Pathways of impending disease flare in African-American systemic lupus erythematosus patients

Abstract

Immune dysregulation in systemic lupus erythematosus (SLE) contributes to increased disease activity. African-American (AA) SLE patients have an increased prevalence of complications from disease flares and end-organ damage that leads to increased morbidity and early mortality. We previously reported alterations in inflammatory and regulatory immune mediator levels prior to disease flare in European American (EA) SLE patients. In the current study, we assessed baseline and follow-up plasma levels of 52 soluble mediators, including innate, adaptive, chemokine, and TNF superfamily members, in AA SLE patients who developed SELENA-SLEDAI defined flare 6 or 12 weeks after baseline assessment. These patients were compared to themselves during a comparable, clinically stable period (SNF, n = 18), or to demographically matched SLE patients without impending disease flare (NF, n = 13 per group). We observed significant (q < 0.05) alterations in 34 soluble mediators at baseline, with increased levels of both innate (IL-1α and type I interferons [IFN]) and adaptive cytokines (Th1-, Th2-, and Th17-type), as well as IFN-associated chemokines and soluble TNF superfamily members weeks before clinical disease flare. In contrast, stable SLE patients exhibited increased levels of the regulatory mediators IL-10 (q ≤ 0.0045) and TGF-β (q ≤ 0.0004). Because heterogeneous immune pathways were altered prior to clinical disease flare, we developed a soluble mediator score that encapsulates all mediators tested. This score is the sum of all log transformed, standardized soluble mediator levels assessed at baseline (pre-flare), weighted by their Spearman correlation coefficients for association with the SELENA-SLEDAI score at time of concurrent flare. While baseline SELENA-SLEDAI scores were similar between flare vs. NF (p = 0.7214) and SNF (p = 0.5387), the SMS was significantly higher in pre-flare SLE patients (Flare vs NF or SNF, p < 0.0001). By capturing alterations in the balance between inflammatory and regulatory mediators associated with SLE pathogenesis, the soluble mediator score approximates the immune status of SLE patients and provides a robust, predictive gauge of impending disease flare.

Keywords: (MeSH): systemic lupus erythematosus; Acute symptom flare; African-Americans; Chemokines; Cytokines; TNF superfamily.

Copyright © 2017 Elsevier Ltd. All rights reserved.

Figures

Figure 1

Soluble mediator levels are altered in African-American (AA) SLE patients with impending disease flare vs. non-flare AA SLE patients. Baseline levels of plasma soluble mediators were assayed in 13 AA SLE patients who experienced disease flare 6–12 weeks post baseline assessment (Flare) vs. 13 demographically matched SLE patients who did not experience a flare (NF). Examined factors included (A) innate mediators, (B) Th1-type mediators, (C) Th17-type mediators, (D) regulatory mediators, (E) IFN-associated chemokines, (F) TNF superfamily, and (G) SCF. Levels are presented as the mean ± SEM. *p<0.05, **p<0.01; ***p<0.001; ****p<0.0001 by Wilcoxon’s matched pairs test.

Figure 2

Soluble mediator levels are altered in African-American (AA) SLE patients with impending disease flare vs. comparable non-flare period. Baseline levels of plasma soluble mediators were assayed in 18 AA SLE patients who experienced disease flare 6–12 weeks post baseline assessment (Flare) vs. comparable non-flare period in the same SLE patients (SNF). Examined factors included (A) innate mediators, (B) Th1-type mediators, (C) Th17-type mediators, (D) regulatory mediators, (E) IFN-associated chemokines, (F) TNF superfamily, and (G) SCF. Levels are presented as the mean ± SEM. *p<0.05, **p<0.01; ***p<0.001; ****p<0.0001 by Wilcoxon’s matched pairs test.

Figure 3

Baseline soluble mediator score, but not baseline clinical disease activity, differentiates African-American (AA) SLE patients with impending disease flare. Baseline SELENA-SLEDAI scores were determined for (A) 13 AA SLE patients who experienced disease flare 6–12 weeks post baseline assessment (Flare) versus 13 race, gender, and age (± 5 years) matched SLE patients with no flare over the 6–12 week follow-up period (non-flare; NF) or (B) scores from 18 AA SLE patients who experienced disease flare 6–12 weeks post baseline assessment (Flare) versus the same patient in year without disease flare (self non-flare; SNF). The soluble mediator score was also calculated for (C) Flare versus NF patients or (D) Flare versus SNF periods. **** p<0.0001 by Wilcoxon’s matched pairs test.