Dry Eye Disease as an Inflammatory Disorder

Purpose: Dry eye disease (DED) is a prevalent inflammatory disorder of the lacrimal functional unit of multifactorial origin leading to chronic ocular surface disease, impaired quality of vision, and a wide range of complications, eventually causing a reduction in quality of life. It still is a frustrating disease because of the present scarcity of therapies that can reverse, or at least stop, its progression.

Methods: A comprehensive literature survey of English-written scientific publications on the role of inflammation in DED.

Results: New investigations have demonstrated that a chronic inflammatory response plays a key role in the pathogenesis of human DED. Additionally, correlations between inflammatory molecules and clinical data suggest that inflammation can be responsible for some of the clinical symptoms and signs.

Conclusions: Research efforts to clarify its pathophysiology are leading to a better understanding of DED, demonstrating that inflammation, in addition to many other factors, plays a relevant role.     

Assessment of Neutrophil-to-Lymphocyte Ratio and Platelet-to-Lymphocyte Ratio in Patients with Dry Eye Disease

Purpose: To evaluate the neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) levels in patients with dry eye disease (DED).

Methods: The white blood cell, neutrophil, platelet, and lymphocyte counts were performed in 78 dry eye patients and 60 controls. The NLR was calculated by dividing neutrophil count by lymphocyte count and the PLR was calculated by dividing platelet count by lymphocyte count.

Results: The mean age was 53.4 ± 3.8 years in the DED group and 52.7 ± 3.4 years in the control group. The mean NLR was 2.6 ± 1.2 and the mean PLR was 138.4 ± 62.6 in the DED group and the mean NLR was 1.84 ± 0.5 and the mean PLR was 118.5 ± 64.7 in the control group. A significant difference was found in the NLR and PLR between the DED and the controls (p = 0.032 and p = 0.026, respectively).

Conclusion: The NLR and PLR values were found higher in patients with dry eye than in healthy subjects.     

Ocular Inflammatory Disorders in Autoimmune Lymphoproliferative Syndrome (ALPS)

Purpose: To describe inflammatory ocular findings in patients with autoimmune lymphoproliferative syndrome (ALPS).

Methods: A retrospective review of medical records for ALPS patients seen at the National Eye Institute between 2003 and 2013.

Results: A total of 29 ALPS patients previously referred for ocular or visual symptoms or with a history of prolonged corticosteroid use, were identified. Mean age was 20 years (range: 4–66 years). The majority were male (n = 21, 72.4%) and Caucasian (n = 24, 82.8%). Ten (34.5%) had abnormal ocular findings, the most common of which was an ocular inflammatory disorder (n = 4, 13.8%). Uveitis was seen in two patients with ALPS-FAS and one with ALPS-U, all of whom required long-term systemic immunosuppression. One patient with ALPS-FAS had a history of optic neuritis.

Conclusions: ALPS can have intraocular inflammatory manifestations that require routine follow-up to ensure appropriate and timely treatment of intraocular disease. Long-term immunosuppression may be needed for patients with ALPS-associated uveitis.     

The Dopaminergic Neuronal System Regulates the Inflammatory Status of Mouse Lacrimal Glands in Dry Eye Disease

PurposeComparison of the parasympathetic and sympathetic neurons, including the dopaminergic neural system, in dry eye (DE)–induced pathophysiology has not been elucidated well. This study investigated the presence of dopamine receptors (DRs) and their functional roles in the lacrimal glands (LGs) of DE-induced mice.MethodsAfter DE was induced in B6 mice for 2 weeks, the expression of tyrosine hydroxylase (TH), dopamine, and DRs (DR1, DR2, etc.) in the LGs and corneas were measured by quantitative RT-PCR, immunoblot, and ELISA. Using flow cytometry and ELISA, immune cell infiltration and inflammatory cytokine expression were determined in DE-induced LGs with or without DR blockers, SCH-23390 (DR1i), or melperone (DR2i). Corneal erosion scores were also investigated.ResultsThe mRNA and protein levels of TH significantly increased in DE-induced LGs. The dopamine concentration of LGs was 9.51 pmol in DE (versus naive: 1.39 pmol; P < 0.001). Both DR1 and DR2 mRNA expression were significantly enhanced in desiccating stress compared with those in naive (3.7- and 2.1-fold, P < 0.001). Interestingly, DR1 and DR2 immunostaining patterns stained independently in DE-induced LGs. CD3⁺ and CD19⁺ cell infiltration was significantly increased by DR2i (P < 0.001) but not by DR1i. Furthermore, IFN-γ, IL-17, and TNF-α were significantly upregulated by DR2i compared with the blow-only condition. The severity of corneal erosion and inflammation was also aggravated by DR2i.ConclusionsUpregulation of DR1 and DR2 was observed in DE-induced mouse LGs. As the inflammatory conditions are aggravated by the inhibition of DRs, especially DR2, their activity may be an important factor preserving ocular surface homeostasis.     

Immunomodulatory Therapy for Ocular Inflammatory Disease: A Basic Manual and Review of the Literature

Corticosteroids are used as first-line treatment for many ocular inflammatory conditions. The risk of adverse effects, however, necessitates conversion to steroid-sparing immunomodulatory therapy (IMT) for disease that is recurrent, chronic, or poorly responsive to treatment. Combination drug treatments with multiple agent ‘recipes’ are also considered. Immunomodulatory agents include the broad categories of antimetabolites (azathioprine, methotrexate, mycophenolate mofetil), alkylating agents (cyclophosphamide, chlorambucil), T-cell inhibitors (cyclosporine, tacrolimus), and cytokines (interferon alfa). This article reviews and summarizes the evidence for IMT agent use in the treatment of various forms of ocular inflammation.     

Etanercept (Enbrel)-Associated Inflammatory Eye Disease: Case Report and Review of the Literature

Purpose: To report a case of severe anterior uveitis flare following the administration of etanercept (Enbrel) for ankylosing spondylitis and to review the literature pertaining to inflammatory eye disease associated with the use of etanercept. Methods: Clinical data were collected from a 52-year-old female with chronic symptomatic ankylosing spondylitis. The relationship between etanercept administration and the patient's systemic and ocular inflammation was assessed. A review of the literature was conducted to identify additional reports. Results: A patient with a history of ankylosing spondylitis exhibited acute exacerbations of uveitis that were temporally related to etanercept injections. Re-challenge was associated temporally with a worsening of symptoms, and drug withdrawal, in concert with aggressive systemic steroid treatment, resulted in rapid resolution. Seventeen cases of inflammatory eye disease (uveitis, scleritis, orbital myositis) believed to be associated with etanercept therapy were found in the recent literature. Conclusions: Ocular inflammation is paradoxically a potential adverse event following the use of etanercept in both previously uninvolved and inflamed eyes. Careful surveillance of patients on etanercept is warranted to assure that flares in ocular inflammation are not secondary to etanercept therapy.     

Thyroid Eye Disease: A Historical Perspective

Within the short period from 1802 to 1840 four physicians from four different countries (Flajani in Italy, Parry in England, Graves in Ireland and Basedow in Germany) independently described a hitherto unknown disease, the hallmark of which were tachycardia and enlargement of the thyroid. Three of the physicians also noted exophthalmos. In sequence, the disease was attributed to primary cardiac disease, then to increased sympathetic nerve discharge, and finally to thyroid hyper-function. The latter concept failed to explain the exophthalmos, which cannot be reproduced by over-dosage of thyroid hormone. Explanations for the exophthalmos went from cardiac failure (causing swelling of the thyroid and retro-orbital tissues), to sympathetic nerve discharge, to over-secretion of TSH, to production within the pituitary of TSH fragments with exophthalmogenic properties, and finally to shared auto-antigens of thyroidal and retroorbital tissue. The latter theory is favoured today, after it had been recognized that thyroid hyperfunction in Graves’ disease was due to auto-antibodies to the thyroidal TSH receptor; such receptors were postulated also to be present in retroorbital tissue. Thus, each generation of scientists explained the pathogenesis of exophthalmos with the methods and concepts available to medical research at any given time. Although big advances have been made, future research may be good for some unexpected surprises.     

Keratitis in Dry Eye Disease and Topical Ciclosporin A

Tear film alterations in dry eye disease (DED) include reduced tear volume and an increase in inflammatory cytokines. Instability and reduced tear production initiate a vicious cycle where hyperosmolarity, ocular inflammation, and apoptosis may induce damage of the ocular surface including keratitis. Topical cyclosporine (CsA) has been used for the treatment of moderate-to-severe DED; however, previous studies failed to demonstrate its benefits by the European Agency standards. A new formulation of CsA 0.1% has been recently approved in the EU to treat severe keratitis in DED patients. Patients with severe keratitis showed a better improvement after 6 months of treatment with CsA compared with vehicle. HLA-DR expression was significantly reduced by CsA treatment. The clinically significant improvement in keratitis associated with the inflammatory biomarker HLA-DR confirms the efficacy of CsA to improve inflammation and its damaging effect on the ocular surface in DED patients.     

Topical Quercetin and Resveratrol Protect the Ocular Surface in Experimental Dry Eye Disease

Purpose: To determine the anti-inflammatory effect of quercetin (QCT), resveratrol (RES), and their combination in a dry eye disease (DED) model.

Methods: 0.01% QCT, 0.1% RES, 0.01% QCT + 0.1% RES (QCT + RES) or vehicle were topically applied in a desiccating stress (DS) mice model. CD4⁺ T cells isolated from DS-exposed mice were transferred to athymic recipient mice. Corneal fluorescein staining, tear production, and tear cytokine levels were evaluated in DS-exposed mice, and conjunctival CD4⁺ T cell infiltration was evaluated in recipient mice.

Results: QCT (p < 0.001) and QCT + RES (p < 0.05) reduced corneal staining in DS-exposed mice. IL-1α tear concentration was reduced by QCT, RES, and QCT + RES (p < 0.05, 0.01 and 0.01, respectively) compared to DS + vehicle mice. CD4⁺ T cells increased in recipients of DS-exposed mice (p < 0.05) and were lower in recipients of QCT- and RES-treated mice (p < 0.05).

Conclusion: The anti-inflammatory effect of QCT, RES, and QCT + RES on DED-experimental model suggests that their topical application could be used for DED treatment.     

Atypical Ocular Presentations of Rosai-Dorfman Disease

Purpose: To report atypical ocular findings of Rosai-Dorfman disease and to determine association with parvovirus 19. Design: The study is an observational case series of three patients that had atypical ocular presentations of Rosai-Dorfman disease. Methods: A multicenter, retrospective case series of 3 patients was evaluated for varied ocular complaints, including enlarging epibulbar masses and uveitis. Histologic specimens were examined retrospectively for parvovirus 19 antigen. Results: Patients presented with ocular findings prior to or concurrently with systemic findings, with and without associated lymphadenopathy. Two cases presented with epibulbar masses, one with the mass as the only sign of disease while the other exhibited multinodal involvement with bilateral epibulbar masses and anterior granulomatous inflammation. Parvovirus B19 antibody staining was negative in these cases. The final case exhibited bilateral anterior granulomatous inflammation and choroidal infiltrates. Conclusions: Ocular findings may be the sole or presenting complaint in Rosai-Dorfman disease prior to recognition of systemic disease and should be considered in the differential diagnosis of epibulbar masses as well as anterior and posterior granulomatous inflammation.     

Eye Care Disparities and Health-Related Consequences in Elderly Patients with Age-Related Eye Disease

ABSTRACT

The elderly population in the United States (age 65 and older) is growing rapidly, estimated by the U.S. Census Department to reach 83.7 million by 2050.¹ Visual impairment increases with age among all racial and ethnic groups.² In the elderly, the most common culprits for vision loss are cataract, glaucoma, and age-related macular degeneration (AMD).² In the developed world, vision loss from cataract has been dramatically reduced by increased access to cataract surgery. However, AMD and glaucoma lead to irreversible vision loss without early diagnosis and intervention. In the U.S., cases of AMD are expected to double by 2050, reaching 17.8 million among patients age 50 or older.³ Similarly, cases of glaucoma are expected to reach 5.5 million by 2050, an increase of over 90% from 2014.³ The visually impaired elderly face disparities in access to eye care, and subsequent general medical and psychosocial complications.     

Economic Burden of Non-Infectious Inflammatory Eye Disease (NIIED) in a Commercially-Insured Population in the United States

ABSTRACT

Purpose: To assess the economic burden of non-infectious in?ammatory eyedisease (NIIED) in a commercially-insured population in the United States

Methods: Adult patients with a NIIED diagnosis between 2006 and 2015 were selected from a de-identified, privately insured claims database and were matched 1:1 to a non-NIIED control. Ophthalmologic complications, direct healthcare resource use and costs, and indirect work loss (from the payer perspective) were calculated for a 12-month period and compared across the 2 cohorts.

Results: Among the 14 876 matched pairs, NIIED patients were significantly more likely than controls to experience ocular complications, including glaucoma and cataracts (p < 0.001). NIIED patients had significantly higher healthcare resource utilization and costs compared with matched controls (relative difference 40%, p < 0.001). NIIED patients missed 12.2 days of work ($2925 annual work-loss costs), 46% more than non-NIIED patients (p < 0.001).

Conclusion: NIIED imposes a significant clinical and economic burden, suggesting an unmet need for expanded access to alternative treatment options.     

Vitamin D and Selenium in a Thyroid Eye Disease Population in Texas

There is growing evidence of thyroid eye disease association with nutritional deficiencies including selenium and vitamin D. We conducted a retrospective chart review of all patients with clinical diagnosis of TED seen at our clinic from 2016 to 2017. Thirty-five patients met inclusion criteria and had serum 25-hydroxyvitamin D levels available, and 19 had selenium levels available. 7/35 (20%) patients had vitamin D deficiency, and 11 (31%) had vitamin D insufficiency, but none had selenium deficiency. Although both selenium and vitamin D supplementation have been recommended for TED, further investigation is necessary to justify supplementation for patients with TED.     

Caspase家族与干眼症的研究进展

Caspase家族是一类同源天冬氨酸特异性半胱氨酸蛋白酶,它们级联活化后降解其产物,参与炎症因子的产生以及细胞凋亡的调节。干眼症是眼科的常见疾病,是一种多因素相互作用所致的一种眼表疾病。细胞凋亡在干眼症的发病机制中占有非常重要的地位,炎症反应也被证实在干眼症的发病机制中发挥重要作用。近年来,人们对Caspase家族的分...     

Prevalence of Dry Eye Disease in Mongolians at High Altitude in China: The Henan Eye Study

Purpose: To estimate the prevalence of dry eye disease, analyze the associations between dry eye symptoms and signs, and identify the risk factors in an elderly Mongolian population at high altitude in China.

Methods: A population-based survey was conducted in 2006. A total of 2,486 Mongolians age 40 and older were selected. Symptoms of dry eye were assessed using a 6-item validated questionnaire. Dry eye disease was defined if participants reported one or more symptoms often or all the time. Positive signs included a tear-film breakup time of ≤10 seconds, a Schirmer test score of ≤ 5mm, or a fluorescein staining score ≥ 1 in one or both eyes. Presence of dry eye symptoms and positive signs were analyzed. Correlations between symptoms and signs, and risk factors were evaluated in a multivariate model.

Results: Of the 1,816 participants, 50.1% (95% confidence interval, 47.8–52.4) were symptomatic. Tear-film breakup time of ≤ 10 seconds was 37.7% (95% confidence interval, 35.5–39.9). A Schirmer test score of ≤ 5mm was 19.9% (95% confidence interval, 18.4–22.1). Fluorescein staining score ≥ 1 was 6.0% (95% confidence interval, 4.9–7.1). The correlation between dry eye symptoms and positive signs (tear-film breakup time of ≤ 10 seconds[r = 0.414, P < 0.001], Schirmer test score of ≤ 5mm [r = 0.164, P = 0.001], and fluorescein staining score ≥1 [r = 0.361, P < 0.001]) were statistically significant. Independent risk factors included increased age, age-related cataract and pterygium.

Conclusion: This study demonstrates a high prevalence rate of dry eye disease in a Mongolian population. Dry eye signs were significantly associated with dry eye symptoms.     

The Association between Diabetes and Herpes Simplex Eye Disease

Purpose: To evaluate the association between diabetes mellitus (DM) and presence and severity of Herpes simplex eye disease (HSED).

Methods: We conducted two sub-studies. We included the patients seen on the Cornea Service of the Wills Eye Hospital from January 2008 to August 2012. Study 1 included 541 patients with HSED and 3226 controls. Study 2 involved 40 diabetic and 120 non-diabetic ocular surface HSED patients. Severity of ocular surface HSED was graded as mild, moderate, or severe, based on best-corrected visual acuity (BCVA). Patients were excluded if they had fewer than two office visits or had non-Herpes simplex-related vision-threatening conditions. Diabetes was graded as: diet group (DM controlled with diet), oral group (DM controlled with oral medications), and insulin group (DM control required insulin).

Results: Five of 541 (0.93%) HSED patients had type 1 DM, similar to 19/3246 (0.59%) controls (p = 0.375); 48 of 541 (8.88%) HSED patients had type 2 DM, similar to 287/3246 (8.84%) controls (p = 0.981). Using multinomial logistic regression analyses, the probability/risk of being in the severe ocular surface HSED group as opposed to the mild ocular surface HSED group were not statistically significantly different between DM patients and those without DM (p = 0.120; OR, 1.900; 95% CI, 0.846–4.266).

Conclusions: There may not be a positive association between type 2 DM and HSED.     

Eye Movements

Objective: To determine the relative frequencies of positive temporal artery biopsies among African American and Caucasian patients at our institution, and to compare clinical and laboratory data. Materials and methods: Clinical and pathologic data were retrospectively collected on patients who underwent a temporal artery biopsy between 1986 and 1995 at a midwestern inner-city hospital with a large African American patient base. Results: A total of 7% of the African American and 17% of the Caucasian patients had positive biopsies. Headache, visual symptoms, jaw claudication, and myalgias/arthralgias occurred with similar frequency among African American and Caucasian patients referred for biopsy. Conclusions: Physicians in tertiary care referral settings serving a large African American population may encounter temporal arteritis among their African American patients more commonly than previously reported.     

Immunopathogenesis of Thyroid Eye Disease: Emerging Paradigms

Graves disease represents a systemic autoimmune process targeting the thyroid, orbit, and pretibial skin. The thyroid dysfunction is treatable, but no consistently effective medical therapy has yet been described for the orbital manifestations of Graves disease, also known as thyroid-associated ophthalmopathy or thyroid eye disease. Several autoantigens are potentially relevant to the pathogenesis of thyroid eye disease. Activating antibodies generated against the thyrotropin receptor can be detected in a majority of patients, and these drive hyperthyroidism. However, stimulating antibodies against the insulin-like growth factor-1 receptor (IGF-1R) may also play a role in the extra-thyroid manifestations of Graves disease. IGF-1R is overexpressed by orbital fibroblasts derived from patients with thyroid eye disease, whereas IGF-1R⁺ T and IGF-1R⁺ B cells are considerably more frequent in Graves disease. Actions of several cytokines and the molecular interplay peculiar to the orbit appear to provoke the inflammation, fat expansion, and deposition of excessive extracellular matrix molecules in thyroid eye disease. Based upon these new insights, several therapeutic strategies can now be proposed that, for the first time, might specifically interrupt its pathogenesis.     

Rectus Muscle Resection for Vertical Strabismus in Thyroid Eye Disease

Purpose: Rectus muscle resection in thyroid eye disease (TED) is generally avoided due to the risk of worsening restriction or reactivating inflammation. However, for some patients with large-angle strabismus or diplopia in primary gaze despite maximum recession surgery, rectus muscle resection may be beneficial. We report our surgical experience with rectus muscle resection in the management of vertical strabismus associated with TED.

Methods: Retrospective review of eight patients with TED and vertical diplopia who underwent vertical rectus muscle resection by a single surgeon (IBM) at a tertiary referral centre in Liverpool, UK, from 2001 to 2013. The goal of surgery was elimination of diplopia in primary and reading position. Vertical deviations were measured in prism dioptres (^?) before and after surgery at one month, four months and final visit by prism alternate cover testing at ? m and 6 m.

Results: The mean ± standard deviation vertical deviation for near and distance reduced significantly from 14.2^? ± 8.4^? and 15.8^? ± 8.8^? pre-operatively to 5.7^? ± 4.9^? and 6.7^? ± 7^? at the four-month visit, respectively (p< 0.05). At the four-month follow-up, five (62.5%) patients achieved binocular single vision in primary and reading position with either no prisms or prisms less than 5^?. Further recession surgery, Harada-Ito procedure, or lateral rectus resection were necessary in four (50%) patients with persistent diplopia. No patient developed recurrence of inflammation or increased muscle restriction.

Conclusions: Vertical rectus resection could be considered as an additional surgical strategy in the management of TED patients with vertical strabismus without adverse sequelae.