An amino acid motif in HLA-DRß1 distinguishes patients with uveitis in juvenile idiopathic arthritis

A.J.W. Haasnoot; M.W. Schilham; S.S.M. Kamphuis; P.C.E. Hissink Muller; A. Heiligenhaus; D. Foell; R.A. Ophoff; T.R.D.J. Radstake; A.I. Den Hollander; T.H.C.M. Reinards; S. Hiddingh; N. Schalij-Delfos; E.P.A.H. Hoppenreijs; M.A.J. van Rossum; C. Wouters; R.K. Saurenmann; N. Wulffraat; R. ten Cate; J.H. de Boer; S.L. Pulit; J.J.W. Kuiper

Juvenile idiopathic arthritis (JIA) is the most common chronic rheumatic disease in childhood, 1,2 affecting approximately 16-150 per 100,000 individuals. 3 As many as 1 in 3 children that suffer from the most common JIA categories, oligoarticular and polyarticular rheumatoid factor-negative JIA, develop uveitis, a chronic inflammatory eye disease, which is the most frequent extra-articular manifestation of JIA. 4, 5 Uveitis threatens the sight of those affected, and can result in complications including macular edema, band keratopathy, cataracts, glaucoma, and hypotony. 4 Because it typically afflicts the young (<7 years old), uveitis dramatically impacts quality of life both in childhood and as an adult. 4, 6 Early detection and adequate ophthalmological management of JIA-associated uveitis are critical to prevent significant, sight-threatening complications. [7] [8] [9] Despite its severity, uveitis is typically insidious in onset and often becomes symptomatic only after irreversible damage has occurred. Consequently, rigorous ophthalmological screening of all JIA patients is required for early detection and treatment of uveitis associated with JIA. 10 Nonetheless, severe ocular complications may already be present at the time of a uveitis diagnosis. Several clinical factors are associated with increased uveitis risk: young age (<7 years old) at JIA onset; the presence of antinuclear antibodies (ANA), elevated erythrocyte sedimentation rate (ESR) at JIA onset, and JIA category (oligoarticular and polyarticular rheumatoid factor (RF)-negative). [10] [11] [12] Sex is also considered a risk factor, though the available epidemiologic data is controversial. Female patients comprise the majority of JIA categories with uveitis, and are therefore observed somewhat more frequently (but only modestly so) in the overall JIA population. The extent to which biological risk for JIAassociated uveitis is sexually dimorphic, however, is not known. 12 Both JIA and JIA-associated uveitis (i.e., JIA-uveitis) are multifactorial autoimmune disorders; each has a strong, though not fully penetrant, genetic predisposition. 4, 13 Both conditions are complex and driven by biological and environmental factors. 4, 13 There have been no reports of observed Mendelian inheritance patterns of uveitis in JIA-affected families, 4 further indicating a complex trait architecture. Genome-wide association studies in JIA individuals (with and without uveitis) have revealed a number of loci associated to the disease, [14] [15] [16] including multiple independent loci in the major histocompatibility complex (MHC) which collectively explain >20% of the phenotypic variation in broadly-defined JIA. 16 A number of HLA types have also been identified as increasing risk of JIA-associated uveitis compared to controls. 4, [17] [18] [19] However, genome-wide genetic markers that distinguish JIA without uveitis from JIA-associated uveitis remain elusive, and the exact disease mechanisms predisposing only a subgroup of children to developing uveitis are unknown. Due to the severity of uveitis and the complications surrounding its detection, biomarkers to predict the development of uveitis would help in early detection of the presence of JIAuveitis in high-risk children without frequent, extensive, and costly screenings for all JIA patients.