Joke H. de Boer

Detection of intraocular antibody production to herpesviruses in acute retinal necrosis syndrome

In order to improve the determination of the causative agent in acute retinal necrosis syndrome, we evaluated the detection of intraocular antibody production to herpesviruses in 28 patients with this disease. Intraocular antibody production was determined by calculation of the Goldmann-Witmer coefficient whereby specific antibody titers in the inflamed eye and circulation are related to the total IgG content in ocular fluid and serum. Specific antibody titers to herpesviruses and Toxoplasma were determined by the indirect immunofluorescence technique. Thirty-five patients with ocular toxoplasmosis, cataract, or proliferative vitreoretinal disorders were tested as controls. By this technique, intraocular antibody production to varicella zoster virus or herpes simplex virus could be established in 16 (57%) of the patients with the typical clinical features of acute retinal necrosis, compared to none of the controls. Of the 33 affected eyes, 21 (64%) had a visual outcome of less than 20/200. We concluded that detection of intraocular antibody production to herpesviruses may be a useful diagnostic tool in establishing the causative agents in acute retinal necrosis.

Rubella Virus–Associated Uveitis: Clinical Manifestations and Visual Prognosis

PURPOSE To investigate the clinical profile of patients with chronic anterior uveitis and intraocular analyses positive for intraocular Rubella virus infection and assess eventual similarities to Fuchs heterochromic uveitis (FHU). DESIGN Retrospective case-control study. METHODS Clinical records of 30 patients with anterior uveitis positive for intraocular antibody production against Rubella virus by Goldmann-Witmer coefficient determination and/or polymerase chain reaction were reviewed and compared with clinical records of 13 patients with chronic anterior uveitis of undetermined origin. Multiple variables were assessed and patient records were evaluated at onset and at one year after their first visit to the University Medical Center Utrecht. RESULTS Patients with Rubella virus-associated uveitis were younger at time of initial ophthalmologic presentation (P = .014). Rubella virus-positive patients presented more frequently with unilateral ocular disease (P < .001), keratic precipitates (KPs; P = .014), iris atrophy and/or heterochromia (P = .051), associated vitreous opacities (P = .024), and cataract (P = .004). Also, the combination of KPs, absence of posterior synechiae, cataract, and vitreous opacities occurred more often in the Rubella virus-positive group (P = .026) and the presence of three or four of these criteria occurred more frequently in the Rubella virus-positive group (P = .004). CONCLUSIONS Rubella virus causes a distinct clinical spectrum of ocular symptoms similar to the FHU syndrome, which suggests that Rubella virus might be involved in the pathogenesis of FHU.

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.

Proposed Outcome Measures for Prospective Clinical Trials in Juvenile Idiopathic Arthritis- Associated Uveitis: A Consensus Effort From the Multinational Interdisciplinary Working Group for Uveitis in Childhood

To develop a set of core outcome measures for use in randomized controlled trials (RCTs) and longitudinal observational studies in juvenile idiopathic arthritis (JIA)–associated uveitis.

Human Leukocyte Antigen-B27–Associated Uveitis: Long-term Follow-up and Gender Differences

PURPOSE To evaluate clinical features and gender differences in human leukocyte antigen (HLA)-B27-associated acute anterior uveitis (AAU) in long-term follow-up. DESIGN Retrospective cohort study. METHODS The clinical records of 177 HLA-B27-positive patients (96 males [54%] and 81 females [46%]) who sought treatment for acute anterior uveitis (AAU) at the University Medical Center Utrecht between January 1995 and December 2005 were evaluated. All patients had a minimum follow-up of at least one year. The clinical data were analyzed at standardized intervals (one, five, and 10 years after the onset of uveitis). RESULTS Average age at onset of AAU was 36 years, with no differences between males and females. HLA-B27-associated systemic disease developed earlier in males than in females (31 vs 37 years; P=.021). Consequently, at onset of AAU, HLA-B27-associated systemic disease were more frequent in males than in females (25/75 [33%] males vs nine/54 [17%] females; P=.030); however over time, males and females were at equal risk of developing a HLA-B27-associated systemic disease. Bilateral uveitis developed more frequently in females (6/45 [13%] of males vs 11/35, [31%] of females; P=.05). In none of the patients did bilateral visual acuity of less than 0.5 develop after the follow-up of 10 years. CONCLUSIONS The long-term visual prognosis of HLA-B27-associated AAU was favorable, despite the frequent attacks of severe AAU. At the onset of AAU, the prevalence of HLA-B27-associated systemic disease was more frequent in males, but after the onset of uveitis, the risk of developing a HLA-B27-associated systemic disease is similar for both males and females.

Male gender and poor visual outcome in uveitis associated with juvenile idiopathic arthritis.

PURPOSE To analyze visual outcome in uveitis associated with juvenile idiopathic arthritis (JIA) according to age of onset of uveitis, gender, and initial manifestation of JIA. DESIGN Retrospective nonrandomized interventional case series. METHODS Visual outcome of 117 affected eyes (65 patients) with JIA-associated uveitis was noted at onset of uveitis and after 1, 3, and 5 years. Visual outcome was analyzed according to gender, age of onset of JIA-associated uveitis (<7 years and >7 years), and initial manifestation of JIA (as uveitis or as arthritis). Linear and logistic regression with generalized estimating equation (GEE) was performed. RESULTS Median age of onset of uveitis was 4.2 years (range 1.5-16). Female-to-male ratio was 3:1. In 15 children (23%) uveitis was diagnosed before arthritis. Visual acuity of boys was significantly worse at 1 and 3 years of follow-up (both P <or= .03) but not at 5 years of follow-up (P = .45). Until 3 years after the diagnosis of uveitis, children with atypical initial manifestation of JIA (uveitis before arthritis) had significantly worse visual acuity compared with children in whom uveitis debuted after arthritis (all P <or= .05). No difference in vision between younger-onset (<7 years) and older-onset (>7 years) groups was noted. Blindness was independently associated with male gender (odds ratio [OR] = 6.61; 95% CI: 1.02-42.98; P = .048). CONCLUSIONS Male gender was an independent risk factor for poor visual prognosis in JIA-associated uveitis. Children in whom uveitis is being diagnosed before arthritis have significantly worse vision until 3 years after uveitis onset.

Identification of New Pathogens in the Intraocular Fluid of Patients With Uveitis

Purpose To determine infectious causes in patients with uveitis of unknown origin by intraocular fluids analysis. Design Case-control study. Methods Ocular fluids from 139 patients suspected of infectious uveitis, but negative for herpes simplex virus, varicella-zoster virus, cytomegalovirus, and Toxoplasma gondii by polymerase chain reaction and/or antibody analysis in intraocular fluids, were assessed for the presence of 18 viruses and 3 bacteria by real-time polymerase chain reaction (PCR). The ocular fluids from 48 patients with uveitis of known etiology or with cataract were included as controls. Results Positive PCR results were found for Epstein-Barr virus, for rubella virus, and for human herpesvirus 6 each in 1 patient and for human parechovirus in 4 patients. Of the human parechovirus–positive patients, 1 was immunocompromised and had panuveitis. The other 3 patients were immunocompetent and had anterior uveitis, all with corneal involvement. Conclusions Human parechovirus might be associated with infectious (kerato)uveitis.

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 <or= .02), but less glaucoma (P = .03). In multivariate analysis male gender appeared to be independently associated with cataract surgery (adjusted hazard ratio [HR] = 4.33; P < .01), CME (HR = 4.59; P = .01), and papillitis (HR = 4.10; P = .01). Development of posterior synechiae was independently associated with initial uveitis (HR = 3.21; P < .01). CONCLUSIONS Male gender and uveitis as initial manifestation of JIA were independently associated with a complicated course of JIA-associated uveitis. Age of onset of JIA-associated uveitis does not seem to have independent prognostic value for the course of this ocular disorder.

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.

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.