Severe Dry Eye Disease Patients Research Articles

Efficacy and Safety of the Melanocortin Pan-Agonist PL9643 in a Phase 2 Study of Patients with Dry Eye Disease.

Purpose: The melanocortin receptor pan-agonist PL9643, a potential therapy for ocular diseases, was investigated in a phase 2, 12-week study in patients with dry eye disease (DED). Methods: This was a placebo-controlled study evaluating efficacy and safety of thrice-daily PL9643. Placebo (vehicle) was similar to tears. Primary endpoints were intra-patient changes in inferior corneal fluorescein staining and ocular discomfort after 12 weeks. Secondary endpoints were changes in additional DED signs or symptoms. Multiple secondary endpoints were not adjusted for multiplicity. Patients with moderate or severe DED were analyzed in addition to the overall intent-to-treat (ITT) population. Results: In the ITT population (n = 160) the PL9643 group did not demonstrate significant treatment difference versus placebo at week 12/day 85 for the primary endpoints (P > 0.05). In patients with moderate or severe DED (n = 53), PL9643 treatment demonstrated either nominally significant (P < 0.05) or trending (P < 0.1) improvement over placebo in mean change from baseline at week 12/day 85 in several sign endpoints, including fluorescein staining in inferior, superior, corneal sum, and total sum regions; Lissamine Green staining in temporal, nasal, conjunctival sum, and total sum regions; and tear film breakup time. Conjunctival redness also showed (nonsignificant) improvement at week 12/day 85. There were no drug-related adverse events (AEs) and no drug-related discontinuations. Conclusions: PL9643 showed no significant efficacy for the ITT population; however, efficacy results across several signs and symptoms in the subpopulation of moderate to severe DED patients, the low number of ocular AEs, and no tolerability issues suggest that PL9643 shows promise as a therapeutic for DED. Clinical Trial Registration number: NCT04268069.

Comparative Evaluation of Matrix Metalloproteinase-9 Immunoassay and Tear Osmolarity Measurement for Diagnosing Severity of Dry Eye Disease.

To evaluate and compare the clinical efficacy of matrix metalloproteinase-9 (MMP-9) immunoassay and tear osmolarity measurement in diagnosing dry eye severity. Dry eye disease (DED) patients underwent diagnostic tests including MMP-9 assay, tear osmolarity measurement, fluorescein tear breakup time, ocular surface staining, anesthetized Schirmer test, Ocular Surface Disease Index questionnaire, and slit-lamp examination. The dry eye parameters were compared according to positive MMP-9 status and increased tear osmolarity. The correlation between dry eye profiles and MMP-9 positivity and high tear osmolarity was also analyzed. Those who tested positive in MMP-9 immunoassay had significantly higher corneal fluorescein staining score and worse DED severity than those who tested negative. The intensity of MMP-9 positivity showed positive correlation with the corneal staining score and DED severity. However, DED patients with high tear osmolarity above 308 mOsm/L did not show significantly different dry eye signs and symptoms compared to those with lower tear osmolarity values. Tear osmolarity was associated with ocular surface staining score in severe DED patients. MMP-9 positivity was associated with ocular surface staining and worse dry eye severity. Therefore, it may be used as a useful indicator of disease severity in conjunction to other diagnostic tests.

Association of Tear Cytokine Concentrations with Symptoms and Signs of Dry Eye Disease: Baseline Data from the Dry Eye Assessment and Management (DREAM) Study

Purpose To describe tear concentrations of IL-1β, Il-6, IL-8, IL-10, IL-17A, IFNγ and TNFα in tears, collected by microcapillaries, and their correlation with symptoms and signs in subjects with dry eye disease (DED) in the DREAM Study. Methods Cytokine levels of patients with moderate to severe DED were determined using a magnetic bead assay. Scores for Ocular Surface Disease Index, corneal and conjunctival staining, tear break-up time (TBUT), and Schirmer’s test were obtained using standardized procedures. Associations of cytokines with each other and signs/symptoms were assessed with Spearman correlation coefficients (r). Results Assay results from 131 patient samples from 10 sites with tear volumes ≥ 4 ul were analyzed. Cytokine concentrations did not correlate with each other in a generally acknowledged pro-inflammatory/anti-inflammatory pattern, such as proinflammatory IL-17A and IFNγ were not inversely correlated to anti-inflammatory cytokine IL-10, and cytokines did not correlate with DED symptoms. Lower corneal staining was correlated with higher concentrations of IL-17A (r= −0.24, p = 0.006), IL-10 (r= −0.25, p = 0.005) and IFNγ (r= −0.33, p = 0.0001). Higher concentrations of IFNγ were associated with lower conjunctival staining (r= −0.18, p = 0.03). Higher concentrations of IL-17A were associated with higher TBUT scores (r = 0.19 p = 0.02). Conclusions Cytokines IL-10, IL-17A and IFNγ were highly correlated with each other but weakly correlated with some DED signs. No key cytokines or definitive expression patterns were identified in this study of moderate to severe DED patients. Further studies addressing various biases, including methodological and sampling biases, and standardization of methodology for inter-laboratory consistency are needed to confirm and establish pathological and clinical relevance of tear cytokines in DED.

The repeatability of corneal topography measurements in severe Dry Eye disease

BackgroundTo determine the repeatability of corneal topography measurements in severe dry eye disease (DED). A comparison of corneal topography parameters between severe DED and healthy subjects was a secondary goal of this study.MethodsSixty-nine patients with severe DED and 46 healthy subjects were enrolled in the study. All participants underwent repeated corneal topography measurements with Pentacam (Oculus, Germany) within a half hour time. Both eyes of the participants were used in statistical analysis. A further subcategorization of severe DED patients was performed according to Ocular Surface Disease Index (OSDI) scores: 32–50, 51–70 and 71–100. The repeatability of corneal parameters was assessed with correlation coefficients (CC).ResultsThe mean age of dry eye patients and healthy subjects were 40.8 ± 13.2 (17–66) and 39.8 ± 8.2 (18–61) years (p:0.604) respectively. No significant differences were found between severe DED and control groups according to analysed corneal parameters in both eyes (p:>0.05). All CCs were greater than 0.9 in severe DED group (p:<0.001). All CCs were also greater than 0.9 in severe DED patients among different OSDI groups (p:<0.001).ConclusionsCorneal topography measurements are highly repeatable in severe DED with Pentacam. This is the first report about this topic. Nonetheless, further studies are needed with different topography devices for validation.

Effect of artificial tears on dynamic optical quality in patients with dry eye disease

BackgroundIn clinical practice, fluctuating vision or decreased quality of vision is a common complaint in DED patients. Our study was designed to investigate the change in dynamic optical quality in dry eye patients after the use of artificial tears.MethodsFifty-nine patients with dry eye disease (DED) and 31 control subjects were included in this prospective case-control study. There was no significant difference in age and sex between these two groups (P = 0.342, P = 0.847, respectively). Clinical evaluation of the ocular surface included Ocular Surface Disease Index (OSDI), tear film break-up time (TBUT), lipid layer thickness (LLT), and Schirmer I test. DED patients were divided into two groups, mild (31 patients) and severe (28 patients). The optical quality of the tear film was measured with the Optical Quality Analysis System (OQAS) using the mean objective scatter index (mean OSI), standard deviation of objective scatter index (SD-OSI) and modulation transfer function cut-off (MTF cut-off). After baseline examinations, one drop of artificial tears (ATs, carboxymethylcellulose ophthalmic solution, 0.5%) was instilled in both eyes, and optical quality parameters were measured again at 5 and 30 min following application of ATs.ResultsAt baseline, the mean OSI was higher in the DED group (0.95 ± 0.54) than in controls (0.54 ± 0.23, P < 0.001). The SD-OSI was also significantly increased in DED patients (0.44 ± 0.71) compared to control subjects (0.12 ± 0.06, P = 0.003). Five minutes after AT instillation, mean OSI and SD-OSI decreased significantly in severe DED patients (P = 0.044; P = 0.018), remained unchanged in mild DED patients, and increased in the control group (P = 0.019; P < 0.001). Thirty minutes after AT instillation, no significant difference in optical quality parameters was observed among the three groups.ConclusionThe effect of ATs on optical quality in patients with DED may differ according to the severity of the disease. Measurement of optical quality might be a promising tool to evaluate the effects of various ATs and possibly individualize treatment in DED patients.

A randomized multicenter clinical evaluation of sequential application of 0.3% and 0.15% hyaluronic acid for treatment of dry eye.

We report the clinical efficacy of sequential applications of 0.3% and 0.15% unpreserved hyaluronic acid (HA) for the treatment of dry eye disease (DED). Randomized clinical trial. Patients over 19years of age with DED level 2 or higher, corneal fluorescein staining (CFS) score > 1, and tear break-up time (TBUT) < 10s were included. Seventy-six patients were randomly assigned to the 0.15% HA group, 0.3% HA group, or combination group. Each group applied two drops of 0.15% or 0.3% HA, or a single drop of both 0.3% and 0.15% HA. Patients were evaluated using the ocular surface disease index (OSDI), CFS and conjunctival fluorescein stain score, TBUT, and blurring/discomfort after application at baseline, 4weeks, and 8weeks. The combination group had the greatest improvement in CFS score from baseline to 8weeks, compared with the 0.15% and 0.3% HA group (p < 0.001). The combined CFS-OSDI responder rates of the combination group (CFS score = 0 and OSDI ≥ 50% improvement at 8weeks) were significantly higher than those of the 0.15% and 0.3% groups (p = 0.037). At 4 and 8weeks, blurring after application in both the 0.3% and combination groups was significantly higher than in the 0.15% group, despite no difference between the 0.3% and combination groups. There were no differences in CFS and conjunctival staining score, TBUT, or OSDI within the three groups at baseline, 4weeks, and 8weeks. Sequential application of 0.3% and 0.15% HA improved symptoms/signs in moderate to severe DED patients.

Age- and Sex-Adjusted Reference Intervals in Tear Cytokine Levels in Healthy Subjects

Alterations in tear cytokine levels have been associated with various ocular disorders as compared to those in healthy subjects. However, age and sex are not always considered in these comparisons. In this study we aimed to establish age and sex reference intervals (RIs) for tear cytokine levels in healthy people. Tear samples were taken from 75 males and 82 females, aged 18–88 years, and tear cytokine levels were determined. Age- and sex-adjusted RIs for epidermal growth factor (EGF), fractalkine, interleukin (IL)-1 receptor antagonist (RA), IL-7, IL-8, interferon inducible protein (IP)-10, monocyte chemotactic protein (MCP)-1, and vascular endothelial growth factor (VEGF) tear cytokine levels in a healthy sample were established using generalized additive for location, scale and shape (GAMLSS) models. RIs were tested in two external samples: a validation sample of 40 individuals with normal results at four Dry Eye Disease (DED) clinical diagnostic tests (OSDI, T-BUT, corneal staining and Schirmer test); and a utility sample of 13 severe DED cases. IL-1RA, IL-8, IP-10, and MCP-1 levels showed a positive association with age, while EGF was negatively correlated. IL-7 concentration increased up to 40 years and again after 70 years, observing a quasi-linear decrease between them. For VEGF, higher levels were observed in the middle-aged range. Regarding sex-influence, fractalkine tear levels were higher in men, whereas those of IL-7, IL-8, and IP-10 were higher in women. Using the estimated age- and sex-adjusted RIs, more than 92% of the validation sample was correctly classified, and 100% of the severe DED patients in the utility sample had concentrations outside the RIs in at least two of the cytokines evaluated.

High Molecular Weight Hyaluronan Promotes Corneal Nerve Growth in Severe Dry Eyes.

The purpose of this study was to investigate the effect of high molecular weight hyaluronan (HMWHA) eye drops on subbasal corneal nerves in patients suffering from severe dry eye disease (DED) and to evaluate the damage of subbasal corneal nerves associated with severe DED. Designed as an international, multicenter study, 16 patients with symptoms of at least an Ocular Surface Disease Index (OSDI) score of 33, and corneal fluorescein staining (CFS) of at least Oxford grade 3, were included and randomized into two study arms. The control group continued to use their individual optimum artificial tears over the study period of eight weeks; in the verum group, the artificial tears were substituted by eye drops containing 0.15% HMWHA. At the baseline visit, and after eight weeks, the subbasal nerve plexus of 16 patients were assessed by confocal laser scanning microscopy (CSLM). The images were submitted to a masked reading center for evaluation. Results showed a significant increase of total nerve fiber lengths (CNFL) in the HMWHA group (p = 0.030) when compared to the control group, where the total subbasal CNFL did not significantly change from baseline to week 8. We concluded that in severe DED patients, HMWHA from topically applied eye drops could cross the epithelial barrier and reach the subbasal nerve plexus, where it exercised a trophic effect.

SPLA2-IIa participates in ocular surface inflammation in humans with dry eye disease

PurposeTo determine the roles of secretory phospholipase A2-IIa (sPLA2-IIa) in the inflammatory responses of the compromised ocular surface. MethodsConjunctival impression cytology (IC) samples and tears were collected from patients with mild to severe non-Sjogren's dry eye disease (DED) and normal controls. The IC samples were analyzed for transcription of sPLA2-IIa and inflammatory cytokine/chemokine genes using quantitative real-time RT-PCR (qRT2-PCR) and pathway-focus PCR-array. The tear samples were analyzed for 13 inflammatory cytokines and chemokines with Millipore 13-Plex kit. Finally, sPLA2-IIa-treated human conjunctival epithelial cell (HCjE) cultures were analyzed with a pathway-focused PCR array. ResultsTranscription of sPLA2-IIa was significantly increased in severe DED patients as compared to those of mild DED patients and normal controls. The transcription of inflammatory cytokines (IL-1β, IL-4, IL-6, IL-17, TNF-α, IFN-γ), chemokines (IL-8, CXCL10, CXCL11, CXCL-14, CCR6, LTB) and matrix metalloproteinase 9 (MMP9) were simultaneously increased in the same IC samples of DED. Concentrations of IL-6 and IL-8 in tears were significantly higher in DED patients than those of the controls and positively correlated to DED severity scores. On the other hand, IL-2, IL-4, IL-10, IL-12 and IFN-γ were significantly lower in DED patients than those in the controls and inversely correlated to DEWS scores. Single treatment of sPLA2-IIa, IL-1β or TNF-α of HCjE cells induced minimal to no PGE2 production. When sPLA2-IIa was added to HCjE cells that were pre-treated with pro-inflammatory cytokines (TNF-α or IL-1β), significant stimulation of PGE2 production was observed, concurrent with the extensive transcriptional changes of many inflammatory cytokines/chemokines and their receptors. ConclusionsPLA2-IIa activity was elevated and not only associated with inflammatory changes in DED patient samples, but was also found to cooperate with TNF- α and IL-1β to induce inflammatory response in human conjunctival epithelial cells. Understanding the roles of sPLA2-IIa in ocular surface inflammation may lead to better strategies for the treatment of chronic inflammation associated with DED and other ocular inflammatory conditions.

Association of Killer Cell Immunoglobulin-like Receptor Genotypes and Haplotypes in Dry Eye Disease Patients Treated with Restasis and Systane

ABSTRACT Purpose: whether the Killer immunoglobulin-like receptor (KIR) genotypes and haplotypes are associated with the improvement in dry eye disease (DED) patients treated with Restasis and Systane (RS) remain unclear. Methods: Polymerase chain reaction with sequence-specific primers (PCR-SSP) was used to analyze KIR genes in a Chinese Han population of 198 severe DED patients treated with RS. Results: The higher frequencies of KIR genotype M, AF, AJ and haplotype 2 and 8 (P = .001, P = .03, P = .004, P = .000 and P = .023, respectively) and the lower frequencies of genotype AG and haplotype 1 (P = .000 and P = .000, respectively) were observed in complete responders (CR) than those in null or partial responders (NPR) of DED patients treated by RS. Conclusions: The patients with KIR genotype M, AF and AJ might be of advantage to therapy with RS, which are useful for improving novel personalized precise therapy strategy in DED patients.

A Phase IV, Multicenter, Randomized, Single-blinded (Evaluator), Active-controlled, Parallel Study for Evaluating HA 0.15% Compared With Cyclosporine 0.05%, and Efficacy of Combination Therapy in Moderate to Severe Dry Eye Disease Patients

A Phase IV, Multicenter, Randomized, Single-blinded (Evaluator), Active-controlled, Parallel Study for Evaluating HA 0.15% Compared With Cyclosporine 0.05%, and Efficacy of Combination Therapy in Moderate to Severe Dry Eye Disease Patients

PP47 Defining The Needs And Preferences Of Patients With Dry Eye Disease

Introduction:Dry eye disease (DED) is a common condition that significantly impacts patients’ quality of life. Previous studies have explored the impact of DED on patients’ lives qualitatively; however, patients’ preference structures have not been thoroughly explored quantitatively.Methods:A targeted literature review and social media listening project guided design of a discussion guide for in-depth patient interviews (n=12). These, in turn, guided construction of a quantitative questionnaire administered to moderate to severe DED patients, 40 per country in Australia, Germany, United States and United Kingdom (total n=160). Patients’ preference structures were explored through an online survey using a self-explicated conjoint methodology, because of its high respondent-friendliness. Additionally, we administered the EQ5D-5L instrument to determine the health states/utilities of patients. Reaction to a hypothetical novel treatment was further obtained to check for convergent validity with the self-explicated conjoint. Finally, we asked respondents to rate the ease and relevance of the questionnaire to them.Results:Qualitative research uncovered important patient perspectives that were built into the quantitative survey. For example, patients seek medical advice when their symptoms are not improving. Patients’ lives are most affected by sensitivity to light, itchy and tired eyes and an inability to perform computer/screen work; however, of most concern/worrying to them is that their DED will get worse and they go blind. Results from the quantitative preference research will also be shared and its implications for future clinical trials in DED outlined. The results of the patient research and preference study are to be shared with health technology assessment (HTA) bodies and regulators through the early dialogue scientific advice process.Conclusions:A process of using qualitative research to determine what matters to patients and then quantification through respondent-friendly preference research can identify outcomes that are most patient-relevant, to inform future drug development strategies.

Correlation Between the Inflammatory Marker HLA-DR and Signs and Symptoms in Moderate to Severe Dry Eye Disease.

To investigate correlations of the inflammatory HLA-DR marker with clinical signs and symptoms commonly used to assess dry eye disease (DED) severity. Baseline data were collected from three clinical studies conducted on moderate to severe DED patients. Characteristics of DED were analyzed and correlations were performed in 311 patients. Data were analyzed after treatment with 1 mg/mL cyclosporine (CsA) and vehicle. We quantified HLA-DR by flow cytometry in impression cytology specimens. We found HLA-DR significantly increased with diagnosis of Sjögren syndrome (P < 0.0001) and meibomian gland disease (P = 0.0223). The strongest significant correlation was seen with the corneal fluorescein staining (CFS, r = 0.30, P < 0.0001). Significant negative relationships were also found with Schirmer's test (r = -0.20, P = 0.0003) and tear break-up time (TBUT, r = -0.13, P = 0.0226). Correlations were statistically significant with total Ocular Surface Disease Index and visual analog scale scores (r = 0.12, P = 0.0426, and r = 0.14, P= 0.0176, respectively). We found HLA-DR arbitrary units of fluorescence were statistically reduced after CsA treatment compared to vehicle (P = 0.022 and P = 0.021 in two studies). In clinical research on DED, discrepancy is often observed between symptoms and signs. We found HLA-DR correlated significantly with CFS clinical signs and to a lower extent Schirmer's test and weakly with TBUT and symptom reporting questionnaires. HLA-DR was reported to be useful for monitoring anti-inflammatory efficacy treatments in DED, which was confirmed with the reduction of HLA-DR while on CsA treatment. Its expression by conjunctival cells has the potential to serve as a biomarker, bridging signs and symptoms in clinical research in DED, but there is still a need for additional validation studies.

Differences in Central Corneal Thickness between Spectral Domain-Optical Coherence Tomography and Ultrasound Pachymetry in Patients with Dry Eye Disease.

Purpose. To compare central corneal thickness (CCT) values via Spectral Domain-Optical Coherence Tomography (SD-OCT) and ultrasonic pachymetry in patients with severe dry eye disease (DED) to determine the level of agreement between these 2 methods. Methods. The paired samples t-test was used to compare CCT values in severe DED patients. Matching analysis between methods was performed using intraclass correlation coefficient (ICC). Intrasession reliability of the measurement methods was calculated via the concordance correlation coefficient (CCC), variation equivalent, and Pearson's correlation coefficient. The Bland-Altman procedure was used to graphically represent the differences between CCT values. Results. The study included 56 eyes of 24 female and 4 male patients. Mean age of the patients was 50.9 ± 11.3 years. Mean CCT via Cirrus SD-OCT was 523.82 ± 30.98 μm versus 530.050 ± 31.85 μm via ultrasonic pachymetry (paired samples t-test, P < 0.001). The Bland-Altman plot showed good agreement between the examiners. The ICC for repeatability was 0.974. The CCC between the 2 methods' CCT values was 0.973. The variation equivalent was 0.976 and Pearson's correlation coefficient was 99.3%, which also indicated high correlation between the 2 methods' measurements. Conclusions. The present findings show that in patients with severe DED Cirrus SD-OCT provides reliable intraobserver CCT values.

Assessment of corneal epithelial thickness in dry eye patients.

To investigate the features of corneal epithelial thickness topography with Fourier-domain optical coherence tomography (OCT) in dry eye patients. In this cross-sectional study, 100 symptomatic dry eye patients and 35 normal subjects were enrolled. All participants answered the ocular surface disease index questionnaire and were subjected to OCT, corneal fluorescein staining, tear breakup time, Schirmer 1 test without anesthetic (S1t), and meibomian morphology. Several epithelium statistics for each eye, including central, superior, inferior, minimum, maximum, minimum - maximum, and map standard deviation, were averaged. Correlations of epithelial thickness with the symptoms of dry eye were calculated. The mean (±SD) central, superior, and inferior corneal epithelial thickness was 53.57 (±3.31) μm, 52.00 (±3.39) μm, and 53.03 (±3.67) μm in normal eyes and 52.71 (±2.83) μm, 50.58 (±3.44) μm, and 52.53 (±3.36) μm in dry eyes, respectively. The superior corneal epithelium was thinner in dry eye patients compared with normal subjects (p = 0.037), whereas central and inferior epithelium were not statistically different. In the dry eye group, patients with higher severity grades had thinner superior (p = 0.017) and minimum (p < 0.001) epithelial thickness, more wide range (p = 0.032), and greater deviation (p = 0.003). The average central epithelial thickness had no correlation with tear breakup time, S1t, or the severity of meibomian glands, whereas average superior epithelial thickness positively correlated with S1t (r = 0.238, p = 0.017). Fourier-domain OCT demonstrated that the thickness map of the dry eye corneal epithelium was thinner than normal eyes in the superior region. In more severe dry eye disease patients, the superior and minimum epithelium was much thinner, with a greater range of map standard deviation.

Association of Killer Cell Immunoglobulin–Like Receptor and Human Leukocyte Antigen-C Genotype with Dry Eye Disease in a Chinese Han Population

Dry eye is one of the most prevalent eye diseases and dry eye disease (DED) is associated with ocular surface inflammation. The interaction between killer cell immunoglobulin-like receptors (KIRs) and human leukocyte antigens (HLAs) regulates the activation of natural killer (NK) cells and certain T cell subsets in response to inflammation. The objective of this study was to explore whether KIR gene and HLA-C allele polymorphisms were associated with DED in a Chinese Han population. Polymerase chain reaction with sequence-specific primers method was used to genotype KIR genes and HLA-C alleles in 106 DED patients and 220 healthy controls. Framework genes KIR2DL4, KIR3DL2, KIR3DL3, and KIR3DP1 were present in all individuals. There were no significant differences in the frequencies of inhibitory KIR genes between the two groups. However, the frequency of KIR2DS2 was significantly higher in severe DED patients than that in healthy controls (p=0.031, odds ratio [OR]=1.828, 95% confidence interval [CI]=1.05-3.17). Significantly different distributions of HLA-C allele groups were not observed in severe DED patients and controls. The frequency of the combination of HLA-C1 allele group with KIR2DS2 was significantly higher in severe DED patients compared with controls (p=0.013, OR=2.083, 95% CI=1.16-3.74). These data suggested that this genotype combination was associated with susceptibility to severe DED and that NK cells might have a role in the pathogenesis of DED. The results led to an interesting future research question of whether or not KIR and HLA-C genotypes were involved in the predisposition to or pathogenesis of DED.

Phase III Safety Evaluation of Cyclosporine 0.1% Ophthalmic Emulsion Administered Twice Daily to Dry Eye Disease Patients for Up to 3 Years

To evaluate cyclosporine 0.1% ophthalmic emulsion over a 1- to 3-year period in moderate to severe dry eye disease patients. Nonrandomized, multicenter, open-label clinical trial extending 2 ophthalmic cyclosporine phase III clinical trials. Four hundred twelve patients previously dosed for 6 to 12 months with cyclosporine 0.05% or 0.1% in prior phase III trials. Patients instilled ophthalmic cyclosporine 0.1% twice daily into both eyes for up to 3 consecutive 12-month extension periods. Corneal staining, Schirmer tests, and symptom severity assessments were conducted during the first 12-month extension, with a patient survey during the second 12-month extension. Biomicroscopy and visual acuity (VA) examinations, intraocular pressure (IOP) measurements, and adverse effects queries occurred at 6-month intervals. Mean duration of treatment was 19.8 months. Improvements in objective and subjective measures of dry eye disease were modest, probably because of prior treatment with cyclosporine. Most survey respondents said their symptoms began to resolve in the first 3 months of cyclosporine treatment during the previous phase III clinical trials. At study exit, VA decreased in 12.6% (93/738) and increased in 5.4% (40/738) of eyes by > or =2 lines; severity of biomicroscopy findings increased in 3.4% (chemosis; 26/760), 7.2% (conjunctival hyperemia; 55/760), or 8.5% (tear film debris; 64/756) of eyes; and mean IOP increased 0.18 mmHg relative to baseline. The most common treatment-related adverse events were burning (10.9% of patients [45/412]), stinging (3.9% [16/412]), and conjunctival hyperemia (3.4% [14/412]). No serious treatment-related adverse events occurred. Most patients (95.2% [140/147]) said they would continue cyclosporine therapy; 97.9% (143/146) would recommend it to other dry eye patients. Therapy of chronic dry eye disease with cyclosporine 0.1% ophthalmic emulsion for 1 to 3 years was safe, well tolerated, and not associated with systemic side effects. The results supplement the safety record of the commercially available cyclosporine 0.05% ophthalmic emulsion.