Zeroing in on canine atopic dermatitis

By Matt Carnett, DVM and Jon Plant, DVM, DACVD

There have been a number of advances in canine atopic dermatitis treatment within the past few years, notably the introduction of the janus kinase inhibitor Apoquel (oclacitinib), manufactured by Zoetis. While the shortage has been aggravating, Apoquel has proven safe and effective for the treatment of canine atopic dermatitis. Recently, Zoetis has conditionally released a new product to veterinary dermatologists that adds to the therapeutic options for one of veterinary medicine’s most common disorders. Currently, the product is called “Canine Atopic Dermatitis Immunotherapeutic” or CADI. It’s a once monthly subcutaneous injection for atopic dermatitis related pruritus that grew from the research that brought us Apoquel.

CADI

Interleukin-31 is a cytokine associated with pruritus and inflammatory cell infiltration into the skin in humans and dogs with atopic dermatitis.¹ IL-31 is produced by activated Th2 lymphocytes and when signaled, binds to a heterodimeric receptor causing initiation of a signal transduction cascade. One of the components of this cascade is the janus kinase system, which is inhibited by oclacitinib.

CADI is a canine monoclonal antibody that specifically targets IL-31, neutralizes it, and prevents binding of the receptor. This inhibits the entire cascade, which in turn decreases janus kinase–mediated itch. In essence, it works like oclacitinib, but earlier in the pathway and with more specificity. A single subcutaneous injection of CADI produces noticeable pruritus relief versus a placebo for up to 56 days.² Veterinary dermatologists are now exploring how CADI is accepted and incorporated into clinical practice. It’s not known when CADI will be more widely available. Hopefully, it will soon be another option veterinarians will have for managing canine atopic dermatitis.

References:

1. Gonzales AJ, Humphrey WR, Messamore JE, et al. Interleukin-31: its role in canine pruritus and naturally occurring canine atopic dermatitis.Vet Dermatol. 2013; 24:48–53

2. https://www.zoetisus.com/products/dogs/il-31/efficacy.aspx

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What makes dogs itch?

Dogs are taken to veterinarians for itching more than for any other medical problem. But what makes dogs itch?  While there are many possible causes, most dogs that are itchy suffer from one of these six conditions:

  • Flea allergy dermatitis
FAD distribution

Flea allergy dermatitis distribution

  • Atopic dermatitis
  • Food allergy dermatitis
  • Contact dermatitis
  • Sarcoptic mange
  • Demodectic mange

To take a quick look at the body locations commonly affected, the symptoms, and the types of lesions associated with each of these conditions, check out www.itchology.com. Itchology is the app for dedicated pet parents to mange their itchy dogs.

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Retrospective evaluation of Apoquel® (oclacitinib) for the treatment of atopic dermatitis. Part 2: monitoring for side effects.

By Jon Plant, DVM, DACVD

In September I reported on the effectiveness of Apoquel® (oclacitinib) in controlling pruritus (itch) in the first 117 dogs that I had treated with this newish medication from Zoetis. When I prescribe Apoquel, I recommend obtaining a baseline complete blood count (CBC), serum chemistry, and urinalysis, with examinations and additional monitoring scheduled at 3, 6 and 12 months. There is no specific guidance from Zoetis or the FDA concerning monitoring the long-term use of Apoquel. This is the level of monitoring that I would do for my own dog taking this new drug, given that it modulates the immune system. Each veterinary practitioner will recommend what they are comfortable with and this may be influenced by experiences (positive or negative) and will likely evolve over time.

I selected several laboratory parameters to analyze over a 6-month period for 66 dogs. Note that this is not a rigorous clinical trial and may well suffer from selection bias. The parameters that I chose to present here are some of those that showed significant changes over time in some of Zoetis’ clinical trials, although in some cases at different time points than mine.

wbc2

 

 

 

 

 

 

 

Descriptive findings: There was a slight decrease in the mean WBC count from day 0, but in none of the dogs did the WBC count fall below the reference range.

The dog with a WBC count of 25,700 at day 0 had generalized, severe pyoderma, a normal body temperature, and was extremely itchy (pruritus visual analog scale score of 10.0). We elected to continue Apoquel despite the elevated WBCs, as well as cefpodoxime.  At his 3 and 6-month examinations, the WBC counts and itch levels were back within normal ranges.

Among individual white blood cell lines, neither mean neutrophil nor mean lymphocyte counts were greatly changed during the 6 months of Apoquel therapy.

neutrophils and lymphocytes

 

 

 

 

 

 

 

 

 

Next time I’ll present data from these dogs for cholesterol, alkaline phosphatase, and globulin.

Have you had a chance to check out Itchology for iPhone?  It’s an easy and fun way for dedicated pet owners to chart their dog’s itch level and treatments, set medication reminders, and look for possible causes and effective treatments. Available on the Apple App Store or visit www.itchology.com for a demo video and more information.

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Apoquel vs. Atopica: a comparison of two medications to control atopic dermatitis in dogs

By Jon Plant, DVM, DACVD

Atopica® (cyclosporine) and Apoquel® (oclacitinib) are separate and distinct medications. Both are used for controlling the signs and symptoms of atopic dermatitis (“allergies”) in dogs. They are two of the most effective allergy treatments for dogs. Let’s see how they compare.

Availability of Atopica and Apoquel

Atopica was FDA approved more than 10 years ago and is widely available as a prescription drug through veterinarians.

Apoquel was launched in January 2014, but the demand quickly exceeded the manufacturing capacity of the manufacturer, Zoetis. This has led to very limited availability and backorders. Most veterinary clinics are unable to order any Apoquel at all. Zoetis anticipates that production will be able to keep up with the demand in the spring of 2015.

Cost of Atopica and Apoquel

Atopica comes in four sizes: 10, 25, 50 and 100 mg capsules. It is dosed based on your dog’s body weight. Each size is priced differently and larger dogs may require more than one capsule. Depending upon your dog’s weight, the initial cost may range from $1.50-$10 per day. Significant rebate programs are often available when purchases are made through veterinarians (as much as 50% off ) but not through online pharmacies. The cost often goes down over time if the dose is able to be reduced.

Apoquel comes in three sizes: 3.6, 5.4, and 16 mg tablets. Dogs less than 90 pounds need only take 0.5 or 1.0 tablet per day, long term. Big dogs will require 1.5 or 2.0 tablets per day. A novel feature of Apoquel is that all three tablets are priced the same. There isn’t much information on the retail pricing of Apoquel available, but it is likely to be around $1.50-$2.00 per tablet in most veterinary hospitals that have it in stock.

Dosing of Atopica and Apoquel

Atopica comes as capsules, which are fairly large in the 100 mg size. Pet owners often find the larger size difficult to administer. The initial dose is 5 mg per kg body weight. In most cases, it is given once daily for the first month. If your dog responds well, the dose can often be reduced to every 48 hours or even twice weekly. It is then given long-term, or at least during the seasons that your dog itches from allergies.

Apoquel comes as scored tablets, which are fairly small and easy to administer. There is a narrow dose range of 0.4-0.6 mg per kg of body weight. Your veterinarian will sometimes need to use half of two different sizes to get the proper dose. For up to 14 days, Apoquel is administered twice daily. In cases of chronic itch in dogs, it is given once daily, long term. Apoquel has a short half-life, meaning that it doesn’t persist for long in the blood stream. Missing even one dose may result in a return of the itching behavior. Establishing a daily routine or setting an iPhone reminder is important. Check out the Itchology app on Facebook, which has a built in medication reminder.

Speed of Atopica and Apoquel in reducing itch

Atopica does not usually achieve its maximum effect on itching until after daily dosing for four weeks.Apoquel vs Atopica

Apoquel reduces itching quickly, often within one day. There is a major reduction in itching within 7 days in most dogs. In a head-to-head study, Apoquel reduced the itch level more than Atopica during the first 14 days. There is often a slight increase in itch level when Apoquel dosing is switched from twice daily to once daily, usually at 14 days of therapy.

Side effects of Atopica and Apoquel

Both Atopica and Apoquel affect the immune system. An allergy is, after all, an overactive immune system. Atopica is considered immunosuppressive, effecting T-cells. Apoquel is considered immunomodulatory, blocking transmission of the itch sensation, among other activities. Both medications have the potential to increase the risk of dogs getting infections. In reality, this is uncommon at recommended doses. In clinical trials, skin infections (pyoderma) do occur, but dogs with allergies often get skin infections whether they are taking one of these medications or not.

Atopica is associated with vomiting and diarrhea more often than Apoquel. In a review study compiling results of 672 dogs treated with Atopica, vomiting occurred in 25% and diarrhea or soft stools in 15% of dogs. Usually, veterinarians and pet owners can overcome this, with a slight modification of dosing.

Apoquel is uncommonly associated with vomiting or soft stools (1-2% of dogs). In most studies, these occur with a similar frequency in placebo-treated dogs and those treated with Apoquel. Because Apoquel is still relatively new, it is prudent to monitor our patients rather closely. I recommend an examination, complete blood panel and urinalysis at 0, 3, and 6 months, then every 6 months while taking Apoquel, for now.

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Retrospective evaluation of Apoquel® (oclacitinib) for the treatment of 117 dogs with atopic dermatitis. Part 1: control of pruritus (itch).

We started hearing about a new drug to control the itch of allergic dermatitis and canine atopic dermatitis in dogs over 1 year of age at the Vancouver World Congress of Veterinary Dermatology. Like most veterinary dermatologists, I was eager to try it in my practice. I started prescribing (oclacitinib) Apoquel® for itchy dogs at SkinVet Clinic in November 2013. Although there are now several peer-reviewed publications on the safety and efficacy of Apoquel , I would like to share my experience with the first 117 dogs that I treated.

The clinical sign of most importance to pet owners of dogs with atopic or allergic dermatitis is pruritus (itch). At SkinVet Clinic, we ask pet owners to grade their dog’s itch level at each examination using a validated visual analog scale (0 – 10). While this is the best method that we have had to grade itch in practice, it gives an incomplete picture of itch severity over time. Soon, pet owners and veterinarians will be able to easily record and view a more complete itch diary using the Itchology app for iPhones (see www.itchology.com for more info and to sign up to get notified when it is released).

Apoquel blogFigure 1 shows the owner-reported itch level of dogs pre-treatment and at months 1, 3 and 6. Both per-protocol data (dogs returned for recommended follow-up examinations at 1, 3, and 6 months) and intent-to-treat (ITT) data (previous value carried forward when dogs did not return for examinations or medication was discontinued) are shown.

  • 117 dogs started taking Apoquel at least 40 days ago (day 0 median = 6.0). Month 1 itch level scores were available for 104 of these (median = 2.5). The ITT data yielded similar results taking into account carried-forward values for the 13 dogs that did not return (median = 2.7).
  • 108 dogs started taking Apooquel at least 3 months ago (day 0 median = 6.0). Month 3 itch level scores were available for 85 of these (median = 2.0). The ITT value was slightly higher (median = 2.5).
  • 91 dogs started taking Apoquel at least 6 months ago (day 0 median of these 91 dogs = 5.7). Month 6 itch level scores were available for 59 of these (median = 2.3). The ITT value was similar (median = 2.5).
  • The percentage of dogs that achieved a level of itch considered “normal” by dog owners (0.0-1.9) was 36.8% at 1 month, 39.8% at 3 months, and 40.7% at 6 months (based on ITT values). Many others were in the “very mild” itch category.

These findings are remarkable, considering that most of the dogs began taking Apoquel during cooler, winter months and follow-up examinations more often occurred during warmer months, when many dogs with allergies would be flaring up. Further, as this was not a rigorous clinical trial, the day 0 itch level was often recorded while the dogs were still taking other medications – from prednisone to Atopica®. (These were discontinued for three days prior to the owner initiating Apoquel, in most cases.) Therefore, it is likely that the day 0 itch level reported here was slightly lower than it would have been with a medication wash-out period.

All in all, Apoquel has performed very well in my hands.

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Itchology App Preview

You will soon have a new tool for the management of itchy dogs. This is going to be a must-have app for veterinarians who treat allergic dermatitis.  Among the features of this iOS app are:

  • Pet parent grading and recording of itch severity
  • Medication tracking
  • Medication and flea product reminders
  • Correlation of itch level with environmental factors
  • Ability to share the information with veterinarians
  • Ability to view your patients’  data from a desktop browser

Take a look at a preview of the app.

Sign up to get notified when the app is released at http://www.itchology.com. It will be free for only a short while and available on the Apple App Store in early November.

Posted in allergic dermatitis, apoquel, Atopic Dermatitis, immunotherapy, Uncategorized | Tagged , , , , , , , , ,

How itchy is your dog, really?

By Jon Plant, DVM, DACVD

Scratching, biting, chewing, rubbing, and excessive licking can all be signs of itch (pruritus) in dogs. A number of methods have been developed to try to quantify itching, but these are most useful in research settings.  One method is to take videos of kenneled dogs, then track all itching behavior seen over a period of time.  Another idea that I have published research itchy-dogon is the use of sophisticated motion sensors attached to dogs’ collars. The most widely used method is to ask the dog’s guardian to rate the level of itch severity on a linear scale.

Why might measuring itch be important, you ask? I think of it like this: would you start a weight loss program without knowing how much you weigh or put a pet on a diet without recording a body condition score?

Excessive itching has a negative impact on dogs’ quality of life.  Surprisingly, most veterinary medical record standards do not require us to record itch severity, although it is one of the most common presenting complaints. A meaningful measure of itch severity that dog owners could share with their veterinarian would be a great step forward in helping pet owners participate in the management of their itchy dogs. As a veterinarian that consults primarily on itchy dogs, I would love to have more accurate information about itch severity in my patients.

Be on the lookout for a product coming out this summer…

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Apoquel Backorder Conspiracy Theories

By Jon Plant, DVM, DACVD

There is a huge demand for Apoquel®, the new Zoetis (NYSE: ZTS) drug for dogs with shutterstock_44704465atopic dermatitis or “allergic” dermatitis. I predict that Apoquel sales will exceed $1 billion per year for Zoetis after the supply issues are resolved. It has dramatically improved the quality of life of most of the dogs that I have been able to treat thus far. The dogs are happy, the pet parents are grateful, and I feel like a hero.

BUT, I am in the fortunate minority of veterinarians that has a reasonable supply, thanks to placing a large order early on, and the Zoetis policy of directing the available supply of Apoquel to the dogs which are already taking it. Many veterinarians are understandably upset that a) they can’t order Apoquel after having talked it up to their clients before the launch, and b) communication from Zoetis was a little herky-jerky for a few months regarding the supply issues that were emerging.

Some veterinarians are voicing conspiracy theories – Zoetis is trying to gin up the demand in order to raise the price, or there is some problem with the manufacturing process that they are hiding. I’ve even read speculation that the shortage is due to a conspiracy by veterinary dermatologists to buy it all up because it could be seen as a threat to referrals!
I don’t buy any of those theories. I suspect the real story goes like this:

  • Zoetis managers remembered the disappointing launches of some other companion animal drugs.
  • A very well-managed marketing strategy was executed, complete with flashy video animations, numerous research presentations, and webcasts for veterinarians at dinner meetings throughout the US.
  • The price was set reasonably, within the reach of many pet owners. This invalidated comparisons to the Atopica® launch, if they were using that to forecast.
  • Someone made a decision not to invest in the facilities that would have allowed for a higher level of Apoquel production, should the need arise.
  • A cumbersome manufacturing and packaging process was chosen which involves shuffling the active ingredient, tablets, and packaged product between countries. Is this really efficient and cost effective, or is it to avoid taxes? I don’t know.
  • Within a few weeks of the launch, it became clear that the amount of Apoquel available would not meet the demand.
  • The decision was made to allocate the available Apoquel supply such that dogs that had already started it would have priority.
  • No veterinarians are able to buy as much Apoquel as they want – some are just able to buy more than others in order to keep some of their current patients on it.

No conspiracy. Someone at Zoetis just didn’t quite believe their own data on the potential size of the market and Apoquel’s effectiveness. In a few years, this shortage will be behind us and many dogs will benefit. That is little consolation for pet owners who are seeking Apoquel now for their itchy dogs.

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Apoquel shortage? Try RESPIT!

By Jon Plant, DVM, DACVD

Bad news, good news about Apoquel® from Zoetis (NYSE: ZTS). We learned last week that the Apoquel backorder situation is likely to continue throughout 2014 and into the summer of 2015. That is very sad news for many itchy dogs and their owners.   On the positive side, those of us who started a lot of dogs on Apoquel when it was first released will seemingly have our current patients’ Apoquel requirements met, with regular allotments available for auto-shipping.

Despite the shortcomings in the supply, I am still a big fan of Apoquel based on my experience treating about 100 dogs. I have seen the pruritus (itch) score drop from a mean of 6.0/10 when beginning therapy to 2.5 after 4 weeks (the first point at which the score was recorded). In most cases, owners report that the pruritus improves within a few days, in accordance with the reports and publications from Zoetis. Meanwhile, I see very few adverse reactions. It is truly amazing and my clients are, on the whole, very grateful.

The Apoquel shortagshutterstock_105010115e leaves veterinarians with the traditional methods of controlling atopic dermatitis (“allergies”). The first step is to make the correct diagnosis by using a validated checklist and ruling out alternative diagnoses (see my short video on diagnosing atopic dermatitis). Once the diagnosis is made, the proven alternatives to Apoquel for effective therapy are:

  • Glucocorticoids – usually effective, but frequently cause undesirable short and long-term side effects.
  • Atopica® — often effective, but may cause vomiting and other gastrointestinal side effects.
  • Allergen testing/immunotherapy – both serum IgE testing and intradermal testing have reliability issues. See my recently published study that demonstrates that there is poor agreement between four serum IgE assays when you take into consideration random agreement.1 What is the value to the pet owner if we can’t be confident that the results are much more accurate than guessing?

All of which led me to develop RESPIT®, regionally-specific immunotherapy, a patent-pending approach that allows veterinarians to effectively desensitize patients with allergen mixtures optimized for their geographic region rather than based on an allergen test of questionable accuracy. Consider the following:

  • Every allergen testing company and most veterinary dermatologists report similar levels of efficacy for their immunotherapy based on these discrepant test results.
  • A committee composed of experts on canine atopic dermatitis found that there was no evidence to recommend one form of testing over another.2
  • Another study found that immunotherapy with a standardized allergen mixture is as effective as immunotherapy based on intradermal test results.3

Why are we still using these tests??? Would we submit blood for CBC’s if every lab gave us different results and we didn’t know which, if any, was accurate? More and more veterinarians are recommending RESPIT, recognizing it as a practical and cost-effective approach when you consider the facts about allergy testing.

Veterinarians can order RESPIT at www.skinvetproducts.com. Pet owners can learn more at http://vetrespit.com/pet-parents.html and request that more information is sent to their veterinarian.

References:

1. Plant JD, Neradelik MB, Polissar NL, et al. Agreement between allergen-specific IgE assays and ensuing immunotherapy recommendations from four commercial laboratories in the USA. Vet Dermatol 2014;25:15-e16. Best Clinical Research by an Established Investigator Award, ECVD-ESVD Congress, 2013.

2. Olivry T, DeBoer DJ, Favrot C, et al. Treatment of canine atopic dermatitis: 2010 clinical practice guidelines from the International Task Force on Canine Atopic Dermatitis. Vet Dermatol 2010;21:233-248.

3. Garfield R. Injection immunotherapy in the treatment of canine atopic dermatitis: comparison of 3 hyposensitization protocols. 8th Annual Members’ Meeting of the American Academy of Veterinary Dermatology & the American College of Veterinary Dermatology 1992:7-8.

 

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Apoquel: now you see it, now you don’t

By Jon Plant, DVM, DACVD

In a somewhat embarrassing setback, yesterday Zoetis (NYSE: ZTS) was forced to inform veterinary customers that Apoquel, their new drug for canine atopic dermatitis, is now on back-order only 3 weeks after its national launch.  Veterinarians who have not ordered Apoquel up until now will not be able to receive any product.  Veterinarians who have ordered Apoquel and have begun treating patients will have a very, very limited supply available while on back-order.

I hope that this back-order situation is as temporary as Zoetis has suggested, but veterinarians are all too familiar with  back-order status dragging on and on with various pharmaceuticals.

While I am certainly not privy to the details of how this shortage in supply or distribution came about, it is perplexing considering that Zoetis has been heavily promoting the drug and the science behind it for a few years, had several months of ordering experience form the veterinary dermatologists in the Early Experience program, and projects that 7 million dogs in the United States are candidates for Apoquel.

I know that this is just a temporary hiccup, but a frustrating one for veterinarians and  the clients that may not be able to refill their pet’s medication.

Update (2/6/14): Dr. Candace Sousa, Associate Director of Veterinary Operations with Zoetis has provided me with some clarification on the short-term Apoquel shortage.  A large supply of tablets has already been manufactured and is stored in Europe, awaiting packaging for distribution in the various countries in which it is being launched. Veterinarians in the US ran through what was anticipated to be a 3-month supply within a few weeks of launch, thus we are waiting on the already manufactured tablets to be packaged appropriately, processed through customs, and shipped to the US distribution centers.

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