Downloaded from http://journals.lww.com/corneajrnl by BhDMf5ePHKav1zEoum1tQfN4a+kJLhEZgbsIHo4XMi0hCywCX1AWnYQp/IlQrHD3i3D0OdRyi7TvSFl4Cf3VC4/OAVpDDa8K2+Ya6H515kE= on 03/19/2021 CLINICAL SCIENCE Differential Diagnosis of Sjo ¨gren Versus Non-Sjo ¨gren Dry Eye Through Tear Film Biomarkers Esen K. Akpek, MD,* Henry Y. Wu, PhD,† Sezen Karakus, MD,* Qin Zhang, MD,† and Sharmila Masli, PhD‡ Purpose: Systemic implications necessitate the identification of dry eye patients with Sjögren syndrome (SS). This study aims to explore the utility of tear MUC5AC and inflammatory cytokine levels in the differential diagnosis of SS-related dry eye. Methods: A prospective, observational, case-control study was conducted on 62 patients (those with a definitive diagnosis of SS dry eye, non-SS dry eye, and age-matched healthy controls with no dry eye). Clinical evaluations included the following tests in the order listed here: noninvasive tear break-up time, osmolarity, tear sampling, Schirmer test without anesthesia, and ocular surface staining (lissamine green for conjunctiva and fluorescein for cornea). Tear MUC5AC levels were assessed with enzyme-linked immunosorbent assay, and cytokines [interferon-gamma, tumor necrosis factor alpha, interleukin (IL)-6, IL-17a, IL-1b, IL-8, IL- 10, and IL-12p70] were measured using a Luminex assay in a masked fashion. Results: The Bulbar conjunctival lissamine green staining score was significantly greater in patients or controls with SS versus non- SS dry eye. This greater conjunctival staining was associated with a reduction in tear MUC5AC (B = 217.8 ng/mL, 95% confidence interval = 231.8 to 23.9, P = 0.01). Among the tear cytokines, a significant association was found between IL-8 levels (hazard ratio [HR] = 1.002, 95% confidence interval = 1.000–1.003, P = 0.03) and SS diagnosis. When patients were stratified based on tear MUC5AC levels, significantly increased tear IL-8 levels were detected in patients with SS dry eye but not with non-SS dry eye, in comparison with healthy controls. Conclusions: Tear levels of goblet cell-specific MUC5AC com- bined with IL-8 can potentially serve as a useful biomarker for differential diagnosis of SS dry eye from non-SS dry eye. Key Words: tear analysis, MUC5AC, Sjögren syndrome, dry eye (Cornea 2020;39:991–997) D ry eye is a prevalent ocular disorder worldwide. 1 Whether locally or systemically initiated, inflammation plays a key role in the pathogenesis of dry eye. 2 Approxi- mately half of the patients with clinically significant dry eye have an underlying systemic inflammatory or autoimmune disease. 3 One serious disease that causes significant dry eye is Sjögren syndrome (SS). SS is an autoimmune disorder characterized by immune-mediated destruction of the salivary and lacrimal glands, with subsequent development of sicca symptoms. It is one of the most common autoimmune diseases in adults, affecting an estimated 4% of the general population. 4–6 Approximately 10% of patients with clinically significant dry eye have underlying SS. 7–9 Currently, the diagnosis of SS among dry eye patients is delayed by about a decade, largely because of the lack of awareness in addition to diversity of patient symptoms and signs, adding to the complexity of diagnosis. 10 Importantly, patients with SS are at risk for many ocular and systemic complications, including the central nervous system and visceral organ involvement as well as lymphoma. 11 In fact, SS is the autoimmune disease most frequently associated with lymphoma. 11 Therefore, identifying the subset of dry eye patients with SS dry eye is relevant. Diagnosis of SS remains challenging mainly because of the lack of definitive diagnostic tests. The presence of aqueous-deficient dry eye is an integral part of the diagnostic criteria for SS. Arguably, the hallmark of SS-related dry eye is conjunctival vital dye staining 12,13 related to the loss or alteration of the ocular surface mucins. 14,15 Conjunctival goblet cells are responsible for the secretion of large gel- forming mucin MUC5AC, which plays an important role in maintenance of the tear film on the ocular surface. 16,17 Reduction of MUC5AC levels in the tears of patients with SS has been demonstrated in a single previous study, 18 albeit without any clinical information on patients or any correla- tions between ocular surface and tear film parameters and the mucin levels. Importantly, there was no non-SS dry eye group, and whether this reduction in MUC5AC is related to the severity of dry eye or specifically to the presence of Received for publication November 18, 2019; revision received January 15, 2020; accepted January 16, 2020. Published online ahead of print April 5, 2020. From the *Ocular Surface Diseases and Dry Eye Clinic, The Wilmer Eye Institute, The Johns Hopkins University School of Medicine, Baltimore, MD; †Novartis Institute of Biomedical Research, Cambridge, MA; and ‡Department of Ophthalmology, Boston University School of Medicine, Boston, MA. S. Masli was supported by Massachusetts Lions Eye Research Fund (MLERF). E. K. Akpek was supported in part by an investigator- initiated research grant from Allergan, Inc., and a grant provided by Jerome L. Greene Sjögren’s Center, Johns Hopkins University (Baltimore, MD). The authors have no conflicts of interest to disclose. E. K. Akpek and S. Masli contributed equally to this study. Correspondence: Sharmila Masli, PhD, Department of Ophthalmology, Boston University School of Medicine, L914, 72 E. Concord St, Boston, MA 02118 (e-mail: smasli@bu.edu). Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved. Cornea  Volume 39, Number 8, August 2020 www.corneajrnl.com | 991 Copyright © 2020 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.