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This study evaluated the long-term progression of DED by analyzing clinical and molecular status, considering the impact of chronic ocular pain. Patients with DED were evaluated at two visits (V1 and V2) separated by at least two years. Evaluations included validated symptom questionnaires alongside slit-lamp examination, corneal sensitivity testing, and sub-basal nerve plexus analysis. Basal tear samples were collected for multiplex quantification of 20 cytokines and substance P (SP), and conjunctival cells were obtained to analyze 25 genes and 12 microRNAs (miRNA). Based on the presence or absence of chronic ocular pain, patients were then divided into two groups. Patients improved in DED-related symptoms, with no changes observed in ocular surface signs. Corneal dendritic cell density decreased, along with epidermal growth factor (EGF), fractalkine, and monocyte chemoattractant protein (MCP-1) tear levels, whereas interleukin (IL)-10 and SP tear levels increased. Neurotrophic tyrosine kinase, receptor, type (NTRK)1 gene expression was significantly downregulated, especially in patients without chronic ocular pain. miR-665 expression decreased significantly in DED patients. Monitoring corneal dendritic cells, tear cytokines, and gene\/miRNA expression offers promising tools for tracking DED progression. Distinguishing the presence of chronic ocular pain as a separate symptom is crucial to optimizing therapeutic strategies and DED progression.<\/jats:p>","DOI":"10.3390\/ijms26188918","type":"journal-article","created":{"date-parts":[[2025,9,16]],"date-time":"2025-09-16T07:33:02Z","timestamp":1758007982000},"page":"8918","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Long-Term Clinical and Molecular Changes in Dry Eye Disease and Chronic Ocular Pain"],"prefix":"10.3390","volume":"26","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8922-039X","authenticated-orcid":false,"given":"Cristina","family":"Valencia-Sandon\u00eds","sequence":"first","affiliation":[{"name":"Institute of Applied Ophthalmobiology (IOBA), Universidad de Valladolid (UVa), Campus Miguel Delibes, Paseo de Bel\u00e9n 17, 47011 Valladolid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5993-5973","authenticated-orcid":false,"given":"Andr\u00e9s \u00c1ngel","family":"Calder\u00f3n-Garc\u00eda","sequence":"additional","affiliation":[{"name":"Institute of Applied Ophthalmobiology (IOBA), Universidad de Valladolid (UVa), Campus Miguel Delibes, Paseo de Bel\u00e9n 17, 47011 Valladolid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7054-3287","authenticated-orcid":false,"given":"Marta","family":"Blanco-V\u00e1zquez","sequence":"additional","affiliation":[{"name":"Institute of Applied Ophthalmobiology (IOBA), Universidad de Valladolid (UVa), Campus Miguel Delibes, Paseo de Bel\u00e9n 17, 47011 Valladolid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3992-991X","authenticated-orcid":false,"given":"Laura","family":"Valencia-Nieto","sequence":"additional","affiliation":[{"name":"Institute of Applied Ophthalmobiology (IOBA), Universidad de Valladolid (UVa), Campus Miguel Delibes, Paseo de Bel\u00e9n 17, 47011 Valladolid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3072-3934","authenticated-orcid":false,"given":"Andrea","family":"Novo-Diez","sequence":"additional","affiliation":[{"name":"Institute of Applied Ophthalmobiology (IOBA), Universidad de Valladolid (UVa), Campus Miguel Delibes, Paseo de Bel\u00e9n 17, 47011 Valladolid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amanda","family":"V\u00e1zquez","sequence":"additional","affiliation":[{"name":"Institute of Applied Ophthalmobiology (IOBA), Universidad de Valladolid (UVa), Campus Miguel Delibes, Paseo de Bel\u00e9n 17, 47011 Valladolid, Spain"},{"name":"Pain Unit, Alliance of University Hospitals, Health System of Castilla y Le\u00f3n, Calle Dulzaina 2, 47012 Valladolid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8178-4836","authenticated-orcid":false,"given":"Margarita","family":"Calonge","sequence":"additional","affiliation":[{"name":"Institute of Applied Ophthalmobiology (IOBA), Universidad de Valladolid (UVa), Campus Miguel Delibes, Paseo de Bel\u00e9n 17, 47011 Valladolid, Spain"},{"name":"Biomedical Research Networking Center in Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN), Campus Miguel Delibes, Paseo de Bel\u00e9n 17, 47011 Valladolid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3673-0585","authenticated-orcid":false,"given":"Mar\u00eda J.","family":"Gonz\u00e1lez-Garc\u00eda","sequence":"additional","affiliation":[{"name":"Institute of Applied Ophthalmobiology (IOBA), Universidad de Valladolid (UVa), Campus Miguel Delibes, Paseo de Bel\u00e9n 17, 47011 Valladolid, Spain"},{"name":"Biomedical Research Networking Center in Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN), Campus Miguel Delibes, Paseo de Bel\u00e9n 17, 47011 Valladolid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1274-7796","authenticated-orcid":false,"given":"Amalia","family":"Enr\u00edquez-de-Salamanca","sequence":"additional","affiliation":[{"name":"Institute of Applied Ophthalmobiology (IOBA), Universidad de Valladolid (UVa), Campus Miguel Delibes, Paseo de Bel\u00e9n 17, 47011 Valladolid, Spain"},{"name":"Biomedical Research Networking Center in Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN), Campus Miguel Delibes, Paseo de Bel\u00e9n 17, 47011 Valladolid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,9,12]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Wolffsohn, J.S., Ben\u00edtez-Del-Castillo, J., Loya-Garcia, D., Inomata, T., Iyar, G., Liang, L., Pult, H., Sabater, A.L., Starr, C.E., and Vehof, J. 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