CPD: OCT masterclass 7

ObjectivesAge-related macular degeneration (AMD), in which oxidative stress, inflammation and metabolic imbalances play a role in its pathogenesis, is one of the leading causes of irreversible vision loss. The kynurenine (KYN) pathway, one of the principal routes of tryptophan (TRP) metabolism, constitutes an important mechanism in retinal neurodegeneration. Based on this information, our study aimed to compare the serum TRP, KYN, kynurenic acid (KYNA), 3-hydroxykynurenine (3HK), 3-hydroxyanthranilic acid (3HAA) and, quinolinic acid (QA) levels of AMD patients and to investigate the diagnostic values ​​of these biomarkers.MethodsSerum samples were collected from AMD patients and control groups. TRP, KYN, KYNA, 3HK, 3HAA, and QA levels were measured using a commercial ELISA method. KYN pathway activity, KYN/TRP and, KYNA/3HK ratios were also assessed. Mann-Whitney U test, ROC analysis, Spearman correlation were applied for statistical comparisons.ResultsAccording to our results, 3HK was significantly higher in the AMD group, while TRP, KYN, QA, and KYNA/3HK ratio were higher in the control. ROC analysis revealed 3HK to be the strongest discriminatory marker. The KYNA/3HK ratio also provided significant diagnostic value. Correlation analysis revealed strong negative correlations between 3HK and KYN, QA, and especially KYNA/3HK. Conversely, strong positive correlations were found between KYN and KYNA/3HK, and between TRP, KYN, QA, and KYNA.ConclusionKYN pathway metabolites exhibit significant alterations in patients with AMD. 3HK levels and the reduction of the KYNA/3HK ratio suggest a disruption of the neurotoxic–neuroprotective balance and imply that KYN pathway dysfunction may play a role in the pathogenesis of AMD. Among the biomarkers examined, 3HK displayed the highest diagnostic performance, while the KYNA/3HK ratio emerged as an additional biological indicator. These findings indicate that 3HK and the KYNA/3HK ratio may serve as potential biomarker candidates for the early diagnosis and monitoring of AMD.

Aflibercept, bevacizumab and ranibizumab are vascular endothelial growth factor inhibitors used for the treatment of wet age-related macular degeneration (wet AMD). Aflibercept and ranibizumab are registered for intraocular use whereas off-label bevacizumab is widely used due to its affordability. As use of aflibercept and ranibizumab induces significantly higher treatment costs compared to off-label bevacizumab, Finnish Choosing Wisely recommendation suggests avoiding expensive drugs as first-line therapy as studies have demonstrated similar effectiveness and safety of AMD drugs (Tuuminen et al. 2019). In Finland, the National Council for Choices in Health Care acknowledges treatment of wet AMD with intravitreal bevacizumab in the publicly funded health care (Tuuminen et al. 2017). When costs of one disease increase more than overall costs in the tax-funded health care system, it is crucial to search means to improve cost-effectiveness of care to be able to ensure required care for all eye diseases. Oslo University Eye Clinic has introduced a practice, where the drug from aflibercept-vial is divided into three prefilled syringes. Using low dead-space syringes, each prefilled syringe contains 0.05 ml aflibercept (Sivertsen et al. 2018). Tays Eye Centre followed by implementing the same policy since October 2016. Safety of compounding aflibercept into prefilled syringes has been shown in few previous studies (Cao et al. 2017; Forooghian et al. 2017). To evaluate real life safety and efficacy of this policy, data from wet AMD eyes treated with aflibercept between September 2015 and October 2017 in Tampere Eye Centre were collected from the electronic medical records. Eyes were divided into two groups: Group 1 treated during 1 September 2015–31 August 2016, and Group 2 during 1 November 2016–31 October 2017. To consider bias, eyes from Group 1 were excluded from Group 2. One eye per patient was included in the analysis (the first eye diagnosed with wet AMD). Data were analysed with spss version 25 (IBM® Statistics SPSS; Armonk, NY, USA) using Mann–Whitney U-test and Pearson Chi square for comparisons. In Group 1, all patients were treated with aflibercept drawn from a vial just prior to the injections. In Group 2, most eyes (mean 86 ± 9%) received aflibercept injections from prefilled syringes, generated by the university hospital pharmacy implementing a validated process. At the beginning of transition period, in November 2016 the divided aflibercept accounted 70% of aflibercept injections and increased to 100% by October 2017. A total of 144 eyes with at least one aflibercept injection were identified in Group 1 and 145 eyes in Group 2. The mean follow-up in both groups was 11 ± 1 months. Numbers of the aflibercept injections administered were 411 and 434 in Groups 1 and 2, respectively. Time from wet AMD diagnosis to the beginning of the study follow-up period was different between the groups (30 versus 25 months, p = 0.01). There were no significant differences between mean visual acuities (Fig. 1A), number of total intravitreal injections (IVIs) given (5 ± 2 versus 6 ± 2 IVIs, p = 0.1), or total number of aflibercept injections given (3 ± 2 IVIs in both groups, p = 0.7). We found similar results in a subgroup analysis with eyes receiving aflibercept injections only (Fig. 1A). No endophthalmitis or other serious adverse effects were observed after aflibercept injections in any group. Our 1-year real-world data indicate that divided aflibercept into prefilled syringes seems to be safe and does not affect the effectiveness of aflibercept but reduces drug related cost significantly (Fig. 1B). The total AMD drug costs of Tays Eye Centre in 2008–2017 were 2.9 million euros. If the most expensive available AMD drug had been used for all patients, the cost would have been 23 million euros which represents a huge cost saving.

Profil épidémiologique et clinique de la dégénérescence maculaire liée à l’âge en milieu camerounais

The need for new drugs to treat dry forms of age-related macular degeneration remains high. A promising approach is repurposing of FDA-approved medications to treat AMD. Databases containing medical and drug records allow for retroactive identification of drugs whose use correlates with reduced AMD diagnosis. This short review summarizes progress in several classes of drugs considered for repurposing: GPR-143 agonists (L-DOPA), anti-diabetic drugs (metformin, acarbose, empagliflozin, fenofibrate), mitochondrial activators (PU-91), and serotonin pathway drugs (fluoxetine, flibanserin, xaliproden, buspirone). The promises and caveats of repurposing are discussed herein.

To assess whether metformin is associated with dry age-related macular degeneration (dAMD) development. In this retrospective cohort study, patients enrolled in a nationwide U.S. medical insurance claims database from 2002 to 2016 were included if they had diabetes mellitus, were ⩾55 years old, and were enrolled for ⩾2 years without a prior AMD diagnosis. The primary exposure was metformin use analyzed as either active or prior use or cumulative metformin dosage over the study period. A time updating Cox proportional hazard regression was used to estimate the hazard ratio of dAMD incidence with metformin exposure. Among 1,007,226 diabetic enrollees, 53.3% were female and 66.4% were white with a mean hemoglobin A1c of 6.8%. Of eligible enrollees, 166,115 (16.5%) were taking metformin at the index date. Over the study period, 29,818 (3.0%) participants developed dAMD. In the active versus prior use of metformin model, active use conferred an increased hazard of developing dAMD (HR, 1.08; 95% CI, 1.04-1.12) while prior use had a decreased hazard (HR, 0.95; 95% CI 0.92-0.98). The cumulative metformin dosage model showed a significant trend toward increased hazard of dAMD incidence with increasing cumulative dosage (p < 0.001), with the lowest dosage quartile having decreased hazard of dAMD incidence (HR, 0.95; 95% CI, 0.91-0.99) and the highest having increased hazard (HR, 1.07; 95% CI, 1.01-1.13). Small, conflicting associations between metformin exposure and development of dAMD were observed depending on cumulative dosage and whether drug use was active, suggesting metformin did not substantially affect the development of dAMD.