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Background/aimsTo evaluate the efficacy, safety and tolerability of enteric-coated mycophenolate sodium (EC-MPS) in combination with low-dose corticosteroids compared with a monotherapy with low-dose corticosteroids in subjects with non-infectious intermediate uveitis (IU).MethodsOpen-label, prospective, controlled, randomised multicentre trial. Patients were randomised in a 1:1 ratio to either the treatment group (prednisolone plus EC-MPS) or control group (prednisolone monotherapy). Patients in the control group who relapsed within 6 months changed to the crossover group (prednisolone plus EC-MPS). Maximum treatment duration was 15 months. The primary endpoint was the time to first relapse in the treatment group and control group.ResultsForty-one patients at eight sites were analysed. Twenty-two patients were allocated to the treatment group, with 19 patients in the control group. A first relapse occurred in 9 patients (40.9%) in the treatment group and 15 patients (78.9%) in the control group (p=0.03). The median time to the first relapse was >15 months for the treatment group and 2.8 months for the control group (p=0.07). The probability of relapse-free survival at month 15 was estimated to be 52.9% in the treatment group and 19.7% in the control group (p=0.01). 15 patients changed to the crossover group. Of these, only four patients developed a second relapse. No safety concerns arose during the trial. Only one patient had to discontinue EC-MPS due to increased liver enzymes.ConclusionEC-MPS can be considered an effective and well-tolerated immunosuppressive drug to prevent relapses in patients with chronic IU.Trial registration numberEUDRACT number: 2009-009998-10, Results.

Purpose Previously we could show increased numbers and densities of dendritic-like cells (DLCs) in the subbasal nerve plexus of the central cornea in patients with herpetic anterior uveitis (HAU). Now we aimed to explore these and other inflammatory cells seen in this layer in different subtypes of anterior uveitis using in vivo confocal microscopy. Methods Consecutive eyes of patients with different types of anterior uveitis, HAU, Fuchs’ uveitis syndrome (FUS), juvenile idiopathic arthritis (JIA) and human leucocyte antigen (HLA)-B27-related anterior uveitis were examined in vivo with the combination of Heidelberg Retina Tomograph II/III and Rostock Cornea Module. The contralateral eye was used as control. Inflammatory cells were defined on the basis of their morphology: type 1 (DLCs) and type 2 (cell bodies lacking dendrites). Frequencies were evaluated statistically in each group. Results The difference between means of type 1 cells density of affected eyes in all four groups was significant (one-way analysis of variance (ANOVA) p=0.039). The difference between means of type 1 cell densities of affected eyes in patients with HAU (96.8±44.2 cells/mm 2 , n=10) and that of patients with FUS (46.4±38.7 cells/mm 2 , n=17) was significant (Tukey9s post hoc p=0.025), whereas the difference between patients with HAU and JIA (53.3±34.5 cells/mm 2 , n=7) and patients with HAU and HLA-B27 (63.1±59.2 cells/mm 2 , n=10) was not significant (Tukey9s post hoc p=0.181 and 0.300). In contrast, the following means resulted from the evaluation of type 2 cells: the difference between means of affected eyes in all four groups was not significant (one-way ANOVA p=0.185). Density means difference of patients with HAU (44.9±22.6 cells/mm 2 , n=5) and that of FUS (20.0±11.0 cells/mm 2 , n=2) and that of patients with JIA (56.0±18.3 cells/mm 2 , n=2) and that of HLA-B27 (36.1±24.1 cells/mm 2 , n=5) was not significant (Tukey9s post hoc p=0.302, 0.877 and 0.739). The contralateral eye of all patient groups showed also an inflammatory cell infiltrate of lesser extent. Conclusions The high density and morphology of DLCs in the central cornea of patients with HAU assessed by confocal microscopy supports the clinical diagnosis of HAU especially when compared with patients with FUS but not when compared with patients with JIA or HLA-B27. Clinical relevance This study suggests that the non-invasive confocal microscopy of the cornea is capable of supporting a clinical diagnosis in patients with uveitis.

Purpose: TNF alpha inhibitors have revolutionized the care of vision-threatening uveitis. This study evaluated the efficacy of adalimumab (ADA) for the treatment of refractory noninfectious uveitis.Design: Randomized, prospective, controlled, two-center clinical trialMethods: Patients with active uveitis despite combined oral low-dose prednisolone and immunosuppression were randomized for additional ADA with corticosteroids in a fixed tapering regime, or corticosteroids only. Primary outcome measure at three months was improved best-corrected visual acuity (BCVA; >2 lines). In case of treatment failure, switch to the other arm was possible.Results: Twenty-five patients (10 ADA, 15 controls) were included. BCVA increased with ADA by > 2 lines in 6/10 patients (60%; mean increase of 0.23 logMAR), but in only 2/15 from controls (13%, mean increase of 0.04 logMAR, Fisher´s exact test p = 0.00221).Conclusions: The results show superiority of ADA over controls in severe ocular inflammation including ant...

Purpose: To analyze the preferred practice respective diagnosis, treatment, and complications in patients with acute retinal necrosis in Germany.Methods: The uveitis-section of the German Ophthalmologic Society developed a questionnaire with 12 questions concerning patients with acute retinal necrosis seen in the 5 years up to August 2009.Results: In total, 35 eye hospitals answered the questionnaire and reported 213 patients with acute retinal necrosis. Diagnosis was made clinically in 86%. Anterior chamber tap, vitreous biopsy, diagnostic vitrectomy, and serology were performed for confirmation. Therapy was started with acyclovir in all institutions, and continued with ganciclovir, foscarnet and brivudine in some cases. Intravitreal injections were performed in 46%. Additional oral steroids were given in 80%. A following oral antiviral treatment was performed in 94%.Conclusions: Relevant variations were seen in diagnosis and treatment practices. The survey outlines the need for a unique diagnost...

Purpose To characterise uveitis in association with multiple sclerosis (MS). Methods We conducted a retrospective chart review of patients with uveitis and MS at two uveitis centres (Portland, Oregon, USA and Heidelberg, Germany). Baseline characteristics and ophthalmic data were collected at the patient9s first and last visits. Additionally, neurological records were obtained when possible. Results We identified 113 patients (196 eyes) with uveitis and MS. Of these, 53 had a diagnosis of MS confirmed by review of neurological records, 50 additional patients fulfilled the Poser criteria for MS and 10 with MS were referred by an outside neurologist. Among them, 83 (73%) were women and the mean age of presentation was 40.6 years (range 13–64 years). The average visual acuity in affected eyes at presentation was 20/39. There were 90 patients (80%) who presented with intermediate uveitis and 24 patients (15%) with anterior uveitis. Posterior and pan-uveitis were found in four patients (3%) and two patients (2%), respectively. During a median follow-up of 3.2 years (range 0.04–21 years), visual acuity improved –0.09 logMar/year. Compared with our location-matched controls with idiopathic intermediate uveitis (n=16), patients with MS and intermediate uveitis were significantly older when diagnosed with uveitis (p=0.027) and more likely to be female (p=0.01). There was no statistical difference in visual acuity or rate of vision change between our cases and controls (p=0.58 and p=0.36, respectively). Conclusions Uveitis with MS generally presents as intermediate uveitis with a minority presenting with anterior uveitis. Patients are significantly older and more likely to be women than patients with idiopathic intermediate uveitis. The visual prognosis is generally favourable.

Background In phenylketonuria presymptomatic treatment following newborn screening prevents severe mental and physical impairment. The reasons for subtle impairments of cerebral functions despite early treatment remain unclear. We assessed a broad spectrum of visual functions in early-treated patients with phenylketonuria and evaluated two hypotheses—the dopamine and the long-chain polyunsaturated fatty acids (LCPUFAs) depletion hypotheses. Methods Contrast sensitivity, colour vision, electroretinography, frequency doubling technology campimetry (FDT), and their relation with blood phenylalanine and docosahexaenoic acid levels were assessed in 36 patients with phenylketonuria and 18 age-matched healthy controls. Results Contrast sensitivity was significantly lower and total error scores in colour vision significantly higher in patients than controls. Electroretinography results differed significantly between patients and controls. We found a trend for the effect of phenylalanine-levels on contrast sensitivity and a significant effect on colour vision/FDT results. Docosahexaenoic acid levels in erythrocytes were not associated with visual functions. Conclusion This is the first evaluation of visual functions in phenylketonuria using a comprehensive ophthalmological test battery. We found no evidence supporting the long-chain polyunsaturated fatty acids depletion hypothesis. However, the effect of phenylalanine-levels on visual functions suggests that imbalance between phenylalanine and tyrosine may affect retinal dopamine levels in phenylketonuria. This is supported by the similar patterns of visual functions in patients with phenylketonuria observed in our study and patients with Parkinson's disease.

RESUME Objective: To assess the 3-year visual outcome of intravitreal bevacizumab in inflammatory ocular neovascularization. Design: Experimental study. Methods: Retrospective multicenter consecutive case series in 81 patients with inflammatory ocular neovascularization refractory to standard therapy and treated with intravitreal bevacizumab. The outcome measures included improvement of best corrected visual acuity expressed as logarithm of minimum angle of resolution (logMAR) and paired comparison decrease in central foveal thickness by optical coherence tomography. Results: Mean best corrected visual acuity improved from baseline 0.699 (6/30 or 20/101) (SD 0.434) to 0.426 (6/16 or 20/53) (SD 0.428) (n 81; p 0.001), a gain of 2.7 lines (median 3 injections; 81 eyes; 81 patients). Paired comparisons revealed significant central foveal flattening at 3 years of 97.9 m( n 51; p 0.001). In a subgroup analysis, visual improvement was significant for ocular histoplasmosis (p 0.026); multifocal choroiditis (p 0.05); serpiginous choroiditis (p 0.028); ocular toxoplasmosis (p 0.042); and punctate inner choroidopathy (p 0.015). In a subgroup analysis, foveal flattening was significant for ocular histoplasmosis (p 0.004); multifocal choroiditis (p 0.007); serpiginous choroiditis (p 0.011); and punctate inner choroidopathy (p 0.001). Of the group, 5 eyes developed submacular fibrosis, 1 eye retinal pigment epithelial tear, and 1 eye macular ischemia in the context of vasculitis. Conclusion: At 3 years, intravitreal bevacizumab sustained significant visual improvement of 2.7 lines and significant foveal flattening of 98 m in a wide variety of inflammatory ocular diseases without major complications after a median of 3 injections. Objet : Evaluation du resultat visuel de 3 annees de traitement intravitreen au bevacizumab pour une neovascularisation oculaire

We aimed to review all uveitis patients with a positive Borrelia serology to evaluate positive results in uveitis subtypes. Further we wanted to test a self-assembled Interferon gamma release assay (IGRA) as a possible supplement method in these patients.Patients where serology for Borrelia was ordered from September 2005 to May 2008, were identified by database search. Patients with positive results in ELISA and Western Blot were retested by a self-assembled IGRA. Bayes Theorem was applied.Testing for Borrelia was ordered for 184 patients. 18 patients (9,8%) showed positive results. 11 were positive for IgG (5,9 %), 3 were positive for IgG and IgM (1,6 %) and 4 for IgM (2,1%). Applying Bayes Theorem, we calculated a posttest-probability of 9% in case of a positive test result. 16 of the 18 patients were retested by IGRA. None of them showed a positive result.A positive serology with uveitis as the only clinical symptom is not sufficient to confirm Borreliosis as 5,9 % of patients with uveitis and a positive IgG serology correspond to the normal spread of Borrelia in the population. Looking at posttest-probability shows a lot of false-positive test results when testing all uveitis patients for Borrelia routinely.

Tubulointerstitial nephritis and uveitis syndrome (TINU) is a specific form of intraocular inflammation (uveitis) combined with kidney disease that was first described in two patients by Dobrin et al. in 1975. Since then, approximately 200 more cases have been published. The cause of the disease is still unknown. A hypersensitivity reaction is suspected, especially an infection or very rarely a medication reaction is thought to trigger the disease. It is considered to be a rare disease and thus unfortunately is still unfamiliar to most ophthalmologists. Therefore, it is frequently overlooked in the differential diagnosis. In this review we want to show advances in diagnostics and treatment as well as progress in deciphering the pathogenesis.Beta-2 microglobulin (Ub2MG) analysis in urine and human leukocyte antigen (HLA) typing is helpful to diagnose TINU cases. A high association of HLA-DRB1*01 has been shown with TINU. A first single case report suggests a common antibody production against ocular and renal proteins.TINU is a common cause of uveitis among patients who present with bilateral, anterior uveitis of sudden onset. It is more frequent in children and apparently in boys. Although the activity of the eye disease can persist for many months, it is usually controlled with little treatment and the outcome is very good.

Purpose To obtain a diagnosis of tuberculosis in patients with a specific subset of uveitis, serpiginous-like choroiditis. This subset has been suspicious for tuberculous etiology in single case reports and old textbooks. Design Retrospective evaluation of a diagnostic test in a specific uveitis cohort. Methods QuantiFERON is an approved, antigen-specific test that utilizes synthetic peptides representing Mycobacterium tuberculosis proteins. After incubation, interferon γ secreted by T lymphocytes in response to these antigens is measured. We used the test in 21 of 26 patients identified from our database with serpiginous-like choroiditis. Rates of QuantiFERON positivity were compared to a group of healthy hospital employees (n = 208), another group of healthy hospital workers after tuberculosis contact (n = 117), and a group of randomly tested patients with other uveitis forms (n = 45). Results Eleven of 21 serpiginous-like choroiditis patients (52%) were tested positive. The rate of QuantiFERON positivity in the healthy control groups was 8.7% and 0.9%, and 13% in the other uveitis subsets. Four of the QuantiFERON-positive serpiginous-like choroiditis patients were treated with standard anti-tuberculostatic therapy; three finished the course and improved. Seven patients are either stable without therapy (n = 4) or on low-dose prednisone (n = 3). Conclusions QuantiFERON testing revealed a high number of positive patients, which indicates a tuberculous etiology in this uveitis subset. Whether bacterial activity or secondary immunologic processes are causative remains a matter of speculation.

The purpose of this review was to provide an overview of current data on antibiotic prophylaxis in ocular toxoplasmosis.Studies showing the prophylactic effect of long-term antibiotics are discussed. Prophylaxis seems to be justified in patients with a high risk of recurrence because of antibiotic's potential side-effects. Therefore, predisposing factors leading to a higher risk of recurrence and the time period during which an antibiotic prophylaxis is most appropriate are reviewed. Finally, a patient-individualized treatment recommendation is summarized.In the current literature, two prospective, randomized case-control studies exist, which show the protective effect of an antibiotic prophylaxis. Hematologic, gastrointestinal and dermatologic complications are potential side-effects. Especially during the first year after suffering a recurrence, an antibiotic prophylaxis seems to be justified. The risk of a recurrence is inter alia influenced by the duration of the disease, the immune status of the host and the patient's age. Therefore, an antibiotic prophylaxis should be considered for patients who have recently been infected with ocular toxoplasmosis, for middle-aged and elderly patients and patients with a compromised immune system. This should be discussed with each patient individually, especially if the lesion is close to the macula.

Objective. To report baseline articular, functional and ocular findings of the first international prospective cohort study of Blau syndrome (BS). Methods. Three-year, multicentre, observational study on articular, functional (HAQ, Childhood HAQ and VAS global and pain), ophthalmological, therapeutic and radiological data in BS patients. Results. Baseline data on the first 31 recruited patients (12 females and 19 males) from 18 centres in 11 countries are presented. Of the 31 patients, 11 carried the p.R334W NOD2 mutation, 9 the p.R334Q and 11 various other NOD2 missense mutations; 20 patients were sporadic and 11 from five BS pedigrees. Median disease duration was 12.8 years (1.1-57). Arthritis, documented in all but one patient, was oligoarticular in 7, polyarticular in 23. The median active joint count was 21. Functional capacity was normal in 41%, mildly impaired in 31% and moderate-severe in 28% of patients. The most frequently involved joints at presentation were wrists, ankles, knees and PIPs. On radiographs, a symmetrical non-erosive arthropathy was shown. Previously unknown dysplastic bony changes were found in two-thirds of patients. Ocular disease was documented in 25 of 31 patients, with vitreous inflammation in 64% and moderate-severe visual loss in 33%. Expanded manifestations (visceral, vascular) beyond the classic clinical triad were seen in 52%. Conclusion. BS is associated with severe ocular and articular morbidity. Visceral involvement is common and may be life-threatening. Bone dysplastic changes may show diagnostic value and suggest a previously unknown role of NOD2 in bone morphogenesis. BS is resistant to current drugs, suggesting the need for novel targeted therapies.

Retrospective, observational case series with follow-up examination to analyse the influence of drug therapy on ocular toxoplasmosis (OT) in terms of recurrence-risk.In this one centre study an existing data set of 84 patients with active OT was used. Drug therapy for 255 active lesions was retrospectively reconstructed. Median recurrence-free survival time was calculated for the different treatment regimes using Kaplan-Meier estimates.20 different regimens were used as treatment of OT in the catchment area of the Interdisciplinary Uveitis Center, University of Heidelberg, Germany. Median recurrence-free survival time was significantly lower after using systemic corticosteroid monotherapy (0.9 years; 95% CI 0.5 to 1.3 years) compared with Toxoplasma gondii-specific antibiotic treatment (3.0 years; 95% CI 2.2 to 3.9 years; p0.001) or compared with no therapy (3.0 years; 95% CI 2.1 to 3.9 years; p=0.006). No difference could be detected when comparing median recurrence-free survival time after using T gondii-specific antibiotics compared with no therapy (p=0.679).Although our study shows that drug therapy seems to influence the risk of recurrence of OT, there is no consensus regarding the choice of antiparasitic agents for treatment regimens in the catchment area of the Interdisciplinary Uveitis Center, University of Heidelberg. Survey results provide useful information for treating physicians and for clinical investigators interested in therapy.

PURPOSE OF REVIEW Interferons were first known for their antiviral action. Immunomodulatory therapy with interferons has been studied in various diseases. This paper summarizes the role and presumed mechanisms of action of type 1 interferons in the treatment of ocular disease. RECENT FINDINGS Preliminary data show beneficial effects of interferons in ocular disease such as Behcet disease and multiple sclerosis-associated uveitis in terms of visual acuity, intraocular inflammation activity, and chronic macular edema. Another mode of application is topical as an adjuvant treatment in viral keratitis or ocular surface malignancies. SUMMARY Interferons are gaining a place in the treatment of ocular disease. Evidence is growing of their potential in ocular Behcet disease and multiple sclerosis-associated uveitis. Randomized, controlled clinical trials are needed to confirm this observation. Further insights into the complex mechanisms of action of interferons in health and disease will increase understanding of their mechanisms of action as a therapeutic substance.

Objective Uveitis or intraocular inflammation is a major cause of visual loss. Acute anterior uveitis (AAU) affects ∼40% of patients with ankylosing spondylitis (AS) but also affects patients with no evidence of spondylarthritis. We sought to determine whether a unique genetic region could be implicated in a specific manifestation—AAU—of a multisystem, inflammatory, genetically complex disease, AS. Methods Individuals from families multiplex for AAU were genotyped at 400 markers representing the ABI PRISM linkage map MD-10, and at the HLA–B, DRB1, DQA1, DQB1, and DPB1 alleles. Among the family members with AAU, 76 affected sibpairs were analyzed (6 without concomitant AS, 12 discordant for AS, and 58 concordant for AS). Two-point and multipoint nonparametric linkage analyses were performed, and 1-parameter allele-sharing model logarithm of odds (LOD) scores were determined. Results As previously reported for AS, linkage at the major histocompatibility complex region (chromosome 6p21) was evident, exhibiting the highest multipoint LOD score (4.96 at marker HLA–B). Strong linkage was seen at a region on chromosome 9p21–9p24, with a LOD score of 3.72 at marker D9S157. When compared with a companion cohort of AS families, the linkage at this region was found in association with AAU but not with AS. A third region on chromosome 1q23–1q31 was observed to have suggestive linkage (LOD 2.05 at marker D1S238), which overlaps with a region associated with AS. Conclusion This is the first study in which a genetic region for AAU has been identified by genome-wide scan. Even though AS was highly prevalent in this cohort of families, a locus at chromosome 9p21–9p24 was identified that uniquely associates with AAU. Identifying the genetic perturbation at this region may advance our understanding of the mechanisms involved in tissue-specific pathology of complex inflammatory diseases.

PURPOSE: To ascertain time patterns of recurrences and factors predisposing for a higher risk of recurrence of ocular toxoplasmosis. METHODS: Retrospective observational case series with follow-up examination. Database of 4,381 patients with uveitis was used. Data of 84 patients with ocular toxoplasmosis (sample group) could be included. RESULTS: Two hundred and eighty active lesions in the first affected eye were detected. The mean number of recurrences per year was 0.29 (standard deviation, 0.24). Median recurrence-free survival time was 2.52 years (95% confidence interval, 2.03-3.02 years). Risk of recurrence was highest in the first year after the most recent episode (26%) implying a decrease with increasing recurrence-free interval. The risk of recurrence decreased with the duration of disease (P < 0.001). Treatment of the first active lesion influenced the risk of recurrence (P = 0.048). Furthermore, the risk of recurrence was influenced by patient age at the time of the first active lesion (P = 0.021) and the most recent episode (P = 0.002). CONCLUSION: A secondary antibiotic prophylaxis could be discussed 1) during the first year after an active lesion has occurred, especially in case of the first active lesion of ocular toxoplasmosis, and 2) in older patients, especially if primarily infected with Toxoplasma gondii at an older age.

Purpose: Comparison between the risk of recurrence during pregnancy with nonpregnant periods in patients with ocular toxoplasmosis (OT). Methods: Records of 40 women were retrospectively reviewed. The women were subdivided into either a pregnant group or a control group formed by nonpregnant women during follow-up. Comparable cases from the literature were added. Mean number of recurrences per year was compared. Results: Eleven women with pregnancies could be included. Six cases from the literature were added (total n = 17). Mean number of recurrences per year during versus not during pregnancy was 0.16 (SD 0.39) versus 0.32 (SD 0.30; p = 0.088), respectively. In the control group (n = 29) the mean number of recurrences per year (0.31; SD 0.27) was significantly higher when compared to cases during pregnant periods (p = 0.002). Conclusion: Adding to published series, the presented data do not provide evidence for a relevant impact of pregnancy on recurrence behavior in OT.

Objective.To report the efficacy of rituximab (RTX) in the treatment of ocular or orbital inflammation accompanying autoimmune diseases refractory to previous standard immunosuppressive therapy.Methods.We reviewed medical records of 9 consecutive patients with noninfectious ocular or orbital inflammation treated with RTX.Results.Over a mean followup of 42 months, 7 patients were in clinical remission, 1 had partial response to treatment, and 1 did not respond. Best corrected visual acuity improved ≥ 1 line in 4 patients, was stable in another 4 patients, and worsened in 1. Concomitant immunosuppressive therapy was tapered in 6 cases. Systemic corticosteroids were tapered or kept below 7.5 mg a day in 5 patients 1 year after the first RTX cycle.Conclusion.RTX therapy, in patients who are refractory to standard immunosuppressive therapy, was effective and showed a beneficial response to treatment including induction of clinical remission of inflammation in most patients.

Objective The aim of this study was to assess the efficacy of adalimumab in patients with active non-infectious uveitis in three different centres. Methods In a retrospective study we identified patients from our databases who were treated with adalimumab. The composite outcome measure for efficacy included reduction of macular oedema by optic coherence tomography, visual acuity, anterior chamber cells, reduction of frequency of flares and reduction of prednisone dose during the treatment. At least one of the criteria had to be improved and none worsened to declare treatment as effective. Results 60 patients with an average age of 37.3 years (range 4–71 years) were treated with adalimumab over an average follow-up period of 87.9 weeks (range 12–222 weeks). The indication for treatment was in 41 (68.3%) patients the activity of both uveitis and systemic disease and in 19 (31.7%) patients uveitis activity only. 15 (25%) patients were treated before with etanercept and 10 (16.7%) patients with infliximab. 49 out of 60 (81.7%) patients improved, while the other 11 (18.3%) patients did not meet improvement criteria and were given additional or alternative immunosuppressive treatment. At the last follow-up, 47 (78.3%) patients were still on adalimumab treatment. 13 (21.6%) patients stopped adalimumab treatment, due to inefficacy in eight, another three patients due to side effects (liver enzyme elevation and furunculosis), one patient due to pregnancy and one patient died. Conclusions This large retrospective case series showed that adalimumab is effective in up to 80% of patients with uveitis.

Purpose To compare interferon (IFN) beta with methotrexate (MTX) in the treatment of intermediate uveitis with macular edema. Design Monocentric, prospective, randomized, controlled clinical trial. Methods setting: Specialized uveitis center at the University of Heidelberg. patient or study population: Patients with either primary intermediate uveitis or uveitis associated with multiple sclerosis. main inclusion criteria: Visual acuity of 20/30 or worse (0.2 logarithm of the minimal angle of resolution) and macular edema of more than 250 μm (central 1-mm in optical coherence tomography; Stratus). Randomization into either IFN beta 44 μg subcutaneously 3 times weekly or 20 mg MTX subcutaneously once weekly. main outcome measures: At 3 months, the primary outcome parameter of mean change in visual acuity was evaluated and efficacy was determined. Secondary parameters were macular edema by optical coherence tomography, inflammatory activity, and retinal sensitivity by microperimetry (MP-1; Nidek). In case of treatment failure, switching to the other treatment arm was possible. Results Nineteen patients were included. Ten were randomized to MTX, and 9 were randomized to IFN beta. At 3 months, visual acuity improved a mean 0.31 logarithm of the minimal angle of resolution (range, −0.02 to −0.96, 15.6 letters on the Early Treatment Diabetic Retinopathy Study chart) in the IFN beta group versus a mean 0.09 logarithm of the minimal angle of resolution (range, 0.12 to −0.38, 4.7 letters) in the MTX arm ( P = .0435, Mann–Whitney U test). Macular thickness decreased by a mean of 206 μm (range, −41 to −416 μm) in the IFN arm, but increased by 47 μm (range, 108 to −28 μm) in the MTX group ( P Conclusions Although the sample size is small, results of the trial support superiority of IFN beta over MTX in the treatment of macular edema in the setting of intermediate uveitis

Purpose. Age-related macular degeneration (AMD) is a heterogeneous condition of high prevalence and complex etiology involving genetic as well as environmental factors. By fundus autofluorescence (FAF) imaging, AMD can be classified into several distinct phenotypes, with one subgroup characterized by fine granular pattern with peripheral punctate spots (GPS[+]). Some features of GPS[+] overlap with Stargardt disease (STGD1), a recessive macular dystrophy caused by biallelic sequence variants in the ATP-binding cassette transporter 4 (ABCA4) gene. The aim of this study was to investigate the role of ABCA4 in GPS[+]. Methods. The ABCA4 gene was sequenced in 25 patients with the GPS[+] phenotype and 29 with geographic atrophy (GA)-AMD but no signs of GPS (GPS[-]). In addition, frequencies of risk-increasing alleles at three known AMD susceptibility loci, including complement factor H (CFH), age-related maculopathy susceptibility 2 (ARMS2), and complement component 3 (C3), were evaluated. Results. We demonstrate that GPS[+] is associated significantly with monoallelic ABCA4 sequence variants. Moreover, frequencies of AMD risk-increasing alleles at CFH, ARMS2, and C3 are similar in GPS[+] and STGD1 patients, with risk allele frequencies in both subcategories comparable to population-based control individuals estimated from 3,510 individuals from the NHLBI Exome Sequencing Project. Conclusions. Our data suggest that the GPS[+] phenotype is accounted for by monoallelic variants in ABCA4 and unlikely by the well-established AMD risk-increasing alleles at CFH, ARMS2, and C3. These findings provide support for a complex role of ABCA4 in the etiology of a minor proportion of patients with AMD.

Objective 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. Methods The literature relating to outcome measures used in studies of uveitis in childhood and adolescence was reviewed. A set of core outcomes and domains was established using the Delphi process. This was reviewed by a representative multinational interdisciplinary working group. Nominal group technique consensus was reached on face and content validity of the range and content of the domains. The outcomes and the appropriate instruments for uveitis trials were adapted to the age ranges of patients with JIA-associated uveitis. Results Consensus was reached that data should be reported at defined time points in longitudinal studies with patients stratified by prognostic markers. Visual acuity testing should be age appropriate. The severity of uveitis (measured as anterior chamber cell grade) and duration of active inflammation should be documented. Visually significant structural complications should be recorded and quantified with standard measures. The responses to treatment and corticosteroid-sparing effects of treatment should be documented. Patient-reported disease activity and age-specific uveitis-related quality of life should be reported using appropriate questionnaires. Conclusion The proposed outcome measures in JIA-associated uveitis should aid in the standardization and comparison of future RCTs of the treatment regimens for this disease. The proposed outcome measures will be verified in a prospective validation study.

PURPOSE. To evaluate the role of fellow eye status in determining progression of geographic atrophy (GA) in patients with age-related macular degeneration (AMD). METHODS. A total of 300 eyes with GA of 193 patients from the prospective, longitudinal, natural history FAM Study were classified into three groups according to the AMD manifestation in the fellow eye at baseline examination: (1) bilateral GA, (2) early/intermediate AMD, and (3) exudative AMD. GA areas were quantified based on fundus autofluorescence images using a semiautomated image-processing method, and progression rates (PR) were estimated using two-level, linear, mixed-effects models. RESULTS. Crude GA-PR in the bilateral GA group (mean, 1.64 mm(2)/y; 95% CI, 1.478-1.803) was significantly higher than in the fellow eye early/intermediate group (0.74 mm(2)/y, 0.146-1.342). Although there was a significant difference in baseline GA size (P = 0.0013, t-test), and there was a significant increase in GA-PR by 0.11 mm(2)/y (0.05-0.17) per 1 disc area (DA; 2.54 mm(2)), an additional mean change of -0.79 (-1.43 to -0.15) was given to the PR beside the effect of baseline GA size. However, this difference was only significant when GA size was ≥1 DA at baseline with a GA-PR of 1.70 mm(2)/y (1.54-1.85) in the bilateral and 0.95 mm(2)/y (0.37-1.54) in the early/intermediate group. There was no significant difference in PR compared with that in the fellow eye exudative group. CONCLUSIONS. The results indicate that the AMD manifestation of the fellow eye at baseline serves as an indicator for disease progression in eyes with GA ≥ 1 DA. Predictive characteristics not only contribute to the understanding of pathophysiological mechanisms, but also are useful for the design of future interventional trials in GA patients.

Tubulointerstitial nephritis and uveitis (TINU) syndrome is a rare form of uveitis. Previously, the authors had demonstrated a strong association of human leukocyte antigen (HLA) DRB1*0102 with TINU. Here, the authors performed HLA analysis on subjects with isolated bilateral sudden-onset uveitis (as in the TINU subtype) or with isolated tubulointerstitial nephritis (TIN).Patients with sudden onset, anterior, bilateral uveitis not fulfilling a diagnosis of TINU were identified. Pathology reports were reviewed to identify subjects with biopsy-proven TIN. Molecular typing of the HLA-DRB1 gene was performed by the Luminex technology-based sequence-specific oligonucleotide (SSO) hybridisation method (One Lambda, Canoga Park, California). HLA-DRB1 allele frequencies were compared with normal published controls (http://www.ncbi.nlm.nih.gov/projects/gv/mhc/ihwg.cgi dbMHC Europe cohort) and the published TINU cohort (n=18).The authors included 28 subjects with uveitis and 14 with TIN. There was a significantly higher frequency of DRB1*0102 in the isolated uveitis cohort versus in normal controls (10.7% vs 0.6%, respectively, p0.0001; RR 14.3 (6.9-29.8)). None of the nephritis patients showed this HLA subtype. Another association with HLA-DRB1*08 was seen in the isolated uveitis cohort with an allele frequency of 10.7% versus 2.7% in normal controls (p=0.0019; RR 4.0 (1.8-9.0)). In contrast, the HLA-DRB1*08 was not different from controls in the TINU cohort (allele frequency 2.8%, p=not significant).The incidence of HLA-DRB1*0102 is increased in sudden-onset bilateral anterior uveitis, as seen in patients with TINU. The same allele does not appear to occur in increased frequency in patients with isolated TIN. HLA DRB1*0102 might predispose to this subset of uveitis.

Purpose To assess the long-term role of bevacizumab (Avastin; Genentech Inc, South San Francisco, California, USA) in inflammatory ocular neovascularization. Design Retrospective multicenter consecutive case series of inflammatory ocular neovascularization. Methods settings: Multicenter institutional and private practices. study population: Patients with inflammatory ocular neovascularization in one or both eyes of varying etiologies who failed standard therapy. intervention: Intravitreal injection of bevacizumab. main outcome measures: Improvement of best-corrected visual acuity (BCVA) expressed as logarithm of minimal angle of resolution (logMAR), and decrease in central foveal thickness as measured by optical coherence tomography at 6, 12, 18, and 24 months of follow-up. Results Mean logMAR BCVA (central foveal thickness) following intravitreal bevacizumab was as follows: baseline, 0.65 (6/27 or 20/90) (338 μm; 99 eyes of 96 patients); 6 months, 0.42 (6/16 or 20/53) (239 μm; 2.0 injections; 81 eyes); 12 months, 0.39 (6/15 or 20/49) (241 μm; 2.3 injections; 95 eyes); 18 months, 0.40 (6/15 or 20/50) (261 μm; 3.0 injections; 46 eyes); and 24 months, 0.34 (6/13 or 20/44) (265 μm; 3.6 injections; 27 eyes). Paired comparisons revealed significant visual improvement at 6 months of 2.4 lines ( P = .000), at 12 months of 2.5 lines ( P = .000), at 18 months of 2.5 lines ( P = .001), and at 24 months of 2.2 lines ( P = .013). Paired comparisons revealed significant central foveal flattening at 6 months of 78 μm ( P = .000), at 12 months of 85 μm ( P = .000), at 18 months of 90 μm ( P = .003), and at 24 months of 77 μm ( P = .022). Three eyes developed submacular fibrosis and 1 eye submacular hemorrhage. Conclusion Intravitreal bevacizumab led in the long-term to significant mean visual improvement of ≥2.2 lines and significant foveal flattening in a wide variety of inflammatory ocular diseases without major complications.

ObjectiveStudies on the epidemiology of uveitis are rare and cohorts are small. We analyzed the frequencies of classified forms of uveitis in all patients at our center.MethodsWe studied 1916 consecutive patients with inflammatory eye disease. Data were analyzed regarding associated systemic disease, infection, ocular syndromes, anatomic localization, age, and sex.ResultsIn 59.1% of patients, a classified form of uveitis was observed: associated systemic diseases in 43.7%, the most frequent ones sarcoidosis (17.4%) and ankylosing spondylitis (16.8%); ocular syndromes in 34.3%, the most frequent HLA-B27-positive anterior uveitis (AU; 35.1%) and Fuchs uveitis syndrome (FUS; 34.3%); and infections in 22.4%, the most frequent herpetic infections (46.1%) and toxoplasmosis (31.5%). We found AU in 45.4% of patients (15.4% HLA-B27-positive AU and 11.3% FUS), intermediate uveitis in 22.9% (unclassified 53.7% and multiple sclerosis 10.3%), and posterior uveitis in 13.5% (24.7% toxoplasmosis). Panuveitis was diagnosed in 6.2% of cases (Behçet’s disease 12.6%; sarcoidosis 10.9%). The remaining 12.0% of cases showed extrauveal manifestations (scleritis, episcleritis, keratitis, optic neuritis, myositis, and orbital inflammation).ConclusionWe describe the largest cohort to date of consecutive patients from a specialized uveitis center. The high frequency of classified disease, nearly 60% in our clinic, shows the usefulness of an interdisciplinary approach, oriented on anatomic presentation.

Background Age-related macular degeneration (AMD) is a prevalent cause of blindness in Western societies. Variants in the genes encoding complement factor H (CFH), complement component 3 (C3) and age-related maculopathy susceptibility 2 (ARMS2) have repeatedly been shown to confer significant risks for AMD; however, their role in disease progression and thus their potential relevance for interventional therapeutic approaches remains unknown. Methodology/Principal Findings Here, we analyzed association between variants in CFH, C3 and ARMS2 and disease progression of geographic atrophy (GA) due to AMD. A quantitative phenotype of disease progression was computed based on longitudinal observations by fundus autofluorescence imaging. In a subset of 99 cases with pure bilateral GA, variants in CFH (Y402H), C3 (R102G), and ARMS2 (A69S) are associated with disease (P = 1.6×10−9, 3.2×10−3, and P = 2.6×10−12, respectively) when compared to 612 unrelated healthy control individuals. In cases, median progression rate of GA over a mean follow-up period of 3.0 years was 1.61 mm2/year with high concordance between fellow eyes. No association between the progression rate and any of the genetic risk variants at the three loci was observed (P>0.13). Conclusions/Significance This study confirms that variants at CFH, C3, and ARMS2 confer significant risks for GA due to AMD. In contrast, our data indicate no association of these variants with disease progression which may have important implications for future treatment strategies. Other, as yet unknown susceptibilities may influence disease progression.

Purpose To report seven cases of uveitis occurring in patients with autoimmune hepatitis (AIH), raising the possibility that uveitis may be an extrahepatic feature of AIH. Design Multicenter, retrospective, observational case series of patients with AIH and uveitis. Methods One index case was identified at Oregon Health & Science University. Further cases were identified by a web-based survey of members of the American Uveitis Society, the International Uveitis Study Group, the Proctor Foundation mailing list server, and the First SUN International Workshop. Respondents were asked to provide clinical information about uveitis phenotype, AIH features, and treatment. Results Clinical information was obtained for seven individuals (four females and three males; age range, seven to 67 years) who suffered from AIH and uveitis. Average duration of follow-up was 5.5 years. All patients had chronic, persistent bilateral uveitis that was anterior (n = 3), intermediate (n = 1), or pan (n = 3) in location. Every patient had complications arising from his or her uveitis, including cataract (n = 5), glaucoma (n = 3), cystoid macular edema (n = 3), and posterior synechiae (n = 3). Final visual acuities ranged from 20/16 to hand movements. To treat the uveitis and/or AIH, the majority of patients required oral prednisone and all seven patients were treated with systemic immunosuppression. Conclusion Despite the small size of this study, our findings suggest an association between AIH and uveitis. The uveitis is chronic, bilateral, and associated with sight-threatening complications, necessitating systemic immunosuppression in some individuals.

Purpose : Bevacizumab is a monoclonal antibody to vascular endothelial growth factor (VEGF) which has been successfully used for the treatment of age-related macular degeneration with choroidal neovascularization. As VEGF is involved in the pathomechanisms of inflammation and endothelial dysfunction the authors used bevacizumab as a last resort treatment in patients with persistent uveitic cystoid macular edema (CME). Patients and methods : Persistent uveitic CME was defined by optical coherence tomography (OCT) measurements >250 mum despite previous treatments. The authors reviewed patients with persistent CME who subsequently had been treated with intravitreous bevacizumab 1.25 or 2.5 mg. Improvement was judged by visual acuity (VA) gain >/=2 lines and thickness reduction in OCT. Results : Eleven eyes of 10 patients were injected since February 2006. Median follow-up was 70 days. Reduction in central retinal thickness could be seen as early as 2 weeks with a mean foveal thickness reduction of 127.2 mum at 4 weeks. Concurrent improvement in VA was seen in 4 of 10 patients, and was unchanged in the others. Four patients received two injections and five patients received three injections. Except for progression of cataract in one eye no ocular or systemic adverse events were recorded. Conclusions : Intravitreal bevacizumab seems to be an effective and safe treatment in the management of refractory inflammatory CME. The effect is transient, and reinjections may be necessary, although the time until reinjection is needed differs individually.

To assess the role of bevacizumab in inflammatory ocular neovascularization.Retrospective, multicenter, consecutive case series of inflammatory ocular neovascularization.Patients with inflammatory ocular neovascularization of varying causes for whom standard therapy failed were treated with intravitreal injection of bevacizumab. Main outcome measures included improvement of best-corrected visual acuity (BCVA) expressed in logarithm of minimum angle of resolution units, response of inflammatory ocular neovascularization by funduscopy and angiography, and decrease in central foveal thickness as measured by optical coherence tomography at the three-month follow-up.At the three-month follow-up, 84 eyes of 79 patients had been treated with a mean of 1.3 injections (range, one to three). Thirty-four eyes showed juxtafoveal choroidal neovascularization (CNV), 34 eyes showed subfoveal CNV, eight eyes showed peripapillary CNV, and 11 eyes showed neovascularization of the disc (NVD) or neovascularization elsewhere (NVE). BCVA improved 2.4 lines from 0.68 (6/28 or 20/94) to 0.44 (6/17 or 20/55) (P.001). BCVA improved by one to three lines in 34.5% of the eyes, by four to six lines in 16.7% of the eyes, and by more than six lines in 14.2% of the eyes. Function was unchanged in 23.8% of the eyes. BCVA worsened in 10.7% (zero to three lines in 7.1%, more than four lines in 3.6%). Central foveal thickness decreased from baseline 346 to 252 microm (P.001). For CNV, 32 eyes (43.2%) had complete regression after the injection, 27 (36.5%) had partial regression, five (6.8%) had no response, and 10 eyes (13.5%) were not evaluated by the contributors. For NVD or NVE, seven eyes (63.6%) had complete regression of new vessels and four eyes (36.4%) had partial regression after the injection.Intravitreal bevacizumab led to short-term significant visual improvement and regression of inflammatory ocular neovascularization in a wide variety of inflammatory ocular diseases.