Miles Stanford

EULAR recommendations for the management of Behçet disease

Objectives: To develop evidence-based European League Against Rheumatism (EULAR) recommendations for the management of Behçet disease (BD) supplemented where necessary by expert opinion. Methods: The multidisciplinary expert committee, a task force of the EULAR Standing Committee for Clinical Affairs (ESCCA), consisted of nine rheumatologists (one who was also a clinical epidemiologist and one also a Rehabilitation Medicine doctor), three ophthalmologists, one internist, one dermatologist and one neurologist, representing six European countries plus Tunisia and Korea. A patient representative was also present. Problem areas and related keywords for systematic literature research were identified. Systematic literature research was performed using Medline and the Cochrane Library databases from 1966 through to December 2006. A total of 40 initial statements were generated based on the systematic literature research. These yielded the final recommendations developed from two blind Delphi rounds of voting. Results: Nine recommendations were developed for the management of different aspects of BD. The strength of each recommendation was determined by the level of evidence and the experts’ opinions. The level of agreement for each recommendation was determined using a visual analogue scale for the whole committee and for each individual aspect by the subgroups, who consider themselves experts in that field of BD. There was excellent concordance between the level of agreement of the whole group and the “experts in the field”. Conclusion: Recommendations related to the eye, skin–mucosa disease and arthritis are mainly evidence based, but recommendations on vascular disease, neurological and gastrointestinal involvement are based largely on expert opinion and uncontrolled evidence from open trials and observational studies. The need for further properly designed controlled clinical trials is apparent.

Intravitreal triamcinolone for uveitic cystoid macular edema: an optical coherence tomography study

PURPOSE To investigate the use of intravitreal injection of triamcinolone acetonide (TA) for the treatment of refractory uveitic cystoid macular edema (CME). DESIGN Prospective, nonrandomized, self-controlled comparative trial. PARTICIPANTS Six patients with chronic CME resistant to treatment with systemic steroids, orbital floor steroids, and cyclosporine A. Three patients were followed for more than 1 year, and the other three for between 3 and 9 months. INTERVENTION Injection of 2 mg of TA into the vitreous cavity. TESTING Optical coherence tomography scanning of the fovea before and after injection and logarithmic minimal angle of resolution visual acuity. MAIN OUTCOME MEASURES Visual acuity, retinal thickness, cystoid space height, and intraocular pressure. RESULTS There was complete anatomic resolution of CME in five of the six cases within 1 week after injection. Cystoid spaces began to return between 6 weeks and 3 months after injection. Two patients with longer term follow-up responded to further orbital floor steroid injection and had no CME 1 year later. One patient had raised intraocular pressure develop, requiring a trabeculectomy. Mean improvement in visual acuity after 12 months was 0.27 (range, 0.14-0.42). CONCLUSIONS Complete anatomic and, to some extent, functional recovery can be induced by intravitreal TA despite long-term refractory inflammatory CME. Optical coherence tomography aids in the management of these cases.

Genome-wide association study identifies variants in the MHC class I, IL10, and IL23R-IL12RB2 regions associated with Behcet's disease

Behçets disease is a genetically complex disease of unknown etiology characterized by recurrent inflammatory attacks affecting the orogenital mucosa, eyes and skin. We performed a genome-wide association study with 311,459 SNPs in 1,215 individuals with Behçets disease (cases) and 1,278 healthy controls from Turkey. We confirmed the known association of Behçets disease with HLA-B*51 and identified a second, independent association within the MHC Class I region. We also identified an association at IL10 (rs1518111, P = 1.88 × 10−8). Using a meta-analysis with an additional five cohorts from Turkey, the Middle East, Europe and Asia, comprising a total of 2,430 cases and 2,660 controls, we identified associations at IL10 (rs1518111, P = 3.54 × 10−18, odds ratio = 1.45, 95% CI 1.34–1.58) and the IL23R-IL12RB2 locus (rs924080, P = 6.69 × 10−9, OR = 1.28, 95% CI 1.18–1.39). The disease-associated IL10 variant (the rs1518111 A allele) was associated with diminished mRNA expression and low protein production.

Endogenous bacterial endophthalmitis: a 17-year prospective series and review of 267 reported cases.

Endogenous bacterial endophthalmitis is a rare but serious condition that occurs when bacteria cross the blood-ocular barrier and multiply within the eye. We provide an overview of endogenous bacterial endophthalmitis by reviewing 267 reported cases and integrating this with our experience of an additional 19 cases. The majority of patients with endogenous bacterial endophthalmitis are initially misdiagnosed and many have an underlying disease known to predispose to infection. This condition is often previously undiagnosed. Blood cultures are the most frequent means of establishing the diagnosis. The most common Gram positive organisms are Staphylococcus aureus, group B streptococci, Streptococcus pneumoniae,and Listeria monocytogenes. The most common Gram negative organisms are Klebsiella spp., Escherichia coli, Pseudomonas aeruginosa, and Neisseria meningitidis. Gram negative organisms are responsible for the majority of cases reported from East Asian hospitals, but Gram positive organisms are more common in North America and Europe. The visual outcome is poor with most cases leading to blindness in the affected eye. Many patients have extraocular foci of infection, with an associated mortality rate of 5%. The outcome of endogenous bacterial endophthalmitis has not improved in 55 years and clinicians need to have a high level of awareness of this commonly misdiagnosed condition.

Comparison between optical coherence tomography and fundus fluorescein angiography for the detection of cystoid macular edema in patients with uveitis

PURPOSE To compare optical coherence tomography (OCT) with fundus fluorescein angiography (FFA) for the detection of cystoid macular edema (CME) in patients with uveitis. DESIGN Prospective comparative observational series. PARTICIPANTS One hundred twenty-one eyes of 58 patients with uveitis of varied causes (seven patients were studied twice). TESTING Patients with suspected CME underwent OCT scanning followed by FFA at the same visit. MAIN OUTCOME MEASURES Detection and distribution of macular edema. RESULTS One hundred eight eyes had similar results on both OCT and FFA in that 67 eyes had CME and 41 eyes had no CME. In 10 eyes subretinal fluid was detected on OCT but not FFA. Five of these eyes had CME on FFA but not OCT. Three other eyes had CME that was detected by FFA but not by OCT. Compared with FFA, the OCT sensitivity for detecting CME was 96% (including the eyes with subretinal fluid), and the OCT specificity was 100%. CONCLUSIONS OCT is as effective at detecting CME as is FFA but is superior in demonstrating axial distribution of fluid.

Ocular Sequelae of Congenital Toxoplasmosis in Brazil Compared with Europe

Background Toxoplasmic retinochoroiditis appears to be more severe in Brazil, where it is a leading cause of blindness, than in Europe, but direct comparisons are lacking. Evidence is accumulating that more virulent genotypes of Toxoplasma gondii predominate in South America. Methods We compared prospective cohorts of children with congenital toxoplasmosis identified by universal neonatal screening in Brazil and neonatal or prenatal screening in Europe between 1992 and 2003, using the same protocol in both continents. Results Three hundred and eleven (311) children had congenital toxoplasmosis: 30 in Brazil and 281 in Europe, where 71 were identified by neonatal screening. Median follow up was 4.1 years in Europe and 3.7 years in Brazil. Relatively more children had retinochoroiditis during the first year in Brazil than in Europe (15/30; 50% versus 29/281; 10%) and the risk of lesions by 4 years of age was much higher: the hazard ratio for Brazil versus Europe was 5.36 (95%CI: 3.17, 9.08). Children in Brazil had larger lesions, which were more likely to be multiple and to affect the posterior pole (p<0.0001). In Brazil, visual impairment (<6/12 Snellen) was predicted for most affected eyes (87%, 27/31), but not in Europe (29%; 20/69, p<0.0001). The size of newly detected lesions decreased with age (p = 0.0007). Conclusions T. gondii causes more severe ocular disease in congenitally infected children in Brazil compared with Europe. The marked differences in the frequency, size and multiplicity of retinochoroidal lesions may be due to infection with more virulent genotypes of the parasite that predominate in Brazil but are rarely found in Europe.

Management of Behçet disease: a systematic literature review for the European League Against Rheumatism evidence-based recommendations for the management of Behçet disease

Objectives: To present and analyse the literature sources regarding the management of Behçet disease (BD) identified during the systematic literature research, which formed the basis for the European League Against Rheumatism (EULAR) evidence-based recommendations for the management of BD. Methods: Problem areas and related keywords regarding the management of BD were determined by the multidisciplinary expert committee commissioned by EULAR for developing the recommendations. A systematic literature research was performed using MedLine and Cochrane Library resources through to December 2006. Meta-analyses, systematic reviews, randomised controlled trials (RCTs), open studies, observational studies, case control studies and case series’ involving ⩾5 patients were included. For each intervention the effect size and number needed to treat were calculated for efficacy. Odds ratios and numbers needed to harm were calculated for safety issues of different treatment modalities where possible. Results: The literature research yielded 137 articles that met the inclusion criteria; 20 of these were RCTs. There was good evidence supporting the use of azathioprine and ciclosporin A in eye involvement and interferon (IFN)α in mucocutaneous involvement. There were no RCTs with IFNα or tumour necrosis factor (TNF)α antagonists in eye involvement. Similarly controlled data for the management of vascular, gastrointestinal and neurological involvement is lacking. Conclusion: Properly designed, controlled studies (new and confirmatory) are still needed to guide us in managing BD.

Behçet’s disease: from Hippocrates to the third millennium

Behçet’s disease (BD) is characterised by recurrent episodes of orogenital aphthae, systemic vasculitis, and systemic and retinal venous thrombosis. An association between HLA-B51 and BD was first identified over 20 years ago, but recently identified gene associations implicate regions both within and without the MHC in the immunological events underlying the lesions in BD. These include allelic variants within the tumour necrosis factor gene region and within the MHC class I chain related gene region, the factor V Leiden mutation, which is associated with retinal vascular occlusion, and alleles of the intercellular adhesion molecule gene. No single causative gene for BD has emerged; the evidence indicates that the underlying immune events in BD are triggered by a microbial antigen and subsequently driven by genetic influences which control leucocyte behaviour and the coagulation pathways. Knowledge of these risk factors may permit a more accurate prognosis for a given patient, and identify new pathways for more targeted intervention than is currently available.

CYTOKINES IN HUMAN INTRAOCULAR INFLAMMATION

The presence of interleukin 6 (IL-6), interleukin 1 (IL-1), interleukin 2 (IL-2) and tumour necrosis factor (TNF) was investigated in vitreous and aqueous aspirates from eyes undergoing vitrectomy for the treatment of different inflammatory conditions. Cadaveric vitreous from 10 normal subjects were used as controls. IL-6 was observed in 5 specimens from eyes with idiopathic uveitis (range = 26-264 pg/ml), in 2 specimens from eyes with uveitis complicated with retinal detachment (28 and 279 pg/ml, respectively), in 6 samples from eyes with diabetic retinopathy (range = 5-480 pg/ml), in one sample from an eye with phacolytic glaucoma (1190 pg/ml) and in one specimen from an eye with Behçets disease (366 pg/ml). Although IL-1 was detected in 80% of all the samples investigated, concentrations of this cytokine greater than 3 pg/ml were only observed in 2 specimens from eyes with uveitis (5 and 20 pg/ml, respectively) and 2 samples from eyes with diabetic retinopathy (3 and 31 pg/ml, respectively). TNF was present in 3 specimens from eyes with uveitis (range = 2-24 pg/ml) and 1 sample from eyes with diabetic retinopathy (4 pg/ml), but was not detected in the eyes with phacolytic glaucoma or Behçets disease. IL-2 (less than 0.1 U/ml) was detected in one sample from an eye with uveitis, one specimen from an eye with uveitis complicated with retinal detachment and 2 samples from eyes with diabetic retinopathy. None of the cytokines measured were detected in any of the control vitreous. The present observations suggest that cytokines, particularly IL-6 and IL-1, may act as local amplification signals in pathological processes associated with chronic eye inflammation.

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.