Corneal Toxicity in Patients Treated by BELANTAMAB MAFODOTIN: How to Improve and Facilitate Patients Follow-Up Using Refractive Shift?

Purpose: Multiple myeloma (MM) is the second most common neoplastic blood disease worldwide. Belantamab mafodotin is a new antibody conjugate anti-B-cell maturation antigen effective against refractory myelomas. It induces intracorneal microcysts leading to refractive fluctuations. The aim of this study is to assess the value of monitoring refractive fluctuations based on the location of microcystic-like epithelial changes (MECs) to facilitate patient follow-up. Methods: This observational and multicentric study was conducted using data collected from several French centers contacted through secure email through a standardized data collection table. Results: The fluctuation of objective refraction in spherical equivalent confirms a significant myopic shift from peripheral to central forms. A decrease in the best-corrected visual acuity (BCVA), an increase in keratometry, and an increase in central epithelial pachymetry have also been observed when MECs migrate toward the center. Conclusion: The myopization found in our study in patients with central and paracentral MECs is consistent with current literature. Fluctuations in BCVA, keratometry, and epithelial pachymetry are also consistent. This study is the first real-world study and highlights heterogeneity in follow-up, emphasizing the need to establish multidisciplinary follow-up strategies. The analysis of refractive fluctuations appears to be a reproducible and noninvasive screening method that could facilitate patient follow-up without the need for consultation focused on corneal diseases.

Dexamethasone Implant under a Proactive Treatment Regimen in Clinical Setting: The ProDEX Study.

PURPOSE: To assess the effectiveness of switching intravitreal dexamethasone implants (DEX-implant) from pro re nata (PRN) treatment regimen to a proactive regimen in patients with macular edema of diverse etiologies. DESIGN: An observational, retrospective, uncontrolled, multicenter, national case series. PARTICIPANTS: Eighty-one eyes from 68 patients treated between October 2015 and June 2023 were included. METHODS: This study included consecutive eyes treated with DEX-implant who were switched from a PRN regimen to a proactive regimen for diabetic macular edema (DME), retinal vein occlusion (RVO), noninfectious uveitis macular edema (UME; including postsurgical macular edema), and radiation maculopathy (RM). MAIN OUTCOME MEASURES: The main outcome measures were change in the best-corrected visual acuity (BCVA), central macular thickness (CMT), and intraocular pressure (IOP) at each visit. RESULTS: According to the etiology, DME represented 49.4% of eyes, UME 24.3%, RVO 21.0%, and RM 6.2%. The mean (standard deviation [SD]) duration of follow-up under the PRN and proactive regimens was 20.6 (13.3) and 14.2 (10.3) months, respectively. Switching from a PRN to a proactive regimen significantly improved mean (SD) BCVA by 3.7 (12.9) ETDRS letters (P = 0.01) with a mean (SD) decrease in CMT of 108.0 (151.4) µm (P < 0.001). The proportion of visits with significant anatomic recurrence (> 50 µm) also decreased from 40.1% to 6.0% after switching to a proactive regimen (P < 0.001). The number of DEX-implant injections significantly increased during the proactive treatment period (P < 0.001), but the change in the number of visits was not significantly different (P = 0.2). The proactive treatment period was not associated with a significant increase in IOP (P = 0.6). CONCLUSIONS: Switching to a proactive regimen in patients already treated with DEX-implant seems to significantly improve BCVA and CMT while maintaining stable IOP. FINANCIAL DISCLOSURES: Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Splenic monocytes drive pathogenic subretinal inflammation in age-related macular degeneration.

Age-related macular degeneration (AMD) is invariably associated with the chronic accumulation of activated mononuclear phagocytes in the subretinal space. The mononuclear phagocytes are composed of microglial cells but also of monocyte-derived cells, which promote photoreceptor degeneration and choroidal neovascularization. Infiltrating blood monocytes can originate directly from bone marrow, but also from a splenic reservoir, where bone marrow monocytes develop into angiotensin II receptor (ATR1)+ splenic monocytes. The involvement of splenic monocytes in neurodegenerative diseases such as AMD is not well understood. Using acute inflammatory and well-phenotyped AMD models, we demonstrate that angiotensin II mobilizes ATR1+ splenic monocytes, which we show are defined by a transcriptional signature using single-cell RNA sequencing and differ functionally from bone marrow monocytes. Splenic monocytes participate in the chorio-retinal infiltration and their inhibition by ATR1 antagonist and splenectomy reduces the subretinal mononuclear phagocyte accumulation and pathological choroidal neovascularization formation. In aged AMD-risk ApoE2-expressing mice, a chronic AMD model, ATR1 antagonist and splenectomy also inhibit the chronic retinal inflammation and associated cone degeneration that characterizes these mice. Our observation of elevated levels of plasma angiotensin II in AMD patients, suggests that similar events take place in clinical disease and argue for the therapeutic potential of ATR1 antagonists to inhibit splenic monocytes for the treatment of blinding AMD.

Real-world experience with brolucizumab in neovascular age-related macular degeneration over 2 years: the REBA extension study.

BACKGROUND: To determine long-term efficacy and safety of intravitreal brolucizumab therapy for neovascular age-related macular degeneration (nAMD) in the real-world setting. METHODS: Retrospective, observational, multicentric study and an extension of the REBA study (Real-world Experience with Brolucizumab in nAMD) to 24 months. The study entailed follow-up of 91 consecutive eyes (67 patients) with nAMD who received brolucizumab therapy and completed 24 months of follow-up. Both treatment-naïve and switch therapy patients were included. All relevant data were collected. The primary outcome measure was changed in best-corrected visual acuity (BCVA) over time. Secondary outcome measures included change in central subfield thickness (CST) and complications. RESULTS: The mean (SD) baseline BCVA was 48.4 (3.5) letters and 36.2 (7.1) letters in treatment-naïve group and switch therapy group, respectively. BCVA gain was + 9.2 (3.7) letters (p = 0.01) and + 7.7 (3.4) letters (p = 0.011), respectively. The change in mean (SD) CST has shown a significant decrease in retinal thickness in treatment-naïve group (from 432.5 (68.4) to 283.0 (51.3) µm; p = 0.018) and in switch therapy group (from 452.5 (40.5) to 271.0 (43.4) µm; p = 0.011) group. One switch patient developed vascular occlusion and another a macular hole after the fifth brolucizumab injection as reported in the primary study. Both patients recovered uneventfully. Three patients demonstrated reversible intraocular inflammation between months 10 and 24. CONCLUSION: Patients showed a significant anatomical and functional response to brolucizumab therapy in the real world, regardless of prior treatment status, until the end of the follow-up period. Overall, 5 significant untoward events were noted.

Long-Term Outcomes of Birdshot Chorioretinopathy Treated with Corticosteroids: A Case Reports.

PURPOSE: To report the progression of patients diagnosed with birdshot chorioretinopathy (BSCR) initially treated with corticosteroids. METHODS: We included 39 BSCR patients that were followed for ≥1 year. We analyzed their progression under treatment after 1, 3, 6 months, 1 year, and at the end of follow-up. In order to determine the efficiency of initial loading doses, patients were classified into two groups according to their initial treatment: methylprednisolone followed by prednisone (n = 28) and prednisone alone (n = 11). RESULTS: At the end of follow-up, 31/39 (79.5%) patients had reached inflammation control. Thirteen out of 28 (46.4%) and 6/11 (54.5%) patients were treated exclusively with corticosteroids, and 18/19 (94.7%) of them had reached inflammation control at the end of follow-up; their mean (range) corticosteroid dose was 3.5 (0-10) mg/day. CONCLUSIONS: We found that the prolonged corticosteroid therapy treatment strategy resulted in inflammation control in half of BSCR patients. This control was maintained with low doses of cortisone, usually <5 mg/day.

The Radiobiological Characterization of Human and Porcine Lens Cells Suggests the Importance of the ATM Kinase in Radiation-Induced Cataractogenesis.

Studies about radiation-induced human cataractogenesis are generally limited by (1) the poor number of epithelial lens cell lines available (likely because of the difficulties of cell sampling and amplification) and (2) the lack of reliable biomarkers of the radiation-induced aging process. We have developed a mechanistic model of the individual response to radiation based on the nucleoshuttling of the ATM protein (RIANS). Recently, in the frame of the RIANS model, we have shown that, to respond to permanent endo- and exogenous stress, the ATM protein progressively agglutinates around the nucleus attracted by overexpressed perinuclear ATM-substrate protein. As a result, perinuclear ATM crowns appear to be an interesting biomarker of aging. The radiobiological characterization of the two human epithelial lens cell lines available and the four porcine epithelial lens cell lines that we have established showed delayed RIANS. The BFSP2 protein, found specifically overexpressed around the lens cell nucleus and interacting with ATM, may be a specific ATM-substrate protein facilitating the formation of perinuclear ATM crowns in lens cells. The perinuclear ATM crowns were observed inasmuch as the number of culture passages is high. Interestingly, 2 Gy X-rays lead to the transient disappearance of the perinuclear ATM crowns. Altogether, our findings suggest a strong influence of the ATM protein in radiation-induced cataractogenesis.

Relevance of Visual Acuity Measurement for Therapeutic Decisions in Diabetic Macular Edema.

This study aimed to determine the validity of basing retreatment decisions on anatomical criteria alone (captured using optical coherence tomography (OCT)-OCT-guided strategy) rather than the gold standard (combined visual acuity (VA) and OCT) in patients with diabetic macular edema (DME). This cross-sectional study included 81 eyes undergoing treatment for DME from September 2021 to December 2021. An initial therapeutic treatment decision based on OCT results was made on inclusion. Subsequently, in light of the patient's VA score, this initial decision was upheld or adjusted, and the sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) were calculated. In 67 out of the 81 eyes included in the study (82.7%), the OCT-guided strategy produced equivalent results to the gold standard. In this study, the OCT-guided retreatment decision strategy yielded sensitivity and specificity of 92.3% and 73.8%, respectively, and PPV and NPV of 76.6% and 91.2%, respectively. These findings differed according to the patient's treatment regimen: the sensitivity and specificity for eyes under a treat and extend regimen was higher, 100% and 88.9%, respectively, than eyes under a Pro Re Nata regimen, 90% and 69.7%, respectively. These findings show that VA testing could be omitted from the follow-up of certain patients with DME treated with intravitreal injections without impacting the quality of care.

Single-Masked Randomized Phase 2 Study Assessing 2 Forms of Hypofractionated Proton Therapy in Patients With Large Choroidal Melanomas.

PURPOSE: Patients with large uveal melanomas are at major risk of liver metastases. Some patients are reluctant to undergo the standard treatment (ie, immediate enucleation). Proton therapy yields 5-year local control rates and eyeball retention of >85% and ≈20% in large uveal melanomas. Patients with T3/T4 uveal melanomas refusing enucleation were randomized between standard 4 to 13 Gy-fraction or moderately hypofractionated 8 to 6.5 Gy-fraction proton therapy. The main endpoint was the 2-year local recurrence-free survival without enucleation. METHODS AND MATERIALS: A single-masked 1:2 randomized phase 2 trial was conducted between 2015 and 2017 with planned endoresection and distance to the posterior pole as strata. Local events were defined as local relapse, or enucleation due to complications or relapse. RESULTS: The 32 patients, with a mean age of 64 years, had T3/4 (N = 17/15), M1 (N = 2) uveal melanomas, of mean tumor diameter and thickness of 16.5 mm and 9.1 mm, and of posterior location in 56.5%. Median follow-up was 56.7 months. The 2-year local recurrence-free survival rate without enucleation was 79% (95% confidence interval, 65%-96%), similar in both arms. There were 9 enucleations, 3 at relapse and 6 for toxicities. Twelve patients had distant metastases. The 2-year-overall survival was 72% (95% confidence interval, 58%-89%). At baseline, visual acuity by average logarithm value of the minimum angle of resolution was 0.68 and 0.70 in the standard and experimental arms, and at last follow-up 2 and 1.7, with mean differences of 1.44 and 1.01, respectively (P = .39). CONCLUSION: An 8-times 6.5 Gy scheme is feasible without deteriorating local control and with similar toxicity rates in patients with large uveal melanomas. Larger studies incorporating adjuvant treatments are warranted.

REAL WORLD STUDY COMPARING PHAKIC VERSUS PSEUDOPHAKIC EYES IN DIABETIC MACULAR EDEMA TREATED WITH DEXAMETHASONE IMPLANT: The PHAKIDEX Study.

PURPOSE: Dexamethasone implant (DEX-implant) is one treatment choice in diabetic macular edema. However, steroid-induced cataract is a common complication when treating a chronic disease and could lead to vision loss. Because of the lack of studies specifically focused on the functional outcomes according to the lens status, the authors therefore aim to analyze the effectiveness and safety of DEX-implant treatment for diabetic macular edema in phakic versus pseudophakic eyes. METHODS: This multicenter, retrospective study conducted in France included eyes of consecutive patients who had received a DEX-implant for diabetic macular edema. RESULTS: A total of 328 eyes were included: 158 eyes (48.2%) were phakic, 167 eyes (50.9%) were pseudophakic and three were unknown. According to the lens status, mean change in best-corrected visual acuity from baseline was never significantly different between phakic and pseudophakic eyes (likelihood ratio test, P = 0.09) nor in the change in central macular thickness (likelihood ratio test, P = 0.79) in multivariate analysis. Cataract surgery was performed in 63 phakic eyes (39.9%) during the study period with a mean delay of 8.1 months (CI95% [6.59-9.69]). The mean change in best-corrected visual acuity between phakic eyes who underwent cataract surgery and those who did not, was not significantly different during the follow-up at each visit. The risk of ocular hypertension was not statistically different between phakic and pseudophakic subsets ( P = 0.9). CONCLUSION: The authors showed here that phakic eyes treated with DEX-implant for diabetic macular edema did not have a significant difference in visual gain in comparison to pseudophakic eyes, with a comparable safety profile.

Melanophages give rise to hyperreflective foci in AMD, a disease-progression marker.

Retinal melanosome/melanolipofuscin-containing cells (MCCs), clinically visible as hyperreflective foci (HRF) and a highly predictive imaging biomarker for the progression of age-related macular degeneration (AMD), are widely believed to be migrating retinal pigment epithelial (RPE) cells. Using human donor tissue, we identify the vast majority of MCCs as melanophages, melanosome/melanolipofuscin-laden mononuclear phagocytes (MPs). Using serial block-face scanning electron microscopy, RPE flatmounts, bone marrow transplantation and in vitro experiments, we show how retinal melanophages form by the transfer of melanosomes from the RPE to subretinal MPs when the "don't eat me" signal CD47 is blocked. These melanophages give rise to hyperreflective foci in Cd47-/--mice in vivo, and are associated with RPE dysmorphia similar to intermediate AMD. Finally, we show that Cd47 expression in human RPE declines with age and in AMD, which likely participates in melanophage formation and RPE decline. Boosting CD47 expression in AMD might protect RPE cells and delay AMD progression.

Visual outcomes of macular melanocytic lesions after early or delayed proton beam therapy.

PURPOSE: During their initial management, some macular melanocytic lesions can be closely monitored to wait for a documented growth before advocating a treatment by irradiation. However, the visual outcomes of this strategy have not yet been assessed. This study compares the visual outcomes of macular melanocytic lesions that underwent delayed proton beam therapy (PBT) after an initial observation to those treated early. METHODS: A total of 162 patients with suspicious melanocytic lesions whose margins were located within 3 mm of the fovea were recruited from two French ocular oncology centers. RESULTS: Overall, 82 patients treated with PBT within 4 months after the initial visit (early PBT group) were compared to 24 patients treated with delayed PBT (delayed PBT group) and 56 patients not treated with PBT (observation group). Visual acuity was not significantly different between baseline and last visit in the observation group (p = 0.325). Between baseline and last visit, the median [IQR] loss in visual acuity was significant in both the early (0.7 [0.2; 1.8], p < 0.001) and the delayed (0.5 [0.2; 1.5], p < 0.001) PBT groups. After irradiation, there was no significant difference between the early and delayed PBT groups for visual loss (p = 0.575), diameter reduction (p = 0.190), and thickness lowering (p = 0.892). In multivariate analysis, history of diabetes mellitus and Bruch's membrane rupture remained significantly associated with greater visual loss (p = 0.036 and p = 0.002, respectively). CONCLUSION: For small lesions in which there is no clear diagnosis of malignant melanoma, an initial close monitoring to document tumor growth does not impact visual prognosis, despite the potential complications associated with the untreated tumor. However, the survival should remain the main outcome of the treatment of these lesions.

Focal Photocoagulation as an Adjunctive Therapy to Reduce the Burden of Intravitreal Injections in Macula Edema Patients, the LyoMAC2 Study.

AIM: To assess the efficacy of focal photocoagulation of capillary macroaneurysms (CMA) to reduce the burden of intravitreal injections (IVI) in patients with macular edema (ME). MATERIALS AND METHODS: Retrospective multicenter study in patients with diabetic ME or ME secondary to retinal vein occlusion (ME-RVO). CMA associated with ME were selectively photocoagulated. Patients were followed for one year after photocoagulation. RESULTS: 93 eyes of 76 patients were included in this study. At 6 months after the laser (n = 93), there was a significant decrease in mean macular thickness (from 354 µm to 314 µm, p < 0.001) and in mean IVI number (from 2.52 to 1.52 at 6 months, p < 0.001). The mean BCVA remained stable (0.32 and 0.31 logMAR at baseline and 6 months, p = 0.95). At 12 months (n = 81/93), there was a significant decrease in mean macular thickness (from 354 µm to 314 µm, p < 0.001) and in mean IVI number (from 4.44 to 2.95 at 12 months, p < 0.001), while the mean BCVA remained stable (0.32 and 0.30 logMAR at baseline and 12 months, p = 0.16). CONCLUSION: Focal laser photocoagulation of CMA seems to be effective and safe for reducing the burden of IVI in patients with ME. Their screening during the follow-up should be considered closely.

Relevance of Visual Acuity Measurement for Therapeutic Decisions in Age-Related Macular Degeneration.

The aim of this study is to assess if the decision to retreat could be determined by anatomical criteria (mostly driven by optical coherence tomography (OCT)-guided strategy) rather than the gold standard (visual acuity (VA) and OCT) in patients with neovascular age-related macular degeneration (nAMD). A cross-sectional study of 142 eyes already treated for nAMD from September 2021 to December 2021 was performed. At inclusion, a first therapeutic decision was made based on the analysis of the OCT. This decision was then maintained or modified after being made aware of the patient's VA. Sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) were calculated. The OCT-guided strategy matched the gold standard for treatment decisions in 131 of the 142 eyes included (92.3%). The sensitivity and specificity of the OCT-guided strategy for the retreatment decision were 94.0% and 89.8%, respectively. PPV and NPV were 92.9% and 91.4%, respectively. Considering the treatment regimen, eyes followed under the Pro ReNata regimen showed better sensitivity (100%) and specificity (93.3%) than eyes followed under the treat and extend regimen (93.5% and 88.6%, respectively). Based on the findings of this study, the follow-up for selected patients with nAMD under anti-VEGF treatment could be monitored without regular VA testing with acceptable performance.

The Effects of Treatment Regimen on the Initial Management of Macular Neovascularization Subtypes in Age-Related Macular Degeneration.

INTRODUCTION: The aim of this study was to evaluate the effect of initial treatment regimen individualization (pro re nata or treat-and-extend [TAE]), according to macular neovascularization (MNV) subtype, on the functional and anatomical response in neovascular age-related macular degeneration (nAMD). The secondary objective was to compare the treatment burden between each MNV subtype. METHODS: Consecutive treatment-naïve nAMD patients were retrospectively included. MNV subtype was graded by 2 independent blinded investigators on multimodal imaging. Functional and anatomical outcomes were analysed according to treatment regimen and MNV subtypes. RESULTS: A total of 281 eyes from 243 patients were included in the study. According to the treatment regimen, there was no significant difference in best-corrected visual acuity gain within the first 2 years of treatment for type 1 (p = 0.106) and type 3 MNV (p = 0.704). Conversely, there was a significant difference in favour of TAE regimen for type 2 (p = 0.017) and type 4 MNV (p = 0.047). Type 1 MNV had a higher proportion of visits with subretinal fluid (p = 0.0007) but not with intraretinal fluid (p = 0.22). The mean interval between the last 2 injections was significantly shorter for type 1 MNV (p = 0.0045). CONCLUSION: The individualization of the initial treatment protocol according to MNV subtype can improve the functional outcome and may decrease the treatment burden.