The enigma of uveitis in juvenile idiopathic arthritis : Genetic, immunologic and clinical aspects

Uveitis associated with juvenile idiopathic arthritis (JIA) is a sight-threatening inflammation of the eye, affecting up to 30% of children with JIA. Despite the fact that the association of uveitis in JIA was already described by Ohm in 1910 and has a life-long impact, it remains a poorly understood condition. The overarching aim of this thesis was to identify clinical and molecular biomarkers and risk factors associated with the occurrence of uveitis in JIA patients. Furthermore, JIA-associated uveitis is classically seen as a disease of childhood, but there are increasing suggestions that patients deal with complications, treatment and disease activity far into young adulthood. Therefore, we studied the prognosis and Quality of Life (QoL) of JIA-associated uveitis patients in early adulthood. First, we studied inflammatory parameters at arthritis onset as possible predictors for the development of uveitis in JIA. We found increased Erythrocyte Sedimentation Rate (ESR) at JIA onset to be predictive for uveitis occurrence in JIA. ESR is already routinely tested in patients at JIA onset, so its use as a biomarker can easily be implemented in daily practice. Furthermore, we conducted a genome wide association study (GWAS) to compare the frequencies of single nucleotide polymorphisms (SNPs) in 192 JIA patients with uveitis and 330 JIA patients without uveitis. We found the YST-motif in the HLA-DRB1 gene to be a genetically distinct, female specific feature of JIA-associated uveitis compared to non-uveitis JIA. In fact, only 1 female uveitis patient (1%) did not carry the YST-motif. Strikingly, this female did not suffer from the characteristic (chronic anterior) uveitis phenotype linked to JIA. This YST-motif association indicates potential involvement of antigen presentation by HLA-DRβ1 in the development of uveitis in JIA. In order to better understand the disease mechanism that distinguishes chronic anterior uveitis in JIA from other forms of childhood uveitis, we measured a panel of 51 soluble mediators in Aqueous Humor (AqH). The levels of interleukin-29 (IL-29)/interferon-λ1 (IFNλ1) were specifically decreased in AqH from JIA-associated uveitis patients compared to idiopathic uveitis. This suggests that IL-29/IFNλ1 signaling might be a specific and important biomarker in JIA-associated uveitis. In the second part of the thesis, we studied the impact of uveitis on the QoL of adolescent JIA patients, by analyzing their scores of three validated QoL questionnaires. The vision-related QoL in JIA was lower in uveitis patients, despite ‘good visual acuity’ according to the criteria of the world health organization (WHO) and standardization of uveitis nomenclature (SUN) international working group. Although, the general QoL scores did not differ between uveitis and non-uveitis JIA patients, the use of systemic immunomodulatory treatment did negatively influence general QoL scores in JIA patients. In a retrospective multicenter cohort study, outlining uveitis activity, complications and visual prognosis of 67 young adult patients with (childhood onset) uveitis and JIA, we found that the bilateral visual outcome of JIA-associated uveitis in adulthood is fairly good, but about one third of all patients developed one visually impaired or blind eye. Also, a fair amount of the patients had ongoing uveitis activity or needed treatment during adulthood as well as surgical interventions