Tear Metabolomes Differentiate Primary Sjögren Syndrome From Other Dry Eye Diseases

Cornea showing dry eye.
The study also identified 9 key metabolites that may be useful in the development of Sjögren syndrome therapeutics.

Tears contain a metabolomic signature that distinguishes primary Sjögren syndrome (pSS) from other dry eye disease etiologies, according to research published in The Ocular Surface. Researchers also identified 9 key metabolites that may be of use for early diagnosis and the development of pSS therapeutics. 

To both identify the metabolomic signature of tears in patients newly diagnosed with pSS vs patients with nonimmune dry eye disease and to evaluate the variations in this metabolic signature by age, sex, immunological status and dry eye severity, researchers conducted the prospective cohort METABOGREN study at a single center between 2017 and 2018. 

Included patients had objective eye dryness defined through a Schirmer I test ≤5 mm/5 min in 1 eye or an OSS ≥3 or tear break-up time (TBUT) test <10 seconds, or a combination, in at least 1 eye. Objective mouth dryness was also defined as a nonstimulated saliva flow ≤1.5 mL/15 min. Patients were prospectively evaluated for pSS criteria and other causes of dry eye syndrome. Participants were included in the study until 2 groups were formed: 40 cases and 40 patients with non-pSS sicca. 

Median age for the study cohort was 60.5 years (range, 46.8-67 years). Patients with pSS differed from those without pSS only in ocular objective assessment of dryness; these patients had more altered Schirmer I tests, tear breakup time, and OSS, as well as more frequent meibomian gland dysfunction (MGD). In the non-PSS group, the use of anticholinergic drugs, tobacco use, post-menopausal status, and MGD were the most common risk factors for dry eye syndrome. 

A total of 188 metabolites were measured, 84 of which were excluded. An unsupervised analysis did not show spontaneous clustering on the principal component analysis. Logistic regression with elastic-net regularization was used to isolate the 19 models with the best AUC (0.84) and a further 5 consistent models with the same 9 metabolites of interest: serine; aspartate; dopamine; lysophosphyatidylcholines (LysoPC) C16:1, C18:1, and C18:2; sphingomyelin (SM) C16:0 and C22:3; and phosphatidylcholine diacyl (PCaa) C42:4. 

In patients with pSS, the ratio of the sum of LysoPC to the sum of PC—an indicator of enzyme phospholipase A2 activity—was increased vs the non-pSS group (77.3 vs 55.3). The ratio of the sum of SM to the sum of the PC, which represented sphingomyelinase activity, was also increased in tears from the pSS group (174.8 vs 24.4). 

Dimensional reduction of the metabolomic signature showed that 2 of the first principal components could explain 74.5% of total variance; 8 of 9 metabolites were primarily distributed in 1 of those components: 6 lipids in PC1 and the amino acids in PC2. 

When controlling for age, sex, anticholinergic drug use, or the presence of anti-SSA antibodies, the association between metabolomic signature and pSS status was not changed. Tobacco use was significantly associated with the lipid component, but not with PC2. After adjusting for dryness severity measurements (Schirmer I test and OSS), the link between PC1 and pSS status disappeared. 

Study limitations include the targeted approach, which limits how wide a part of the tear metabolome was covered, as well as the lack of a healthy control group and the exclusion of patients in the earliest stages of pSS. 

“The metabolomic signature identified here could be helpful as an early biomarker of pSS,” according to researchers. “This signature has high diagnostic performance with a simple method to collect the tears that can be easily reproduced in clinics. It would be interesting to test whether one or more of the 9 metabolites identified here could be validated as a clinical relevant tear biomarker of pSS in a larger multicentric study.” 


Urbanski G, Assad S, Chabrun F, et al. Tear metabolomics highlights new potential biomarkers for differentiating between Sjögren’s syndrome and other causes of dry eye. Ocul Surf. 2021;22:110-116. doi:10.1016/j.jtos.2021.07.006