Genetic studies link JIA subtypes to adult diseases, show uniqueness of systemic disease
FROM ANNALS OF THE RHEUMATIC DISEASES
Two new studies of the genetic relationships between the seven designated categories of juvenile idiopathic arthritis (JIA) provide compelling support for reclassification of the categories, particularly for systemic JIA, and give evidence that some of the categories have clear equivalents in the realm of adult-onset diseases.
The International League of Associations for Rheumatology (ILAR) classification system (J Rheumatol. 2004;31:390-2) that defined the seven juvenile idiopathic arthritis (JIA) categories – systemic arthritis, oligoarticular arthritis, rheumatoid factor (RF)–negative polyarticular arthritis, RF-positive polyarticular arthritis, psoriatic arthritis (PsA), enthesitis-related arthritis (ERA), and undifferentiated arthritis – is problematic because the long-term outcome and response to treatment varies not only between subtypes but also within the subtypes, suggesting that these subgroups do not yet represent uniform groups of patients,” Wendy Thomson, PhD, professor of genetic epidemiology at the University of Manchester (England) and a senior author on both studies, explained in an interview.
“Despite the differences between the subtypes, current treatments of this disease often involve using the same drugs across all subtypes of JIA,” said Dr. Thomson, who is also deputy director of the Arthritis Research UK Centre for Genetics and Genomics at the university. “Understanding the genetic basis of the subtypes of this disease could help understand the cause of this disease and identify more appropriate treatment options [because] the current classification is largely based on clinical data and it is proposed that the addition of genetic data could improve classification.”
Interrelationships between JIA categories and adult disease
The first of these studies found that particular alleles in the human leukocyte antigen (HLA) region that have been associated with the different JIA categories strongly correlate some of the categories with one another, and that each JIA category potentially has an adult-onset counterpart based on shared HLA associations. It is the largest investigation of association of the HLA region with JIA and its categories to date, according to the researchers (Ann Rheum Dis. 2016 Dec 20. doi: 10.1136/annrheumdis-2016-210025).
In particular, the investigators demonstrated for the first time that RF-negative polyarticular JIA and oligoarticular JIA are genetically similar in their HLA associations. They also reported that RF-positive polyarthritis shares an association with adult seropositive rheumatoid arthritis and that combined data for oligoarthritis and RF-negative polyarthritis share the same association with adult seronegative RA. In addition, the researchers generated support for genetic associations between the particular JIA categories that are most commonly thought to have adult counterparts, such as ERA and adult ankylosing spondylitis (AS) as well as juvenile PsA and adult PsA.
Dr. Thomson and her coinvestigators used ImmunoChip genotype array data for 191,494 single nucleotide polymorphism (SNP) markers from the HLA region of 5,737 JIA patients and 16,403 controls in the United States, United Kingdom, Canada, Norway, and Germany to impute classical HLA alleles as well as specific amino acid positions within HLA alleles that may play an important functional role. After quality-control measures for the data were put in place, comparisons between 5,043 JIA cases and 14,390 controls showed that oligoarthritis and RF-negative polyarthritis were the most common and homogeneous JIA categories investigated (2,409 and 1,525 patients, respectively), and that they share a significant association across the HLA spectrum, meaning that they are genetically similar. When combined, the data from these two JIA categories correspond with seronegative rheumatoid arthritis in adults, while RF-positive polyarthritis on its own has an association with seropositive rheumatoid arthritis involving histidine at position 13 of the HLA-DRB1 allele. As expected, the most significant association between the ERA category and AS was for HLA-B*27. For juvenile PsA, no associations reached genome-wide level of significance, although HLA-C*0602 was modestly associated with juvenile PsA, and it is known to be associated with adult-onset PsA and is the primary HLA association in psoriasis.
“The results of this study have important implications for understanding disease pathogenesis, etiology, and potential future therapeutic strategies for JIA categories,” Dr. Thomson and her coauthors wrote, adding that “heterogeneity of JIA remains a key challenge to pediatric rheumatologists; however, these results may inform the debate on classification and help define a more biological-driven and molecular-driven classification system.”
Uniqueness of systemic JIA
In the second of the two studies, investigators from many different childhood arthritis study groups focused on systemic JIA (sJIA), also known in the past as Still’s disease. According to the authors, it is the first large-scale genomic study of sJIA ever published (Ann Rheum Dis. 2016 Dec 7. doi: 10.1136/annrheumdis-2016-210324).
