Long-Term Follow-Up of Patients with Scleritis After Rituximab Treatment Including B Cell Monitoring.

PURPOSE: We report the long-term effect of rituximab (RTX) in scleritis and determine the value of B-cell monitoring for the prediction of relapses. METHODS: We retrospectively studied 10 patients with scleritis, who were treated with RTX. Clinical characteristics were collected, and blood B-cell counts were measured before the start of RTX, and at various time points after treatment. RESULTS: Clinical activity of scleritis decreased after RTX treatment in all patients within a median time of 8 weeks (range 3-13), and all reached remission. The median follow-up was 101 months (range 9-138). Relapses occurred in 6 out of 10 patients. All relapses, where B-cell counts were measured (11 out of 19), were heralded by returning B cells. However, B cells also returned in patients with long-term remissions. CONCLUSIONS: RTX is a promising therapeutic option for scleritis. Recurrence of B cells after initial depletion does not always predict relapse of scleritis.

A pilot study into bosentan (Tracleer®) as an immunomodulating agent in patients with Behçet's disease.

BACKGROUND: Behçet's disease (BD) is an auto-inflammatory vasculitis characterized by aphthous oro-genital ulcers, inflammatory skin changes and uveitis. Treatment is mainly immunosuppressive. Interestingly, elevated endotheline-1 (ET-1) levels suggest a possible beneficial effect of treatment with an ET-1 receptor antagonist. OBJECTIVE: The aim of our study was to investigate the possible beneficial effect of the ET-1 inhibitor bosentan. METHODS: We performed a prospective double-blind placebo controlled pilot study into the effect and safety of bosentan in BD patients. Disease activity was measured using the Behçet Disease Current Activity Form. The primary objective of the study was to determine whether bosentan is therapeutically effective in patients with BD. Secondary endpoints were safety, tapering of medication and the effect of bosentan on possible disease activity markers such as ET-1, circulating endothelial cells (CECs), soluble interleukin-2 receptor (sIL2R) and cytokine levels. RESULTS: Ten patients were randomized to either bosentan or placebo. Overall, no effect on disease activity was observed, although one patient responded clinically and continued treatment after the study period. Despite one SAE, bosentan seems safe to use. No effect on tapering of medication, CECs, sIL2R and cytokine levels was found. In the bosentan group, ET-1 levels were elevated during the treatment period, with no correlation with disease activity. CONCLUSIONS: Although this is a small pilot study, bosentan appears to be safe in BD patients. One patient had a durable and significant clinical response. Our observations should be confirmed and extended in a larger patient cohort to be of significant impact in the treatment options for BD.

Non-arteritic anterior ischaemic optic neuropathy sequential to SARS-CoV-2 virus pneumonia: preventable by endothelial protection?

We present a case of non-arteritic anterior ischaemic optic neuropathy (NAION) with no ocular or systemic risk factors in a patient who recovered from a recent SARS-CoV-2 pneumonia. NAION is the most common acute optic neuropathy among individuals over 50 years of age. It results from a transient hypoperfusion of the optic nerve head circulation, especially in patients with low vascular compliance due to ocular or systemic risk factors. We attribute the ophthalmological condition to a SARS-CoV-2 virus-associated endotheliopathy that can be prevented with timely protection of endothelial function with vitamins D and K2.

Choriocapillaris Assessment In Patients Under Mek-Inhibitor Therapy For Cutaneous Melanoma: An Optical Coherence Tomography Angiography Study.

PURPOSE: The present study investigates by optical coherence tomography angiography (OCTA) the retinal capillary plexus and choriocapillaris flow voids and their possible correlation with MEKAR. METHODS: 34 eyes of 17 patients (61.5 years [30.4-77.4]) with stage IV cutaneous melanoma were included prospectively. All patients showed disease progression under treatment with Nivolumab/Ipilimumab and were subsequently treated with the MEK-inhibitor Trametinib 2 mg once daily. At the start and every 6 weeks during follow-up of 4 months, patients underwent a complete ophthalmologic exam, OCTA and when needed fluorescein angiography. RESULTS: Statistical analysis was performed on 17 eyes of 9 patients. Eight patients were excluded due to missing OCTA images or due to drop-out because of decease or change of treatment. Comparing vessel area density (P = .625 and 0.681, respectively), vessel skeleton density (P = .996 and 0.766, respectively) of the superficial and deep capillary plexus, flow void number and total flow void area (mm2 and %) (P = .495; 0.197 and 0.298, respectively) of choriocapillaris slab, before and after treatment, revealed no significant difference. The evolution of choriocapillaris flow void parameter did not significantly differ in patients, who developed MEKAR compared to patients who did not. CONCLUSION: In patients receiving MEK-inhibitor with and without MEKAR, no significant different characteristics of the retinal capillary plexus and choriocapillaris were found. These data suggest that the development of MEKAR, has no correlation with vascular alteration.

No Evidence of Varicella-Zoster Virus Infection in Temporal Artery Biopsies of Anterior Ischemic Optic Neuropathy Patients With and Without Giant Cell Arteritis.

BACKGROUND: To test the hypothesis that varicella-zoster virus (VZV) infection contributes to temporal arteritis pathogenesis, comprehensive in situ analysis was performed on temporal artery biopsies of 38 anterior ischemic optic neuropathy (AION) patients, including 14 (37%) with giant cell arteritis. METHODS: Biopsies were completely sectioned, and, on average, 146 serial sections per patient were stained for VZV glycoprotein E. RESULTS: Four of 38 AION patients showed VZV glycoprotein E staining, but VZV infection was not confirmed by staining for VZV IE63 protein and VZV-specific polymerase chain reaction on adjacent sections. CONCLUSIONS: This study refutes the premise that VZV is casually related to AION with and without giant cell arteritis.

ADALIMUMAB THERAPY FOR REFRACTORY BIRDSHOT CHORIORETINOPATHY.

PURPOSE: To report the outcome of using adalimumab to treat birdshot chorioretinopathy. METHODS: Retrospective case series of 19 patients (38 eyes) with HLA-A29-positive birdshot chorioretinopathy who received adalimumab treatment. Patients had been refractory to previous standard systemic immunomodulatory therapy. They received biweekly subcutaneous injections of 40 mg of adalimumab. Outcome measures were change in visual acuity, fluorescein angiography, and optical coherence tomography features, the concomitant use of immunosuppressive drugs, and the occurrence of adverse effects between 1 year before, at baseline, and after 1 year of adalimumab treatment. RESULTS: Mean Snellen visual acuity at 1-year follow-up was 20/28, an improvement from 20/43 at the start of the treatment (P = 0.011) and equal to the visual acuity 1 year before the treatment (20/29). Only 2 of the 9 patients who had complete fluorescein angiography and optical coherence tomography results after the 1 year of treatment were completely free of inflammation signs at the end of the follow-up. Half (53%) of 17 patients were receiving adalimumab monotherapy after 1 year of treatment, an increase from 21% at the start of treatment (P = 0.047). Three of the 19 patients reported possible side effects; 2 discontinued treatment within 1 year. CONCLUSION: The results suggest that adalimumab is effective at improving visual acuity and at tapering concomitant immunomodulatory therapy, in patients with refractory birdshot chorioretinopathy. However, complete remission is rarely achieved.

Association of Axial Length With Risk of Uncorrectable Visual Impairment for Europeans With Myopia.

IMPORTANCE: Myopia (ie, nearsightedness) is becoming the most common eye disorder to cause blindness in younger persons in many parts of the world. Visual impairment due to myopia is associated with structural changes of the retina and the globe because of elongation of the eye axis. How axial length-a sum of the anterior chamber depth, lens thickness, and vitreous chamber depth-and myopia relate to the development of visual impairment over time is unknown. OBJECTIVES: To evaluate the association between axial length, spherical equivalent, and the risk of visual impairment and to make projections of visual impairment for regions with high prevalence rates. DESIGN, SETTING, AND PARTICIPANTS: This cross-sectional study uses population-based data from the Rotterdam Study I (1990 to 1993), II (2000 to 2002), and III (2006 to 2008) and the Erasmus Rucphen Family Study (2002 to 2005) as well as case-control data from the Myopia Study (2010 to 2012) from the Netherlands. In total, 15 404 individuals with data on spherical equivalent and 9074 individuals with data on axial length were included in the study; right eyes were used for analyses. Data were analyzed from September 2014 to May 2016. MAIN OUTCOMES AND MEASURES: Visual impairment and blindness (defined according to the World Health Organization criteria as a visual acuity less than 0.3) and predicted rates of visual impairment specifically for persons with myopia. RESULTS: Of the 15 693 individuals included in this study, the mean (SD) age was 61.3 (11.4) years, and 8961 (57.1%) were female. Axial length ranged from 15.3 to 37.8 mm; 819 individuals had an axial length of 26 mm or greater. Spherical equivalent ranged from -25 to +14 diopters; 796 persons had high myopia (ie, a spherical equivalent of -6 diopters or less). The prevalence of visual impairment varied from 1.0% to 4.1% in the population-based studies, was 5.4% in the Myopia Study, and was 0.3% in controls. The prevalence of visual impairment rose with increasing axial length and spherical equivalent, with a cumulative incidence (SE) of visual impairment of 3.8% (1.3) for participants aged 75 years with an axial length of 24 to less than 26 mm and greater than 90% (8.1) with an axial length of 30 mm or greater. The cumulative risk (SE) of visual impairment was 5.7% (1.3) for participants aged 60 years and 39% (4.9) for those aged 75 years with a spherical equivalent of -6 diopters or less. Projections of these data suggest that visual impairment will increase 7- to 13-fold by 2055 in high-risk areas. CONCLUSIONS AND RELEVANCE: This study demonstrated that visual impairment is associated with axial length and spherical equivalent and may be unavoidable at the most extreme values in this population. Developing strategies to prevent the development of myopia and its complications could help to avoid an increase of visual impairment in the working-age population.

Increasing Prevalence of Myopia in Europe and the Impact of Education.

PURPOSE: To investigate whether myopia is becoming more common across Europe and explore whether increasing education levels, an important environmental risk factor for myopia, might explain any temporal trend. DESIGN: Meta-analysis of population-based, cross-sectional studies from the European Eye Epidemiology (E(3)) Consortium. PARTICIPANTS: The E(3) Consortium is a collaborative network of epidemiological studies of common eye diseases in adults across Europe. Refractive data were available for 61 946 participants from 15 population-based studies performed between 1990 and 2013; participants had a range of median ages from 44 to 78 years. METHODS: Noncycloplegic refraction, year of birth, and highest educational level achieved were obtained for all participants. Myopia was defined as a mean spherical equivalent ≤-0.75 diopters. A random-effects meta-analysis of age-specific myopia prevalence was performed, with sequential analyses stratified by year of birth and highest level of educational attainment. MAIN OUTCOME MEASURES: Variation in age-specific myopia prevalence for differing years of birth and educational level. RESULTS: There was a significant cohort effect for increasing myopia prevalence across more recent birth decades; age-standardized myopia prevalence increased from 17.8% (95% confidence interval [CI], 17.6-18.1) to 23.5% (95% CI, 23.2-23.7) in those born between 1910 and 1939 compared with 1940 and 1979 (P = 0.03). Education was significantly associated with myopia; for those completing primary, secondary, and higher education, the age-standardized prevalences were 25.4% (CI, 25.0-25.8), 29.1% (CI, 28.8-29.5), and 36.6% (CI, 36.1-37.2), respectively. Although more recent birth cohorts were more educated, this did not fully explain the cohort effect. Compared with the reference risk of participants born in the 1920s with only primary education, higher education or being born in the 1960s doubled the myopia prevalence ratio-2.43 (CI, 1.26-4.17) and 2.62 (CI, 1.31-5.00), respectively-whereas individuals born in the 1960s and completing higher education had approximately 4 times the reference risk: a prevalence ratio of 3.76 (CI, 2.21-6.57). CONCLUSIONS: Myopia is becoming more common in Europe; although education levels have increased and are associated with myopia, higher education seems to be an additive rather than explanatory factor. Increasing levels of myopia carry significant clinical and economic implications, with more people at risk of the sight-threatening complications associated with high myopia.

Prevalence of refractive error in Europe: the European Eye Epidemiology (E(3)) Consortium.

To estimate the prevalence of refractive error in adults across Europe. Refractive data (mean spherical equivalent) collected between 1990 and 2013 from fifteen population-based cohort and cross-sectional studies of the European Eye Epidemiology (E(3)) Consortium were combined in a random effects meta-analysis stratified by 5-year age intervals and gender. Participants were excluded if they were identified as having had cataract surgery, retinal detachment, refractive surgery or other factors that might influence refraction. Estimates of refractive error prevalence were obtained including the following classifications: myopia ≤-0.75 diopters (D), high myopia ≤-6D, hyperopia ≥1D and astigmatism ≥1D. Meta-analysis of refractive error was performed for 61,946 individuals from fifteen studies with median age ranging from 44 to 81 and minimal ethnic variation (98 % European ancestry). The age-standardised prevalences (using the 2010 European Standard Population, limited to those ≥25 and <90 years old) were: myopia 30.6 % [95 % confidence interval (CI) 30.4-30.9], high myopia 2.7 % (95 % CI 2.69-2.73), hyperopia 25.2 % (95 % CI 25.0-25.4) and astigmatism 23.9 % (95 % CI 23.7-24.1). Age-specific estimates revealed a high prevalence of myopia in younger participants [47.2 % (CI 41.8-52.5) in 25-29 years-olds]. Refractive error affects just over a half of European adults. The greatest burden of refractive error is due to myopia, with high prevalence rates in young adults. Using the 2010 European population estimates, we estimate there are 227.2 million people with myopia across Europe.

Diagnosis and treatment of uveitis; not restricted to the ophthalmologist.

Uveitis is associated with a wide range of underlying causes. Familiarity with its clinical manifestations, referral indications, and treatment strategies are required for the optimal use of current therapeutic options. Uveitis can be caused by infectious and non-infectious factors, resulting in differing prognoses and treatments. The treatment of chronic, non-infectious uveitis has profoundly changed in the last years due to the advent of biologicals, but also of intraocular therapies. In severe uveitis, treatment of the underlying cause, whether ocular or systemic, is required to prevent severe loss of vision. For these purposes, a multidisciplinary clinical approach is important, which is addressed in this review. Relevance for patients: A broad understanding of the different causes of uveitis and the implementation of disease-tailored, multidisciplinary management of uveitis is expected to improve treatment outcomes for patients with different types of uveitis.

[Diagnosis and treatment of uveitis; not restricted to the ophthalmologist]. / Diagnose en behandeling van uveїtis; niet beperkt tot de oogarts.

Visual symptoms due to uveitis involve a wide range of possible causes. Familiarity with its clinical manifestations, referral indications and treatment strategies is required for the optimal use of current therapeutic options. Uveitis can be caused by infectious and non-infectious factors, resulting in differing prognoses and treatments. The treatment of chronic, non-infectious uveitis has profoundly changed in the last years due to the advent of biological therapies. In severe uveitis, treatment of the underlying cause is required for the prevention of the loss of vision; multidisciplinary team collaboration is therefore important.

Factor Xa and thrombin stimulate proinflammatory and profibrotic mediator production by retinal pigment epithelial cells: a role in vitreoretinal disorders?

BACKGROUND: Vitreoretinal disorders, including proliferative vitreoretinopathy (PVR), proliferative diabetic retinopathy (PDR) and exudative age-related macular degeneration (AMD), are a major cause of visual impairment worldwide and can lead to blindness when untreated. Loss of blood-retinal barrier (BRB) integrity associated with vitreoretinal fibrin deposition, inflammation, fibrosis and neovascularization contribute to the pathophysiological processes in these disorders. Retinal pigment epithelial (RPE) cells are well recognized to contribute to vitreoretinal inflammation/fibrosis and are likely to encounter contact with coagulation factor upon loss of BRB integrity. METHODS: An extensive study was performed in which we examined the effect of factor Xa and thrombin on the production of a broad panel of cytokines/chemokines and growth factors by RPE cells. For this purpose we used the ARPE-19 cell line as well as primary RPE cells, a glass slide based array that allows simultaneous detection of 120 cytokines/chemokines and growth factors, ELISA and real-time-quantitative PCR. The involved signaling cascade was examined using specific inhibitors for protease activated receptor (PAR)1, PAR2 and nuclear factor kappa-B (NF-κB). RESULTS: Factor Xa and thrombin regulated the production of cytokines and growth factors (including GM-CSF, IL-6, IL-8, MCP-3, PDGF-AA, PDGF-BB, TIMP-1 and TGF-α) that fit well in the pathobiology of vitreoretinal disease. Blocking studies revealed that the effects were mediated via PAR1 induced NF-κB activation. CONCLUSIONS: Our findings suggest that factor Xa and thrombin can drive vitreoretinal inflammation and fibrosis and should be considered as treatment targets in vitreoretinal disorders such as PVR, PDR and AMD.

[Micro-incision transconjunctival vitrectomy--a safe alternative for conventional vitrectomy]. / Transconjunctivale micro-incisie-vitrectomie. Veilig alternatief voor de conventionele vitrectomie.

A vitrectomy is an operation in which the vitreous gel is removed for the treatment of various eye disorders. In the last years new methods have been introduced with the incisions becoming smaller, resulting in a shorter operation time and less trauma to the eye. The newer transconjunctival 23-gauge (G) and 25G vitrectomies are especially suitable for treating less complex vitreo-retinal defects such as epiretinal macular membranes and vitreous haemorrhage. The conventional 20G vitrectomy is, however, the treatment of choice for complex ophthalmic defects such as extensive traction membranes and removal of lens fragments after complicated cataract surgery.

Whole orbital tissue culture identifies imatinib mesylate and adalimumab as potential therapeutics for Graves' ophthalmopathy.

BACKGROUND AND AIMS: Biologicals and small inhibitory molecules are used to treat inflammatory diseases, but their efficacy varies upon clinical application. Using a whole orbital tissue culture system, we tested the potential efficacy of imatinib mesylate (a tyrosine kinase inhibitor that blocks platelet-derived growth factor (PDGF)-receptor, c-Abl and c-Kit activity) and adalimumab (an anti-TNF-α antibody) for the treatment of Graves' ophthalmopathy (GO). METHODS: Orbital fat tissue from GO patients (n=10) was cultured with or without imatinib mesylate or adalimumab. PDGF-B and tumour necrosis factor (TNF)-α mRNA expression levels were determined in the primary orbital tissue, and interleukin (IL)-6 and hyaluronan were measured in tissue-culture supernatants. RESULTS: Imatinib mesylate significantly (p=0.005) reduced IL-6 and hyaluronan production. The inhibition of hyaluronan production correlated positively and significantly (p<0.05) with the PDGF-B mRNA level in the primary tissue. Adalimumab also significantly (p=0.005) reduced IL-6 production. The amount of IL-6 inhibition correlated positively with the TNF-α mRNA level in the primary tissue, but this was not significant. CONCLUSIONS: Imatinib mesylate can be expected to reduce inflammation and tissue remodelling in GO, while adalimumab can be mainly expected to reduce inflammation. This in vitro tissue-culture model may, in future, prove valuable to test novel therapeutics for their presumed effect in GO as well as in other inflammatory diseases.

The neonatal Fc receptor is expressed by human retinal pigment epithelial cells and is downregulated by tumour necrosis factor-alpha.

BACKGROUND/AIMS: The neonatal Fc receptor (FcRn) protects immunoglobulin G (IgG) from catabolism, controls its transport between cell layers and extends its serum half-life. In the human, vitreous IgG can be found, but how vitreous IgG is processed or transported is currently unknown. The FcRn is a candidate molecule to regulate these processes. The authors examined FcRn expression and regulation in human retinal pigment epithelium (RPE) cells. METHODS: In three primary RPE cell cultures (from three donor eyes) and in the human RPE cell line ARPE-19, FcRn and beta-2-microglobulin (ß2M) mRNA levels were determined by real-time quantitative PCR. FcRn protein expression was analysed by western blot studies. Stimulation experiments were performed with recombinant human tumour necrosis factor (TNF)-α and interferon (IFN)-γ. HT-29, THP-1 and HeLa cell lines were used as FcRn positive and negative non-ocular controls, respectively. RESULTS: Expression of FcRn mRNA and protein was demonstrated in all three RPE cultures. After stimulation with TNF-α, FcRn expression is downregulated in RPE cells and upregulated in HT-29 and THP-1 cells. IFN-γ has no effect on FcRn expression in RPE cells. CONCLUSIONS: Human RPE cells express FcRn. The proinflammatory cytokine TNF-α downregulates FcRn expression. The authors speculate that the FcRn may play a pivotal role in the immune privilege of the human eye.

[Sarcoidosis: changing insights in therapy]. / Sarcoïdose: verandering in therapeutische inzichten.

Sarcoidosis is a granulomatous disease of unknown etiology. Standard treatment with immune suppressants such as glucocorticoids is started when vital organ function is threatened. Biotechnology has resulted in new treatments ('biologicals'), in particular monoclonal antibodies, that may be effective in the treatment of sarcoidosis. In patients with sarcoidosis, only the use of monoclonal antibodies that block tumour necrosis factor (TNF) has been studied scientifically, other biologicals hardly at all. TNF-blockers are used at present in patients with therapy refractory sarcoidosis.

A genome-wide association study identifies a susceptibility locus for refractive errors and myopia at 15q14.

Refractive errors are the most common ocular disorders worldwide and may lead to blindness. Although this trait is highly heritable, identification of susceptibility genes has been challenging. We conducted a genome-wide association study for refractive error in 5,328 individuals from a Dutch population-based study with replication in four independent cohorts (combined 10,280 individuals in the replication stage). We identified a significant association at chromosome 15q14 (rs634990, P = 2.21 × 10⁻¹4). The odds ratio of myopia compared to hyperopia for the minor allele (minor allele frequency = 0.47) was 1.41 (95% CI 1.16-1.70) for individuals heterozygous for the allele and 1.83 (95% CI 1.42-2.36) for individuals homozygous for the allele. The associated locus is near two genes that are expressed in the retina, GJD2 and ACTC1, and appears to harbor regulatory elements which may influence transcription of these genes. Our data suggest that common variants at 15q14 influence susceptibility for refractive errors in the general population.

Progressive loss of cones in achromatopsia: an imaging study using spectral-domain optical coherence tomography.

PURPOSE: Achromatopsia (ACHM) is a congenital autosomal recessive cone disorder with a presumed stationary nature and only a few causative genes. Animal studies suggest that ACHM may be a good candidate for corrective gene therapy. Future implementation of this therapy in humans requires the presence of viable cone cells in the retina. In this study the presence of cone cells in ACHM was determined, as a function of age. METHODS: The appearance and thickness of all retinal layers were evaluated by spectral-domain optical coherence tomography (SD-OCT) in 40 ACHM patients (age range, 4-70 years) with known mutations in the CNGB3, CNGA3, and PDE6C genes. A comparison was made with 55 healthy age-matched control subjects. RESULTS: The initial feature of cone cell decay was loss of inner and outer segments with disruption of the ciliary layer on OCT, which was observed as early as 8 years of age. Cone cell loss further progressed with age and occurred in 8 (42%) of 19 patients below 30 years and in 20 (95%) of 21 of those aged 30+ years. Retinal thickness was significantly thinner in the fovea of all patients (126 µm in ACHM vs. 225 µm in the control; P < 0.001) and correlated with age (ß = 0.065; P = 0.011). Foveal hypoplasia was present in 24 (80%) of 30 patients and in 1 of 55 control subjects. CONCLUSIONS: ACHM is not a stationary disease. The first signs of cone cell loss occur in early childhood. If intervention becomes available in the future, the present results imply that it should be applied in the first decade.