Dry eye-related tear biomarkers MMP-2, MMP-13, and IFN-γ: potential predictors of Type III acute acquired concomitant esotropia

Abstract

Background: Acute acquired concomitant esotropia (AACE) causes diplopia and asthenopia, severely affecting quality of life. This study aimed to explore the association between dry eye (DE) tear film biomarkers and Type III AACE.

Methods: We enrolled 52 patients (52 eyes) with Type III AACE and 50 controls (50 eyes). Assessments included tear meniscus height (TMH), tear film non-invasive break-up time (NIBUT), corneal fluorescein staining (CFS), Schirmer's test (ST), and the Dry Eye-Related Quality of Life Score (DEQS). Tear samples were analyzed for cytokine levels using a multiplex immunoassay. Logistic regression analyses identified risk factors, and a random forest classifier evaluated predictive performance.

Results: Patients with Type III AACE without DE showed significantly reduced NIBUT and elevated levels of cytokines (e.g., MMP-2, MMP-13, and IFN-γ) compared to normal controls (all P < 0.05). Near-distance work duration showed a moderate positive correlation with Galectin-3 (r = 0.64, P < 0.05). MMP-2, MMP-13, and IFN-γ were identified as independent risk factors (arear under the curve (AUC): 0.91, 0.91, 0.94). The random forest model achieved an AUC of 1.00.

Conclusion: Elevated tear levels of MMP-2, MMP-13, and IFN-γ were strongly associated with Type III AACE, highlighting their potential as predictive biomarkers.

Keywords: Acute acquired concomitant esotropia; Dry eye; Random forest models; Risk factors; Tear film biomarkers.

Fig. 1

Flowchart of our study. AACE acute acquired concomitant esotropia, DE dry eye, BCVA best-corrected visual acuity, LogMAR logarithm of the minimum angle of resolution, SE spherical equivalents, NDA near deviation angle, DDA distant deviation angle, DNW duration of near-distance work, TMH tear meniscus height, NIBUT non-invasive break-up time, CFS corneal fluorescein staining, ST Schirmer’s test, DEQS Dry Eye-Related Quality of Life Score

Fig. 2

Correlation of tear cytokines and clinical parameters in patients with Type III AACE. A cluster heatmap was used to visualize the correlations among a large set of variables using color gradients, where red indicates positive correlations and blue indicates negative correlations. The absolute value 0.8–1.0 is a high correlation, 0.5–0.8 is a medium correlation, 0.3–0.5 is a weak correlation, and 0–0.3 is no correlation. The heatmap revealed two prominent clusters of cytokines with moderate correlations. The larger cluster included IFN-γ, MMP-13, and MMP-2, whereas the smaller cluster comprised CX3CL1, IL-4, and IL-17/IL-17A. AACE acute acquired concomitant esotropia, BCVA best-corrected visual acuity, LogMAR logarithm of the minimum angle of resolution, SE spherical equivalents, NDA near deviation angle, DDA distant deviation angle, DNW duration of near-distance work, TMH tear meniscus height, NIBUT non-invasive break-up time, CFS corneal fluorescein staining, ST Schirmer’s test, DEQS Dry Eye-Related Quality of Life Score. *Spearman correlation analysis

Fig. 3

Evaluation of the predictive algorithm of the Random Forest model. a Confusion Matrix. b Classification Report Heatmap. c Receiver operating characteristic (ROC) Curve for dataset

Fig. 4

Importance of features for Type III AACE prediction. AACE acute acquired concomitant esotropia, BCVA best-corrected visual acuity, SE spherical equivalents, DDA distant deviation angle, DNW duration of near-distance work, NIBUT non-invasive break-up time, CFS corneal fluorescein staining, ST Schirmer’s test, TMH tear meniscus height, DEQS Dry Eye-Related Quality of Life Score

Fig. 5

Cross-validation scores (five-fold) for top features of tear cytokines. The mean cross-validation scores for top 3 features (MMP-13, MMP-2, IFN-γ), top 4 features (MMP-13, MMP-2, IFN-γ, and MMP-1) and top 5 features (MMP-13, MMP-2, IFN-γ, MMP-1, and Galectin-9) were 0.96, 0.96, and 0.95, respectively. No significant differences were found among the groups (all P > 0.05)

Fig. 6

ROC curve for top 3 features of tear cytokines. Cutoff values based on Youden's Index: MMP-13: 2.56 (363.08 pg/mL), MMP-2: 3.36 (2290.87 pg/mL), IFN-γ: 1.32 (20.89 pg/mL)