Defining Discordance between Signs and Symptoms in Dry Eye Disease: Insights from the DRy Eye Assessment and Management (DREAM) Study.

OBJECTIVE To evaluate symptom-sign discordance in dry eye disease (DED) using three distinct analytical frameworks in a large prospective cohort and to identify associated systemic risk factors.

DESIGN Secondary analysis of a multicenter randomized clinical trial.

PARTICIPANTS A total of 535 participants enrolled in the Dry Eye Assessment and Management (DREAM) study with moderate to severe DED.

METHODS Discordance was assessed at baseline using three approaches: (1) a rank-based comparison of symptom-sign severity; (2) a discomfort-based classification using Brief Ocular Discomfort Inventory (BODI) questionnaire; and (3) a novel temporal method evaluating symptom-sign changes between months 3 and 12. Patients were categorized as concordant, symptom-dominant, or sign-dominant discordant using each method. Multivariable regression models were used to identify predictors of discordance.

MAIN OUTCOME MEASURES Prevalence and characteristics of symptom-sign discordance across methods; strength of associations between symptoms, discomfort, and clinical signs; and clinical and systemic predictors of discordance.

RESULTS Using the rank-based method, 77% of patients were discordant. Symptom-dominant discordance (37.8%) was associated with younger age and greater ocular discomfort, while sign-dominant discordance (39.3%) was more common in patients with Sjögren's syndrome and was associated with greater relief from treatment. Discomfort-based analysis showed strong correlations between ocular discomfort and subjective symptoms (ρ=0.47, p<0.001), but weak associations with clinical signs. Temporal analysis revealed 46% of patients had discordant symptom-sign trajectories over 9 months, while 54% demonstrated concordance. Concordance was highest for TBUT (47.5%) and lowest for Schirmer's test (32.7%). Antidepressant use was associated with concordance, while female sex and higher bodily pain scores were associated with symptom-dominant discordance.

CONCLUSIONS Symptom-sign discordance in DED is common, multifactorial, and persists over time. This is the first study to apply and compare three discordance classification methods in a single cohort. Each offers distinct clinical utility, allowing clinicians to better stratify DED patients and enabling more targeted treatment and referral strategies, thus improving outcomes.