Arthritis Cure Currently, medications are focused on decreasing symptoms of the disease. Pain-relieving medications include acetaminophen and non- ...
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sJIA is among the most severe childhood inflammatory diseases. First described by Sir George Frederic Still over a century ago, sJIA is marked by arthritis and systemic inflammation with quotidian fever, evanescent salmon pink skin rash, lymphadenopathy, hepatosplenomegaly and serositis.2 ,4 It is frequently complicated by macrophage activation syndrome, a potentially lethal form of hemophagocytic lymphohistiocytosis.5 Although sJIA only constitutes approximately 10% of JIA in populations of European descent,1 for 1 last update 2020/05/28 ,,5 its disproportionately large share of the morbidity and mortality observed in JIA6 underscores the importance of understanding and targeting its root causes.
The unique clinical characteristics of sJIA suggest that it is distinct from other forms of JIA, leading to the contention by some that sJIA should be separated from other forms of JIA and labelled as an autoinflammatory disease.7 This has been challenged by identification of autoantibodies in some patients with sJIA.8 Furthermore, while the systemic inflammatory features of sJIA seem to distinguish it from other forms of JIA, most children with sJIA eventually shed these features, leaving up to half of children with a persistent form of arthritis that is similar to the oligoarticular and polyarticular forms of JIA.5 ,9 Finally, significant differential effects of anticytokine agents have been observed between sJIA and other forms of JIA.10 However, due to the highly variable therapeutic responses to each agent in sJIA, this has not concretely advanced our understanding of how sJIA mechanistically relates to other forms of JIA.
One approach to evaluate the similarity of diseases is to examine shared pathophysiology through statistical comparisons of for 1 last update 2020/05/28 disease-specific genetic association data.11 For example, studies of inflammatory bowel disease and spondyloarthritis have identified shared genetic risk factors, providing rationale for similar treatment choices.11 In JIA, the majority of genetic and genomic investigations have focused on the combination of the most common subtypes, oligoJIA and RF–polyJIA (henceforth referred to in this manuscript as polygoJIA),12 ,13 but until recently,14 because of insufficient numbers of patients with sJIA, there have been only underpowered genetic studies and no genome-wide studies of sJIA. Comparisons of the genomic underpinnings of sJIA relative to other forms of JIA have therefore also been lacking.One approach to evaluate the similarity of diseases is to examine shared pathophysiology through statistical comparisons of disease-specific genetic association data.11 For example, studies of inflammatory bowel disease and spondyloarthritis have identified shared genetic risk factors, providing rationale for similar treatment choices.11 In JIA, the majority of genetic and genomic investigations have focused on the combination of the most common subtypes, oligoJIA and RF–polyJIA (henceforth referred to in this manuscript as polygoJIA),12 ,13 but until recently,14 because of insufficient numbers of patients with sJIA, there have been only underpowered genetic studies and no genome-wide studies of sJIA. Comparisons of the genomic underpinnings of sJIA relative to other forms of JIA have therefore also been lacking.
To gain insight into the pathogenesis of sJIA, we established the International Childhood Arthritis Genetics (INCHARGE) consortium. Together, we gathered the largest sJIA study population ever assembled, which included 982 children from nine countries on three continents. Using this collection, we performed the first genome-wide association study (GWAS) of sJIA. We recently reported the results of our intensive examination of the major histocompatibility complex (MHC) locus in this study population, which identified the class II human leucocyte antigen (HLA) region as a strong sJIA susceptibility locus.14 Here, we report the findings of the GWAS, beyond the MHC locus. Using the GWAS results, we have performed the first direct comparison of the genetic architecture of sJIA with those of the most common forms of JIA.
Peripheral blood specimens were collected from children diagnosed with sJIA according to the International League of Associations for Rheumatology (ILAR) criteria2 by paediatric rheumatologists at participating medical centres in nine countries (see online supplementary text and figure S1). Blood samples were also obtained from geographically matched control subjects. In addition, single nucleotide polymorphism (SNP) genotype data from geographically matched control populations were used, when available. The INCHARGE project was granted institutional review board (IRB) approval by the University of Manchester. Subjects were enrolled in accordance with all local ethics regulations, with the approval of local IRBs at each contributing medical centre, and with informed parental consent.
Arthritis Curehow to Arthritis Cure for Genomic DNA was extracted from peripheral blood samples. Samples were genotyped at the National Human Genome Research Institute (Bethesda, Maryland, USA) using Human Omni1M arrays (Illumina) in accordance with the manufacturer''s clinical history, etiology, and pathology. Lancet 1896;147:1120–5. doi:10.1016/S0140-6736(01)61263-7
Competing interests AAG: consulting fees and honoraria from Novimmune, Novartis, Roche. AM: consulting fees and honoraria from Abbvie, Boehringer, Celgene, CrescendoBio, Janssen, Meddimune, Novaris, NovoNordisk, Pfizer, Sanofi Aventis, Vertex and Servier, contributions have been received by G. Gaslini Hospital and the PRINTO network by BMS, GlaxoSmithKline, Hoffman-La Roche, Novartis, Pfizer, Sanofi Aventis, Schwarz Biosciences, Abbot, Francesco Angelini S.P.A., Sobi, and Merck Serono. MG: consulting and speaker fees from SOBI and Novartis, unrestricted grants to Eurofever from SOBI and Novartis. SP: consulting fees from Novartis. EDM: consulting fees from Novartis. LRW: speaker fees from Pfizer.
Ethics approval University of Manchester.
Provenance and peer review Not commissioned; externally peer reviewed.
Arthritis Curehow to Arthritis Cure for Data sharing statement The quality control processed directly genotyped SNP genotype data from sJIA cases genotyped for this study will be deposited into the National Institutes of Health’s Database of Genotypes and Phenotypes, where allowable by the Ethics and consent documents. The future use of these data will be dictated by the terms of Ethics and consent documents and the institutional certifications provided by the collaborating centres.
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