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Cytopoint a better option ?
|Should My Dog Take Atopica ?|
|What About My Cat ?|
Advances our understanding of the immune system and what underlies itching have changed the medication option landscape for your dog. Apoquel®, a Zoetis product, is a medication designed to interrupt the inflammatory process that occur in the skin of dogs with allergies (it blocks 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 didn't know what many of them did. The Australian chemist jokingly named the two new ones JAKs (“just another kinase”). But even then, he had an inkling that they might be important. 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 we currently known are JAK1, JAK2, JAK3, TYK2.
As soon as the functions of the JAK messengers were understood, pharmaceutical companies went to work developing compounds that might block their actions. 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 and ulcerative colitis. The company that devoted the most effort was Pfizer. Zoetis is the animal spin-off of the Pfizer Pharmaceutical Company.
JAK inhibitors, like Apoquel® (oclacitinib) for itching in dogs and the one Pfizer markets for humans with RA, ulcerative colitis or psoriasis: Xeljanz (tofacitinib), pharmacists refer 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.
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 (Apoquel®) for use in dogs. The compounds differ in their “head groups”- something that affects their stability and potency within the body and, hopefully, influences which JAKs they target most.
Well, it is and, in most cases, it does.
But here is the potential problem you need to be aware of: If you read the link to a paper Zoetis published when it was still part of Pfizer (ref), you will see that Apoquel does not entirely focus on inhibiting interlukin-31 (IL-31), the compound driving your dog's urge to itch. Apoquel has the potential to reduce the ability of the other JAKs to perform their positive and important functions. Unfortunately, no small molecule medications yet discovered targets only IL-31, They all have the potential to interrupt the production of many other compounds and processes that defend the body. That is why the FDA recently changed the label warnings for Xeljanz, Apoquel's "sister" human drug. (ref)
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. Theoretically, another drug Zoetis produces, Cytopoint®, targets only IL-31. In contrast to Apoquel, a "small molecule drug", pharmacists call Cytopoint and drugs like it "large molecule drug" (="Biologics") because the molecules of those drugs are too big to be absorbed intact through you or your dog's the intestine. (ref) So they must all be given by injection. Popular human "large molecule drug" (and Cytopoint®) are all monoclonal antibodies (MABs).
Because no one is really happy with the safety and side effects of oral corticosteroids or Atopica® - the only other effective treatment options available for your dog until recently. The side effects of both are substantial and dose-size and length-of-time on the medication dependent. Antihistamines, lotions, desensitization shots & drops, antibiotics supplements and special diets although usually safe, are often minimal effective (if at all) in the treatment of the canine allergies (atopy) underlying your dog's chronic itching.
Oral and Injectable Steroids (corticosteroids, prednisone, prednisolone, triamcinolone, etc.) are all quite dramatic in blocking the itch and allowing your pet's traumatized skin to heal. But their prolonged use at effective doses often causes worrisome side effects: weight gain, excessive water consumption and urination, elevation in liver enzymes, behavioral changes, weakened ligaments, muscle loss, thin skin, blood cell changes, etc. Those meds are also implicated as triggers for pancreatitis , Cushing's disease and diabetes. Although less dangerous, corticosteroids are only partially effective on their own when they are applied as topically sprays.
Oral cyclosporin-A (Atopica®) is also usually effective. But it may cause vomiting, and has the potential to cause considerably more serious side effects over time. (ref)
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 for some patients. But they do not address the underlying causes of canine allergic skin disease or itching.
I am also 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, when successful, avoids exposing your pet to the side effects of powerful drugs. But I have just not been impressed by the results of those desensitization procedures in the majority of allergic dogs. If you elect to go that rout, you might consider having your veterinarian cut to the chase with a commercial, regionally-prepared allergen mixture such as Respit®.
Food Allergies tend to be over-diagnosed in itchy dogs. Dog food companies heavily market those products with those deceptive claims. Those hypoallergenic and novel protein diets are occasionally, but infrequently, helpful in canine atopy cases. I would still give them an early limited try since food allergies account for, perhaps, 5-8% of dog skin itch problems. Just don't try to judge their benefits when other forms of therapy are ongoing. Food intolerances in dogs are more common - but considerably more likely to result in digestive disturbances and diarrhea that in itchy skin.
Antibiotics for the secondary staph skin infections that often accompany canine allergic skin disease do offer many pets temporary relief. But repeated or persistent use of antibiotics is an invitation for the introduction of antibiotic-resistant bacteria like staphylococcus into your household. (ref) Regardless of hygienic attempts you make to prevent it, resistant mutant bacteria strains in you pets often quickly spread to human family members and vice versa. .(ref1 ,ref2 , ref3 , ref4) Nevertheless, pharmaceutical companies still intensively market antibiotics to veterinarians and the owners of itchy pets (ref) Surface antiseptic products accomplish much the same thing without that inherent danger.
For a review of all the current potential treatments available to your veterinarian to battle skin allergies in your dog (until now), go here.
Apoquel (Oclacitinib maleate) was developed and is sold to veterinarians by Zoetis Pharmaceutical Corporation. As I previously mentioned, until 2012, Zoetis was the Animal Health Division of Pfizer. Pfizer had 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 Pfizer research depth, they looked to canine skin allergy treatment. Estimates are that 8.2 million canine pets suffer from allergic skin disease – 10% of the US 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 in an attempt to have its greatest inhibitory affect on your dog’s JAK1 system because Pfizer research indicated that JAK1 activated much of the processes causing your pet’s itch 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 launched and available to dog owners January 20, 2014. For a time, it was. But as I began writing this article in September of 2014, Zoetis had begun severely limiting its distribution. The official reason given was “production challenges”. (ref) My Zoetis drug rep told me in April of that year that sufficient supply was available again. In the interval, dogs already taking Apoquel and veterinarians who had previously ordered the product received priority. In succeeding years, there has been no disruptions in supply.
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 those treatments combined with Apoquel; but that the possible combined effects have “not been investigated in any meaningful way so far”.
Very little unbiased information is available to you on the internet. I do not know of any sources (other than this site) written by non-stakeholders. That 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. Any data can be honestly presented in many ways. Experimental designs can be consciously or unconsciously 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 for Apoquel 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 Elvis' process along a bit. If you have had good or bad experiences using Apoquel in your dog, please let me know what they were 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. Due to Apoquel's immunosupressive qualities, 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 less drastic treatments and modifications to your dog’s lifestyle have failed. That includes extremely strict flea control, time-occupying activities for dogs that suffer from boredom, behavior modifying techniques for those that lick from separation anxiety, diet trials, feeding schedule modifications and the like.
As I mentioned earlier, the four JAKs are messenger molecules that deliver instructions and news to cells throughout the body. When those body cells receive messages, they respond in pre-programmed ways. As I also pointed out, there is a great deal that we do not yet know about all the processes that are under their control or the consequence of interrupting their their messages.
Apoquel was designed to be most effective at blocking the production of IL-31. IL-31 triggers the release of JAK1 and JAK2 pathways. (ref) 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 with reduced JAK1. (ref) JAK1 is also an important messenger in the IgE processes needed to destroy virus, bacteria, fungi and parasites invading your pet. This is the process that we think 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 individual cells within the organ. 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 JAK2 messenger compounds die midway through pregnancy due to a lack of red blood cells. Adult mice with a JAK2 deficiency have problems producing milk.
JAK3 seems to confine its regulating activities to the immune 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 JAK explanation was not confusing enough, the four JAKs can, apparently, chat with one another in making decisions. (ref1) (ref2) So that factor (and perhaps medications like Apoquel) that influence one JAK member, can have effects on the actions of the other three.
I am not overly concerned with the short-term use of Apoquel in your dog. But I do tend to be cautious – particularly when tinkering with incompletely-understood vital body systems when so little long-term safety information is available.
For dogs with a 1-2 month-long seasonal itch, for stopgap relief in a fleabite-sensitive pet that picked up fleas, or a dog that just needs fast short-term relief do to an itch flare-up, Apoquel appears to be a suitable option. But we know too little about the long-term effects of this drug for me to be confident about the safety of its use as a long term solution to your dog's itch problem. Zoetis should now have client data from dogs that have been taking Apoquel for 5-6 years. I do not believe that information has been shared outside of Zoetis. Generally, corporations quickly release to the public news that is clear-cut and positive. Only one pertinent article appeared in the intervening 6 years. (ref)
All I have is the Freedom of Information Report issued by the FDA when they approved Apoquel in 2013. You can read that here. A deficiency in that report is that 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 a dog with a quirky immune system likely to receive Apoquel. 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 draw a different conclusion. Another reason to keep those positive and negative emails coming to enhance the feedback page.
Considerably more data has been accumulated and published regarding another JAK inhibitor similar to Apoquel®: tofacitinib (Xeljanz®). Xeljanz, another Pfizer developed product, began its clinical trials in humans 2007 as a treatment for rheumatoid arthritis. 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. Xeljanz was designed to preferentially inhibit JAK1 and JAK3, and, to a lesser extent, it 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 mixed it up in an ointment for humans with atopic dermatitis or psoriasis in an attempt to control itching. (ref) Read the information Pfizer released about the occurrence of side effects related to Xeljanz through 2017 here.
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) In March of 2017, the EMA reversed their decision and approved it.
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 spans. 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 accepted 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 administration of a lower doses over longer periods. But that is not a hard and fast rule among medications.
We all spend much of our lives making risk/benefit decisions. I currently recommend to my clients that they try Zoetis' Cytopoint® first. That is because so far, it appears that Cytopoint is more focused on interrupting itch-related IL-31 processes and leaving other systems intact. But when Cytopoint is not an option, I have minimal worries about the short-term use of Apoquel in dogs because the other older treatment options like steroids and cyclosporin/Atopica are so imperfect. I would be even more inclined to try occasional Apoquel therapy in my dog when other approaches have failed or are impractical.
I would consider Apoquel for longer periods for my dog, but only when careful monitored. My dog, Maxx is atopic. If Maxx was suffering and unhappy under his 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 for him to have a somewhat shorter life in happy contentment than a longer one in misery. Effective medications that treat chronic diseases in all of us often present the same dilemma.
There are inherent dangers in blocking broadly-based, poorly understood, biological process. It might also turn out that certain breeds and certain ages of dogs are better candidates for Apoquel use than others. I mentioned earlier that certain breeds were found to have idiosyncrasies in their JAK-related processes. (rptref) Investigators have found immunological differences in other breeds as well. (ref)
I would go with the lowest effective dose of Apoquel that brought relief to my dog. According to Zoetis: “In a canine flea allergic dermatitis model, oclacitinib [Apoquel] produced sustained and reproducible anti-pruritic [anti-itch] effects at dosages as low as 0.11 mg/lb (0.25 mg/kg) twice daily.” (rptref) I would never use Apoquel as a substitute for life changes or prescription medications directed at killing fleas. I would read the owner feedback page on this site from time to time. I would consider increased susceptibility to infections a red flag warning that the Apoquel dose or time on the medication needed to be reduced or discontinued. When my dog's itching had seasonal or intermittent peaks, I would pick the trough (low itch) periods to discontinue Apoquel in the hope that those break times might give my dog's positive tumor-scavengering processes a period to work at their full effectiveness. (ref1, ref2, ref3)
That decision will change as veterinarians gain more experience dispensing this medication and more dogs have been taking it for lengthy periods. For now I would base periodic tests on the side effects noted in the Apoquel trials as well as those known to occur with its sister drug, tofacitinib (Xeljanz®). Those are infections and changes in white and red blood cell numbers.
Warning signs of impending problems are often noticed by owners earlier than blood changes: negative changes in their pets habits, energy level, body weight, gum color, coughing, nasal drainage, increased breathing rate, an enlarged lymph node or lump, changed elimination habits, lower appetite, fever, etc. No one knows what is normal for you pet as well as you do. If something noticeably changes, it needs to be discussed with your veterinarian.
An elevated temperature (fever) at home is considerably more significant than an elevation at your vet’s office. Agitated, worried or exited pets often run hot at the animal clinic.
One might perhaps monitor 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) With any of these sort of tests, a baseline test before the drug is started is quite important. Facilities that might have the ability to monitor your dog's CD4 T-cell numbers over time include the Clinical Immunology Department of Colorado State Veterinary School, the Laboratory of Clinical Pathology of North Carolina State University and Idexx's Molecular Diagnostic Laboratory. I know they were attempting that in cats that were FLV-positive.
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/Xeljanz®, is capable of reactivating human herpes virus (Herpes Zoster/shingles). (ref) So 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 dog. (ref)