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

Comment on: Moroni G, Gatto M, Tamborini F, et al. Lack of EULAR/ERA-EDTA response at 1 year predicts poor long-term renal outcome in patients with lupus nephritis. Ann Rheum Dis 2020; 79:1077-1083. Link: https://ard.bmj.com/content/79/8/1077

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.

Lupus nephritis (LN) is the most common severe organ involvement of Systemic lupus erythematosus (SLE), affecting 25 to 60% of patients. In developed countries, the estimated 5-year risk of end-stage renal disease (ESRD) is 11%, and in patients with diffuse proliferative LN up to 40% of patient can develop ESRD in the long-term, despite standard-of-care treatment of LN.1 So far, tested composite and single short-term variables did not univocally function as long-term prognostic markers of chronic kidney disease (CKD). Identification of reliable short-term predictors is an unmet need in clinical practice to help guiding treatment decisions. In this study, Moroni et al tested the ability of the EULAR/ERA-EDTA definition of response 2 to therapy at 1 year, along with covariates, to predict the long-term development of CKD. The study included 381 patients, mostly Caucasians, from 3 Italian referral centres, with biopsy-proven LN that received induction treatment between 1970 and 2016 and with a median follow-up of 10.7 years. In this cohort, 26% and 58% achieved partial and complete renal response, respectively, one year after starting induction treatment for LN. Independent predictors of CKD in multivariable analysis, were: no EULAR/ERA-EDTA response at 12 months (HR 5.165, 95% CI 2.770 to 7.628), and persistent arterial hypertension (HR 3.154, 95% CI 1.500 to 4.547). This study may have been underpowered to discriminate between complete and partial renal response to prevent CKD.

These results provide evidence for the importance of achieving early response to treatment of LN to maximize the chances of long-term renal survival. There is still an unmet need for identifying early predictors of response to induction treatment that can guide the clinician to adjust therapy in order to optimise the chance of reaching renal remission up to 12 months. The rate of complete renal response at 1 year remains low and new therapies and treatment strategies are needed.

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 Maggio 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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