Clinical benefits and potential risks of adalimumab in non-JIA chronic paediatric uveitis

Purpose: To describe the treatment results with adalimumab in chronic paediatric uveitis, not associated with juvenile idiopathic arthritis (JIA). Methods: Medical records of children with non-JIA-uveitis were reviewed retrospectively. Children without an underlying systemic disease were pre-screened with brain magnetic resonance imaging (MRI) to exclude white matter abnormalities/demyelination. Results: Twenty-six patients were pre-screened with brain MRI, of whom adalimumab was contraindicated in six patients (23%) with non-anterior uveitis. Forty-three patients (81 eyes) were included. Disease inactivity was achieved in 91% of the patients after a median of three months (3–33). Best-corrected visual acuity (BCVA) improved from 0.16 ± 0.55 logarithm of the minimum angle of resolution (logMAR) at baseline to 0.05 ± 0.19 logMAR at 24 months (p = 0.015). The median dosage of systemic corticosteroids was reduced to 0 mg/day at 24 months of follow-up (versus 10 mg/day at baseline; p < 0.001). Adalimumab was discontinued in thirteen children due to ineffectiveness (n = 8), side effects (n = 1), long-term inactivity of uveitis (n = 3) or own initiative (n = 1). Relapse of uveitis occurred in 19 (49%) patients, 5 (26%) of them without an identifiable cause. Conclusion: Adalimumab is effective in the treatment of non-JIA-uveitis in paediatric patients by achieving disease inactivity in the majority of the patients, improving BCVA and decreasing the dose of corticosteroids. Adverse events and side effects are limited. Pre-screening with MRI of the brain is recommended in paediatric patients with intermediate and panuveitis

Serum Biomarkers of Vascular Involvement in Childhood Uveitis

Purpose: Nonanterior uveitis frequently involves the retinal vasculature; however, no molecular markers associated with the retinal vascular disease are currently known. In this study, we aimed to identify serum biomarker signatures associated with retinal vascular involvement in noninfectious pediatric uveitis. Methods: We performed a 384-plex targeted proteomic analysis of serum samples of 154 noninfectious pediatric uveitis patients diagnosed with nonanterior uveitis (n = 74), idiopathic chronic anterior uveitis (iCAU, n = 36), or juvenile idiopathic arthritis– associated uveitis (JIA-U, n = 44), as well as 22 noninflammatory pediatric controls. Data on retinal vascular involvement (i.e., papillitis, cystoid macular edema, retinal vasculitis, or retinal capillary leakage on optical coherence tomography and/or fluorescein angiography) were used to stratify cases in the nonanterior uveitis group. Results: In the analysis of nonanterior uveitis, we identified nine proteins significantly associated with retinal vascular involvement, including F13B, MYOM3, and PTPN9. These proteins were enriched through pathway enrichment analysis for the coagulation cascade. Comparing cases and controls, we identified 63 differentially expressed proteins, notably proteins involved in platelet biology and complement cascades, which could be primarily attributed to differences in serum proteomes between anterior uveitis and nonanterior uveitis groups. Conclusions: Serum proteins related to the coagulation and complement cascade are associated with retinal vascular involvement in pediatric uveitis patients. Our results indicate involvement of mediators that could interact with the microcirculation in pediatric uveitis and might serve as potential biomarkers in personalized medicine in the future. Translational Relevance: Our targeted proteomics analysis in serumof pediatric uveitis patients indicates involvement of mediators that could interact with the microcirculation in pediatric uveitis and might serve as potential biomarkers in personalized medicine in the future

Involvement of the systemic microcirculation in pediatric uveitis

BACKGROUND: Pediatric uveitis is a severe inflammatory ocular condition that can lead to sight-threatening complications and can negatively impact quality of life. The retinal microcirculation is often affected in intermediate uveitis and panuveitis. Here, we examined the extraocular (i.e., systemic) microcirculation in pediatric uveitis cases and healthy controls using nailfold capillaroscopy (NFC). METHODS: We performed NFC in 119 children with noninfectious uveitis and 25 healthy pediatric controls, and assessed the following parameters: capillary density (number of capillaries/mm), dilated capillaries (apex > 20 µm), avascular area, the presence of microhemorrhages, and capillary morphology. Differences in NFC parameters between cases and controls were calculated using regression analysis after adjusting for age and sex. RESULTS: The mean (± SD) age of the patient group was 13.7 (± 3) years, with 56% females; 46%, 18%, and 36% of cases presented as anterior uveitis, intermediate uveitis, and panuveitis, respectively, with an overall mean disease duration of 4.7 (± 4.0) years. Compared to the control group, the pediatric uveitis cases had a significantly higher number of dilated capillaries/mm and a higher prevalence of ramified capillaries. Moreover, compared to the control group the intermediate uveitis cases had a significantly higher number of dilated capillaries, whereas the anterior uveitis cases had a lower capillary density and a higher prevalence of ramified capillaries. CONCLUSIONS: Children with uveitis without systemic disease can present with changes in systemic microcirculation. These changes vary amongst the subtypes of uveitis

A Blood Protein Signature Stratifies Clinical Response to csDMARD Therapy in Pediatric Uveitis

Purpose: To identify a serum biomarker signature that can help predict response to conventional synthetic disease-modifying antirheumatic drug (csDMARD) therapy in pediatric noninfectious uveitis. Methods: In this case-control cohort study, we performed a 368-plex proteomic analysis of serum samples of 72 treatment-free patients with active uveitis (new onset or relapse) and 15 healthy controls. Among these, 37 patients were sampled at diagnosis before commencing csDMARD therapy. After 6 months, csDMARD response was evaluated and cases were categorized as “responder”or “nonresponder.”Patients were considered “nonresponders” if remission was not achieved under csDMARD therapy. Serum protein profiles were used to train random forest models to predict csDMARD failure and compared to a model based on eight clinical parameters at diagnosis (e.g., maximum cell grade). Results: In total, 19 of 37 (51%) cases were categorized as csDMARD nonresponders. We identified a 10-protein signature that could predict csDMARD failure with an overall accuracy of 84%, which was higher compared to a model based on eight clinical parameters (73% accuracy). Adjusting for age, sex, anatomic location of uveitis, and cell grade, cases stratified by the 10-protein signature at diagnosis showed a large difference in risk for csDMARD failure (hazard ratio, 12.8; 95% confidence interval, 2.5–64.6; P = 0.002). Conclusions: Machine learning models based on the serum proteome can stratify pediatric patients with uveitis at high risk for csDMARD failure. Translational Relevance: The identified protein signature has implications for the development of clinical decision tools that integrate clinical parameters with biological data to better predict the best treatment option

Tocilizumab as an Effective Treatment Option in Children with Refractory Intermediate and Panuveitis

Purpose: To describe the results of tocilizumab treatment in children with refractory non-anterior uveitis.Methods: A case series of seven children with refractory non-anterior uveitis (onset ≤16 years) with leakage on fluorescein angiogram (FA) were treated with tocilizumab intravenously every 4 weeks (eight mg/kg). Minimum follow-up was 6 months. Reported outcomes are changes in BCVA, central macular thickness (CMT) on OCT image, FA scores, dose of systemic steroids, complications and side effects.Results: In all patients, there was an improvement of macular edema and capillary leakage on FA. The median FA score decreased from 14 (10-18) at baseline to 8 (2-9) after 6 months of treatment (p = .018). The CMT decreased from 321 (314-384) to 295 (255-312) (p = .043). BCVA improved in five eyes and worsened in one eye due to cataract. No systemic or ocular complications were reported.Conclusion: Tocilizumab is an effective therapeutic option for reducing disease activity in children with refractory non-anterior uveitis

Improved clinical outcomes in patients with juvenile idiopathic arthritis associated uveitis in the last decade

Purpose: The purpose of the study was to analyse the development of ocular complications and visual prognosis in juvenile idiopathic arthritis associated uveitis (JIA-uveitis) compared to the previous decade in the light of new treatment guidelines. Methods: In this retrospective cohort, 143 patients with JIA-uveitis were stratified into two cohorts based on the year of diagnosis of uveitis, <2010 (n = 61) and ≥2010 (n = 82). Development of ocular complications and visual outcomes were analysed by univariate and multivariate methods. Treatment with systemic corticosteroids and immunomodifying medication (IMT) were documented. Results: In total, 109 and 133 affected eyes, respectively, for cohort 1 (<2010) and cohort 2 (≥2010) were included for analysis. In the multivariate analysis with correction for paired eyes, patients in cohort 1 were at higher risk for cataract surgery (p = 0.03) and secondary glaucoma (p = 5.15 × 10−3). Also, the number of eyes that were legally blind and visually impaired at 5 years of follow-up was significantly higher in cohort 1 (7% versus 2% and 8% versus 0%, p = 0.01 respectively). The number of patients that started IMT was significantly higher in cohort 2 (57% versus 98%, p = 2.17 × 10−6). In cohort 2, both methotrexate and anti-TNF-α therapy were prescribed earlier in the disease course (1.41 versus 0.05 years, p = 8.31 × 10−6 and 6.07 versus 1.84 years, p = 5.14 × 10−5 respectively). Conclusions: The prognosis of JIA-uveitis has improved during the last decade. There is a reduction in the number of cataract surgeries and secondary glaucoma and fewer patients lose their vision parallel with earlier access to tertiary care and earlier introduction of IMT

The Role of the Retinal Nerve Fiber Layer Thickness on OCT in the Evaluation of Papillitis in Childhood Uveitis

PURPOSE: To investigate the diagnostic value of using retinal nerve fiber layer thickness measured on optical coherence tomography (OCT-RNFL) to diagnose papillitis in pediatric uveitis. DESIGN: Retrospective cohort study. METHODS: Demographic and clinical data were collected retrospectively for 257 children with uveitis (with 455 affected eyes). Receiver operating characteristic (ROC) analysis was performed to compare fluorescein angiography (FA, the diagnostic gold standard for papillitis) to OCT-RNFL in a subgroup of 93 patients. An ideal cut-off value for OCT-RNFL was then determined by calculating the highest Youden index. Finally, a multivariate analysis was applied to the clinical ophthalmological data. RESULTS: Based on a subset of 93 patients who underwent both OCT-RNFL and FA, the ideal cut-off OCT-RNFL for diagnosing papillitis was >130 µm, with 79% sensitivity and 85% specificity. Among the entire cohort, the prevalence of OCT-RNFL >130 µm was 19% (27/141), 72% (26/36), and 45% (36/80) in patients with anterior uveitis, intermediate uveitis, and panuveitis, respectively. Our multivariate analysis of the clinical data revealed that OCT-RNFL >130 µm was associated with a higher prevalence of cystoid macular edema, active uveitis, and optic disc swelling on fundoscopy, with odds ratios of 5.3, 4.3, and 13.7, respectively (all P 130 µm in approximately one-third of all children with uveitis and was particularly prevalent in cases of intermediate uveitis and panuveitis

Clinical Course and Outcome in Pediatric Idiopathic Chronic Anterior Uveitis

PURPOSE: To examine the clinical course and outcome in children with idiopathic chronic anterior uveitis (iCAU), and to compare the results with those of age-matched children with juvenile idiopathic arthritis−associated uveitis (JIA-U). DESIGN: Retrospective cohort study. METHODS: Data regarding ocular complications, visual acuity, and systemic treatment were retrospectively collected for 2 patient groups that were matched regarding age and year of uveitis diagnosis. Outcome was evaluated using survival analysis. RESULTS: The iCAU and JIA-U groups included 48 patients with 83 affected eyes and 48 patients with 73 affected eyes, respectively. Multivariate analyses showed that iCAU was associated with a higher prevalence of posterior synechiae (adjusted hazard rate [aHR] = 3.63; P <.001) and cataract surgery (aHR = 2.90; P =.006). Baseline visual acuity was worse in the iCAU group compared to the JIA-U group (20/25 vs 20/20, respectively; P <.001), but improved in the iCAU group after 5 years (20/20 vs 20/20, respectively; P =.052). At the 5-year follow-up, the younger children with iCAU (≤8 years of age at diagnosis) had a higher prevalence of posterior synechiae (aHR = 2.56; P =.007), secondary glaucoma (aHR = 16.0; P =.020), and cataract surgery (aHR = 4.79; P =.004) compared to older children with iCAU (≥9 years at diagnosis). CONCLUSIONS: Vision-threatening ocular complications are more common in children with iCAU compared to children with JIA-U, particularly in cases in which the onset of uveitis occurred at ≤8 years of age. However, the long-term vision of these children can be improved with adequate treatment

Uveitis Associated with Juvenile Idiopathic Arthritis

Juvenile idiopathic arthritis (JIA) is the most common cause of uveitis in children. While symptoms are usually mild, persistent eye inflammation could lead to severe complications and impaired vision. It is essential that JIA patients at risk are diagnosed with uveitis early, receive adequate treatment, and avoid developing complications, such as cataract, glaucoma, and amblyopia. The purpose of this mini-review is to summarize the screening strategies and clinical management for JIA-associated uveitis (JIA-U) as well as the current state of molecular markers linked to this condition. Because glaucoma is one of the most common causes of visual loss in JIA-U, special focus will be put on this serious complication. We conclude by describing the current evidence regarding the long-standing question of whether chronic anterior uveitis without arthritis may be the same disease entity as JIA-U

Methotrexate therapy associated with a reduced rate of new-onset uveitis in patients with biological-naïve juvenile idiopathic arthritis

OBJECTIVE: To study the effect of methotrexate (MTX) therapy on new-onset uveitis in patients with biological-naïve juvenile idiopathic arthritis (JIA). METHODS: In this matched case-control study, we compared MTX exposure between cases with JIA-associated chronic uveitis (JIA-U) and patients with JIA and without JIA-U at the time of matching (controls). Data were collected from electronic health records of the University Medical Centre Utrecht, the Netherlands. Cases with JIA-U were matched 1:1 to JIA control patients based on JIA diagnosis date, age at JIA diagnosis, JIA subtype, antinuclear antibodies status and disease duration. The effect of MTX on JIA-U onset was analysed using a multivariable time-varying Cox regression analysis. RESULTS: Ninety-two patients with JIA were included and characteristics were similar between cases with JIA-U (n=46) and controls (n=46). Both ever-use of MTX and exposure years were lower in cases with JIA-U than in controls. Cases with JIA-U significantly more often discontinued MTX treatment (p=0.03) and out of those who did, 50% afterwards developed uveitis within 1 year. On adjusted analysis, MTX was associated with a significantly reduced new-onset uveitis rate (HR: 0.35; 95% CI: 0.17 to 0.75). No different effect was observed between a low (<10 mg/m2/week) and standard MTX dose (≥10 mg/m2/week). CONCLUSION: This study demonstrates an independent protective effect of MTX on new-onset uveitis in patients with biological-naïve JIA. Clinicians might consider early initiation of MTX in patients at high uveitis risk. We advocate more frequent ophthalmologic screening in the first 6-12 months after MTX discontinuation