PROGRESSION OF PERIPAPILLARY AND MACULAR CHORIORETINAL ATROPHY IN MULTIFOCAL CHOROIDITIS IS ASSOCIATED WITH PERIATROPHIC INFLAMMATORY PLUMES.

PURPOSE: To investigate peripapillary atrophy and macular chorioretinal scars in eyes affected by multifocal choroiditis and panuveitis. METHODS: This retrospective cohort study reviewed the medical records, fundus photographs, and spectral-domain optical coherence tomographic scans of 31 eyes from 19 patients. RESULTS: Patients had a mean age of 45 years (range 24-69 years). The average follow-up duration was 7 years (range, 2.5-14.5 years), with 14 patients undergoing immunosuppressive treatment. In the group of 31 eyes, 20 showed peripapillary plumes of ill-defined hyperreflectivity at the termination border of the retinal pigment epithelium. These plumes, extending from bare Bruch membrane to the outer nuclear layer, sometimes undermined the adjacent retinal pigment epithelium. They responded to corticosteroid treatment and resembled the material under the retinal pigment epithelium in acute lesions. Among 20 eyes with these peripapillary inflammatory lesions, 16 (80%) experienced increased atrophy, in contrast to none in the eyes without these lesions ( P < 0.001). Similar patterns were observed at the edges of macular chorioretinal atrophy. This observation occurred in patients using immunosuppressive medication who were otherwise thought to be under adequate control. CONCLUSION: In patients with multifocal choroiditis and panuveitis, previously unrecognized plumes of smoldering inflammatory activity at the borders of chorioretinal atrophy appears to be linked to atrophy expansion. The recognition of this phenomenon may require a reappraisal of treatment of multifocal choroidopathies to help mitigate the expansion of atrophy in these eyes.

X-Linked Retinoschisis: Novel Clinical Observations and Genetic Spectrum in 340 Patients.

PURPOSE: To describe the natural course, phenotype, and genotype of patients with X-linked retinoschisis (XLRS). DESIGN: Retrospective cohort study. PARTICIPANTS: Three hundred forty patients with XLRS from 178 presumably unrelated families. METHODS: This multicenter, retrospective cohort study reviewed medical records of patients with XLRS for medical history, symptoms, visual acuity (VA), ophthalmoscopy, full-field electroretinography, and retinal imaging (fundus photography, spectral-domain [SD] OCT, fundus autofluorescence). MAIN OUTCOME MEASURES: Age at onset, age at diagnosis, severity of visual impairment, annual visual decline, and electroretinography and imaging findings. RESULTS: Three hundred forty patients were included with a mean follow-up time of 13.2 years (range, 0.1-50.1 years). The median ages to reach mild visual impairment and low vision were 12 and 25 years, respectively. Severe visual impairment and blindness were observed predominantly in patients older than 40 years, with a predicted prevalence of 35% and 25%, respectively, at 60 years of age. The VA increased slightly during the first 2 decades of life and subsequently transitioned into an average annual decline of 0.44% (P < 0.001). No significant difference was found in decline of VA between variants that were predicted to be severe and mild (P = 0.239). The integrity of the ellipsoid zone (EZ) as well as the photoreceptor outer segment (PROS) length in the fovea on SD OCT correlated significantly with VA (Spearman's ρ = -0.759 [P < 0.001] and -0.592 [P = 0.012], respectively). Fifty-three different RS1 variants were found. The most common variants were the founder variant c.214G→A (p.(Glu72Lys)) (101 patients [38.7%]) and a deletion of exon 3 (38 patients [14.6%]). CONCLUSIONS: Large variabilities in phenotype and natural course of XLRS were seen in this study. In most patients, XLRS showed a slow deterioration starting in the second decade of life, suggesting an optimal window of opportunity for treatment within the first 3 decades of life. The integrity of EZ as well as the PROS length on SD OCT may be important in choosing optimal candidates for treatment and as potential structural end points in future therapeutic studies. No clear genotype-phenotype correlation was found.

Idiopathic Multifocal Choroiditis and Punctate Inner Choroidopathy - Evaluation of Risk Factors for Increased Relapse Rate: A 2-Year Prospective Observational Cohort Study.

INTRODUCTION: The aim of this study was to describe the course of disease in patients with idiopathic multifocal choroiditis (MFC) and punctate inner choroidopathy (PIC) and to identify risk factors associated with an increased relapse rate of disease activity. METHODS: In this prospective observational cohort study, demographical and clinical data were collected concerning the relapses rate of disease activity, the conclusions of the multimodal imaging results, treatment, complications, and self-reported quality of life. Disease activity was defined as new inflammatory lesions or active inflammation in preexisting chorioretinal lesions either with or without active choroidal neovascularization (CNV). Linear regression analysis was performed to identify risk factors associated with an increased relapse rate. RESULTS: In total, 122 eyes of 82 patients (93% females) were included with a median age (IQR) of 45 (37-54) years. A history of secondary CNV was present in 66% of the eyes. During follow-up, the best-corrected visual acuity remained stable despite a median relapse rate (IQR) of 1.0 (0.25-3). Cycles of oral corticosteroids were given in 59% of the patients, 72% were treated at baseline or started treatment during follow-up with a disease-modifying antirheumatic drug (DMARD), and 35% with a biological agent in addition to the DMARD. Both a history of secondary CNV (B = 1.2, 95% CI: 0.7-1.7, p = 3.6 × 10-5) and high myopia (<-6 diopters) (B = 0.6, 95% CI: 0.1-1.1, p = 0.02) independently increased the relapse rate of disease activity. DISCUSSION/CONCLUSION: A history of secondary CNV and high myopia were associated with an increased relapse rate of disease activity. Moreover, the results of this study emphasize the challenging character of treating patients with MFC/PIC.

EVALUATION OF TUMOR NECROSIS FACTOR INHIBITOR THERAPY IN SUSAC SYNDROME.

PURPOSE: To evaluate the effect of tumor necrosis factor (TNF) inhibitor therapy on ocular relapses in patients with Susac syndrome. METHODS: Multicenter retrospective cohort study of patients diagnosed with Susac syndrome according to classical clinical criteria. We evaluated the disease activity before and after introduction of anti-TNF therapy and its value as a steroid-sparing agent. RESULTS: Five patients were included. All were initially treated with a combination of corticosteroids and classical immunosuppressive drugs. Infliximab was started in three patients, and adalimumab was started in two patients. Patients had on average 5 ocular relapses during a mean follow-up time of 2.59 years before introducing a TNF inhibitor, corresponding with on average 1.93 relapses per year. After the introduction of an anti-TNF agent, this number was reduced by factor 5.51 to an average of 0.35 relapses per year for a mean follow-up of 2.86 years (P = 0.10). Before anti-TNF introduction ocular relapses occurred at a mean daily dose of 34 mg of prednisone, whereas with anti-TNF treatment, corticosteroid administration could be completely stopped in four patients with one patient still needing 5 mg daily (P = 0.10). Infliximab and adalimumab generally were well tolerated, and no serious adverse events were reported. CONCLUSION: Although not statistically significant, our results suggest that anti-TNF therapy can be a valuable option for the treatment of ocular Susac syndrome and may especially be considered in those patients unresponsive to more conventional immunosuppressive treatment.

VISUAL ACUITY IN PSEUDOXANTHOMA ELASTICUM.

PURPOSE: To assess the age-specific proportion of visual impairment in patients with pseudoxanthoma elasticum (PXE) and to compare this with foveal abnormality and similar data of late age-related macular degeneration patients. METHODS: Cross-sectional data of 195 patients with PXE were reviewed, including best-corrected visual acuity and imaging. The World Health Organisation criteria were used to categorize bilateral visual impairment. These results were compared with similar data of 131 patients with late age-related macular degeneration from the Rotterdam study. RESULTS: Overall, 50 PXE patients (26.0%) were visually impaired, including 21 (11%) with legal blindness. Visual functioning declined with increasing age. In patients older than 50 years, 37% was visually impaired and 15% legally blind. Foveal choroidal neovascularization was found in 84% of eyes with a best-corrected visual acuity lower than 20/70 (0.30) and macular atrophy in the fovea in 16%. In late age-related macular degeneration patients, 40% were visually impaired and 13% legally blind. Visual impairment started approximately 20 years later as compared with PXE patients. CONCLUSION: Visual impairment and blindness are frequent in PXE, particularly in patients older than 50 years. Although choroidal neovascularization is associated with the majority of vision loss, macular atrophy is also common. The proportion of visual impairment in PXE is comparable with late age-related macular degeneration but manifests earlier in life.

Pseudoxanthoma elasticum - Genetics, pathophysiology, and clinical presentation.

Pseudoxanthoma elasticum (PXE) is an autosomal-recessively inherited multisystem disease. Mutations in the ABCC6-gene are causative, coding for a transmembrane transporter mainly expressed in hepatocytes, which promotes the efflux of adenosine triphosphate (ATP). This results in low levels of plasma inorganic pyrophosphate (PPi), a critical anti-mineralization factor. The clinical phenotype of PXE is characterized by the effects of elastic fiber calcification in the skin, the cardiovascular system, and the eyes. In the eyes, calcification of Bruch's membrane results in clinically visible lesions, including peau d'orange, angioid streaks, and comet tail lesions. Frequently, patients must be treated for secondary macular neovascularization. No effective therapy is available for treating the cause of PXE, but several promising approaches are emerging. Finding appropriate outcome measures remains a significant challenge for clinical trials in this slowly progressive disease. This review article provides an in-depth summary of the current understanding of PXE and its multi-systemic manifestations. The article offers a detailed overview of the ocular manifestations, including their morphological and functional consequences, as well as potential complications. Lastly, previous and future clinical trials of causative treatments for PXE are discussed.

Bruch's Membrane Calcification in Pseudoxanthoma Elasticum: Comparing Histopathology and Clinical Imaging.

Purpose: To investigate the histology of Bruch's membrane (BM) calcification in pseudoxanthoma elasticum (PXE) and correlate this to clinical retinal imaging. Design: Experimental study with clinicopathological correlation. Subjects and Controls: Six postmortem eyes from 4 PXE patients and 1 comparison eye from an anonymous donor without PXE. One of the eyes had a multimodal clinical image set for comparison. Methods: Calcification was labeled with OsteSense 680RD, a fluorescent dye specific for hydroxyapatite, and visualized with confocal microscopy. Scanning electron microscopy coupled with energy-dispersive x-ray spectroscopy (SEM-EDX) and time-of-flight secondary ion mass spectrometry (TOF-SIMs) were used to analyze the elemental and ionic composition of different anatomical locations. Findings on cadaver tissues were compared with clinical imaging of 1 PXE patient. Main Outcome Measures: The characteristics and topographical distribution of hydroxyapatite in BM in eyes with PXE were compared with the clinical manifestations of the disease. Results: Analyses of whole-mount and sectioned PXE eyes revealed an extensive, confluent OsteoSense labeling in the central and midperipheral BM, transitioning to a speckled labeling in the midperiphery. These areas corresponded to hyperreflective and isoreflective zones on clinical imaging. Scanning electron microscopy coupled with energy-dispersive x-ray spectroscopy and TOF-SIMs analyses identified these calcifications as hydroxyapatite in BM of PXE eyes. The confluent fluorescent appearance originates from heavily calcified fibrous structures of both the collagen and the elastic layers of BM. Calcification was also detected in an aged comparison eye, but this was markedly different from PXE eyes and presented as small snowflake-like deposits in the posterior pole. Conclusions: Pseudoxanthoma elasticum eyes show extensive hydroxyapatite deposition in the inner and outer collagenous and elastic BM layers in the macula with a gradual change toward the midperiphery, which seems to correlate with the clinical phenotype. The snowflake-like calcification in BM of an aged comparison eye differed markedly from the extensive calcification in PXE. Financial Disclosures: Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

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.

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.

Exploring Imaging Characteristics Associated With Disease Activity in Idiopathic Multifocal Choroiditis: A Multimodal Imaging Approach.

PURPOSE: To identify characteristics on multimodal imaging (MMI) in idiopathic multifocal choroiditis (MFC) that can identify inflammatory activity and distinguish choroidal neovascularization (CNV) activity from inflammatory activity. DESIGN: Prospective cohort study. METHODS: MMI consisted of spectral-domain optical coherence tomography (angiography) (SD-OCT(A)), fundus autofluorescence, fundus photography, infrared imaging, fluorescein angiography (FA), and indocyanine green angiography (ICGA). MMI characteristics obtained during active and inactive disease were compared within the same lesion. Secondly, MMI characteristics were compared between active inflammatory lesions with and without CNV activity. RESULTS: Fifty patients (110 lesions) were included. In 96 lesions without CNV activity, the mean focal choroidal thickness was increased during the active disease (205 µm) compared to the inactive disease (180 µm) (P ≤ .001). Lesions with inflammatory activity typically demonstrated moderately reflective material located in the sub-retinal pigment epithelium (RPE) and/or in the outer retina with disruption of the ellipsoid zone. During the inactive stage of the disease, the material disappeared or became hyperreflective and indistinguishable from the RPE. During the active stage of the disease, the area of hypoperfusion in the choriocapillaris significantly increased as visualized on both ICGA and SD-OCTA. CNV activity in 14 lesions was associated with subretinal material with a mixed reflectivity and hypotransmission of light to the choroid on SD-OCT and leakage on FA. SD-OCTA identified vascular structures in all active CNV lesions and in 24% of lesions without CNV activity (showing old, quiescent CNV membranes). CONCLUSION: Inflammatory activity in idiopathic MFC was associated with several MMI characteristics, including focally increased choroidal thickness. These characteristics can guide clinicians in the challenging process of the evaluation of disease activity in idiopathic MFC patients.

Association of Risk Variants in the CFH Gene With Elevated Levels of Coagulation and Complement Factors in Idiopathic Multifocal Choroiditis.

Importance: Idiopathic multifocal choroiditis (MFC) is poorly understood, thereby hindering optimal treatment and monitoring of patients. Objective: To identify the genes and pathways associated with idiopathic MFC. Design, Setting, and Participants: This was a case-control genome-wide association study (GWAS) and protein study of blood plasma samples conducted from March 2006 to February 2022. This was a multicenter study involving 6 Dutch universities. Participants were grouped into 2 cohorts: cohort 1 consisted of Dutch patients with idiopathic MFC and controls, and cohort 2 consisted of patients with MFC and controls. Plasma samples from patients with idiopathic MFC who had not received treatment were subjected to targeted proteomics. Idiopathic MFC was diagnosed according to the Standardization of Uveitis Nomenclature (SUN) Working Group guidelines for punctate inner choroidopathy and multifocal choroiditis with panuveitis. Data were analyzed from July 2021 to October 2022. Main outcomes and measures: Genetic variants associated with idiopathic MFC and risk variants associated with plasma protein concentrations in patients. Results: This study included a total of 4437 participants in cohort 1 (170 [3.8%] Dutch patients with idiopathic MFC and 4267 [96.2%] controls; mean [SD] age, 55 [18] years; 2443 female [55%]) and 1344 participants in cohort 2 (52 [3.9%] patients with MFC and 1292 [96.1%] controls; 737 male [55%]). The primary GWAS association mapped to the CFH gene with genome-wide significance (lead variant the A allele of rs7535263; odds ratio [OR], 0.52; 95% CI, 0.41-0.64; P = 9.3 × 10-9). There was no genome-wide significant association with classical human leukocyte antigen (HLA) alleles (lead classical allele, HLA-A*31:01; P = .002). The association with rs7535263 showed consistent direction of effect in an independent cohort of 52 cases and 1292 control samples (combined meta-analysis OR, 0.58; 95% CI, 0.38-0.77; P = 3.0 × 10-8). In proteomic analysis of 87 patients, the risk allele G of rs7535263 in the CFH gene was strongly associated with increased plasma concentrations of factor H-related (FHR) proteins (eg, FHR-2, likelihood ratio test, adjusted P = 1.1 × 10-3) and proteins involved in platelet activation and the complement cascade. Conclusions and relevance: Results suggest that CFH gene variants increase systemic concentrations of key factors of the complement and coagulation cascades, thereby conferring susceptibility to idiopathic MFC. These findings suggest that the complement and coagulation pathways may be key targets for the treatment of idiopathic MFC.

IS VAGINAL DELIVERY HARMFUL TO PATIENTS WITH PSEUDOXANTHOMA ELASTICUM?

BACKGROUND/PURPOSE: To investigate the effect of a vaginal delivery (VD) on retinal pathology in patients with pseudoxanthoma elasticum. METHODS: Retrospective case series. All 14 consecutive women with pseudoxanthoma elasticum who visited the ophthalmology department during pregnancy and after delivery between 2010 and 2018 were included. Prepartum and postpartum imaging consisted of color imaging, near-infrared imaging, and optical coherence tomography and was assessed on occurrence of (sub)retinal hemorrhages and change in angioid streaks. RESULTS: Fourteen patients (15 deliveries) were included, of whom 11 patients (79%) had a VD and three patients (21%) a secondary caesarian section. Data of three patients with VD (four deliveries) could not be assessed for (sub)retinal hemorrhage within 10 weeks postpartum. The median age at delivery was 31 years (IQR 29-37). One patient with VD (9%) had a choroidal neovascularization and was treated with anti-VEGF injections before assisted delivery. All patients had angioid streaks in the central 5,500 µ m of the posterior pole of both eyes. After delivery, no patient in the VD or caesarian section group presented with progression of angioid streaks or (sub)retinal hemorrhage. CONCLUSION: Pushing during the expulsion phase of VD seems safe in pseudoxanthoma elasticum patients without active choroidal neovascularization, and the presence of angioid streaks alone should not be an indication for elective caesarian section.

Idiopathic multifocal choroiditis and punctate inner choroidopathy: an evaluation in pregnancy.

PURPOSE: To evaluate the clinical course of idiopathic multifocal choroiditis (MFC) and punctate inner choroidopathy (PIC) and the efficacy and safety of treatment options during pregnancy. METHODS: Patients with MFC or PIC and a pregnancy in 2011-2019 from two academic centres were enrolled. For the most recent pregnancy, data on best-corrected visual acuity (BCVA) before and after pregnancy, relapse rate in pregnancy and postpartum period and obstetric, maternal and neonatal outcomes were collected. Treatment regimens consisted of a wait-and-see regime and an immunosuppressive treatment regime with systemic corticosteroids and/or azathioprine, both combined with intravitreal antivascular endothelial growth factor injections when indicated. RESULTS: Sixteen women (26 affected eyes) were included. Median Snellen BCVA was 20/19 before pregnancy and 20/18 after delivery. In seven pregnancies a wait-and-see regime and in nine pregnancies an immunosuppressive treatment regime was carried out. Fourteen intravitreal anti-VEGF injections were given in six pregnancies. The relapse rate during pregnancy was 44% and in the postpartum period 31%. Maternal/obstetrical and fetal complications occurred in 31% and 13% of the pregnancies, respectively. Fifteen healthy children were born and one pregnancy ended in a stillbirth in a patient with a complicated obstetrical history. One patient treated with azathioprine developed intrahepatic cholestasis of pregnancy (ICP). CONCLUSIONS: Among women with MFC and PIC BCVA remained stable during pregnancy despite a relapse rate of 44% in pregnancy. No major maternal, obstetric and fetal complications occurred in pregnant patients treated with systemic corticosteroids, azathioprine or intravitreal anti-VEGF injections, though one patient developed ICP while treated with azathioprine.

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 end points and optimal patient selection for future therapeutic trials. DESIGN: International, multicenter, retrospective cohort study. SUBJECTS: Eighty-two patients with GUCY2D-associated LCA or CORD from 54 families. METHODS: Medical records were reviewed for medical history, best-corrected visual acuity (BCVA), ophthalmoscopy, visual fields, full-field electroretinography, and retinal imaging (fundus photography, spectral-domain OCT [SD-OCT], fundus autofluorescence). MAIN OUTCOMES MEASURES: Age of onset, evolution of BCVA, 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 times were 5.2 years (interquartile range [IQR] 2.6-8.8 years) for LCA and 7.2 years (IQR 2.2-14.2 years) for CORD. Generally, LCA presented in the first year of life. The BCVA in patients with LCA ranged from no light perception to 1.00 logarithm of the minimum angle of resolution (logMAR) and remained relatively stable during follow-up. Imaging for LCA was limited but showed little to no structural degeneration. In patients with CORD, progressive vision loss started around the second decade of life. The BCVA declined annually by 0.022 logMAR (P < 0.001) with no difference between patients with the c.2513G>A and the c.2512C>T GUCY2D variants (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 that of the external limiting membrane (ELM) on SD-OCT correlated significantly with BCVA (Spearman ρ = 0.744, P = 0.001, and ρ = 0.712, P < 0.001, respectively) in those with CORD. CONCLUSIONS: Leber congenital amaurosis associated with GUCY2D caused severe congenital visual impairment with relatively intact macular anatomy on funduscopy and available imaging, suggesting 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 end points for therapeutic studies of GUCY2D-associated CORD.

Central Multifocal Choroiditis: Platelet Granularity as a Potential Marker for Treatment With Steroid-Sparing Immunomodulatory Therapy.

Purpose: We aimed to evaluate the blood cell composition in patients with central multifocal choroiditis (cMFC), a rare form of posterior uveitis predominantly affecting young myopic women. Methods: In this retrospective observational case-control study, a 104-parameter automated hematocytometry was conducted by the Cell-Dyn Sapphire hematology analyzer for 122 cases and 364 age- and sex-matched controls. Cox proportional regression analysis was used to assess the relation between the blood cell composition and the time between disease onset (first visit) and the start of systemic corticosteroid-sparing immunomodulatory therapy (IMT). Results: At a false discovery rate of 5% (Padj), we identified a decrease of blood monocytes in cases with cMFC, which could be attributed to disease activity. Cox proportional hazard analysis including age and sex revealed that increased platelet granularity (measured by mean intermediate angle scatter) was an independent risk factor for treatment with IMT (hazard ratio = 2.3 [95% confidence interval = 1.28 - 4.14], Padj = 0.049). The time between the first presentation and the start of IMT was 0.3 years in the group with an increased platelet granularity and 3.4 years in the group without increased platelet granularity. Conclusions: Patients with cMFC demonstrated a decrease in blood monocytes. Moreover, platelet granularity could potentially be used as a marker for treatment with IMT.

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 (ß: 0.39, 95%CI:-0.62;-0.17) and total (ß: 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.

The Extent of Angioid Streaks Correlates With Macular Degeneration in Pseudoxanthoma Elasticum.

PURPOSE: To investigate whether the extent of Bruch's membrane calcification is associated with choroidal neovascularization (CNV) and macular atrophy in patients with pseudoxanthoma elasticum (PXE) by using the extent of angioid streaks as a surrogate marker for the degree of Bruch's membrane calcification. DESIGN: Retrospective cross-sectional study. METHODS: We investigated 301 patients with PXE (median age, 52 years; range, 9-79 years) in a tertiary referral center. For both eyes, we graded the extent of angioid streaks, that is, their distance from the optic disc, into 5 groups. Imaging was systematically assessed for signs of CNV and macular atrophy. Associations between the extent of angioid streaks and CNV or macular atrophy were investigated using regression analysis. RESULTS: CNV was present in 148 patients (49%) and retinal atrophy in 71 patients (24%). The extent of angioid streaks was associated with older age (P for trend = 1.92 × 10-15) and a higher prevalence of CNV and/or macular atrophy (P for trend = 4.22 × 10-10 and P for trend = 5.17 × 10-6, respectively). In addition, the extent of angioid streaks was associated with the presence of CNV when adjusted for age and sex (odds ratio, 1.9; 95% confidence interval, 1.3-2.9) and with more severe macular atrophy (proportional odds ratio, 2.3; 95% confidence interval, 1.5-3.6). CONCLUSIONS: In patients with PXE, longer angioid streaks are associated with an increased risk of CNV and macular atrophy, even after adjustment for age. These findings are relevant when counseling PXE patients on their visual prognosis.

The efficacy of adalimumab in treating patients with central multifocal choroiditis.

PURPOSE: To evaluate the efficacy of adalimumab in patients with central multifocal choroiditis (cMFC) refractory to conventional corticosteroid-sparing immunomodulatory agents (IMT). METHODS: Medical records were reviewed from all patients with cMFC and treated with adalimumab with follow-up of at least 12 months. The study focused on the 12 months prior to and after the start of adalimumab. The imaging results were independently evaluated by two ophthalmologists. The main outcomes were the number of patients without a relapse of disease activity in 12 months after the start of adalimumab and the ability to stop the systemic corticosteroids to evaluate the corticosteroid-sparing effect. RESULTS: Twelve patients (18 eyes) were included. In 8/12 (67%) patients no relapse of disease activity was observed in the 12 months after the start of adalimumab. In 9/12 patients the systemic corticosteroid treatment could be stopped and in an additional 2 patients tapered to ≤7,5mg daily. In the 12 months before the start of adalimumab, the patients experienced a median of 3 (range 2-4) relapses of disease activity. Nine patients experienced relapses while treated with a combination of systemic corticosteroids (mean dose 13,6 mg; range 5-25 mg) and IMT. Moreover, 3 patients treated with IMT, experienced relapses after tapering and stopping the systemic corticosteroids. In all eyes (n = 5) with CNV before the start of adalimumab, the intravitreal anti-VEGF injections could be stopped after the start of adalimumab. CONCLUSIONS: AND IMPORTANCE: Adalimumab may be effective in patients with cMFC refractory to IMT and may be considered as a treatment option in patients with cMFC.