Hemophagocytic Lymphohistiocytosis Gene Variants in Childhood-Onset Systemic Lupus Erythematosus With Macrophage Activation Syndrome.

OBJECTIVE: Macrophage activation syndrome (MAS), a life-threatening complication of systemic lupus erythematosus (SLE), resembles familial hemophagocytic lymphohistiocytosis (HLH), an inherited disorder of hyperinflammation. We compared the proportion of patients with childhood-onset SLE (cSLE) with and without MAS who carried low-frequency HLH nonsynonymous variants. METHODS: We enrolled patients from the Lupus Clinic at SickKids, Toronto. Demographic and clinical features were extracted from the SLE database and ancestry was genetically inferred using multiethnic genotyping array data. Patients with MAS (based on expert diagnosis) underwent either paired-end whole-exome sequencing (WES; read depth: 70-118X) or whole-genome sequencing (WGS). Patients without MAS had WGS (read depth: 37-40X). In 16 HLH genes, we prioritized low-frequency (minor allele frequency [MAF] < 0.05) exonic nonsynonymous variants. We compared the proportion of patients with and without MAS carrying HLH variants (Fisher exact test, P < 0.05). MAFs were compared to an ancestrally matched general population (Trans-Omics for Precision Medicine [TOPMed] and Genome Aggregation Database [gnomAD]). RESULTS: The study included 81 patients with cSLE, 19 of whom had MAS. We identified 47 unique low-frequency nonsynonymous HLH variants. There was no difference in the proportion of patients with and without MAS carrying ≥ 1 HLH variants (37% vs 47%, P = 0.44). The MAS cohort did not carry more HLH variants when compared to an ancestrally matched general population. CONCLUSION: In a single-center multiethnic cSLE cohort, we found no difference in the proportion of patients with MAS carrying nonsynonymous HLH genetic variants compared to patients without MAS. To our knowledge, this is the first study to examine the frequency of HLH genetic variants in relation to MAS among patients with cSLE. Future studies are required to validate our findings.

Impact of Disease Duration on Vascular Surrogates of Early Atherosclerosis in Childhood-Onset Systemic Lupus Erythematosus.

OBJECTIVE: To determine whether longer disease duration negatively impacts carotid intima-media thickness (CIMT), flow-mediated dilation (FMD), and pulse wave velocity (PWV) in a cohort of patients with childhood-onset systemic lupus erythematosus (SLE), and to compare CIMT, FMD, and PWV in patients with childhood-onset SLE with those in healthy children and explore determinants of vascular test results in childhood-onset SLE. METHODS: Cross-sectional analysis was performed in a prospective longitudinal cohort of patients with childhood-onset SLE at the latest followup visit. Clinical and laboratory data were collected for patients with childhood-onset SLE. CIMT, FMD, and PWV were measured using standardized protocols in patients with childhood-onset SLE and healthy children. Correlations between disease duration and results of the 3 vascular tests were performed. Vascular data in patients with childhood-onset SLE were compared with those in healthy children. Multivariable linear regression was used to identify determinants of CIMT, FMD, and PWV in childhood-onset SLE. RESULTS: Patients with childhood-onset SLE (n = 149) and healthy controls (n = 178) were enrolled. The median age of the patients was 17.2 years (interquartile range [IQR] 15.7-17.9 years), and their median disease duration was 3.2 years (IQR 1.8-4.9 years). The median age of the healthy children was 14.7 years (IQR 13.1-15.9 years). Longer disease duration correlated with worse FMD (r = -0.2, P = 0.031) in patients with childhood-onset SLE. Patients with childhood-onset SLE had smaller (better) CIMT, higher (better) FMD, and similar PWV compared with healthy controls. Linear regression analysis explained <24% of the variation in vascular test results in patients with childhood-onset SLE, suggesting that other variables should be explored as important determinants of CIMT, FMD, and PWV. CONCLUSION: In this cohort of 149 patients with childhood-onset SLE, patients did not have worse CIMT, FMD, or PWV than did healthy controls. Longer disease duration was associated with worse FMD, suggesting progressive endothelial dysfunction over time.