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

Davies, Joseph E.; Midgley, Angela; Carlsson, Emil; Donohue, S.; Bruce, Ian N.; Beresford, Michael W.; Hedrich, Christian M.

doi:10.1136/rmdopen-2020-001257

Cited by 31 publications

(25 citation statements)

References 37 publications

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“…35 Additionally, a combination of serum S100A8/A9 and S100A12 was shown to predict rituximab treatment response in lupus nephritis. 36 The expression of the proinflammatory proteins S100A9 and S100A12 was found to be significantly increased in monocytes and neutrophils at day five after rituximab treatment. Conversely, S100A8/A9 and S100A12 serum levels significantly decreased and therefore secretion by effector cells is lower at day five after treatment.…”

Section: Discussionmentioning

confidence: 93%

Characterization of tumor response after administration of rituximab in pediatric B-NHL

Bethke¹,

Varga²,

Weinhage³

et al. 2021

Preprint

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Background Mature aggressive B-cell lymphoma are heterogenous malignancies that make up more than half of all diagnosed Non-Hodgkin lymphoma in children and adolescents. The overall survival rate increased over the last decades to 80–90%, due to fine tuning of polychemotherapy. However, new therapeutic implications are needed to further increase the overall survival. Current clinical trials analyze the therapeutic effect of rituximab in pediatric patients, while the mechanism of action in vivo is still not fully understood. Methods Effector molecules important for tumor defense were analyzed before and at day five after rituximab treatment via flow cytometry. Serum rituximab levels were measured with an ELISA. Results We evaluated patient parameters that may affect treatment response in relation to rituximab administration and serum rituximab levels. We indeed found a reduction of FcγRII levels after rituximab treatment in monocyte subtypes, while FcγRI expression was significantly increased, pointing to exhaustion of FcγRII mediated B cell depletion and compensation via FcγRI mediated trogocytosis. Serum levels of proinflammatory marker proteins S100A8/A9 and S100A12 significantly decreased after treatment to normal levels from an overall proinflammatory state before treatment. CD57, perforin and granzyme B expression decreased after treatment, probably due to exhaustion of NK cells. Conclusion The highlighted effects of rituximab treatment on patient’s immune response help understanding the biology behind tumor defense mechanisms and effector function. After subsequent studies, these novel insights might be translated into patient care and could contribute to improve treatment of pediatric patients with mature aggressive B-cell lymphoma.

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Section: Discussionmentioning

confidence: 93%

Characterization of tumor response after administration of rituximab in pediatric B-NHL

Bethke¹,

Varga²,

Weinhage³

et al. 2021

Preprint

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“…Taken together, our results emphasise the need to identify novel biomarkers that will improve the predictive accuracy for treatment response in patients with SLE over and above the modest performance of clinical factors alone. Urinary biomarkers have recently been demonstrated to predict treatment response to rituximab in LN at 6 months 35. Adding such factors into our models would likely further improve their predictive value.…”

Section: Discussionmentioning

confidence: 98%

Predictors of treatment response in a lupus nephritis population: lessons from the Aspreva Lupus Management Study (ALMS) trial

McDonald

Yiu

et al. 2022

Lupus Sci Med

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ObjectivesTo identify predictors of overall lupus and lupus nephritis (LN) responses in patients with LN.MethodsData from the Aspreva Lupus Management Study (ALMS) trial cohort was used to identify baseline predictors of response at 6 months. Endpoints were major clinical response (MCR), improvement, complete renal response (CRR) and partial renal response (PRR). Univariate and multivariate logistic regressions with least absolute shrinkage and selection operator (LASSO) and cross-validation in randomly split samples were utilised. Predictors were ranked by the percentage of times selected by LASSO and prediction performance was assessed by the area under the receiver operating characteristics (AUROC) curve.ResultsWe studied 370 patients in the ALMS induction trial. Improvement at 6 months was associated with older age (OR=1.03 (95% CI: 1.01 to 1.05) per year), normal haemoglobin (1.85 (1.16 to 2.95) vs low haemoglobin), active lupus (British Isles Lupus Assessment Group A or B) in haematological and mucocutaneous domains (0.61 (0.39 to 0.97) and 0.50 (0.31 to 0.81)), baseline damage (SDI>1 vs =0) (0.38 (0.16 to 0.91)) and 24-hour urine protein (0.63 (0.50 to 0.80)). LN duration 2–4 years (0.43 (0.19 to 0.97) vs <1 year) and 24-hour urine protein (0.63 (0.45 to 0.89)) were negative predictors of CRR. LN duration 2–4 years (0.45 (0.24 to 0.83) vs <1 year) negatively predicted PRR. The AUROCs of models for improvement, CRR and PRR were 0.56, 0.55 and 0.51 respectively.ConclusionsBaseline variables predicted 6-month outcomes in patients with SLE. While the modest performance of models emphasises the need for new biomarkers to advance this field, the factors identified can help identify those patients who may require novel treatment strategies.

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“…Davies et al. ( 37 ) found that serum and urine S100A8 levels were elevated in patients with SLE, and the urine/serum ratios were elevated in patients with active LN. Tantivitayakul et al.…”

Section: Discussionmentioning

confidence: 99%

Glomerular Expression of S100A8 in Lupus Nephritis: An Integrated Bioinformatics Analysis

et al. 2022

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IntroductionLupus nephritis (LN) is a major risk factor of morbidity and mortality. Glomerular injury is associated with different pathogeneses and clinical presentations in LN patients. However, the molecular mechanisms involved are not well understood. This study aimed to explore the molecular characteristics and mechanisms of this disease using bioinformatics analysis.MethodsTo characterize glomeruli in LN, microarray datasets GSE113342 and GSE32591 were downloaded from the Gene Expression Omnibus database and analyzed to determine the differentially expressed genes (DEGs) between LN glomeruli and normal glomeruli. Functional enrichment analyses and protein–protein interaction network analyses were then performed. Module analysis was performed using the Search Tool for the Retrieval of Interacting Genes/Proteins and Cytoscape software. Immunofluorescence staining was performed to identify the glomerular expression of S100A8 in various International Society of Nephrology/Renal Pathology Society (ISN/RPS) class LN patients. The image of each glomerulus was acquired using a digital imaging system, and the green fluorescence intensity was quantified using Image-Pro Plus software.ResultsA total of 13 DEGs, consisting of 12 downregulated genes and one upregulated gene (S100A8), were identified in the microarray datasets. The functions and pathways associated with the DEGs mainly include inflammatory response, innate immune response, neutrophil chemotaxis, leukocyte migration, cell adhesion, cell–cell signaling, and infection. We also found that monocytes and activated natural killer cells were upregulated in both GSE113342 and GSE32591. Glomerular S100A8 staining was significantly enhanced compared to that in the controls, especially in class IV.ConclusionsThe DEGs identified in the present study help us understand the underlying molecular mechanisms of LN. Our results show that glomerular S100A8 expression varies in different pathological types; however, further research is required to confirm the role of S100A8 in LN.

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

Cited by 31 publications

References 37 publications

Characterization of tumor response after administration of rituximab in pediatric B-NHL

Characterization of tumor response after administration of rituximab in pediatric B-NHL

Predictors of treatment response in a lupus nephritis population: lessons from the Aspreva Lupus Management Study (ALMS) trial

Glomerular Expression of S100A8 in Lupus Nephritis: An Integrated Bioinformatics Analysis

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