To assess the incidence of Stargardt disease (STGD1) and to evaluate demographics of incident cases.For this retrospective cohort study, demographic, clinical and genetic data of patients with a clinical diagnosis of STGD1 were registered between September 2010 and January 2020 in a nationwide disease registry. Annual incidence (2014-2018) and point prevalence (2018) were assessed on the basis of this registry.A total of 800 patients were registered, 56% were female and 83% were of European ancestry. The incidence was 1.67-1.95:1,000,000 per year and the point prevalence in 2018 was approximately 1:22,000-1:19,000 (with and without 10% of potentially unregistered cases). Age at onset was associated with sex (p = 0.027, Fisher's exact); 1.9x more women than men were observed (140 versus 74) amongst patients with an age at onset between 10 and 19 years, while the sex ratio in other age-at-onset categories approximated one. Late-onset STGD1 (≥45 years) constituted 33% of the diagnoses in 2014-2018 compared to 19% in 2004-2008. Diagnostic delay (≥2 years between the first documentation of macular abnormalities and diagnosis) was associated with older age of onset (p = 0.001, Mann-Whitney). Misdiagnosis for age-related macular degeneration (22%) and incidental STGD1 findings (14%) was common in patients with late-onset STGD1.The observed prevalence of STGD1 in real-world data was lower than expected on the basis of population ABCA4 allele frequencies. Late-onset STGD1 was more frequently diagnosed in recent years, likely due to higher awareness of its phenotype. In this pretherapeutic era, mis- and underdiagnosis of especially late-onset STGD1 and the role of sex in STGD1 should receive special attention.
Purpose: To assess the phenotypic variability and natural course of inherited retinal diseases (IRDs) caused by EYS mutations. Methods: Multiethnic cohort study (N = 30) with biallelic EYS variants from a clinical IRD database (retinitis pigmentosa [RP], N = 27; cone-rod dystrophy [CRD], N = 1; and macular dystrophy, N = 2). In vitro minigene splice assay was performed to determine the effect on EYS pre-mRNA splicing of the c.1299+5_1299+8del variant in macular dystrophy patients. Results: We found 27 different EYS variants in RP patients and 7 were novel. The rate of visual field loss of the V4e isopter area was −0.84 ± 0.44 ln(deg2) per year, and the rate of visual acuity loss was 0.75 Early Treatment Diabetic Retinopathy Study letters per year. Ellipsoid zone width was correlated with area of the hyperautofluorescent ring, with rs = 0.78 and P < 0.001. Rate of decline in ellipsoid zone width was −57 ± 17 μm per year (P < 0.01) (n = 14) or −3.69% ± 0.51% from baseline per year (P < 0.001). An isolated CRD patient carried a homozygous EYS variant (c.9405T>A), previously identified in RP patients. Two siblings with macular dystrophy carried compound heterozygous EYS variants: c.1299+5_1299+8del and c.6050G>T. The former was novel and shown to result in skipping of exon 8, and the latter was a known RP variant. Conclusions: We report on EYS-associated macular dystrophy, extending the spectrum of EYS-associated IRDs. We observed heterogeneity between RP patients in age of onset and disease progression. Identical EYS variants were found in cases with RP, CRD, and macular dystrophy. Screening for EYS variants in CRD and macular dystrophy patients might increase the diagnostic yield in previously unsolved cases.
Anti-tumor necrosis factor alpha (anti-TNF- alpha ) antibodies have been used for the treatment of chronic inflammatory diseases such as rheumatoid arthritis (RA) and psoriasis arthritis. Such antibody therapies result in a severe interference with the patient's immune system. Increased rates of upper respiratory tract infection, reactivation of latent tuberculosis, and other systemic infectious diseases have been reported among patients receiving anti-TNF- alpha antibodies.As a note of caution, we describe a 57-year-old woman who received therapy with anti-TNF- alpha antibodies for RA refractory to methotrexate. After almost 2 years of treatment, she developed a severe cytomegalovirus (CMV) retinitis of the right eye.Laboratory assays revealed an immune status with nearly total loss of the cellular immune response and partial reduction of the humoral immune response. Intravenous treatment with ganciclovir, followed by oral administration of valganciclovir, resulted in an ophthalmological remission. Cessation of immunosuppressive therapy led to partial immunological reconstitution in the patient. Six months after discontinuation of immunosuppressive therapy, CMV retinitis of the left eye occurred but was treated successfully with a second course of oral valganciclovir.In the light of this first reported case of a serious CMV infection following therapy with anti-TNF- alpha antibodies, CMV infection should be considered in symptomatic patients.
Comparing the efficacy of intravitreal injections of bevacizumab to ranibizumab in the treatment of macular edema (ME) resulting from retinal vein occlusion (RVO).Comparative, randomized, double-masked, multicenter, noninferiority clinical trial. The noninferiority margin was 4 letters.Patients with vision loss resulting from ME secondary to a branch or (hemi) central RVO who might benefit from anti-vascular endothelial growth factor treatment were eligible for participation.From June 2012 through February 2018, 277 participants were randomized to receive injections of 1.25 mg bevacizumab (n = 139) or 0.5 mg ranibizumab (n = 138). The follow-up was 6 months with a monthly dosing interval.The primary outcome was a change in visual acuity from baseline at 6 months. Changes in the central area thickness and safety were studied as secondary outcomes.The mean visual acuity (±standard deviation) improved, with 15.3±13.0 letters for bevacizumab and 15.5±13.3 letters for ranibizumab after 6 months of monthly treatment. The lower limit of the 2-sided 90% confidence interval was -1.724 letters, which is within the noninferiority margin of 4 letters. Even in the branch and (hemi-)central RVO subgroups, minimal differences were found in visual acuity outcomes between treatment arms. Changes in central area thickness on OCT at 6 months did not differ significantly between treatment groups, with a decrease of 287.0±231.3 μm in the bevacizumab group and 300.8±224.8 μm in the ranibizumab group. Severe adverse events (SAEs) were also distributed equally over both treatment groups: 10 participants (7.1%) in the bevacizumab group and 13 participants (9.2%) in the ranibizumab group experienced SAEs.This study showed, based on the change in visual acuity, that bevacizumab is noninferior to ranibizumab for patients with ME resulting from RVO of either subtype when receiving monthly injections for a period of 6 months. In addition, anatomic and safety outcomes did not differ between treatment groups. Based on our findings, bevacizumab may be an effective alternative to ranibizumab.
Gene-based therapies for inherited retinal dystrophies (IRDs) are upcoming. Treatment before substantial vision loss will optimize outcomes. It is crucial to identify common phenotypes and causative genes in children. This study investigated the frequency of these in pediatric IRD with the aim of highlighting relevant groups for future therapy.
<b><i>Introduction:</i></b> In this paper, we report a case of visual impairment during treatment with sunitinib in a patient with metastatic renal cell carcinoma. <b><i>Methods:</i></b> Retrospective chart review was used. <b><i>Case Presentation:</i></b> We describe a 74-year-old male with metastatic renal cell carcinoma who was treated with sunitinib and experienced severe loss of visual acuity due to serous retinal detachment and intraretinal fluid. Upon discontinuation of sunitinib, the retinal fluid resolved, and visual acuity was restored. <b><i>Conclusion:</i></b> Serous retinal detachment has been described as a side effect of sunitinib use. Discontinuing sunitinib promptly resolved the subretinal fluid collections and restored vision.
Abstract Purpose The HELIOS (Health Economics with Lucentis in Observational Settings) study was designed on request of the Dutch Health Authority for an observational study to assess the effectiveness and safety of ranibizumab for neovascular age‐related macular degeneration (wet AMD ) in daily practice. Methods The HELIOS study was a 2‐year prospective, observational, open‐label, multicentre study involving 14 sites. Patients with wet AMD were enrolled and observed for a period of 24 months. The data were collected at baseline and at the visits closest around the time‐points 3, 6, 12, 18 and 24 months after inclusion. Results Treatment with ranibizumab resulted in prevention of vision loss. The mean ETDRS score increased from 45.1 letters at baseline to 48.5 letters at 24 months. This was achieved with a mean of 7.8 injections over 24 months. Stabilization of visual acuity was also reflected by the scores on the quality of life EQ ‐5D questionnaire, which did not significantly change over the study period. The more subjective EQ ‐ VAS questionnaire showed an overall improvement. The VFQ ‐25 questionnaire was also mostly stable over time. After 24 months, 32.2% of the patients gained ≥1 letter and 17.1% gained >15 letters. Patients completing the loading phase were better responders, as demonstrated by increased long‐term visual acuity. In addition, ranibizumab was well tolerated and had a safety profile commonly seen in routine clinical practice. Conclusion This study demonstrates that also in daily practice ranibizumab was effective in preventing vision loss over a period of 24 months. No new safety findings were identified.
Hintergrund: Neben der gesteigerten Zellproliferation stellt die Entdifferenzierung von Linsenepithelzellen zu myofibroblastenartigen Zellen einen wesentlichen Mechanismus bei der Nachstarentwicklung dar. Diese Entdifferenzierung geht einher mit Expression von α-smooth muscle actin (α-SMA). In dieser Studie wurde der Einfluss der Wachstumsfaktoren bFGF, TGF-β2, EGF und IGF-1 auf die Expression von α-SMA bei porcinen Linsenepithelzellen untersucht. Material und Methoden: Porcine Linsenepithelzellen wurden über einen Zeitraum von sieben Tagen in serumfreiem Medium ohne bzw. mit 1 - 50 ng/ml bFGF, TGF-β2, EGF oder IGF-1 kultiviert. Die α-SMA-Expression wurde immunzytochemisch mit einem monoklonalen Antikörper detektiert und der Anteil an α-SMA-positiven Zellen im Vergleich zur Gesamtzellzahl ausgewertet. Die statistische Auswertung erfolgte mit dem Student-t-Test für ungepaarte Stichproben. Ergebnisse: Der Anteil an α-SMA-positiven Zellen lag bei den Zellen, die über sieben Tage in serumfreiem Medium kultiviert worden waren, bei 36 ± 11,9 % (Mittelwert ± Standardabweichung). BFGF reduzierte diesen Anteil dosisabhängig auf 11,2 ± 7,3 % bei einer Konzentration von 50 ng/ml (p < 0,0001). EGF reduzierte den Anteil auf 25,1 ± 15,7 % (p = 0,05) bei einer Konzentration von 50 ng/ml. IGF-1 (10 ng/ml) verminderte den Anteil an entdifferenzierten Zellen auf 16,8 ± 5,8 %, was jedoch nicht signifikant war (p = 0,0787). TGF-β (50 ng/ml) erhöhte den Anteil an α-SMA-positiven Zellen geringfügig auf 44,2 ± 13,8 %. Nach einer Kulturperiode von sieben Tagen war dieser Anstieg jedoch nicht signifikant (p = 0,1202). Schlussfolgerungen: BFGF und EGF reduzierten die α-SMA-Expression von Linsenepithelzellen statistisch signifikant im Gegensatz zu TGF-β und IGF-1, die keinen signifikanten Einfluss hatten. Diese Ergebnisse können so interpretiert werden, dass bei der Nachstarentwicklung bFGF und EGF nicht primär über den Mechanismus der Zellentdifferenzierung wirken.
Editor, There is growing interest in monitoring treatment patterns and outcomes associated with anti-vascular endothelial growth factor agents in real world settings. AURA was an international, retrospective observational study conducted in Canada, France, Germany, Ireland, Italy, the Netherlands, the United Kingdom (UK), and Venezuela; the design (including ethics approval), participants and global outcomes of AURA are described in detail elsewhere (Holz et al. 2015). AURA showed that visual acuity (VA) outcomes achieved following ranibizumab use in patients with neovascular age-related macular degeneration (nAMD) were worse than those observed in clinical trials (Holz et al. 2015). These findings, which are also mirrored in some other real world studies (Rakic et al. 2013; van Asten et al. 2015), may be explained by several interacting factors, including resource patterns like the use of a loading scheme. Although the AURA data are now well established, we explored the Netherlands cohort in more detail as country-specific data are lacking, and we wanted to examine the impact of treatment and monitoring patterns after the loading phase on VA outcome in a real world setting. Patients from the Netherlands (n = 337), UK (n = 355) and all ‘other’ cohorts (n = 1094) who received a loading scheme in AURA were analyzed. The mean baseline VA (letter score) was lower in the Netherlands (50.4) than in UK (54.3) or ‘other’ cohorts (56.8). The mean change in VA (letters) from baseline to year 1 was higher in the Netherlands (+3.9) and UK (+6.8) compared with ‘other’ cohorts (+1.5); the corresponding values at year 2 were: Netherlands (+2.6), UK (+4.8) and ‘other’ cohorts (−0.6; Fig. 1). Following diagnosis, patients in the Netherlands received treatment much earlier (59.9 days) than those in UK (139.2 days) and ‘other’ cohorts (102.0 days). Over 2 years, patients in the Netherlands cohort received fewer injections compared with UK cohort, but more injections compared with ‘other’ cohorts (8.8, 9.3, and 6.8 injections, respectively). The duration between completion of the loading scheme and the first treatment in the maintenance phase was similar for patients in the Netherlands (102.1 days) and UK (102.8 days) cohorts, but was longer in the ‘other’ cohorts (145.6 days). In terms of monitoring, the mean numbers of VA tests and optical coherence tomography (OCT) images over 2 years were higher in UK than in the Netherlands or ‘other’ cohorts (18.0, 7.0, 8.5 VA tests and 16.9, 6.0, 5.6 OCTs, respectively). The proportion of patients who discontinued was higher in the Netherlands (53.1%) and ‘other’ cohorts (55.8%) compared with UK (14.1%) over 2 years. There were several reasons for discontinuations, including stable disease, treatment failure, or change of treating physician. Overall, these findings highlighted better VA outcomes in the Netherlands and UK compared with ‘other’ cohorts despite the use of a loading scheme; there was also a similar rate of VA decline over time in all three cohorts. This indicates that other factors may influence long-term maintenance. Outcomes in the Netherlands were achieved with a comparably high injection rate but less monitoring than in UK. It is possible that more frequent monitoring in the Netherlands could optimize the balance between injection use, VA outcomes, and dropouts. A more intensive ranibizumab regimen (with more frequent injections, monitoring, and visits) appeared to be associated with greater VA improvements in AURA (Holz et al. 2016, 2017). These issues still warrant further investigation in the real world setting, with the aim of identifying the optimal balance between resource patterns and outcomes. Data slides from this analysis can be downloaded via [https://onlinelibrary.wiley.com/journal/17553768].
