BackgroundIn 2012, a European initiative called Single Hub and Access point for pediatric Rheumatology in Europe (SHARE) was launched to optimise and disseminate diagnostic and management regimens in Europe for children and young adults with rheumatic diseases. Juvenile idiopathic arthritis (JIA) is the most common rheumatic disease in children and uveitis is possibly its most devastating extra-articular manifestation. Evidence-based guidelines are sparse and management is mostly based on physicians’ experience. Consequently, treatment practices differ widely, within and between nations.ObjectivesTo provide recommendations for the diagnosis and treatment of JIA-associated uveitis.MethodsRecommendations were developed by an evidence-informed consensus process using the European League Against Rheumatism standard operating procedures. A committee was constituted, consisting of nine experienced paediatric rheumatologists and three experts in ophthalmology from Europe. Recommendations derived from a validated systematic literature review were evaluated by an Expert Committee and subsequently discussed at two consensus meetings using nominal group techniques. Recommendations were accepted if >80% agreement was reached (including all three ophthalmologists).ResultsIn total, 22 recommendations were accepted (with >80% agreement among experts): 3 on diagnosis, 5 on disease activity measurements, 12 on treatment and 2 on future recommendations.ConclusionsThe SHARE initiative aims to identify best practices for treatment of patients suffering from JIA-associated uveitis. Within this remit, recommendations for the diagnosis and treatment of JIA-associated uveitis have been formulated by an evidence-informed consensus process to suggest a standard of care for JIA-associated uveitis patients throughout Europe.

Human and murine studies showed that GM-CSF exerts beneficial effects in intestinal inflammation. To explore whether GM-CSF mediates its effects via monocytes, we analyzed effects of GM-CSF on monocytes in vitro and assessed the immunomodulatory potential of GM-CSF–activated monocytes (GMaMs) in vivo. We used microarray technology and functional assays to characterize GMaMs in vitro and used a mouse model of colitis to study GMaM functions in vivo. GM-CSF activates monocytes to increase adherence, migration, chemotaxis, and oxidative burst in vitro, and primes monocyte response to secondary microbial stimuli. In addition, GMaMs accelerate epithelial healing in vitro. Most important, in a mouse model of experimental T cell–induced colitis, GMaMs show therapeutic activity and protect mice from colitis. This is accompanied by increased production of IL-4, IL-10, and IL-13, and decreased production of IFN-γ in lamina propria mononuclear cells in vivo. Confirming this finding, GMaMs attract T cells and shape their differentiation toward Th2 by upregulating IL-4, IL-10, and IL-13 in T cells in vitro. Beneficial effects of GM-CSF in Crohn’s disease may possibly be mediated through reprogramming of monocytes to simultaneously improved bacterial clearance and induction of wound healing, as well as regulation of adaptive immunity to limit excessive inflammation.

Increased S100A8/A9 and S100A12 levels are found in the serum and aqueous humor of patients with autoimmune uveitis. Serum levels reflect activity of joint and eye disease.

ObjectiveTo analyze the prognostic value of demographic, clinical, and therapeutic factors and laboratory biomarkers and to assess their role in predicting uveitis occurrence in patients with juvenile idiopathic arthritis (JIA).MethodsPatients with JIA were enrolled within the first year after JIA diagnosis. Demographic and clinical parameters were documented. Serum samples were collected at study enrollment, at 3‐month follow‐up visits within the first year, and then every 6 months. A multivariable Cox regression analysis was performed to evaluate the impact of demographic, clinical, laboratory, and therapeutic parameters on uveitis onset.ResultsWe included 954 JIA patients (67.2% female, 54.2% antinuclear antibody [ANA] positive, mean ± SD age at onset 7.1 ± 4.6 years). Uveitis occurred in 133 patients (observation period 44.5 months). Young age at JIA onset and ANA positivity were significantly associated with the onset of uveitis (both P < 0.001). Treatment of arthritis with methotrexate alone (hazard ratio [HR] 0.18 [95% confidence interval (95% CI) 0.12–0.29], P < 0.001) or combined with etanercept (HR 0.10 [95% CI 0.04–0.23], P < 0.001) or adalimumab (HR 0.09 [95% CI 0.01–0.61], P = 0.014) reduced the risk of uveitis onset and the occurrence of uveitis‐related complications. Predictors of uveitis onset included elevated erythrocyte sedimentation rate at baseline (HR 2.36 [95% CI 1.38–4.02], P = 0.002) and continuing moderate or high disease activity during follow‐up as measured by the 10‐joint clinical Juvenile Arthritis Disease Activity Score (HR 4.30 [95% CI 2.51–7.37], P < 0.001). Additionally, S100A12 levels ≥250 ng/ml at baseline were significantly associated with the risk of uveitis (HR 2.10 [95% CI 1.15–3.85], P = 0.016).ConclusionApart from demographic risk factors and treatment modalities, JIA disease activity scores and laboratory biomarkers could be used to better define the group of JIA patients at high risk of uveitis onset.

Objective To define predictors for the 2-year outcome in terms of achieving inactivity, subsequent uveitis reactivation and occurrence of uveitis-related complications of JIA-associated uveitis. Methods Demographic and clinical parameters and serum samples of JIA-associated uveitis patients enrolled in ICON at ⩽1 year of JIA diagnosis were collected at study enrolment, every 3 months during the first year and subsequently every 6 months. Predictors for the 2-year outcome were evaluated by linear mixed models. Results Of 954 JIA patients included, uveitis occurred in 106 up to the first 2-year follow-up, with 98 of them having complete ophthalmological documentation. In 81.8% and 80.0% of patients, uveitis inactivity was achieved at the 1- and 2-year follow-up after uveitis onset, respectively. JIA onset after the age of 5 years, no use of topical corticosteroids, and adalimumab treatment were significantly associated with an inactive uveitis for at least 6 months ( n = 57). Correlates for subsequent uveitis reactivation ( n = 16, 30.2%) were age at uveitis onset ⩽5 years and active disease (clinical Juvenile Arthritis Disease Activity Score >4.5). Uveitis-related complications were present in 29.8% of patients at first uveitis documentation and in 30.7% and 32.8% at 1- and 2-year follow-up, respectively. Older age at JIA onset, short duration between JIA and uveitis onset, high anterior chamber (AC) cell grades, poor visual acuity, and topical steroid use at first uveitis documentation correlated with uveitis-related complications. Conclusion In addition to demographic risk factors, JIA disease and uveitis activity scores and adalimumab are significant predictors for the 2-year outcome of JIA-associated uveitis patients.

Uveitis describes a heterogeneous group of inflammatory eye diseases characterized by infiltration of leukocytes into the uveal tissues. Uveitis associated with the HLA haplotype B27 (HLA-B27) is a common subtype of uveitis and a prototypical ocular immune-mediated disease. Local immune mechanisms driving human uveitis are poorly characterized mainly due to the limited available biomaterial and subsequent technical limitations. Here, we provide the first high-resolution characterization of intraocular leukocytes in HLA-B27-positive (n = 4) and -negative (n = 2) anterior uveitis and an infectious endophthalmitis control (n = 1) by combining single-cell RNA-sequencing with flow cytometry and protein analysis. Ocular cell infiltrates consisted primarily of lymphocytes in both subtypes of uveitis and of myeloid cells in infectious endophthalmitis. HLA-B27-positive uveitis exclusively featured a plasmacytoid and classical dendritic cell (cDC) infiltrate. Moreover, cDCs were central in predicted local cell-cell communication. This suggests a unique pattern of ocular leukocyte infiltration in HLA-B27-positive uveitis with relevance to DCs.

Objective Enthesitis-related arthritis (ERA) represents a subgroup of juvenile idiopathic arthritis (JIA) which is regularly accompanied by anterior uveitis. This study describes the prevalence and characteristics of ERA-related uveitis. Methods Cross-sectional data from the National Pediatric Rheumatological Database (NPRD) were used to characterize ERA-related uveitis (ERA-U). In addition to sociodemographic parameters, we documented the occurrence of uveitis and course of disease - including symptoms, visual acuity, and complications - as well as JIA characteristics such as disease activity (cJADAS10), functional ability (CHAQ score), laboratory parameters, and treatment. Results In the years from 2002 to 2014, 3,778 (15.2%) of a total of 24,841 JIA patients recorded in the NPRD had ERA, and 280 (7.4%) of them had developed uveitis. Detailed ophthalmological documentation by an uveitis add-on module was available for 22.9% of these patients. Uveitis onset was acutely symptomatic in 63% of patients. Patients with uveitis were more frequently male, HLA-B27 positive, and younger at ERA onset, and they had higher ESR values at first uveitis documentation than those without uveitis. Uveitis was diagnosed at a mean age of 11.5 (± 3.9) years (50% within two years after ERA onset). Systemic treatment with corticosteroids and synthetic and biologic disease-modifying antirheumatic drugs was associated with a (not significantly) lower risk of developing uveitis. Conclusion The course of disease in ERA-U patients is frequently similar to HLAB27-associated uveitis in adults; however, a subgroup of patients presents with asymptomatic uveitis.

Patients with juvenile idiopathic arthritis often develop chronic anterior uveitis (JIAU). JIAU patients possess a particularly high risk for developing secondary glaucoma when inflammatory inactivity has been achieved. By using multiplex bead assay analysis, we assessed levels of pro- and anti-inflammatory cytokines, chemokines, or metalloproteinases in the aqueous humor (AH) of patients with clinically inactive JIAU with (JIAUwG) or without secondary glaucoma (JIAUwoG), or from patients with senile cataract as controls. Laser-flare photometry analysis prior to surgery showed no significant differences between JIAUwG or JIAUwoG. Compared with the control group, levels of interleukin-8, matrix metalloproteinase-2, -3, -9, serum amyloid A (SAA), transforming growth factor beta-1, -2, -3 (TGFβ-1, -2, -3), and tumor necrosis factor-alpha in the AH were significantly higher in patients with clinically inactive JIAUwG or JIAUwoG. Samples from JIAwoG patients displayed significantly higher levels of SAA (P < 0.0116) than JIAUwG patients. JIAUwG patients showed an increased level of TGFβ-2 in AH samples compared with JIAUwoG (P < 0.0009). These molecules may contribute to the clinical development of glaucoma in patients with JIAU.