Localized alopecia and suppression of hypothalamic-pituitary-adrenal (HPA) axis in dogs following treatment with difluprednate 0.05% ophthalmic emulsion (Durezol®)

Abstract

Background Despite the common use of topical ophthalmic corticosteroids in dogs, detailed reports on systemic and dermatologic adverse effects are limited. Results Nine purpose-bred research Beagles were treated with difluprednate 0.05% ophthalmic emulsion in one or both eyes 2–3 times daily. Some difluprednate treated dogs developed mild to severe alopecia of the periocular region, face, and distal pinna (5/9). The median duration of treatment prior to onset of dermatologic signs for difluprednate treated dogs was 550 days (453–1160 days). Diagnostic testing included complete blood count (CBC) and serum biochemistry, adrenocorticotropic hormone (ACTH) stimulation testing combined with endogenous ACTH measurement, and skin biopsy. The CBC and chemistry were within normal limits for all dogs. There were varying degrees of suppression of the hypothalamic-pituitary-adrenocortical (HPA) axis with difluprednate treatment. Dogs with the most profound alopecic changes had less pronounced HPA axis suppression compared to dogs with no integumentary changes. Skin biopsies demonstrated follicular atrophy and follicular keratosis. When topical difluprednate was reduced to unilateral therapy, the hair regrew on the untreated side of the face. In addition to the affected research dogs, a 7-year old female spayed Chihuahua that was being treated as a clinical patient with long-term difluprednate 0.05% ophthalmic emulsion developed generalized hypotrichosis on the head and body and a potbellied appearance. ACTH stimulation testing revealed suppression of the HPA axis with a mild increase in serum alkaline phosphatase (ALP) activity and a urine specific gravity of 1.016. The combination of clinical signs and laboratory abnormalities was supportive of iatrogenic hyperadrenocorticism. Conclusions In dogs long-term use of difluprednate ophthalmic emulsion results in HPA axis suppression and in some cases iatrogenic hyperadrenocorticism. A novel pattern of localized alopecia is suspected to be related to dermal absorption and local action due to superior potency and penetration compared to other commonly utilized ophthalmic corticosteroids.

Prednisolone and dexamethasone are systemically absorbed after topical application of ophthalmic suspensions in healthy dogs

“…The degree to which different ophthalmic glucocorticoid drugs are absorbed systemically may influence a veterinarian's decision on which medications to use to treat anterior uveitis, especially in small dogs with hyperadrenocorticism or preexisting liver disease. Suppression of the HPAA has been reported following long term use of 0.05% difluprednate ophthalmic emulsion 40 and 1% prednisolone acetate ophthalmic suspension for 2 weeks in dogs. 41,42 Topical application of 0.1% dexamethasone suspension 4 times daily to both eyes in Beagles also resulted in adrenal suppression as well as histopathologic changes in the liver.…”

Role of Inflammation in Canine Primary Glaucoma

“…Corticosteroids —Corticosteroid-induced IOP elevation is relatively common in humans, presumably related to lowered aqueous humor outflow from the deposition of extracellular material in the trabecular meshwork [ 51 ]. In contrast, most corticosteroids do not appear to influence IOP in dogs, including hydrocortisone [ 52 ], prednisone [ 53 ], prednisolone acetate [ 54 ], triamcinolone acetonide [ 55 ], and difluprednate [ 56 ]. For triamcinolone acetonide, intravitreal injection of the long-acting corticosteroid did not induce sustained IOP elevation over 3 months of monitoring IOPs [ 55 ].…”

“…For triamcinolone acetonide, intravitreal injection of the long-acting corticosteroid did not induce sustained IOP elevation over 3 months of monitoring IOPs [ 55 ]. For difluprednate, wiltype purpose-bred beagle dogs received topical difluprednate 2–3 times daily for an extended period (413–764 days) as controls in a gene therapy trial; selected dogs developed periocular alopecia and suppression of the hypothalamic-pituitary-adrenal axis, however none were reported to have ocular hypertension as an adverse effect of chronic corticotherapy (Dr. András Komáromy, personal communication) [ 56 ]. The one exception appears to be dexamethasone, with IOP shown to increase following a single intravenous administration of dexamethasone in healthy dogs [ 57 ], and following repeated topical 0.1% dexamethasone in beagles with inherited POAG [ 58 ].…”