Gene-expression analysis of adult-onset Still's disease and systemic juvenile idiopathic arthritis is consistent with a continuum of a single disease entity

Abstract

Background: Adult-onset Still's disease (AOSD), a rare autoinflammatory disorder, resembles systemic juvenile idiopathic arthritis (SJIA). The superimposable systemic clinical features of AOSD and SJIA suggest both clinical phenotypes represent the same disease continuum with different ages of onset. To further characterize the similarity between AOSD and SJIA at the molecular level, 2 previously identified response gene sets in SJIA were used to investigate how genes that respond to interleukin (IL)-1β inhibition with canakinumab in SJIA patients behave in AOSD patients with active disease prior to IL-1β targeting therapy, relative to healthy subjects.

Findings: All genes downregulated in SJIA patients following canakinumab treatment were upregulated in most patients with active AOSD prior to canakinumab treatment, relative to healthy subjects. A few patients with milder AOSD had expectedly gene-expression patterns that resembled those in healthy subjects. Comparison of the gene-expression patterns with neutrophil counts showed a correlation between elevated neutrophil numbers and upregulation of canakinumab-responsive genes. Correspondingly, most genes upregulated following canakinumab treatment in patients with SJIA patients were downregulated in the majority of AOSD patients.

Conclusions: These results further support the concept of a Still's disease continuum that includes both a pediatric/juvenile onset (SJIA) and adult onset (AOSD) form.

Trial registration: ClinicalTrials.gov NCT02204293.

Fig. 1

Comparison of gene-expression data for patients with AOSD prior to canakinumab treatment and healthy subjects. Dots show expression levels of individual genes where the average value in healthy subjects is shown on x axis and the average value in patients with AOSD is shown on y axis. Genes represented in red are those previously found to respond to canakinumab treatment in patients with SJIA. Genes downregulated by canakinumab in patients with SJIA were upregulated in untreated patients with AOSD, relative to healthy subjects (plot on left). Correspondingly, most genes previously found to be upregulated by canakinumab in SJIA were downregulated in untreated patients with AOSD (plot on right). P values refer to significance of differential expression of canakinumab gene sets

Fig. 2

Color-coded expression values of genes down regulated following canakinumab treatment in patients with SJIA. Gene-expression values are shown for healthy subjects and patients with AOSD prior to canakinumab treatment. Transcripts shown in rows and patient samples in columns. For patients with AOSD, baseline (BL) blood cell counts are also provided (bottom)

Fig. 3

Color-coded expression values of genes up regulated following canakinumab treatment in patients with SJIA. Gene-expression values are shown for healthy subjects and patients with AOSD prior to canakinumab treatment. Transcripts shown in rows and patient samples in columns. For patients with AOSD, baseline (BL) blood cell counts are also provided (bottom)