title: Clinical utility of objective tests for dry eye disease:  variability over time and implications for clinical trials and disease management.
abstract: OBJECTIVE
  To evaluate the efficacy of commonly used biomarkers in dry eye disease management in a longitudinal observational case series study followed by an interventional study in a subset of subjects treated with cyclosporine A (0.05%).
  
  
  METHODS
  Bilateral tear osmolarity, Schirmer, tear film breakup time (TBUT), staining, meibomian grading, and Ocular Surface Disease Index were measured for a period of 3 consecutive months in participants recruited from a clinic-based population at 2 study sites. Fifty-two subjects completed the study (n = 16 mild/moderate, n = 36 severe; age, 47.1 ± 16.1 years). After the 3-month observation period, severe dry eye patients were prescribed topical cyclosporine A and evaluated for an additional 3 months.
  
  
  RESULTS
  Tear osmolarity (8.7 ± 6.3%) exhibited significantly less variability over a 3-month period than corneal staining (12.2 ± 8.8%, P = 0.040), conjunctival staining (14.8 ± 8.9%, P = 0.002), and meibomian grading (14.3 ± 8.8%, P < 0.0001) across the entire patient population. Osmolarity also demonstrated less variation than TBUT (11.7 ± 9.0%, P = 0.059), Schirmer tests (10.7 ± 9.2%, P = 0.67), and Ocular Surface Disease Index (9.3 ± 7.8%, P = 0.94), although the differences were not significant. Variation in osmolarity was less for mild dry eye patients (5.9 ± 3.1%) than severe dry eye patients (10.0 ± 6.9%, P = 0.038). After treatment, average osmolarity and variability were lowered from 341 ± 18 mOsm/L to 307 ± 8 mOsm/L (P < 0.0001, n = 10). A downward trend in symptoms followed changes in osmolarity, declining from 44 ± 17 mOsm/L to 38 ± 18 mOsm/L (P = 0.35). None of the other signs demonstrated a change after treatment.
  
  
  CONCLUSIONS
  Over a 3-month period, tear film osmolarity was found to have the lowest variability among commonly used signs of dry eye disease. Reductions in osmolarity preceded changes in symptoms during therapy.
authors.affiliation: TearLab Corporation, San Diego, CA, USA. bdsulliv@mac.com
authors.forename: Benjamin D
authors.initials: BD
authors.lastname: Sullivan
authors.forename: Leslie A
authors.initials: LA
authors.lastname: Crews
authors.forename: Barış
authors.initials: B
authors.lastname: Sönmez
authors.forename: Maria F
authors.initials: MF
authors.lastname: de la Paz
authors.forename: Ebru
authors.initials: E
authors.lastname: Comert
authors.forename: Victor
authors.initials: V
authors.lastname: Charoenrook
authors.forename: Aline L
authors.initials: AL
authors.lastname: de Araujo
authors.forename: Jay S
authors.initials: JS
authors.lastname: Pepose
authors.forename: Michael S
authors.initials: MS
authors.lastname: Berg
authors.forename: Valerie P
authors.initials: VP
authors.lastname: Kosheleff
authors.forename: Michael A
authors.initials: MA
authors.lastname: Lemp
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D015415:Biomarkers; D002986:Clinical Trials as Topic; D016572:Cyclosporine / Q000627:therapeutic use*; D003941:Diagnostic Techniques, Ophthalmological; D015352:Dry Eye Syndromes / Q000175:diagnosis* / Q000188:drug therapy*; D005260:Female; D006801:Humans; D007166:Immunosuppressive Agents / Q000627:therapeutic use*; D008297:Male; D008875:Middle Aged; D009994:Osmolar Concentration; D011446:Prospective Studies; D013666:Tears / Q000737:chemistry*; D013997:Time Factors; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D015415:Biomarkers; D007166:Immunosuppressive Agents; D016572:Cyclosporine