AB0721 From Undifferentiated Connective Tissue Disease to Identifiable Disease: Precursors of Systemic Sclerosis and Systemic Lupus Erythematosus

Abstract

BackgroundThe pathogenesis of systemic lupus erythematosus and systemic sclerosis is characterized by derangements of the innate and adaptive immune systems, and inflammatory pathways leading to autoimmunity, chronic cytokine production, and chronic inflammation. Diagnosis is rooted in meeting established criteria. However, in pre-clinical states criteria is not fulfilled but biochemical and autoimmune derangements are present. Understanding the underlying processes responsible for disease pathogenesis in pre-clinical states, which place patients at increased risk for the development of established connective tissue diseases, presents a prognostic opportunity, and could enable timely treatment leading to limiting disease progression.ObjectivesWe aim to describe the role of the innate and adaptive immune system in the pre-clinical states of UCTD-risk-SSc and prescleroderma, the underlying immune dysregulation in these pre-clinical states, and the evolution of antibodies from nonspecific antinuclear antibodies to specific prior to SLE development.MethodsOur search strategy was developed alongside an experienced information specialist. We searched the databases EMBASE and MEDLINE with restrictions for the English language. Reference lists of all primary studies and review articles were searched for additional references. Studies reported in full-text and abstract formats were included.ResultsMultiple cytokines are observed to increase along a disease spectrum from UCTD-risk-SSc to classified SSc and include sICAM-1, CCL2, CXCL8, ang-2, CXCL16, e-selectin, and IL-13. The mechanism of action of these cytokines includes transmigration of lymphocytes endothelium, innate immune cell activation and signal propagation, and extracellular matrix deposition. The progressive nature of cytokine increase through a spectrum from pre-clinical to clinical emphasizes disease evolution and enables the discernment of patients who may warrant early intervention. Furthermore, there are disease markers which are observed to be predictive of established SSc and include sIL-2Rα, PIIINP, CXCL4, CXCL10, and CXCL11. Pre-clinical SLE is characterized by an evolving IFN signature and progressive SLE-specific antibody formation prior to disease classification.ConclusionThe coordinated dysregulation of the innate and adaptive immune systems, and inflammatory signalling pathways leads to the pathogenesis of connective tissue disease. Our improved understanding of these underlying aberrations in pre-clinical stages of disease will serve to better identify patients at increased risk.