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.
Courtesy University of Manchester
Dr. Wendy Thomson
“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).
“[sJIA] is characterized by prominent systemic inflammation and has a rare adult-onset counterpart; and undifferentiated arthritis includes arthritis that does not fit into any single category,” the authors wrote, adding that 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 labeled as an autoinflammatory disease.”
The investigators carried out SNP genotyping on 982 children with sJIA in the United States, United Kingdom, Germany, Turkey, Italy, Brazil, Argentina, Canada, and Spain, along with 431 healthy children without sJIA who came from the same countries. A total of 7,579 control patients also underwent genotyping. Ultimately, 770 sJIA and 6,947 control subjects completed the study. sJIA was then compared with other JIA subtypes by using weighted genetic risk scores.
Comparison of the data sets for sJIA with those for the combined categories of RF-negative polyarticular JIA and oligoarticular JIA, as well as for the individual category of RF-positive polyarticular JIA, showed that sJIA has a distinct genetic architecture that separates it from those JIA categories, providing further evidence that sJIA should be classified separately from other forms of JIA and, potentially, treated differently as well.
According to Dr. Thomson, the finding “provides important evidence that sJIA should be considered a unique disease with its own specific disease mechanisms.” Dr. Thomson explained that “knowing more about the genetic risk factors of this disease might give a greater understanding of the disease processes involved in this condition and ultimately lead to novel therapies for this severely disabling disease.”
Funding for the first study was provided by the Wellcome Trust, the National Institutes of Health, the Doris Duke Charitable Foundation, the Medical Research Council, the Canadian Institutes of Health Research, the Liaison Committee between the Central Norway Regional Health Authority and the Norwegian University of Science and Technology, the Juvenile Diabetes Research Foundation International, and the Texas Scottish Rite Hospital for Children. Funding for the second study was provided by intramural research programs of the National Institute of Arthritis and Musculoskeletal and Skin Diseases and the National Human Genome Research Institute, individual NIH grants, and grants from charitable foundations, advocacy organizations, and the governments of individual researchers’ countries. Dr. Thomson did not report any relevant financial disclosures; however, a number of coauthors reported potential conflicts of interest.