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Objectives IgA2 anti-dsDNA has recently emerged as a biomarker of response to combination therapy in systemic lupus erythematosus (SLE). We sought to investigate clinical correlates of IgA subclass anti-dsDNA antibodies in a large cohort of lupus patients who were refractory to conventional immunosuppressive therapy.Methods Serum levels of C3, C4, and anti-dsDNA autoantibody titres were assessed in a UK registry of biologic-treated SLE patients (BILAG-BR; n=105) and a single centre cohort with milder disease (n=59). IgA1 and IgA2 anti-dsDNA were measured using an in-house ELISA, while C3, C4, and IgG anti-dsDNA were obtained from routine clinical assays. Statistical analyses included Fisher’s exact test, Kruskal-Wallis test and logistic regression.Results Among the refractory BILAG-BR cohort, 40% were positive for IgA2 anti-dsDNA (AU >= 12.5), compared to 18.6% in the non-refractory cohort. Analysis of IgG, IgA1 and IgA2 anti-dsDNA autoantibodies in the refractory cohort revealed that IgG+IgA1-IgA2- anti-dsDNA was the most common (n=36), followed by triple-positive IgA1+IgA2+IgG+ anti-dsDNA (n=29). Compared with IgG+IgA1-IgA2- and other antibody groups, triple-positive IgG+IgA1+IgA2+ individuals had significantly higher proportions of low C4 (86% in IgG+IgA1+IgA2+ vs 48% in IgG+IgA1-IgA2- vs 44% in others, p = 0.00294) and low C3 (79% in IgG+IgA1+IgA2+ vs 39% in IgG+IgA1-IgA2- vs 15% in others, p = 0.00386). Patients in the triple-positive cohort also had significantly higher BILAG disease activity compared to IgG+IgA1-IgA2- patients as defined by the numerical BILAG scoring system (p = 0.043). Triple-positive antibody status (IgG+IgA1+IgA2+) conferred the highest risk of severe renal disease (OR=4.91, p=0.003), followed by single IgG-anti-dsDNA antibody positivity (OR=3.75, p=0.008) compared to other antibody profiles.Abstract PO:08:222 Figure 1Conclusions SLE patients with concurrent IgG, IgA1, and IgA2 anti-dsDNA antibodies represent a distinct, high-risk subgroup characterised by hypocomplementemia, heightened disease activity, and an increased risk of active renal involvement. These findings indicate that triple-positive anti-dsDNA status may serve as a valuable biomarker for disease stratification in severe SLE.Figure 1. Triple-positive anti-dsDNA defines a subset of patients with severe disease. (A) IgA1/IgA2/IgG anti-dsDNA autoantibodies in refractory SLE patients. (B) Association of low C4 and autoantibody status. (C) Association of low C3 and autoantibody status. (D) Total numerical BILAG score by autoantibody status.