High Interleukin 21 Levels in Patients with Systemic Lupus Erythematosus: Association with Clinical Variables and rs2221903 Polymorphism

Abstract

Background: Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by autoantibody production and diverse tissue and organ inflammatory affections. Interleukin 21 (IL-21) is implicated in B cell survival, proliferation, differentiation, class switching, and immunoglobulin production; therefore, it is considered a key cytokine in the pathogenesis of SLE. However, its association with disease activity and clinical phenotypes remains unclear. We aimed to evaluate the association of IL-21 levels with the disease activity and clinical phenotypes in patients with SLE. Also, we analyzed the IL21 polymorphisms associated with increased IL-21 levels. Methods: The IL-21 serum levels were determined using the enzyme-linked immunosorbent assay (ELISA) method. The rs2221903 and rs2055979 polymorphisms were assessed in 300 healthy controls (HCs) and 300 patients with SLE by the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) technique. The levels of IL-21 were monitored during follow-up visits in 59 patients with SLE. Results: The patients with SLE showed higher IL-21 levels compared to the HCs. The IL-21 levels did not correlate with Mex-SLEDAI and were not different in patients with inactive, mild-moderate, and severe disease. The IL-21 levels were increased in patients with hematological affection. The ROC curve analysis revealed that the IL-21 levels had good predictive power in discriminating among patients with SLE and HCs. In a follow-up analysis, the levels of IL-21 remained higher in the patients with SLE even when the patients were in remission. Also, the rs2221903 polymorphism was associated with increased IL-21 levels. Conclusions: This study highlights the importance of IL-21 as a key cytokine in SLE. IL-21 levels are higher in patients with SLE and remain increased regardless of disease activity. According to the ROC analysis, IL-21 is a potential biomarker of SLE. Further longitudinal studies are needed to explore the relationship between IL-21 and the clinical phenotypes of SLE.

Keywords: IL21 polymorphism; Interleukin 21; systemic lupus erythematosus.

Figure 1

Evaluation of IL-21 levels according to clinical characteristics in patients with SLE. Comparison of IL-21 levels between HCs and patients with SLE (a), IL-21 levels according to disease activity (b), hematological domain (c) and chronicity (d), IL-21 levels according to anti-dsDNA status (e), and IL-21 performance as biomarker diagnosis in SLE (f). Patients with SLE were stratified according to Mex-SLEDAI score as follows: inactive (0–1), mild–moderate (2–6), and severe (≥7) disease. Hematological domain (Hem) included lymphopenia (<1.2 × 10³/µL), leukopenia (<4.0 × 10³/µL), thrombocytopenia (<100 × 10³/µL), and hemolytic anemia. Data are shown as median and IQR. p-value was obtained through Mann–Whitney U test, Kruskal–Wallis test with Dunn’s post hoc test, and Spearman’s correlation test, according to case. Area Under the Curve was calculated through ROC curves. ns, no significative.

Figure 2

Comparison of IL-21 levels in patients with SLE based on type of treatment. Patients with SLE who were either treatment-naïve or treated showed similar concentrations of IL-21 (a) regardless of whether they were undergoing induction or maintenance treatment (b). IL-21 level comparison between patients with SLE at basal and follow-up recruitment stratified according to remission and active disease (c). Paired comparison of IL2-1 in patients with SLE at baseline and follow-up (d), as well as stratified by remission (e) and active (f) disease groups. Data are shown as median and IQR. p-value was obtained through Mann–Whitney U test and Wilcoxon test according to case. ns, no significative.

Figure 3

Comparison of IL-21 levels based on codominant and dominant models of rs2221903 polymorphism (+3268 T>C) in IL21 gene. IL-21 levels according to codominant model (a) and dominant model (b) of rs2055979 polymorphism of IL21 gene. Data are shown as median and IQR. p-value was obtained through Mann–Whitney U test and Kruskal–Wallis test with Dunn’s post hoc test according to case. IQR, interquartile range; HCs, healthy controls; SLE, systemic lupus erythematosus.