Sponsored by an educational grant from Zoetis
- The cytokine interleukin (IL)-31 is important in sending the signals to the brain that result in pruritus in dogs with canine atopic dermatitis (CAD).
- A new generation of CAD therapeutics, including APOQUEL®, a Janus kinase inhibitor, and CYTOPOINT™, a monoclonal antibody that blocks canine IL-31, is now available.
- APOQUEL (oclacitinib), an oral tablet, provides fast, effective, and safe relief—without the side effects of steroids—from itch associated with any allergic dermatitis and is particularly useful during the diagnostic workup of the allergic dog.
- CYTOPOINT, a monthly injectable, provides sustained relief in dogs with CAD and can be used in dogs of any age, dogs with comorbidities, and in conjunction with other medications.
Dr. Gloyd: As background, what do we now know about canine atopic dermatitis (CAD)?
Dr. Rosychuk: The more we learn, the more we realize how complex this disease is. We would still characterize CAD as a genetically predisposed allergic skin disease manifested clinically by pruritus and inflammation. We still believe IgE is part of the story, but perhaps not to the degree that we once thought. More recently we have learned a lot more about other mediators, such as interleukin-31 (IL-31). Today, we understand there are both neurologic and immune components to CAD, as well as mechanical defects in the skin barrier.
Figure 1 The cytokine IL-31 is released from Th2 lymphocytes and directly activates sensory neurons in the dermis to induce pruritus. The cytokines IL-2, -4, -6, and -13 promote the inflammatory process through activities involving mast cells, eosinophils, and dendritic cells, among others.
Exposure to environmental and other allergens is thought to be predominantly transcutaneous, with Langerhans cells in the epidermis trapping and presenting the antigen(s) to T lymphocytes (Figure 1). This pathomechanism is likely potentiated in many dogs with atopic dermatitis by a defective epidermal barrier (especially the lipid components). Immunologically, atopic dogs respond to allergen presentation with a T-helper type 2 (Th2) response. These Th2 cells produce cytokines that are pro-inflammatory and pruritogenic. The pro-inflammatory cytokines (interleukins 2, 4, 6, and 13) drive the inflammatory response that characterizes allergic dermatitis.
In addition, Th2 cells produce IL-31, a pruritogen that is key in signaling peripheral nerves to send signals to the brain to induce itch. Activated T cells are primed to respond in this exaggerated manner upon subsequent exposure to the same allergen, causing the chronic, often progressive nature of the disease. The Th2 cells stimulate B cells to produce allergen-specific IgE, which has relevance to degranulation of mast cells and release of inflammatory mediators upon subsequent allergen exposure. However, with the more recent elucidation of the central role of IL-31 as a specific inducer of itch, the focus has moved away from mast cells and IgE somewhat.
Dr. McKay: Genetic predisposition can impact both immune hypersensitivity and also potentially predispose to barrier defects. There can be differences in clinical signs not just between breeds, but also within a specific breed, depending on the genetics of the dog, where the dog lives, and the time of year. An individual dog can be severely affected in one location where allergen levels may be very high—and in another, not have as many flares. The same is true in people.
Dr. Lewis: I think skin barrier defects are an element of the disease that many practitioners are still not focusing on. Barrier defects not only allow increased exposure to allergens, they may also be the reason why we see so many secondary infections. The infections, because of the pruritus, are a significant part of the clinical disease and reason for patient presentation. It’s really critical that we recognize the barrier problem and work to restore a functional barrier. Good management means prevention—identifying and avoiding exposure to known allergens and providing specific care to minimize the impact of barrier defects with topical therapies.
A Stepwise Approach to a Diagnosis by Exclusion
Dr. Gloyd: Why is it so important to rule out parasites, infection, and other causes of itch?
Dr. Stokking: Atopic dermatitis is a diagnosis of exclusion in dogs (see Diagnosis by Exclusion). Every time a dog presents with an itch—whether it’s the first time or the 21st time—always make certain it is not an infection or parasites. Every atopic dog should be on year-round flea control for that very reason. Fleas can be a year-round problem in most parts of the United States. In a dog with flea allergy, it only takes one flea bite to incite a flare. The same is true if there is an underlying food allergy—it only takes ingestion of a small amount of the food allergen to initiate scratching. Seasonal history of pruritus is often a feature that puts atopic dermatitis higher on the list of rule-outs.
Diagnosis by Exclusion
A systematic approach to itchy dogs, applied at each presentation and recheck, avoids unnecessary treatment failures:
- Is there anything about the lesions or on skin cytology that would suggest the probable role of a secondary Staphylococcus or yeast infection? Cytology and culture may be important.
- Could the pruritus be caused by a parasite, most commonly fleas or scabies mites? Skin scrapings and evaluation of parasite control measures on all pets in the household should be considered.
- Is there any possibility that diet may be important, especially in non-seasonal disease? Have we ruled out food allergy or has the dog had a dietary indiscretion?
- If infection, parasites, and food allergy have been systematically ruled out and the dog is still pruritic, a diagnosis of atopic dermatitis is appropriate.
Dr. McKay: I’ve had dogs with pruritus that are responding poorly to conventional therapies, and I have performed just one more skin scraping—only to find scabies mites! When a patient’s pruritus starts in the spring, it can be easy to default to a diagnosis of atopy when you fail to rule out all other differentials.
Dr. Hansen: You have to do your due diligence every time. A flea-allergic dog that is not on flea preventative in January because it lives in Chicago may have been exposed to fleas if it was boarded or traveled, or because flea burdens can be maintained through winter in controlled home climates.
Dr. Lewis: We can all get caught by zeroing in too fast based on one element of the story that seems to make sense. You need a systematic approach, and use it every time.
Current Treatment Options—Overview
Dr. Gloyd: Multimodal therapy is typically advocated for dogs with CAD. Let’s talk about specific treatments.
Dr. Hansen: Controlling the itch is key— when the patient first presents, while you are pursuing a diagnostic workup, or when the dog already diagnosed with atopic dermatitis has a flare of the disease.
Dr. Stokking: Yes, I agree. Glucocorticoids have traditionally been one of the most common treatments used in atopic dogs. While glucocorticoids treat the clinical signs by suppressing inflammation, they don’t address the underlying cause. In addition, because glucocorticoid receptors are present in every cell in the body, there can be significant adverse effects with long-term use that affect most organ systems, such as adrenal suppression, liver issues, cutaneous atrophy, and hair loss. These adverse effects may be seen whether they’re used systemically or topically. We have far better treatments available now.
Dr. Gloyd: Do antihistamines have a benefit in treating allergic and atopic dogs?
Dr. Rosychuk: Overall, success with antihistamines is probably between 15% and 25%. It can take a lot of trial and error to find which antihistamine works for an individual. An advantage of antihistamines is that they are very well tolerated, and because of this it is not uncommon for us to use combinations of two antihistamines at the same time. I think individuals that benefit from antihistamine therapy tend to be more mildly affected with allergy. The bottom line, however, is the success rate is low.
Dr. Gloyd: What about cyclosporine for atopic dogs?
Dr. Hansen: The rationale for cyclosporine is that it only affects T-helper cells so it might be safer than steroids for long- term therapy. The main drawback is that it doesn’t have any immediate effect. Most owners want their dog to stop itching tomorrow, not in 3 or 4 weeks. Besides gastrointestinal side effects in over 30% of dogs, gingival hyperplasia and—with high doses—deep fungal infections can occur.
Dr. Lewis: In my hands, there’s still a place for cyclosporine with an atopic dog with significant secondary skin changes, inflammation, and scarring, for example, in their ears and/or on their feet.
Dr. McKay: I don’t think we’re ever going to find one drug that works in 100% of our population because of the complex pathophysiology of this disease. That’s why I keep a number of different antipruritic drugs in my arsenal—so I can find the one that is best for each patient.
Dr. Gloyd: Where does antigen-specific immunotherapy (ASIT) fit in your overall management?
Dr. Stokking: Veterinary dermatologists seem to report better success rates with desensitization than many general practitioners. That could be because desensitization does not work in a dog that is not atopic or not allergic to environmental allergens; and owners seeking a specialist referral are more willing to allow a thorough diagnostic workup. Remember that the serum tests and even intradermal testing can show “positive results” in dogs that are not atopic. ASIT has to be tailored to the individual patient; it is not a one-size-fits-all protocol.
New Science Opens the Way for New Therapies
Dr. Gloyd: Let’s talk about the new generation of CAD therapeutics. Where does APOQUEL® (oclacitinib) fit in your arsenal?
Dr. McKay: APOQUEL is a Janus kinase (JAK) inhibitor. Blocking this enzyme in allergic and atopic patients decreases inflammation and pruritus. APOQUEL can deliver on two key points in managing atopic disease: 1) it quickly reduces pruritus, within 4 hours of administration, which is what owners want to see, and 2) it reduces the inflammation, redness, and irritation of the skin. I find it very helpful for many patients. APOQUEL is labeled for control of pruritus associated with allergic dermatitis as well as atopic dermatitis in dogs. This is a huge advantage: it can be used to control the itch during the initial workup while you determine if it’s due to flea allergy, food allergy, or atopic disease. I find it is well tolerated. I’ve rarely had issues of GI upset. I would say the overall success rate in my hands is over 90%.
Dr. Rosychuk: APOQUEL can be used to control pruritus while waiting for ASIT to have an effect (which may take several months). APOQUEL is also useful in controlling pruritus while preparing a patient for intradermal testing; unlike glucocorticoids, APOQUEL does not affect intradermal testing so it can be administered up until the day of the test.
Dr. McKay: APOQUEL has been a game-changer for so many of my patients, especially those for whom nothing else has worked. It really improves the quality of life for both patients and families.
Dr. Gloyd: What about the newest class of CAD therapeutics, antibody therapy, or biologic therapy?
Dr. Rosychuk: Biologic therapies have been used in human medicine for a long time. Depending on the disease they treat, biologic therapies can target receptors on cell surfaces, tumor cells, and various biochemical mediators such as cytokines. Antibody therapies are most often used to treat chronic conditions such as asthma or rheumatoid arthritis in people.
Figure 2 CYTOPOINT™ neutralizes IL-31 in circulation before it binds to cell surface receptors and blocks downstream signaling.
Dr. Stokking: CYTOPOINT™ is a monoclonal antibody (mAb) that blocks canine IL-31. It is one of the first antibody therapies available in veterinary medicine. Recent research has demonstrated the importance of IL-31 as a key cytokine involved in CAD. CYTOPOINT is a caninized mAb, which means that it is almost identical to natural canine IgG, minimizing the possibility of being recognized as foreign by a dog’s immune system. This caninization (or speciation) of the antibody is critically important to the safety and efficacy of a therapeutic antibody. CYTOPOINT works by binding to circulating IL-31 before it binds to the surface receptor on cells, and blocking the downstream signal that stimulates the itch response in the dog (Figure 2).
Dr. McKay: In trying to explain this medication to my clients, I ask them to imagine that CYTOPOINT is a lock, and the key is IL-31. By binding IL-31 in circulation, we’re turning it off so that it cannot fit in a lock anywhere else in the body and exert its effect. In human medicine, they use the term precision therapy to describe monoclonal antibody therapy. For our veterinary patients, a precise treatment that targets only cytokine IL-31 is going to help improve safety. It works primarily by stopping itch, which can cause inflammation, without effects on important aspects of immune surveillance or other arms of the immune system.
Dr. Gloyd: Let’s talk about some of the basic properties of CYTOPOINT.
Dr. Rosychuk: CYTOPOINT is given as a subcutaneous injection according to the package insert. It is available in 1-mL vials in four concentrations (10, 20, 30, or 40 mg); each vial is for single use only, and should be discarded after puncture. CYTOPOINT is very well tolerated; it’s been exceedingly uncommon for us to see any local injection-site reactions.
Dr. Hansen: It’s almost too easy. We must be very cautious and emphasize the need to do a complete workup on the dog for underlying cause rather than just treating the pruritus.
Dr. Gloyd: What is the safety profile of CYTOPOINT?
Dr. Hansen: Safety studies and clinical experience, so far, have not identified any effects on other parts of the body as a result of inhibition of IL-31. In addition, biologic therapeutics, unlike traditional pharmaceutical agents, do not need to be metabolized by the liver or kidney. The mAb is degraded in the body just like any other protein by intracellular catabolism independent of the liver and kidneys, likely contributing to the very good safety profile.
Dr. Stokking: For that reason, we don’t see any interactions with drugs that are metabolized by those organs. Consequently, there’s no pretreatment laboratory testing required before using CYTOPOINT. Repeat injections are administered in my hospital, which gives me a chance to re-evaluate that patient and monitor the response to treatment, unlike dogs on oral or topical medications, which I dispense for the owner to administer.
Dr. McKay: Pet owners and veterinarians might be aware of other antibody therapies used in human medicine and assume that the side effects they hear described in advertisements for those products are relevant to CYTOPOINT. However, you cannot generalize about biologic therapies in that way or make that type of comparison. When it comes to biologic therapy, the target and its role in the target species is key.
Dr. Hansen: We use CYTOPOINT in all types of patients with atopic dermatitis, and have not seen any significant side effects. I have not found a patient yet in which it would be contraindicated. A very small percentage of dogs that I have treated have experienced transient lethargy after the first few injections, but it has never become a clinical issue or required treatment.
Dr. McKay: Not a side effect per se, but one point I think is relevant for veterinarians to remember is that this is a refrigerated product. It is helpful to let the vial warm up to room temperature before you administer it because otherwise the injection may cause some discomfort and the owner may perceive the injection as painful, which it is not.
Dr. Gloyd: What about efficacy? How long does it routinely take before you have blocked that itch?
Dr. Stokking: My initial goal was just to block the itch, and that’s certainly the most important effect. I see a demonstrable response in most of my patients in 24 to 48 hours. But I feel like I’m being pleasantly surprised by seeing the skin lesions start to resolve, more than what I would have expected by only decreasing scratching and itching.
Dr. Lewis: We’ve had individuals where pruritus has been markedly better within hours of an injection. Three days may be the maximum time for CYTOPOINT to really kick in.
Dr. Gloyd: What is the duration of effect?
Dr. Hansen: The label says it can be repeated monthly, as needed. In our experience, there have been dogs in which the itch starts to creep back before the month is up, but other dogs can go 6 or 8 weeks, and even longer.
Dr. McKay: I live in an area with a seasonal climate so I am tracking some of these dogs pretty closely. When spring hits, depending on their allergies, I have seen the effect lasting a bit shorter at the height of the season.
Key Benefits of CYTOPOINT
- A biologic antibody therapy that specifically targets and blocks IL-31, one of the key cytokines involved in triggering itch in dogs
- Administered via subcutaneous injection, aids in the reduction of clinical signs (itching and skin lesions) of atopic dermatitis in dogs for 4 to 8 weeks
- A long-term therapy that allows repeated dosing at 4- to 8-week intervals to help control the clinical cause of itch in CAD
- Based on the specificity of the antibodies and the downstream target effects, CYTOPOINT is not expected to negatively impact or impair normal immune function. In the clinical studies to date, no systemic reactions have been observed (Zoetis, data on file, 2016).
- Like other naturally occurring antibodies, CYTOPOINT is eliminated via normal protein degradation pathways and not metabolized by the liver nor excreted through the kidneys.
- Unlike steroids, CYTOPOINT can be used concurrently with common therapies, including but not limited to vaccinations, allergen-specific immunotherapy, anti-infectives, anti-inflammatories, and many other drugs.
Dr. Hansen: We practice in northern Virginia and we put a lot of our dogs on CYTOPOINT in the fall. I expected them to do pretty well in the winter, but I was pleasantly surprised when the spring hit and we didn’t see any shortening of duration of action. I don’t know whether it’s because we don’t have as many inflammatory factors here, or if the atopic dermatitis hadn’t had a chance to really accelerate. But the effect was still 4 to 6 to 8 weeks in the spring.
Dr. Stokking: I live in a non-seasonal area and I’m seeing a 4- to 6-week duration of effect. My patients that have the most severe, chronic CAD that have failed to respond to combinations of all other therapeutics don’t respond as quickly as my patients with less severe disease. Some of them will start to show a beneficial response only after the second or third injection. I have seen an added benefit in some severely affected patients whose owners have persevered and allowed me to do multiple monthly injections.
Dr. Rosychuk: Individual patients always have a slightly different response to any treatment. At Colorado State, we’ve looked retrospectively at the individuals that we’ve treated and the duration of antipruritic activity associated with a given CYTOPOINT administration. For 60% of patients, that duration was 4 weeks; for 10% it was 5 weeks; for 5% it was 6 weeks; for 20% it was 3 weeks; and for 5% it was 2 weeks. We’ve also noticed the tendency to have the duration of benefit shorten with seasonal worsening of signs in a small number of individuals. We’ve looked at chronicity of disease and severity and these factors have not been good predictors of response to CYTOPOINT.
Dr. Gloyd: What do you say to owners to help set expectations on treatment results?
Dr. Stokking: I tell them that most owners see an effect in 1 to 2 days. If I’m treating a dog with a concurrent infection, they may see some improvement in a few days but it may take up to a week to really see the maximum benefit. If their pet is not better in a week, I tell them to let me know. I don’t get many calls back. Most of the time, I get emails saying, “I can’t believe my dog is not scratching and itching anymore.” I also involve them in the treatment process by telling them they will see when itch recurs and their dog is ready to come back for another treatment.
Dr. Gloyd: When itching returns, is it gradual?
Dr. Rosychuk: This is one way CYTOPOINT is different from APOQUEL. With APOQUEL, it is very clear when the antipruritic effect has worn off—it’s dramatic. For CYTOPOINT, it’s much more gradual.
Dr. Gloyd: What’s the longest that you have used CYTOPOINT in a patient so far?
Dr. Hansen: The majority of our patients have been on the full 8 months of therapy since CYTOPOINT became available. (Starting in October 2015, prior to full licensure, CYTOPOINT was known as Canine Atopic Dermatitis Immunotherapeutic.) It has retained its efficacy for those long-term patients. I have not seen any side effects at this point; it is being very well tolerated.
Dr. Gloyd: What is your experience with efficacy of CYTOPOINT in the patients you have treated on an ongoing basis with multiple monthly injections?
Dr. Hansen: I have treated a number of patients on an ongoing basis. Each patient is a little bit different with regard to how often they need to be treated, but in my cases, the fifth and sixth injections have been universally as effective as the first injection.
Dr. Stokking: In my experience, sometimes the longer the dog is treated, the longer the interval between injections.
Dr. Lewis: That has been my experience, too. The effect seems to last a bit longer as dogs are on therapy longer, with the exception of some of those patients with seasonal flares.
Dr. Gloyd: Do you use CYTOPOINT in both big and small dogs?
Dr. Hansen: When we first started using CYTOPOINT, we used it mostly in smaller dogs. But we had an 80-pound, non-seasonal, itchy dog come in for non-dermatologic medical reasons, and we could not use other therapies in that patient. We gave the dog a CYTOPOINT injection and it provided relief from the itch for 3 months. The second injection also lasted 3 months. Since then, we’ve given it to other large dogs and I have been very pleased with the duration of therapy.
Dr. Gloyd: What is your experience with dogs that don’t respond?
Dr. Stokking: I have a hard time identifying any patients that were absolute failures.
Dr. Hansen: I’ve looked through our data and we had three patients (out of 107 we treated) where the owners did not feel there was much improvement. In two or three other cases, the owners were very happy with the degree of improvement—they got 6 hours sleep rather than 4 hours—but I was not overwhelmed with the response.
Dr. McKay: The only failures I have seen with CYTOPOINT were in dogs that I ultimately diagnosed with methicillin-resistant Staph infection. I gave them the CYTOPOINT injection, sent them home with their beta-lactam antibiotic, and these clients reported that their dogs were no better. When they returned, we found that the dogs had persistent infections. I think these cases represented failure to control the secondary infections rather than a CYTOPOINT treatment failure.
Dr. Rosychuk: Our success rate in dogs documented to have CAD has been 97%, and to date we’ve only had three failures not associated with any secondary infection. In patients with an infection, particularly methicillin-resistant infection, the fact that CYTOPOINT does not have immunosuppressive properties at all is an advantage over other immunomodulating therapies that may be considered to control itch in these dogs.
Dr. Gloyd: What about CYTOPOINT use in dogs that cannot take other medications, or those that are already on other maintenance therapies for their atopic disease but still have flares?
Dr. Stokking: One of the great things about CYTOPOINT is you can use it in dogs on other medications—for allergies or otherwise. I frequently use it in conjunction with APOQUEL. I also use CYTOPOINT to help reduce the need for other concomitant allergic therapies. For example, I have an atopic shepherd that also has lymphoma in remission; CYTOPOINT provided a very unique opportunity to manage this dog’s dermatologic disease. He’s no longer receiving steroids for the lymphoma and the atopy is being managed with only CYTOPOINT.
Dr. Gloyd: What are some of the advantages of this product over steroids and other therapies?
Dr. Rosychuk: A recent report at the World Congress of Veterinary Dermatology documented that you don’t have to take dogs off CYTOPOINT to do allergy testing. That’s another big advantage—you can control the itch and still do the diagnostics. You can’t do that with steroid therapy. You can also use CYTOPOINT to help provide relief to the patient during the initial several weeks of an 8-week food trial. Once the antipruritic effect of the CYTOPOINT has worn off, the benefit of the diet alone can be ascertained. It makes owners much more accepting of the recommendation of a food trial if they know the itch can be controlled during much of the trial.
Dr. McKay: CYTOPOINT has been wonderful in cases where I want something that’s going to add an element of itch control with a really good safety profile and without being concerned about drug interactions. I have quite a few patients that are atopic and have a history of demodicosis or concurrent neoplasia: previously I had to make very difficult choices with these dogs but I do not have any concerns using CYTOPOINT in these patients.
Dr. Stokking: Young atopic dogs under a year of age are a patient population where there really aren’t any other choices that are beneficial. APOQUEL is not labeled for dogs less than one year of age but we can use CYTOPOINT in these patients.
Dr. Rosychuk: CYTOPOINT has also been a real boon in older dogs on multiple medications, where we’re worried about interactions with other drugs.
Dr. Gloyd: How are you managing rechecks?
Dr. Hansen: Once individuals have been well controlled and secondary issues have been taken care of, we set aside appointment slots for people to drop in and our technicians give the injection. If issues are recognized by the technician, they are addressed with the dermatologist at that time. This has gone very smoothly for us and clients love it because they’re just in and out.
Dr. Rosychuk: We do the same in our clinic. For those clients who come in “as necessary” for the shots, it is generally not an emergency where you have to get them in the very next day because there is a gradual return of the pruritus in dogs on CYTOPOINT therapy.
Communicating with Owners of Atopic Dogs About Therapeutic Options
- With new therapies, the likelihood that we can help control the clinical signs that are affecting the quality of life of the dog and its family are very high while we work to diagnose exactly what is causing this allergic condition.
- However, this is a condition that is going to require lifelong management; and we are going to have to partner together to work through what the underlying cause is: infectious/parasitic, food, inhalant or contact allergies, etc.
- There will be occasional flares—may be due to seasonal exposure to allergens, fleas, or other sources or secondary infections. It’s better to stay ahead of the curve.
- Briefly outline the choices on a whiteboard or notepad—keep it simple.
Dr. Gloyd: As a general practitioner, how do I communicate with owners about treatment options?
Dr. Stokking: It could be difficult for the general practitioner to be able to carve out the time from a 15-minute appointment to really have that discussion with the owner. As specialists, we have that luxury in our consultations. General practitioners need to develop talking points to have a succinct, but informative discussion (see Communicating with Owners of Atopic Dogs About Therapeutic Options).
Dr. Lewis: I think it’s important when talking about treatment options that we don’t make the decisions for the owner. I try to give them all the choices and the pros and cons of each so they can decide what is the best option for their dog. I consider a couple of factors: age and overall health of the dog, seasonality, compliance, and cost for that size dog.
Dr. Gloyd: What do you think is the greatest advantage of CYTOPOINT?
Dr. Stokking: Safety.
Dr. McKay: Efficacy.
Dr. Lewis: Ease of administration.
Dr. Hansen: Compliance.
IMPORTANT SAFETY INFORMATION
Do not use APOQUEL in dogs less than 12 months of age or those with serious infections. APOQUEL may increase the chances of developing serious infections, and may cause existing parasitic skin infestations or pre-existing cancers to get worse. APOQUEL has not been tested in dogs receiving some medications including some commonly used to treat skin conditions such as corticosteroids and cyclosporines. Do not use in breeding, pregnant, or lactating dogs. Most common side effects are vomiting and diarrhea. APOQUEL has been used safely with many common medications including parasiticides, antibiotics and vaccines.
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