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 serum of 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.

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.

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.

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.

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.

Next-Generation HLA Sequence Analysis Uncovers Shared Risk Alleles Between Clinically Distinct Forms of Childhood Uveitis.

Purpose: Classical alleles of the human leukocyte antigen (HLA) complex have been linked to specific entities of pediatric noninfectious uveitis, yet genetic predisposition encoded by the HLA super-locus across the patient population remains understudied. Methods: We performed next-generation full-length sequencing of HLA-A, HLA-B, HLA-C, HLA-DPB1, HLA-DQB1, and HLA-DRB1 in 280 cases. Dense genotype data from 499 Dutch controls from Genome of the Netherlands were imputed using an HLA-specific reference panel (n = 5225 samples from European ancestry). Cases and controls were compared using logistic regression models adjusting for sex. Results: In total, 179 common and rare alleles were detected. Considering all cases and controls, HLA-DQB1*04:02 and HLA-DRB1*08:01 were identified as the principal HLA association, which was mainly driven by 92 cases with juvenile idiopathic arthritis-associated uveitis (JIA-U). The HLA-DQB1*04:02-HLA-DRB1*08:01 haplotype was also the primary association for the phenotypically similar idiopathic chronic anterior uveitis without arthritis (CAU). Also, HLA-DQB1*05:03 was an independent risk allele for CAU, but not in JIA-U. Analysis of 185 cases with other forms of uveitis revealed HLA-wide associations (P < 2.79 × 10-4) for HLA-DRB1*01:02, HLA-DRB1*04:03, and HLA-DQB1*05:03, which could be primarily attributed to cases with panuveitis. Finally, amino acid substitution modeling revealed that aspartic acid at position 57 that distinguishes the risk allele HLA-DQB1*05:03 (for CAU and panuveitis) from nonrisk alleles, significantly increased the binding capacity of naturally presented ligands to HLA-DQ. Conclusions: These results uncovered novel shared HLA associations among clinically distinct phenotypes of pediatric uveitis and highlight genetic predisposition affecting the antigen presentation pathway.

Whole Transcriptome Analysis Reveals Heterogeneity in B Cell Memory Populations in Patients With Juvenile Idiopathic Arthritis-Associated Uveitis.

Purpose: Patients with juvenile idiopathic arthritis (JIA) are prone to developing chronic anterior uveitis (JIA-U+). Although several risk factors for JIA-U+ have been identified, the underlying etiology is poorly understood. Histopathological studies demonstrate B cell infiltrates in eye tissues of patients with JIA-U+. Methods: We performed transcriptome profiling of peripheral blood CD19-positive B cells taken from 14 cases with JIA-U+, 13 JIA cases without uveitis (JIA-U-), and five healthy controls. Deconvolution-based estimation was used to determine the immune cell fractions for each sample. Results: Deconvolution results revealed that naive B cells made up on average 71% of the CD19-positive cell fractions analyzed. Differential expression analysis identified 614 differentially expressed genes (DEGs) between the groups at nominal significance and six genes at a false discovery rate of 5% (FDR < 0.05). Head-to-head comparison of all JIA-U- versus JIA-U+ revealed no DEGs in the CD19+ B cell pool (FDR < 0.05). However, principal component analysis based on a panel of key genes for B cell subsets revealed that JIA-U+ cases bifurcate into distinct clusters, characterized by markedly disparate expression for genes associated with specific memory B cell populations. CIBERSORT analysis of the overall transcriptome of the new uveitis cluster identified an increased proportion of memory B cells. Conclusion: These data show that JIA-U- and JIA-U+ have a globally similar transcriptome considering the global peripheral CD19-positive B cell pool. However, heterogeneity in B cell memory genes among cases with uveitis suggests a role for specific memory B cell subsets in the etiology of JIA-U+.

Pitfalls in Diagnosing Neuraminidase Deficiency: Psychosomatics and Normal Sialic Acid Excretion.

Neuraminidase deficiency (mucolipidosis I, sialidosis types I and II, cherry-red spot myoclonus syndrome) is a lysosomal storage disorder with an expanding clinical phenotype. Here, we report the striking diagnostic history of late-onset neuraminidase deficiency in two sisters, currently aged 14 (patient 1) and 15 (patient 2).Patient 1 was referred for evaluation of her vision after a traffic accident. During this examination, nummular cataract, macular cherry-red spot, and optic nerve atrophy were seen. Furthermore, tremors were noticed in her arms and legs. This combination suggested a lysosomal storage disorder. Her family history revealed an older sister, patient 2, who had a long history of unexplained neurologic symptoms; she was under unsuccessful treatment for conversion disorder. Patient 2 showed identical ophthalmological findings. In retrospect, she had presented with avascular osteonecrosis of the right femur head at age 9.Urinary oligosaccharide patterns and enzyme activity revealed neuraminidase deficiency in both patients. Urinary-bound sialic acid levels were normal. Sequencing of NEU1 demonstrated two known compound heterozygous mutations (c.1195_1200dup p.His399_Tyr400dup; c.679G>A, p.Glu227Arg).The substantial time window between onset of typical symptoms and diagnosis in patient 2 suggests inadequate awareness of lysosomal storage disorders among clinicians. Of special interest is the observation that normal urinary sialic acid levels do not exclude neuraminidase deficiency. Urinary oligosaccharide screening is essential to diagnosis in such cases. In addition, patient 2 is the fourth case in the literature with a history of femur head necrosis. Bone defects might therefore be an early manifestation of late-onset neuraminidase deficiency.

Infiltration of Plasma Cells in the Iris of Children With ANA-Positive Anterior Uveitis.

PURPOSE: We investigated inflammatory cell infiltrates in iris biopsies in uveitis associated with juvenile idiopathic arthritis (JIA) in comparison with other pediatric uveitis entities and noninflammatory pediatric controls. METHODS: Iridectomy specimens were obtained during elective trabeculectomy from 31 eyes of 25 patients: 12 eyes with JIA-associated uveitis, 13 eyes with other uveitis entities, and 6 eyes with open angle nonuveitic juvenile glaucoma. Histopathologic and immunohistochemical analyses were performed. A semiquantitative scoring system was used with a scale ranging from 0 to 4 depending on the number of stained cells. RESULTS: An inflammatory infiltrate was present in 8/12 (67%) specimens with JIA-associated uveitis. The cellular infiltrate in JIA specimens was characterized by the presence of CD138+ plasma cells and CD68+ macrophages, while the presence of CD20+, CD4+, and CD8+ cells was variable. Presence of plasma cells in the inflammatory infiltrates in anterior uveitis correlated with antinuclear autoantibody (ANA) positivity regardless of the diagnosis of JIA. CD4+ and CD8+ T cells were not always detectable in the iris biopsies of all childhood uveitis patients, although a slight predominance of CD4+ cells was noted. CONCLUSIONS: Children with ANA-positive anterior uveitis often show an infiltrate of plasma cells, regardless of the diagnosis of JIA. The iris of JIA-associated uveitis patients is additionally characterized by the presence of various numbers of macrophages.

Pathogenesis of juvenile idiopathic arthritis associated uveitis: the known and unknown.

Juvenile idiopathic arthritis (JIA) is the most common childhood rheumatic disease and the most prevalent systemic disorder in children with uveitis. The current prevailing opinion is that JIA is a multifactorial, genetically predisposed autoimmune disorder that can be influenced by environmental factors and infections; the specific pathogenesis of JIA-associated uveitis is not understood, however, nor has the relationship between the eye and joint inflammation been established. Nevertheless, subtypes of JIA that are associated with uveitis, oligoarthritis, polyarticular rheumatoid factor negative, and psoriatic arthritis appear to have common pathogenicity. We summarize our current knowledge regarding the pathogenesis of JIA-associated uveitis and discuss the possible role of immune responses and cytokine involvement, genetic associations, and the influence of external triggers in this disease-an association that is supported by data obtained from arthritis research and experimental uveitis models.

Impact of ocular graft-versus-host disease on visual quality of life in patients after allogeneic stem cell transplantation: questionnaire study.

PURPOSE: To determine the influence of ocular complications on quality of life (QoL) 3 years after allogeneic stem cell transplantation (allo-SCT). METHODS: All 54 adult patients that underwent and survived allo-SCT in 2006/2007 in our centre received two questionnaires (VFQ-25: visual function questionnaire-25 and OSDI: ocular surface disease index). In addition, the following data were included: gender, age, underlying disease, presence of chronic and/or ocular graft-versus-host disease (GVHD), number of visits to an ophthalmologist, manifestations of dry eye disease, the duration of follow-up and treatment for ocular GVHD. RESULTS: Ocular GVHD developed in 26% (14 of 54) of patients and 71% (10 of 14) received treatment for ocular GVHD. The presence of ocular GVHD correlated with the severity of systemic GVHD (correlation coefficient: 0.52, p = 0.00). The Karnofsky scores were significantly lower in the patients with ocular GVHD compared to the patients with no ocular GVHD (p = 0.001). Karnofsky scores were weakly correlated with the severity of systemic GVHD (correlation coefficient: 0.25, p = 0.03. Three years after the all-SCT, OSDI and VFQ-25 scores were significantly impaired in patients with ocular GVHD [mean: 76.5; range (46.1-100) and mean: 31.1; range (0-72.9)] compared to patients with no ocular GVHD [mean: 89.4; range (45.2-100) and mean: 12.9; range (0-58.3); p = 0.02]. The scores of the VFQ-25 were significantly lower in the domains of general health, ocular pain, social functioning and role difficulties. CONCLUSION: The long-term vision-related QoL measured by the OSDI and VFQ-25 was impaired in patients with ocular GVHD.

Intraocular biomarker identification in uveitis associated with juvenile idiopathic arthritis.

PURPOSE: To investigate the presence of biomarkers in aqueous humor (AH) from patients with uveitis associated with juvenile idiopathic arthritis (JIA). METHODS: AH (N = 73) AND SERUM (N = 105) SAMPLES FROM 116 CHILDREN WERE ANALYZED USING SURFACE ENHANCED LASER DESORPTION/IONIZATION TIME OF FLIGHT MASS SPECTROMETRY (SELDI-TOF MS). THE SAMPLES WERE DIVIDED INTO THE FOLLOWING GROUPS: JIA, silent chronic anterior uveitis (AU), other uveitis entities, and noninflammatory controls. Statistical biomarker identification was performed using the SELDI-ToF Biomarker Analysis Cluster Wizard followed by multivariate statistical analysis. Biochemical identification of biomarkers was performed by polyacrylamide gel protein separation, followed by liquid chromatography tandem mass spectrometry. ELISA was performed in a number of AH samples representing all four study groups. RESULTS: In the JIA group, one AH protein peak at mass/charge (m/z) 13,762 had qualitative and quantitative differences in expression compared with the other uveitis entities and the controls, but not to the group of silent chronic AU. Its quantitative expression in AH of patients with JIA and other silent chronic AU was positively associated with uveitis activity. The protein at m/z 13,762 in AH was identified as transthyretin (TTR). The TTR concentration in AH differed significantly between the study groups (P = 0.006) with considerably higher TTR concentrations in JIA and silent chronic AU samples positive for m/z 13,762 than those of the other uveitis and control groups. CONCLUSIONS: TTR is a potential intraocular biomarker of JIA- associated uveitis. Its role in the pathogenesis of silent chronic AU with and without arthritis needs further investigation.

Ocular complications in children within 1 year after hematopoietic stem cell transplantation.

IMPORTANCE: It is essential to have insights into the risk of ocular involvement after hematopoietic stem cell transplantation (HSCT) in the pediatric population because young and severely ill children are unaware of their ocular problems. OBJECTIVE: To study the development of ocular complications in children within 1 year after HSCT. DESIGN AND SETTING: This prospective study includes all consecutive patients who had undergone an HSCT at the Wilhelmina Children's Hospital, University Medical Center Utrecht, Utrecht, the Netherlands, in 2009 and 2010. PARTICIPANTS: Forty-nine consecutive patients underwent systematic ophthalmologic evaluations before HSCT, before leaving the HSCT unit after HSCT, and 3, 6, and 12 months after HSCT. Additional examinations were performed during systemic viral reactivations. MAIN OUTCOME MEASURE: Development of ocular complications, including uveitis, hemorrhagic complications, optic disc edema, and dry eye syndrome. RESULTS: Thirteen patients (27%) developed an ocular complication after HSCT. These complications included DES (n = 7 [14%]), (sub)retinal hemorrhage (n = 6 [12%]), optic disc edema (n = 3 [6%]), chorioretinal lesions (n = 2 [4%]), vitritis (n = 1 [2%]), and increased intraocular pressure (n = 1 [2%]). Median time to the development of dry eye syndrome was 5 months after HSCT, whereas all other ocular complications were detected within the first 3 months after HSCT. In most cases, the symptoms were mild and self-limiting. Children with malignant disease had a higher risk of the development of ocular complications compared with children with nonmalignant disease. CONCLUSIONS AND RELEVANCE: Ocular complications in pediatric HSCT patients are common, although mostly mild. The risk of viral uveitis development during systemic viral reactivations is low; however, the potential risk of vision-threatening complications in this population cannot be ruled out.

The effect of an Ahmed glaucoma valve implant on corneal endothelial cell density in children with glaucoma secondary to uveitis.

PURPOSE: To assess the effect of Ahmed glaucoma valve implants on corneal endothelial cell density (ECD) in children with uveitic glaucoma. DESIGN: Cross-sectional study. METHODS: setting: Institutional. patientpopulation: Eighty eyes from 42 patients diagnosed with uveitis before the age of 16. Twenty-eight eyes had an Ahmed glaucoma valve implant because of secondary glaucoma. Fifty-two eyes without an implant served as controls. intervention orobservationprocedure(s): Corneal ECD was examined cross-sectionally using a noncontact specular microscope. Univariate and multivariate generalized estimating equations analyses with correction for paired eyes were performed. mainoutcomemeasure(s): Correlation of ECD with the presence of an Ahmed glaucoma valve implant and with the time following implantation. RESULTS: ECD was significantly lower in the Ahmed glaucoma valve group than in controls (2359 and 3088 cells/mm(2), respectively; P < .001) following an average of 3.5 years after Ahmed glaucoma valve implantation. Presence of an Ahmed glaucoma valve implant, previous intraocular surgery, age, duration of uveitis, and history of corneal touch by the implant tube were all significantly associated with decreased ECD. Following a multivariate analysis, presence of an Ahmed glaucoma valve implant (B = -340; adjusted P < .011) and older age (B = -58; adjusted P = .005) remained independently associated with decreased ECD. Within the implant group, the age-adjusted time interval following Ahmed glaucoma valve implantation was highly correlated with decreased ECD (B = -558, P < .001). CONCLUSIONS: Ahmed glaucoma valve implants in children with uveitic glaucoma are independently associated with decreased ECD, and this effect is associated with the time interval following Ahmed glaucoma valve implantation.

The clinical course of juvenile idiopathic arthritis-associated uveitis in childhood and puberty.

AIM: The long-term course of juvenile idiopathic arthritis (JIA)-associated uveitis is not known yet. This study investigates the course and activity of JIA-associated uveitis in childhood and puberty. DESIGN: Retrospective study of the clinical data of 62 JIA patients with uveitis. The main outcome measurements consisted of uveitis activity measured as mean cell grade in the anterior chamber, topical and systemic medication and ocular complications related to disease activity. All data were scored and evaluated per year of age. RESULTS: Uveitis activity took a biphasic course with a quiet phase around the age of 9 years and showed increased activity during early teenage years. The biphasic course was significantly related to age (p=0.048) but not to uveitis duration. More patients were treated with systemic immunosuppressive medication in estimated puberty years (63% in boys, 53% in girls) compared with prepuberty years (46% and 28%, respectively), although the difference was only significant in girls (p<0.001). The presence of cystoid macular oedema and papillitis was not significantly related to estimated puberty, but the development of an hypotonous eye was more frequently observed in boys in estimated puberty years (p=0.026). CONCLUSIONS: JIA-associated uveitis appears to take a biphasic course with the second phase of activity during early teenage years and more treatment with systemic immunosuppressive medication occurred during estimated puberty compared with prepuberty years.

Intermediate uveitis and alopecia areata: is there a relationship? Report of 3 pediatric cases.

Three previously healthy children, aged 5, 8, and 15 years, with idiopathic intermediate uveitis (IU) and alopecia areata (AA) are described. These are the first 3 cases of which we are aware with this coexistence. The results of extensive diagnostic evaluations were negative in all 3 cases. AA preceded the diagnosis of bilateral IU in 1 child and followed within several months after IU diagnosis in 2 children. The severity of uveitis ranged from mild to sight-threatening, and hair loss ranged from local lesions in 2 cases to total alopecia in 1 case. Pathogenesis of both diseases is discussed. Theoretically, the coexistence of IU and AA might be based on the similarities in their complex pathogenesis. However, more research is needed to evaluate if the coexistence is based on an association between 2 autoimmune disorders or is a coincidence.

Relapse rate of uveitis post-methotrexate treatment in juvenile idiopathic arthritis.

PURPOSE: To evaluate the efficacy of methotrexate (MTX) and the effect of its withdrawal on relapse rate of uveitis associated with juvenile idiopathic arthritis (JIA). DESIGN: Retrospective case series. METHODS: Data of 22 pediatric JIA patients who were being treated with MTX for active uveitis were studied retrospectively. Relapse rate after the withdrawal of MTX was established. Anterior chamber (AC) inflammation, topical steroid use during the first year of MTX treatment, and associations of relapses after the withdrawal were evaluated statistically. Duration of MTX treatment and its withdrawal was determined individually in collaboration with a rheumatologist with an intention to continue the treatment for at least 1 year and to withdraw in case of inactivity of uveitis and arthritis. Inactivity of uveitis was defined as the presence of ≤0.5+ cells in the AC. RESULTS: Eighteen patients (18/22; 82%) showed improvement of their uveitis with a significant decrease in activity of AC inflammation after a minimal period of 3 months of MTX treatment. A topical steroid-sparing effect was observed when MTX was administered for a period of 3 to 9 months. MTX was discontinued because of inactive uveitis in 13 patients. In 9 patients (8/13; 69%) a relapse of uveitis was observed after a mean time of 7.5 months (± SD 7.3). Six patients (6/13; 46%) had a relapse within the first year after the withdrawal. Relapse-free survival after withdrawal of MTX was significantly longer in patients who had been treated with MTX for more than 3 years (P = .009), children who were older than 8 years at the moment of withdrawal (P = .003), and patients who had an inactivity of uveitis of longer than 2 years before withdrawal of MTX (P = .033). Longer inactivity under MTX therapy was independently protective for relapses after the withdrawal (hazard ratio = 0.07; 95% confidence interval 0.01-0.86; P = .038), which means that 1-year increase of duration of inactive uveitis before the withdrawal of MTX results in a decrease of hazard for new relapse of 93%. CONCLUSIONS: A high number of patients with inactive uveitis relapse quickly after the withdrawal of MTX. Our results suggest that a longer period of inactivity prior to withdrawal and a longer treatment period with MTX reduce the chance of relapse after withdrawal.

Intraocular and plasma HIV-1 RNA loads and HIV uveitis.

OBJECTIVE: The objective of this study was to analyze human immunodeficiency virus (HIV) dynamics across the blood-retinal barrier and to determine whether the high levels of HIV in the eye are associated with any ocular disorders in HIV-infected patients. DESIGN: This study included a prospective case series of 40 HIV-positive patients with uveitis. INTERVENTION: Clinical and laboratory examinations included plasma and intraocular HIV-1 RNA loads as well as the clinical manifestations of uveitis. RESULTS: Intraocular HIV-1 RNA was detected in 32% (13/40) of HIV-positive patients with uveitis. Intraocular HIV-1 RNA loads were associated with high HIV-1 RNA plasma loads (P < 0.001) and not being on HAART therapy (P = 0.005). In addition, detectable intraocular HIV-1 RNA levels were higher in patients with the absence of retinal lesions (P = 0.008). In three patients, the HIV load in the eye largely exceeded that of plasma. These three patients had all bilateral anterior uveitis and/or vitritis without retinal lesions and exhibited no evidence of other intraocular infectious agents causing uveitis than HIV itself. CONCLUSION: The eye can form a sanctuary where HIV might replicate and cause an inflammatory reaction.

Male gender as a risk factor for complications in uveitis associated with juvenile idiopathic arthritis.

PURPOSE: To analyze the role of baseline factors in long-term development of ocular complications in uveitis associated with juvenile idiopathic arthritis (JIA). DESIGN: Retrospective nonrandomized interventional case series. METHODS: Data of 117 affected eyes (65 patients) with JIA-associated uveitis with a minimum follow-up of 1 year were obtained. Development of complications was analyzed univariately and multivariately in relation to gender, age of onset of uveitis (<7 years or >7 years), and initial manifestation of JIA (as uveitis or as arthritis). RESULTS: Female-to-male ratio was 3:1 and follow-up for uveitis ranged from 1.1 to 27.5 years (median 7.6 years). Time interval between arthritis and uveitis was shorter in boys (median 0.3 year) than in girls (median 1.0 year) (P < .01). At 5 years of follow-up boys suffered more frequently from cystoid macular edema (CME) (50% vs 4%; P < .01) and papillitis (31% vs 2%; P < .01), and needed more cataract surgery (59% vs 32%; P = .02). At 5 years of follow-up children with initial uveitis had more posterior synechiae, band keratopathy, and CME (all P