Proinflammatory adaptive cytokine and shed tumor necrosis factor receptor levels are elevated preceding systemic lupus erythematosus disease flare

Abstract

Objective: Systemic 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.

Methods: Fifty-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.

Results: Compared 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.

Conclusion: The 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.

Conflict of interest statement

Disclosure: The authors report no conflicts of interest

Copyright © 2014 by the American College of Rheumatology.

Figures

Figure 1

Increased adaptive immunity pathways and soluble TNF superfamily members, and decreased levels of regulatory mediators, in SLE patients with impending flare. Plasma was procured at baseline from SLE patients who exhibited disease flare 6 to 12 weeks later (black bar) and demographically matched SLE patients who did not exhibit flare (NF, stripped bar). Levels of Th1 (A), Th2 (B), and Th17 (C) type cytokines, as well as chemokines (D), soluble TNF superfamily members (E), regulatory mediators (F), and IL-1RA:IL-1β ratio (G) in 56 EA SLE patients (mean ± SEM) were measured. Significance was determined by Wilcoxon matched-pairs test. * p< 0.05, **p < 0.01, *** p < 0.001, **** p, 0.0001

Figure 2

SLE patients have altered baseline mediators in adaptive immunity pathways and soluble TNF superfamily members during pre-flare periods compared to the same patients during non-flare periods. Plasma was procured at baseline from 13 SLE patients who exhibited disease flare 6 to 12 weeks later (black bar) and from the same patients in a separate year of the study when they did not exhibit disease flare (SNF, gray bar). Plasma Th1 (A), Th2 (B), and Th17 (C) type cytokines, as well as chemokines (D), soluble TNF superfamily members (E), regulatory mediators (F), and IL-1RA:IL-1β ratio (G) were measured (mean ± SEM). Significance was determined by Wilcoxon matched-pairs test. * p< 0.05, **p < 0.01, *** p < 0.001, **** p, 0.0001

Figure 3

Soluble mediators of inflammation in SLE patients which are elevated compared to healthy controls, but which do not discriminate between impending disease flare and non-flare. Plasma levels of BLyS, APRIL, IL-15, IL-2Rα, MIG, MIP-1α, and MIP-1β were measured and compared between (A) pre-flare SLE patients (black bar), matched non-flare SLE patients (NF, striped bar), and matched healthy controls (HC, white bar) or (B) SLE patients during a pre-flare period (black bar), the same SLE patients during a non-flare period (SNF, gray bar), and matched healthy controls (HC, white bar). Data are shown as mean ± SEM; significance between SLE patients (Flare and NF/SNF) and HC was determined by Wilcoxon matched-pairs test. * p< 0.05, **p < 0.01, *** p < 0.001, **** p, 0.0001

Figure 4

Higher Soluble Mediator Scores in SLE patients with impending flare. Soluble Mediator Scores from baseline (pre-vaccination) plasma levels were determined for each SLE patient who exhibited disease flare within the following 12 weeks relative to (A) a demographically matched SLE patient who did not exhibit disease flare (NF, p < 0.0001 by Wilcoxon matched-pairs test) or (B) the same SLE patient in a separate year of the study with no observed disease flare (SNF, p = 0.002 by Wilcoxon matched-pairs test). Data presented as Box and Whisker (median ± max and min) graphs. C. Soluble Mediator Scores for each SLE patient were compared between year of impending disease flare (Flare) and year of non-flare (SNF) in B.

Figure 5

Summary of altered soluble mediators in SLE patients prior to disease flare. Inflammatory mediators which were significantly higher in SLE patients with impending disease flare (compared to NF/SNF and HC) are listed in red, while those significantly higher in the NF/SNF groups (compared to pre-flare and HC) are listed in blue. Those mediators which were found to be higher in SLE patients compared to HC, but not different between groups of SLE patients, are dashed. SLE patients with impending disease flare have increased innate and adaptive mediators of inflammation, including those from Th1, Th2, and Th17 pathways. In addition inflammatory chemokines and soluble TNFR superfamily members are elevated. SLE patients who are in a period of non-flare (NF/SNF groups) have higher regulatory mediators, including IL-10, TGF-β, and IL-1RA