The majority of adults with cSLE in this large cohort developed significant damage at young age and have impaired HRQOL without achieving drug free remission, illustrating the great impact of cSLE on future life. This article is protected by copyright. All rights reserved.
In clinical practice NP events presenting in SLE are too often attributed to an immune-mediated origin. Multidisciplinary reassessment avoids misclassification in NPSLE. Multidisciplinary reassessment is the reference standard in NP events presenting in SLE and cannot be replaced by available attribution models.
Background and objectiveSystemic sclerosis (SSc) is a severe autoimmune disease, in which the pathogenesis is dependent on both genetic and epigenetic factors. Altered gene expression in SSc monocytes, particularly of interferon (IFN)-responsive genes, suggests their involvement in SSc development. We investigated the correlation between epigenetic histone marks and gene expression in SSc monocytes.MethodsChromatin immunoprecipitation followed by sequencing (ChIPseq) for histone marks H3K4me3 and H3K27ac was performed on monocytes of nine healthy controls and 14 patients with SSc. RNA sequencing was performed in parallel to identify aberrantly expressed genes and their correlation with the levels of H3K4me3 and H3K27ac located nearby their transcription start sites. ChIP-qPCR assays were used to verify the role of bromodomain proteins, H3K27ac and STATs on IFN-responsive gene expression.Results1046 and 534 genomic loci showed aberrant H3K4me3 and H3K27ac marks, respectively, in SSc monocytes. The expression of 381 genes was directly and significantly proportional to the levels of such chromatin marks present near their transcription start site. Genes correlated to altered histone marks were enriched for immune, IFN and antiviral pathways and presented with recurrent binding sites for IRF and STAT transcription factors at their promoters. IFNα induced the binding of STAT1 and STAT2 at the promoter of two of these genes, while blocking acetylation readers using the bromodomain BET family inhibitor JQ1 suppressed their expression.ConclusionSSc monocytes have altered chromatin marks correlating with their IFN signature. Enzymes modulating these reversible marks may provide interesting therapeutic targets to restore monocyte homeostasis to treat or even prevent SSc.
Objective Long-term outcome data in adults with childhood-onset SLE are limited. Here, we report the effects of cSLE on education, vocation and employment in a large cohort of adults with cSLE. Methods Patients were seen for a single study visit containing a structured history and physical examination. Medical records were retrieved to supplement information obtained during the study visit. Education and employment status were assessed by questionnaires. Health-related quality of life (HRQOL) was measured with the SF36. Results 106 cSLE patients (93% female, 73% white), with a median disease duration of 20 years, completed the visit and questionnaires. Almost all patients stated that cSLE had influenced their education, but level of completed education was similar to the general Dutch population. Half of the patients had adjusted their vocational choice due to the disease. Still, 44% of patients who had finished education did not have a paid job. Of the employed patients, 61% worked part-time. Disease damage was equally prevalent in patients with and without paid employment. A high percentage of patients (51%) were declared work disabled, which was related to damage. Patients who did not have paid employment were often work disabled. Both had a negative influence on HRQOL. Conclusion The effect of cSLE on academic achievements and employment is substantial, despite adjusting educational and vocational choices to the disease. Ongoing support, not only to help patients find suitable education and vocation, but also to offer guidance regarding potential adjustments during their career, is necessary to optimise participation in the community.
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