Candidate Tear-Based Uveitis Biomarkers in Children with JIA Based on Arthritis Activity and Topical Corticosteroid Use

Ilaria Maccora; Mekibib Altaye; Kenneth D Greis; Hermine I Brunner; Alexandra Duell; Wendy D Haffey; Tiffany Nguyen; Megan Quinlan-Waters; Grant S Schulert; Alyssa Sproles; Virginia Miraldi Utz; Sherry Thornton; Sheila T Angeles-Han

doi:10.1080/09273948.2024.2428846

Candidate Tear-Based Uveitis Biomarkers in Children with JIA Based on Arthritis Activity and Topical Corticosteroid Use

Ocul Immunol Inflamm. 2024 Nov 25:1-10. doi: 10.1080/09273948.2024.2428846. Online ahead of print.

Authors

Ilaria Maccora^{1

2}, Mekibib Altaye³, Kenneth D Greis⁴, Hermine I Brunner^{5

6}, Alexandra Duell⁵, Wendy D Haffey⁴, Tiffany Nguyen⁷, Megan Quinlan-Waters⁵, Grant S Schulert^{5

6}, Alyssa Sproles⁵, Virginia Miraldi Utz^{8

9}, Sherry Thornton^{5

6}, Sheila T Angeles-Han^{5

6

8

9}

Affiliations

¹ Department of Neurosciences, Psychology, Drug Research and Child Health (NEUROFARBA), University of Florence, Florence, Italy.
² Rheumatology Unit, ERN ReCONNET Center, Meyer Children's Hospital IRCCS, Florence, Italy.
³ Division of Biostatistics and Epidemiology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA.
⁴ Proteomics and Mass Spectrometry Laboratory, University of Cincinnati, Cincinnati, Ohio, USA.
⁵ Division of Rheumatology, Cincinnati Children's Hospital Medical Center and Department of Pediatrics, University of Cincinnati, Cincinnati, Ohio, USA.
⁶ Department of Pediatrics, College of Medicine, University of Cincinnati, Cincinnati, Ohio, USA.
⁷ School of Medicine, University of Louisville, Louisville, Kentucky, USA.
⁸ Abrahamson Pediatric Eye Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA.
⁹ Department of Ophthalmology, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA.

PMID: 39586039
DOI: 10.1080/09273948.2024.2428846

Abstract

Background: Uveitis is an inflammatory ocular disease secondary to disruption of the retinal pigmented epithelium (RPE) and blood retinal barrier (BRB). Known clinical factors do not accurately predict uveitis risk in Juvenile Idiopathic Arthritis (JIA). Tear fluid is easily obtained for biomarker study. We aim to identify tear-based markers associated with the presence of uveitis in children with JIA.

Methods: In a cross-sectional comparative cohort study, tears were collected by Schirmer strips from children with oligoarticular JIA-associated uveitis (JIA-U) and JIA without uveitis (JIA-no-U). A tandem isotope tagging (iTRAQ and TMT) strategy was used for relative quantitation via nanoLC-MS/MS to quantify proteins in the affected eye. Log transformed relative protein abundance of protein levels was compared between groups using Wilcoxon exact test. We explored the influence of arthritis activity and topical corticosteroids (CS) use on protein levels. STRING analysis was performed.

Results: Tear samples of 14 JIA-U and 14 JIA-no-U patients were analyzed. Thirteen proteins were differentially expressed between both groups. Stratified analysis based on arthritis activity (inactive arthritis) and topical CS (off CS) showed that alpha-2-macroglobulin (p = 0.012), apolipoprotein A1 (p = 0.036), S100A9 (p = 0.05), haptoglobin (p = 0.066), and transthyretin (p = 0.066) consistently differentiated between both groups. On STRING analysis, these proteins were associated with the RPE, BRB, and inflammation.

Conclusion: Importantly, we identified proteins involved in the RPE, BRB, and immune response that were differentially abundant in the tears of children with JIA-U compared to JIA-no-U, regardless of arthritis activity or topical CS. Candidate tear-based biomarkers may represent a non-invasive means to detect uveitis.

Keywords: Children; JIA; proteomic; tear; uveitis.

Plain language summary

Question: Is it possible to identify tear-based biomarkers able to identify patients with uveitis in children with Juvenile Idiopathic Arthritis (JIA)?Findings: We identified proteins involved in the immune response and in the retinal barrier that were differentially abundant in the tears of children with JIA-Uveitis compared to JIA-no-Uveitis.Meaning: Tears may be a suitable sample to identify children with JIA with and without uveitis in a non-invasive and objective way.