Objectives <p>Primary Sjogren’s syndrome (pSS) is an autoimmune condition characterized by glandular dysfunction. The roles of nitrotyrosine-modified (NT)-protein adducts and anti-NT-peptide adduct autoantibodies in disease progression and their potential as biomarkers remain underexplored. In this study, we assessed NT-protein adducts, related autoantibodies, and their associations with disease progression in pSS patients and their transformation into secondary SS with rheumatoid arthritis (RA-sSS).</p> Methods <p>The serum levels of proteins, NT-protein adducts, and autoantibodies against novel pSS-specific component C3 (C3)^914–926 and C4b-binding protein alpha chain (C4BPA)^336–353 were analyzed via proteomics and immunoassays. The statistical significance of the odds ratios (ORs) was estimated. Biomarker combinations were assessed for diagnostic performance.</p> Results <p>NT-protein adduct levels progressively increased across groups, reflecting increasing nitrosative stress. Elevated NT-protein adducts (OR = 4.542) and reduced levels of specific autoantibodies, such as IgA anti-C3^914−926 (OR = 12.503), IgA anti-C3^914−926 NT (OR = 12.758), IgA anti-C4BPA^336−353 (OR = 15.962), IgM anti-C4BPA^336−353 NT (OR = 2.471), and IgG anti-C4BPA^336−353 NT (OR = 5.302), were identified as risk factors for disease progression in patients with pSS; in particular, NT-protein adducts (OR = 8.005) increased disease transformation to RA-sSS. LightGBM achieved the highest performance (AUC = 0.991) in distinguishing pSS from HCs, whereas XGBoost performed best (AUC = 0.876) in differentiating pSS from RA-sSS.</p> Conclusions <p>Our findings suggest that elevated NT-protein adducts may signify an increased risk for disease progression in pSS patients and transformation to RA-sSS. Machine learning integration of NT-protein adducts, autoantibodies, and traditional biomarkers may enhance early SS diagnosis.</p> <p><Table Float="No" ID="Taba"> <tgroup cols="2"> <colspec colname="c1" colnum="1" /> <colspec colname="c2" colnum="2" /> <tbody> <row> <entry align="left" nameend="c2" namest="c1"> <p>Key Points</p> <p>• <i>The elevated nitrotyrosine-modified protein adducts may emerge as significant biomarkers of disease progression in pSS and its transformation into RA-sSS..</i></p> <p>• <i>The reduced specific autoantibodies, such as IgA anti-C3</i>^{<i>914-926</i>}<i>, IgA anti-C3</i>^{<i>914-926 NT</i>}<i>, IgA anti-C4BPA</i>^{<i>336-353</i>}<i>, IgM anti-C4BPA</i>^{<i>336-353</i>}<i> NT, and IgG anti-C4BPA</i>^{<i>336-353</i>} <i>NT, were associated with increased risks of disease progression in pSS.</i></p> <p>• <i>Integration of NT-protein adducts, autoantibodies, and traditional biomarkers enhances diagnostic accuracy for SS.</i></p> </entry> </row> </tbody> </tgroup> </Table></p>