Management of inflammation in dry eye disease: Recommendations from a European panel of experts.

INTRODUCTION: Early initiation of anti-inflammatory therapies is recommended for dry eye disease (DED) to break the vicious cycle of pathophysiology. However, there is limited guidance on how to implement topical ciclosporin (CsA) and corticosteroid treatment into clinical practice. This expert-led consensus provides practical guidance on the management of DED, including when and how to use topical CsA. METHODS: A steering committee (SC) of seven European DED experts developed a questionnaire to gain information on the unmet needs and management of DED in clinical practice. Consensus statements on four key areas (disease severity and progression; patient management; efficacy, safety and tolerability of CsA; and patient education) were generated based on the responses. The SC and an expanded expert panel of 22 members used a nine-point scale (1 = strongly disagree; 9 = strongly agree) to rate statements; a consensus was reached if ≥75% of experts scored a statement ≥7. RESULTS: A stepwise approach to DED management is required in patients presenting with moderate corneal staining. Early topical CsA initiation, alone or with corticosteroids, should be considered in patients with clinical risk factors for severe DED. Patient education is required before and during treatment to manage expectations regarding efficacy and tolerability in order to optimise adherence. Follow-up visits are required, ideally at Month 1 and every 3 months thereafter. Topical CsA may be continued indefinitely, especially when surgery is required. CONCLUSION: This consensus fills some of the knowledge gaps in previous recommendations regarding the use of topical corticosteroids and CsA in patients with DED.

Tear and ocular surface disease biomarkers: A diagnostic and clinical perspective for ocular allergies and dry eye disease.

Validated biomarkers to be used as biological tools for managing ocular surface diseases (OSDs) are still an unmet need in daily clinical practice. Many studies have contributed to the already extensive list of candidate biomarkers for these disorders. Dry eye (DE) and ocular allergy (OA) are complex and multifactorial diseases, often coexisting and with overlapping symptoms. The purpose of this review is to present a comprehensive updated revision of the most relevant biomarkers of DE and OA, with an emphasis on quantitative analyses and correlations with clinical parameter data. Analysis of biomarkers common for these pathologies has highlighted an important physiological process. Namely, the interleukin proteins (IL-1α, IL-1ß and IL-17), tumour necrotic factor (TNFα) and interferon gamma (IFNγ; Th1-Th7 pathway) and IL-4, IL-5 and IL-13 (Th2 pathway) seem to represent similar inflammatory mechanisms. Moreover, changes in the levels of mucins (MUC1, MUC2, MUC4, MUC5 and MUC16) are common alterations in the tear film mucous layer. We also examine the current state of medical devices and the main limitations to their use in clinical practice. Translational research in biomarkers for clinical practice depends on a feasible transition from the laboratory to the point-of-care. This requires large-scale, coordinated clinical validation campaigns to select the biomarkers with the highest specificity and sensitivity and significant correlation with clinical parameters. Moreover, technical limitations of multiplexed quantitation systems must be overcome to detect and measure the levels of several biomarkers in very small samples. To ensure the future of biomarker research, significant progress is necessary in a number of fields. There is an urgent need for global unification of clinical classification and diagnostics criteria. Widespread integration of proteomic and transcriptomic data is paramount for performing meaningful analyses using appropriate bioinformatics tools and artificial intelligence systems.

Topical insulin for refractory persistent corneal epithelial defects.

PURPOSE: To evaluate insulin eye drops for persistent epithelial defects (PEDs) that are refractory to usual treatment in clinical practice and to analyze how it may improve epithelization. METHODS: A prospective non-randomized hospital-based study was performed. Patients with PEDs that were refractory to conventional treatment were treated with insulin eye drops four times a day. Patients' demographics, PED etiology, concomitant treatments, and comorbidities were reviewed. The rate of PED closure and epithelial healing time were considered the primary outcome measures. RESULTS: 21 patients were treated with insulin drops (12 females and 9 males; mean age 72.2 years). Mean PED area before treatment was 17.6 ± 16.5 mm2 (median 13.2; range 3.9-70.6). PED comorbidities included seven eyes with infectious keratitis (33%), five eyes with calcium keratopathy (24%), ocular surgery on three eyes (14%), three eyes with lagophthalmos (14%), two eyes with bullous keratopathy (10%), and one patient with herpetic eye disease (5%). The eyes of 17 patients (81%) with refractory PEDs had reepithelized and four patients (19%) had still presented an epithelial defect by the end of the study follow-up period, although it had decreased in size. In patients where PED closure was achieved, mean time until reepithelization was 34.8 ± 29.9 days (median 23; range 7-114). In the remaining patients, a mean area reduction of 91.5% was achieved for the PEDs. CONCLUSION: Topical insulin can promote and accelerate corneal reepithelization of refractory PEDs. It also offers many other advantages, including excellent tolerance, availability, and cost-effectiveness.

Neurotrophic keratopathy.

Neurotrophic Keratopathy (NK) refers to a condition where corneal epitheliopathy leading to frank epithelial defect with or without stromal ulceration (melting) is associated with reduced or absent corneal sensations. Sensory nerves serve nociceptor and trophic functions, which can be affected independently or simultaneously. Loss of trophic function and consequent epithelial breakdown exposes the stroma making it susceptible to enzymatic degradation. Nerve pathology can range from attrition to aberrant re-generation with corresponding symptoms from anaesthesia to hyperaesthesia/allodynia. Many systemic and ocular conditions, including surgery and preserved medications can lead to NK. NK can be mild (epithelium and tear film changes), moderate (non-healing epithelial defect) or severe (stromal melting and perforation). Moderate and severe NK can profoundly affect vision and adversely impact on the quality of life. Medical management with lubricating agents from artificial tears to serum/plasma drops, anti-inflammatory agents, antibiotics and anti-proteases all provide non-specific relief, which may be temporary. Contact lenses, punctal plugs, lid closure with botulinum toxin and surgical interventions like tarsorrhaphy, conjunctival flaps and amniotic membrane provide greater success but often at the cost of obscuring sight. Corneal surgery in a dry ocular surface with reduced sensation is at high risk of failure. The recent advent of biologicals such as biopolymers mimicking heparan sulfate; coenzyme Q10 and antisense oligonucleotide that suppress connexin 43 expression, all offer promise. Recombinant nerve growth factor (cenegermin), recently approved for human use targets the nerve pathology and has the potential of addressing the underlying deficit and becoming a specific therapy for NK.

Confocal Microscopy Observation of Cornea Verticillata After Vandetanib Therapy for Medullary Thyroid Carcinoma.

PURPOSE: To report 2 cases of cornea verticillata (CV) after vandetanib treatment for medullary thyroid carcinoma (MTC). METHODS: In this retrospective interventional, case-report study, 2 patients who under vandetanib treatment for MTC were referred to our ophthalmology department because of vision complaints. Both subjects underwent a complete ophthalmologic examination, including confocal microscopy (CM) using the Heidelberg Retina Tomograph and Rostock Cornea Module. RESULTS: A 70-year-old man and a 43-year-old woman, both with a history of MTC under treatment with vandetanib for 5 months and 30 months, respectively, presented with blurred vision. In both patients, a mild CV pattern was observed although deposits were more evident in the male patient. CM images showed hyperreflective deposits in the corneal epithelium and subepithelial nerve plexus. Bright microdots were also seen throughout the stroma, along with a few hyperreflective keratocytes in the anterior stroma. CONCLUSIONS: In both patients, vandetanib seemed to be the cause of CV. The CM images supported the idea of drug-lipid complex deposits in vandetanib-induced CV.

Clinical impact of inflammation in dry eye disease: proceedings of the ODISSEY group meeting.

Dry eye disease (DED) is a common, multifactorial ocular condition with major impact on vision and quality of life. It is now well recognized that the pathophysiology of chronic DED can include a cycle of inflammation involving both innate and adaptive immune responses. Recently, in vitro/in vivo models have been used to obtain a better understanding of DED-related inflammatory processes at molecular/cellular levels although they do not truly reproduce the complex and chronic hallmarks of human DED. In clinical DED research, advanced techniques such as impression cytology, conjunctival biopsy, in vivo confocal microscopy and multiplex tear analyses have allowed an improved assessment of inflammation in DED patients. This was supported by the identification of reliable inflammatory markers including matrix metalloproteinase-9, human leucocyte antigen-DR or intercellular adhesion molecule-1 in tears and impression cytology samples. One of the current therapeutic strategies focuses on breaking the inflammatory cycle perpetuating the ocular surface disease, and preclinical/clinical research has led to the development of promising anti-inflammatory compounds. For instance, cyclosporine, already approved in the United States, has recently been authorized in Europe to treat DED associated with severe keratitis. In addition, other agents such as corticosteroids, doxycycline and essential fatty acids, through their anti-inflammatory properties, show encouraging results. We now have a clearer understanding of the inflammatory processes involved in DED, and there is hope that the still emerging preclinical/clinical findings will be translated into new and highly effective therapies for patients in the near future.

Tear cytokine profile of glaucoma patients treated with preservative-free or preserved latanoprost.

PURPOSE: To determine variations in cytokine levels of glaucoma patients treated either with preservative-free latanoprost or preserved latanoprost, relative to healthy individuals. METHODS: Tear samples were collected from 39 healthy subjects, 20 glaucoma patients treated with preserved latanoprost, and 20 patients treated with preservative-free latanoprost. A set of 27 inflammatory cytokines was analyzed in each group, including interleukin (IL)-1ß, IL-1ra, IL-2, IL-4, IL-5, IL-6, IL-7, IL-8, IL9, IL-10, IL-12 (p70), IL-13, IL-15, IL-17, eotaxin, fibroblast growth factor (FGF) basic, granulocyte colony stimulating factor (G-CSF), granulocyte monocyte colony stimulating factor (GM-CSF), interferon (IFN)-γ, interferon gamma-induced protein (IP)-10, monocyte chemo attractant protein (MCP)-1MCAF, macrophage inflammatory protein (MIP)-1α, MIP-1ß, platelet-derived growth factor (PDGF)-BB, regulated on activation, normal T cell expressed and secreted (RANTES), tumor necrosis factor (TNF)-α and vascular endothelial growth factor (VEGF). Cytokine concentrations were obtained by the Bio-Plex Human Cytokine Immunoassay. Non-invasive tear breakup time (NI-TBUT), tear meniscus height, corneal fluorescein staining, conjunctival hyperemia and ocular surface disease index (OSDI) were assessed in patients treated with preservative-free and preserved latanoprost. RESULTS: The levels of IL-2, IL-5, IL-10, IL-12 (p70), IL-13, IL-15, IL-17, FGF basic, PDGF-BB, and TNF-α were significantly higher in patients receiving preserved latanoprost, compared to normal controls (p < 0.05). The expression of all the cytokines studied remained statistically invariable in patients receiving preservative-free latanoprost, compared to healthy subjects (p > 0.05). Ocular surface parameters were not significantly different in both glaucoma groups, and no correlation between these clinical parameters and cytokine levels was observed. CONCLUSIONS: Treatment with preserved latanoprost has a direct impact on tear cytokine levels, whereas this effect is not observed upon preservative-free latanoprost instillation.

Changes in visual function under mesopic and photopic conditions after intrastromal corneal ring segment implantation for different stages of keratoconus.

PURPOSE: To analyze and compare the changes in visual function under mesopic and photopic conditions in different stages of keratoconus before and after Keraring intrastromal corneal ring segment (ICRS) implantation. SETTING: Clinico San Carlos Hospital and Faculty of Optics and Optometry, Complutense University, Madrid, Spain. DESIGN: Case series. METHODS: Keratoconic eyes were evaluated under mesopic (0.1 to 0.2 candelas [cd]/m(2)) and photopic (85 cd/m(2)) conditions. LogMAR high-contrast corrected distance visual acuity (CDVA) and low-contrast CDVA were assessed using the Bailey-Lovie test and logarithmic contrast sensitivity, using the Pelli-Robson test. RESULTS: The study evaluated 12 eyes with stage I keratoconus, 21 eyes with stage 2, and 14 eyes with stage 3. The mean change in photopic high-contrast CDVA was 0.16 logMAR ± 0.20 (SD) (P<.00001). Photopic low-contrast CDVA increased by a mean of 0.14 ± 0.26 logMAR (P=.0005), photopic contrast sensitivity by a mean of 0.09 ± 0.22 logMAR (P=.005), and mesopic high-contrast CDVA by a mean of 0.10 ± 0.26 logMAR (P=.03). There were no significant differences between stages. Surgery did not affect the mean changes in mesopic low-contrast CDVA or mesopic contrast sensitivity for any stage. CONCLUSIONS: Implantation of ICRS in keratoconic eyes increased photopic high-contrast CDVA, low-contrast CDVA, and contrast sensitivity. Under low luminance, the mean changes in high-contrast CDVA, low-contrast CDVA, and contrast sensitivity did not worsen after ICRS implantation performed 5.0 mm from the visual axis, despite the rings being partially superimposed on the mydriatic pupil.

Effect of lubricating eyedrops on ocular light scattering as a measure of vision quality in patients with dry eye.

PURPOSE: To determine light scattering by the eye as a measure of optical quality using the Optical Quality Analysis System in patients with mild to moderate dry-eye disease and to examine change patterns after lubricating eyedrop use. SETTING: Hospital Clínico San Carlos, Madrid, Spain. DESIGN: Evaluation of diagnostic test or technology. METHODS: Eyes with mild to moderate dry-eye disease (study group) and healthy eyes (control group) were examined in a single visit. All patients completed a questionnaire to assess dry-eye disease symptoms (ocular surface disease index [OSDI]). Signs of dry eye were recorded as the tear breakup time, Schirmer I test, and corneal staining score. Scattered light was measured as the objective scatter index (OSI) at 0.5-second intervals over 20 seconds without blinking. The measurements were repeated 5, 10, 20, 30, 45, and 60 minutes after eyedrop instillation, and the OSI change rate was calculated. RESULTS: The OSI was significantly higher in the study group (25 eyes) than in the control group (10 eyes). After eyedrop instillation in the study group, the OSI change rate decreased significantly from baseline at each time point (P<.001, 45 minutes; P<.01, 60 minutes). No significant differences in the OSI change rate were detected between time points except between 45 minutes and 60 minutes (P<.01). A correlation was observed in all the dry-eye variables except the corneal staining score. CONCLUSION: Lubricating eyedrops improved ocular scattering in patients with mild to moderate dry eye for at least 60 minutes after instillation. FINANCIAL DISCLOSURE: No author has a financial or proprietary interest in any material or method mentioned.

Treatment of refractory uveitis with adalimumab: a prospective multicenter study of 131 patients.

OBJECTIVE: To evaluate adalimumab therapy in refractory uveitis. DESIGN: Prospective case series. PARTICIPANTS: A total of 131 patients with refractory uveitis and intolerance or failure to respond to prednisone and at least 1 other systemic immunosuppressive drug participated. INTERVENTION: Patients received a 40 mg adalimumab subcutaneous injection every other week for 6 months. The associated immunosuppressants were tapered after administering 3 adalimumab injections (week 6). MAIN OUTCOME MEASURES: Degree of anterior and posterior chamber inflammation (Standardization of Uveitis Nomenclature Working Group criteria), immunosuppression load (as defined by Nussenblatt et al), visual acuity (logarithm of the minimal angle of resolution [logMAR]), and macular thickness (optical coherence tomography). RESULTS: There were 61 men and 70 women (mean age, 27.3 years). The most common causes were juvenile idiopathic arthritis in 39 patients, pars planitis in 16 patients, and Behçet's disease in 13 patients. Twenty-seven patients had uveitis of idiopathic origin. Inflammation in the anterior chamber was present in 82% of patients and in the vitreous cavity in 59% of patients. Anterior chamber inflammation and vitreous inflammation decreased significantly (P < 0.001) from a mean of 1.51 and 1.03 at baseline to 0.25 and 0.14, respectively, at 6 months. Macular thickness was 296 (102) µ at baseline versus 240 (36) µ at the 6-month visit (P < 0.001). Visual acuity improved by -0.3 logMAR in 32 of 150 eyes (21.3%) and worsened by +0.3 logMAR (-15 letters) in 5 eyes (3.3%). The dose of corticosteroids also decreased from 0.74 (3.50) to 0.20 (0.57) mg/kg/day (P < 0.001). Cystoid macular edema, which was present in 40 eyes at baseline, showed complete resolution in 28 eyes at 6 months. The mean suppression load decreased significantly (8.81 [5.05] vs 5.40 [4.43]; P < 0.001). Six months after the initiation of the study, 111 patients (85%) were able to reduce at least 50% of their baseline immunosuppression load. Only 9 patients (6.9%) had severe relapses during the 6 months of follow-up. CONCLUSIONS: Adalimumab seems to be well tolerated and helpful in decreasing inflammatory activity in refractory uveitis and may reduce steroid requirement. Further controlled studies of adalimumab for uveitis are warranted.

Activation of MAPK signaling pathway and NF-kappaB activation in pterygium and ipsilateral pterygium-free conjunctival specimens.

PURPOSE: To evaluate mitogen-activated protein kinases (MAPKs) and nuclear factor-κB (NF-κB) signaling pathways in pterygium and pterygium-free conjunctivas. METHODS: Primary pterygia (n = 21), ipsilateral superior-temporal bulbar conjunctivas (n = 8), and healthy conjunctival (n = 5) biopsy specimens were analyzed. Total and phosphorylated (phospho) levels of extracellular-regulated 1/2 (ERK1/2), p38, and c-jun N-terminal (JNK) MAPKs and NF-κB inhibitor-alpha (IκΒ-α) were analyzed by immunobead-based assay. Tissue phospho-, total protein, and activation values determined by phospho/total ratios were compared. Correlation among those values and clinical parameters were determined. Average-linkage hierarchical cluster analysis identified patients with similar protein activation values. The k-nearest neighbor classifier predicted the origin of specimens based on protein levels. RESULTS: Pterygium samples had significantly lower total JNK and IκΒ-α levels than did healthy conjunctivas. Decreased total JNK and IκΒ-α and increased phospho-IκΒ-α levels and phospho/total ratio of JNK and IκΒ-α were present in ipsilateral conjunctivas compared with healthy conjunctivas. Protein levels were correlated among them in pterygium, ipsilateral, and healthy conjunctivas and with sun exposure, pterygium grade, and pterygium measurements. Cluster analysis of activation values and ratios in pterygium and ipsilateral-conjunctiva revealed different groups of patients with similar values. Prediction accuracy was 70% to 80% for the classifiers phospho- and total protein levels and phospho/total ratio. CONCLUSIONS: Pterygium and pterygium-free ipsilateral conjunctivas had alterations in MAPK and NF-κB pathways not present in healthy conjunctivas. The high prediction accuracy based on phospho- and total protein levels and phospho/total ratio of ERK1/2, p38, JNK, and IκB-α suggests these molecules as potential biomarkers of inflammation in pterygia.

Pterygium surgery: conjunctival autograft using a fibrin adhesive.

PURPOSE: To evaluate the efficiency and safety of using a fibrin adhesive (Tissucol Duo, Baxter AG, Vienna, Austria) to avoid the need for sutures during conjunctival autograft surgery for primary pterygium. METHODS: Twenty patients (20 eyes) with primary nasal pterygium were subjected to conjunctival autograft surgery. The free conjunctival graft placed over the bare sclera was fixed to the surrounding conjunctiva and cornea using the fibrin glue. An occlusive patch was applied. The outcome of surgery and any possible complications were periodically assessed. RESULTS: Mean patient age was 54.9 years (28-75 years). The mean follow-up time was 26.05 +/- 3.15 (SD) weeks. The time of surgery was 15 to 20 minutes. During the postoperative course, none of the patients felt pain, and only 5/20 (25%) had the mild sensation of the presence of a foreign body. In 18/20 (90%) patients, the conjunctival autograft was observed to be correctly positioned and fixed in all the follow-up exams. No sutures were used during or after surgery. There were no cases of regrowth of the pterygium. CONCLUSION: Our findings demonstrate the safety and efficiency of Tissucol Duo as a conjunctival adhesive for pterygium autograft surgery as treatment of primary pterygium. Because of its fast and easy application, this product considerably reduces the time of surgery. Its use also avoids complications derived from sutures and diminishes the sensation of a foreign body in the eye following surgery.

Bilateral lid margin ulcers as the initial manifestation of Crohn disease.

PURPOSE: To report an unusual bilateral ulcerative lid involvement as the presenting manifestation of a severe Crohn disease. DESIGN: Observational case report. METHOD: Description of an otherwise healthy woman who initially presented with bilateral ulcerative lid involvement before the discovery of an extensive ulcerative intestinal inflammatory disease. RESULTS: A 32-year-old woman presented with bilateral ulcerative blepharitis. She also complained of aphthous oral lesions and diarrheic episodes for the previous 3 days. Impression cytology of the lid ulcers showed conjunctival cells, together with the presence of lymphocytes and macrophages. Colonoscopy and colonic biopsy were characteristic of Crohn disease. The treatment with systemic corticosteroids healed bowel, oral, and lid margin ulcerative lesions. CONCLUSION: The simultaneous appearance of ulcerative lesions in the intestinal mucosa and in the mucocutaneous lid margin and the comparable features encountered in the cytologic studies indicate that ulcerative lid margin disease could be an ocular manifestations of Crohn disease.

Lens fluorophotometry after trabeculectomy in primary open-angle glaucoma.

OBJECTIVE: To evaluate the loss of lens transparency incurred by patients undergoing trabeculectomy. DESIGN: A prospective cohort study. PARTICIPANTS AND CONTROLS: Data corresponding to 33 eyes of 33 consecutive patients with primary open-angle glaucoma (POAG) subjected to trabeculectomy (group 1) were compared with those corresponding to 12 eyes of 12 patients with POAG receiving topical antiglaucomatous treatment (group 2). INTERVENTION: Lens fluorophotometry was performed on the group 1 patients before and 12 months after surgery. In group 2, fluorophotometry was conducted at the onset of the study and at 12 months of follow-up. MAIN OUTCOME MEASURES: Starting and final lens autofluorescence and transmittance values corresponding to each subject group were compared. RESULTS: In group 1, starting and final autofluorescence was 556.3 +/- 184.3 and 691.1 +/- 179.3 Eq ng/ml, and starting and final transmittance was 0.78 +/- 0.11 and 0.67 +/- 0.14, respectively. Respective values for group 2 were 574.3 +/- 94.8 and 595.2 +/- 107.0 Eq ng/ml and 0.72 +/- 0.17 and 0.71 +/- 0.16. The mean change between final and initial autofluorescence was statistically different between groups (134.7 +/- 123.7, group 1, 20.9 +/- 25.1 Eq ng/ml, group 2; P < 0.001). Similarly, a significant difference (P < 0.001) in transmittance change was observed between the surgery and control groups (-0.11 +/- 0.072, group 1; 0.02 +/- 0.008, group 2) CONCLUSIONS: It was demonstrated by lens fluorophotometry that trabeculectomy in POAG leads to a loss in lens transparency.