Objective Macrophage activation syndrome (MAS), a life-threatening inflammatory complication, is increasingly recognized in childhood-onset SLE (cSLE). It can be a challenge to differentiate active cSLE from MAS. We generated decision rules for discriminating MAS from active cSLE in newly diagnosed patients. Methods We conducted a retrospective cohort study of consecutive, newly diagnosed, active cSLE patients with fever, requiring hospital admission to SickKids from January 2003 - December 2007 (cohort 1), and January 2008 - December 2013 (Cohort 2). All patients met ≥4 ACR or SLICC criteria, were steroid naïve and infection free. MAS was diagnosed based on expert opinion. Recursive partitioning was applied to each cohort to derive a decision rule based on clinical and laboratory features, distinguishing MAS from non-MAS cSLE. Each decision rule was applied to the alternate, independent cohort. Sensitivity and specificity of these decision rules were compared to existing criteria. Results Cohort 1 (n=34) and cohort 2 (n=41) each had 10 MAS patients. Recursive partitioning in cohort 1 identified ferritin ≥699 μg/L, as the sole best discriminator between MAS and non- MAS patients (R2=0.48) and in cohort 2 ferritin ≥1107 μg/L, followed by lymphocytes < 0.72 x103/mm3 were the best discriminators for MAS (R2=0.52). Cross-validation of our decision rules maintained 90-100% sensitivity and 65-85% specificity. Conclusion Our decision rule demonstrated improved performance compared to preliminary guidelines for MAS in cSLE from the Lupus Working Group of the Paediatric Rheumatology European Society, and familial Hemophagocytic Lymphohistiocytosis diagnostic criteria. Validation in independent cohorts is required.
Objective Macrophage activation syndrome (MAS), a life-threatening complication of SLE, resembles familial hemophagocytic lymphohistiocytosis (fHLH), an inherited disorder of hyperinflammation. We compared the proportion of childhood-onset SLE (cSLE) patients with and without MAS, who carried low-frequency HLH non-synonymous variants. Methods We enrolled patients from the Lupus Clinic at SickKids, Toronto. Demographic and clinical features were extracted from the lupus 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 (read-depth:70-118X) or whole-genome sequencing. Non-MAS patients had whole-genome sequencing (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's exact test, P<0.05). MAFs were compared to an ancestrally-matched general population (TOPMed and gnomAD). Results The study included 81 patients, 19 with MAS. We identified 47 unique low-frequency non-synonymous HLH variants. There was no difference in the proportion of MAS and non-MAS patients carrying ≥1 HLH variants (37% versus 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 MAS patients carrying non-synonymous HLH genetic variants compared to patients without MAS. This is the first study to examine the frequency of HLH genetic variants in relation to MAS among cSLE patients. Future studies are required to validate our findings.
Objective The aim of this study was to examine the impact of timing of a childhood‐onset systemic lupus erythematosus (SLE) diagnosis relative to menarchal status, on final height, accounting for disease‐associated factors. Methods We conducted a cohort study of female patients age <18 years at childhood‐onset SLE diagnosis, followed at a tertiary care pediatric center from July 1982 to March 2016 and restricted to patients with documented age of menarche and final height. We compared final height between patients diagnosed pre‐ and postmenarche. We tested the association of the timing of childhood‐onset SLE diagnosis with final height, adjusted for ethnicity, in linear regression models. We performed subgroup analyses of patients with growth during follow‐up, additionally adjusting for average daily corticosteroid dose and disease activity. Results Of 401 female childhood‐onset SLE patients in the study, 115 patients (29%) were diagnosed premenarche and 286 (71%) postmenarche. Patients diagnosed premenarche were older at menarche compared with patients diagnosed postmenarche (mean ± SD age 13.5 ± 1.4 versus 12.5 ± 1.3 years; P < 0.001). The mean ± SD final height for girls diagnosed postmenarche (161.4 ± 6.9 cm) was greater than for those diagnosed premenarche (158.8 ± 7.3 cm; P = 0.001). In regression analysis, those diagnosed postmenarche were significantly taller than those diagnosed premenarche, as adjusted for ethnicity and disease severity (mean ± SD β = 2.6 ± 0.7 cm; P = 0.0006). Conclusion In this large cohort study of girls with childhood‐onset SLE, patients diagnosed postmenarche achieved a taller final height than those diagnosed premenarche, even after accounting for ethnicity and disease severity.
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