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Lupus nephritis: New predictors of renal outcomes and treatment strategies.

Comment on Vanarsa K, Soomro S, Zhang T, et al. Quantitative planar array screen of 1000 proteins uncovers novel urinary protein biomarkers of lupus nephritis. Ann Rheum Dis 2020; 79:1349-1361. Link: https://ard.bmj.com/content/79/10/1349

Commented by: Luís Sousa Inês, MD, PhD. CHUC Lupus Clinic, Rheumatology Department. Centro Hospitalar Universitário de Coimbra (CHUC). Coimbra, Portugal. Faculty of Health Sciences. University of Beira Interior. Covilhã, Portugal.

Discovering biomarkers of lupus nephritis (LN) from blood or urine could greatly facilitate longitudinal monitoring of SLE patients at regular intervals in order to closely track and predict LN disease activity, progression and treatment response to guide tailored therapy accordingly. So far, many studies have failed to find biomarkers of LN reliable for use in clinical practice. In this study by Vanarsa et al., it was used a novel microarray to screen and quantify 1000 proteins in the urine of 24 subjects (15 with active SLE and 9 healthy controls) in order to identify potential urinary biomarkers for renal involvement in patients with SLE. Screening revealed 64 proteins to be significantly elevated in SLE urine, of which 17 were selected for ELISA validation in an independent cohort of 78 subjects (SLE patients with inactive, active non-renal and active LN, and healthy controls), a cohort of 20 LN patients with concurrent renal biopsies, a longitudinal cohort of 7 SLE patients, and a cohort of 47 non-SLE patients with chronic kidney disease. Emerged as novel biomarkers in the urine: Angptl4, L-selectin, TPP1, TGFβ1, TSP-1, FOLR2 and PDGF-Rβ, that successfully distinguished active LN patients from active non-renal lupus patients. Urine Angptl4, L-selectin and TPP1, in combination, offered the best discrimination of active LN from active non-renal SLE, with an area under the receiver operating curves of 0.97.

This study uncovers novel urinary protein biomarkers that shows promise at tracking concurrent or pending LN flares. Additional longitudinal studies with larger sample size and more representative of the SLE population is warranted to investigate how these urinary molecules relate to renal pathology, disease progression, treatment response over time and long-term renal and patient outcome.

References:

  1. Tektonidou M, Dasgupta A, Ward MM. Risk of End-Stage Renal Disease in Patients With Lupus Nephritis, 1971–2015. A Systematic Review and Bayesian Meta-Analysis. Arthritis Rheum 2016; 68:1432-1441.
  2. Fanouriakis A, Kostopoulou M, Cheema K, et al. 2019 Update of the Joint European League Against Rheumatism and European Renal Association–European Dialysis and Transplant Association (EULAR/ERA–EDTA) recommendations for the management of lupus nephritis. Ann Rheum Dis 2020; 79:713-723.
  3. Houssiau FA, Vasconcelos C, D’Cruz D, et al. Immunosuppressive therapy in lupus nephritis: the Euro-Lupus Nephritis Trial, a randomized trial of low-dose versus high-dose intravenous cyclophosphamide. Arthritis Rheum 2002; 46: 2121-31.
  4. Ward M, and Tektonidou MG. Belimumab as Add-on Therapy in Lupus Nephritis. N Engl J Med 2020; 383:1184-1185.
  5. Atisha-Fregoso Y, Malkiel S, Harris KM, et al. CALIBRATE: A Phase 2 Randomized Trial of Rituximab Plus Cyclophosphamide Followed by Belimumab for the Treatment of Lupus Nephritis. Arthritis Rheumatol 2020 Aug 4. [Epub ahead of print] doi: 10.1002/art.41466.

A high burden of SLE risk genes is associated with persistent activation of the interferon system in patients with lupus.

25 May 2026

Comment on: Single-cell RNA-seq reveals a persistent interferon signature in immune cells from  systemic lupus erythematosus patients with high versus low polygenic risk scores despite antimalarial  treatment. J Autoimmun. 2026 May 12:161:103575. doi: 10.1016.  Commented by: Lars Rönnblom, Department of Medical Sciences, Uppsala University, Sweden.    Genome-wide association studies have identified more than 300 loci associated to increased risk for  SLE. For the majority of the gene variants in these loci the functional consequences in the SLE disease  process are unknown. However, a large proportion of identified risk genes are connected to the  interferon signaling pathway and contribute to the interferon signature in SLE. Calculating a polygenic  risk score (PRS) is a method to quantify the cumulative genetic burden in a single patient and studies  have shown that patients with a high PRS have a more severe disease phenotype with increased  organ damage and reduced survival, compared to individuals with a low PRS.   Antimalarial therapy is a well-established treatment of SLE and have shown efficacy in a large  proportion of patients. The therapeutic effect is partly mediated by down regulation of the activated  interferon system, which is connected to clinical response. However, despite therapeutic  concentrations of hydroxychloroquine, many patients still have flares and accumulation of organ  damage. The main objective of the present study was therefore to clarify if antimalarial treatment has  different effects in patients with a high or a low PRS.  SLE patients in remission with a high or a low PRS were compared in gene expression profile at single  cell level on peripheral blood mononuclear cells. A total of 6 healthy controls and 16 matched  patients treated with similar antimalarial doses, but no corticosteroids, were investigated. On  average, 9636 cells were analyzed from each donor and 2724 genes detected per cell. Despite similar  clinical picture, patients with a high PRS had a prominent interferon signature across multiple  immune cell types, compared to patients with a low PRS who had a weak expression of interferon  stimulated genes only in monocytes. Pathway analysis revealed that the interferon signaling pathway 

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