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.

Interleukin-35 as a New Biomarker of Renal Involvement in Lupus Nephritis Patients

“…Previous investigators have reported that chemokines took part in inflammation via attracting T cells in the target organ (Cao et al 2003;Liao et al 2017). Moreover, increased levels of chemokines in SLE were well confirmed (Wong et al 2008;Munroe et al 2017), and might lead to the accumulation of IL-35 in renal tissue. This, in part, may explain the decrease in serum concentrations of IL-35 in LN patients.…”

“…Production of autoantibody and immune complex deposition with subsequent infiltration of inflammatory cells, and perturbed cytokine activities are central to both onset and progression of renal pathology (Waldman and Madaio 2005;Rahman and Isenberg 2008;Munroe et al 2017). Furthermore, it has been suggested by several studies that regulatory T cells (Treg), as well as its associated cytokines such as interleukin , play a pivotal role in the progression of SLE (Valencia et al 2007;Bonelli et al 2008;Tselios et al 2014;Cai et al 2015a, b).…”

Adults with systemic lupus exhibit distinct molecular phenotypes in a cross-sectional study

“…In a large, longitudinal cohort of pediatric SLE patients, Banchereau and colleagues [18] identified transcriptional modules that change over time with disease activity and identify clinical subsets of pediatric SLE patients. In addition, our group has identified soluble mediators, including cytokines, chemokines, adhesion molecules, and soluble receptors that associate with risk of SLE disease flare [19,20]. Although the specific pathways that distinguish an impending disease flare differ somewhat between European American and African American cohorts and likely vary between individual patients, an assay that simultaneously surveys multiple immune pathways accurately identified SLE patients at higher risk of future enhanced disease activity [19,20].…”

Biomarkers in connective tissue diseases

“…A combined soluble mediator score incorporating 52 analytes was increased in patients with impending flare compared to either matched stable patients or the same patients during a clinically stable period. 44, 45 This score accurately predicted flare in both European American and African American study groups. Accurate prediction of SLE flare may allow early treatment or prevention of flares.…”