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Symptom-based stratification of heterogeneous symptoms of dry eye disease in patients with Sjögren’s syndrome

Eye volume 39, pages 2415–2422 (2025)Cite this article

Subjects

Abstract

Objective

We aimed to use symptom-based stratification to identify the subtype-specific pathophysiology of dry eye disease (DED) in Sjögren’s syndrome (SS).

Methods

We retrospectively enrolled patients with SS who visited Juntendo University Hospital between October 2017 and July 2023 and were diagnosed with DED (2016 Asia Dry Eye Society guideline). The DED subtype and pathophysiology were classified under five distinct tear film breakup patterns: area, line, spot, dimple, and random breaks. Based on responses to the Japanese version of the Ocular Surface Disease Index (J-OSDI), spectral clustering was used to stratify participants; inter-cluster comparison of J-OSDI total scores and key DED-related objective findings was undertaken.

Results

Among the 239 participants, DED prevalence was the highest in Cluster 3 (98.2%), followed by clusters 2 (83.4%) and 1 (4.1%). J-OSDI total scores were the highest in Cluster 3 (64.6 points) and lowest in Cluster 1 (2.1 points) (P < 0.001). Prevalence of line and area breaks (aqueous-deficient type) was highest in Cluster 1 (81.6%) whereas dimple and spot breaks (decreased-wettability type) were most prevalent in Cluster 2 (21.0%). Random breaks (increased evaporation) were observed most frequently in Cluster 1 (8.2%). Median MBI was shortest in Cluster 3 (7.1 s), followed by Cluster 2 (8.6 s) (P = 0.003). The median serum anti-SS-A/Ro concentration was highest in Cluster 3 (32.0 U/mL; P = 0.018). Cluster 2 showed a notable discrepancy between subjective symptoms and CFS scores.

Conclusions

Using symptom-based DED severity of SS, we successfully stratified patients into three clusters to potentially facilitate type-customised interventions to improve treatment efficacy.

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Fig. 1: Symptom-based stratification of patients with SS based on J-OSDI using dimensionality reduction.
Fig. 2: Cluster-stratified heatmap of DED examination-ascertained severity.
Fig. 3: Cluster-stratified comparison of FBUP-distribution proportions.

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Data availability

All relevant data are included within the manuscript and its supplementary materials.

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Acknowledgements

The authors thank Professor Shigeki Aoki, Head of the Data Science, at Juntendo University Graduate School of Medicine, for fostering a supportive and collaborative research environment, and thank the nurses and orthoptists, of the Department of Ophthalmology, at Juntendo University Faculty of Medicine, for data collection and measurements undertaken for the DED diagnosis.

Funding

This research was funded by the Japan Agency for Medical Research and Development (24hma322004s0803 [TI]), JST FOREST program (JPMJFR234I [TI]), Japan Society for the Promotion of Science, Grants-in-Aid for Scientific Research (grant numbers: 23K16364 [AMI], 23K18406 [TI], 24K19796 [AE], 25K20553 [KN], and 25K12857 [TI]), and OTC Self-Medication Promotion Foundation 2019, 2021, and 2024 (TI), Research Grants in the Natural Sciences 2024, The Mitsubishi Foundation (TI), and Suzuken Memorial Foundation 2024 (TI). The funding sources had no role in the study design, data collection, analysis, interpretation, writing of the report, or decision to submit the article for publication.

Author information

Authors and Affiliations

  1. Data Science, juntendo University Graduate School of Medicine, Tokyo, Japan

    Momona Tamagawa & Takenori Inomata

  2. Department of Hospital Administration, Juntendo University Graduate School of Medicine, Tokyo, Japan

    Ken Nagino, Akie Midorikawa-Inomata, Atsuko Eguchi & Takenori Inomata

  3. Department of Ophthalmology, Juntendo University Graduate School of Medicine, Tokyo, Japan

    Ken Nagino, Jaemyoung Sung, Yuki Morooka, Tianxiang Huang, Shintaro Nakao & Takenori Inomata

  4. Department of Telemedicine and Mobile Health, Juntendo University Graduate School of Medicine, Tokyo, Japan

    Ken Nagino, Akie Midorikawa-Inomata & Takenori Inomata

Authors
  1. Momona Tamagawa
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Contributions

MT was responsible for methodology, data curation, visualisation, formal analysis, investigation, writing-original draft preparation, and writing- reviewing and editing. KN was responsible for methodology, data curation, validation, visualisation, formal analysis, investigation, writing-original draft preparation, and writing- reviewing and editing. JS conducted the investigation and wrote the original draft and reviewed and edited the manuscript. AMI performed validation, investigation, funding, writing-original draft preparation, and writing- reviewing and editing. AE performed validation, funding, writing-original draft preparation, and writing- reviewing and editing. TH performed data curation, writing-original draft preparation, and writing- reviewing and editing. SN performed supervision, writing-original draft preparation, and writing- reviewing and editing. TI was responsible for conceptualisation, methodology, data curation, validation, visualisation, formal analysis, investigation, funding, writing-original draft preparation, and writing- reviewing and editing.

Corresponding author

Correspondence to Takenori Inomata.

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Competing interests

KN and AMI received personal fees from InnoJin, Inc., outside of the submitted work. SN reports grants from Kowa Company. Ltd., Mitsubishi Tanabe Pharma Corporation, Alcon Japan, Ltd., Santen Pharmaceutical Co., Ltd., Machida Endoscope Co., Ltd., Wakamoto Pharmaceutical Co., Ltd., Bayer Yakuhin, Ltd., Senju Pharmaceutical Co., Ltd., Nippon Boehringer Ingelheim Co., Ltd., Chugai Pharmaceutical Co., Ltd., Hoya Corporation, and Novartis Pharma KK, outside the submitted work. TI reports non-financial support from Lion Corporation and Sony Network Communications Inc., grants from Johnson & Johnson Vision Care, Inc., Yuimedi, Inc., ROHTO Pharmaceutical Co., Ltd., Kobayashi Pharmaceutical Co., Ltd., Kandenko Co., Ltd., and Fukoku Co., Ltd., personal fees from Santen Pharmaceutical Co., Ltd., InnoJin, Inc., and Ono Pharmaceutical Co., Ltd., outside the submitted work. The remaining authors declare no competing interests.

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Tamagawa, M., Nagino, K., Sung, J. et al. Symptom-based stratification of heterogeneous symptoms of dry eye disease in patients with Sjögren’s syndrome. Eye 39, 2415–2422 (2025). https://doi.org/10.1038/s41433-025-03880-5

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