In Childhood SLE, Quest for Biomarkers Is Making Progress

Several potential biomarkers have emerged, although most still require significant validation before they can be used in the clinic.

The goal of finding biomarkers for childhood onset systemic lupus erythematosus (SLE) is still a work in progress, although new research is helping to create momentum, particularly with regard to lupus nephritis (LN) biomarkers, according to a new report in Rheumatic Disease.

About 1 in 5 cases of SLE globally begin during childhood, and patients whose SLE begins in childhood face a greater risk of renal involvement and end-stage renal disease (ESRD), said co-authors Ellen M. Cody, MD, and Hermine I. Brunner, MD, MSc, MBA, both of Cincinnati Children’s Hospital Medical Center.

“Notably, about 10% of children with proliferative LN progress to ESRD within 5 years of diagnosis,” they noted.

Early identification and treatment can significantly reduce that risk, a fact that makes finding meaningful biomarkers all the more important, they added. Kidney biopsy remains the most reliable way to diagnose childhood SLE, and several urine-based biomarkers have been investigated. However, no single biomarker has yet to emerge as a reliable indicator of SLE, Cody and Brunner said.

Meanwhile, more success has been found looking at combination biomarkers. For instance, an algorithm called renal activity index of lupus (RAIL) uses 6 urinary proteins and has been shown to predict 90% of cases with high LN activity. RAIL uses monocyte chemoattractant protein 1, neutrophil gelatinase-associated lipocalin, kidney inflammation molecule 1, adiponectin, ceruloplasmin, and hemopexin.

A different combination biomarker panel assesses alpha-1-acid glycoprotein (AGP), ceruloplasmin (CP), lipocalin-like prostaglandin D synthase, and transferrin. Separate studies have shown this assay has an ability to identify cases of LN with high accuracy, the investigators said. AGP was able to predict upcoming LN flares, and CP was associated with renal remission. Still, the only urinary biomarkers currently approved for clinical use are urinalysis and urine-protein-to-creatinine ratio, the investigators said.

There are also 4 other biomarkers—antibodies against nucleosomes, complement component 1q, glomerular basement membrane, and serum high-mobility group box 1 protein—that appear to be more present in serum samples of patients with LN and that have been shown to have a greater than 90% ability to predict LN in patients with childhood SLE, the authors said.

The authors also said aberrant noninflammatory clearance of neutrophils is associated with SLE, but it is not yet clear whether the neutrophil extracellular traps burden can be used to single out SLE from other rheumatic diseases. Research into microRNA signatures has shown potential, but Cody and Brunner said larger validation cohorts would be needed to prove the efficacy of such biomarkers. Lastly, hypo- and hypermethylation of certain genes have been associated with childhood SLE and could prove to be notable biomarkers for childhood SLE and inflammatory burden, the investigators said.

Looking at the situation as a whole, Cody and Brunner wrote that significant progress is being made.

“Biomarkers of LN activity are the furthest along in that several identified urine biomarkers and biomarker panels seem to accurately capture active renal inflammation and anticipate the course of LN,” they concluded. Yet, these biomarkers can only make a difference in the clinic if they are further validated and if easy-to-use commercial platforms are developed, they concluded.

Reference

Cody EM, Brunner HI. Biomarkers in childhood-onset systemic lupus erythematosus. Rheum Dis Clin North Am. 2022;48(1):271-285. doi:10.1016/j.rdc.2021.09.003