observing any recurrence in symptoms or signs is a positive provocation and the first step for a tentative diagnosis. The most critical step to confirm of diagnosis is then the second resolution of signs without any other therapeutic change when the challenge food/items are discontinued. Absolute confirmation requires multiple episodes of positive provocation, evidenced by symptom exacerbation, with the addition of specific ingredients added to the elimination diet and subsequent resolution of those symptoms when withdrawn. This is referred to as ingredient provocation testing and is essential in confirming the diagnosis. Ingredient provocation testing is how to determine which diets, commercial or home cooked are options for long term management. There is no perfect diet and even hydrolyzed diets are not always effective and in some cases the dog may react to the hydrolyzed protein.
Alleviating the pruritic sensation.
A variety of non specific therapies as well as therapies for secondary diseases may be used to decrease or eliminate the sensation of pruritus until a specific diagnosis and therapy can be determined. In some cases these non specific therapies or therapy for secondary diseases may work so well that clients will elect to utilize them long term. The most commonly recommended therapies are listed in table 2.
Table 2 Therapeutic Regimens
Options for long term control of atopic dermatitis.
Long term control of atopic dermatitis is usually accomplished with a combination of fatty acids(FA), topical therapy(TopT), plus minus antihistamines(Ah), allergen specific immunotherapy(ASIT), cyclosporine(Cyclosp) or continuous systemic glucocorticoids(SGluco) and preferable are utilized in that respective order. Many differing opinions exist on how an atopic dermatitis case should be managed. Personally I can say if I owned an atopic dog I would start with a diet change and intermittent antimicrobial therapy. If not controlled to satisfaction with that and it required long term continuous therapy for the atopic dermatitis I would start with allergy testing and ASIT, then topical therapy, then cyclosporine, then antihistamines or combinations and lastly long term systemic glucocorticoids. However in dealing with clients we cannot just say what we would do. We need to base decisions of a variety of factors.
The 11 factors I use with clients in determining the preferences for selection of treatment(s) are presented in the following list and major ones are presented in table 2.
1. ease of treatment,
2. possibility for good long term compliance,
3. adverse reactions not acceptable even on short term
4. side effects though acceptable to clients
5. long term safety
6. side effects that may be seen but not necessarily associated with the therapy
8. cost of therapy
9. cost of monitoring therapy
10. ease of monitoring
11. legal requirements
Diet and topical therapy should be incorporated into all allergic dermatitis cases.
The advent of diets designed for allergic dermatitis in dogs has greatly facilitated the use of fatty acids for the treatment of atopic dermatitis. The diets are generally high in omega 3 fatty acids such as gamma linolenic, dihomo gamma linolenic, and eicosapentanoic acid due to the addition of fish oils or other ingredients. Some diets such as Skin Support Diet (Royal Canin) have other elements that have been shown to improve the epidermal barrier against trans epidermal water loss. Controlled blinded trials have shown the important of feeding diets designed for atopic dogs with the benefits likely coming from the omega 3 in the diets. One study showed efficacy with 53% lower total pruritus scores than controls and 54% of dogs improved compared to 31% of the controls. Another study evaluated 4 diets and the most effective diet was a fish and potato based diet with CADESI decreasing from 22.5 to 5.5 and PVAS 3.2 to 2.3 after 8 weeks. Fatty acids have also been described to have a synergistic effect on other therapies for atopic dermatitis. The synergistic effect and because of their ease of use, excellent compliance and relative low cost it is easy to be the first recommendation for all allergic dogs.
Topical therapy in the form of shampooing has also shown some efficacy for atopic dermatitis and pruritus. With weekly shampooing signs are improved in some dogs and though not evaluated it is the authors experience daily bathing is highly effective for atopic dermatitis. Non infected pruritic dogs failing to respond to daily bathing are more likely to have adverse food reaction, flea allergy or scabies. Recently phytosphingosine, a natural skin component essential for normal lipid barrier function, has been added to a line of products (Douxo Calm, Sogeval) designed for allergic pruritic dogs. Controlled documentation of efficacy has not been evaluated and needs to be done. The theory is that topical therapy aids for several reasons, especially from cooling and cleaning the skin with removal of offending allergens. This is supported by the findings that a whirlpool in water, without shampooing is also helpful. Adverse effects are very rare though anecdotally folliculitis may be induced with bathing and rare reports of contaminated shampoos leading to folliculitis and deep infections and death due to superficial suppurative necrolysis suggest bathing is not totally benign. Due to the relative safety and benefit frequent bathing is recommended for any client with an atopic dog.
Allergy testing and basic ways to adjust allergen specific immunotherapy.
Allergen specific immunotherapy (ASIT) is the treatment of choice in atopic dermatitis cases that are not controlled to the owners satisfaction with bathing, fatty acids, antihistamines and specific therapies for secondary problems. To do this allergy testing is required to identify offending allergens. Though IDT is preferred by most specialists results based on serum in vitro testing are as good if cases are atopic dermatitis. Numerous protocols for allergen-specific immunotherapy are used. I have also been trying lower dose in more cases and though no review has been completed my impression is this is helpful. Whatever the protocol used the important thing to realize is all protocols are a starting point and adjustments may and often should be made based on the pets response. It is common for adjustments to be made within the first two to four months and that is why rechecks are important at these time frames. Some cases require adjustments within the first month and this can only be detected if they are not put on glucocorticoids during the induction phase. This has been reported by another dermatologist who immediately cuts the concentration in half when patients react to an injection while trying to build up to the final maintenance dose by the first 28 days of therapy. My response in that situation is to go back to the last dose with no reaction and repeat it twice then see if we can build back up. If the pet again reacts then the last dose it did not react to is that pets maximum injection volume and concentration. During the induction phase some pets react to vials of lower concentration (1,000 -2,000PNU/ml). In this case I also back up but do eventually try multiple times to at least reach a dose of 0.05cc of the maintenance vial at the higher PNU/ml. This is because the low concentration vials do not have the same expiration time. When cases have to stay on low concentration vials (100-200PNU/ml or 1,000 to 2,000PNU/ml) which I have occasionally have had to do then new allergen solutions are made from the maintenance vial every two months. These cases will usually require a short frequency so shots are given every 2-3 days for life.
There are a number of ways to try and adjust allergen-specific immunotherapy. The volume of solution and therefore the total amount of protein injected can be changed. The interval between injections can be changed so that shots are given more frequent (closer together) or less frequent (farther apart). A second set of antigens either containing other allergens the pet is allergic to or a combination with some the same and new antigens may be initiated along with the original set of antigens. Two other changes that can be made require remixing or reformulating the antigens. These are the concentration of antigen (protein level/volume) and the ingredients in each set of antigen. Typically I will use a PNU concentration for my maintenance dose of 10,000 - 20,000 PNU/ml with the largest concentration per item being 20,000 PNU/ml. Most commonly I change the volume of antigen formula injected or the frequency of the injections. My rule of thumb for injections is to try and reach at 0.1ml per day and if they are not responding or are responding well then I will slowly reduce to 0.05ml per day. Initially if the frequency is between 10 and 20 days then I will keep the dose at 1.0ml unless there are reactions correlated with the injections. If injections are given less often than every 10 days then they do not get the full ml. Dogs that receive shots every 5 days usually get 0.5ml or less it they are at 7 days the most is 0.7ml. However occasionally I will go higher than this dose but it will be a level worked up to and not started at. I usually will try to get the maintenance dose to about 0.05ml/day and most dogs end up from 0.03ml to 0.01ml per day.
To adjust for reactions the client must be educated about what reactions to watch for. The first 30 minutes and preferably one hour dog following the injections the client should be around and able to observe the pet. Any reactions should be noted and communicated to the veterinarian. Reactions that require contacting the veterinarian immediately include hives, facial swelling, vomiting, diarrhea, weakness or collapse. Evidence of milder allergic reactions that should be reported to the veterinarian prior to giving any more injections are increased itching, listlessness, sleepiness, and anxiousness. Pain or swelling at the injection site is infrequent and minimal if shots are done correctly and animals trained to accept the shot as a reward situation. Intradermal injections are a cause for these reactions. In rare cases after many injections some animals may develop a swelling subq or dermal and in these cases moving the shots around may alleviate this. Other reactions that may be seen are panting, hyperactivity, increased bowel sounds, changes in urinary habits, and frequent swallowing. Most reactions occur relatively rapidly after the injections but changes in activity and pruritus may occur one or two days later. Patterns of pruritus in relation to when shots are given should be observed for, as this is often the basis for making adjustments in the treatment protocol. It is helpful to have client's grade pruritus and note locations of pruritus. Grading from 1 (no pruritus) to 10 (most severe pruritus for this dog prior to hyposensitization) should be done prior to staring the therapy and as frequently as the client can during the first few months of therapy. Some clients will keep a diary, which may be very helpful in determining allergen adjustments.
Using cyclosporine most effectively.
Micro emulsified cyclosporine is most commonly used at 5mg/kg q24h. It is sometimes used at a lower dose if concurrent drugs that inhibit cytochrome P 450 are given concurrently, such ketoconazole. It is important to warn owners lower doses are less effective and when used concurrently with ketoconazole some dogs will not respond and side effects are more common. It may take 2-4 weeks to see a response. Once a response is seen then the dose may be tapered. In some cases it is better to continue the induction dose until clinical improvement is complete or reached a steady state of response. Tapering is done by maintaining the dose at 5mg/kg but changing to q48h and with continued response is seen for another month then further tapering to q72 hrs is tried. Again if there is still an excellent response after another month further tapering to every q 4-7d dosing may be tried. In some cases long term remissions may be seen once the drug is discontinued, though the frequency of this needs to be determined in more controlled study. It make take several months for signs to return and this effect is another way to manage some cases, by going on and off the drug long term. This is another way to keep the costs of therapy within a clients comfort level. Some dogs may end up on relatively low levels of drug long term by doing the tapering or going on and off the drug. This makes the overall cost low enough to have even large dogs that initially may seem expensive to treat actually respond well at an affordable cost.
Adverse reactions have been reported in a study of up to 268 atopic dogs[. Based on this study, other reports and my experience the most commonly encountered side effects are vomiting and diarrhea. Many dogs only vomit once or twice then tolerate the drug. Vomiting may also be decreased by giving the drug concurrently with food or pretreatment with metoclopramide 0.2 to 1mg/kg q24h. My approach is to warn an owner vomiting occurs in about 15% of cases and if it does at the second dose give the drug with food and if vomiting occurs again we have them use metoclopramide pre treat for one week. Once the dog tolerates the drug we again try giving it on empty stomach. If necessary we will give it with food long term.
Diarrhea though less common than vomiting is the number one adverse reaction resulting is discontinuation of the drug. When is occurs I have the clients temporarily stop the treatment until normal bowel movements have returned then try treating again with the addition of metronidazole and fiber added to the diet. Other side effects that have resulted in lowering the dose or discontinuing therapy are hirsutism and gingival hyperplasia. Hirsutism is often a generalized thickened more dense hair coat often associated with increased shedding. In other cases there are patterns where the hair growth is exceptionally long. This seems to most often affect the paws and head or face region. Gingival hyperplasia may resolve with dose reduction though sometimes stopping therapy completely may be needed. Antibiotic therapy may also be tried and there is a report azithromycin helps this adverse reaction.
Papillomatous hyperplasia may also be seen and recently these were examined and are usually negative for papillomavirus. A more recent study showed that these lesions likely represent multiple causes and two of nine dogs were positive for papilloma virus. However we have been cautioned about an increased incidence of infections especially viral. Bacterial infections are also a concern and may appear as atypical lesionsA high incidence of nephrotoxicity and hepatic toxicity is seen in humans but has not been observed in dogs. This is more of a concern when ketoconazole is used for concurrently either for Malassezia or as dose sparing agent. Elevated blood pressure is also a major concern in humans and though rare in dogs should be monitored for.
Monitoring serum levels of cyclosporine is not recommended as serum levels of cyclosporine generally do not correlate with clinical responses. However there may be some value to monitor these levels when clinical responses are not seen. If levels are still in the low therapeutic range dosages can be increased in an attempt to obtain a response. As we have not had long term experience with this drug in thousands of cases some routine monitoring is warranted. Complete blood counts, chemistry profiles, urinalyses and blood pressure testing is indicated at some frequency which may vary from 4-12 months.
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