Background and aims Patients with systemic lupus erythematosus (SLE) have a wide spectrum of clinical manifestations and disease activity. This has made it extremely difficult to demonstrate superiority of novel treatments in clinical trials. Our goal is to establish an autoantibody classification system of SLE subgroups of which one represents a more homogeneous SLE population with active disease.

Methods We first established the global SLE autoantibody reactivity profile by comparing SLE serum samples with healthy controls. High-content profiling revealed an extended autoantibody repertoire with reactivity to cytokines, interferon (IFN) and IFN pathway proteins. Based on screens with >700 SLE samples, we designed the multiplex NavigAID SLE array consisting of 86 diagnostic and novel antigens.

Results Starting with 86 NavigAID SLE antigens we stratified SLE into five subgroups with reactivity towards distinct subsets of antigens. For example, patients with nephritis could be subclassified into two subsets according to the presence of anti-dsDNA or anti-neutrophil cytoplasmic antibodies (ANCA) revealing the heterogeneity of SLE. Reactivity to anti-IFN pathway proteins was associated with high disease activity, whereas patients with low disease activity had only few autoantibodies. We also found SLE patients who were tested positive for anti-nuclear autoantibodies (ANA), but did not exhibit the typical SLE reactivity profile. These patients may have been misclassified based on their positive ANA test result and maybe considered as potential outliers in clinical trials.

Conclusions Autoantibody profiling using 86 antigens provides an opportunity for identifying subgroups of patients with distinct marker profiles for designing clinical trials and evaluating clinical response in defined patient subgroups.