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Lupus nephritis biomarkers: moving toward an omic-driven approach

Presented by
Prof. Chaim Putterman, Albert Einstein College of Medicine, USA
ACR 2020
Lupus nephritis affects up to 60% of patients with systemic lupus erythematosus. Current biomarkers are not reliable, but a novel “omic”-driven approach might be a more successful way for risk prediction.

“In lupus nephritis, we believe that ‘time is kidney’,” said Prof. Chaim Putterman (Albert Einstein College of Medicine, USA) [1]. Lupus nephritis (LN) is a major risk factor for morbidity and mortality in systemic lupus erythematosus (SLE). According to a study, delay between the detection of the onset of renal disease and renal biopsy was a significant predictor for subsequent renal insufficiency and death due to lupus renal involvement. Therefore, biomarkers are of particular importance in LN, because early diagnosis and treatment make a difference. Prompt therapy with prednisone and immunosuppressive agents in LN has a beneficial effect on long-term prognosis.

Unfortunately, increasing double-stranded (ds)DNA antibodies, presently used as biomarkers, were predictive of flares in some, but not all, studies. Therefore, more reliable flare predictors are urgently needed. There is a need for better biomarkers for differentiating lupus versus other diseases, measuring disease activity, predicting outcomes/response to therapy, allowing assessment of response to therapy, and predicting long-term prognosis.

Promising agents are cell-bound complement activation products (CB-CAPs). Studies have shown that CB-CAPs can be helpful in the diagnosis of lupus and are more reliable than anti-dsDNA. Abnormalities in CB-CAPs are associated with higher disease severity in lupus patients.

“Terminal complement activation has also been assessed as a possible biomarker in LN. Tubular C9-positive staining was observed in 23% of biopsies of patients with LN and those patients had significantly higher proteinuria, interstitial fibrosis, and chronicity indices,” Prof. Putterman explained.

Big data are the new kid on the block, namely “omics”-driven research instead of hypothesis-driven research. In this approach, instead of a single marker, rather all molecules are assessed, so in more breadth than depth. “Instead of focusing on an individual molecule, we are profiling many analytes simultaneously. If you look at 5, 6, or 7 markers at a time, those perform much better than just a single mediator,” Prof. Putterman stated. In one study, 1,000 proteins in the urine of SLE patients were assessed using a quantitative planar protein microarray. In this study, the proteins angptl4, L-selectin, and TGF-β1 were associated with disease activity and were best at tracking concurrent or pending disease flares.

Concerning LN, urine proteins that best distinguish active LN from inactive disease are ALCAM, VCAM-1, Hemopexin, and TFP-1. The CD6-ALCAM pathway is an important driver of inflammation in LN and may also be an interesting target for drug development. Itolizumab is the first antibody that binds to CD6 and decreases pro-inflammatory cytokine secretion. It is now entering a phase-1 trial.

However, anti-dsDNA antibodies and complement components are still the best markers for early diagnosis of LN available today. “My prediction is that the goals of precision medicine in SLE will be realised through big data approaches, rather than tests on single mediators,” Prof. Putterman concluded.

  1. Putterman C. New biomarkers in lupus nephritis. 4S060, ACR Convergence 2020, 5-9 Nov.

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