Clive Edelsten

An evaluation of baseline risk factors predicting severity in juvenile idiopathic arthritis associated uveitis and other chronic anterior uveitis in early childhood

Background/aims: The clinical course for childhood chronic anterior uveitis can vary from mild, self limiting disease to bilateral blindness. The purpose of this study was to identify those risk factors at onset that predict disease severity. Methods: A retrospective case note review of all patients with painless anterior uveitis diagnosed from 1982 to 1998. Patients were divided into two cohorts based on route of referral, diagnosis, and compliance with treatment. The standard cohort consisted of only those diagnosed from routine screening of juvenile idiopathic arthritis. Results: Complications—cataract surgery, ocular hypertension treatment, and visual acuity <6/24. Remission: inactive uveitis on no topical treatment for >6 months. Results—163 patients were included. 34 patients (21%) developed at least one complication. The most significant predictor of complications was severe disease at onset (p = 0.001). Other factors included uveitis at the first examination (p = 0.034), membership of the non-standard cohort (p = 0.0001), non-oligoarticular disease (p = 0.02), and late onset arthritis (p = 0.024). Male sex was associated with increased complications in the standard cohort (p = 0.001). Factors predisposing to remission included membership of the standard cohort (p = 0.003), onset after 1990 (p = 0.016), white race (p = 0.015), mild disease onset (p = 0.003), and a long gap between arthritis and uveitis onset (p = 0.015). Conclusions: It is possible to characterise the severity of those with childhood chronic anterior uveitis at the onset of disease. The majority of patients remit without visually disabling complications. It may be possible to reduce the complication rate by targeting aggressive immunosuppression on high risk patients before complications develop.

Visual loss associated with pediatric uveitis in English primary and referral Centers

PURPOSE Pediatric uveitis is rare and has been reported to cause increased rates of visual loss compared with adult patients. The reasons for this are unclear. Only one study has been population-based, so the effect of referral bias is not known. We examined the pattern of disease in primary and referral centers to establish the unique characteristics of uveitis in children. DESIGN Case control study. METHODS Retrospective, multicenter, observational study of uveitis starting before the age of 20 years. Two hundred forty-nine patients were recruited from three primary and two referral ophthalmic units. Age-related differences in types of uveitis and systemic disease between hospitals were characterized, as were associations with visual loss. RESULTS The incidence of uveitis in district hospitals at less than 16 years of age was 4.9/100,000: the most frequent diagnosis was idiopathic uveitis (78%). In referral cohorts the most frequent diagnosis was juvenile idiopathic arthritis-associated uveitis (67%). Other systemic diseases were rare. The most frequent type of uveitis at 0 to 7 years of age was chronic anterior uveitis, posterior uveitis in 8- to 15-year-olds, and acute anterior uveitis in 16- to 19-year-olds. Visual loss (any eye < 6/12) occurred in 17% and was not associated with age, sex, or hospital cohort. It was most frequent in posterior uveitis (25%). Treatment variables were independent predictors of visual loss: systemic treatment 2.2 (1.1- 4.6), surgical intervention 8.2 (3.8-17.6). CONCLUSIONS Idiopathic uveitis was three times more common in district hospitals. Visual loss was similar to adult uveitis in this study. The increased frequency of severe chronic anterior uveitis in children aged 0 to 7 years and posterior uveitis in older children aged 8 to 15 years accounts for the rate of visual loss seen in previous studies.

Factors related to severe uveitis at diagnosis in children with juvenile idiopathic arthritis in a screening program.

PURPOSE To identify factors associated with severe uveitis at diagnosis of eye disease in children with juvenile idiopathic arthritis (JIA) who were observed in a screening program, and to identify temporal changes in findings associated with screening during the period 1986 to 2000. DESIGN Case control study. METHOD Uveitis was defined as being severe at diagnosis if there were associated synechiae, cataracts, or retinal edema. Clinical factors for all patients undergoing screening for JIA-associated uveitis from 1986 to 2000 at one institution were studied retrospectively. Children with severe uveitis at diagnosis (cases) were compared with those with mild uveitis at diagnosis and those who never developed uveitis during follow-up in the screening program (controls). RESULTS Severe uveitis was present at diagnosis in 22 (5.4%) of 409 patients. Male patients were more likely to have severe uveitis at diagnosis (odds ratio [OR] 3.7 [95% confidence interval 1.3 to 10.7], P =.014). A longer interval from the onset of arthritis symptoms to the diagnosis of uveitis was associated with a reduced risk of severe uveitis at diagnosis (OR 0.95 [0.91 to 1.0], P =.044). There was no difference in the frequency of severe uveitis at diagnosis between two screening periods: 1986 to 1993 (before American screening guidelines were published) and 1994 to 2000. CONCLUSIONS Male children are more likely than female children to have severe uveitis at diagnosis. The proportion of children with severe uveitis at diagnosis has not changed since current screening guidelines have been widely publicized, suggesting the need for refinements in screening procedures to target high-risk children with increased surveillance.

Review for Disease of the Year: Epidemiology of Juvenile Idiopathic Arthritis and its Associated Uveitis: The Probable Risk Factors

Abstract Juvenile idiopathic arthritis (JIA) is the most common systemic disease associated with uveitis in childhood. The frequency of JIA-associated uveitis (JIAU) varies geographically, and between ethnicities. Uveitis risk is high in JIA associated with oligoarthritis, young age at arthritis onset and ANA positivity. Gender alters risk for the incidence of JIA and the severity of JIAU. Familial cases support the possible role of genetic influences in the pathogenesis. Arthritis typically precedes the uveitis, but uveitis may occur up to seven years following the arthritis onset. Although complications still occur, the frequency of bilateral blindness has dropped, probably by both improved screening of high-risk patients with JIA, and the increased use of early immunosuppression. However, there is still continuing persistence of JIAU into adulthood. For improvement of epidemiological knowledge of this complicated disease, large, well-defined, long-term population-based registries are needed with the application of universally agreed case definitions and outcome measures.

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.

The ocular and systemic prognosis of patients presenting with sarcoid uveitis

Purpose To describe the visual and systemic outcomes in patients presenting with sarcoid uveitis.Methods Seventy-five patients with definite or presumed sarcoid uveitis were followed up for a median of 4 years. The patients came from a primary ophthalmic referral centre and a specialist uveitis centre. The prognostic value of demographic and clinical features at the onset of disease were studied. Baseline and outcome variables were analysed by survival analysis.Results After 10 years, 54% of patients retained normal visual acuity and 4.6% had lost vision to less than 6/36 in both eyes. Fifty-one per cent required oral steroids for uveitis and a further 11% needed additional immunosuppressants. Twenty-one per cent of patients had undergone a surgical procedure. At the onset of uveitis the lung was the most common organ involved (35%). After 10 years follow-up disease spread to other organs in 13 patients (17%); in 8 of 13 patients this was the central nervous system. The only outcome associated with baseline variables was bilateral visual loss, which was more likely in those over 40 years at presentation (p = 0.004).Conclusions The ocular prognosis of sarcoid uveitis is unrelated to the extent of disease at onset. Patients with extraocular disease fared no differently from those with isolated ocular disease. Patients with sarcoid uveitis are at risk of neurological involvement for at least 15 years.

The efficacy of systemic corticosteroids in sight-threatening retinal vasculitis.

This study was undertaken to assess the efficacy of a standard regime of high-dose systemic oral corticosteroids in the management of retinal vasculitis. The study was performed because the single most common reason for referral to our specialist clinic is the apparent failure of patients to respond to a course of systemic steroids, which in most cases appeared to be due to an inadequate initial dose. A retrospective study of 29 patients (30 treatment episodes) with sight-threatening retinal vasculitis managed initially with high-dose systemic steroids was evaluated 1 year after treatment. Patients included in the study all started treatment with ≥ 1 mg/kg prednisolone and remained on a high steroid dose (≥40 mg prednisolone) for at least 5 weeks. No patient was on any other immunosuppressive agent at the start of the study. Therapeutic success for this regime, as judged by improvement in visual acuity, was 60%, improving to 77% with addition of other immunosuppressive agents. Eight patients required additional immunosuppressives. Although documented side-effects of steroids were common (50% of cases managed on steroids alone), in only 5 patients were they therapeutically important. Twelve of the 22 patients managed on high-dose steroids alone were off treatment at 12 months. There was no correlation at any stage between visual acuity, activity index or relapses and the final visual outcome at 12 months. Seven cases had a poor visual outcome and the causes for this included relapse in the twelfth month of follow-up, persistent cystoid macular oedema and lens opacity. These results suggest that high-dose oral steroids should be tried in the initial management of such patients before contemplating other more complicated regimes or accepting a poor visual outcome.

Adalimumab plus Methotrexate for Uveitis in Juvenile Idiopathic Arthritis

BACKGROUND Adalimumab, a fully human anti–tumor necrosis factor α monoclonal antibody, is effective in the treatment of juvenile idiopathic arthritis (JIA). We tested the efficacy of adalimumab in the treatment of JIA‐associated uveitis. METHODS In this multicenter, double‐blind, randomized, placebo‐controlled trial, we assessed the efficacy and safety of adalimumab in children and adolescents 2 years of age or older who had active JIA‐associated uveitis. Patients who were taking a stable dose of methotrexate were randomly assigned in a 2:1 ratio to receive either adalimumab (at a dose of 20 mg or 40 mg, according to body weight) or placebo, administered subcutaneously every 2 weeks. Patients continued the trial regimen until treatment failure or until 18 months had elapsed. They were followed for up to 2 years after randomization. The primary end point was the time to treatment failure, defined according to a multicomponent intraocular inflammation score that was based on the Standardization of Uveitis Nomenclature criteria. RESULTS The prespecified stopping criteria were met after the enrollment of 90 of 114 patients. We observed 16 treatment failures in 60 patients (27%) in the adalimumab group versus 18 treatment failures in 30 patients (60%) in the placebo group (hazard ratio, 0.25; 95% confidence interval [CI], 0.12 to 0.49; P<0.0001 [the prespecified stopping boundary]). Adverse events were reported more frequently in patients receiving adalimumab than in those receiving placebo (10.07 events per patient‐year [95% CI, 9.26 to 10.89] vs. 6.51 events per patient‐year [95% CI, 5.26 to 7.77]), as were serious adverse events (0.29 events per patient‐year [95% CI, 0.15 to 0.43] vs. 0.19 events per patient‐year [95% CI, 0.00 to 0.40]). CONCLUSIONS Adalimumab therapy controlled inflammation and was associated with a lower rate of treatment failure than placebo among children and adolescents with active JIA‐associated uveitis who were taking a stable dose of methotrexate. Patients who received adalimumab had a much higher incidence of adverse events and serious adverse events than those who received placebo. (Funded by the NIHR Health Technology Assessment Programme and Arthritis Research UK; SYCAMORE EudraCT number, 2010–021141–41.)

Are cytokine gene polymorphisms associated with outcome in patients with idiopathic intermediate uveitis in the United Kingdom

Background/aim: Competing levels of cytokines, either locally within the eye or systemically, may influence the eventual outcome of ocular inflammation. Polymorphism in the promoter part of the genes controlling cytokine production may result in either higher or lower production of the relevant cytokine to a given stimulus. The authors hypothesised that such polymorphisms may relate to visual outcome in patients with idiopathic intermediate uveitis. Methods: DNA was obtained from 125 patients with idiopathic intermediate uveitis and analysed for the interleukin 10 IL-10–1082G/Α and IL-10–819C/T, and interferon γ IFNγ 874T/A gene polymorphisms. Associations with disease were calculated by both allelic frequency and haplotype analysis, and associations between ocular disease outcomes and the presence of polymorphisms were identified. A bad outcome was defined as loss of vision <6/12 Snellen in both eyes at 5 years from presentation when the eyes were quiet. Results: An initial screen showed that the 874T allele of the IFNγ gene was more prevalent in patients than controls (χ2 = 7.9; p = 0.004 OR 1.7; 95% CI 1.2 to 2.6 (Pc = 0.02), whereas the IL-10-1082/−819 AT haplotype of the interleukin 10 (IL-10) gene was not. Analysis of disease outcome showed an association between IL-10–1082 AA homozygosity and bad outcome (χ2 = 13; p = 0.0003). Moreover, the two cytokine polymorphisms taken together showed that up to 75% of patients with a poor visual outcome had the combined IFNγ 874TA or TT genotype together with the IL-10–1082AA genotype (χ2 = 13.2 p = 0.0008 OR 6.4; 95% CI 1.85 to 23.6 Pc = 0.1). Conclusion: These results show that disease outcome in intermediate uveitis may be partly determined by a complex interplay between cytokine genes and these results may have implications for future treatment with biological agents that target these cytokines.

Serpiginous choroiditis: an unusual presentation of ocular sarcoidosis.

Awhitewomandevelopedintermittentbilateralanterior uveitis at the age of 23 that requiredtopical steroids, and occasionally systemicprednisolone,tocontrol. At33shedevelopedanoptic neuropathy that resolved spontaneously.DespitetheabsenceofanysystemicsymptomsaKveimtest waspositive. Examinationat age44showedvisualacuityintherighteyeof6/4andinthe left eye of6/18 with a left relative afferent