Background/Purpose: Systemic lupus erythematosus (SLE) is characterised by the production of a multitude of autoantibodies (abs). The diagnosis of SLE is supported by the presence of certain abs; however, currently used abs either demonstrate high sensitivity across connective tissue diseases (e.g., ANA) or high specificity yet low sensitivity (e.g., anti-dsDNA and anti-Sm). To improve diagnostic procedures and prognostication, identification of better biomarkers of early and accurate SLE diagnosis is imperative. Our objective was to perform a broad screen of IgG and IgA antibodies to autoantigen specificities in SLE versus primary Sjögren’s disease (SjD), systemic sclerosis (SSc), and healthy controls (HC) to identify novel abs that potentially could aid in differentiating SLE from HC and other diseases.

Methods: We analysed plasma samples from patients with SLE (n=229), SjD (n=146), SSc (n=139) and 196 matched HC from the European PRECISESADS project (NTC02890121). Samples were screened for IgG and IgA seroreactivity against a panel of 1,609 protein autoantigens using KREX-based i-Ome arrays (Sengenics). Measurement of IgG anti-dsDNA and anti-Sm antibody levels was conducted using an automated chemiluminescent immunoanalyser (IDS-iSYS). Analysis of differentially abundant abs (DAabs) was performed with the limma R package after adjustments for age, gender, and polyspecific antibody reactivity. The level of significance was set at p< 0.05 and |fold change| >1.5. Receiver Operating Characteristic (ROC) analysis was carried out for each DAab, yielding sensitivity, specificity, area under the curve (AUC), and accuracy.

Results: Among
1,609 autoantigens, levels of both IgG and IgA abs against LIN28A, a protein that regulates cellular growth and differentiation that is currently linked with cancer progression, were significantly elevated in SLE compared with SjD, SSc, and HC. Specifically, IgG anti-LIN28A was elevated in SLE compared with HC (sen=0.77, spe=0.69, AUC=0.80), SjD (sen=0.71, spe=0.75, AUC=0.78), and SSc (sen=0.67, spe=0.84, AUC=0.81). Moreover, IgA anti-LIN28 was elevated in SLE compared with HC (sen=0.65, spe=0.83, AUC=0.80), SjD (sen=0.59, spe=0.82, AUC=0.76), and SSc (sen=0.61, spe=0.91, AUC=0.83). By contrast, anti-LIN28A antibody levels were not significantly elevated in SjD versus HC (logFC=0.07, p=0.22 for IgG and logFC=0.08, p=0.21 for IgA) or in SSc versus HC (logFC=-0.02, p=0.95 for IgG and logFC=-0.04, p=0.50 for IgA). Anti-LIN28A outperformed anti-dsDNA (sen=0.31, spe=1.00 across all comparisons) and anti-Sm (sen=0.04, spe=1.00 across all comparisons) in distinguishing SLE from HC (AUC=0.65 for anti-dsDNA and AUC=0.52 for anti-Sm), SLE from SjD (AUC=0.65 for anti-dsDNA and AUC=0.52 for anti-Sm), and SLE from SSc (AUC=0.64 for anti-dsDNA and AUC=0.52 for anti-Sm).

Conclusion: Anti-LIN28A demonstrated high specificity and sensitivity in distinguishing SLE from healthy individuals and other autoimmune diseases. Both IgG and IgA anti-LIN28A outperformed anti-dsDNA and anti-Sm in diagnostic metrics. Exploration of the role of LIN28A in SLE pathogenesis is warranted. Upon validation in other cohorts, determination of anti-LIN28A could aid in improving diagnostics in SLE.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/igg-and-iga-anti-lin28a-outperform-anti-dsdna-and-anti-sm-in-distinguishing-sle-from-health-and-other-autoimmune-diseases/