Review: Genetics and the Classification of Arthritis in Adults and Children

Abstract

Current classification of primary inflammatory arthritis begins from the assumption that adults and children are different. No form of juvenile idiopathic arthritis bears the same name as an adult arthritis, a nomenclature gap with implications for both clinical care and research. Recent genetic data have raised questions regarding this adult/pediatric divide, revealing instead broad patterns that span the age spectrum. Combining these genetic patterns with demographic and clinical data, we propose that inflammatory arthritis can be segregated into 4 main clusters, largely irrespective of pediatric or adult onset: seropositive, seronegative (likely including a distinct group that usually begins in early childhood), spondyloarthritis, and systemic. Each of these broad clusters is internally heterogeneous, highlighting the need for further study to resolve etiologically discrete entities. Eliminating divisions based on arbitrary age cutoffs will enhance opportunities for collaboration between adult and pediatric rheumatologists, thereby helping to promote the understanding and treatment of arthritis.

Figure 1. Overlap of genetic susceptibility between JIA and other forms of inflammatory arthritis

Loci include HLA regions associated with each disease and non-HLA loci meeting genome-wide significance in oligoarticular and RF-negative polyarticular JIA (17, 25). HLA alleles or amino acids are shown as red up arrows when conferring risk or green down arrows when protective. Non-HLA loci are marked in red if the lead SNP is the same as, or in linkage disequilibrium (R²>0.5) with, the listed polygoJIA SNP. In every case where markers were correlated, the direction of association was the same. Pink circles indicate potential overlap, where both diseases achieve genome-wide significance but with SNPs that are not in close linkage disequilibrium (R²<0.5), potentially reflecting distinct variants (direction of effect not specified). Other associated autoimmune diseases are listed in the last column, per Hinks et al. (17). References: polygoJIA (17, 25, 38); seronegative RA (47, 86, 87); seropositive polyJIA (25, 32, 33); RA (majority seropositive) (16, 88); psoriatic JIA (25); PsA (–94); ERA (25); ankylosing spondylitis (–98); sJIA (64, 65). Abbreviations: Chr, chromosome; HLA, human leukocyte antigen; polygoJIA, oligoarticular and RF-negative polyarticular JIA; RA, rheumatoid arthritis; JIA, juvenile idiopathic arthritis; T1D, type 1 diabetes; Vit, vitiligo; T1Dab, type 1 diabetes antibodies; MS, multiple sclerosis; AITD, autoimmune thyroid disease; SLE, systemic lupus erythematosus; SSc, systemic sclerosis; PBC, primary biliary cirrhosis; IBD, inflammatory bowel disease; HT, hypothyroidism.

Figure 2. Four major clusters of arthritis as informed by human genetics

ILAR categories of JIA are depicted as boxes. Early-onset arthritis is depicted as a subcategory within seronegative arthritis.