Background/Purpose: Childhood-onset Systemic Lupus Erythematosus (cSLE) is a clinically heterogeneous autoimmune disease. We hypothesized that similarity network fusion (SNF) a data driven method would identify relatively clinically homogeneous subgroups of patients that may represent SLE endotypes with distinct genetics.

Methods: We included patients diagnosed with cSLE between January 1992-October 2023. All patients met 2019 ACR-EULAR classification criteria and were genotyped on an Illumina multiethnic array. Ungenotyped SNPs were imputed with TopMed as a referent. We extracted SLE manifestations, date of each manifestation onset and demographic characteristics from a dedicated Lupus database. Ancestry was genetically inferred using principal components and ADMIXTURE with 1000 Genomes as a referent. We used time to each SLE manifestation onset from SLE diagnosis to identify patient subgroups with SNF. We conducted Kaplan Meir analyses and ran Cox proportional-hazard models on the time from SLE diagnosis to onset of specific manifestations between SNF clusters. We tested cluster differences in demographic and manifestation prevalences using χ² or Fisher’s exact test, and time to each SLE manifestation onset with log rank tests. We calculated additive, allelic weighted SLE non-HLA and HLA polygenic risk scores (PRS) using alleles from a transancestral GWAS of SLE. Models adjusted for sex and ancestry determined the relationship between PRS and cluster membership.

Results: Our cohort included 442 cSLE patients. 83% were female and the median age of SLE diagnosis was 13.6 years (Q1-Q3:12.0-15.8). Our cohort was primarily composed of patients of European (27%) and East Asian (26%) ancestry. SNF identified 2 clusters. The majority of patients in cluster 1 (n=203) were of European ancestry (42%) and cluster 2 (n=239) had a high prevalence of patients of East Asian (30%) and South Asian (22%) ancestry (P=3×10^-9; Figure 1). Patients in cluster 2 had a higher prevalence, and earlier onset of class III/IV lupus nephritis, hypocomplementemia, fever, anti-dsDNA and anti-Smith antibodies compared to patients in cluster 1 (P< 1×10^-7; Figure 2). The risk of developing 12 cSLE manifestations at any point in time was higher in patients in cluster 2 compared to cluster 1 (HR >1.4;P<4×10^-3). SLE PRSs were not associated with cluster membership (Non-HLA SLE PRS: OR 0.9, 95% CI 0.8-1.2; P=0.5; HLA SLE PRS: OR 1.3, 95% CI 0.8-2.0;P=0.3).

Conclusion: In a large multiethnic cohort of cSLE patients, we used data-driven methods to identify two cSLE patient clusters. The cluster with more severe disease and earlier onset had a greater proportion East Asian and South Asian patients compared to the cluster with milder disease. Next steps include an HLA-wide analysis of cluster membership.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/identifying-homogeneous-endophenotypes-in-childhood-onset-systemic-lupus-erythematosus-with-similarity-network-fusion/