Submitted by: Patricia Shea, DVM
Treatment of the feline atopic syndrome-a systematic review.
Mueller RS, Nuttall, T, et al.
This is the fourth and final paper in a comprehensive review of available published literature regarding etiopathogenesis, diagnosis, and treatment of allergic diseases of the skin and gastrointestinal and respiratory tracts in cats. These diseases fall under the umbrella term feline atopic syndrome (FAS). Feline Atopic Skin Syndrome (FASS) refers to allergic skin disease in cats not associated with dietary hypersensitivities or insect allergens.
FASS can manifest as a number of different cutaneous reaction patterns. Signs of FASS can comprise a number of different cutaneous reaction patterns, including miliary dermatitis, self-induced alopecia or hypotrichosis, eosinophilic granuloma complex, and/or excoriations or ulcers on the head and neck. The diagnosis of FASS is a diagnosis of exclusion; other etiologies, such as flea or other insect bite hypersensitivities or food allergy, must be ruled out prior to establishing a diagnosis of FASS. Therefore, intradermal and serum allergy testing without considering history, clinical signs, and exclusion of other differential diagnoses in a patient is not the way to diagnose FASS.
This paper offers an analysis of the available published evidence, including prospective and retrospective studies, clinical trials, and case series, for the various treatments available for FASS and feline asthma, the respiratory component of FAS. Treatments available for FAS include allergen avoidance, allergen immunotherapy, systemic, topical, and inhaled (for feline asthma only) glucocorticoids, cyclosporine, oclacitinib, bronchodilators (for feline asthma only), oral H1 R-antihistamines, essential fatty acids and palmitoylethanolamide (PEA), maropitant, antibiotics, doxycycline in feline asthma, inhaled lidocaine in feline asthma, and stem cell therapy.
A summary table of these treatments, with quality of evidence and strength of recommendation scores, is available in the paper, as are individual tables summarizing responses to treatment and quality of evidence scores from published papers evaluating most treatments individually. The published evidence for treatment of FAS is much more limited than that for similar conditions in dogs; increasing numbers of high-quality, randomized controlled trials of treatments for environmental allergies in dogs are taking place. More such studies for cats are strongly recommended by the authors.
Allergen avoidance, recommended for asthmatic cats, is considered common sense and potentially effective, but there is limited evidence for this in published studies, and no such evidence is available for cats with FASS. Moreover, in many cases, this is not feasible for cats sensitized to environmental allergens.
Allergen-specific immunotherapy (ASIT) has been evaluated in cats with FASS in five retrospective studies, as well as in case series and case reports. Five studies also addressed the use of ASIT in asthmatic cats. Efficacy of ASIT for FASS ranged between 45% and 75%, which is about the same as ASIT efficacy reported in dogs. In asthmatic cats, of five studies, three were performed on cats with experimentally induced asthma. Although the number of studies of ASIT in cats with FASS or asthma is few, and some of these have only been presented as abstracts, ASIT appears to have demonstrated efficacy in FASS and moderate-to-good efficacy in feline asthma. No adverse effects of ASIT were reported in 10 of the studies, but in two reports on rush immunotherapy for FASS, two of four cats had increased pruritus and two of four developed a dermal alopecic nodule.
Glucocorticoids in various formats are among the most widely used treatments for FAS in general, including both FASS and asthma. Published outcome data for treatment of FASS with systemic glucocorticoids is available for 63 cats; oral drugs used included methylprednisolone, triamcinolone, and prednisolone. The use of these medications resulted in a significant decrease in pruritus and lesion scores, and in those animals that responded to treatment, response was observed within 7-14 days. As this data was generated in three prospective double-blinded randomized controlled trials (RCTs), the authors concluded that the evidence for use of systemic glucocorticoid treatment in FASS is good.
Medications that performed best in these RCTs in terms of promoting remission of FASS signs were methylprednisolone (1.4-1.5 mg/kg PO once daily for four->six weeks) and triamcinolone (0.18 mg/kg PO once daily for > six weeks). Prednisolone at 1 mg/kg PO once daily for four weeks was less effective and created an improvement in clinical signs in only about half of the patients. Once the animal is in remission, the medication should be tapered to the lowest dose and longest dosing interval that maintains remission.
One safety study in 14 cats compared the use of 4.4 mg/kg prednisolone PO once daily with 0.55 mg/kg dexamethasone PO once daily for 56 days. The doses of these two drugs utilized in the study were considered equipotent. Although none of the cats actually became hyperglycemic, results of this research demonstrated increased glycosuria and increased serum fructosamine concentrations as well as decreased insulin sensitivity and secretion in the dexamethasone-treated group compared to those receiving prednisolone. Monitoring cats on long-term treatment with systemic glucocorticoids, especially more diabetogenic drugs such as dexamethasone, is strongly recommended.
Oral systemic glucocorticoids and/or inhaled glucocorticoids are also a mainstay of therapy in asthmatic cats, and the current evidence is considered good for their use. However, most feline asthma research to date has been performed on small numbers of cats experimentally sensitized to Bermuda grass, Ascaris suum, or household dust mites. More research on cats with naturally occurring asthma is definitely necessary.
Inhaled fluticasone at various dosages (44, 110, or 220 mcg twice daily) administered in randomized controlled trials to asthmatic cats results in decreases in airway eosinophils, airway inflammation, and airway hyperresponsiveness. Studies of inhaled glucocorticoids in feline asthma therapy do not report adverse effects—either they were not observed or not mentioned. Monitoring of cats on long-term inhaled glucocorticoid therapy is nonetheless recommended by the authors. There is documented evidence of hypothalamic-pituitary-adrenal axis suppression in cats with high doses of inhaled budesonide and flunisolide. Although inhaled bronchodilators are frequently recommended in the treatment of feline asthma, there are no studies that have evaluated their use in naturally occurring feline asthma, and the two studies performed in experimentally sensitized cats provided no evidence supporting the use of inhaled bronchodilators. These drugs are nonetheless recommended for rescue in acute asthmatic episodes and in conjunction with inhaled glucocorticoids, for long-term management of feline asthma.
Cyclosporine, now generally used in the veterinary formulation Atopica for Cats, rather than in human formulations, may also be used in FASS, especially in patients who may suffer significant adverse effects from glucocorticoids, such as cats with diabetes mellitus or congestive heart failure. Efficacy of this drug at varying doses, usually 7 mg/kg PO once daily, was good in the treatment of a variety of cutaneous reaction patterns associated with FASS. There is currently no published evidence regarding the efficacy of cyclosporine in feline asthma.
Gastrointestinal adverse effects—vomiting, diarrhea, and/or anorexia, are relatively common with cyclosporine therapy. Also, those cats who get infected with toxoplasmosis while receiving cyclosporine are more likely to experience more severe clinical signs or even die. Cats already infected with Toxoplasma gondii before receiving cyclosporine are not reported to shed oocysts or experience a recurrence of clinical signs. Evaluation of Toxoplasma antibody titers prior to starting cyclosporine therapy is prudent, and treatment of seronegative cats with outdoor access, who are known to hunt, or who are fed raw meat, may be risky.
Oclacitinib, known under the brand name Apoquel, is only labeled for the treatment of allergic dermatitis in dogs. This drug is a janus kinase (JAK) inhibitor, blocking mostly JAK1 and some JAK3, which in turn inhibits signal transduction of many pro-inflammatory, pro-allergic, and pruritogenic cytokines. Oclacitinib is more rapidly eliminated in the cat than in the dog, so a shorter dosing interval and/or higher doses of this medication may be required for efficacy in cats. In four studies involving 48 cats, a good response was obtained in most with a dose of 1 mg/kg PO once or twice daily. Those animals who responded to treatment did so within a month, and the drug appeared to be clinically well tolerated. Very limited evidence exists for the use of oclacitinib in experimentally induced feline asthma, and there is none for the use of this drug in naturally occurring feline asthma.
In the case of H1 R-antihistamines, treatment outcome data were available for 164 cats with FASS. Those cats who responded to treatment with this drug class did so within 3-10 days of starting treatment and would also relapse within two to three days of stopping treatment. Based on the published evidence available, oral antihistamines provided a mild and limited benefit to some cats with FASS. The best results with antihistamines are likely to be obtained with early or mild disease, and when they are given pre-emptively rather than reactively. Chlorpheniramine at 2 mg/cat PO twice daily for 14 days had the best response. Other medications, including loratidine, cetirizine, clemastine, and cyproheptadine HCl, demonstrated marginal responses in most cats, and the use of cyproheptadine HCl was associated with significant adverse effects (vomiting, polyphagia, altered behavior) in a significant number of patients. There is no evidence for the use or benefit of H1 R-antihistamines in feline asthma.
Essential fatty acids (EFAs) and ultramicronized palmitoylethanolamide (PEAum) have also been recommended as therapies for FASS. PEAum is a derivative of fat and an endocannabinoid. It can bind to cells and reduce pain and swelling. In cats with miliary dermatitis, there is limited evidence for moderate efficacy of EFA supplementation. There is moderate evidence of moderate efficacy of PEAum in FASS. In feline asthma, there is insufficient evidence for the efficacy of either EFAs or PEAum.
Maropitant has also been studied as a treatment for FASS, at a dose of 2 mg/kg PO once daily for four weeks in 12 cats. Ten of the 12 cats experienced improvement of over 50% in lesion resolution, and pruritus in 11/12 decreased by over 50%. No evidence currently exists for the use of maropitant as a treatment for feline asthma.
Antibiotics also appear to be of limited use in FASS and feline asthma. One study demonstrated high efficacy of amoxicillin-clavulanate at 12-14.6 mg/kg PO twice daily for three weeks (along with flea control) in the treatment of eosinophilic plaques and indolent ulcers; however, all of the patients had cytological evidence of infection of these lesions with neutrophils and intracellular bacteria prior to starting the antibiotic therapy. There is no published evidence recommending the use of antibiotics in feline asthma. Current antibiotic stewardship guidelines for the treatment of skin infections recommend the use of topical antimicrobial treatment rather than systemic antibiotic therapy, and when systemic antibiotic therapy is necessary, using the drug with the narrowest spectrum for the shortest period of time required to clear the infection.
Inhaled nebulized lidocaine has been studied in human asthma patients and is considered beneficial and useful for its corticosteroid-sparing effects. One cross-over study in healthy cats and experimentally sensitized asthmatic cats showed that inhaled nebulized lidocaine may be helpful as adjunctive therapy in this species, facilitating beneficial effects on airflow obstruction.
Finally, mesenchymal stem cell (MSC) therapy may have a place in the treatment of feline asthma. In a small RCT, experimentally sensitized asthmatic cats were treated with allogenic adipose-derived MSCs. All of the cats treated with the MSCs experienced diminished airway hyper-responsiveness compared to those receiving placebo. When the cats were evaluated with thoracic computed tomography, lung attenuation, and bronchial wall thickening were significantly reduced in those cats treated with MSCs compared to those treated with placebo. While this study was quite limited, the possibility of mild- to moderate long-term efficacy of MSC therapy in feline asthma appears promising.
Given that FASS and feline asthma are likely to have a multifaceted etiology, combining and individualizing treatments may be necessary to resolve clinical signs and improve quality of life. Identification and elimination of overlapping problems that may cause similar signs such as ectoparasites and endoparasites, food allergens, bacterial skin infections, yeast overgrowth, and other comorbidities are mandatory of a case before embarking on a treatment regimen for FASS. The same is true for feline asthma. In many cases, more potent treatments, such as systemic glucocorticoids, cyclosporine, or oclacitinib, are likely to be required to induce remission. Once remission is achieved, treatments with potent agents can be tapered and/or switched to less potent treatments such as ASIT, EFAs, and antihistamines, to maintain remission.