Cytopoint® Versus Apoquel® For My Itchy Dog – Which Is The Safer Choice?
Which Is More Effective, Can I Use Both ?
Ron Hines DVM PhD
When I began this article on Zoetis’ Cytopoint® (lokivetmab), Zoetis hadn’t gotten around to naming it yet – just called it CADI. The drug was approved by the USDA in 2016 (The FDA approves and monitors Apoquel® because it is a “drug” – the USDA approves Cytopoint® because it is a “biological”. However the USDA has no expertise or effective monitoring system for biologicals. In Europe, the EMA does both “drugs” and biologicals. The EMA is considerably more demanding when it comes to documenting efficacy (=does it work?) and safety. At the time, it was unclear to a lot of us why Zoetis was planning to market two competitive drugs to treat the same condition. Over time, that became apparent. The Company realized that Apoquel®, because of its broader action, had more potential to produce undesirable side effects. They hoped that Cytopoint® which is thought to targeted only a single signaling compound for itch and inflammation, IL-31 , would be more precise in its actions.
Zoetis also saw Cytopoint® as a good entry door to the precision drug market for animals. That follows the same trend occurring in human medicine – to use large, complex, bioengineered antibodies ( read here ) instead of smaller molecule drugs (like Apoquel®) to treat complex diseases. Subsequently Zoetis purchased the only competing company in that business, a small Irish company called Nexvet Biopharma. It was a bargain at $85 million because it came with expertise and a patent to produce ranevetmab, a “caninized” form of tanezumab that might help dogs with arthritis. Zoetis figured that that alone could earn them US $400 million annually. (read here)
What Are The Differences Between Cytopoint® And Apoquel®?
Apoquel tablets bring dramatic relief to most dogs with skin allergies. The medication short circuits your pet’s “misinformed” immune system that has mistaken harmless things in the environment for things that might be dangerous if they invaded its body. It would be a superb drug – if it did only that. But it works at such a high level in the itch cascade (open the diagram at the top) that it can also interfere with a lot of important positive defenses that Nature designed your dog’s immune system to perform. When the inflammatory cascade is blocked at that high a level, your pet’s defenses against cancer, and infection are put at some risk as well. Now all medications have risks. Zoetis, the USDA, the EMA, many veterinarians and pet owners concluded that relief from the discomforts of canine atopy was worth taking those longer-term risks. Apoquel is a small molecule, so it can be absorbed when you give it orally. Cytopoint® is a large molecule – too large to pass intact through your pet’s intestine. That is why it must be injected. Pfizer, the parent company of Zoetis uses injection fear to market Apoquel’s human “cousin” medication, Xeljanz®. They call it the “unjection”.
Apoquel® blocks a whole family of messenger chemicals produced by your dog’s immune system cells. They are called cytokines. Some of those messages encourage needless inflammation; but some of those same processes are essential elements of immunity and other body activities. (read here)
Cytopoint® is a sophisticated monoclonal antibody (mAb) that targets and neutralizes a single itch-generating molecule also produced by your dog’s immune system cells, Interleukin 31 (IL-31). Although many cells in your pet’s body have the capacity to produce IL-31,most appears to be produced by a type of lymphocyte that originated in your pet’s thymus gland , and later disperse to guard entrances to your pet’s body, the T helper cells (aka Th2 cells, CD4+ T cells). ( read here & here )
As I previously mentioned, monoclonal antibodies are too large and complex to be absorbed intact when they are given by mouth to your dog but smaller molecules like Apoquel® can be given orally to your pet and still be effective. The European directions say not to give Cytopoint® to dogs weighing under 3 kg (6.6 lbs) ; the US insert I am reading says to give 0.09 ml/lb from a 10 mg vial to dogs under 5 lbs (2.3 kg). Thinks change, read the insert that came with the product you are currently using.
Apoquel® is not approved for dogs that are less than one year old. Cytopoint® gives no age restrictions. Apoquel® is not suggested for use in breeding dogs, or dogs that are pregnant or lactating. It has not been tested in combination with corticosteroids, cyclosporin/Atopica®, or other immunosupressive drugs. Cytopoint® does not give those restrictions. Directions just states that it has not been tested in pregnant, nursing or breeding animals.
Is Cytopoint® A Safer Medicine For My Itchy Dog Than Apoquel Prednisone Or Atopica?
I believe it is.
Folks who track your veterinary hospital visits say that one in six dogs that come through a veterinarian’s door do so because they are itching. And of that group of clients, 15-20% leave with a diagnosis of atopic dermatitis or AD. So a lot of dog owners leave with pills or injections and they need to consider the safety as well as the effectiveness of the medicines they agree to.
Prednisone is the ultimate shotgun medication for itchy dogs – and Atopica®, not much of an advance. Both were front line medications that veterinarians used to treat itchy dogs and cats before scientists gained a deeper understanding of the itch process. Prednisone and prednisolone still have very justifiable short term uses in treating itch (pruritus) in our pets today. That is because the newer, finer-tuned, alternatives are not effective in every dog. Not every dog owner in the world has the income or even the access to medications like Cytopoint®. Corticosteroids like prednisone, Aristocort® or Temaril-P® exert their influence in almost every cell in your dog’s body to one extent or another. ( read here ) They are fine for extinguishing or lessen short-term itching flare-ups; but I do not suggest them for long term or frequent use when it can be avoided. When used too frequently, they can all produce the same signs as Cushing’s disease , weaken joints, liver and blood glucose issues and increased obesity. Prednisone is so powerful in its itch-relieving abilities that Zoetis still consider it the gold standard in itch relief to which all other itch relief products are compared. (read here)
There are no one-size-fits-all solutions in life. I do not believe that dog owners who feel their dog is better off relieved from the misery of chronic dermatitis with corticosteroids like prednisone or immunosuppressants like Atopica should be criticized. No one knows your dog and your circumstances better than you do and for some, the quality of their pet’s life today overrides worries about the future. For others, the cost of these fancy medications is just too great. But as a veterinarian, I feel its my job to make you aware of what might or might not occur farther down the road so that you can make decisions that best fit your situation.
I hope that Cytopoint® will be more precise in what it does in your pet’s body than corticosteroids, Atopica or even Apoquel®. It was designed to go after just one messenger molecule involved in itch, IL-31, – not a whole class of messenger molecules like Apoquel®, prednisone or Atopica® do. Cytopoint® is veterinary medicine’s first venture into a group of medications never before used. So there is no doubt in my mind that veterinarians, dog owners, the USDA and the pharmaceutical companies themselves are still quite early into the learning experience.
To date, we only have a couple of Zoetis-funded studies of a few healthy young beagles that were followed for relatively short periods of time. ( see here ) Zoetis references “data on file” in a lot of their Cytopoint® brochures that discuss the safety and effectiveness of Cytopoint®. But they were not willing to let me peek at that data when I asked them. Once a drug gains governmental approval, there is no incentive for drug companies like Zoetis to continue formal research on their products. After approval, its strictly feedback from pet owners like you that modifies opinions, helps motivate the USDA to look out for your pet’s interests and drives change. I believe that from what we know about Cytopoint® it should be safer than Apoquel®. I am not alone. Veterinary school students have a soft heart and a penchant for adopting star-crossed, health-issue dogs. Reading their online chatter blogs, its apparent to me that most of the veterinary students with atopic pets and the dermatology professors they interact with believe that Cytopoint® is a safer drug than Apoquel®.
Safety aside, Cytopoint® is approved for dogs less than one year of age and Apoquel is not. Unlike Apoquel®, Cytopoint® has not been associated with liver changes. Cytopoint® is probably less likely to negatively affect pets with multiple health issues. Things like increased susceptibility to infections, concurrent tumors, blood abnormalities or the many medications used to treat them.
There are some other factors to consider: Some dogs accept tablets more readily than injections and vice versa. In some dogs, skin allergies are seasonal, so Apoquel® side effects are less of an issue. Canine atopy (= skin allergy= allergic dermatitis= AD) is a highly complex process with many alternative routs that lead to the same urge to scratch. So one drug or the other could have quite different effects in one dog versus another.
Some believe that dogs receiving Cytopoint® need less frequent or less extensive laboratory monitoring than those receiving Apoquel® or other drugs. Cytopoint® is really too new to the market to conclusively say that. It is also already apparent that there is high dog-to-dog variability in the effectiveness of Cytopoint®. Because Cytopoint® was tailor-made to be accepted by only a dog’s immune system, you cannot give it to your cat. Although Apoquel® is not approved for cats; it has been given to cats experimentally. (read here)
How Does Cytopoint® Work Anyway?
No one completely understands. In their original submissions to the EMA, Zoetis suggested that Cytopoint® decreases the skin inflammation that produces itching by blocking IL-31. (EMEA/V/C/003939/0000) Later they suggest that the drug primarily blocks nerve transmission of itch signals from your dog’s skin to its brain. In others they suggest that both occur. That is understandable because both Cytopoint® and Apoquel® came onto the market long before scientists understood much about the complex signaling systems that they affect. They still don’t. Sanofi’s mAb, human atopy drug Dupixent® developed in mice, blocks IL-4 & IL-13 to stop itching, not IL-31. (read here and here )
I believe that Cytopoint’s acts primarily by blocking nerve sensations. In most dogs when it is effective, it acts too fast for it to be working on the actual inflamed skin. That does not mean that your pet’s skin isn’t going to get any better when on Cytopoint®. It just going to take time. Ninety percent of the damage you see in an itchy dog’s skin is caused by the dog scratching itself and with that gone or reduced, your dog’s skin is going to heal – just as it would wearing an Elizabethan collar. There are others who disagree as to where IL-31 has its effects and they have their evidence as well. (read here)
Is Cytopoint® As Effective As Apoquel®?
In some cases it will probably not be because it is more precise (focused) in what it does. Think of the difference between a shotgun (Apoquel) and a rifle (Cytopoint). But of the two, Cytopoint® is certainly worthy of being your first try. Most dog owners are quite happy with the results. When Cytopoint® is counterproductive, administration is commonly accompanied by a a musty skin odor and the report of skin greasiness. I attribute that to a staphylococcal infection. Staphylococcus is a normal part of your dog’s skin flora. It is your dog’s immune systems duty to confine those staphylococcus bacteria to the surface of the skin and not allow them to invade the deeper layers. (read here) In some dogs, it appears that Cytopoint® blocks that ability. Staph is also a major player in dog ear infections. The majority of dog taking Cytopoint® do not face those issues.
Your dog’s immune system is lifelong learning system. No two dogs encounter the same life experiences or what their immune system is asked to do to defend your pet against environmental threats real and perceived. So no two immune systems will react identically to drugs. That is why mAbs like Cytopoint® and inflammation inhibitors like Apoquel® are going to give a lot of relief to some dogs, moderate relief to some dogs and little to others. You or your veterinarian won’t know which is most effective for your dog until you try them. I would begin with Cytopoint® because, the current opinion is that it is safer. The feedback I get from dog owners who have used both is that the anti-itch effects of Apoquel® were usually more dramatic than Cytopoint®. But I would first see if Cytopoint® injections alone or along with topicals are sufficient to reduce your pets itching to acceptable levels (I did not saying itch-free – I said acceptable levels). The same goes for Apoquel®. Some dogs are given the double, 2-dose- per-day suggested for the first 14 days indefinitely. Perhaps unrealistic improvement was what they or their veterinarian demanded. Perhaps they could not or would not use the topicals that give added relief. Clients tell me that those stubborn Apoquel-resistant cases are also the ones least likely to get a full 4 week relief from Cytopoint®. But most tell me that they are still happy they made the switch because skin tumors shrunk or disappeared and abnormal blood work results improved.
An underlying problem for dog owners, and veterinarians alike is that we tend to treat AD (allergic skin disease) as if it was one disease. It is not. It is many diseases. All the dogs itch, their skin gets red, they smell, their hair falls out. But the system responsible is extremely complex and can go wrong at many different points and in many different ways. In some dogs, the problems might be an immune system prone to make errors, in others genetics that favor defects in the dog’s skin barrier, in others promiscuous antibodies ( read here ) So one treatment is never going to cure all dogs. That’s why desensitization (allergy shots) might still be worthwhile for a few dogs ( read here ), diet modification for a few, immune suppression for some and topical medications for others. Veterinarians have no tests that will predict which dogs will do best on which treatment(s).
As you can see from my diagram at the top of this page, your pet’s itch is the end result of a complex process (the itch cascade) in which a great number of chemical players and cells take part and communicate with each other (=crosstalk ) (antigens,T-cells, antibodies, messenger chemicals, receptor stations [=docking stations], skin barrier defects, sensory nerves that lead to the brain). The immune system has fail-safe avenues (pathways), so if one road to itching is blocked, another one can sometimes take its place (it is a very plastic system). That is why anti-itch medications that work great at first may gradually loose their effectiveness. If you want to delve deeper than my short explanation, an article focused on allergic skin disease in humans describes all that well. (read here) If you want a copy of the full article ask me.
No one has studies why some dogs itch and others don’t. But we do know from humans and mice that the amount of IL-31 goes up as we age. ( read here ) We know that some humans and mice are just prone to produce too much IL-31 (“over-express”) even without allergies and that some humans itch because they produce antibodies against their own normal tissues (autoantibodies). ( read here & here)
Ear infections and paw licking are the hardest symptoms of dog allergies (AD) to cure since they often have other drivers (contributing factors) in addition to allergy. Your dog’s personality has a large effect on its inclination to lick its paws and its grooming behavior – particularly in the cupcake breeds. Floppy eared, compressed faced and wrinkly skinned dogs develop the majority of their ear problems because of their conformation and skin composition (defective collagen). Scooting can be related to perineal (rear end) or vaginal itching, but also to dietary-driven anal anal gland impaction , bowl issues like IBD, early age neutering or urinary tract issues. None of those causes are likely to respond to Apoquel® or Cytopoint®.
How Long Does It Take A Cytopoint® Injection To Work?
About 80% show improvement in the first 24 hours. The rest that are going to show improvement usually do so by the end of the second day. There are a few exceptional cases where it might take up to three days. It will take considerably longer for your dog’s skin damage to heal and its hair to grow back. If your dog is already on Apoquel®, a gradual decrease in Apoquel® as it transitions to Cytopoint® is probably going to give your pet a smoother transition. The EMA says that Cytopoint® starts working within 8 hours and I have known some cases where relief began even faster. But there doesn’t seem to be much relationship between how rapid relieve for your dog begins and how long that relief will last.
Some pet owners might have already had experience with periodic injections given by a veterinary dermatologist to desensitize their dog. That veterinarian might have indicated that with time, your dog might require fewer or no additional injections. That is not the case with Cytopoint® – if it actually “cured” a dog, we would have to rethink what we believe we know about the drug and the itch process. Monoclonal antibody therapies rarely get more effective with time. Usually they are either effective by the third injection or they remain ineffective indefinitely. Of course, when allergies are seasonal, a drug like Cytopoint® might appear more effective or less effective depending on the time of the year.
How Long Does The Relief Of A Cytopoint® Injection Last?
Zoetis advertises 4-8 weeks of relief from a single injection. But 3-5 weeks – with the average being about 3.5 – 4 weeks before dogs begin to lick their paws again – is more realistic. My feedback indicates that very few dogs remain under itch control for as long as 8 weeks. But I do occasionally get emails about those 8-week miracles. Zoetis also conducted unpublished studies that showed that the half-life of a Cytopoint® injection (the time that half of the drug still remained in your dog) was approximately 9 days – not a month. (EMA/CVMP/113787/2017) The same report suggested that the amount of the drug remaining in your dog’s body might build up over time with repeated monthly injections and that that might increase the drug’s anti-itch effects. No evidence was given. One can still dream for 8-week protection. The Cytopoint® minimum monthly dose is 2 mg/kg. There is a human anti-IL-31 drug in development for itching called nemolizumab. In one study, it appeared to suppress itching in 5 out of 6 monkeys for almost 2 months when given at half the Cytopoint® dose. (read here) There are also cases where Cytopoint® started off quite effective after the first shot or two but then slowly lost its effectiveness during later injections. That sort of effect has been seen with other similar biological medications. ( It is believed to be associated with the patient developing antibodies that attack and neutralize drugs like Cytopoint®. (ADAs=anti-idiotypic antibodies)The EMA report I mentioned earlier said that Zoetis detected none of those anti-drug antibodies in 18 beagle dogs it gave Cytopoint® injections to over a 30-day period. The EMA then requested a field study. One hundred and forty-two client-owned dogs with AD were given Cytopoint® injections monthly for 3 month. Three developed ADAs. Post-injection hives are sometimes associated with the development of ADAs; although sensitivities to other constituents in the Cytopoint® bottle and pre-existing autoimmune issues have the potential to cause hives too.
How Frequently Can Cytopoint® Be Given?
To satisfy the EMA, Zoetis reported no health changes in beagles given 1, 3 or 9 mg/kg three times during 1 month (2 mg/kg is the minimum suggested Cytopoint® dose). Later, they repeated the experiment and gave six more beagles 1 or 9 mg/kg once a month for 7 months and still saw no side effects. Although the current package insert says, “give every 4-8 weeks as needed”, there are veterinarians who give it more frequently in dogs that do not obtain sufficient relief for the full 4 weeks. I do not know of any dogs that were given Cytopoint® more frequently than every 3.5-4 weeks that developed problems that were thought to be associated with giving those shots closer together than suggested on the label. But check now and then with my Cytopoint Comments page to see what feedback arrives.
This IL-31 That Cytopoint® Neutralizes , Why Does It Exist In The First Place And What Is The Point Of Itching Anyway?
IL-31 is an important player in at least some cases of itching. Every furry or feathered animal on this planet itches (A “genetically conserved” behavior). So there must be some good reasons for itching. When it is not misdirected it is self-protective (as are other skin sensations such as touch, pain, vibration, cold and heat). At the level of your dog’s brain (higher up the line than where Apoquel® and Cytopoint® work), it is due, at least in part, to the release of a nerve signal transmitter (neurotransmitter NPPB). That is the same or a similar compound to BNP , what damaged hearts release. (read here) NPPB also acts as an antimicrobial peptide (it kills bacteria and fungi). NPPB ’s other biological actions include, widening of skin blood vessels (vasorelaxation) and decreasing renin and aldosterone blood levels which increases the blood supply to your dog’s skin. When this reaction is triggered, protective antibodies and germ-fighting cells arrive at your dog’s skin via its blood stream. In times of troubled skin, a large blood supply is often helpful in resolving skin issues. But if your dog’s skin were always highly vascular (lots of blood and blood vessels), its skin would be much less durable. Its skin would bleed too much from minor injuries. Too much body heat would be lost and bacteria and parasites would find cuts and nicks a much easier entry into your dog’s body. Scratching, when not misdirected, also helps in removing irritating surface contaminants and dispersing or killing, flies, mosquitoes, lice etc.
Veterinarians know very little about what IL-31’s other normal roles in your dog’s body are. But it is a basic finding in medical research that messenger chemicals in the IL-31 family are used in different parts of the body for different purposes. We also know that some of IL-31’s functions change depending on the animals’ stage of development and age. We also know that IL-31 docking stations (the specific receptors for IL-31, ie IL-31RA) exist in many tissues throughout your dog’s body. What roles stimulating those docking stations with IL-31 play and what the consequences of interrupting those message pathways with Cytopoint® will be is unknown. We know that a lot of sensory nerves are receptive to IL-31. We know that along with nerves, the basic cells of your dog’s skin (keratinocytes) receive IL-31 messages as well. So does the lining of your pet’s lungs and its muscle cells. (read here , ask for it in English). We know that eosinophils, white blood cell involved in allergies, and other cells involved in body defenses receive IL-31 messages too. ( read here ) Low levels of IL-31 also naturally occur in your dog’s thymus gland, testis, spleen, and kidneys. We do not know what its functions are in those locations. When a drug like Cytopoint® cancels IL-31 messages, cells with the IL-31 receptor are going to act somewhat differently. But neither I nor Zoetis can tell you how. On a comforting note, I can tell you that mice that have been bred to lack all of their IL-31 mailboxes appear – at first glance – to be normal. But I can’t seem to find anyone who has kept them longer than they needed to to complete their experiments or paid much attention to their general health and behavior. On another positive note, Cytopoint® might even be helpful to dogs with inflammatory bowel disease – since IL-31 stimulation is thought to play a role in chronic intestinal inflammation as well. (read here) (let me know if you find this to be the case in your pet)
As if that were not complicated enough, I am embarrassed to tell you that the IL-31 “mailboxes” (IL-31Rα receptors) receive and are activated by a second type of message (you see, the IL-31 receptor is a dimer – a dual function receptor). These mailboxes also accepts messages from another signaling compound called oncostatin M (OSM ) whose normal functions are just as poorly understood and complex as IL-31. ( read here ) We also know that the effects of OSM appear to intensify when IL-31 is blocked or removed. (read here) Cytopoint® is not known to directly affect OSM; but its presence at normal levels is critical to good health. We also know that many messenger chemicals in the IL-6 family where IL-31 belongs have redundant (overlapping) positive duties in the body.
What – If Any – Might Be The Side Effects Of Cytopoint®?
Most dogs have no immediate side effects to Cytopoint® injections. It has not been on the market long enough to judge its long-term effects. Although rare, I suppose post-injection mopeness (lethargy), eye irritations and hives are the most common side effects reported. But quite a few dogs aren’t themselves for a day or two after a visit to an animal hospital for any reason. Its just not one of their favorite destinations. Your dog thought you were just taking it out for a drive and then, BINGO! Most of the other reported side effects of Cytopoint® are minor. They include occasional post-injection vomiting and diarrhea which could also be psychosomatic.
Even rarer are severe reactions that affect breathing. The kind one occasionally sees after a variety of pet vaccinations. ( read here ) When they occur, it is most commonly in the bulldog-like breeds that have trouble obtaining enough air even on their best days. It is also very difficult to decide if such an attack was due to the agitation of being brought to an animal hospital, the restraint necessary to inject the dog, or overheating that might have occurred in the process. I attribute hot spots that occur after a Cytopoint® injection to be more likely due to incomplete relief than to some side effect of the drug.
Although Cytopoint® instructions suggest that the complete dose be given in one location; some bigger dogs flinch less and show less signs of injection discomfort when the dose is divided and given at two locations. Allowing the refrigerated vial warm to room temp before injection also helps.
Some folks report that their dogs gain weight on Cytopoint®. Perhaps they just feel better and are more inclined to a hearty appetite. Perhaps there is more to it than that. But most owners report that their dog’s weight didn’t change.
More About Staphylococcus
When your dog develops a staph skin infection while taking Cytopoint® or Apoquel® or when taking neither, I suggest that you first try medicated shampoos to see if they might get the problem under control ? Remember, antibiotics are a scorch-earth option – they destroy the good bacteria on the inside and outside of your pet as well as the bad ones and probiotics aren’t going to bring enough of the good ones back. (read here) My preference is for canine skin care products that contain benzoyl peroxide, chlorhexidine or povidone iodine as their active ingredients. ( read here , here & here )
There are veterinary dermatologists who recommend you rinse your dog with a 0.005% solution of household bleach (hypochlorite) to kill staphylococci. ( read here ) I use a lot of Clorox in my practice to disinfect utensils, cages and floors. But it has been so hard on my hands over the years that I have never considered applying bleach to animals and don’t suggest that you do. Trihalomethanes that bleach generate are another worry. Scrubs and lotions that contain hexachlorophene are great at reducing staph skin counts. But they are also too harsh on the skin of dogs for application to large areas – particularly when those areas are inflamed. Antibacterial wipes containing nisin are also available. I have no experience using them.
All medicated shampoos are most effective when massaged well and left on your dog for at least 10 minutes before you wash it off. Avoid getting any in your pet’s eyes. After these shampoos have been thoroughly rinsed and dried, some dogs benefit from an emollient lotion designed to enhance filaggrin function. Filaggrin forms a part of your pet’s natural skin barrier against staph. It promotes normal skin acidity (pH), moisture retention and resistance to future staphylococcus penetration. Some of these products also contain high linoleic/oleic sunflower seed oil, others mineral oil, glycerin, propylene glycol and various carrier oils. I would avoid any that have lauryl sulfate or fragrances as ingredients.