Top

Published in:

Open Access 01-12-2015 | Short Report

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

Authors: Nanguneri Nirmala, Arndt Brachat, Eugen Feist, Norbert Blank, Christof Specker, Matthias Witt, Jan Zernicke, Alberto Martini, Guido Junge

Published in: Pediatric Rheumatology | Issue 1/2015

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.

Jamilloux Y, Gerfaud-Ventin M, Martinon F, Belot A, Henry T, Sève P. Pathogenesis of adult-onset Still’s disease: new insights from the juvenile counterpart. Immunol Res. 2015;61:53–62.CrossRefPubMed

Martini A. It is time to rethink juvenile idiopathic arthritis classification and nomenclature. Ann Rheum Dis. 2012;71:1437–9.CrossRefPubMed

Fautrel B. Adult-onset Still disease. Best Pract Res Clin Rheumatol. 2008;22:773–92.CrossRefPubMed

Luthi F, Zufferey P, Hofer MF, So AK. “Adolescent-onset Still’s disease”: characteristics and outcome in comparison with adult-onset Still’s disease. Clin Exp Rheumatol. 2002;20:427–30.PubMed

Uppal SS, Pande IR, Kumar A, Kailash S, Sekharan NG, Adya CM, et al. Adult onset Still’s disease in northern India: comparison with juvenile onset Still’s disease. Br J Rheumatol. 1995;34:429–34.CrossRefPubMed

Still GF. On a form of chronic joint disease in children. Med Chir Trans. 1897;80:47–60.9.PubMedCentralPubMed

Frosch M, Metze D, Foell D, Vogl T, Sorg C, Sunderkötter C, et al. Early activation of cutaneous vessels and epithelial cells is characteristic of acute systemic onset juvenile idiopathic arthritis. Exp Dermatol. 2005;14:259–65.CrossRefPubMed

Kim HA, An JM, Nam JY, Jeon JY, Suh CH. Serum S100A8/A9, but not follistatin-like protein 1 and interleukin 18, may be a useful biomarker of disease activity in adult-onset Still’s disease. J Rheumatol. 2012;39:1399–406.CrossRefPubMed

Chen D-Y, Chen Y-M, Lan J-L, Lin C-C, Chen H-H. Potential role of TH17 cells in the pathogenesis of adult-onset Still’s disease. Rheumatology. 2010;49:2305–12.CrossRefPubMed

10.

Kötter I, Wacker A, Koch S, Henes J, Richter C, Engel A, et al. Anakinra in patients with treatment-resistant adult-onset Still’s disease: four case reports with serial cytokine measurements and a review of the literature. Semin Arthritis Rheum. 2007;37:189–97.CrossRefPubMed

11.

Avau A, Put K, Wouters CH, Matthys P. Cytokine balance and cytokine-driven natural killer cell dysfunction in systemic juvenile idiopathic arthritis. Cytokine Growth Factor Rev. 2015;26:35–45.CrossRefPubMed

12.

Félix FH, Leal LK, Fontenele JB. Cloak and dagger: the case for adult onset still disease and hemophagocytic lymphohistiocytosis. Rheumatol Int. 2009;29:973–4.CrossRefPubMed

13.

Ravelli A, Grom AA, Behrens EM, Cron RQ. Macrophage activation syndrome as part of systemic juvenile idiopathic arthritis: diagnosis, genetics, pathophysiology and treatment. Genes Immun. 2012;13:289–98.CrossRefPubMed

14.

Pascual V, Allantaz F, Arce E, Punaro M, Banchereau J. Role of interleukin-1 (IL-1) in the pathogenesis of systemic onset juvenile idiopathic arthritis and clinical response to IL-1 blockade. J Exp Med. 2005;201:1479–86.PubMedCentralCrossRefPubMed

15.

Fall N, Barnes M, Thornton S, Luyrink L, Olson J, Ilowite NT, et al. Gene expression profiling of peripheral blood from patients with untreated new-onset systemic juvenile idiopathic arthritis reveals molecular heterogeneity that may predict macrophage activation syndrome. Arthritis Rheum. 2007;56:3793–804.CrossRefPubMed

16.

Ruperto N, Quartier P, Wulffraat N, Woo P, Ravelli A, Mouy R, et al. A phase II, multicenter, open-label study evaluating dosing and preliminary safety and efficacy of canakinumab in systemic juvenile idiopathic arthritis with active systemic features. Arthritis Rheum. 2012;64:557–67.CrossRefPubMed

17.

Ruperto N, Brunner HI, Quartier P, Constantin T, Wulfraat N, Horneff G, et al. Two randomized trials of canakinumab in systemic juvenile idiopathic arthritis. N Engl J Med. 2012;367:2396–406.CrossRefPubMed

18.

Kontzias A, Efthimiou P. The use of Canakinumab, a novel IL-1β long-acting inhibitor, in refractory adult-onset Still’s disease. Semin Arthritis Rheum. 2012;42:201–5.CrossRefPubMed

19.

Laskari K, Tzioufas AG, Moutsopoulos HM. Efficacy and long-term follow-up of IL-1R inhibitor anakinra in adults with Still’s disease: a case-series study. Arthritis Res Ther. 2011;13:R91.PubMedCentralCrossRefPubMed

20.

Efthimiou P, Kontzias A, Ward CM, Ogden NS. Adult-onset Still’s disease: can recent advances in our understanding of its pathogenesis lead to targeted therapy? Nat Clin Pract Rheumatol. 2007;3:328–35.CrossRefPubMed

21.

Fitzgerald AA, Leclercq SA, Yan A, Hornik JE, Dinarello CA. Rapid responses to anakinra in patients with refractory adult-onset Still’s disease. Arthritis Rheum. 2005;52:1794–803.CrossRefPubMed

22.

Petryna O, Cush JJ, Efthimiou P. IL-1 Trap rilonacept in refractory adult onset Still’s disease. Ann Rheum Dis. 2012;71:2056–7.CrossRefPubMed

23.

Nordström D, Knight A, Luukkainen R, van Vollenhaven R, Rantalaiho V, Kajalainen A, et al. Beneficial effect of interleukin 1 inhibition with anakinra in adult-onset Still’s disease. An open, randomized, multicenter study. J Rheumatol. 2012;39:2008–11.CrossRefPubMed

24.

Naumann L, Feist E, Natusch A, Langen S, Krause A, Buttgereit F, et al. IL1-receptor antagonist anakinra provides long-lasting efficacy in the treatment of refractory adult-onset Still’s disease. Ann Rheum Dis. 2010;69:466–7.CrossRefPubMed

25.

Brachat A, Grom A, Wulffraat N, Brunner H, Quartier P, Brik R, et al. Changes in gene expression and inflammatory proteins in systemic juvenile idiopathic arthritis patients on canakinumab therapy. Ann Rheum Dis. 2014;73(Suppl2):62.CrossRef

26.

ClinicalTrials.gov. NCT02204293. https://clinicaltrials.gov/ct2/show/NCT02204293. Accessed November 18, 2015.

27.

Wu D, Lim E, Vaillant F, Asselin-Labat ML, Visvader JE, Smyth GK. ROAST: rotation gene set tests for complex microarray experiments. Bioinformatics. 2010;26:2176–82.PubMedCentralCrossRefPubMed

Title: Gene-expression analysis of adult-onset Still’s disease and systemic juvenile idiopathic arthritis is consistent with a continuum of a single disease entity
Authors: Nanguneri Nirmala
Arndt Brachat
Eugen Feist
Norbert Blank
Christof Specker
Matthias Witt
Jan Zernicke
Alberto Martini
Guido Junge
Publication date: 01-12-2015
Publisher: BioMed Central
Published in: Pediatric Rheumatology / Issue 1/2015
Electronic ISSN: 1546-0096
DOI: https://doi.org/10.1186/s12969-015-0047-3

Keynote webinar | Spotlight on medication adherence

Springer Medicine

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

Findings

Conclusions

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Background

Findings

Conclusions

Please log in to get access to this content

Other articles of this Issue 1/2015

Preliminary experience using milnacipran in patients with juvenile fibromyalgia: lessons from a clinical trial program

Screening assays for primary haemophagocytic lymphohistiocytosis in children presenting with suspected macrophage activation syndrome

Reviewer acknowledgement 2014

Design and acceptance of Rheumates@Work, a combined internet-based and in person instruction model, an interactive, educational, and cognitive behavioral program for children with juvenile idiopathic arthritis

Cognitive behavioral group intervention for pain and well-being in children with juvenile idiopathic arthritis: a study of feasibility and preliminary efficacy

An evaluation of a juvenile idiopathic arthritis retreat for families