Reduced Levels of Tear Lacritin Are Associated With Corneal Neuropathy in Patients With the Ocular Component of Sjögren's Syndrome

Purpose To determine whether levels of endogenous tear protein, lacritin, are linked to altered corneal innervation and dry eye severity in patients with Sjögren's syndrome (SS). Methods Clinical data were obtained from 10 SS and 10 age-matched controls. Enzyme-linked immunosorbent assay was used to assess total tear lacritin extracted from Schirmer strips. Western blot was used to detect active lacritin monomer (∼25 kDa), active lacritin fragment (∼12-15 kDa), and inactive tissue transglutaminase-generated lacritin (≥40 kDa). In vivo confocal microscopy was used to assess nerve fiber density (NFD) and length (NFL). Relationships between nerve morphology and tear lacritin were examined by Spearman correlation. Diagnostic performance of tear lacritin was analyzed using receiver operating characteristic. Results Active tear lacritin was significantly reduced in SS patients (3.72 ± 5.62 [SS] versus 18.17 ± 4.57 ng/100 ng total tear protein [controls]; P < 0.001), while inactive lacritin was increased (84.99% ± 11.15% [SS] versus 51.04% ± 12.03% [controls]; P < 0.001). Nerve fiber density (21.70 ± 18.93 vs. 31.80 ± 9.35; P = 0.03) and NFL (4.18 ± 3.44 vs. 6.54 ± 2.47; P < 0.05) were significantly decreased in SS patients compared to controls. Reduced NFL (r = 0.74, P < 0.01) and NFD (r = 0.70, P < 0.01) were highly correlated with reduced tear lacritin. Similarly, total tear lacritin was highly correlated with Schirmers (r = 0.77, P < 0.01), ocular staining (r = -0.80, P < 0.01), and corneal sensitivity (r = 0.81, P < 0.01). Tear lacritin showed equivalent or better diagnostic performance compared to traditional clinical measures for SS (100.00% sensitivity, 85.71% specificity, cutoff = 14.50 ng/100 ng tear protein). Conclusions Reduced tear lacritin levels in SS patients are highly correlated with clinical signs of dry eye, as well as decreased NFD and NFL. Lacritin and its components provide excellent diagnostic sensitivity and specificity in SS.