Update on treatment of atopic dermatitis
UPDATE ON TREATMENT OF ATOPIC DERMATITIS
Anthony Yu DVM, MS, ACVD
Yu of Guelph Veterinary Dermatology
1460 Gordon Street, Guelph, Ontario, Canada N1L 1C8
In order to effectively control a patient with atopic dermatitis, an understanding of the pruritic threshold, summation of effect and the three pathways of pruritus are key. Pruritic threshold, similar to the pain threshold, is variable between patients. Even clinically predisposed atopic patients from the same litter, living in the same house, exposed to the same allergens may have varying clinical appearances whereby the pet with the lower pruritic threshold will exhibit pruritus and allergic symptoms while its littermate may be able to tolerate the same allergen load because of its elevated threshold or tolerance levels. Summation of effect refers to the addition of multiple contributing factors (e.g. Malassezia or Staphylococcal infections, fleas, food or pollens during the peak allergy season, dust mites, mold spores) that push a patient above their pruritic threshold. Treatment modalities that typically help decrease allergen load below a patient’s pruritic threshold include avoidance (ectoparasite, food, environment) and allergen specific immunotherapy either by subcutaneous injection or daily oral administration for allergens that cannot be avoided.
Less specific symptomatic therapy typically focuses on controlling inflammation and itch. There are three pathways by which our patients may manifest their itch: 1) Inflammatory itch mediated by inflammatory cytokines and the complement cascade; 2) Neurogenic itch mediated by Interleukin-31 (IL-31) and other similar cytokine that mediate pruritus through Janus Kinase/STAT signal transduction at the nerve endings in the skin; and 3) Behavioural or anxiety-related itch, which may be mediated through learned behaviours and the serotonin receptors. When selecting medications for pruritic atopic patients, using a combination of therapies that address one or all three pathways of itch will be based on history and clinical signs.
Owner compliance and adherence to a treatment protocol is key to a successful outcome when treating any skin disease, especially a life-long condition such as atopic dermatitis. Compliance requires that the client understands both their pet’s diagnosis, mechanisms by which their prescribed medications function, and that the goal of treatment is primarily to control their signs of atopic dermatitis, as opposed to curing it, using the safest and cost-effective therapy with the least amount of work for the owner. Setting aside enough examination time to educate your client on their pet’s condition, written discharge summaries, client education handouts and web-based videos, along with follow-up visits and calendars all help to promote better understanding and compliance ultimately leading to successful management of your atopic patient.
Avoidance of the offending allergen is the ideal approach to treatment of the atopic patient however it is often difficult to achieve. Aeroallergens floating into the yard from a 75 km radius, mold spores that are ubiquitous in both the outdoor as well as indoor environment, and dust mites on the owner’s and pet’s bed as well as the couch, carpet and heating ducts, make it impossible to eliminate all allergens from the environment. The goal, in fact, is to minimize contributing factors to bring a pet closer to or below their allergic threshold. Interventions such as flea control, microporous mattress and pillow covers, room HEPA filters, frequent vacuuming, Dust Mite X® for carpets and upholstery, maintaining humidity levels between 40-45%, removal of carpeting and potted indoor plants when possible, heating duct cleaning, keeping pets indoors when mowing the lawn and outdoors when vacuuming, use of hypoallergenic detergents and cleaning supplies will all help and have little to no negative side effects for the patient.
Shampoo therapy has gained increased importance in the management of atopic dermatitis as percutaneous absorption is now likely the primary route of allergen exposure. Bathing using COOL to COLD water at least once weekly helps to 1) wash off superficial allergens that accumulate on the skin; 2) rehydrate the skin barrier; and 3) controls overgrowth of bacteria and Malassezia, minimizing allergen exposure to the dermal immune.
ALLERGEN SPECIFIC IMMUNOTHERAPY
Allergen specific immunotherapy (ASIT) is the only targeted approach for atopic patients that may lead to immunomodulation and the development of tolerance with little to no adverse effects. All other therapies provide temporary symptomatic relief and carry greater risk of adverse side effects.
ASIT is accomplished by the administration of increasing concentrations of allergens up to maintenance doses, using standard or rush protocols administered by subcutaneous, oral, or recently by intralymphatic route in veterinary medicine. The ultimate goal is for ASIT to stimulate allergen‐specific tolerance resulting in a curative effect for a long period of time. The methods by which ASIT elicit their response early in the process include desensitization of FcεRI (high‐affinity receptor for the Fc region of immunoglobulin E)-mediated basophil/mast cell responses along with allergen-mediated upregulation of H2R and downregulation of FcεRI. Later responses involve upregulation of markers associated with dendritic cells driving differentiation of TGF-beta and IL-10-producing T-regulatory and B-regulatory tolerogenic cells and subsequent activation of B cells to synthesize allergen‐blocking factors, particularly IgG4 “blocking antibodies” and suppression of IgE antibodies.
The benefits of this therapy include the paucity of adverse effects, the cost effectiveness especially in large-breed dogs due to the weight-independent dosing regimen, and the potential to eventuate a cure. Successful outcomes are dependent on concentration of ASIT being used (i.e. 10,000 pnu vs 20,000 pnu), inclusion of appropriate antigens into the ASIT, adjustments in the ASIT schedule based on clinical response and allergen load, as well as controlling any secondary factors that may arise (e.g. bacterial and/or Malassezia infections). It should be emphasized however, that clients choosing this therapeutic alternative should not expect an immediate “light-switch type” response, rather “re-training” of the patient’s immune response to environmental may take several months to years to achieve optimal results, and that treatment using a combination of immunotherapy and/or symptomatic therapy, may be lifelong in the majority of patients. Thus, it is common to incorporate anti-pruritic therapy especially during the induction phases of ASIT.
Selecting an anti-pruritic therapeutic protocol for your patient will depend on the severity of skin signs, the owner’s ability to administer medications and the type of itch the patient is experiencing:
i) Inflammatory Itch - Itch induced by pro-inflammatory mediators including histamine, prostaglandins, and proteases as well as pro-inflammatory cytokines including IL4, IL5, IL13, TNF-alpha
ii) Neurogenic Itch – Centrally and peripherally mediated itch induced by neuropeptides such as Substance P and cytokines affecting the cutaneous nerve endings including thymic stromal lymphopoietin (TSLP), IL31, nerve growth factor (NGF), gastrin releasing peptide (GRP) and B-Type Natriuretic Peptide (BNP).
iii) Psychologic or anxiety-related itch – Activation of the hypothalamic-pituitary axis (HPA), as well as the sympathetic and serotonergic nervous systems in response to psychological stress, resulting in alteration of serotonin levels and increased expression and secretion of catecholamines, and a host of other molecules along with learned itch behaviour from negative reinforcement or anxiety-relieving habit.
Based on the suspected contributing mechanism of itch, monotherapy or sometimes a multimodal approach is necessary to provide relief for a patient.
a) Anti-inflammatory Itch
Patients that experience pruritus with INFLAMMATION and INFECTIONS require medications that address cytokine and complement-induced inflammation including antihistamines, cyclosporine, and/or steroids.
Antihistamines provide 18-32% efficacy in controlling allergic symptoms. They are best used as a preventative or in the early stages of the allergic response, or in combination with other therapies when trying to capitalize on their synergistic activity to taper the use of more potent anti-inflammatory agents such as steroids. Sedation is the main adverse effect noted, especially when using first-generation antihistamines as they cross the blood brain barrier. There are several subclasses of antihistamines: Ethanolamine (e.g. clemastine, diphenhydramine); Ethylenediamine (e.g. tripelennamine); Piperazine (e.g. hydroxyzine, cetirizine); Piperidine (e.g. fexofenadine, cyproheptadine); Alkylamine (e.g. chlorpheniramine); and Phenothiazine (e.g. trimeprazine) with varying effects due to their active ingredient or metabolites. This is likely one of the reasons for the variable responses noted and explains why there are still over 20 different products available over-the-counter. In general, I tend to use cetirizine (Reactine®, Zyrtec®) 0.5-1.0 mg/kg in the MORNINGS and diphenhydramine (Benadryl®) 2.2-4.4 mg/kg in the EVENINGS.
Cyclosporine (Atopica®) is a macrolide derived from a fungus that targets T- lymphocytes binding immunophilin (cyclosporine binds cyclophilin, tacrolimus binds macrophilin) and thus inhibits calcineurin, thereby decreasing stimulation of Nuclear Factors of Activation (NF-ATp) resulting in decreased production of interleukin-2 (IL2) thus suppressing T-lymphocytes proliferation and the allergic response. Other cyclosporine effects that modulate the allergic response include: 1) decreasing Langerhans cell migration & ability to process antigen; 2) inhibiting the release of pre-formed mediators from mast cells and basophils; 3) decreasing synthesis of TGF-α and -β, IFN-γ, GM-CSF, IL-2, IL-3, IL-4, and IL-5; and 4) has a cytostatic effect on keratinocytes of the epidermis to help re-establish the skin barrier. As cyclosporine’s effects are targeted at inflammatory cells (unlike systemic steroids), the number and severity of adverse reactions is limited. As well, cyclosporine provides anti-neurogenic activity by calcineurin inhibition on nerves binding to capsaicin receptor TRPV1 resulting in a burn then cool sensation.
The dose of cyclosporine used to treat atopic dermatitis is 3-7mg/kg/day per os, an anti-inflammatory dose and carries fewer side effects than the immunosuppressive doses of 10-20mg/kg. Side effects include transient vomiting & diarrhea, anorexia, and reversible gingival hyperplasia. The GI effects can be mitigated by freezing the capsules and refrigerating the liquid formats. Once clinical signs are 100% controlled, cyclosporine is tapered by extending the interval between administration by 1 day per month (i.e. q48hrs for one month, then q 72 hours for one month) to the lowest effective dose, realizing that an increase to once daily may be necessary to control symptoms during peak allergy seasons. Annual bloodwork and urinalysis are recommended for any medications used for protracted periods. Dosage reduction of 50-67% may be required when cyclosporine is co-administered with medications that inhibit of P-450 microsomal enzyme metabolism including ketoconazole, itraconazole, fluconazole, metoclopramide, erythromycin, methylprednisolone, allopurinol, diltiazem and verapamil. As well, note that some medications may lower the efficacy of cyclosporine by increasing its metabolism or excretion including rifampin, phenobarbital, and phenytoin.
Glucocorticoids applied topically or given systemically have been the mainstay in the treatment of atopic dermatitis. A meta-analysis of therapeutics used to treat atopic dermatitis reported good evidence for high efficacy of oral and topical glucocorticoids and low harm of short-term treatment. Topical triamcinolone, betamethasone, mometasone and various forms of topical hydrocortisone have been used with success in veterinary dermatology. Oral glucocorticoids include methylprednisolone, prednisone and prednisolone (0.4-1 mg/kg), trimeprazine/prednisolone (Temaril-P® USA/Vanectyl-P® Canada; 1 tablet per 10 kg/day) and dexamethasone (0.05 mg/kg) are administered daily for 7 days then tapered to every other day or less pending response. Adverse effects included polyphagia, PU/PD, weight gain and/or intermittent GI signs. The benefit of long-term treatment with glucocorticoids must be weighed against the risk of adverse drug effects impacting on health and quality of life. Concurrent use of other anti-inflammatory and/or antineurogenic therapy has resulted in synergistic responses, permitting lowering or elimination of steroid use.
b) Neurogenic Itch
Pruritic patients with little to no inflammation, infection or otitis will benefit from either oclacitinib (Apoquel®) OR lokivetmab (Cytopoint®). These medications help to block IL31-mediated pruritus at both the cutaneous nervous system and the dorsal root ganglia hence eliminated traumatically-induced inflammation but have little to no effect on allergy-mediated inflammation at their current recommended maintenance doses.
Oclacitinib (Apoquel®) is a selective inhibitor of Janus kinase 1 (and 3) that quickly blocks IL-31 mediated itch at cutaneous nerve endings. Oclacitinib is dosed at 0.4-0.6 mg/kg twice daily for 14 days, then decreased to 0.4-0.6 mg/kg once daily or split twice daily as needed to control itch. Oclacitinib can rarely be tapered beyond once daily is using the medication as a monotherapy to control atopic dermatitis. At higher doses (0.4-0.6 mg/kg BID or greater), oclacitinib provides anti-inflammatory effects by decreasing the production of interleukin (IL)-2, IL-4, IL-6 and IL-13 as well as blocking inflammation caused by IL31-induced itch. Banovic et al (2019) noted that at lower maintenance doses, the effects on interleukin (IL)-2, IL-4, IL-6 and IL-13 mediated inflammation are negligible in vitro. Oclacitinib is not approved for dogs less than 12 months of age, should not be used in dogs with serious illness as it may alter local immune function increasing susceptibility to infections, allowing Demodex mites to proliferate and altering responses to neoplastic conditions. Rare gastrointestinal signs, interdigital cysts, histiocytomas, lethargy, polyphagia, weight gain, and increased aggression have been noted, with adverse reactions resolving with discontinuation of Apoquel. As it does not calm skin inflammation at the maintenance doses, bacterial and yeast dermatitis & otitis persists. CBC, chemistry panels and urinalysis are recommended for patients where Apoquel is chronically administered, and more frequently in patients with any concurrent metabolic abnormalities.
Lokivetmab (Cytopoint®) is an injectable monoclonal caninized antibody directed against IL-31 that it administered at 1-3mg/kg subcutaneously every 4-8 weeks as needed to control itch. Note, due to the targeted nature of this medication, it does not control pro-inflammatory cytokine induced inflammation. Anti-itch effects are typically noted with hours to days. As lokivetmab is metabolized by protein reprocessing or degradation by the immune system, there are currently no labeled contraindications for its use with other medications, nor for use in puppies, patients on medications or with nephropathies, hepatopathies and neoplasias can benefit from its anti-itch effects. About 1.5% to 2.0% of dogs can develop anti-Cytopoint IgG and negate its positive effects. As it is caninized, use in species other than dogs is not recommended. Anecdotal reports on the ACVIM listserv, cautions use of lokivetmab in patients with existing inflammatory bowel syndrome, autoimmune hemolytic anemia and immune-mediated thrombocytopenia. This may potentially be due to undiscovered functions for IL31 that have yet to be elucidated. Lastly, cost may be a factor in large breed dogs at the North American labeled dose of 2mg/kg every 4-8 weeks but is equivalent to a month’s worth of Apoquel when the European dose of 1mg/kg monthly is administered.
c) Psychologic or anxiety-related itch
Atopic patients with anxiety may surmount the effects of anti-inflammatory and antineurogenic therapy. A history of thunderstorm, firework, or separation anxiety-related increased licking, scratching and chewing help to discern when to institute behavioural modification and anxiolytic therapy. Use of dog appeasing pheromones and anxiolytic medications such as tricyclic antidepressants, amitriptyline and clomipramine (1-2 mg/kg BID) or serotonin-reuptake inhibitors, paroxetine and fluoxetine (0.5-2 mg/kg q24h) must always be accompanied by behaviour modification techniques. Planned departure techniques minimizing and desensitizing to predeparture clues (picking up keys, mobile phones or shoes), counter conditioning the negative association with leaving, providing additional environmental, social and exercise enrichment should be customized to the patient’s needs and incorporated as part of a multi-modal approach.
MULTI-MODAL ANTI-INFLAMMATORY THERAPY – A “FOREST FIRE” ANALOGY
Even with the introduction of non-steroidal alternatives such as cyclosporine with long-lasting effects equivalent to those of steroids, glucocorticoids remain one of the only treatment options that will give the patient immediate relief or “put out a fire” within 24-48 hours. If the analogy of a forest fire is used, the “fire retardant” dropped from airplanes is the steroid, while the other therapeutic options such as Omega-3 fatty acids, antihistamines, dietary restriction, flea control, epidermal barrier repair, cyclosporine and allergen specific immunotherapy are the “trench diggers” controlling the fire from spreading. I currently position the oclacitinib and lokivetmab in the “fire retardant” group. The incorporation of this multi-modal approach to control the allergic reactions prevents damage to the epidermal barrier, calms the inflammation and microenvironment, hence minimizes recurrence of secondary infections. I typically have client error on the side of giving a little extra steroid to prevent a secondary infection rather than to give too little steroid and have to return to 4-weeks’ worth of antimicrobial therapy to treat infections.
Using a MULTIMODAL approach, all of the above can also be used in combination with adjunctive therapy such as topical anti-inflammatory agents (Tacrolimus (ProTopic® 0.1%); Hydrocortisone aceponate 0.0584% (Cortavance®) spray; Mometasone (Elocon®, Mometamax®); and Pramoxine local anesthetic (Relief®, ResiProx®, Gold Bond Anti-Itch Lotion®). Also, dietary restriction may be used longterm or during peak allergy seasons to minimize cutaneous adverse food reaction’s contribution to the allergen load.
PREVENTATIVE USE OF ANTI-INFLAMMATORY MEDICATIONS
Lastly, once a pattern of seasonal reactions has been established and appears quite predictable, use of cyclosporine, steroids or other anti-inflammatory medications in advance of the allergy season may allow the owner to start at maintenance control doses as opposed to using high loading doses to put out the fire first before moving to maintenance therapy. Ultimately this approach will help minimize cost and side effects associated with high daily doses of allergy medications as well as prevent costly secondary infections such as Staphylococcus and Malassezia dermatitis.
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