The study protocol was approved by the National Eye Institute Internal Review Board. All patients completed an informed consent prior to examination. Consecutive patients with diagnosed primary Sjögren's syndrome were recruited from the NIH Clinical Center, Bethesda, MD. The diagnosis of primary Sjögren's syndrome was based on European-American criteria, which requires at least four of the following six features: signs and symptoms of dry eye and of dry mouth, histopathologic evidence of inflammation on minor salivary gland biopsy, and positive anti-Ro or anti-La antibodies.
Before the clinical examination, a trained interviewer administered two questionnaires (described further below) to measure VT-HRQ to each patient. The subsequent clinical examination included a comprehensive anterior segment evaluation, including slit lamp biomicroscopy, evaluation of lid margin thickness and hyperemia, conjunctival erythema, chemosis, tear film debris and mucus, and extent of meibomian gland plugging. Tests of tear function and ocular surface status were performed as described below.
The OSDI  (provided by Allergan, Inc. Irvine, CA) was used to quantify the specific impact of dry eye on VT-HRQ. This disease-specific questionnaire includes three subscales: ocular discomfort (OSDI-symptoms), which includes symptoms such as gritty or painful eyes; functioning (OSDI-function), which measures limitation in performance of common activities such as reading and working on a computer; and environmental triggers (OSDI-triggers), which measures the impact of environmental triggers, such as wind or drafts, on dry eye symptoms. The questions are asked with reference to a one-week recall period. Possible responses refer to the frequency of the disturbance: none of the time, some of the time, half of the time, most of the time, or all of the time. Responses to the OSDI were scored using the methods described by the authors . Subscale scores were computed for OSDI-symptoms, OSDI-function, and OSDI-triggers, as well as an overall averaged score. OSDI subscale scores can range from 0 to 100, with higher scores indicating more problems or symptoms. However, we subtracted the OSDI overall and subscale scores from 100, so that lower scores would indicate more problems or symptoms.
The 25-item NEI Visual Function Questionnaire (NEI-VFQ) [41, 42] is a non-disease-specific (i.e., "generic") instrument designed to measure the impact of ocular disorders on VT-HRQ. Depending on the item, responses to the NEI-VFQ pertain to either frequency or severity of a symptom or functioning problem. A recall period is not specified in the questionnaire. Responses to the NEI-VFQ were scored using the methods described by the authors . Subscale scores for general vision, ocular pain, near vision, distance vision, social functioning, mental functioning, role functioning, dependency, driving, color vision, and peripheral vision, as well as an overall score, were computed. The NEI-VFQ scores can range from 0–100, with lower scores indicating more problems or symptoms.
Schirmer tests of tear production without and with anesthesia were performed by inserting a Schirmer tear test sterile strip (35 mm, Alcon Laboratories, Inc, Fort Worth, TX) into the inferior fornix, at the junction of the middle and lateral third of the lower eyelid margin, for 5 minutes with the eyes closed. The extent of wetting was measured by referring to the ruler provided by the manufacturer on the envelope containing the strips. Possible scores range from 0 to 35 mm, with lower scores indicating greater abnormality in tear production. This test was repeated after instillation of topical anesthetic, 0.5% proparacaine . A Schirmer without anesthesia score of ≤ 5 mm in at least one eye is one required element of dry eye, as defined by the European-American Sjögren's syndrome diagnostic criteria .
The assessment of ocular surface damage was performed by a cornea specialist using vital dye staining with 2% unpreserved sodium fluorescein and then 5% lissamine green dye. The corneal, temporal, and nasal regions of the conjunctiva were scored individually from 0–5 (for fluorescein) and 0–5 (for lissamine green) using the Oxford grading scheme . The Oxford score was derived by adding the scores for corneal fluorescein and nasal plus temporal conjunctival lissamine green staining. Total Oxford score could range from 0–15. The van Bijsterveld score  (VB) was assessed using lissamine green staining of the cornea (0–3) and conjunctiva (0–3). Total VB score could range from 0–9. For all staining tests, higher scores indicate worse ocular surface damage.
Tear film stability was assessed using fluorescein tear film breakup time (TBUT). Five microliters of 2% sodium fluorescein was instilled into the inferior fornix and the patient was asked to blink several times. Using the cobalt blue filter and slit lamp biomicroscopy, the duration of time required for the first area of tear film breakup after a complete blink was determined. If the TBUT was less than 10 seconds, the test was repeated for a total of 3 values and the average was calculated.
For analysis, for each individual, the maximum (worse) score for the two eyes was used for Oxford score and VB, and the minimum (worse) score for the two eyes was used for Schirmer with and without anesthesia and for TBUT. TBUT values greater than or equal to 10 seconds  were coded as 10 (normal) and < 10 seconds was defined as abnormal. Schirmer without anesthesia score result of ≤ 5 mm or VB ≥ 4 were used as objective evidence of dry eye, following the European / American criteria for the diagnosis of dry eye for Sjogren's syndrome .
Hypotheses of specific associations were formulated based on the areas and domains assessed by the two VT-HRQ instruments. Scatterplots and Spearman's correlation coefficient (ρ)  were used to examine associations between pairs of variables. Multiple linear regression  was used to assess the strength of association between pairs of variables while adjusting for confounders (e.g., age).