Urine and serum S100A8/A9 and S100A12 associate with active lupus nephritis and may predict response to rituximab treatment

Jennifer C Davies, Angela Midgley, Emil Carlsson, Sean Donohue, Ian N Bruce, Michael W Beresford, Christian M Hedrich, Jennifer C Davies, Angela Midgley, Emil Carlsson, Sean Donohue, Ian N Bruce, Michael W Beresford, Christian M Hedrich

Abstract

Background: Approximately 30% of patients with the systemic autoimmune/inflammatory disorder systemic lupus erythematosus (SLE) develop lupus nephritis (LN) that affects treatment and prognosis. Easily accessible biomarkers do not exist to reliably predict renal disease. The Maximizing SLE Therapeutic Potential by Application of Novel and Systemic Approaches and the Engineering Consortium aims to identify indicators of treatment responses in SLE. This study tested the applicability of calcium-binding S100 proteins in serum and urine as biomarkers for disease activity and response to treatment with rituximab (RTX) in LN.

Methods: S100A8/A9 and S100A12 proteins were quantified in the serum and urine of 243 patients with SLE from the British Isles Lupus Assessment Group Biologics Register (BILAG-BR) study and 48 controls matched for age using Meso Scale Discovery's technology to determine whether they perform as biomarkers for active LN and/or may be used to predict response to treatment with RTX. Renal disease activity and response to treatment was based on BILAG-BR scores and changes in response to treatment.

Results: Serum S100A12 (p<0.001), and serum and urine S100A8/A9 (p<0.001) levels are elevated in patients with SLE. While serum and urine S100 levels do not correlate with global disease activity (SLE Disease Activity Index), levels in urine and urine/serum ratios are elevated in patients with active LN. S100 proteins perform better as biomarkers for active LN involvement in patients with SLE who tested positive for anti-double-stranded DNA antibodies. Binary logistic regression and area under the curve analyses suggest the combination of serum S100A8/A9 and S100A12 can predict response to RTX treatment in LN after 6 months.

Conclusions: Findings from this study show promise for clinical application of S100 proteins to predict active renal disease in SLE and response to treatment with RTX.

Keywords: Arthritis; Cytokines; Inflammation; Juvenile; Lupus Erythematosus; Psoriatic; Systemic.

Conflict of interest statement

Competing interests: None declared.

© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY. Published by BMJ.

Figures

Figure 1
Figure 1
Serum and urine S100 protein levels in patients with SLE and controls. A total of 235 patients with SLE and 48 age-matched controls were analysed for S100 protein concentrations in the serum (A, B; n=235) and urine (C, D; n=192). Differences were tested using Mann-Whitney tests. Next, patients with SLE were grouped based in disease activity (E–H; SLEDAI scores: 0–4 ‘no/mild’ activity (n=61), 5–10 ‘moderate’ (n=87), and ≥11 ‘high/very high’ (n=81). S100 protein concentrations in serum (E–F; n=229) and urine (G, H; n=187) samples are displayed. Differences were tested using Kruskal-Wallis test with Dunn’s multiple comparison post hoc test were applied. HC, healthy controls; SLE, systemic lupus erythematosus; SLEDAI, SLE Disease Activity Index.
Figure 2
Figure 2
Serum and urine S100 protein levels indicate active renal disease. Serum and urine samples from 133 patients with SLE with active renal disease and from 85 patients without or inactive renal disease were included. While S100A8/A9 serum levels did not differ between (A), Serum S100A12 (B), urine S100A8/A9 (C) and S100A12 (D) levels were increased in patients with SLE with active when compared with inactive or no renal disease. Findings were reflected by S100 ratios between urine and serum (E, F). Differences were tested using Mann-Whitney U tests. SLE, systemic lupus erythematosus.

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