Non-IgG Anti-Double-Stranded DNA Antibodies in Systemic Lupus Erythematosus: Biomarkers of Extrarenal Disease Activity

Objectives In murine models of systemic lupus erythematosus (SLE), anti-double-stranded DNA (anti-dsDNA) IgM has been shown to protect against lupus nephritis (LN), and some researchers suggest that an increased IgG/IgM anti-dsDNA ratio and the combination of IgA and IgG anti-dsDNA better correlate with LN than IgG anti-dsDNA. However, studies exploring non-IgG isotypes in relation to SLE disease activity in non-LN remain scarce. Herein, we aimed to assess whether IgM and IgA antibodies, and their ratios with IgG, are associated with extrarenal disease activity in SLE and to determine if IgG-only testing may overlook clinically relevant isotype patterns in non-LN SLE patients. Methods We studied 87 adult (≥18 years) SLE patients from a Canadian cohort without current LN, all with detailed clinical phenotyping. Serum IgG, IgM, and IgA anti-dsDNA levels were measured by ELISA. Extrarenal disease activity was quantified using the clinical SLEDAI-2K (cSLEDAI; range 0–12). Associations between individual isotypes and isotype ratios (IgM/IgG, IgM/IgA) and cSLEDAI were examined using Spearman’s correlation. Group comparisons across predefined activity categories were performed with Mann-Whitney U tests (2 groups) or Kruskal-Wallis tests with post hoc multiple-comparison correction (>2 groups). Results Of 87 non-LN SLE patients, 51 (58%) were clinically active (cSLEDAI ≥1). In this active subgroup, IgM anti-dsDNA levels were inversely correlated with disease activity (r = −0.34, p = 0.016), whereas IgG and IgA anti-dsDNA levels showed no significant correlation with cSLEDAI. A lower IgM/IgA anti-dsDNA ratio was also associated with higher disease activity (r = −0.30, p = 0.033), while the IgM/IgG ratio was not. Patients with high disease activity (cSLEDAI >6) had significantly lower IgM anti-dsDNA levels than those with mild/moderate activity (p = 0.0028). When disease activity was categorized as inactive (cSLEDAI 0), mild/moderate (1-7), and high (≥8), IgM anti-dsDNA levels remained lowest in the high-activity group, with significant differences between inactive vs high (p = 0.046) and mild/moderate vs high (p = 0.0278). Conclusion In non-LN SLE, lower IgM anti-dsDNA levels and a reduced IgM/IgA ratio are associated with higher extrarenal disease activity, whereas IgG and IgA anti-dsDNA alone do not track clinical activity. These findings support a potential protective/regulatory role of IgM anti-dsDNA and suggest that IgG-only testing may miss clinically relevant isotype patterns.