Proof-of-concept and Randomized, Placebo-controlled Trials of an FcRn Inhibitor, Batoclimab, for Thyroid Eye Disease.

CONTEXT: Inhibition of the neonatal fragment crystallizable receptor (FcRn) reduces pathogenic thyrotropin receptor antibodies (TSH-R-Ab) that drive pathology in thyroid eye disease (TED). OBJECTIVE: We report the first clinical studies of an FcRn inhibitor, batoclimab, in TED. DESIGN: Proof-of-concept (POC) and randomized, double-blind placebo-controlled trials. SETTING: Multicenter. PARTICIPANTS: Patients with moderate-to-severe, active TED. INTERVENTION: In the POC trial, patients received weekly subcutaneous injections of batoclimab 680 mg for 2 weeks, followed by 340 mg for 4 weeks. In the double-blind trial, patients were randomized 2:2:1:2 to weekly batoclimab (680 mg, 340 mg, 255 mg) or placebo for 12 weeks. MAIN OUTCOME: Change from baseline in serum anti-TSH-R-Ab and total IgG (POC); 12-week proptosis response (randomized trial). RESULTS: The randomized trial was terminated because of an unanticipated increase in serum cholesterol; therefore, data from 65 of the planned 77 patients were analyzed. Both trials showed marked decreases in pathogenic anti-TSH-R-Ab and total IgG serum levels (P < .001) with batoclimab. In the randomized trial, there was no statistically significant difference with batoclimab vs placebo in proptosis response at 12 weeks, although significant differences were observed at several earlier timepoints. In addition, orbital muscle volume decreased (P < .03) at 12 weeks, whereas quality of life (appearance subscale) improved (P < .03) at 19 weeks in the 680-mg group. Batoclimab was generally well tolerated, with albumin reductions and increases in lipids that reversed upon discontinuation. CONCLUSIONS: These results provide insight into the efficacy and safety of batoclimab and support its further investigation as a potential therapy for TED.

Postoperative results after iris reconstruction with an Artificialiris® implant with consideration of the cause of the iris defects.

PURPOSE: To test the hypothesis that severely damaged eyes are more likely to experience postoperative complications after an ArtificialIris® (AI) implantation than other iris defects. METHODS: Patients after iris reconstruction with an AI were included in this consecutive case series of the Department of Ophthalmology, University of Mainz, Germany. Best-corrected visual acuity (BCVA), objective refraction (KR 8900 Topcon, Tokyo, Japan) and Scheimpflug imaging of the anterior segment with Pentacam® (Oculus, Wetzlar, Germany)and postoperative complications were evaluated. RESULTS: Thirty-two eyes of 32 patients after AI implantation were included, separated in partial or total aniridia in a closed globe (group 1, n = 16) and after perforating globe injury (group 2, n = 16). Two or more previous surgeries in the corresponding eye were found in two patients (12.5%) in group 1 and eleven patients (69%) in group 2 (p = 0.001). The time span between initial trauma or iris defect and AI implantation was not significantly related to the occurrence and severity of postoperative complications (p = 0.89). Postoperative complications were classified into mild and severe and showed no differences between group 1 and group 2 (mild: 1 vs. 0; p = 0.52; severe: 5 vs. 6 p = 0.8). CONCLUSION: AI implantation is a treatment option for various iris defects. An individual, case-based decision should be made with strict indication also considering other possible methods for pupil reconstruction. The postoperative outcome is not affected by the time point of AI implantation. So, an implantation is already possible as early as six weeks after the previous trauma.

Short- and long-term agreement and reproducibility of 48-hours intraocular pressure measurements in glaucoma patients.

BACKGROUND: Glaucomatous eyes often show strong intraocular pressure (IOP) fluctuations and individual measurements at different time points are necessary for personalized therapy. To survey IOP variations 48-hours diurnal and nocturnal IOP measurements were performed on two consecutive days. Aims of this study were to investigate the short-term repeatability of 48-hours measurements within one patient's IOP profile and long-term repeatability between two separate IOP profiles of the same patient. METHODS: A retrospective cohort study was performed evaluating data of 90 glaucoma patients in a German university medical center between 2006 and 2013. All patients underwent two separate diurnal IOP profiles of 48 h. IOP was measured at 8 am, 2 pm, 6 pm, 9 pm using Goldmann applanation tonometry and at 12 midnight using Perkins tonometry in supine position on two consecutive days. Intraclass correlation coefficients (ICC) were calculated to evaluate agreement for the same time points (each time point agreement) and for consecutive measurements within the IOP profiles (between time point agreement). ICC ≤ 0.4 was defined as poor agreement, 0.4-0.75 as moderate and ≥ 0.75 as excellent. Differences between time points were investigated by Bland Altman plots. RESULTS: Each time point measurements of profile 1 showed moderate to excellent agreement (ICCs 0.62-0.93). There was a moderate to excellent agreement for measurements between time points of profile 1 (ICCs day one 0.57-0.86, day two 0.71-0.90). Profile 2 was performed at a median interval of 12.0 months (quartiles 11.0 to 21.0). Each time point agreements within profile 2 showed ICCs from 0.23 to 0.81. It showed moderate to excellent agreement for changes between time points (ICCs 0.53-0.94). Day two demonstrated ICCs from 0.74 to 0.88. Long term IOP repeatability (over both pressure profiles) showed moderate to good agreement (ICCs 0.39-0.67). CONCLUSIONS: Short and long-term agreement of IOP measurements evaluated by diurnal IOP profiles is moderate to good. Due to mostly moderate agreements, which we believe represent IOP fluctuations, we conclude that it is necessary to perform 48-hours IOP profiles to gain a better overview of the individual IOP fluctuations.

Functional results and photic phenomena with new extended-depth-of-focus intraocular Lens.

BACKGROUND: Evaluation of clinical and functional results of a new extended depth of focus intraocular lens (EDOF-IOL). METHODS: Fourteen cataract patients (28 bilateral implantations) were assessed for uncorrected (UDVA) and corrected (CDVA) distance visual acuities; uncorrected (UNVA), distance-corrected (DCNVA) and best corrected (CNVA) near visual acuities; and uncorrected (UIVA) and distance-corrected (DCIVA) intermediate visual acuities - as well as binocular defocus curves. Photopic and mesopic contrast sensitivity was recorded. Reading acuity was evaluated using an electronic reading desk at fixed distances and at the patient's preferred near and intermediate distances. Visual symptoms were assessed with a halo and glare simulator plus a patient questionnaire which also recorded quality of life. RESULTS: Median postoperative monocular UDVA was 0.13logMAR (range - 0.08 to 0.42logMAR), median CDVA was - 0.01logMAR (range - 0.20 to 0.22logMAR), median UIVA at 80 cm was - 0.05logMAR (range - 0.18 to 0.58logMAR) and median UNVA at 40 cm was 0.14logMAR (range - 0.10 to 0.64logMAR). Binocular uncorrected reading acuity was 0.10logMAR at 40 cm and 0.11logMAR at 80 cm. Patients preferred a median intermediate reading distance of 62.8 cm over the predetermined 80 cm, which allowed them to read smaller letter size but did not improve reading acuity. Patients reported a high rate of spectacle independence and satisfaction in everyday life and little to no dysphotopsia. CONCLUSION: The Mini WELL Ready IOL provided good postoperative functional results at far and intermediate distances and improved the visual and reading acuity at reading distance. The lens caused little to no dysphotopsia. TRIAL REGISTRATION: The study protocol was registered at the German Clinical Trials Register: DRKS00007837 (Registered Date: March 9th, 2015).

Hydrophilic intraocular lens opacification after posterior lamellar keratoplasty - a material analysis with special reference to optical quality assessment.

BACKGROUND: Laboratory analysis and optical quality assessment of explanted hydrophilic intraocular lenses (IOLs) with clinically significant opacification after posterior lamellar keratoplasty (DMEK and DSAEK). METHODS: Thirteen opacified IOLs after posterior lamellar keratoplasty, 8 after descemet stripping automated endothelial keratoplasty (DSAEK), 3 after descemet membrane endothelial keratoplasty (DMEK) and 2 after both DSAEK and DMEK were analysed in our laboratory. Analyses included optical bench assessment for optical quality, light microscopy, scanning electron microscopy (SEM) and energy dispersive X-Ray spectroscopy (EDS). RESULTS: In all IOLs the opacification was caused by a thin layer of calciumphosphate that had accumulated underneath the anterior optical surface of the IOLs in the area spared by the pupil/anterior capsulorhexis. The calcifications lead to a significant deterioration of the modulation transfer function across all spatial frequencies of the affected IOLs. CONCLUSIONS: The instillation of exogenous material such as air or gas into the anterior chamber increases the risk for opacification of hydrophilic IOLs irrespective of the manufacturer or the exact composition of the hydrophilic lens material. It is recommended to avoid the use of hydrophilic acrylic IOLs in patients with endothelial dystrophy that will likely require procedures involving the intracameral instillation of air or gas, such as DMEK or DS(A)EK.

Outer Plexiform Layer Structures Are Not Altered Following AAV-Mediated Gene Transfer in Healthy Rat Retina.

Ocular gene therapy approaches have been developed for a variety of different diseases. In particular, clinical gene therapy trials for RPE65 mutations, X-linked retinoschisis, and choroideremia have been conducted at different centers in recent years, showing that adeno-associated virus (AAV)-mediated gene therapy is safe, but limitations exist as to the therapeutic benefit and long-term duration of the treatment. The technique of vector delivery to retinal cells relies on subretinal injection of the vector solution, causing a transient retinal detachment. Although retinal detachments are known to cause remodeling of retinal neuronal structures as well as significant cell loss, the possible effects of this short-term therapeutic retinal detachment on retinal structure and circuitry have not yet been studied in detail. In this study, retinal morphology and apoptotic status were examined in healthy rat retinas following AAV-mediated gene transfer via subretinal injection with AAV2/5.CMV.d2GFP or sham injection with fluorescein. Outer plexiform layer (OPL) morphology was assessed by immunohistochemical labeling, laser scanning confocal microscopy, and electron microscopy. The number of synaptic contacts in the OPL was quantified after labeling with structural markers. To assess the apoptotic status, inflammatory and pro-apoptotic markers were tested and TUNEL assay for the detection of apoptotic nuclei was performed. Pre- and postsynaptic structures in the OPL, such as synaptic ribbons or horizontal and bipolar cell processes, did not differ in size or shape in injected versus non-injected areas and control retinas. Absolute numbers of synaptic ribbons were not altered. No signs of relevant gliosis were detected. TUNEL labeling of retinal cells did not vary between injected and non-injected areas, and apoptosis-inducing factor was not delocalized to the nucleus in transduced areas. The neuronal circuits in the OPL of healthy rat retinas undergoing AAV-mediated gene transfer were not altered by the temporary retinal detachment caused by subretinal injection, the presence of viral particles, or the expression of green fluorescent protein as a transgene. This observation likely requires further investigations in the dog model for RPE65 deficiency in order to determine the impact of RPE65 transgene expression on diseased retinas in animals and men.

Rotation and decentration of an undersized plate-haptic trifocal toric intraocular lens in an eye with moderate myopia.

We present the case of a 56-year-old woman with moderate myopia and bilateral cataract who had cataract extraction and intraocular lens (IOL) implantation. Due to the patient's desire for spectacle independence, a trifocal IOL with toric correction for astigmatism was implanted. During the follow-up, it became obvious that the implanted IOL had rotated and tilted due to insufficient fixation in the large capsular bag of the myopic eye. An IOL explantation was therefore performed, and the original IOL was exchanged for a bifocal toric IOL with a larger overall diameter. Stable fixation of the IOL in the capsular bag was achieved, and after surgery in the second eye, the patient recovered good bilateral vision. This case illustrates the need for careful selection of IOL diameter and sizing even in patients with moderate myopia due to the potentially larger ocular dimensions in these patients.