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Virginia Pascual, MD, Peter Nigrovic, MD, Linda Hiraki, MD, Carola Garcia de Vinuesa, MD, PhD and Deepak Rao, MD, PhD

Weill Medical College of Cornell University, Boston Children's Hospital, The Hospital for Sick Children, The Australian National University and The Brigham and Women’s Hospital

Molecular fingerprinting of lupus in children

The Global Team Science Award project led by Dr. Virginia Pascual aims to study childhood-onset systemic lupus erythematosus (cSLE) to understand not only lupus in children but the onset at any age for the following reasons: cSLE is very severe in the symptoms children present with as well as the consequences of lupus and its treatment; children with lupus often have a strong connection between their genetic makeup (DNA) and their disease; children also lack other illnesses that could complicate the understanding of research findings.

Dr. Pascual’s team of Lupus of Early Onset (LEO) investigators will perform a two-part project. The first project will track 75 pediatric SLE patients at multiple timepoints from when they first develop the disease and at various timepoints to record the type, features and activities of immune cells and antibodies present in their blood. Investigators will compare these results to data they already have on hand from other studies investigating lupus in humans and from preclinical models mimicking lupus disease in humans. Investigators will do this comparison to pinpoint biomarkers which may be used to separate patients into major disease groups within pediatric SLE. The second project will study the genetic makeup of more than 700 pediatric SLE patients and their family members to determine which alterations in the genetic makeup of children with SLE (relative to their family members) can serve as a predictor of major pediatric SLE disease groups identified in project 1. This will allow Dr. Pascual’s team to characterize, as never before, the full extent to which patterns in their DNA contribute to disease risk. Ultimately, this can help form the basis for personalized therapy for people with lupus of any age.

What this study means for people with lupus:

“Together, these studies represent the largest and most comprehensive investigation of childhood lupus to date.,” said Dr. Pascual. “Our findings will begin to penetrate the veil of complexity surrounding lupus, ultimately allowing us to understand which patients – children or adults – are likely [to] respond best to specific treatments.”

Childhood-onset systemic lupus erythematosus (cSLE) is life-changing because of its unusual severity and the intrinsic vulnerability of the children affected. It also represents a remarkable scientific opportunity. Lupus presenting in very young children is commonly monogenic in origin, while onset in later childhood or adolescence typically reflects enrichment for lower-penetrance risk variants. Further, compared with adults, children present with fewer of comorbidities to confound immunophenotyping data. Together, these features render cSLE especially suitable to define distinct pathways to disease that will form the basis for personalized therapy for lupus presenting at any age.

The Lupus of Early Onset (LEO) investigators are an international team of 5 Co-PIs (Pascual, Nigrovic, Hiraki, Rao, Vinuesa) and 5 co-investigators (Elemento, Gutierrez-Arcelus, Lewandowski, Vogel, Baxter) who here propose the hypothesis that cSLE represents distinct biological subgroups that can be identified through multi-modal clinical, immune, and genetic profiling. We approach this hypothesis in >700 cSLE patients collected by LEO investigators at major research hubs and in the Center for Disease Control (CDC)-sponsored Childhood Arthritis & Rheumatology Research Alliance (CARRA) SLE Registry. This work will proceed in two interconnected and synergistic Projects.

In Project 1, we will stratify cSLE patients according to multi-modal correlates of disease activity based on deep immunophenotyping. In 75 cSLE patients followed longitudinally from disease onset, we will perform serial whole-blood RNAseq, CyTOF, CITE-seq with B cell and T cell receptor repertoires at the single-cell level, and deep antibody profiling. Defining features that vary directly with disease activity, informed by data from new murine models of monogenic human lupus, we will develop comprehensive biomarkers that define major pathophysiologic groups within cSLE.

In Project 2, we will perform whole genome sequencing in >700 closely phenotyped patients across the full spectrum of cSLE, complemented by sequencing of 60 family members of cSLE patients selected as especially informative with respect to novel genetic causes of disease. We will categorize rare and common variants by biological pathways to develop genetic risk scores predictive of the immunophenotypes defined in Project 1 and, secondarily, other clinical and molecular phenotypes.

Together, these studies represent the largest and most comprehensive investigation of cSLE to date, providing a unique opportunity to overcome the intrinsic heterogeneity of lupus. Ultimately, this strategy will contribute to the identification of robust biomarkers to stratify patients and predict their response to targeted therapeutic interventions.

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