Background: SLE remains one of the most complex diseases in medicine, with protean alterations in immune system function contributing to autoimmunity, tissue inflammation and damage, and diverse clinical manifestations. While considerable advances in understanding the molecular pathways and mediators involved in SLE have led to identification of rational therapeutic targets, a full understanding of the upstream etiologic drivers of the disease and how genetic risk and environmental stimuli shape the evolution of the disease and its clinical heterogeneity requires continued investigation.

Objectives: To review recent literature relevant to the etiology, pathogenesis and heterogeneity of SLE.

Methods: Review and synthesis of recent literature.

Results: Recent advances in characterizing the mechanisms of regulation and degradation of endogenous nucleic acids, particularly insights derived from disorders based on a variety of single gene mutations that result in production of type I interferon, suggest potential drivers of type I interferon production in SLE. The functional alterations in many aspects of T and B cell function in patients with SLE, some attributable to type I interferon, continue to be identified. Potential contributions of the microbiome expand our view of candidate disease-enhancing factors. Interest in defining patients at risk for evolving from pre-clinical to clinical disease that fulfills classification criteria for SLE may help to identify the essential elements of lupus pathogenesis and suggest approaches for disease prevention.

Conclusion: Endogenous nucleic acids have emerged as compelling candidates for drivers of lupus pathogenesis, along with their traditional role as antigenic targets of lupus autoantibodies. Although the clinical heterogeneity of SLE has confounded efforts to successfully test new therapies, advances in identifying sources of nucleic acids stimulating type I interferon and alterations in adaptive immune system function help us move toward a synthetic understanding of disease pathogenesis and suggest that therapeutic regimens targeting both innate and adaptive immune systems might be required to control or prevent disease.

REFERENCES:

[1] Crow MK, Olferiev M, Kirou KA. Type I interferons in autoimmune disease. Annu Rev Pathol. 2019

[2] Uggenti C, Lepelley A, Crow YJ. Self-awareness: Nucleic acid-driven inflammation and the type I interferonopathies. Annu Rev Immunol. 2019.

Disclosure of Interests: None declared

DOI: 10.1136/annrheumdis-2019-eular.8452