Abstract
Non-infectious, autoimmune anterior uveitis is a significant cause of
ocular disease in both dogs, horses, and humans with
the potential for significant vision loss. The mainstay of treatment is
topical and/or systemic corticosteroids, however, animals,
similar to humans, are not uncommonly resistant to therapy.
Additionally, prolonged corticosteroid treatment may cause systemic
and ocular toxicity. We describe here a case of steroid-resistant
uveitis successfully treated with GLS-1027, an immunomodulatory
compound that inhibits Th17 maturation and release of multiple
inflammatory cytokines involved in the pathogenesis of uveitis.
GLS-1027 may provide an alternative as a steroid-sparing therapeutic
option.
Introduction
Non-infectious, anterior uveitis is a significant cause of ocular
disease in dogs, horses, humans, and other species that has the
potential to lead to vision loss and blindness. While the disease is
most commonly considered as autoimmune for humans and the
most common etiology in dogs [1,2] infectious disease neoplastic
etiologies must also be considered [2,3]. In all species, the primary
goal of treatment is sight preservation with secondary goals
to limit pain, discomfort, photophobia, and in dogs minimizing
secondary sequelae such as posterior synechia [3]. In animals,
topical corticosteroid treatment combined with topical mydriatics
with or without the use of systemic anti-inflammatory medications
represents the standard of care for anterior uveitis [2,4]. While
immunosuppressives are considered the standard for steroidresistant
disease in humans [5], these are seldom used in animals
due to toxicity and cost. Studies in animals have reported that
approximately 1-35% of the total topical corticosteroid dose is
systemically absorbed, [4] and may result in systemic side effects,
including endocrinopathies [3]. Steroid-induced ocular pathology,
including the development of glaucoma, cataract formation,
and keratopathy are not uncommon in dogs with prolonged
corticosteroid use [4] with a similar side effect profile for humans.
Therefore, a safe and effective alternative to corticosteroid
treatment for chronic recurrent idiopathic uveitis is warranted.
Autoimmune uveitis in humans [6] and horses [7,8] has been
attributed to Th17 mediated pathology with a complex interplay
between a number of inflammatory cytokines including TNFα and
IL-6. GLS-1027, [S,R]-3-phenyl-4,5-dihydro-isoxazoleacetic acid,
is a small molecule compound with anti-inflammatory activity
currently in clinical development. GLS-1027 is a potent inhibitor
of lipopolysaccharide (LPS)-induced inflammation characterized
by normalization of levels of the cytokines tumor necrosis factor
(TNFα), interleukin (IL) 1β, and IL-6 both in vitro and in murine
animal models [9-12]. Additional unpublished data has shown
that GLS-1027 inhibits IL-17 and IL-23 mediated activation and
downregulates Th17 T cells.
In this paper, we describe a case report of the use of GLS-1027
to treat canine uveitis.
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