Oligoarticular Juvenile Idiopathic Arthritis

Incidence

Reports of the incidence of oligoarthritis are difficult to interpret because of the variation in criteria used to classify the patients. Using information from hospitals and community physicians, Andersson-Gare et al. determined an annual incidence of oligoarthritis (EULAR criteria) of 7 per 100,000 children younger than 16 years of age in Sweden. Using the same criteria, a Norwegian study reported a somewhat higher incidence of 11.2 per 100,000 per year. It should be noted that 42% of these children were HLA-B27–positive, strongly suggesting that children with enthesitis-related arthritis (ERA) or juvenile ankylosing spondylitis (JAS), which can also present with fewer than four active joints at onset, were included in the group. In studies that used the ACR criteria, estimates of the incidence have ranged from less than 1 per 100,000 per year in Japan to more than 18 per 100,000 per year in Finland. Estimates based on the ILAR criteria calculated an incidence of 6.5 per 100,000 for oligoarthritis in Olmsted County, Minnesota, between 1994 to 2013. In this population, the incidence was 8.5 per 100,000 among girls and 4.5 per 100,000 among boys.

Prevalence

The prevalence of oligoarthritis in reported studies varies greatly depending on the criteria used; whether the study was hospital-, clinic-, or community-based; and the geographical location of the study. Using information from hospitals and community physicians, Andersson-Gare et al. found 146 children with oligoarthritis (EULAR) in a population of 400,600 children younger than 16 years of age, a prevalence of 36 per 100,000. In the study by Manners and Diepeveen, oligoarthritis fulfilling the EULAR criteria for juvenile chronic arthritis (JCA) was found in 9 of 2241 12-year-old school children who were examined by the authors of the study. This prevalence (400 per 100,000) is markedly higher than that reported in other studies but may be closest to reality because it was community based and verified by physical examination by a pediatric rheumatologist.

Age at Onset

Oligoarthritis has a striking age-at-onset distribution, with a peak incidence between 1 and 3 years of age ( Fig. 19.1 ). A small proportion of children with oligoarthritis have disease onset after this time, but when this occurs it raises the possibility of alternative diagnoses, such as ERA, JAS, or psoriatic arthritis.

Sex Ratio

In North America and Europe, oligoarthritis is predominantly a disease of girls, with a female-to-male ratio of approximately 3:1. In children with oligoarthritis and uveitis, the ratio of girls to boys is even higher at 5:1 to 6.6:1. In parts of Asia and Africa, ^, however, oligoarthritis occurs predominantly in boys, and uveitis is reportedly rare.

HLA Genes

Numerous studies on HLA genes were carried out before 1997 and therefore were based on the prior classification systems (ACR—juvenile rheumatoid arthritis [JRA]; EULAR—JCA), which limits some of the generalizability to patients classified according to current ILAR criteria.

A number of HLA genes are associated with oligoarthritis, or subsets of oligoarthritis. The unusual disease association of an A locus antigen, A2, has been reported in children with JRA (ACR criteria) in general and in early-onset pauciarticular JRA in girls in particular.

An increase in the HLA-B27 allele in early studies reflects the inclusion of children with JAS (similar to ERA of the ILAR classification) who would be excluded from the ILAR oligoarthritis categories.

Extensive work has been published on association to class II alleles ( Table 19.1 ). A large study carried out by Hinks et al. in 2016 that included 5043 JIA cases and 14,390 controls found HLA associations to be similar in oligoarticular and RF-negative polyarticular JIA. The strongest association was found within the antigen-binding groove of HLA-DRB1 at amino acid position 13. However, for oligoarthritis and RF-negative polyarthritis, the most common categories of JIA, glycine13 confers the strongest risk; serine13 also confers a risk effect but histidine13 is protective. Also the association of the HLA-DPB1∗0201 haplotype with oligoarthritis as classified by ACR or EULAR was confirmed in oligoarticular and RF-negative polyarticular JIA patients, as well as the association to the HLA class 1 haplotype A∗02 with an association with a specific amino acid at position 95. According to their analyses, the total HLA region explained only 8% of the phenotype variance, but the amino acid at position 13 contributed 50% of it.

Non-HLA Genes

A number of genes involved in antigen presentation or cytokine expression may be important in establishing a predisposition to JIA. IL-1A2, a variant of the IL-1β gene, is associated with early-onset oligoarthritis. Children with extended oligoarthritis (ILAR criteria) were shown to have a high frequency of the interleukin (IL)-1 receptor antagonist gene IL1RN∗2 . The gene for the cytokine IL-1β, or a gene for which its polymorphism is a marker, may contribute risk for early-onset disease and uveitis.

Crawley et al. ^, found a decrease in the IL-10 phenotype associated with low IL-10 production in children with arthritis affecting fewer than five joints, compared with those with more than four affected joints. The frequency of the tumor necrosis factor (TNF)-α2 microsatellite allele was significantly increased in Latvian children with oligoarticular JCA, and the frequency of TNF-α9 was significantly decreased in this population. ^, The TNF-α2 allele is associated with high TNF-α production. Zeggini et al. reported an increased frequency of the intronic +851 TNF single nucleotide polymorphism (SNP) in persistent oligoarticular JIA. Kaalla et al. have performed a meta-analysis of data regarding four SNPs in loci that had previously been associated with JIA: MIF (G173C), TNFA (G308A and G238A), and PTPN22 (C1858T). In case control studies, the strongest non-HLA genetic association was found for the protein tyrosine phosphatase nonreceptor 22 (PTPN22), a gene located on chromosome 1p13.3-13.1 that encodes lymphoid protein tyrosine kinase, an enzyme that negatively regulates T cells.

PTPN22, STAT4, and PTPN2 variants IL-2, IL-2RA, IL-2RB, as well as IL-6 and IL-6R variants were confirmed to be associated with oligoarticular and RF-negative polyarticular JIA. Like PTPN22, PTPN2 also encodes a protein tyrosine phosphatase involved in T-cell regulation. The signal transducer and activator of transcription factor 4 (STAT4) is thought to play an important role in T-cell differentiation, and IL-2 and IL-6 are common promoters of inflammation, with IL-2 and its receptor playing a marked role for T cells and IL-6 for B cells.

The analysis in 2816 cases with oligoarticular and polyarticular RF-negative JIA and 13,056 controls by the International JIA Immunochip Consortium also confirmed three loci that had previously been associated (HLA, PTPN22, and PTPN2) but found 14 additional loci, of which several reached levels of significance for the first time within this large study. A higher risk was described for PTPN22, PTON2, ATP8B2-IL6R, STAT4, ERAP2-LNOEP, FAS, SH2B3-ATXN2, and UB2L3, whereas a lower risk was described for IL-2, IL-2RA, IL-2RB, ANKRD55, C5, ZFP36L1, TYK2, and RNX1.