Assessment of angiogenesis-related parameters in juvenile idiopathic arthritis-associated uveitis.

PURPOSE: Juvenile idiopathic arthritis-associated uveitis (JIAU) may run a chronic and treatment-resistant course, and occasionally, alterations of the iris vasculature may be observed clinically. METHODS: Iris tissue (IT), aqueous humor (AH) and serum samples from patients with clinically inactive JIAU (n = 30), acute anterior uveitis (AAU; n = 18), and primary open angle glaucoma (POAG; n = 20) were obtained during trabeculectomy or cataract surgery. Samples were analyzed by RNA-Seq, qRT-PCR, LC-IMS, Western-Blot, and LEGENDplex™ analysis. Pattern of iris vasculature in JIAU patients was assessed qualitatively via fluorescein and indocyanine green angiography (FLA/ICGA). RESULTS: RNA-Seq of IT showed significantly differential expression (DE) of 136 genes between JIAU and POAG, of which 15 were associated with angiogenesis. qRT-PCR, performed to validate RNA-Seq results, showed upregulation of the angiogenesis-related genes Kdr, Angpt-1, Tie-1, Tie-2 and Mmrn2 in IT (JIAU vs POAG, p > 0.05). LC-IMS of IT revealed a total number of 56 DE proteins (JIAU vs POAG), of which Angiopoetin, Lumican and Decorin were associated with angiogenesis and showed increased (p > 0.05) expression on Western-Blot analysis. LEGENDplex™ analysis showed upregulation of ANGPT-2 in AH from JIAU compared to AAU and POAG, whereas VEGF was upregulated in AAU. Iris vascular leakage, hypoperfusion and neovascularization were observed by FLA/ICGA in JIA patients with treatment-refractory complicated course of uveitis. CONCLUSION: Angiogenesis-related factors could play a role in long-standing complicated JIAU, leading to clinically visible alterations in selected cases.

Juvenile idiopathic arthritis in multiplex families: longitudinal follow-up.

OBJECTIVE: To describe the physical, social, educational and employment status and clinical outcomes of patients with juvenile idiopathic arthritis (JIA) from multiplex families. METHODS: All familial JIA patients were treated and had regular follow-up between 1990 and 2015 at King Faisal Specialist Hospital and Research Center (KFSH-RC), Riyadh, were included. Demographic data, disease duration, active arthritis and articular and extra-articular damage at last follow-up visit were reviewed. Additionally, social, educational and employment history were obtained via personal or phone interviews. RESULTS: Twenty-three patients (20 females) belonging to 10 families were included. The mean age was 14.6 (±9) years with mean disease duration of 11.4 (±9) years and mean follow-up duration of 10.5 (±6). Fourteen patients had systemic JIA while eight patients had polyarticular subtype, and one patient had psoriatic arthritis. All patients received concomitant treatment. Twenty-one patients commenced biologic agents; treatment switched to another agent in all of them because of inadequate response. Most patients had progressive disease course. Twelve patients had active polyarthritis and 22 patients showed evidence of articular damage. All patients had raised inflammatory markers. Eighteen patients had short stature and 11 patients had delayed puberty. Two patients had lower limb lymphedema and one patient had a single kidney with refractory hypertension. Three patients underwent hip arthroplasty. Seventeen patients had satisfactory educational achievement and four patients were in employment. Two patients died due to infection. CONCLUSION: Our results showed the largest familial clusters of JIA in the Middle East. Patients with familial JIA had refractory disease with progressive disease course.

HLA genotyping as first-line screening tool for coeliac disease in children with juvenile idiopathic arthritis.

OBJECTIVES: Coeliac disease (CD) and juvenile idiopathic arthritis (JIA) often coexist. This association warrants assessment for CD in patients with JIA. We evaluated the clinical relevance and cost-effectiveness of human leucocyte antigen (HLA) genotyping in first-line screening for development of CD in children with JIA. PATIENTS AND INTERVENTIONS: 95 patients with JIA were screened for CD using CD-specific antibodies. In case of positivity, a small intestinal biopsy was performed to confirm diagnosis. In addition, HLA genotyping was performed. 110 age-matched and sex-matched Caucasian children from the same geographical area served as controls. RESULTS: CD was diagnosed in 4 of 95 patients with JIA (4.2%), a rate significantly higher compared with controls (p<0.02) and 14 times higher than in the general population. Twenty-six patients (27.4%) had one of the variants of the risk genotypes. All four patients diagnosed with CD had a HLA-DQ2.5 genotype: one was homozygote, the remainder heterozygote. Twenty-two patients are, judging by their HLA genotypes, at risk of developing CD and require repeated serological screening. None of the 69 patients without HLA-DQ2/DQ8 genotypes had CD-specific antibodies. Screening with HLA genotyping becomes cheaper than screening without after the second determination. CONCLUSIONS: In our cohort of patients with JIA, lack of HLA-DQ2/DQ8 genotypes identified a majority not at risk of CD in whom repeated serological testing is unnecessary. Genotyping is nowadays the most efficient and cost-effective way to screen for CD risk in JIA.

Pathway analysis based on Monte Carlo Cross-Validation in polyarticular juvenile idiopathic arthritis.

INTRODUCTION: Juvenile idiopathic arthritis (JIA) is a common chronic disease with onset before the 16 years old in a child. Polyarticular JIA has been reported as the main form of JIA in several locations. Until now, understanding of the genetic basis of JIA is incomplete. The purpose of this study was to identify pathway pairs of great potential functional relevance in the progression of polyarticular JIA. MATERIALS AND METHODS: Microarray data of 59 peripheral blood samples from healthy children and 61 samples from polyarticular JIA were transformed to gene expression data. Differential expressed genes (DEG) between patients and normal controls were identified using Linear Models for Microarray Analysis. After performed enrichment of DEG, differential pathways were identified with Fisher's test and false discovery rate. Differential pathway pairs were constructed with random two differential pathways, and were evaluated by Random Forest classification. Monte Carlo Cross-Validation was introduced to screen the best pathway pair. RESULTS: 42 DEG with P-values<0.01 were identified. 19 differential pathways with P-values<0.01 were identified. Area under the curve (AUC) of pathway pairs was generated with RF classification. After 50 bootstraps of Monte Carlo Cross-Validation, the best pathway pair with the highest AUC value was identified, and it was the pair of tumoricidal function of hepatic natural killer cells pathway and erythropoietin signaling pathway. CONCLUSION: These identified pathway pairs may play pivotal roles in the progress of polyarticular JIA and can be applied for diagnosis. Particular attention can be focused on them for further research.