Distinct IgM and IgG autoantibody profiles characterize incomplete and classified systemic autoimmune diseases

Incomplete lupus erythematosus (ILE) and non-Sjögren's disease sicca (nSjD-sicca) are clinically heterogeneous, incompletely classified autoimmune conditions that share features with systemic lupus erythematosus (SLE) and Sjögren's disease (SjD), respectively. Although some patients progress to classified disease, many remain stable. The immunologic features distinguishing incomplete from established autoimmune disease remain poorly defined. We sought to characterize and compare autoantibody immune signatures across ILE, SLE, nSjD-sicca, and SjD using expanded autoantibody profiling. Serum samples were obtained from patients with ILE (n=80), SLE (n=80), nSjD-sicca (n=52), SjD (n=60), and matched healthy controls (n=79). Initial screening was performed using the Bio-Rad BioPlex 2200. Expanded profiling utilized the GeneCopoeia Human Autoimmune Array (120 autoantigens) with parallel IgM and IgG detection. Traditional screening demonstrated expected patterns: ILE (anti-nRNP 26.3%; anti-chromatin 25.0%), SLE (anti-SmRNP 40.0%; anti-dsDNA 31.3%), nSjD-sicca (anti-La 9.6%), and SjD (anti-Ro/SSA 53.3%). Expanded analysis revealed significantly increased IgM autoreactivity in ILE compared with SLE (BH-FDR-adjusted p<0.05), targeting nuclear (KU, Nup62, CENP-A/B), cytokine (IFN-α1, IFN-ϵ, IL-15, GM-CSF), mitochondrial (M2), extracellular matrix (collagen IV, fibrinogen), vascular (β2-glycoprotein I, AGTR), and gut-associated antigens (tissue transglutaminase, intrinsic factor). In contrast, SLE demonstrated enriched IgG responses to canonical nuclear antigens, including core histone and dsDNA. Within the sicca spectrum, Ro52 (TRIM21) IgG autoantibodies were significantly increased in SjD compared to nSjD-sicca. These findings indicate that incomplete autoimmune disease states exhibit distinct IgM-dominant autoantibody profiles rather than simply attenuated versions of the IgG dominant responses in classified disease, highlighting the potential value of isotype-specific profiling for disease classification.