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Systemic lupus erythematosus (SLE) is a complex autoimmune disease in which the pathophysiology includes immune dissonance, genetic predisposition, epigenetic dysregulation, and dysbiosis of microbiota. SLE is life-threatening, more prevalent in women, and characterized by organ damage and a relapsing remitting course. SLE has highly heterogeneous clinical manifestations, which overlap with many other rheumatoid diseases, hematopoietic malignancies, and infections, which can hamper diagnosis. SLE is most likely to affect the skin, joints/muscles, kidneys, and blood vessels.