Should I Giving My Allergic Dog Apoquel
To Stop Its Itching And Scratching ?
Ron Hines DVM PhD..........................................................................What About My Cat ?
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Recent advances our understanding of the immune system and the inflammatory process are changing the medication landscape for you and your pet. It is the fall of 2014 and there is a treatment option for your allergic dog that was not available last fall. Apoquel, a Zoetis product, is a medication designed to interrupt the inflammatory process that occurs in the skin of most dogs with allergies (blocks or inhibits the pro-inflammatory cascade).
In the late 1980s, an Australian chemist isolated two kinase molecules. (ref) At the time, kinases were already know to be important messenger/signaling compounds that the body’s cells use to communicate with one another. There were a lot of them and scientists did not know what the function of many of them were. The Australian chemist jokingly named the two JAKs (“just another kinase”). But even then, he had an inkling that they might be of importance. As knowledge of their function increased and two more were discovered, a more serious name for them was substituted- Janus Kinase Inhibitors. They were found to be key elements in the control of body growth and development, white and red blood cell formation, immunity, inflammation and policing the body against tumor formation. The four currently known are named JAK1, JAK2, JAK3, TYK2.. JAK1 and JAK3 are particularly important for the proper functioning of your pets antibody-producing cells (B-cells) and its “policing” cells (T-cells). (ref)
As soon as the significance of JAKs were grasped, pharmaceutical companies saw opportunity and went to work developing compounds that might block their action. They knew that compounds that could block the action of JAKs (Janus Kinase Inhibitors or jakinhibs ) might have potential uses fighting abnormal immune-related processes in people – diseases like rheumatoid arthritis, psoriasis, Crohn’s disease, ulcerative colitis, leukemia and even aspects of CPOD. Some could even regrow hair. (ref) The company that devoted the most resources to this effort was Pfizer. Zoetis is the animal spin-off of the Pfizer Company.
JAK inhibitors, like Apoquel (oclacitinib) and one marketed for humans with RA, Xeljanz (tofacitinib), are often referred to as “small-molecule” pharmaceuticals. That means they are molecules that are small enough in structure to enter the body when you or your pet take them orally rather than large molecules, like the Humira, Enbrel or Remicade you see advertised on TV , which must be given by injection for inflammatory problems. JAK inhibitors like Apoquel target (“neutralize”) several cytokines that are acting as messenger compounds in the inflammatory process occurring in your allergic dog’s skin. Without these functional cytokine messengers, the complex process of inflammation and itching that torments your pet should subside.
As of September, 2014, I know of nine JAK-inhibiting compounds that are under development and examination. Tofacitinib, ruxolitinib, baricitinib, decernotinib, filgotinib, and oclacitinib. Only tofacitinib and ruxolitinib have been approved yet by the FDA for use in humans and only oclacitinib for use in dogs. The compounds differ in their “head groups”- something that affects their stability and potency within the body and, hopefully, influences the JAK they target most.
Well, it is and, in most cases, it does.
But here is a potential problem we need to consider:
Veterinarians cannot simply interrupt the production of the four JAKs. They are not something your pet’s body can live very long without. A deficiency of JAK3 leads to increased susceptibility to infections. Adequate JAK2 is necessary to produce red blood cells (erythropoesis) and a lack of JAK1 leads to neurological (nerve) and lymphocyte abnormalities. Both portions of your pet’s immune system, its antibody system (B cells) and its killer-cell system (Cell-mediated immunity) require that a sufficient amount of JAK3 be present.
Because no one is really happy with the treatment options currently available for your atopic (skin allergy) dog. They all have their drawbacks, and limitations – both in effectiveness and the more powerful ones (corticosteroids and Atopica) can also cause potential serious side effects that are dose-size and length-of-time on the medication dependent.
Antihistamines, although safe, have shown to be only minimal effective (if at all) in the treatment of canine skin allergies.
Oral and Injectable Steroids (corticosteroids, prednisone, prednisolone, triamcinolone, etc.) are all quite dramatic in preventing itching and allowing your pet's traumatized skin to heal. But prolonged use at high doses always cause worrisome side effects – weight gain, excessive water consumption and urination, elevation in liver enzymes, behavioral changes, weakened ligaments, muscle loss, thin skin, etc. These meds are also thought to be triggers for pancreatitis , Cushing's disease and diabetes. Corticosteroids are rarely effective on their own when only applied topically.
Oral cyclosporin-A (Atopica) is usually effective. But it may cause vomiting, and has the potential to cause more serious side effects over time.
Topical tacrolimus ointment often helps resolve localized skin lesions. But its not generally effective on its own in cases related to generalized skin allergies.(ref)
Fatty acid supplements seem helpful to some patients. But they do not address the underlying causes of canine allergic skin disease or itching.
I am not an enthusiastic fan of skin tests or blood tests to identify possible allergens in your dog’s environment because I do not believe that these tests often lead to benefits that are sufficient to justify the procedure. Read about that here. It is true that desensitization, if successful, avoids exposing your pet to the side effects of powerful medications. But I have just not been impressed by the results of those procedures in most allergic dogs. If you elect to try that rout, you might consider having your veterinarian cut to the chase with a commercial regionally-prepared allergen mixture such as Respit.
Food Allergies are probably over-diagnosed in dogs (they account for, perhaps 5-10%). Hypoallergenic diets are occasionally, but not frequently, helpful in canine atopy cases but you should always give them a try. Food intolerances are more common - but considerably more likely to result in digestive disturbances and diarrhea that in itching problems.
Antibiotics for the secondary staph infections that often accompany allergic skin disease do offer pets temporary relief. But repeated or persistent use of antibiotics is an invitation for the introduction of antibiotic-resistant bacteria into your household. Regardless of hygienic attempts to prevent it, resistant bacteria strains in you pets often quickly spread to your human family members and vice versa. .(ref1 ,ref2 , ref3 , ref4) Never the less, pharmaceutical companies still intensively market antibiotics to veterinarians and the owners of itchy pets (ref) (when surface antiseptics accomplish much the same without this inherent danger)
For a review of all the current potential treatments available to your veterinarian to battle skin allergies (until now), go here.
Apoquel (Oclacitinib maleate) was developed and is sold to veterinarians by Zoetis Pharmaceutical Corporation. Until 2012, Zoetis was the Animal Health Division of Pfizer. Pfizer has invested more into advancing the understanding of the role of JAKs and into engineering new JAK inhibitors than any other company I know of. (ref)
When Zoetis, looked for opportunities to benefit from that research, they looked to canine skin allergy treatment. Estimates are that 8.2 million canine pets suffer from short and long term allergic skin disease – 10% of the dog population. So Zoetis saw a potential blockbuster drug in Apoquel and promoted it to pet owners and veterinarians accordingly. (ref)
Apoquel (oclacitinib) is rapidly absorbed and fast acting (within a day). Its particular structure was engineered to have its greatest inhibitory affect on your dog’s JAK1 because Pfizer research indicated that JAK1 activated much of the processes causing your pet’s discomfort (scratching, rubbing, chewing). Those processes are though to be due to the liberation of certain other cytokines (particularly interleukin-31). It was hoped that concentrating Apoquel’s activity on JAK1 would allow the other JAKs to continue their important roles such as JAK2’s beneficial effects on blood cells. Read in detail about that here.
Apoquel was set to be launched and be available after January 20, 2014. For a time, it was. But as I write this article in September, 2014, Zoetis has severely limited its distribution. The official reason given was “production challenges”. (ref) Reps tell me that sufficient supply should again be available by April, 2015. Until that time, dogs already taking Apoquel and veterinarians who have previously ordered the product will receive priority.
Zoetis does not recommend using Apoquel at the same time that corticosteroids or Atopica/cyclosporin are being given to your dog. They say they have not accumulated negative data regarding the use of these treatments combined with Apoquel; but that the possible effects have “not been investigated in any meaningful way so far”.
Very little unbiased information is available. I do not know of any articles (other than this one) by non-stakeholders. This is the new norm in today’s pharmaceutical industry. (ref) All published studies I know of were funded by Pfizer or conducted by their scientists in-house. You can read the key Zoetis-sponsored study here.
When commercial interests rather than academic curiosity are your only source of information on anything, it can be quite hard to separate fact from hype. Data can be honestly presented in many ways. Experimental designs can be manipulated to ones advantage and to fit ones goals. It has been my experience that the best place to get unbiased information about something is not from someone who has something he or she wants to sell to you.
In a year or three that is going to change because like Elvis once said, “Truth is like the sun. You can shut it out for a time, but it ain't goin' away.”
I am going to try to speed that process along a bit. If you have had good or bad experiences using Apoquel in your dog, please let me know and I will put your anonymous response here. Pet owners and veterinarians can report side effects (adverse events) to the FDA or to the product’s manufacturer. They rarely do. It is estimated that only about 1% of human adverse drug events are ever reported to the FDA. (ref)
Dogs under one year of age did not react well to Apoquel. Zoetis also suggests that Apoquel not be given to dogs intended to be bred, pregnant or nursing dogs nor to those receiving other medications that affect the pet’s immune system. It should not be given to dogs with known cancer or mange. (ref)
I would also suggest that this medication not be given to itchy pets until all less drastic treatments and modifications to your dog’s lifestyle have failed. That includes strict flea control, time-occupying activities for dogs that suffer from boredom, behavior modifying techniques for those that lick from separation anxiety, diet and feeding schedule modifications, etc.
As I mentioned earlier, the four JAKs are messenger molecules that deliver instructions and news to cells throughout the body. When those cells receive those messages, they respond in pre-programmed ways. As I also pointed out, there is a great deal that we do not yet know about the processes that are under their control or the consequence of interrupting those processes.
Apoquel was designed to be most effective at blocking the production of JAK1.
Mice that produce no JAK1 die before birth or shortly thereafter. Some theorize that they die because they cannot nurse. We also know tat JAK1 is important in programmed cell death (apoptosis) and in the constant surveillance required to destroy abnormal cells and cells that have become cancerous before they form discrete tumors. So certain chemicals and environmental contaminants that are known to be tumor-stimulating (carcinogenic) could, conceivably, be more so in animals lacking JAK1. (ref)
JAK1 is an important messenger in the processes needed to destroy virus, bacteria, fungi and parasites invading your pet. This is the process that has gone awry in allergic dogs (ref)
JAK2 is a messenger involved in the growth of tissue. It appears to coordinate the growth of individual cells in an organ by transmitting messages between them. As such, it is important in coordinating the production of bone marrow stem cells that have the potential to become red blood cells, white blood cells or blood platelets. Scientists do not yet know all the processes that JAK2 is involved in; but embryonic mice lacking this compound die midway through pregnancy due to a lack of red blood cells. Adult mice with a JAK2 deficiency have problems producing milk. (ref)
JAK3 seems to confine its regulating activities to the cells that produce your dog’s antibodies (B-cells) and those that attack things (T-cells) that the pet's body - rightly or wrongly - has decided are foreign invaders. You can gain some insight into what a lack of JAK3 might do by looking at dogs (and children) that cannot perform those activities due to breaks elsewhere in this complex process. They are at very high risk of infectious diseases (SCID). SDIC naturally occurred in Basset Hounds, Welsh Corgies and Jack Russell Terriers as well as children. (ref)
TYK2 (tyrosine-protein kinase) is also a critical factor in the proper function of the immune system. Its many roles are still poorly understood – even though it was the first JAK to be discovered.
As if my explanation was not confusing enough, the four JAKs can, apparently, chat with one another. (ref1) (ref2) So that factors (and perhaps medications) that influence one JAK member, can have effects on the actions of the others.
I am not overly concerned with short-term uses of Apoquel in your dog.
But I do tend to be cautious – particularly when tinkering with incompletely-understood vital body systems with so little long-term safety information available.
For the dog with a month-long seasonal itch, for stopgap relief in a fleabite-sensitive pet that picked up fleas, or one that just needs fast short-term relief do to an itch flare-up of any sort, Apoquel appears to be a suitable option.
But we just do not know enough about the long-term effects of this drug on your pet to be confident about the pros and cons of its use as a permanent solution. Zoetis should now have data from dogs that have been on Apoquel for four years. I do not believe that information has been shared outside of the Industry. Generally, news that is clear-cut and positive is quickly released to the public.
All we have is the Freedom of Information Report issued by the FDA when they approved Apoquel in 2013. You can read it here.
For a start, only 24 one year old beagles were used in the initial testing. I do not know why but, perhaps, pressure on the industry to minimize the use of research animals had something to do with that (ref)
Beagles are a breed known for their robust health and strong immune system – not the kind of dog with a quirky immune system likely to receive Apoquel (such as labs, goldens or terriers). During the 26 week study, some dogs receiving Apoquel developed viral skin tumors, abscesses between their toes and abnormally enlarged lymph nodes. Five treated dogs had microscopic evidence of pneumonia and others showed evidence that their number of protective lymphocytes and bone marrow cells were reduced. A concurrent study in six month old beagles given 3 and 5 times the recommended Apoquel dose was discontinued after four months because of the development of bacterial pneumonia and generalized mange. (To my knowledge, studies of new drugs at this stage generally screen them at 10 times the suggested dose [ref]) So although Zoetis markets this drug as a JAK1 inhibitor targeting IL-31, it appeared to me that the medication was also suppressing facets of the immune system not involved in itching. I am only trained as a veterinarian and microbiologist. Perhaps an immunologist or pharmaceutical bench scientist would reach a different conclusion.
Considerably more data has been accumulated and published regarding another JAK inhibitor, tofacitinib, that began its clinical trials in 2007. It is the molecule I marked T in the picture above. O represents the structure of Apoquel. You can see that much of the structure is quite similar. Tofacitinib (Xeljanz) is a human medication approved by the FDA to treat another immunologically-based disease, rheumatoid arthritis in humans. Xeljanz is also a Pfizer-developed product. It was designed to preferentially inhibit JAK1 and JAK3, and, to a lesser extent, inhibits JAK2. (ref) More recent studies vary in their conclusions as to its selectivity among the JAK messengers. It can't be that different from Apoquel because Pfizer recently mixed it up in an ointment for humans with atopic dermatitis or psoriasis to control itching. (ref)
Tofacitinib is quite effective in alleviating the debilitating pain of rheumatoid arthritis. However, the FDA suggests it be use only in patients whose discomfort cannot be controlled with other medications. That is because of the side effects the compound has been known to cause. I am sure that the newness of Jakinibs (JAK inhibitors) and our imperfect understanding of the processes they control had something to do with that recommendation too.
As of 9/14, the product insert displays a warning that patients taking the medication are at a higher risk of serious infection as well as infection with organisms that a robust immune system would usually overcome. It also warns of the reactivation of infections that are currently latent or walled off within the body as well as various cancers (malignancies) . (ref)
The FDA granted Pfizer ’s request to market tofacitinib in the United States in 2012. The vote was 8 to 2. In 2013, the EMA (the FDA’s European counterpart) denied Pfizer a similar request, stating that the benefits of the drug did not outweigh its risks. (ref)
A problem with interspecies (human to dog or vice versa) comparisons of similar drugs is the shorter life span of dogs and the accelerated tissue damage often associated with shorter life span. That is a prime reason rats are used to screen medicines for possible long term side effects. The laboratory rat's average life span is 2.5-3.5 years. So just like hair coat graying, a side effects or drug problems that might take 10-15 years to become apparent in humans might occur much sooner in our dogs. To speed the revelation of those problems, increased dose is an acceptable scientific research method. That is why I am concerned with the high-dose side effects and mortality within the beagle study. Sometimes, increased doses over short periods mimics the effects of increased administration of a lower doses over longer periods. But that is not a hard and fast or universal rule among medications.
I can not answer that question for you.
You make the important decisions for your dog. Much in our lives is a risk/benefit decision and no two people are likely to make the same decisions all of the time - even when presented with considerably more information than I can present to you about Apoquel.
There are inherent dangers in blocking broadly-based biological process that are as yet so poorly understood. Yet, even with our current limited knowledge about this drug, I would have minimal worries about the short-term use of Apoquel in my dog because the other treatment options are so imperfect. I would be even more inclined to try this medication when other approaches have failed for your dog or are impractical.
I would only consider it for longer periods under careful monitoring. If my dog was suffering and unhappy under its current allergy treatment plan, I would consider Apoquel even if potential side effects turned out to have negative long-term consequences on its health or were life-shortening. That is because I love my dog and would prefer it to have a somewhat shorter life in happy contentment than a longer one in suffering. Effective medications that treat chronic diseases in all of us often present this same dilemma.
We do not live in a static world. We know that Apoquel is often effective in treating canine atopy (allergic skin disease in dogs). And we may learn with time that the risks involved in using it are the same or less than the risks of medications like corticosteroids or cyclosporin. We may learn the opposite. As of 9/14 no one has presented sufficient evidence one way or the other. That will be accumulated over time as the experiences of individual dog owners become generally known.
It might also turn out that certain breeds are better candidates for Apoquel use than others. I mentioned earlier that certain breeds were found to have idiosyncrasies in JAK-related processes. (repeat ref) Investigations have found immunological differences in other breeds as well. (ref)
I would go with the lowest effective dose that brings relief to a specific dog. “In a canine flea allergic dermatitis model, oclacitinib produced sustained and reproducible anti-pruritic [anti-itch] effects at dosages as low as 0.11 mg/lb (0.25 mg/kg) twice daily.” (repeat ref) I would never use it as a substitute for life changes or prescription medications directed at killing fleas.
That decision too will change as veterinarians gain more experience dispensing this medication.
For now I would base them on the side effects noted in the Apoquel trials as well as those known to occur with its sister drug, tofacitinib. Those are– infections, changes in white and red blood cell numbers and cancer.
Monitoring for infections and prompt treatment with appropriate antibiotics would be high on my list. Warning signs for those problems are often first noted by owners who observe changes in their pets habits, energy level, body weight, gum color, coughing, nasal drainage, increased breathing rate, changed elimination habits, appetite, etc. No one knows what is normal for you pet as well as you do. JAK-inhibitor medications are not known to change mood or behavior. If something noticeably changes, it needs to be looked into.
Other times, a careful veterinary examination will pick problems up – things like increased gum disease, enlarged lymph nodes, elevated body temperature, etc. An elevated temperature at home is considerably more significant than a half-degree elevation at the vet’s office. Agitated, worried or exited pets often run a bit hot at the animal clinic.
I would also run periodic blood work (CBC and blood chemistries) and urine exams (urinalysis) on dogs receiving this medication - although subtle decreases the dog’s defenses against infection may not be apparent in the standard blood tests we veterinarians often run. I would also check these pets periodically for ringworm. Paws need to be checked periodically for infections between the toes and at the first sign of limping or abnormal odor.
The problem with veterinarians monitoring for early neoplasia (cancer) - is that most tumors initially exist (begin) as “microtumors” that we cannot readily detect. (ref) One function of certain cells the JAK-inhibitors suppress (CD4+ T cells) is to keep many of those tumors under control. (ref) Similar T-cell suppression can occur with the use of the human Pfizer product, Xeljanz/ tofacitinib. (ref) It could turn out that the remaining level of an important subset of these cells ( CD8+ T-cells) in dogs taking Apoquel (or the dog's CD4+:CD8+ ratio) will , in the future, help to predict the likelihood of similar side effects (tumor growth and increased susceptibility to infections). (ref) Perhaps monitoring the dogs CD4+/CD8+ T cell numbers and ratios. (ref) Several veterinary college diagnostic laboratories around the US have the ability to determine if a dog's CD8+ T-cell numbers remain adequate. However, this would be a novel use for the test that your veterinarian would have to explore without much local guidance. That is because the forefront of this research is not in the United States, it is in Holland (Netherlands). (ref)
A large number of dogs have been exposed to Canine herpesvirus-1 (CHV-1) during their life (said to be 20% to 98% of dogs , depending on the region). Like all herpes virus, CHV-1 is never completely eliminated from the body – only suppressed. The human JAK inhibitor, tofacitinib, is capable of reactivating human herpes virus (Herpes Zoster/shingles). (ref) So until we have more data, I would also be on the lookout for corneal eye problems, vaginal or penile secretions, discharges from the nose or kennel cough-like syndromes in my pet. (ref)
Canine distemper virus is a morbillivirus closely related to human measles virus. The same CD4+/CD8+T Cell systems that are supressed by JAK inhibitor medications are thought to be responsible for a great deal of the long-lasting immunity children receive from their MMR vaccinations. (ref) What, if any, effects Apoquel will have on your dog's vaccination immunity to distemper is unknown.