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Special Issue  |   November 2018
Sjögren's Syndrome, Non-Sjögren's Syndrome, and Graft-Versus-Host Disease Related Dry Eye
Author Affiliations & Notes
  • Yoko Ogawa
    Department of Ophthalmology, Keio University School of Medicine, Tokyo, Japan
  • Correspondence: Yoko Ogawa, Department of Ophthalmology, Keio University School of Medicine, 35 Shinanomachi, Shinjyuku, Tokyo 160-8582, Japan; yoko@z7.keio.jp
Investigative Ophthalmology & Visual Science November 2018, Vol.59, DES71-DES79. doi:10.1167/iovs.17-23750
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      Yoko Ogawa; Sjögren's Syndrome, Non-Sjögren's Syndrome, and Graft-Versus-Host Disease Related Dry Eye. Invest. Ophthalmol. Vis. Sci. 2018;59(14):DES71-DES79. doi: 10.1167/iovs.17-23750.

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Abstract

I have reviewed available literature on dry eye related to Sjögren's syndrome (SS), non-Sjögren's syndrome (non-SS), and graft-versus-host disease (GVHD) to examine aqueous tear deficient dry eye as a subtype of dry eye. This section will focus on clinical studies regarding those subtypes of dry eye. I searched the PubMed database from 1990–2017 for discussion of clinical features, diagnostic criteria, and risk factors of SS, non-SS, and GVHD-related dry eye. In addition, therapeutic options for each subtype of dry eye are described. Although the clinical presentations of SS and chronic graft-versus-host disease (cGVHD) are similar, ocular surface fibrotic changes are characteristic of ocular GVHD but not SS- or non-SS-related dry eye. Recently, diagnostic criteria for each disease have been proposed and include the American College of Rheumatology/European League Against Rheumatism (ACR-EULAR) for SS and the International Chronic Ocular GVHD consensus criteria. Although there has been gradual progress, there are currently no specific therapies and few approved treatment options for these intractable diseases, including SS and GVHD. As judged by the findings, these subtypes of dry eye are different clinical entities from simple dry eye. Therefore, novel therapies, specific to these subtypes of dry eye, may be required in the future.

I will highlight clinical research advances in aqueous tear deficient dry eye, including dry eye related to Sjögren's syndrome (SS), non-Sjögren's syndrome (non-SS), and graft-versus-host disease (GVHD) as subtypes of dry eye. The etiology of aqueous tear deficient dry eye is a loss of aqueous tear secretion by the lacrimal glands and accessory glands in addition to water secretion by the conjunctiva, leading to an unstable tear film accompanied by dryness of the ocular surface.1,2 
Tear film plays an important role in maintaining corneal and conjunctival integrity by protecting against microbial invasion and preserving visual acuity. Tear secretion is controlled by corneal sensitivity, conjunctival goblet cells, epithelial secretory vesicles, main lacrimal glands, meibomian glands, accessory lacrimal glands and the interconnecting innervation. Damage to any aspect of these components leads to dry eye.3 
Although SS and GVHD are classified as “aqueous tear deficient dry eye,” multiple components—including aqueous tear, mucin deficiency and tear evaporation, especially in severe dry eye patients suffering from SS and GVHD—are frequently damaged.1,2 
Sjögren's Syndrome-Related Dry Eye
Sjögren's syndrome (SS) is a chronic autoimmune exocrinopathy that occurs primarily in women (17:1; female to male in the Japanese population) and is characterized by destruction of the lacrimal and salivary glands with lymphocytic infiltration, leading to dry eye and dry mouth.4 The prevalence of SS patients is reported to be 0.05% in Japan4 and 0.07% in the United States.5 Diagnostic criteria for Sjögren's syndrome were proposed by the ACR-EULAR in 2016. These diagnostic criteria may become the gold standard for diagnosing Sjögren's syndrome. In a timely manner, Tsuboi et al.6 reported a comparison of the diagnostic criteria for SS outlined by the ACR-EULAR and the Japanese revised criteria in 1999, ACR 2013, and ARCG 2002.6 They reported that the sensitivity of the ACR-EULAR criteria (95.4%) was significantly higher than the other three groups' criteria (82.1%, 89.4%, and 79.1%, respectively; P < 0.001), and the specificity of the ACR-EULAR criteria (72.1%) was statistically lower than those of the other three sets of criteria (90.9%, 84.3%, and 84.8%, respectively; P < 0.001). The 1999 Japanese revised criteria may be suitable for the Japanese Sjögren's syndrome population. 
Symptoms of dry eye are usually more severe and persistent, with chronic pain, in SS than in non-SS.7 Several questionnaires that are often used to assess dry eye in clinical trials include the Ocular Surface Disease Index (OSDI), the McMonnies questionnaire, the Standard Patient Evaluation of Eye Dryness, and the Dry Eye-Related Quality of Life Score (DEQS).79 Recently, ACR-EULAR developed an international consensus disease activity index, the EULAR Sjögren's Syndrome Patient Reported Index (ESSPRI) and EULAR Sjögren's Syndrome Disease Activity Index (ESSDAI).7 That questionnaire has been translated into Japanese and was approved by a Japanese SS committee. 
The clinical findings of SS represent severe dry eye with intense fluorescein, rose bengal or lissamine green staining on the cornea and conjunctiva.7 Severe dry eye other than SS and non-SS dry eye including ocular GVHD, ocular cicatricial pemphigoid and Stevens-Johnson syndrome frequently shows cicatricial changes on the tarsal and bulbar conjunctiva, including limbal stem cell deficiency.10 However, SS-related dry eye commonly does not involve limbal stem cell deficiency and usually does not exhibit excessive fibrosis on the ocular surface such as corneal and conjunctival fibrosis.10 Corneal vital staining and ocular surface inflammation were significantly more intense in SS-related dry eye than in non-SS dry eye.11 Additionally, corneal staining counts and ocular surface inflammation were significantly increased (P < 0.05), and the tear film breakup time (TFBUT) and Schirmer I test results were significantly shorter (P < 0.05). Finally, there were fewer corneal nerve fibers, and the number of local lymphocytes was significantly increased. There are also several methods of evaluating and grading staining, such as the 1995 NEI/Industry Workshop system, the Oxford System, and the Ocular Staining Score (OSS) proposed by the Sjögren's International Collaborative Clinical Alliance (SICCA).7,12 
SS in younger generations, including pediatric SS, exists as an early stage of SS without reduced basal and reflex tearing. Children may not express their symptoms correctly13; furthermore, their hidden symptoms or a change in symptoms from dryness to an unpleasant feeling may lead to nonattendance at school.13 Since symptoms in juvenile SS dry eye may be overlooked, this clinical entity should receive more attention before it develops adult SS.14,15 
Schirmer's test is one of the methods used to evaluate aqueous-deficient dry eye.7 Clinicians use a value of less than 5 mm without anesthesia to define dry eye with a combination of TFBUT and ocular surface staining. Reflex tearing, which is thought to reflect lacrimal gland function, is severely damaged in typical SS-related dry eye, with reflex tearing of less than 10 mm.16,17 In the most severe cases of SS related-dry eye, the value of Schirmer's test, with or without nasal stimulation, declines to almost zero. 
TFBUT is important for diagnosing tear film instability, and the subtypes of dry eye can be differentiated by observing the pattern of tear breakup. In typical SS-related dry eye, area and line breaks are mainly detected according to Yokoi's classification.18 Spot, dimple, or random breaks can co-exist in SS-related dry eye18 because the meibomian gland,19 conjunctival microvilli,20 and goblet cells are often simultaneously affected in severe cases. 
Among SS patients, bilateral lacrimal gland enlargements should receive much attention because approximately 5%–10% of long-standing SS patients may develop malignant lymphoma.21 In addition, IgG4-related ophthalmic disease needs to be excluded when lacrimal gland swelling is observed. Extraglandular manifestations—including neurological signs, skin rashes, interstitial pneumonitis, and lymph node swelling—should be examined periodically in addition to dry eye in daily clinical practice. Blood analysis of anti-SSA antibody, anti-SSB antibody, rheumatoid factor, and anti-ANA antibody is recommended.5 
The meibomian gland, one of the specialized sebaceous glands, is significantly more damaged in SS patients (57.9%) than in non-SS patients (18.5%; P = 0.005).19 In addition, the lid margin, located at the juncture between the mucosal membrane and the skin of eyelid, is frequently affected in SS-related dry eye patients.22 Androgen deficiency is a critical etiologic factor in the pathogenesis of dry eye and meibomian gland dysfunction that influences the development of SS-related dry eye.23 
Corneal nociceptors are thought to be a sentinel for tear evaporation.24 Corneal neuropathic pain is associated with autoimmune disease such as SS seen predominantly in women.24,25 Corneal nerve abnormality in the early phase of SS has been reported using in vivo confocal microscopy and may be an initial sign of SS-related dry eye disease.26 Neuroinflammation is associated with dry eye conditions and discomfort in SS. In addition, it is likely that the cold thermoreceptor TRPM8 is linked to dry eye, particularly to unpleasantness in dry eye related to this disease.27 
Treatment
Tear lubrication is required, depending on the severity of the SS dry eye case. Use artificial tears, mucin-producing eyedrops, punctal plug, or surgical occlusion for aqueous-deficient dry eye. For SS patients, it is essential to use preservative-free topical reagents. Topical diquafosol and rebamipide were approved for the treatment of dry eye in Japan in 201028 and 2011,29 respectively. Diquafosol is reported to be effective for SS dry eye in the long term.30,31 Diquafosol is a dinucleotide derivative and has purinoreceptor P2Y2 receptor agonist activity. It stimulates on P2Y2 receptors at the ocular surface, producing tear and mucin secretion from the conjunctiva through elevated intracellular calcium concentrations.3235 Rebamipide, known as a mucosal protective and anti-inflammatory agent, is also recommended for SS dry eye.3638 
The SS clinical practice guidelines in Japan (released by the Sumida group in 2017)39 provided evidence for the treatment of SS-related dry eye by diquafosol,31 rebamipide,39 and hyaluronic acid.40 
According to Japanese SS clinical practice guidelines,39 systemic corticosteroid is not recommended for SS dry eye and dry mouth as exocrinopathy.41 Rebamipide is available in Japan and has anti-inflammatory effects through inhibition of CD4 and macrophage activation.21 Topical cyclosporine 0.05% (Restasis) is approved for the treatment of dry eye by the FDA and European Medicine Agency (EMA).9 Ikervis, known as cyclosporine cationic emulsion, has been approved by the EMA42 in Europe and in some countries in Asia, including South Korea, Bangladesh, and Myanmar.43 Recently, topical lifitegrast, an integrin inhibitor known as a lymphocyte function-associated antigen-1 (LFA-1) antagonist, was approved by the FDA for the treatment of dry eye.44 Topical tacrolimus is an immunosuppressant that is 10 times more potent than cyclosporine. Further protocols for tear film-oriented therapy proposed by the Japan Dry Eye Society include low-dose corticosteroid therapy for anti-inflammatory treatment of dry eye disease (available in the public domain, http://www.dryeye.ne.jp/public_dryeye/tfot/index.html), described in detail in another section of this review article. 
SS dry eye is frequently associated with evaporative in addition to aqueous-deficient dry eye. Therefore, treatment of the meibomian gland and eyelid is often required. Warm compression, lid hygiene, topical and oral antibiotics, and oil-containing eyedrops may be helpful to alleviate dry eye.45 Omega 3-containing fish oil was reported to be effective for SS-related MGD.22 
Rituximab is a chimeric monoclonal antibody targeted against the pan-B-cell marker CD20, and abatacept is a immunomodulatory drug that acts as an inhibitor of T cell activation via co-stimulatory blockade.7 Both may improve SS dry eye and are recommended as biological reagents for systemic treatment according to SS clinical practice guidelines.7,39 Other biological reagents are not recommended for treating SS dry eye, according to Japanese SS guidelines. 
Non-Sjögren's Syndrome-Related Dry Eye
This subtype of dry eye is an aqueous-deficient dry eye with decreased tear production and a low value on Schirmer's test (less than 5 mm) without SS. The majority of conditions in this subtype of dry eye have an unknown etiology. Basal tearing is reduced but reflex tearing is preserved, with mild ocular surface staining as determined by fluorescein, rose bengal, or lissamine green dye staining on the ocular surface.16,46 In non-SS dry eye, tear film breakup patterns may show line breaks according to Yokoi's classification.18 
Dry eye in aged populations is categorized as this subtype of dry eye. Low-grade chronic inflammation might be partially related to aging-related dry eye,47 as previously reported by lacrimal gland inflammation in histopathological analysis for aged subjects48 and animal ocular surface and lacrmimal gland studies.4953 Autoimmune diseases—such as rheumatoid arthritis, systemic lupus erythematosus, progressive systemic sclerosis, and autoimmune thyroiditis without SS—are categorized in this group. In the absence of SS, dry eye is usually not severe.7 However, even in non-SS–type dry eye disease, confocal microscopy has revealed abnormal nerve morphology and inflammatory cell infiltration in the cornea. 
IgG4-related disease is a newly categorized subtype of autoimmune disease characterized by the infiltration of IgG4-positive plasmacytes and elevated serum IgG4 concentration, with enlargement of and masses in various organs including the lacrimal gland, salivary gland, and pancreas.5456 IgG4-related ophthalmic disease was originally referred to as Mikulicz's disease, in which dry eye usually does not become severe.56,57 
MGD is present in patients with non-SS dry eye compared with normal subjects; however, the severity is lower in the non-SS dry eye subtype than in the SS subtype of dry eye.58 
Treatment
Regarding the first choice of treatment for this subtype of dry eye, it is desirable to use preservative-free topical artificial tears because preservatives can be a risk factor for the ocular surface in all types of dry eye. The second choice may be hyaluronic acid, diquafosol, or rebamipide. Punctal plug and surgical occlusion of puncta are recommended if the dry eye is resistant to the above-mentioned treatments. This type of dry eye can usually be treated with topical eyedrops without systemic treatment or amniotic membrane transplantation (AMT) or limbal stem cell transplantation. Improvements in psychological mood, quality of sleep,59,60 duration of sleep,61 and adequate support have been observed through exercise, supplementation,9 and oil-containing eyedrops,9 and these approaches are valuable treatment options for this type of dry eye in particular. 
Chronic Graft-versus-Host Disease–Related Dry Eye
Chronic graft-versus-host disease (cGVHD) is a major cause of morbidity and mortality in patients undergoing allogeneic hematopoietic stem cell transplantation (HSCT) in clinical settings.62 cGVHD is an inflammatory or fibrotic phenomenon that develops several months after transplantation. The principal target organs of cGVHD are the eye, liver, skin, lung, gastrointestinal tract and mouth.63 Dry eye disease has been recognized as a major complication in patients who develop cGVHD after allogeneic HSCT.10,6468 In most cases, severe dry eye progresses rapidly after the onset of symptoms and can lead to blindness.69,70 Because of the increasing number of long-term survivors who have received allogeneic HSCT, dry eye has a significant impact on these patients' quality of vision and quality of life.71,72 Despite improvements in the therapy for acute GVHD, specific therapies remain a substantial problem with little progress. These findings suggest that these two conditions may be different clinical entities. 
Recently, the number of HSCT recipients has been increasing, attracting more attention with more papers being published. More than 30 papers were published in 2015, the highest number ever. Regarding the natural course of dry eye before and after HSCT, good reflex tearing is reported to be present before HSCT but starts to decline at around 3 months after HSCT and declines to less than 10 mm around 6 months after HSCT,73 probably because of the timing of tapering systemic immunosuppressants. Considering Yokoi's tear film breakup patterns,18 line breaks may initially occur at the onset of dry eye and gradually develop into area breaks in later stages. 
In acute GVHD, chemosis, injection, and pseudomembrane should receive much attention by internists and ophthalmologists.74 Just before the onset of dry eye, pseudomembrane may occur as a result of changes in immunological conditions.75 Histopathological findings of pseudomembrane show infiltration of macrophages in the necrotic epithelia,75 which produce a large amount of cytokines, leading to a cytokine storm on the ocular surface. Macrophages release chemokines such as stromal derived factor-1, which attract fibroblast chemotaxis.76 According to our earlier reports of lacrimal gland biopsy performed for diagnostic purposes, immunocompetent cells—including T cells and macrophages as well as activated and donor-derived fibroblasts expressing HLA class II and co-stimulatory molecules—interact with T cell infiltrates in pathogenic areas and myxedematous fibrotic areas already exist in the early phases of dry eye (Fig.).77,78 Conjunctival fibrosis including fibrovascular tissue, symblepharon, and fornix shortening, all characteristic features of cGVHD-related dry eye.74,7981 Other features of ocular surface fibrosis include limbal stem cell deficiency, neovasculization, conjunctivalization, and spontaneous punctal occlusion.79,80,82,83 The onset of dry eye disease is approximately 6 to 18 months after HSCT.73,84 Risk factors of dry eye include recipients who are older, higher amounts of CD34+ cells infused,85 and female-to-male transplantation.86,87 Dry eye is the most severe after peripheral blood stem cell transplantation in bone marrow, followed by bone marrow and cord blood transplantation.88 Glaucoma, cataract, infection, and corneal perforation should be prevented as side effects that occur after topical or systemic corticosteroid administration for preventing or treating GVHD.89 
Figure
 
Proposed treatments based on the pathogenic process of chronic ocular GVHD. The ocular surface is already in a proinflammatory state, leading to the generation of danger signals due to irradiation and massive chemotherapy before hematopoietic stem cell transplantation (HSCT). After HSCT, donor immune cells infiltrate into recipient tissues, interact with recipient cells, and generate a large amount of proinflammatory cytokines and chemokines and sterile inflammation from the debris of damaged epithelia. Previous symptoms of acute ocular GVHD including pseudomembrane exacerbate ocular surface inflammation and lead to homing of donor or recipient fibroblasts. Ocular surface barrier function is disturbed by inflammation, mechanical stress of tarsal fibrosis or tear film substances. One study showed migrated donor-derived mesenchymal stromal/stem cells expressing MHC class II interact with T cells to produce IL-6 followed by an increase in IL-17 and reduction in regulatory T cells similar to autoimmune pathology. Activated donor-derived fibroblasts produce excessive extra cellular matrix, leading to vision-threatening pathogenic fibrosis, resulting in rapidly progressive dry eye related to cGVHD. Therefore, immunosuppressant agents (target sites are fibroblasts or macrophages and T cell interactions) and anti-fibrotic agents (target sites are fibroblasts) are necessary to treat this intractable disease. ⋇, currently available topical and systemic medication in US or Japan; #, target sites still at the basic research level; $, ongoing clinical trials.
Figure
 
Proposed treatments based on the pathogenic process of chronic ocular GVHD. The ocular surface is already in a proinflammatory state, leading to the generation of danger signals due to irradiation and massive chemotherapy before hematopoietic stem cell transplantation (HSCT). After HSCT, donor immune cells infiltrate into recipient tissues, interact with recipient cells, and generate a large amount of proinflammatory cytokines and chemokines and sterile inflammation from the debris of damaged epithelia. Previous symptoms of acute ocular GVHD including pseudomembrane exacerbate ocular surface inflammation and lead to homing of donor or recipient fibroblasts. Ocular surface barrier function is disturbed by inflammation, mechanical stress of tarsal fibrosis or tear film substances. One study showed migrated donor-derived mesenchymal stromal/stem cells expressing MHC class II interact with T cells to produce IL-6 followed by an increase in IL-17 and reduction in regulatory T cells similar to autoimmune pathology. Activated donor-derived fibroblasts produce excessive extra cellular matrix, leading to vision-threatening pathogenic fibrosis, resulting in rapidly progressive dry eye related to cGVHD. Therefore, immunosuppressant agents (target sites are fibroblasts or macrophages and T cell interactions) and anti-fibrotic agents (target sites are fibroblasts) are necessary to treat this intractable disease. ⋇, currently available topical and systemic medication in US or Japan; #, target sites still at the basic research level; $, ongoing clinical trials.
Meibomian gland dysfunction is the second-most frequent ocular complication after HSCT. Approximately 48% of recipients develop HSCT.73 Confocal studies and infrared meibography revealed severe inflammation and extensive fibrosis in cGVHD-related dry eye recipients in comparison with the conditions in the non-GVHD group.90,91 The mean fibrosis grade was significantly higher in the DE/cGVHD group than in the non-DE/non-cGVHD group (P < 0.0001; 1.39 ± 0.71 grade, 0.06 ± 0.25 grade, respectively).90 However, we need to examine MGD in the early stages before and after HSCT92 because various types of MGD are already present before HSCT.93 
The 2014 NIH diagnostic criteria stated ocular cGVHD as a new onset of dry eye in the post-transplant patient.62 Additional symptoms may include photophobia, periorbital hyperpigmentation, or blepharitis. Examination by ophthalmologists is necessary for diagnostic confirmation of keratoconjunctivitis sicca, cicatricial conjunctivitis, or punctate keratopathy. Schirmer's test was removed from the 2014 NIH diagnostic criteria.62 Japanese and Asian diagnostic criteria for dry eye also removed the Schirmer's test value in 2016 and 2017 for diagnosing dry eye.2 In those cases, TFBUT and tear breakup pattern as assessed by fluorescein staining are necessary and important for evaluating tear film stability, so that ophthalmologists can accurately diagnose dry eye.2,18 However, scoring using vital staining by fluorescein, lissamine green, or rose bengal dye plus identifying the value of Schirmer's test still have significance in understanding and evaluating the disease process, confirming the cause of dry eye and the severity of this disease subtype. Therefore, removal of Schirmer's test from diagnostic criteria does not mean that clinicians should omit the evaluation of ocular surface staining and Schirmer's test in the clinical setting. 
The International Chronic Ocular GVHD Consensus meeting was held between 2010 and 2016 and included 18 ophthalmologists from the United States, Brazil, India, South Korea, China, Japan, and The Netherlands. The consensus group identified four subjective and objective variables when measuring patients following allogeneic HSCT: OSDI, Schirmer's score without anesthesia, corneal staining, and conjunctival injection. New diagnostic criteria for chronic ocular GVHD have been proposed by the Consensus Group.65 Those subjective and objective variables are used worldwide for diagnosing dry eye. Three studies from ours and other institutes validated the newly proposed criteria and showed good agreement between the international chronic ocular GVHD Consensus Group scores (ICOS) and some clinical parameters, including tear film osmolality,94 best clinical practices,95 and immune cell and corneal sub-basal nerve abnormality by in vivo confocal study.96 One study showed only a weakly positive correlation with subepithelial fibrosis and severe dry eye measured by using ICOS, although there is no significant correlation among subepithelial fibrosis, meibomian gland atrophy, and ICOS.91 Two major review articles62,97 cited the International Consensus Diagnostic Criteria and evaluated the consensus scores.65 As for GVHD-related dry eye (but not common dry eye), it is better to evaluate ocular surface staining and the value of Schirmer's test to determine the severity of dry eye and the disease process. However, we always need to pay attention and update criteria for ICOS according to changes of the diagnostic criteria in other committees to standardize the criteria for patients and clinicians. For ICOS, it might be better to include TFBUT for diagnosing dry eye related to cGVHD at next stage. 
Corneal findings using in vivo confocal microscopy (IVCM) have been reported when assessing the cornea in ocular GVHD.96,98,99 The diagnostic values of both the Japanese dry eye score and the international chronic ocular GVHD scores were significantly associated with the level of tortuosity, branching of sub-basal nerves, density of epithelial DCs, and GICs in the cornea.96 
Involvement of the conjunctiva mucosal membrane is an important factor for predicting systemic GVHD or determining treatment modality.64,65,80 Early prophylaxis, diagnosis, and treatment can be accomplished by examining the eye in detail. In this regard, a prospective study evaluating a comprehensive ophthalmic evaluation pre- and post-transplantation is needed to diagnose new-onset dry eye or other chronic ocular GVHD-related and non-GVHD complications. Detailed communications concerning the dose of systemic and local immunosuppressants, as well as the timing of commencement and cessation of treatment, are needed worldwide between transplant internists and ophthalmologists and across clinical practice to improve patients' quality of life and life expectancy. 
Treatment
Treatment variations for ocular GVHD consist of lubrication, stabilization of tear film, prevention of tear evaporation, decreased ocular surface inflammation, epithelial support, systemic immunosuppression, supportive care, lid and meibomian gland care, and other local surgical treatments as reported by recent studies.9,64,67,97,100,101 
Artificial tears without preservatives and oral secretagogues (such as pilocarpine or cevimeline) are recommended for lubricants. In Japan and Korea, topical diquafosol is available to retain tear fluid by stimulating the P2Y2 receptor on conjunctival epithelium. A retrospective study on the long-term use of diquafosol for mild to moderate dry eye disease related to GVHD reported no major complications.102 Diquafosol is also known to stabilize the tear film by promoting secretory and membrane-binding mucin secretion. A good response was obtained in this retrospective study for corneal fluorescein staining, BUT, and conjunctival injections. Punctal plug and surgical punctal occlusion103 can be applicable to retain tear fluid if the abovementioned treatment is insufficient. Lubricant may also be useful for washing out debris and cytokines in the tear film layer in dry eye secondary to cGVHD. 
For ocular surface inflammation, topical preservative-free methylprednisolone, cyclosporine A, and tacrolimus have been shown to be beneficial against inflammation.104 The mechanism of action of tacrolimus is reported to be inhibition of T cell function through inhibition of the calcineurin enzyme.104 Short-term, low-dose, and preservative-free corticosteroids are useful because the recipients would have already received a large amount of systemic corticosteroid prophylaxis for systemic GVHD. In the United States, the FDA has approved lifitegrast (Xiidra), a topical integrin antagonist.44,105 Lifitegrast may have benefit as an anti-inflammatory reagent in ocular GVHD. Anakinra (IL-1Rα) has potential for the treatment of ocular GVHD as a biological agent by suppressing IL-1-mediated inflammation by competitively inhibiting the binding of IL-1α and IL-1β to IL-1 receptor I.106 Tranilast is N-(3′,4′-dimethoxycinnamoyl)-anthranilic acid and an analog of a tryptophan metabolite.107 It has a pleiotrophic inhibitory effect on allergy, fibrosis, inflammation, and oxidative stress.108111 Topical tranilast has been reported in a small number of cGVHD-related dry eye patients.112 Additionally, topical tranilast has been approved as an anti-allergic drug and is available in Japan but not the United States. It has an anti-inflammatory effect by reducing the recruitment of T cells through an inhibitory effect of CXCL9,108 an anti-oxidative stress effect through the inhibition of thiorexin-interacting protein (TXNIP),111 and an anti-fibrotic effect by inhibition of fibroblast activation.113 
Rebamipide is approved for the treatment of dry eye disease in Japan and can be used for ocular GVHD. Two cases have been reported of long-term combined use of rebamipide and diquafosol for ocular GVHD. In this case report, functional visual acuity remarkably improved after topical rebamipide application.114 In particular, tarsal conjunctival fibrosis is a characteristic of ocular GVHD. Topical rebamipide may reduce the friction between the tarsal conjunctiva and ocular surface, resulting in benefits for GVHD-related dry eye patients. 
Epithelial support therapies include the use of autologous sera. Autologous sera includes epidermal growth factor, hepatocyte growth factor, fibronectin, neurotrophic growth factor, vitamin A, and selenoprotein P—all of which have been shown to play roles in the maintenance of ocular surface epithelia.115 This is a safe and effective therapy because there is a low frequency of side effects and irritation the patient's own sera is used.78,116 Recently, cryopreserved allogeneic sera has been reported for patients with difficulty obtaining their own blood.117 Autologous platelet lysate application, which means plasma rich in platelet-derived growth factors (PDGFs) eyedrops as a biologically active reservoir,9 is considered when treating ocular GVHD refractory to topical conventional therapy.118 
Bandage contact lens and scleral lenses can stabilize the tear film and restore normal corneal and conjunctival epithelial cell turnover. They provide a tear reservoir between the lens and corneal surface, a shield effect that protects the ocular surface in cases of extreme dryness and mechanical stress from trichiasis, preventing adhesion of bulbar and tarsal conjunctiva or dysfunctional eyelid abnormality.64,97,100 Caution is warranted regarding contact lens-induced keratitis, infection. or corneal perforation. 
Sutured amniotic membrane transplantation (AMT) is used for severe conjunctival fibrosis, inflammation, and limbal stem cell deficiency.97 Non-sutured multilayerd AMT, non-sutured AMT on a ring, corneal transplantation, and epithelial sheet transplantation are also required for some treatment-resistant cases of severe cGVHD-related dry eye.9,64,97 
The U.S. Food and Drug Administration (FDA) approved Imbruvica (ibrutinib), a kinase inhibitor for the treatment of adult patients with chronic GVHD after failure of one or more treatments.119 Imbruvica is the first FDA-approved therapy for the treatment of cGVHD, having been granted Priority Review and Breakthrough Therapy designations, receiving an Orphan Drug designation. 
At the basic research level, there are several ocular GVHD animal models120123 and several candidates that may be applicable for developing new therapies in the future. Heavy chain hyaluronan pentraxin 3 (HC-HA/PTX3) is a complex purified from human amniotic membrane and is known to exert anti-inflammatory and antifibrotic actions.124 HC-HA/PTX3 significantly reduced the gene expression of fibrosis-related genes, including collagen type I, collagen type III, and NF-kB in murine lacrimal glands induced by cGVHD.10 
Another intervention involving the reduction of endoplasmic reticulum (ER) stress was performed as an anti-aging strategy. ER stress signaling was elevated in target organs, including lacrimal glands affected by cGVHD and an inhibitor of ER stress, 4-phenylbutyric acid, could ameliorate cGVHD-related ER stress to improve the survival rate and the appearance of the skin and haunched position of cGVHD model mice.125 
Recent study shows effects of vascular adhesion protein-1 inhibitor on cGVHD lacrimal gland and conjunctiva,126 suggesting that vascular changes contribute the pathogenic process of chronic ocular GVHD. 
The tissue renin-angiotensin system in the lacrimal gland and its implications in pathological fibrosis have been studied in cGVHD. Angiotensin type II receptor antagonist can be a novel therapeutic approach for cGVHD-related dry eye and has been tested in an animal model (Fig.).127 cGVHD is a multi-organ immune-mediated fibrotic disease; therefore, we need to pay close attention to ocular signs of the development of systemic cGVHD and continue collaborative work with diverse departments, including internal medicine, oral medicine, dermatology, psychiatry, and pediatrics with clinical and research staff. It is of paramount importance to provide long-term physical and mental support for chronic GVHD patients since this disease is persistent and intractable. 
Acknowledgments
Supported in part by Japanese Ministry of Education, Science, Sports, Culture and Technology, #23592590, #26462668, and #18K09421 and the Japanese Ministry of Health, Labour and Welfare of Japan Labour Sciences Research Grants for Research on Intractable Diseases (The Research Team for Autoimmune Diseases). Funding of the publication fee and administration was provided by the Dry Eye Society, Tokyo, Japan. The Dry Eye Society, the Japanese Ministry of Education, Science, Culture, Sports and Technology, and The Research Team for Autoimmune Diseases had no role in the contents or writing of the manuscript. 
Disclosure: Y. Ogawa, P 
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Figure
 
Proposed treatments based on the pathogenic process of chronic ocular GVHD. The ocular surface is already in a proinflammatory state, leading to the generation of danger signals due to irradiation and massive chemotherapy before hematopoietic stem cell transplantation (HSCT). After HSCT, donor immune cells infiltrate into recipient tissues, interact with recipient cells, and generate a large amount of proinflammatory cytokines and chemokines and sterile inflammation from the debris of damaged epithelia. Previous symptoms of acute ocular GVHD including pseudomembrane exacerbate ocular surface inflammation and lead to homing of donor or recipient fibroblasts. Ocular surface barrier function is disturbed by inflammation, mechanical stress of tarsal fibrosis or tear film substances. One study showed migrated donor-derived mesenchymal stromal/stem cells expressing MHC class II interact with T cells to produce IL-6 followed by an increase in IL-17 and reduction in regulatory T cells similar to autoimmune pathology. Activated donor-derived fibroblasts produce excessive extra cellular matrix, leading to vision-threatening pathogenic fibrosis, resulting in rapidly progressive dry eye related to cGVHD. Therefore, immunosuppressant agents (target sites are fibroblasts or macrophages and T cell interactions) and anti-fibrotic agents (target sites are fibroblasts) are necessary to treat this intractable disease. ⋇, currently available topical and systemic medication in US or Japan; #, target sites still at the basic research level; $, ongoing clinical trials.
Figure
 
Proposed treatments based on the pathogenic process of chronic ocular GVHD. The ocular surface is already in a proinflammatory state, leading to the generation of danger signals due to irradiation and massive chemotherapy before hematopoietic stem cell transplantation (HSCT). After HSCT, donor immune cells infiltrate into recipient tissues, interact with recipient cells, and generate a large amount of proinflammatory cytokines and chemokines and sterile inflammation from the debris of damaged epithelia. Previous symptoms of acute ocular GVHD including pseudomembrane exacerbate ocular surface inflammation and lead to homing of donor or recipient fibroblasts. Ocular surface barrier function is disturbed by inflammation, mechanical stress of tarsal fibrosis or tear film substances. One study showed migrated donor-derived mesenchymal stromal/stem cells expressing MHC class II interact with T cells to produce IL-6 followed by an increase in IL-17 and reduction in regulatory T cells similar to autoimmune pathology. Activated donor-derived fibroblasts produce excessive extra cellular matrix, leading to vision-threatening pathogenic fibrosis, resulting in rapidly progressive dry eye related to cGVHD. Therefore, immunosuppressant agents (target sites are fibroblasts or macrophages and T cell interactions) and anti-fibrotic agents (target sites are fibroblasts) are necessary to treat this intractable disease. ⋇, currently available topical and systemic medication in US or Japan; #, target sites still at the basic research level; $, ongoing clinical trials.
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