Anti-nucleosome antibodies outperform traditional biomarkers as longitudinal indicators of disease activity in systemic lupus erythematosus

Abstract

Objective: The aim of this study was to determine whether anti-nucleosome antibodies function as activity-specific biomarkers in SLE.

Methods: Fifty-one patients were recruited and followed prospectively with periodic clinical and biochemical assessments over a 14-month period. Disease activity was determined by the SLEDAI-2K. Anti-nucleosome antibody levels were measured by an ELISA and its utility as an activity-specific biomarker as compared with that of anti-dsDNA antibodies and C3 was assessed both at baseline and in longitudinal analysis.

Results: Anti-nucleosome antibodies were significantly elevated in SLE patients vs controls and showed a moderate positive correlation with disease activity. The utility of anti-nucleosome antibodies in identifying patients with active disease in a cross-sectional analysis was comparable to that of anti-dsDNA antibodies and C3. Analysis of variance demonstrated that the level of anti-nucleosome antibodies and C3 varied significantly with changes in disease activity over time. Changes in clinical state were not mirrored by changes in anti-dsDNA antibodies. In time-dependent analysis, anti-nucleosome antibodies showed a better fit over time than anti-dsDNA antibodies and C3. In pairwise comparisons, C3 and anti-nucleosome antibodies outperformed other models, including the conventional pairing of C3 and anti-dsDNA antibodies, however, no biomarker alone or as a group accurately predicted impending remissions or exacerbations.

Conclusion: Anti-nucleosome antibodies demonstrate greater fidelity as a biomarker for changes in SLE disease activity than traditional biomarkers, supporting the routine monitoring of this antibody in clinical practice.

Keywords: anti-nucleosome antibodies; biomarkers; disease activity; systemic lupus erythematosus.

Fig. 1

Association between anti-nucleosome antibody levels, serological variables and disease activity (A) Scatter plots showing anti-nucleosome antibody levels in control and patient sera. Each symbol represents the determination for a single individual, with the mean for each group indicated by the solid horizontal line. Groups were compared using a non-parametric Mann–Whitney test. The threshold for anti-nucleosome positivity is shown as the dotted horizontal line. (B and C) Comparison of anti-dsDNA and C3 levels with anti-nucleosome levels in patient sera utilizing Spearman’s correlation analysis. (D–F) Relationship between mS-2K and anti-dsDNA, C3 and anti-nucleosome levels using Spearman’s correlation. mS-2K: modified SLEDAI-2K.

Fig. 2

Relationship of marker levels to mS-2K Association between change in mS-2K (ΔSLEDAI) and change in biomarker levels (expressed as the log₂-fold change). Clinically relevant change in disease activity was defined as a change in mS-2K score of ± 4 (indicating an event). The number of events was: C3, 435 total (99, ≤ −4; 278, −3 to 3; 58, ≥4); anti-dsDNA antibody, 437 total (100, ≤−4; 279, −3 to 3; 58, ≥4); anti-nucleosome antibody, 155 total (32, ≤−4; 102, −3 to 3; 21, ≥4). (A) shows all data including outliers. In (B) the scale has been enlarged to better demonstrate the differences observed. One-way ANOVA indicated that changes in C3 (P = 3.49E-03) and anti-nucleosome antibody (P = 4.37E-02) levels showed significant variation with changes in disease activity. mS-2K: modified SLEDAI-2K; ANOVA: analysis of variance.