Introduction
Canine atopic dermatitis (CAD) and feline allergic skin syndrome (FASS) are common skin diseases in small animal practices. Much is known about the pathogenesis of atopic dermatitis in the dog,1–6 but less is known about allergic skin syndrome in the cat.7 Altered T-cell responses5 and epidermal barrier changes8 have been reported as the major pathogenic changes, but the pathogenesis is not completely elucidated. Clinical signs and diagnostic criteria of CAD have been identified in large clinical trials.9–11 Briefly, CAD is a skin disease with an allergic reaction to mostly environmental allergens and is characterized by pruritus, particularly affecting the face, ears, and distal limbs. More recently, reviews have summarized what is known about the clinical signs and diagnosis of FASS.12,13 In summary, self-induced alopecia, military dermatitis, head and neck pruritus, and lesions of the eosinophilic granuloma complex can all be due to environmental allergens in the cat, although food allergens, ectoparasites, and other diseases are frequent differential diagnoses that need to be excluded. In both species, a test reliably differentiating animals with environmentally induced allergic skin disease from animals showing signs due to other skin diseases does currently not exist, and the disease is diagnosed by exclusion of all relevant differential diagnoses as appropriate in each individual patient.
Although a number of drugs have been reported to be effective in canine and feline allergic skin disease due to environmental allergens,14–16 allergen (-specific) immunotherapy is currently the only causative and definite treatment.17,18 Allergen immunotherapy consists of the administration of offending allergens to an allergic patient with the aim of decreasing the exaggerated immune response to those allergens by inducing a regulatory response with an increase of regulatory T cells and downregulating the inflammatory response. In the dog, this increase in FoxP3+ Treg cells and concurrent increased concentrations of interleukin-10 and transforming growth factor-β have been documented.19
Injections with the allergen extract are classically given subcutaneously. Oral immunotherapy is more widely used in North America compared to the rest of the work, but published studies20–22 evaluating oral administration are scarce, and solid scientific evidence for its efficacy is currently lacking. More recently, intralymphatic immunotherapy (ILIT) has been introduced in human23–25 and canine medicine.21,26–29 The aim of this review is to provide the clinician with a summary of allergen immunotherapy in small animal practice.
Practical Considerations for Treatment Selection
Before considering allergen immunotherapy, the costs, risks, and benefits of this treatment need to be discussed with the owners (Figure 1). This discussion should take place before an allergy test is initiated. The most crucial matter of discussion is the fact that currently there is no reliable prognostic factor that predicts the outcome of allergen immunotherapy early on. The time to maximal benefit may be months up to 1 year. Consequently, owners need to be prepared to treat their pets with immunotherapy for up to a year before deciding on treatment outcomes.
Flow diagram with images that depicts the practical considerations for initiating allergen immunotherapy in patients with canine atopic dermatitis or feline allergic skin syndrome.
Citation: Journal of the American Veterinary Medical Association 261, S1; 10.2460/javma.22.12.0576
The reported success rates vary in different studies17,18,30 with different protocols and allergens, but approximately two-thirds of atopic patients eventually benefit enough to be considered a treatment success, which in most published studies is an improvement in clinical signs of more than 50%. However, only 1 in 5 animals will eventually be in complete remission on immunotherapy only, without the need for any other medication.31
The most frequent adverse effect of allergen immunotherapy is an increase in pruritus with the injections of allergen extract,17 which will typically lead to a decrease in extract volume and/or a premedication with for example antihistamines, glucocorticoids, or oclacitinib shortly before the injection. Local swellings at the injection site are also regularly seen and are typically nonpainful and transitory. The most severe, but extremely rare, adverse effect associated with allergen immunotherapy is an anaphylactic reaction that can occur shortly after the injection and requires immediate emergency therapy with epinephrine, fluid therapy, and possibly glucocorticoids. Anaphylaxis is more likely during the induction phase in humans; this may well be true for animals also, although no reliable data exist in dogs and cats.
The cost of immunotherapy depends on the type and protocol of immunotherapy chosen, the country of residence, and individual patient factors such as the maintenance dose and frequency of injections needed. In the discussion with the owner prior to the treatment decision, the total cost including allergen extract, syringes and needles, injection fees, and recheck fees for the next 12 months should be cited.
AIT is most suited for young animals with clinical signs for most or all of the year, as it requires significant financial and personal effort and its effects can only be evaluated after several months to a year of therapy. In those animals, the benefits of successful therapy outweigh the risk that treatment is not effective and a significant amount of money was spent without a good result.
Allergen Selection
As stated above, FASS as well as CAD are diagnoses of exclusion. No current test reliably differentiates dogs and cats with environmental allergens from nonaffected normal animals or animals with other pruritic skin diseases, and false-positive reactions are common in intradermal tests32–34 as well as serum tests for allergen-specific IgE.32 Such tests are consequently not suitable for the diagnosis and should only be recommended and undertaken in animals where owners decided on allergen immunotherapy as a preferred treatment option.
Allergens for the allergen extract to be used for treatment should be chosen based on a positive reaction on the test (independent of the type of testing, serum testing for allergen-specific IgE, or intradermal testing) in conjunction with a history compatible with exposure to this particular allergen.35 For example, strong reactions to tree pollens in a temperate climate are probably not clinically relevant in a dog with perennial clinical signs of similar severity throughout the year, as in such an environment, most trees pollinate only in early to late spring and do not cause clinical signs all year round. Pollination periods of allergenic plants are available on various websites in most countries; an example for the United States can be found at https://www.pollen.com (last accessed on December 12, 2022). Similarly, reactions against dust mites are most likely irrelevant in an animal with clinical signs in summer only, as dust mite antigens are present all year round in most houses and, if anything, may increase indoors in winter in some situations.
The number of allergens that can be included in 1 vial of allergen extract varies depending on the size of the vial, the injection protocols, and the concentration of the allergens in the solution. In North America, aqueous solutions are used predominantly and the consensus among clinicians is that many if not all of the different allergens causing positive reactions can and should be included in the extract. In Europe, alum-precipitated allergens are used and the number of allergens per vial is limited; most patients receive immunotherapy with up to 4 allergens, and in selected patients, up to 8 allergens are chosen. However, the success rate of allergen immunotherapy in studies conducted in Europe21,29,36,37 is similar to that seen in studies in North America and Australia19,38–40 and well-done, double-blinded comparisons do not exist.
Immunotherapy Induction
In the induction period, an increasing amount of allergen extract is administered subcutaneously in intervals from a few days to a few weeks, depending on the protocol used. After several weeks to months, a maintenance dose is reached; in most protocols, this is 1 mL of the extract that is then injected every 3 to 4 weeks initially. To avoid confusion and to reach the maintenance dose faster, rush protocols have been published. The ultimate rush immunotherapy (RIT) completes the induction period in 1 day,29,36,39,41 this type has been associated in a double-blinded, randomized study39 with a time to maximal benefit of 6.8 months compared to 9.2 months with the classical induction. In another study,42 an escalation protocol abbreviating the induction from 3 months to 28 days was compared with the standard protocol and had a higher number of adverse effects, although almost all mild and self-limiting. One dog in each group vomited once after an injection; the 1 in the RIT group showed additional swelling and erythema of the paws and periocular area. All others showed increased pruritus and/or erythema. However, clinical efficacy was not evaluated in that study.
With oral or rather oromucosal immunotherapy, allergen extract is administered typically onto the buccal mucosa once to twice daily with a pump spray. In 1 trial,20 10 dogs with perennial atopic dermatitis and positive reactions to mite antigens received glycerinated extracts of Dermatophagoides farinae, Dermatophagoides pteronyssinus, and/or Tyrophagus putrescentiae in accordance with each dog’s individual test results for 6 months. The product was supplied in 3-pump dispenser bottles of increasing concentrations with a small hook-like nozzle. Owners administered the extract by hooking the nozzle over the teeth in the lower jaw. Twice daily, 0.1 ml of extract was administered into the sublingual area, initially with the first (lowest concentration) bottle for the first 2 months, followed by the second bottle for 2 months, and then the third (highest concentration) bottle thereafter. A significant decrease in lesions, scores, pruritus scores, and the amount of prednisolone administered concurrently was seen after 6 months.20 In another study,43 lesion scores improved significantly in the 17 dogs completing the trial after sublingual RIT with subsequent therapy for 6 months. Unfortunately, pruritus scores were not reported. Adverse effects were not seen in either of those studies. Unfortunately, studies evaluating larger numbers of dogs for a longer treatment period are not published to the author’s knowledge.
Three injections of allergen extract into the lymph node in humans are associated with long-lasting increased tolerance and fewer adverse effects than classical immunotherapy.23–25 In veterinary medicine, this long-lasting effect could not be confirmed for most dogs.27,28 However, injecting 0.1 mL of allergen extract into the lymph node was safe21,26,28,29 and showed a success rate comparable to classical immunotherapy and RIT.
Maintenance Therapy
For subcutaneous immunotherapy, the maintenance protocol per package insert of most companies is 1 ml of allergen extract every 3 to 4 weeks. This protocol is suitable for some patients. However, to optimize the efficacy, the dose and frequency of the injections need to be adjusted in some patients. If the patient’s pruritus increases directly after the injection and gradually decreases again during the next few days, the amount injected should be decreased by 25% to 50%, depending on the severity of the pruritus. In contrast, if the pruritus increases 1 week before the injection, it is advisable to decrease the time period between injections by 1 week. Concurrently, the dose administered may be decreased by 20% to 25%. Several such adaptions may be needed before the ideal amount and frequency are determined for a particular patient. In 1 study,44 the average maintenance dose was 0.15 ml of aqueous allergen extract every 10 days, emphasizing the importance of tailoring the therapy to each individual patient. In 1 large recent study45 using alum-precipitated allergens in more than 600 dogs, the protocol had to be adapted in 10% of the patients. In contrast, in the author’s clinic, also using alum-precipitated allergens, approximately half of the patients receive adapted maintenance therapy.
To the author’s knowledge, there is only 1 published study21 evaluating long-term ILIT treatment in 10 dogs. Most studies26–29 only used 4 to 7 subsequent monthly intralymphatic injections. In 2 of those studies,28,29 AIT was continued with subcutaneous injections after this initial period. The long-term effects of repeated intralymphatic injections of allergen extracts over years are unknown and adjuvant-associated allergens were mentioned to be of particular potential concern.29 In a recent double-blinded, randomized trial29 comparing ILIT and RIT, there was no difference between the 2 groups regarding outcome and time to maximal improvement.
Long-term Management, Outlook, and Prognosis
If after 12 months of allergen immunotherapy there is no clinical improvement and no prominent decrease in required antipruritic therapy, then the patient is considered a treatment failure and immunotherapy is discontinued. If however there is improvement, therapy is continued.
From then on, there are 3 different options for owners. AIT can be continued forever unchanged as long as the patient is improved or even in remission. Long-term adverse effects of this therapy are not reported, and when there is complete remission of a patient on just immunotherapy, many owners will be reluctant to “change a winning horse.”
Alternatively, the time period between injections can gradually be increased after a couple of years of successful AIT, until the allergen extract is injected every 8 weeks and the animal can be kept on this maintenance therapy long term. In those cases, the cost of maintenance therapy is typically reasonable and much less than during the initiation of the therapy with allergy testing and induction adding additional expenses. Consequently, this is also a sensible option for many clients.
Finally, AIT can be discontinued after a couple more years, as is typically done with human patients. In humans, clinical signs will often recur after a few years. Due to the limited life span of dogs and cats, improvement lasting for a few years may be all that is required. However, when immunotherapy is ceased, rapid recurrence of clinical signs within months is also a possible consequence.
Concurrent Symptomatic Therapy
As stated above, in many patients AIT will improve clinical signs, but complete remission is only achieved in a minority of dogs and cats. Consequently, a number of animals are on concurrent symptomatic therapy intermittently to control allergic flares or permanently to keep them in complete remission. A concise review of symptomatic therapy was published elsewhere.16 However, scientific studies evaluating concurrent therapies with AIT are scarce, and treatment recommendations are based on the first principles and pathophysiology of the disease as well as the mechanism of action of the recommended drugs.
All patients with increased pruritus should be evaluated for secondary infections commonly associated with such flares. In addition, practitioners should check if treatment for ectoparasites such as fleas is up to date. Allergic flares are commonly treated with highly effective drugs such as glucocorticoids, oclacitinib, and lokivetmab short term. Those drugs have a fast onset of action, and improvement of pruritus should be seen within days. Oclacitinib and glucocorticoids for allergic flares of an otherwise well-controlled dog are typically administered for a few days to a week or 2 and subsequently discontinued. One injection of lokivetmab should be sufficient for an allergic flare.
For animals with permanent residual pruritus, the above-mentioned medications are usually not the first choice. First, oclacitinib and glucocorticoids given permanently affect T-cell function and AIT induces a regulatory T-cell response. Although there are no scientific studies in dogs and cats evaluating the influence of such drugs on the treatment outcome, it seems prudent to limit their use to short treatment intervals. Second, oclacitinib and lokivetmab are costly and often control the disease on their own, so combining those drugs long-term with AIT is only recommended in patients not responding to them individually. Consequently, most patients on a combination therapy of AIT and symptomatic medications will be treated with essential fatty acids, moisturizing shampoos, antihistamines, or (in the case of localized disease) topical hydrocortisone aceponate.
Conclusion
Allergen immunotherapy is a causative treatment option for dogs with AD and cats with FASS that combines a good success rate with low adverse effects short and long term. It should be recommended particularly for younger animals with clinical signs induced by environmental allergies after a thorough discussion of costs, adverse effects, and success rates. Maintenance therapy should be adapted to the individual patient.
Acknowledgments
Dr. Mueller has acted as a consultant or received support for studies or lectures from Artuvet, Bayer Animal Health, Ceva Animal Health, Ecuphar, Elanco Animal Health, Greer Laboratories, Heska Laboratories, Hill’s, Royal Canin, MSD Animal Health, Nextmune, Synlab, Virbac Animal Health, and Zoetis.
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