THU0249 Functional Clusters of Autoantibodies Targeting TLR and Smad Pathways Define New Subgroups in Systemic Lupus Erythematosus

Background The molecular targets of the vast majority of autoantibodies in systemic lupus erythematosus (SLE) are unknown. Multiple recent failures of new therapies in SLE clinical trials demonstrate the need for improved classification of SLE based on pathogenesis. Objectives To identify novel autoantibodies in SLE for the development of an improved assay for diagnosis and identification of autoantibody clusters for classification of SLE subgroups. Methods We used a baculovirus-insect cell expression system to create an advanced protein microarray with 1545 full-length human proteins. All proteins were expressed with a biotin carboxyl carrier protein (BCCP) folding tag, so that only correctly folded proteins were bound to the array. Sera were assayed from three independent cohorts of SLE individuals (total n=277) and age, gender and ancestry-matched controls (n=280). Results We confirmed 116 proteins (FDR Conclusions Novel autoantibodies, especially from cluster SLE1b and SLE3, identified in this study may improve diagnosis of SLE, through identification of SLE patients who are negative for ANA or dsDNA antibodies. SLE patients clustered into four groups with autoantibody responses against networks of proteins with related cellular or immunological functions, suggesting that different pathogenic mechanisms underlie the four SLE subgroups. Thus the autoantigen clusters may be clinically useful for stratifying SLE patients for specific therapies: SLE patients with TLR signaling autoantigens might preferentially benefit from B cell targeting therapies; SLE patients with autoantibodies against SMAD2/5 and related pathway autoantigens might benefit from TGF-β targeting therapies. Disclosure of Interest M. Lewis: None declared, M. McAndrew Employee of: Oxford Gene Technology, C. Wheeler Employee of: Oxford Gene Technology, N. Workman Employee of: Oxford Gene Technology, P. Agashe: None declared, J. Koopmann: None declared, E. Uddin Employee of: Oxford Gene Technology, L. Zou: None declared, R. Stark: None declared, J. Anson Employee of: Oxford Gene Technology, A. Cope: None declared, T. Vyse: None declared