Molecular and Serological Intraocular Fluid Analysis of Coxiella burnetii-seropositive Patients with Concurrent Idiopathic Uveitis

Purpose: Previous studies have suggested a link between Q fever and uveitis. We determined whether Coxiella burnetii causes intraocular infection in C. burnetii-seropositive patients with idiopathic uveitis. Methods: From a retrospective observational case series, paired aqueous humor and serum samples from 10 C. burnetii-seropositive patients with idiopathic uveitis were examined for intraocular antibody production by using the Goldmann-Witmer coefficient and by polymerase chain reaction (PCR). Results: Although intraocular IgG against C. burnetii was detected, no intraocular antibody production was observed (low Goldmann Wittmer coefficients). All PCR results were negative. Conclusions: Uveitis due to an intraocular infection with C. burnetii is unlikely

Is arterial stiffness in the carotid artery associated with choroidal thinning in patients with pseudoxanthoma elasticum or controls?

Purpose: Patients with pseudoxanthoma elasticum (PXE) develop calcification of Bruch's membrane (BM) and choroidal thinning, as well as calcification of intracranial arteries, leading to arterial stiffness. We investigated whether arterial stiffness is associated with choroidal thinning in PXE patients, besides the presumed effect of BM calcification. Methods: Cross-sectional study with 75 PXE patients and 40 controls. Macular choroidal thickness was measured using optical coherence tomography scans. Functional magnetic resonance imaging was used to calculate the pulsatility index (PI) of the carotid siphon as a measure of arterial stiffness. Associations between PI and choroidal thickness were investigated using linear mixed effects models adjusted for age and ocular axial length. Furthermore, we investigated choroidal thickness in relation to the presence of retinal pigment epithelium (RPE) atrophy, its topographical distribution and age. Results: Median age was 58 years (IQR 53–66) in PXE patients and 62 years (IQR 56–67) in controls (p = 0.08). Pseudoxanthoma elasticum (PXE) patients had a thinner choroid than controls (138 μm versus 248 μm, p < 0.01). No association was observed between PI and choroidal thickness in PXE patients (β = −1.6, 95% CI −59.4 to 54.5) nor in controls (β =−47.6, 95% CI −129.7 to 31.9). In PXE patients, RPE atrophy was associated with a thinner choroid (p < 0.01). Also, the nasal choroid was thinner than the temporal choroid, and choroidal thickness already decreased with age in PXE eyes without RPE atrophy. Conclusion: There was no independent association between measures of arterial stiffness and choroidal thinning in PXE patients and controls. Probably, changes in BM lead to choroidal thinning in PXE

Genotype-phenotype correlation in pseudoxanthoma elasticum

Background and aims: Pseudoxanthoma elasticum (PXE) is caused by variants in the ABCC6 gene. It results in calcification in the skin, peripheral arteries and the eyes, but has considerable phenotypic variability. We investigated the association between the ABCC6 genotype and calcification and clinical phenotypes in these different organs. Methods: ABCC6 sequencing was performed in 289 PXE patients. Genotypes were grouped as two truncating, mixed, or two non-truncating variants. Arterial calcification mass was quantified on whole body, low dose CT scans; and peripheral arterial disease was measured with the ankle brachial index after treadmill test. The presence of pseudoxanthoma in the skin was systematically scored. Ophthalmological phenotypes were the length of angioid streaks as a measure of Bruchs membrane calcification, the presence of choroidal neovascularizations, severity of macular atrophy and visual acuity. Regression models were built to test the age and sex adjusted genotype-phenotype association. Results: 158 patients (median age 51 years) had two truncating variants, 96 (median age 54 years) a mixed genotype, 18 (median age 47 years) had two non-truncating variants. The mixed genotype was associated with lower peripheral (13: 0.39, 95%CI:-0.62;-0.17) and total (13: 0.28, 95%CI:-0.47;-0.10) arterial calcification mass scores, and lower prevalence of choroidal neovascularizations (OR: 0.41 95%CI:0.20; 0.83) compared to two truncating variants. No association with pseudoxanthomas was found. Conclusions: PXE patients with a mixed genotype have less severe arterial and ophthalmological phenotypes than patients with two truncating variants in the ABCC6 gene. Research into environmental and genetic modifiers might provide further insights into the unexplained phenotypic variability

Perspectives and Update on the Global Shortage of Verteporfin (Visudyne®)

An ongoing global shortage of verteporfin (Visudyne®) limits the treatment possibilities for several chorioretinal diseases, including central serous chorioretinopathy, choroidal hemangioma, and polypoidal choroidal vasculopathy. Verteporfin is required to perform photodynamic therapy in these ocular diseases. Therefore, the current situation has a substantial impact on eye care worldwide. The worldwide supply of verteporfin appears to be manufactured by a single factory, which is situated in the United States. The distribution of verteporfin is done by different companies for different regions of the world. Official communication on the shortage by the responsible companies has been scarce and over the past years several promises with regards to resolution of the shortage have not been fulfilled. The delivery of new batches of verteporfin is at irregular intervals, unpredictable, and may not be fairly balanced between different regions or countries in the world. To ensure a fair distribution of available verteporfin within a country, several measures can be taken. In the Netherlands, a national committee, consisting of ophthalmologists, is in place to arrange this. On the European level, the European Union and European Medicine Agency have plans to monitor medicine shortages more closely and to intervene if necessary. With a more intensified monitoring and regulation of medicine supplies, future impending shortages may be prevented. Remarkably, the amount of medicine shortages is increasing, having a significant and sometimes irreversible impact on patient care. Thus, efforts should be undertaken to minimize the consequences and, whenever possible, to prevent future medicine shortages

A cis-regulatory element regulates ERAP2 expression through autoimmune disease risk SNPs

Single-nucleotide polymorphisms (SNPs) near the ERAP2 gene are associated with various autoimmune conditions, as well as protection against lethal infections. Due to high linkage disequilibrium, numerous trait-associated SNPs are correlated with ERAP2 expression; however, their functional mechanisms remain unidentified. We show by reciprocal allelic replacement that ERAP2 expression is directly controlled by the splice region variant rs2248374. However, disease-associated variants in the downstream LNPEP gene promoter are independently associated with ERAP2 expression. Allele-specific conformation capture assays revealed long-range chromatin contacts between the gene promoters of LNPEP and ERAP2 and showed that interactions were stronger in patients carrying the alleles that increase susceptibility to autoimmune diseases. Replacing the SNPs in the LNPEP promoter by reference sequences lowered ERAP2 expression. These findings show that multiple SNPs act in concert to regulate ERAP2 expression and that disease-associated variants can convert a gene promoter region into a potent enhancer of a distal gene

A Disease-Associated MicroRNA Cluster Links Inflammatory Pathways and an Altered Composition of Leukocyte Subsets to Noninfectious Uveitis

PURPOSE. The cause of noninfectious uveitis (NIU) is poorly understood but is considered to be mediated by a complex interplay between genetic, environmental, and-relatively unexplored-epigenetic factors. MicroRNAs (miRNAs) are noncoding small RNAs that are important epigenetic regulators implicated in pathologic signaling. Therefore, we mapped the circulating miRNA-ome of NIU patients and studied miRNA perturbations within the broader context of the immune system.METHODS. We designed a strategy to robustly identify changes in the miRNA profiles of two independent cohorts totaling 54 untreated patients with active and eye-restricted disease and 26 age-matched controls. High-resolution miRNA-ome data were obtained by TaqMan OpenArray technology and subsequent RT-qPCR. Flow cytometry data, and proteomic data spanning the cellular immune system, were used to map the uveitis-miRNA signature to changes in the composition of specific leukocyte subsets in blood.RESULTS. Using stringent selection criteria, we identified and independently validated an miRNA cluster that is associated with NIU. Pathway enrichment analysis for genes targeted by this cluster revealed significant enrichment for the PI3K/Akt, MAPK, FOXO, and VEGF signaling pathways, and photoreceptor development. In addition, unsupervised multidomain analyses linked the presence of the uveitis-associated miRNA cluster to a different composition of leukocyte subsets, more specifically, CD16(+)CD11c(+)HLA-DR- cells.CONCLUSIONS. Together, this study identified a unique miRNA cluster associated with NIU that was related to changes in leukocyte subsets demonstrating systemic changes in epigenetic regulation underlying NIU

The Natural History of Leber Congenital Amaurosis and Cone-Rod Dystrophy Associated with Variants in the GUCY2D Gene

OBJECTIVE: To describe the spectrum of Leber congenital amaurosis (LCA) and cone-rod dystrophy (CORD) associated with the GUCY2D gene, and to identify potential clinical endpoints and optimal patient selection for future therapeutic trials. DESIGN: International multicenter retrospective cohort study. SUBJECTS: 82 patients with GUCY2D-associated CORD and LCA from 54 molecularly confirmed families. METHODS: Data were gathered by reviewing medical records for medical history, symptoms, best-corrected visual acuity (BCVA), ophthalmoscopy, visual fields, full-field electroretinography and retinal imaging (fundus photography, spectral-domain optical coherence tomography (SD-OCT), fundus autofluorescence). MAIN OUTCOMES MEASURES: Age of onset, annual decline of visual acuity, estimated visual impairment per age, genotype-phenotype correlations, anatomic characteristics on funduscopy, and multimodal imaging. RESULTS: Fourteen patients with autosomal recessive LCA and 68 with autosomal dominant CORD were included. The median follow-up time was 5.2 years (interquartile range (IQR), 2.6-8.8) for LCA, and 7.2 years (IQR, 2.2-14.2) for CORD. Generally, LCA presented in the first year of life. The BCVA in LCA ranged from no light perception to 1.00 logMAR, and remained relatively stable during follow-up. Imaging for LCA was limited, but showed little to no structural degeneration. In CORD, progressive vision loss started around the second decade of life. The annual decline rate of visual acuity was 0.022 logMAR (P A and the c.2512C>T GUCY2D variant (P = 0.798). At the age of 40 years the probability of being blind or severely visually impaired was 32%. The integrity of the ellipsoid zone (EZ) and external limiting membrane (ELM) on SD-OCT were correlated significantly with BCVA (Spearman's ρ = 0.744, P = 0.001 and ρ = 0.712, P < 0.001, respectively) in CORD. CONCLUSION: LCA due to variants in GUCY2D results in severe congenital visual impairment with relatively intact macular anatomy on funduscopy and available imaging, suggesting a long preservation of photoreceptors. Despite large variability, GUCY2D-associated CORD generally presented during adolescence with a progressive loss of vision and culminated in severe visual impairment during mid to late-adulthood. The integrity of the ELM and EZ may be suitable structural endpoints for therapeutic studies in GUCY2D-associated CORD

Potential Predictors of Poor Visual Outcome in Human Leukocyte Antigen-B27-Associated Uveitis

Purpose: To identify potential predictors of permanent vision loss in patients with human leukocyte antigen (HLA)-B27-associated uveitis in a tertiary referral center. Design: Retrospective case-control study. Methods: The charts of 212 patients (338 eyes) with HLA-B27-associated uveitis that visited the University Medical Center Utrecht with a follow-up of at least 6 months were retrospectively studied. Clinical features at presentation and during follow-up were compared to final visual outcome in quiescent state. Eyes with (sub-) normal vision (>20/50) were compared with visually impaired (≤20/50) and blind (≤5/50, or a visual field of 21 mm Hg, hypotony, and panuveitis to be potential predictors at presentation, and the development of secondary glaucoma or hypotony to be predictors of blindness or visual impairment during follow-up. Conclusions: The long-term visual prognosis of HLA-B27-associated uveitis is relatively good, but the true incidence of permanent vision loss is probably still underestimated. Our findings highlight the importance of proper control of intraocular pressure

Prevalence and characteristics of ocular pain in non-infectious uveitis : A quality of life study

Background/aim To survey the frequency, character, severity and impact of ocular pain on quality of life in adult patients with non-infectious uveitis (NIU). Methods This patient-requested cross-sectional survey study describes the results of three self-administered questionnaires (the National Eye Institute Visual Function Questionnaire, the 36-Item Short Form Health Survey (SF-36) and the McGill Pain Questionnaire Dutch Language Version) from 147 patients with NIUs from a university-based tertiary referral centre in Utrecht. Results The mean Visual Function Questionnaire (VFQ) Ocular Pain Score of all patients with NIU was 72 (±24), which is significantly lower than an ocular disease-free reference group (90±15, P<0.0001), indicating more ocular pain. This was true for all types of NIU, regardless of the localisation: although Ocular Pain Scores were lower in patients with anterior uveitis (AU) compared with patients with non-AU (mean 62 (±24) vs 74 (±24), P=0.04), patients with non-AU still scored substantially lower than the reference group that had no ocular history (P<0.0001). Patients with NIU also scored significantly lower on all other VFQ subscales as well as on the SF-36 subscales Role Limitations due to physical problems', 'Vitality', eneral health' and 'Bodily Pain' compared with controls. The VFQ Ocular Pain subscale correlated with other quality of life subscales (both VFQ-25 and SF-36), indicating a relationship between pain and quality of life. Conclusion This study shows that ocular pain is highly prevalent in patients with NIU, regardless of the localisation. Furthermore, ocular pain has an impact on quality of life