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Purpose: Scleritis is an extremely painful and potentially blinding inflammation of the sclera with unknown pathogenesis and unpredictable course. To gain insight in its disease process and identify biomarker candidates, we performed extensive proteomics in serum and tear fluid., Design: Prospective multicenter cohort study., Participants: A total of 121 patients with noninfectious scleritis (of which 39 active cases), 30 healthy controls, and 23 disease controls (uveitis and rheumatoid arthritis) were enrolled in the Netherlands from 2020 to 2022., Methods: Serum, tear fluid of both eyes, and clinical data were gathered. The level of 368 inflammatory proteins was measured using proximity extension assays. Results were validated in an independent cohort of 15 patients with scleritis, and using addressable laser bead immunoassay, or enzyme-linked immunoassays. In addition, we studied an extended panel of matrix metalloproteinases in tear fluid of necrotizing scleritis with addressable laser bead immunoassay., Main Outcome Measures: Statistically significant differences in the level of inflammatory proteins between patients with scleritis and control groups., Results: Proteomics revealed 18 significantly upregulated or downregulated serum proteins in active scleritis cases compared with all control groups in both the discovery cohort and the validation cohort. The most upregulated protein was nuclear migration protein nudC (NudC; P  = 0.0032), a protein involved in neurogenesis. The other significant hits included proteins involved in T-cell activation, apoptosis, epithelial barrier maintenance, and angiogenesis. Our tear fluid analysis showed matrix metalloproteinase 9 (MMP9) to be upregulated in the tear fluid of patients with scleral necrosis., Conclusions: The results of our proteomics analysis suggest a role for neurogenesis, T-cell activation, disruption of epithelial barrier, and angiogenesis in the pathogenesis of scleritis, and highlight MMP9 and NudC as biomarkers with potential clinical relevance., Funding Disclosures: The authors have no proprietary or commercial interest in any materials discussed in this article., (© 2023 by the American Academy of Ophthalmology.)

Responsiveness to tumour necrosis factor (TNF) inhibitors has been associated with the TNF-α G-308A polymorphism in rheumatoid arthritis. The aim of this study was to examine the association between the presence of this polymorphism and the response to TNF inhibitors in patients with refractory sarcoidosis. Patients (n=111) who started TNF-inhibitor treatment (76 infliximab, 35 adalimumab) were followed for at least 1 year. The main symptoms in these patients were fatigue (n=100, 90.1%), small fibre neuropathy (n=91, 82.0%), pulmonary involvement (n=69, 62.2%), and/or uveitis (n=31, 27.9%). Patients were additionally genotyped for the presence of the TNF-α G-308A polymorphism. Treatment response was assessed using clinical outcome measures and questionnaires. Three-quarters (n=83, 74.8%) of the patients responded well. Of the patients without the variant A-allele 93.6% (73 out of 78, p<0.001) improved, while 30.3% (10 out of 33) of variant A-allele carriers responded favourably to TNF inhibitors. For patients with the GG-genotype, the probability of improving compared with remaining stable or deteriorating was three times higher (risk ratio 3.09, 95% CI 1.84-5.20). Sarcoidosis patients without the TNF-α -308A variant allele (GG-genotype) had a three-fold higher response to TNF inhibitors (adalimumab or infliximab). Further research is needed to evaluate the value of genotyping for the TNF-α G-308A polymorphism in order to tailor TNF-inhibitor treatment., (©ERS 2014.)