2016 Zoetis Dermatology Symposium - Audience Q&A from NAVC

2016 Zoetis Dermatology Symposium - Audience Q&A from NAVC

The following are the speaker responses to questions from the audience during the Symposium sponsored by Zoetis held Monday, March 7, 2016 at WVC in Las Vegas, NV.

The opinions expressed in these answers are those of the speakers and do not necessarily reflect the official label recommendations and point of view of the company or companies that manufacture and/or market any of the pharmaceutical agents, products, or services mentioned.

Session 2: Innovative Therapies for Skin Disease: What’s on the Horizon?

Douglas J. DeBoer, DVM, DACVD
University of Wisconsin, Madison, WI

Peter H. Eeg, BSc, DVM
Poolesville Veterinary Clinic, Poolesville, MD

1. Can Apoquel be given on an as-needed basis for pruritic flare-ups or tapered beyond SID to maybe every other day dosing?

Dr. Eeg:  Apoquel does not need to be tapered; in my experience, it can be started and stopped as needed. Apoquel also has about an 18-hour effect period, so trying to use it every other day does not provide consistent coverage for chronic AD cases. In my practice we administer Apoquel for the recommended 14-day period every 12 hours. Then we recheck the patient to discuss long-term once-daily maintenance. 

Dr. DeBoer: Apoquel acts very quickly but has a short half-life, so yes it can be given “as needed.” However, it usually doesn’t work out very well given every other day because on the day it’s not given, the pet will typically be itchy.

2. How are the monoclonal antibodies (mAbs) better than traditional allergy immunotherapy? 

Dr. DeBoer: The two therapies (mAbs and allergen-specific immunotherapy, or ASIT) are actually two different— and maybe complementary— therapies. The goal of ASIT is to alter or “normalize” the patient’s immune response to the relevant allergens. The goal of the current mAb treatment (anti-IL-31) is to target a single cytokine to reduce itch and skin lesions. Thus, under the concept of multimodal therapy, the anti-IL31 mAb would be useful to immediately reduce itch; then ASIT would be used at the same time to slowly, over time, alter the immune response towards normal.

Dr. Eeg: Anti-IL-31 mAbs are antibodies specifically designed to bind to interleukin-31 (IL-31) cytokines and remove them from circulation so they cannot attach to the receptor sites that begin the itch/inflammatory pathways. Since they are so targeted, they are a much more precise way to manage AD. In my experience in the conditional release period use at our clinic, the response has been excellent or very good in all patients that fit the AD diagnosis.

3. Are there in-house tests available for the detection of IL-31 to diagnose atopic dermatitis? 

Dr. DeBoer: No, there are not—there are not even commercial assays available; this is a research tool only at this time. Unfortunately—and related to the complex pathophysiology of AD—simply measuring IL-31 would not be very valuable. For example, in studies, IL-31 was detectable only in about 60% of atopic dogs.

Dr. Eeg: As I understand the data, it indicates that the cytokines targeted act locally and are rarely found in measurable amounts in the serum.  It was only identified in the serum in about 60% of the dogs.  So a negative test would not exclude a clinical diagnosis of AD.

4. Is there a possibility for monoclonal antibodies being a benefit for food-allergic pets?

Dr. Eeg: Currently I do not see that it is being studied for food-allergic pets. But that could be a consideration for future studies of the anti-IL-31 mAb.

Dr. DeBoer: It is possible that anti-IL-31 mAb may decrease the itch associated with food allergy. I don’t have any personal experience with that yet. Of course, even if it works, it would only be used temporarily while a diet trial was in effect.

5. Are there monoclonal antibodies being developed for use in cats?

Dr. Eeg: I have not heard of any discussion about mAbs being evaluated in cats at this time.

Dr. DeBoer: Not that we know of, but of course it will come eventually!

6. Do you worry about using monoclonal antibodies in dogs with a previous vaccine reaction?

Dr. DeBoer: Interesting question. We know that dogs with reactions to vaccination may be primed to react against other things as well. However, the caninized anti-IL-31 mAb is not really a foreign antigen to a dog (as is vaccine antigen) and therefore it is much less possible that a reaction could occur.

Dr. Eeg: Remember vaccines are antigens that are designed to stimulate the dog’s immune system and sensitize it to the specific antigen. Anti-IL-31 mAB have been specifically engineered to bind to IL-31 cytokines that are circulating in the dog’s blood stream due to allergic stimulation. In my experience with the anti-IL-31 mAb I have used as part of the conditional release no adverse reactions have been noted in my patients.

7. How great is your concern for cancer development in pets on Apoquel?

Dr. Eeg: In my personal experience over the last three years, I have not experienced what I believe is a direct correlation between Apoquel administration and development of cancer.  I have also not seen any data that confirms a relationship between the use of Apoquel and the development of neoplasia in dogs. The FDA placed a warning that Apoquel may exacerbate neoplasia on the label due to the class of drug to which Apoquel belongs. It is also important to note that in safety studies with laboratory beagles treated at up to 5X the label dose for 26 weeks, no malignant neoplasia was seen.

Dr. DeBoer: Nonexistent, at least at this point! There is no known relationship between the use of Apoquel and the development of neoplasia in dogs. The incidence of neoplasia in Apoquel-treated dogs in the field and continuation studies occurred no more frequently than is seen in the general population of dogs. The FDA placed a warning that Apoquel may exacerbate neoplasia on the label due to the class of drug to which Apoquel belongs.  During the pre-approval testing program, over 1500 dogs globally were enrolled in clinical trials evaluating Apoquel, some for longer than 2 years. Dogs with pre-existing, malignant neoplasia were not allowed to enroll in these studies; as a result the relationship between Apoquel and exacerbation of neoplasia has not been studied. While the Continuation Therapy program did not have a control group for comparison, the rate of neoplasia in these middle-aged to older dogs was not greater than what would be expected in an aging population of dogs. Development of malignant neoplasia was not seen in the Apoquel high-dose safety studies with laboratory beagles treated at up to 5X the label dose for 26 weeks.

8. Can Apoquel be used long term at BID dosing? What are the side effects? 

Dr. DeBoer: BID dosing would be off-label. However, I hear your concern here—in some dogs, the antipruritic effect does not seem to last a full 24 hours. In such cases, it would be your decision as the responsible veterinarian to proceed with off-label, BID dosing. BID dosing will not allow the dog’s cytokine response to “recover” for a while, as with once-daily dosing. I don’t think there would be any new side effects to watch out for; it’s just that there might be a greater chance that the known side effects (rare demodicosis; rare lowering in WBC) would occur.

Dr. Candace Sousa, Zoetis: Since the half-life of Apoquel is relatively short, administering the tablet once daily in the evening provides the dog enough control of itch to comfortably sleep through the night and into the following day. If the dog’s allergy has been well-controlled on once daily Apoquel and there is a flare of itch and inflammation the dog should be re-checked by the veterinarian to rule out flare factors such as skin infections, parasites or other non-allergic diseases.

9. How long are you seeing efficacy with the anti-IL-31 mAb? We were seeing close to 30 days in our practice and now we have some who responded for only 1 to 2 weeks. We have treated about 30 cases. 

Dr. Eeg: In my general practice, I have patients that require repeat injections from 29 to 54 days. They all seem to be very consistent in their requirements. In the cases where breakthrough itch has been noted, I use it as a clinical indicator that I have to re-evaluate the case to be sure no other conditions are present that may be exacerbating the AD.

Dr. Candace Sousa, Zoetis: During the Conditional License Program we are collecting data on second and third injection frequency. That data hasn’t been analyzed yet, but I can tell you what I hear in one-offs. We know from the clinical trial that pruritus, if we just look at that measure, was reduced quickly and that reduction remained in the mild or lower range for about 35 to 42 days (Figure 1). In some cases the owners are reporting acceptable reduction for 8 weeks or longer, but I can’t tell you how often that happens. Maybe those are dogs with seasonal AD. We are also being asked about the ability to administer another dose prior to monthly and we know that should be safe. As in all cases, we advise ruling out compounding / complicating factors such as a secondary infection, etc. And much of this also depends on an owner definition of “response.”  

2016zoetisderm sig improvementinpruritus

Figure 1.

So all I can say is that you can administer the product monthly as needed with your ability to administer sooner or longer if the pet needs it. By the third injection the antibody should achieve steady state. We’ll know more about the duration as we go to full licensure the end of this year or early 2017.

10. How quickly does CADI decrease the pruritus?

Dr. Eeg: In every case we have used the conditional release CADI mAbs we have seen response in 24 to 96 hours. Some patients have not shown peak effect until one week out. When we re-dose them, their return to their previous reduced pruritic state is within 24 hours. 

Session 3: Food Allergy: Skin Disease or GI Disease?

Stanley Marks, BVSc, PhD, DACVIM (SAIM, Oncology), DACVN
University of California, Davis, CA

1. What do you tell clients that are fixated on “grains” as the allergen in their pet’s food?

Dr. Marks: Whole grains, rather than being fillers, contribute valuable nutrients including protein, vitamins, minerals, essential fatty acids, and fiber to foods while helping to keep the fat and calories lower than if animal products were used in their place. Even refined grains such as white rice can have beneficial health implications depending on the type of food and the pet. Dogs and cats can efficiently digest and use nutrients from grains. Allergies to grains are relatively uncommon in dogs and cats. It is becoming more common in the saturated pet food market for manufacturers to perpetuate myths to sell products and increase market share. Grain-free foods are often an example of this strategy. Many such products merely substitute highly refined starches such as those from potatoes or tapioca in place of grains. These ingredients often provide fewer nutrients and less fiber than whole grains while costing more.

(Source of information: Dr. Lisa Freeman, DVM, DACVN. Critical Updates on Canine and Feline Health. 2014 NAVC/WVC Proceedings)

2. You mentioned that increased permeability of the GI tract could be caused by early weaning.  Will that affect the dog for its entire life?

Dr. Marks: Maturation of the intestinal barrier in infants is critical to healthy intestinal function throughout life, and there is compelling evidence that intestinal illnesses associated with intestinal barrier dysfunction are more common in adults that were formula fed as infants than in those that were breast fed. It is well-established that intestinal barrier dysfunction can lead to gastrointestinal illness in infants and is a risk factor for inflammatory and autoimmune disease during adulthood. Since it is difficult to permanently alter intestinal barrier integrity in adults, greater success may be achieved by intervening in early in life to ensure the intestinal barrier matures appropriately, improving health during both infancy and adulthood. It is plausible that disorders such as canine parvovirus or other severe enteropathies during puppyhood could affect intestinal barrier function and predispose adult dogs to acquired disorders such as inflammatory bowel disease (IBD) or other autoimmune disorders.

3. In an effort to avoid Maillard compound formation, is feeding raw protein diets better for pets with CAFR (cutaneous adverse food reaction)?

Dr. Marks: The theoretical benefits of feeding raw protein diets to avoid Maillard compound formation must be weighed against the risks of bacterial contamination and zoonotic disease transmission when feeding raw diets. In addition, many of the raw diets are not complete and balanced and should be evaluated by a veterinary nutritionist for adequacy. To date, there have been no published studies that specifically compared the feeding of a raw protein diet with an isonitrogenous commercial diet containing processed proteins for dogs and cats with CAFR.

4. If you have a client feeding a home-cooked diet, do you recommend adding in a vitamin and mineral supplement as well?

Dr. Marks: It is pivotal that home-cooked diets be formulated by a veterinary nutritionist to ensure that the diet is complete and balanced and formulated for the animal’s life stage (growing puppy versus adult, etc). In addition, all home-cooked diets (whether cooked or raw) will need to be supplemented with micronutrients and vitamins.

5. How can you tell the difference between a fiber-responsive colitis and CAFR?

Dr. Marks: The clinical signs of a dog (or cat) with fiber-responsive colitis can appear virtually identical to an animal with CAFR having concurrent diarrhea; however, most animals with classic fiber-responsive colitis do not have pruritus and do not have CAFR. For this reason, one should feed an elimination or hydrolyzed protein diet if the animal has evidence of pruritus and concurrent enteropathy manifested with diarrhea, borborygmi, or increased gas production. In contrast, one can feed an elimination diet or a fiber-enriched diet to an animal that has signs of colitis without concurrent pruritus. 

6. Do you recommend prescription diets or home-cooked diets only for elimination trials or are over-the-counter (OTC) novel protein diets acceptable?

Dr. Marks: I generally advocate commercial diets (prescription or OTC novel protein diets) before recommending home-cooked diets unless the animal has a specific dietary need that cannot be met with a commercial diet (CAFR with concurrent renal disease or CAFR with concurrent pancreatitis, etc). I usually advocate prescription diets over OTC novel protein diets during the initial course of management, but will suggest switching to an OTC diet containing the same novel protein source if the owner has financial constraints. 

7. What is the best recipe for a home-cooked diet?

Dr. Marks: There is no single “best recipe” for a home-cooked diet because this will be heavily influenced by the palatability of the diet, the specific reason(s) for the home-cooked diet (novel, single protein source vs fat restriction vs protein restriction), and the overall health of the animal. 

8. Would raw diets be inherently less allergenic? Should we be supporting this more in practice?

Dr. Marks: There is a theoretical basis for the benefits of raw diets for the management of CAFR and diet-responsive enteropathies; however, clinical trials supporting these claims are lacking. These studies should be completed; however, it will be essential to ensure that the raw diets and the commercial diets being compared are isonitrogenous and isocaloric and have the identical ingredients. 

9. What do you think is the mechanism underlying food-responsive diarrhea?

Dr. Marks: The underlying mechanism of food-responsive diarrhea is not well understood; however, polymorphisms of genes encoding Toll-like receptors 4 and 5 have been documented in German shepherd dogs. Dysbiosis of the intestinal microbiota is a probably component of food-responsive diarrhea and studies in affected dogs have documented an increase in Proteobacteria phyla and a decrease in phyla Firmicutes and Bacteroidetes. Importantly, the prevalence of true food allergy among food-responsive cases has not been well investigated.

10. What about use of probiotics to reduce a patient’s vulnerability?

Dr. Marks: Probiotics have been investigated for their role in preventing and managing atopic dermatitis (AD) in human infants with mixed results. Probiotics, especially L. rhamnosus GG, seem to be effective for the prevention of AD. They were also found to reduce the severity of AD in approximately half of the randomized controlled trials (RCTs) evaluated, although they were not found to change significantly most of the inflammatory markers measured in the majority of the RCTs evaluated. More RCTs need to be conducted to elucidate whether probiotics are useful for the treatment or prevention of AD. Probiotics are currently being investigated for their role in managing dogs and cats with acute and chronic enteropathies, and results have been mixed depending on the cause of the underlying enteropathy and probiotic strain tested. 

11. Does fish oil supplement potentially react if concerned with fish allergies?

Dr. Marks: Veterinary nutritionists for the most part are not concerned about adverse responses to fish oil and routinely include it in novel homemade diets. For pets with documented or suspected adverse reactions to fish, we recommend omitting the fish oil initially to ensure the diet change is tolerated, then add it later assuming the pet is otherwise stable. Another option is the algal-sourced DHA oil (most branded products are actually this: http://www.dsm.com/markets/foodandbeverages/en_US/products/nutritional-lipids/life-dha.html ). Veterinary nutritionists use this for owners who are vegetarian and who object to fish oil. 

12. Do the hydrolyzed protein diets also have contamination issues?

Dr. Marks: Any commercial diet (hydrolyzed or intact protein) is potentially susceptible to contamination issues and the risk of this problem is minimized with appropriate quality control measures in the processing plant. 

13. After a GI insult/event, such as parvo, does it make sense to feed a hydrolyzed diet until the mucosal barrier is healed to avoid inciting an allergic response?

Dr. Marks: The optimal diet to feed a puppy or kitten immediately following a severe GI insult has not been defined, although there are a plethora of supplements that have been fed to human infants and rodent or porcine models to enhance intestinal barrier function following insults to the barrier. Prebiotic supplementation to formula-fed infants increased Bifidobacteria counts and reduced the occurrence of diarrhea four-fold. Some food components such as curcumin, a polyphenolic from turmeric, reduced inflammation in a mouse model of colonic inflammation. Black tea has multiple effects on physical aspects of the intestinal barrier in that it can improve tight junction integrity and speed gastrointestinal transit. Some polyunsaturated fatty acids (PUFAs) are able to decrease intestinal permeability and reduce intestinal inflammation. Bovine colostrum and goat milk powder were shown to reduce heat-induced intestinal hyperpermeability in a rat model. Additionally, food components can promote immune system development and homeostasis (immunological barrier). For example, lectin from kidney beans can accelerate the process of intestinal mucosa maturation in piglets. The benefits of hydrolyzed diets being fed after a GI insult (eg, parvo) have not been investigated to date, although there are theoretical benefits that support the application of these diets or the feeding of digestible diets containing a different protein source to that fed immediately prior to the onset of the parvovirus infection.

14. What is your experience and opinion of standard process or other Eastern medicine supplements for the GI tract?

Dr. Marks: I have minimal experience with the use of Eastern medicine supplements for the GI tract. I have included findings from several different studies evaluating this modality in human patients with IBD. There are diverse rates of use of complementary and alternative medicines (CAMs) across Asia. In seven randomized controlled trials of patients with Crohn’s disease (CD), Artemisia absinthium (wormwood) and Tripterygium wilfordii were superior to placebo in terms of inducing remission and preventing clinical recurrence of postoperative CD, respectively. In two systematic reviews, omega-3 fatty acids did not appear to be effective for the maintenance of CD remission. Effective anti-inflammatory moieties have yet to be defined. Another problem is the indiscriminate use of various CAMs without sufficient evidence in patients with IBD. More studies are needed to determine the efficacy and safety of CAM in such patients. 

15. What diets do we feed if the dog has been fed prior chicken or soy and now hydrolyzed protein causes them to have worsening of signs. What do you feed them in the meantime?

Dr. Marks: I would choose a novel protein source diet (commercial) if feasible as my first option. Assuming that there are no other commercial diet options, I would feed a home-cooked diet for the animal using a novel, single protein source. This diet does not have to be complete and balanced if fed for 3 to 4 weeks, and you could feed the diet for several weeks to ensure that it is palatable and not associated with a worsening of clinical signs before having it balanced by a veterinary nutritionist. Lastly, Blue Buffalo has formulated a hydrolyzed salmon diet, although I have not used this diet to date.  

Session 4: Report Card on New Therapies in Dermatology

Thomas P. Lewis II, DVM, DACVD
Dermatology for Animals. Gilbert, AZ

M. Nell Dalton, DVM, MS
Animal Medical Center, Boise, ID

1. Does sublingual immunotherapy (SLIT) have the same possible prophylactic reaction as subcutaneous immunotherapy (SQIT)? 

Dr. Lewis: We have less “long-term” knowledge of SLIT in veterinary medicine regarding the potential for prevention of additional allergy development compared with the experience of injectable immunotherapy. My “impression” in the field after 3 years of utilization of SLIT is that it is as effective for preventing the atopic dermatitis from worsening over time as are the injectable protocols.

2. What are your thoughts about intradermal testing and specific immunotherapy based on that testing versus generic serums based on regional allergen profiles?

Dr. Lewis: After 25 years of being a passionate allergist and trying to hone my skills in immunotherapy, I have seen without a doubt that the contents of allergy immunotherapy matters! No doubt there are some patients who will exhibit a nonspecific positive response to immunotherapy. But I have had countless patients where manipulation and adjustments of the allergen contents based on the patient’s exposure to allergens, and when they were flaring, resulted in a positive response. If a clinician is administering immunotherapy of any type (SQIT or SLIT) and not looking at a pollen count every day, he or she is not adequately prepared to make these adjustments.

3. Can immunotherapy ever be stopped in pets like you can in humans? 

Dr. Lewis: Yes, immunotherapy remains the only therapy that has a chance to “cure” a patient with atopic dermatitis. One study in dogs showed 15% of dogs with atopic dermatitis were cured of their disease with immunotherapy. That number may actually be even higher because many clients do not want to stop immunotherapy because of fears of regression of the disease. 

4. Can you switch to the subcutaneous route for long-term management once you have a good response to sublingual immunotherapy to decrease the frequency? 

Dr. Lewis: My recommendation in this scenario would be to decrease the frequency of the sublingual immunotherapy to every other day, or even less.

5. What cancers developed in the dogs on Apoquel?  

Background information from Zoetis: There is no known relationship between the use of Apoquel and the development of neoplasia in dogs. The incidence of neoplasia in Apoquel-treated dogs in the field and continuation studies occurred no more frequently than is seen in the general population of dogs. The FDA placed a warning that Apoquel may exacerbate neoplasia on the label due to the class of drug to which Apoquel belongs. During the pre-approval testing program, over 1500 dogs globally were enrolled in clinical trials evaluating Apoquel, some for longer than 2 years. Dogs with pre-existing, malignant neoplasia were not allowed to enroll in these studies; as a result the relationship between Apoquel and exacerbation of neoplasia has not been studied. While the Continuation Therapy program did not have a control group for comparison, the rate of neoplasia in these middle-aged to older dogs was not greater than what would be expected in an aging population of dogs. Development of malignant neoplasia was not seen in the Apoquel high dose safety studies with laboratory beagles treated at up to 5X the label dose for 26 weeks.

6. Do you have concerns with the use of Apoquel when Demodex is diagnosed? 

Background information from Zoetis: The Apoquel label states that Apoquel may increase susceptibility to infection, including demodicosis, and that dogs should be monitored for the development of demodicosis but there is no contraindication to use in dogs that have been previously treated for demodicosis. If demodicosis is diagnosed in a dog with allergic dermatitis that is being treated with Apoquel, the veterinarian and pet owner should decide on continued use. Two (2) cases of demodicosis were reported in the dogs treated with Apoquel at the label dose in the clinical field studies and Continuation Therapy study (N=239). In the atopic dermatitis clinical efficacy study, an 8.5-year-old, female-spayed, purebred golden retriever developed demodicosis of the lip area with lymphadenopathy and was withdrawn from the study following 28 days of Apoquel administration. The demodicosis resolved with treatment. In the Continuation Therapy study, a 6.2-year-old, male-castrated, Scottish terrier with pre-existing diabetes mellitus was diagnosed with demodicosis following 273 days of treatment. Skin scrapings of the ears and hocks were positive for Demodex. The dog was removed from the study and the condition resolved with treatment. Treatment with Apoquel was restarted approximately 8 months later and the dog has had no recurrence of demodicosis after an additional 8 months of therapy (as of May 1, 2013).

7. What do you use to treat Demodex if NexGard fails to control it?

Dr. Dalton: Regardless of the medication used for treating Demodex, it is recommended that treatment results are monitored with monthly skin scrapes. The treatment interval should continue one month past the THIRD negative skin scrape. No mites, alive or dead, mite parts or eggs should be found on the negative scrapes. If the NexGard (afoxalaner; Merial) is not effective I would choose either Bravecto (fluralaner; Merck) or Simparica (sarolaner; Zoetis). All of these medications are currently off label for treatment of Demodex. The treatment interval for Demodex in the canine can be varied. If the animal is not responding or worsening, a metabolic workup should be considered as should referral to a dermatologist. 

 

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