Identification of Ocular Autoantigens Associated With Juvenile Idiopathic Arthritis-Associated Uveitis

The purpose of the current study was to analyze the binding patterns of serum autoantibodies from juvenile idiopathic arthritis (JIA) and JIA-associated uveitis (JIAU) patients to proteomes from different ocular tissues and to identify potential ocular autoantigens in JIAU. Proteomes from porcine iris, ciliary body, or retina tissue were isolated, separated using 2D-gel electrophoresis, and transferred to a blotting membrane. The binding pattern of serum antibodies from JIA or JIAU patients or healthy controls to ocular proteins was visualized by using anti-human IgG secondary antibodies and chemiluminescence reaction. Selected protein spots were excised from silver-stained 2D gels and subjected to mass spectrometry. Serum antibodies binding to ocular proteins were detected in all patient groups and healthy controls. Irrespective of the patient groups, serum antibodies bound to 49 different protein spots of the retina proteome, to 53 of the ciliary body proteome, and to 44 of the iris proteome. The relative binding frequency of sera to these iris protein spots was significantly higher in JIAU than in JIA patients or healthy controls. Particularly in JIAU patients, cluster analyses indicated a broad range of serum antibodies directed against ocular antigens, mostly in the iris proteome. Iris proteins frequently bound by serum antibodies in all groups were identified as tubulin beta chain, vimentin, ATP synthase subunit beta, actin, and L-lactate dehydrogenase B chain. Iris proteins exclusively bound by JIAU serum antibodies were heat shock cognate 71 kDa protein and keratin. Although serum autoantibody binding to ocular antigens was not disease-specific, a significant diversity of autoantibodies against a broad range of antigens, particularly from the iris tissue, was detected in JIAU patients. As the iris is a major site of inflammation in JIAU, the present data give further evidence that autoantibodies may be involved in JIAU immunopathology

Consensus-based recommendations for the management of uveitis associated with juvenile idiopathic arthritis:the SHARE initiative

BACKGROUND: In 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. OBJECTIVES: To provide recommendations for the diagnosis and treatment of JIA-associated uveitis. METHODS: Recommendations 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). RESULTS: In 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. CONCLUSIONS: The 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

Occurrence and Risk Factors for Macular Edema in Patients with Juvenile Idiopathic Arthritis-Associated Uveitis.

PURPOSE To analyze occurrence and risk factors for macular edema (ME) in juvenile idiopathic arthritis-associated uveitis (JIA-U). METHODS Retrospective analysis of patients with JIA-U at a tertiary referral uveitis center between 2000 and 2019. Epidemiological data and clinical findings before ME onset were evaluated. RESULTS Out of 245 patients, ME developed in 41 (18%) of the 228 JIA-U patients for whom data documentation was complete during the follow-up (mean 4.0 ± 3.8 years). Risk factors (univariable logistic regression analysis) at baseline for subsequent ME onset included older age at initial documentation at institution (hazard ratio, HR 1.19, p < 0.0001), longer duration of uveitis at initial documentation (HR 1.17, p < 0.0001), worse best-corrected visual acuity (BCVA; HR 2.49, p < 0.0001), lower intraocular pressure (IOP; HR 0.88, p < 0.01), band keratopathy (HR 2.29, p < 0.01), posterior synechiae (HR 2.55, p < 0.01), epiretinal membrane formation (HR 6.19, p < 0.0001), optic disc swelling (HR 2.81, p < 0.01), and cataract (HR 4.24, p < 0.0001). Older age at initial documentation at institution (HR 1.55, p < 0.001), worse BCVA (HR 28.56, p < 0.001), and higher laser-flare photometry (LFM) values (HR 1.003, p = 0.01) were independent risk factors for ME manifestation. Patients with ME revealed significant changes in BCVA, LFM, and IOP and new optic disc swelling at 6 and 3 months before ME onset compared to timepoint of ME occurrence (p < 0.05, each). CONCLUSION ME is a common complication of JIA-U. Demographic risk factors and courses of IOP, BCVA, and LFM may indicate patients at risk for ME onset

Adherence to ophthalmological screening recommendations and course of uveitis in children with juvenile idiopathic arthritis: data from the Inception Cohort of Newly diagnosed patients with JIA (ICON-JIA) study.

OBJECTIVES As JIA-associated uveitis (JIAU) is asymptomatic in the majority of patients, ophthalmologic screening examinations are recommended, depending on the risk constellation for uveitis development. This study analyses disease characteristics in JIAU depending on adherence with the screening intervals. METHODS 953 patients were included in the ICON registry. In patients without uveitis, ophthalmologic screening was recommended in accordance with the standards currently applied in Germany. Dates and results of the screening examinations were noted for each patient. RESULTS Until the 3-year-follow up, uveitis developed in 133 of 953 JIA patients. In 56 of them, uveitis was present before study inclusion, and those were excluded from the prospective analysis. For the remaining 897 JIA patients, screening results were available in 557, 46 of whom developed uveitis. In those patients, adherence with the suggested screening intervals until uveitis onset was assessed, and patients were classified accordingly: screenings as recommended (Sc+ group, n=356) vs. infrequent screening (Sc- group, n=201). Non-adherence with the screening schedule significantly correlated with younger age at study inclusion and JIA diagnosis, shorter JIA disease duration, JIA oligoarthritis subtype and positive antinuclear antibody status. The Sc+ group had a better visual acuity (VA) at initial uveitis diagnosis, however, at the 3-year-follow up, VA and uveitis complication rates did not differ significantly. CONCLUSIONS Especially high-risk patients often do not adhere to the initial frequently recommended screening intervals, resulting in a reduced visual acuity at initial uveitis diagnosis. A recommendation for changing the current screening intervals cannot be deduced from our data

The effect of methotrexate and sulfasalazine on the course of HLA-B27-positive anterior uveitis: results from a retrospective cohort study.

PURPOSE To investigate the effect of methotrexate (MTX) or sulfasalazine (SSZ) on the course of HLA-B27-positive, remitting acute anterior uveitis (AAU). METHODS Forty-six patients with HLA-B27-positive AAU with or without associated systemic rheumatic disease either receiving MTX (n = 20), SSZ (n = 13), or no systemic immunomodulating treatment (Ctrl; n = 13) were studied retrospectively. Best-corrected visual acuity (BCVA), AAU relapse rate, and occurrence of uveitis-related ocular complications were analyzed at baseline (BL) and at 12-month follow-up (FU). RESULTS Groups did not differ regarding age, gender, and presence of associated systemic diseases. BCVA at baseline was significantly worse in patients receiving MTX (logMAR 0.39 ± 0.4) than in those treated with SSZ (0.17 ± 0.2; P = 0.05) or in controls (Ctrl; 0.14 ± 0.2; P = 0.009). At the 12-month endpoint, MTX treatment was associated with significantly improved BCVA (0.18 ± 0.4 logMAR; P = 0.004). In contrast, BCVA did not significantly change in patients treated with SSZ (0.17 ± 0.3 logMAR) or in the controls (0.11 ± 0.2 logMAR). The annual uveitis relapse rate significantly decreased with MTX (BL 3.6 ± 2.4 relapses to FU 0.7 ± 0.8; P = 0.0001) and SSZ (BL 3.6 ± 1.9 to FU 1.8 ± 2.4, P < 0.01), but not in the controls (BL 1.9 ± 1.4 vs 1.9 ± 1.7 FU). The complication rate was slightly reduced with MTX (BL 1.75 ± 1.2 complications present versus FU 1.3 ± 1.2, P = 0.09) but not with SSZ (BL 0.9 ± 0.8 to FU 1.3 ± 1.4; P = 0.4) or in the controls (BL and FU 1.0 ± 0.95; P = 0.7). CONCLUSIONS MTX and SSZ reduced the uveitis relapse rate in HLA-B27-positive AAU patients, with MTX showing a beneficial effect on AAU-related macular edema

Elevated S100A8/A9 and S100A12 Serum Levels Reflect Intraocular Inflammation in Juvenile Idiopathic Arthritis-Associated Uveitis: Results From a Pilot Study.

PURPOSE Juvenile idiopathic arthritis-associated uveitis (JIAU) is the most common uveitis entity in childhood. As S100A8/A9 and S100A12 proteins are valuable biomarkers in childhood arthritis, we investigated the occurrence of these proteins in childhood uveitis. METHODS Serum samples from patients with JIAU (n = 79) or idiopathic anterior uveitis (IAU, n = 24), as well as from nonuveitic controls (n = 24), were collected. Furthermore, aqueous humor samples (JIAU n = 17, nonuveitic controls n = 16, IAU n = 12) were obtained. Samples were analyzed for S100A8/A9 and S100A12 protein levels by ELISA. Intergroup comparisons were performed, involving patient data, clinical data, and S100 levels. RESULTS S100A8/A9 and S100A12 serum levels were elevated in IAU and JIAU patients as compared to nonuveitic controls (all P < 0.05). S100 serum levels in JIAU patients were higher in active arthritis (not significant; P = 0.289 for S100A8/A9 and P = 0.196 for S100A12) and active uveitis (P = 0.010 for S100A8/A9 and P = 0.026 for S100A12) than in controls. No significant differences in S100 levels were found in a subgroup analysis for sex, antinuclear antibody (ANA) status, disease duration, or presence of uveitis complications. In JIAU patients, S100 serum levels correlated with age and age at onset of uveitis. A longitudinal analysis in JIAU patients showed a correlation of serum S100A8/A9 and S100A12 levels with uveitis activity (both P = 0.03). S100A8/A9 levels in aqueous humor of patients with JIAU (P = 0.001) and IAU (P = 0.0002) were increased as compared to nonuveitic controls. CONCLUSIONS 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

Effect of Adalimumab on Peripheral Blood Mononuclear Cells in Non-Infectious Uveitis

<p><i>Purpose:</i> This study analyzed the effect of adalimumab on peripheral blood mononuclear cells (PBMCs) in uveitis.</p> <p><i>Methods:</i> PBMCs and serum S100A12 levels from 14 uveitis patients and 28 healthy controls were analyzed. Patient samples were taken before (w0), and 6 (w6) and 12 (w12) weeks after initiation of adalimumab therapy.</p> <p><i>Results:</i> Monocytes expressing CD124, CD86, CD39, CD115, and MHCII were decreased in patients. Adalimumab induced CD86+ and CD39+ monocytes, and further decreased the frequency of MHCII- and CD124-positive cells. Patients (w0) had increased percentages of Th1-, Th17-, and Th2 cells and T cell subsets showed a pro-inflammatory polarization (<i>p</i> = 0.02 ratio Th17/Treg patients w0 vs controls), which was reduced upon adalimumab treatment (<i>p</i> = 0.05 w0 vs w6). S100A12 levels were increased in patients (<i>p</i> = 0.02) and reduced under treatment (<i>p</i> = 0.02 for w6/w12).</p> <p><i>Conclusions:</i> The phenotype of PBMCs from uveitis patients is modified upon adalimumab treatment. Serum S100A12 levels reflect the systemic immune response.</p

Increased Circulating Proinflammatory T Lymphocytes in Children with Different Forms of Anterior Uveitis: Results from a Pilot Study

<p><i>Purpose</i>: To characterize peripheral blood T cells in juvenile idiopathic arthritis-associated uveitis (JIAU).</p> <p><i>Methods</i>: Blood samples were taken from children with JIAU (n = 18), JIA without ocular involvement (n = 11), idiopathic anterior uveitis (IAU, n = 12), and healthy controls (n = 11). Cells were stained for T cell surface markers, and intracellular cytokine staining was performed after cell stimulation and analyzed by flow cytometry.</p> <p><i>Results</i>: The Th1/Th2 ratio was increased in JIAU patients. Numbers of IL-13-expressing cells an level of IL-13 and IL-10 expression per cell were increased in all patient groups; whereas, percentages of IL-5-expressing T cells were decreased. Numbers of proinflammatory Th17 cells and T cells expressing CTLA-4 were increased in all patient groups; whereas, γ/δ T cell numbers were decreased. Results from JIA and IAU were similar.</p> <p><i>Conclusion</i>: T cell subtypes and potential T cell function are altered in pediatric patients with uveitis and arthritis as compared to healthy children.</p

Risk Factors and Biomarkers for the Occurrence of Uveitis in Juvenile Idiopathic Arthritis: Data From the Inception Cohort of Newly Diagnosed Patients With Juvenile Idiopathic Arthritis Study.

OBJECTIVE To 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). METHODS Patients 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. RESULTS We 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). CONCLUSION Apart 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