Sjögren's syndrome(SS)is a chronic autoimmune disease that affects exocrine glands, especially salivary and lacrimal glands. The main clinical manifestations are dry mouth and dry eyes, but also multi-organ and multi-system can be involved. Cold agglutinin disease(CAD)is an autoimmune disease characterized by red blood cell agglutination in the blood vessels of extremities caused by cold agglutinin at low temperature, resulting in skin microcirculation disturbance, or hemolytic anemia. Cold agglutinin disease is divided into two categories, primary cold agglutinin disease and secondary cold agglutinin disease. Primary cold agglutinin disease is characterized with cold agglutinin titer of 1 ∶4 000 or more and positive Coomb's test. However, the Coomb's test is not necessarily positive and the cold agglutinin titer is between 1 ∶32 and 1 ∶4 000 in secondary cold agglutinin disease. Here, we reported an elderly patient admitted to hospital due to fever. He was diagnosed with respiratory infection, but he showed incompletely response to the anti-infection treatment. Further laboratory tests showed the patient with positive ANA and anti-SSA antibodies. Additionally, the patient complained that he had dry mouth and dry eyes for 1 year. Schirmer test and salivate gland imaging finally confirmed the diagnosis Sjogren's syndrome. During the hospital stay, the blood clots were found in the anticoagulant tubes. Hemolytic anemia was considered as the patient had anemia with elevated reticulocytes and indirect bilirubin. In addition, further examination showed positive cold agglutination test with a titer of 1 ∶1 024, and cold agglutinin disease was an important type of cold-resistant autoimmune hemolytic anemia. Furthermore, the patient developed cyanosis after ice incubating at the tip of the nose. Hence, the patient was diagnosed as CAD and he was successfully treated with glucocorticoids instead of anti-infection treatments. Hence, the patient was diagnosed with SS combined with secondary CAD. SS combined CAD are rarely reported, and they are both autoimmune diseases. The abnormal function of B lymphocytes and the production of autoantibodies might be the common pathogenesis of them. Cold agglutinin disease can lead to severe hemolytic anemia, even life-threatening. In clinical practice, timely recognizing and dealing with CAD might promote the prognosis of the patient.
Male ; Humans ; Aged ; Anemia, Hemolytic, Autoimmune/diagnosis* ; Sjogren's Syndrome/diagnosis* ; Anemia, Hemolytic/complications* ; Dry Eye Syndromes/complications* ; Autoantibodies

Dry eye syndrome is a multifactorial disease of the ocular surface characterized by a loss of homeostasis of the tear film, and accompanied by ocular symptoms. Tear film instability and hyperosmolarity, ocular surface inflammation and damage, and neurosensory abnormalities play etiological roles. Symptom screening with the Five-item Dry Eye Questionnaire or Ocular Surface Disease Index can be used to identify the possibility that a patient might have DED dry eye syndrome and triggers. The results of these screening tools can lead to performing diagnostic tests of (ideally non-invasive) breakup time, osmolarity and ocular surface staining with fluorescein and lissamine green (observing the cornea, conjunctiva and eyelid margin). Meibomian gland dysfunction, lipid thickness/dynamics and assessments of the volume and severity of tear allow the subclassification of dry eye syndrome as predominantly evaporative or aqueous deficient, which informs the management of dry eye syndrome. A staged management algorithm was derived that presents a stepwise approach to implementing the various management and therapeutic options according to disease severity.
Conjunctiva ; Cornea ; Diagnosis ; Diagnostic Tests, Routine ; Dry Eye Syndromes ; Eyelids ; Fluorescein ; Homeostasis ; Humans ; Inflammation ; Mass Screening ; Meibomian Glands ; Osmolar Concentration ; Tears

PURPOSE: To analyze the relationship between ocular surface disease index and tear film lipid layer thickness (LLT) using a LipiView II® (LipiView® Ocular Surface Interferometer, TearScience®, Morrisville, NC, USA) interferometer. METHODS: Forty-nine patients diagnosed with dry eye syndrome were recruited for this prospective study. Patients completed ocular surface disease index questionnaires. We performed slit lamp examination, Schirmer test, corneal and conjunctival fluorescein staining, measured tear film break-up time, and graded meibomian gland dysfunction. Tear LLT, blinking time, and dynamic meibomian imaging were analyzed using a LipiView II® ocular interferometer. To control for missing data, we analyzed four sets of imputated data via the multiple imputation method and performed Pearson correlation analysis. Patients were assigned to one of two LLT categories (LLT < 60 or LLT ≥ 60) and Chi-square test was performed. RESULTS: Among ocular surface disease parameters, tear film break-up time (tBUT) had a statistically significant correlation with average and maximum LLT (average LLT; p = 0.008, 0.035, 0.006, 0.049, maximum LLT; p = 0.006, 0.042, 0.020, 0.049, Pearson correlation analysis with multiple imputation) but there was no significant correlation with minimum LLT (minimum LLT; p = 0.048, 0.090, 0.079, 0.039). Of the patients with a relatively thick average LLT or maximum LLT (LLT ≥ 60 nm), 80% and 88% had a tBUT < 10, respectively. Conversely, 39% and 47% of patients with relatively thin average LLT (LLT < 60 nm) had a tBUT < 10 (average LLT; p = 0.013, maximum LLT; p = 0.039). CONCLUSIONS: Average LLT and maximum LLT were significantly correlated with tBUT. Patients with a relatively thin average or maximum LLT tended to have a shorter tBUT. Based on these results, measuring tear film LLT using a LipiView II® interferometer may be useful in the diagnosis and follow-up of patients with evaporative dry eye.
Blinking ; Diagnosis ; Dry Eye Syndromes ; Fluorescein ; Follow-Up Studies ; Humans ; Interferometry ; Meibomian Glands ; Methods ; Prospective Studies ; Slit Lamp ; Tears*

PURPOSE: To evaluate the diagnostic value of tear film osmolarity for non-Sjogren dry eye syndrome through measuring the correlation between tear osmolarity and several conventional dry eye parameters. METHODS: In this observational cross-sectional study, 274 patients (274 eyes) with non-Sjogren dry eye syndrome were examined using tear film osmolarity and the following conventional dry eye parameters: Schirmer's test, tear film break-up time, ocular surface disease index (OSDI), and corneal staining score. The correlations between tear film osmolarity and each conventional dry eye parameter were assessed using Spearman's correlation coefficients. RESULTS: The mean tear film osmolarity of the study population was 296.34 ± 21.08 mOsm/L. The tear film osmolarity was significantly negatively correlated with the Schirmer's test value (r = -0.431, p < 0.001) and tear break-up time (r = -0.131, p = 0.031), while it was significantly positively correlated with the OSDI scores (r = 0.191, p = 0.001) and corneal staining scores (r = 0.150, p = 0.013). CONCLUSIONS: Tear film instability was significantly correlated with other conventional dry eye parameters. However, additional studies are required to determine its feasibility as a stand-alone diagnostic tool.
Cross-Sectional Studies ; Diagnosis* ; Dry Eye Syndromes ; Humans ; Osmolar Concentration* ; Tears*

PURPOSE: To evaluate the efficacy of strip meniscometry test for dye eye syndrome (DES) by measuring the correlation between strip meniscometry and conventional test measurements. METHODS: All subjects were examined using the Schirmer test, tear breakup time (TBUT) and strip meniscometry using SMTube (Echo Electricity Co., Ltd., Fukushima, Japan). Tear meniscus height (TMH), tear meniscus depth (TMD) and tear meniscus area (TMA) were measured using Fourier-domain optical coherence tomography. The DES group (n = 46 eyes) was compared with the normal group (n = 30 eyes) and correlation was assessed using Spearman's correlation coefficient. RESULTS: Strip meniscometry measurement was significantly correlated with Schirmer score (r = 0.6080, p < 0.01), TBUT (r = 0.5980, p < 0.01), TMH (r = 0.6210, p < 0.01), TMD (r = 0.6080, p < 0.01) and TMA (r = 0.6370, p < 0.01). Strip meniscometry was significantly lower in the DES group (4.58 ± 1.94 mm) than the normal group (7.07 ± 2.61 mm, p < 0.05). CONCLUSIONS: Strip meniscometry was significantly correlated with other conventional test measurements for dry eye syndrome. Strip meniscometry is less time consuming and a less invasive method than the Schirmer test. Strip meniscometry could be an efficient tool to evaluate patients with dry eye syndrome in a clinical setting.
Diagnosis* ; Dry Eye Syndromes* ; Electricity ; Humans ; Methods ; Tears ; Tomography, Optical Coherence

PURPOSE: To investigate the properties of angiogenin (ANG) as a potential tool for the diagnosis and grading of dry eye syndrome (DES) by analyzing tear protein profiles. METHODS: Tear samples were collected with capillary tubes from 52 DES patients and 29 normal individuals as controls. Tear protein profiles were analyzed with an immunodot blot assay as a screening test. To confirm that the tear ANG levels were in inverse proportion to the disease severity grade, the ANG and lactoferrin (LF) tear contents of normal controls and DES patients were compared in an enzyme-linked immunosorbent assay. RESULTS: In the immunodot blot assay, the ANG area was lower in patients with grades 3 and 4 DES than in normal controls. The areas of basic fibroblast growth factor, transforming growth factor β2, and interleukin 10 were significantly greater than those of normal controls only in grade 4 DES patients, but these proteins were not linearly correlated with dry eye severity. Upon enzyme-linked immunosorbent assay analysis, the mean concentrations of ANG and LF decreased significantly as dry eye severity increased, except between grades 1 and 2. In addition, the ratios of ANG and LF to total tear proteins were correlated significantly with DES severity. CONCLUSIONS: ANG level was significantly lower in DES patients than in normal controls, and was significantly correlated with the worsening severity of DES, except between grades 1 and 2, as was LF. Therefore, ANG may be a useful measure of DES severity through proteomic analysis.
Adult ; Aged ; Angiogenesis Inducing Agents/pharmacology ; Dry Eye Syndromes/*diagnosis/metabolism ; Enzyme-Linked Immunosorbent Assay ; Female ; Follow-Up Studies ; Humans ; Immunoblotting ; Male ; Middle Aged ; Proteomics/methods ; Ribonuclease, Pancreatic/*pharmacology ; Severity of Illness Index ; Tears/chemistry ; Young Adult

The effect of hydroxychloroquine (HCQ) on dry eye has not been fully determined. This study aimed to compare the 12-week efficacy of HCQ medication with that of a placebo in the management of dry eye in primary Sjögren's syndrome (pSS). A double-blind, randomized control study was conducted in 39 pSS subjects from May 2011 through August 2013. pSS was diagnosed based on the classification criteria of the American-European Consensus Group. Subjects received 300 mg of HCQ or placebo once daily for 12 weeks and were evaluated at baseline, 6, and 12 weeks, with a re-visit at 16 weeks after drug discontinuance. The fluorescein staining score, Schirmer test score, tear film break-up time (TBUT), and ocular surface disease index (OSDI) were measured, and tears and blood were collected for ESR, IL-6, IL-17, B-cell activating factor (BAFF), and Th17 cell analysis. Color testing was performed and the fundus was examined to monitor HCQ complications. Twenty-six subjects completed the follow-up. The fluorescein staining score and Schirmer test score did not differ significantly. The OSDI improved with medication in the HCQ group but was not significantly different between the groups. TBUT, serum IL-6, ESR, serum and tear BAFF, and the proportion of Th17 cells did not change in either group. HCQ at 300 mg daily for 12 weeks has no apparent clinical benefit for dry eye and systemic inflammation in pSS (ClinicalTrials.gov. NCT01601028).
Aged ; B-Cell Activating Factor/analysis/blood ; Blood Sedimentation ; Double-Blind Method ; Drug Administration Schedule ; Dry Eye Syndromes/complications/*drug therapy ; Enzyme-Linked Immunosorbent Assay ; Female ; Humans ; Hydroxychloroquine/*therapeutic use ; Interleukin-16/analysis/blood ; Interleukin-17/analysis/blood ; Male ; Middle Aged ; Placebo Effect ; Prospective Studies ; Sjogren's Syndrome/*complications/diagnosis ; Th17 Cells/cytology/immunology ; Treatment Outcome

Dry eye syndrome (DES) is recognized as a public health concern. One of the pathophysiologies in the development of DES is inflammation, and metabolic syndrome (MetS), which is highly prevalent in the general population, is a well-known chronic and systemic inflammatory condition. Despite the increasing interest regarding a relationship between DES and MetS, information is lacking on the association between DES and MetS and its individual components. We investigated the association between DES symptoms and MetS and its components among adults aged ≥ 19 years using population-based data from the Korea National Health and Nutrition Examination Survey V. A sample group of 15,294 adults (42.67% men and 57.33% women) completed household interviews in which they provided blood (for high-density lipoprotein cholesterol, triglyceride, and glucose) and anthropometric measurements (including waist circumference, weight, and height) to define MetS. We also collected information regarding sociodemographic and behavioral risk factors. The survey results showed that 11.50% of men and 22.35% of women experienced DES and 5.30% of patients had both DES and diagnosis of MetS, including 204 men and 606 women. Thus, no significant difference was observed between DES and the diagnosis of MetS according to sex (P = 0.4008 in men; P = 0.0804 in women); however, a significant association was observed between DES and hypertriglyceridemia in women (OR, 1.13; 95% CI, 1.01-1.29). Therefore, hypertriglyceridemia might be an important factor in the association between DES and MetS. Further longitudinal research is needed to evaluate this relationship.
Adult ; Aged ; Blood Glucose/analysis ; Body Height ; Body Weight ; Cholesterol, HDL/blood ; Cross-Sectional Studies ; Dry Eye Syndromes/complications/*diagnosis/epidemiology ; Female ; Humans ; Hypertriglyceridemia/complications/diagnosis ; Interviews as Topic ; Male ; Metabolic Syndrome X/complications/*diagnosis/epidemiology ; Middle Aged ; Nutrition Surveys ; Prevalence ; Republic of Korea/epidemiology ; Risk Factors ; Sex Factors ; Triglycerides/blood ; Waist Circumference ; Young Adult

PURPOSE: To evaluate the repeatability of non-invasive tear film break-up time and identify its relationships with dry eye parameters. METHODS: A total of 100 participants (50 with dry eye, and 50 in the control group) were enrolled prospectively. Non-invasive keratograph first (NIKf-BUT) and average (NIKav-BUT) break-up times were evaluated 2 times using Keratograph 4 (Oculus, Wetzler, Germany), and then tear film break-up time with fluorescein (FBUT) was measured. The correlation analyses were performed between non-invasive parameters (NIKf-BUT and NIKav-BUT) and FBUT. Intra-observer agreements of NIKf-BUT and NIKav-BUT were assessed using intraclass correlation coefficients (ICC). The receiver operating characteristic (ROC) curve technique was used to evaluate the non-invasive method in the diagnosis of dry eye. RESULTS: The correlation analyses revealed positive correlation between NIKav-BUT and FBUT in both groups (dry eye; r = 0.66, p < 0.001 and control group; r = 0.77, p < 0.001). The ICCs of NIKf-BUT and NIKav-BUT were 0.72 and 0.94 in the dry eye, respectively, and 0.70 and 0.91 in the control group. NIKav-BUT was not different from FBUT in either group. The areas under the ROC curves of NIKf-BUT and NIKav-BUT were 0.917 and 0.980, respectively. CONCLUSIONS: The high ICCs verified the repeatability of NIKf-BUT and NIKav-BUT. NIKav-BUT showed no difference from FBUT and positive correlation with FBUT. NIK-BUT showed high diagnostic power and can be considered a new parameter to evaluate dry eye syndrome.
Diagnosis ; Dry Eye Syndromes ; Fluorescein ; Methods ; Prospective Studies ; ROC Curve ; Tears*

BACKGROUNDDry eye patients suffer from all kinds of symptoms. Sometimes, the clinical signs evaluation does not disclose any obvious difference in routine examination; in vivo confocal microscopy (IVCM) is a powerful tool for ocular surface disease. This study aimed to clarify meibomian gland (MG) alterations in dry eye patients with different symptoms and to compare the findings using IVCM.

METHODSA total of sixty patients were recruited, all subjected to Ocular Surface Disease Index (OSDI) and Salisbury Eye Evaluation Questionnaire (SEEQ), and questionnaires for the assessment of dry eye symptoms before clinical sign examinations were given to the patients. Finally, IVCM was applied to observe MG's structure. Statistical analysis was performed using the t-test, Mann-Whitney U-test and Spearman correlation analysis. The differences were statistically significant when P< 0.05.

RESULTSIn the severe symptom group, OSDI and SEEQ scores were significantly higher (P< 0.05) compared with the mild symptoms group. All other clinical sign examinations had no statistical difference in the two groups (P> 0.05). However, all the IVCM-observed data showed that patients with severe symptoms had more significant fibrosis in MG (acinar unit area 691.87 ± 182.01 μm2 for the severe, 992.17 ± 170.84 μm2 for the mild; P< 0.05) and severer decrease in the size of MG acinar units than those observed in patients with mild symptoms (MG acinar unit density [MGAUD] 70.08 ± 18.78 glands/mm2, MG acinar unit longest diameter [MGALD] 51.50 ± 15.51 μm, MG acinar unit shortest diameter [MGASD] 20.30 ± 11.85 μm for the severe, MGAUD 89.53 ± 39.88 glands/mm2, MGALD 81.57 ± 21.14 μm, MGASD 42.37 ± 14.55 μm for the mild;P< 0.05). Dry eye symptoms were negatively correlated with MG confocal microscopic parameters and positively correlated with conjunctival inflammatory cells and Langerhans cells (P< 0.05).

CONCLUSIONSIVCM application provides a strong support to differentiate dry eye patients with different symptoms: meibomian gland dysfunction (MGD) plays a pivotal role in dry eye aggravation, and using IVCM to observe MG fibrosis, changes in size and density of MG as well as status of inflammation cells can help not only correctly diagnose the type and severity of dry eye, but also possibly prognosticate in routine eye examination in the occurrence of MGD.

Adult ; Aged ; Dry Eye Syndromes ; diagnosis ; physiopathology ; Eyelid Diseases ; diagnosis ; physiopathology ; Female ; Humans ; Male ; Meibomian Glands ; pathology ; physiopathology ; Microscopy, Confocal ; methods ; Middle Aged