Long-term rebamipide and diquafosol in two cases of immune-mediated dry eye.

Dry-eye disease is a multifactorial disorder of the tear film and ocular surface involving tear deficiency, excessive tear evaporation, and tear instability.1 One of the causes of tear film instability is an ocular surface disturbance resulting from mucin dysfunction, which can occur in Sjogren syndrome (SS), ocular cicatricial pemphigoid (OCP), and graft-versus-host disease (GVHD).2,3 Although several therapies have been developed to relieve the signs and symptoms of dry eye, some dry-eye patients do not respond to conventional eye drops. Recently, new mucin-related drugs have been approved for treating dry eye: diquafosol ophthalmic solution (3% Diquas; Santen Pharmaceutical Co Ltd, Tokyo, Japan)4,5 and rebamipide (Mucosta ophthalmic suspension UD2%; Otsuka Pharmaceutical Co Ltd, Tokyo, Japan).6,7 These new eye drops have increased the therapeutic options for dry-eye patients. Diquafosol is a dinucleotide, purinoreceptor P2Y2 receptor agonist. It stimulates P2Y2 receptors at the ocular surface, promoting tear secretion and inducing mucin secretion through elevated intracellular Ca++ concentrations.8 Mucin helps to maintain the wetness of the ocular surface, and its underproduction causes several types of dry-eye disease. In addition to maintaining hydration and lubrication of the epithelial surface, diquafosol repairs the damaged epithelial barrier through improving the functions of mucin for this disease.2 Rebamipide is a mucosal protective medicine.9,10 It increases gastric endogenous prostaglandins E2 and I2 to promote gastric epithelial mucins, which scavenge oxygen free radicals and have other anti-inflammatory actions. Rebamipide’s biological effects include cytoprotection, wound healing, and inflammation prevention9,11 in a variety of tissues as well as gastrointestinal mucosa.10,12 With respect to dry eye, rebamipide promotes the healing of corneal and conjunctival injuries by increasing secretion of both membrane-associated and secreted-type mucins. Rebamipide has been approved for treatment of dry eye in Japan since January 2012 and is being developed for this use in the United States. Several studies have reported the effectiveness of administration of diquafosol eye drops, which appear to be effective for SS, tear film instability, and the short tear break-up time (TBUT) type of dry eye.4,5,13 However, there is no information about the effects of long-term treatment with rebamipide and/or diquafosol eye drops for specific disease-associated dry-eye conditions including those associated with chronic graft-versus-host disease (cGVHD) and OCP (see Supplement Digital Content 1, available online at http://links.lww.com/OPX/A201). Chronic GVHD–related dry-eye disease is a major late complication after allogeneic hematopoietic stem cell transplantation that affects a patient’s visual function and quality of life.14,15 Other target organs of cGVHD include the mouth, skin, liver, lung, and intestine.15,16 The pathogenic process of cGVHD-related dry eye involves ocular surface and lacrimal gland dysfunction resulting from inflammation and immune-mediated fibrosis.17 In particular, previous reports suggest that mucin expression was reduced by the ocular surface epithelia in cGVHD-related dry eye.3,18 On the other hand, OCP is a rare autoimmune disease, characterized by a linear deposition of immunoglobulin on the conjunctival basement membrane and blistering on the mucous membrane, including the conjunctiva.19 In this disease, sight is threatened because of conjunctival inflammation, fibrosis, and corneal and conjunctival epitheliopathy.19 Here, we describe and discuss two cases of dry-eye disease. One is associated with cGVHD, and the other, with OCP-like disease. They were treated effectively with the long-term use of a combination of rebamipide and diquafosol eye drops. Because cGVHD-related dry eye and OCP affect the mucosal membrane on the ocular surface, including mucin expression and the morphology of the ocular surface epithelia, we reasoned that the mucin-related effects on tear stability by both medicines, the increased water production by diquafosol, and the anti-inflammatory effect of rebamipide might be synergic. Our findings indicated that these two medicines may be effective for treatment of certain subclasses of dry-eye disease in which the dry eye is assessed to be mild to moderate.1