ObjectiveSystemic lupus erythematosus (SLE) is a multifaceted disease characterized by immune dysregulation and unpredictable disease activity. This study sought to evaluate the changes in plasma concentrations of soluble mediators that precede clinically defined disease flares.MethodsFifty‐two different soluble mediators, including cytokines, chemokines, and soluble receptors, were examined using validated multiplex bead‐based or enzyme‐linked immunosorbent assays in plasma from 28 European American patients with SLE who developed disease flare 6 or 12 weeks after a baseline assessment (preflare), 28 matched SLE patients without impending flare (nonflare), and 28 matched healthy controls. In a subset of 13 SLE patients, mediators within samples obtained preceding disease flare were compared with those within samples from the same individual obtained during a clinically stable period without flare.ResultsCompared to SLE patients with clinically stable disease, SLE patients with impending flare had significant alterations (P ≤ 0.01) in the levels of 27 soluble mediators at baseline; specifically, the levels of proinflammatory mediators, including Th1‐, Th2‐, and Th17‐type cytokines, were significantly higher several weeks before clinical flare. Baseline levels of regulatory cytokines, including interleukin‐10 and transforming growth factor β, were higher in nonflare SLE patients, whereas baseline levels of soluble tumor necrosis factor receptor type I (TNFRI), TNFRII, Fas, FasL, and CD40L were significantly higher (P ≤ 0.002) in preflare SLE patients. The normalized and weighted combined soluble mediator score was significantly higher (P ≤ 0.0002) in preflare samples from SLE patients compared to samples from the same patients obtained during periods of stable disease.ConclusionThe levels of proinflammatory adaptive cytokines and shed TNF receptors are elevated prior to disease flare, while the levels of regulatory mediators are elevated during periods of stable disease. Alterations in the balance between inflammatory and regulatory mediators may help identify patients at risk of disease flare and help decipher the pathogenic mechanisms of SLE.