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The article presents a study on the relation between familial uveal and cutaneous melanoma. The study was participated by ten siblings in a single nuclear family. The findings of the study strengthen the link between uveal melanoma, atypical nevi and cutaneous melanoma. Individuals with a personal or family history of uveal melanoma are recommended to be screened for uveal and cutaneous melanoma. A comment on the study is presented.

Introduction: Gout, a common comorbidity of chronic kidney disease (CKD), is associated with high morbidity and healthcare utilization. However, a large proportion of gout remains undermanaged or untreated which may lead to worse patient outcomes and greater healthcare costs. This study estimates the present and future health and economic burden of controlled and uncontrolled gout in a virtual United States (US) CKD population., Methods: A validated microsimulation model was used to project the burden of gout in patients with CKD in the USA through 2035. Databases were utilized to build a virtual CKD population of "individuals" with controlled or uncontrolled gout. Modelling assumptions were made on the basis of the literature, which was sparse in some cases. Health and economic outcomes with the current care (baseline) scenario were evaluated, along with potential benefits of urate-lowering intervention scenarios., Results: The prevalence of comorbid gout and CKD in the USA was projected to increase by 29%, from 7.9 million in 2023 to 9.6 million in 2035 in the baseline scenario. Gout flares, tophi, and comorbidity development were also projected to increase markedly through 2035, with the economic burden of gout in the CKD population subsequently increasing from $38.9 billion in 2023 to $47.3 billion in 2035. An increased use of oral urate-lowering therapies in undermanaged patients, and pegloticase use in patients refractory to oral urate-lowering therapies were also project to result in 744,000 and 353,000 fewer uncontrolled gout cases, respectively, by 2035. Marked reductions in complications and costs ensued., Conclusions: This study projected a substantial increase in comorbid gout and CKD. However, improved use of urate-lowering interventions could mitigate this growth and reduce the health and economic burdens of gout., (© 2024. The Author(s).)

Objective: Monosodium-urate (MSU) crystal deposits can be visualized and quantified with dual-energy CT (DECT). Pegloticase lowers serum urate (SU) in uncontrolled gout patients, with methotrexate (MTX) co-therapy recommended to increase SU-lowering response rate and decrease infusion reaction risk. The literature on serial DECT-imaging during pegloticase+MTX co-therapy is sparse, with only 2 prior cases of rapid MSU deposition depletion with subsequent bone-erosion remodeling reported from a small open-label trial. Here, we report DECT findings during pegloticase treatment in a larger number of patients from a randomized controlled trial to confirm bone-erosion remodeling that follows MSU depletion with pegloticase. The influence of length-of-therapy is also explored., Methods: Patients received pegloticase (8mg every 2weeks)+MTX (15mg/week orally) or pegloticase+placebo (PBO) during the MIRROR RCT trial. A subset underwent DECT-imaging on Day1 (first pegloticase infusion) and at Weeks 14, 24, and 52. Patients with paired baseline-Week 52 images were included. Imaged regions with baseline MSU-crystal volume (V MSU )<0.5cm 3 were excluded to minimize artifact contributions. V MSU and bone-erosion remodeling were assessed., Results: Eight patients (6 MTX, 2 PBO) were included. Included patients had received 52weeks (5 MTX), 42weeks (1 PBO), and 6weeks (1 MTX, 1 PBO) of pegloticase therapy. Patients who prematurely discontinued pegloticase maintained SU<6mg/dL on allopurinol (n=2)/febuxostat (n=1). At Week 52, V MSU had markedly decreased in both the pegloticase+MTX and pegloticase+PBO treatment groups, with faster depletion during pegloticase therapy. Bone-erosion remodeling was observed in 29/42 (69%) evaluated erosions: 29 (69%) size decrease, 4 (9.5%) recortication, 3 (7.1%) new bone formation., Conclusion: Rapid V MSU depletion during pegloticase therapy was observed with concomitant bone remodeling within 1year. Following pegloticase discontinuation, V MSU reduction slowed or stopped even when SU was maintained<6mg/dL with oral ULT., Clinical Trial Registration: NCT03994731., (Copyright © 2024 The Author(s). Published by Elsevier Masson SAS.. All rights reserved.)

Background/purpose: Little is known about long-term clinical outcomes or urate-lowering (ULT) therapy use following pegloticase discontinuation. We examined ULT use, serum urate (SU), inflammatory biomarkers, and renal function following pegloticase discontinuation., Methods: We conducted a retrospective analysis of gout patients who discontinued pegloticase using the Rheumatology Informatics System for Effectiveness (RISE) registry from 1/2016 to 6/2022. We defined discontinuation as a gap ≥ 12 weeks after last infusion. We examined outcomes beginning two weeks after last dose and identified ULT therapy following pegloticase discontinuation. We evaluated changes in lab values (SU, eGFR, CRP and ESR), comparing on- treatment (≤ 15 days of the second pegloticase dose) to post-treatment., Results: Of the 375 gout patients discontinuing pegloticase, median (IQR) laboratory changes following discontinuation were: SU: +2.4 mg/dL (0.0,6.3); eGFR: -1.9 mL/min (- 8.7,3.7); CRP: -0.8 mg/L (-12.8,0.0); and ESR: -4.0 mm/hr (-13.0,0.0). Therapy post-discontinuation included oral ULTs (86.0%), restarting pegloticase (4.5%), and no documentation of ULT (9.5%), excluding patients with multiple same-day prescriptions (n = 17). Oral ULTs following pegloticase were: 62.7% allopurinol, 34.1% febuxostat. The median (IQR) time to starting/restarting ULT was 92.0 days (55.0,173.0). Following ULT prescribing (≥ 30 days), only 51.0% of patients had SU < 6 mg/dL. Patients restarting pegloticase achieved a median SU of 0.9 mg/dL (IQR:0.2,9.7) and 58.3% had an SU < 6 mg/dL., Conclusion: Pegloticase treats uncontrolled gout in patients with failed response to xanthine oxidase inhibitors, but among patients who discontinue, optimal treatment is unclear. Based on this analysis, only half of those starting another ULT achieved target SU. Close follow-up is needed to optimize outcomes after pegloticase discontinuation., (© 2024. The Author(s).)

Chronic kidney disease (CKD) and gout commonly co-occur. Pegloticase lowers serum urate (SU) in uncontrolled gout patients but antidrug antibodies limit urate-lowering response and increase infusion reaction (IR) risk. Methotrexate (MTX) co-administration increases pegloticase response rate and mitigates IR risk but CKD limits MTX use. This pooled case series examined pegloticase + MTX co-therapy in uncontrolled gout patients with and without CKD. Cases of pegloticase + MTX co-therapy in existing datasets were retrospectively examined. Baseline eGFR classified patients as CKD (eGFR < 60 mL/min/1.73 m2) or non-CKD (eGFR ≥ 60 mL/min/1.73 m2). Patient characteristics, treatment parameters, laboratory values, urate-lowering response rate (≥12 pegloticase infusions received and SU < 6 mg/dL just before infusion 12), and AEs were examined. Fifteen CKD (eGFR: 43.2 ± 11.3 mL/min/1.73 m2; SU: 8.6 ± 2.2 mg/dL), 27 non-CKD (eGFR: 82.9 ± 19.0 mL/min/1.73 m2; SU: 9.5 ± 1.7 mg/dL) patients were included. Comorbidity profiles were similar, but CKD patients were older (72.0 ± 9.9 vs 52.3 ± 14.3 years) and more often female (33.3% vs 7.4%). Treatment parameters were similar with 4-week MTX Run-in followed by mean of 14.7 ± 8.1 [CKD] vs 14.1 ± 7.1 [non-CKD] pegloticase infusions. However, CKD patients had lower MTX dose (14.8 ± 5.8 vs 19.3 ± 4.9 mg/week). Urate-lowering response was similar (92% vs 86%). eGFR increased during treatment in 60% of CKD (+11.5 ± 20.9 mL/min/1.73 m2, 87% stable/improved CKD-stage) and 44% of non-CKD (+4.2 ± 15.0 mL/min/1.73 m2) patients. AEs were similar (≥1 AE CKD: 53%, non-CKD: 67%; gout flare most-reported). One case each of pancytopenia and IR (mild) occurred in non-CKD patients. These real-world data show similar pegloticase + MTX efficacy in CKD and non-CKD patients. No new safety signals were identified, with most CKD patients showing renal function stability or improvement during therapy., (Copyright © 2024 the Author(s). Published by Wolters Kluwer Health, Inc.)

Objective: To assess 12-month safety and efficacy of pegloticase + methotrexate (MTX) versus pegloticase + placebo (PBO) cotherapy in a PBO-controlled, double-blind trial (A randomized, double-blind, placebo-controlled, multicenter, efficacy and safety study of methotrexate to increase response rates in patients with uncontrolled gout receiving pegloticase [MIRROR RCT])., Methods: Patients with uncontrolled gout (serum urate level [SU] ≥7 mg/dl, oral urate-lowering therapy failure or intolerance, and presence of one or more gout symptoms [one or more tophi, two or more flares in 12 months, gouty arthropathy]) were randomized 2:1 to receive pegloticase (8-mg infusion every 2 weeks) with blinded MTX (oral 15 mg/week) or PBO for 52 weeks. Efficacy end points included proportion of responders (SU level <6 mg/dl for ≥80% of examined month) in the intent-to-treat population (ITT) (all randomized patients) during month 6 (primary end point), month 9, and month 12; proportion with resolution of one or more tophi (ITT); mean SU reduction (ITT); and time to SU-monitoring pegloticase discontinuation. Safety was evaluated via adverse event reporting and laboratory values., Results: Month 12 response rate was significantly higher in patients cotreated with MTX (60.0% [60 of 100] vs. 30.8% [16 of 52]; difference: 29.1% [95% confidence interval (CI): 13.2%-44.9%], P = 0.0003), with fewer SU discontinuations (22.9% [22 of 96] vs. 63.3% [31 of 49]). Complete resolution of one or more tophi occurred in 53.8% (28 of 52) versus 31.0% (9 of 29) of MTX versus PBO patients at week 52 (difference: 22.8% [95% CI: 1.2%-44.4%], P = 0.048), more than at week 24 (34.6% [18 of 52] vs. 13.8% [4 of 29]). Consistent with observations through month 6, pharmacokinetic and immunogenicity findings showed increased exposure and lower immunogenicity of pegloticase when administered with MTX, with an otherwise similar safety profile. No infusion reactions occurred after 24 weeks., Conclusion: Twelve-month MIRROR RCT data further support MTX cotherapy with pegloticase. Tophi resolution continued to increase through week 52, suggesting continued therapeutic benefit beyond month 6 for a favorable treatment effect., (© 2023 Horizon Therapeutics PLC and The Authors. ACR Open Rheumatology published by Wiley Periodicals LLC on behalf of American College of Rheumatology.)

Introduction: Gout is an inflammatory, metabolic disease associated with a high comorbidity burden including cardiovascular disease, hypertension, type 2 diabetes, hyperlipidemia, renal disease, and metabolic syndrome. Approximately 9.2 million Americans have gout, making prognosis and treatment outcome predictors highly important. About 600,000 Americans have early-onset gout (EOG), generally defined as first gout attack at ≤ 40 years of age. However, data on EOG clinical features, comorbidity profile, and treatment response are sparse; this systematic literature review provides insight., Methods: PubMed and American College of Rheumatology (ACR)/European Alliance of the Associations for Rheumatology (EULAR) abstract archives were searched for early-onset gout, "early onset gout," and ("gout" AND "age of onset"). Duplicate, foreign language, single case report, older (before 2016), and irrelevant/data insufficient publications were excluded. The age of diagnosis categorized patients as having common gout (CG, generally > 40 years) or EOG (generally ≤ 40 years). Applicable publications were extensively reviewed/discussed among authors for inclusion/exclusion consensus., Results: A total of 283 publications were identified, with 46 (35 articles, 10 abstracts) reviewed and 17 (12 articles, 5 abstracts) ultimately included. Eleven reported clinical characteristics, with 6 EOG-CG retrospective/cross-sectional comparisons. Gout diagnosis preceded cardiometabolic comorbidity and renal comorbidities were less prevalent in EOG than CG patients. EOG patients had more severe disease (more gout flares, polyarticular disease), higher pre-therapy serum urate (SU), and worse oral urate-lowering therapy response. Genetics-focused publications reported higher incidences of dysfunctional urate transporter mutations in EOG patients., Conclusions: This review suggests that EOG is more recalcitrant to urate-lowering therapy, is associated with urate transporter defects, and carries heavy disease burden. Therefore, early rheumatology referral and urate-lowering in a treat-to-target fashion may benefit EOG patients. Interestingly, EOG patients had fewer cardiometabolic comorbidities at diagnosis than CG patients, presenting a potential "window of opportunity" to attenuate cardiometabolic comorbidity development with SU control. Preventing gout-related suffering and health burden is particularly important in these young EOG patients who will live with gout and its sequelae for decades., (© 2023. The Author(s).)

Objective: Patients with uncontrolled/refractory gout have heavy disease burden, but few treatment options. Pegloticase lowers serum urate (SU), but anti-drug antibodies can limit treatment efficacy. Evidence supports immunomodulator-pegloticase co-administration to increase sustained urate-lowering rates, but published cases are limited. This study investigated experience with pegloticase-immunomodulation co-therapy at two community rheumatology practices., Methods: Patients initiating pegloticase with immunomodulation in 2017 or later were included. Patient/treatment characteristics and proportion of responders (≥ 12 pegloticase infusions, SU < 6 mg/dl at infusion-12) were examined. Patients on therapy at data collection with < 12 infusions were excluded from response analyses. eGFR before and after therapy was examined., Results: Thirty-four patients (79% male, 62.4 ± 16.3 years) with uncontrolled gout (SU = 9.1 ± 2.0 mg/dl, 91% tophaceous) were included. Most-reported comorbidities were hypertension (76%), obesity (71%), osteoarthritis (68%), and CKD (47%). Pre-therapy eGFR was 65.4 ± 25.2 ml/min/1.73 m 2 (41% eGFR < 60 ml/min/1.73 m 2 ). All patients initiated immunomodulation before (5.3 ± 3.0 weeks, n = 32) or at (n = 2) first pegloticase infusion. Subcutaneous methotrexate (15.4 ± 4.9 mg/week, n = 20), oral methotrexate (15.3 ± 3.6 mg/week, n = 9), mycophenolate mofetil (1000 mg/day, n = 3), and azathioprine (100 mg/day, n = 2) were administered. Patients received 14.6 ± 7.1 infusions over 28.5 ± 14.9 weeks. Overall response rate was 89%, ranging among immunomodulators (subcutaneous methotrexate: 93%, oral methotrexate: 89%, mycophenolate mofetil: 100%, azathioprine: 50%). On average, eGFR increased during therapy (+ 10.3 ± 16.9 ml/min/1.73 m 2 ), with CKD stability/improvement in 85%. Nineteen patients (56%) experienced gout flares. No infusion reactions or infections were noted. No new safety concerns were identified., Conclusions: These real-world findings provide further support for increased pegloticase response rates when co-treatment with immunomodulating therapy is used., (© 2022. The Author(s).)

Objective: Thyroid eye disease (TED) is an autoimmune, inflammatory disease resulting in retro-orbital fat and extraocular muscle expansion. TED quiets ("inactivates") as inflammation wanes; however, signs/symptoms often persist. Signs/symptoms of the disease and the impact on quality of life (QoL) were examined in noninflammatory and inflammatory TED., Methods: Data of patients with moderate-to-severe TED were collected from treating physicians. Clinical activity score (CAS, 6/7 measures available) was used to classify TED as inflammatory (CAS ≥ 3) or noninflammatory (CAS = 0 or 1). QoL impact was scored as 1 = "not at all impaired" to 7 = "extremely impaired." Patients with noninflammatory TED were further grouped into longer (>3 years) and shorter (≤3 years) disease courses., Results: Patients with inflammatory (N = 307) and noninflammatory (N = 281) TED had comparable age (50.0 ± 13.3 years vs 48.3 ± 13.8 years), gender (66% men vs 64% women), TED duration (4.0 ± 4.9 years vs 4.6 ± 5.5 years), and proportion of smokers (15% vs 11%). The most common signs/symptoms of noninflammatory TED included ocular dryness/grittiness (77%), proptosis (56%), excessive tearing (43%), soft tissue edema (42%), conjunctival redness (24%) decreased vision (24%), and eye muscle involvement (22%; 14% had diplopia). All signs/symptoms were less frequently reported in these patients than in those with inflammatory TED. QoL was impacted by noninflammatory TED, although to a lesser degree than the inflammatory disease (3.6 ± 1.5 vs 4.7 ± 1.4). However, mental health issues were similarly reported. Patients with noninflammatory TED with a longer disease course (9.0 ± 6.0 years) had similar QoL impact, mental health diagnoses, and TED signs/symptoms as those with a shorter disease course (1.4 ± 1.0 years)., Conclusion: The signs/symptoms of TED often chronically persist long after TED has "quieted," continuing to impact a patient's QoL and mental health. These data suggest that moderate-to-severe TED should be thought of as a robust symptomatic chronic disease, regardless of its inflammatory status., (Copyright © 2022 AACE. Published by Elsevier Inc. All rights reserved.)

Background: Pegloticase, a PEGylated uricase for uncontrolled gout, rapidly lowers serum urate (SU). Not all patients complete a full-therapy course because anti-pegloticase antibodies can develop, causing efficacy loss and infusion reactions. The literature and clinical trial data indicate that methotrexate co-administration markedly improves pegloticase response rates from the established monotherapy response rate of 42%. Unfortunately, methotrexate use is restricted by kidney disease, which is often present in uncontrolled gout patients. Leflunomide is less restricted in patients with renal dysfunction. This study examined the treatment response rate of pegloticase co-administered with leflunomide., Methods: Patients co-treated with pegloticase (8 mg biweekly infusion) and oral leflunomide (20 mg/day) were included. Patient/treatment characteristics and safety parameters (adverse events [AEs], laboratory parameters) were examined. Pre-infusion prophylaxis was administered (day of infusion: IV solumedrol, night before and morning of infusion: oral fexofenadine or diphenhydramine). Patients were considered treatment responders if ≥ 12 pegloticase infusions were administered and pre-infusion SU < 6 mg/dl at infusion-12., Results: Ten patients (five male, 72.7 ± 12.5 years) were included. The most common comorbidities were chronic kidney disease (90%), hypertension (70%), diabetes mellitus (60%), obesity (60%), and congestive heart failure (50%). Baseline SU was 7.1 ± 2.4 mg/dl and nine patients (90%) had subcutaneous tophi noted. Seven patients (70%) met responder criteria, receiving 26.6 ± 14.0 infusions (range 13-55) with a pre-infusion-12 SU of 0.9 ± 1.5 mg/dl. The three non-responders received < 12 infusions because of unrelated AEs or loss of follow-up. Three patients (30%) experienced AEs. One had unrelated cardiac disease worsening and three gout flares, one had a pre-infusion solumedrol reaction (wooziness/loss of consciousness), and one had two mild, transient increases in liver enzymes., Conclusions: This study supports leflunomide as co-therapy to pegloticase in uncontrolled gout patients. Heterogeneity and high comorbidity burden in uncontrolled gout patients makes having a variety of immunomodulators options important., (© 2022. The Author(s).)

Refractory, or uncontrolled, gout is a chronic, progressive, inflammatory arthropathy resulting from continued urate deposition after failed attempts to lower serum uric acid below the therapeutic threshold with oral urate-lowering therapies such as allopurinol and febuxostat. Recombinant uricase is increasingly being used to treat refractory gout; however, the immunogenicity of uricase-based therapies has limited the use of these biologic therapies. Antidrug antibodies against biologic therapies, including uricase and PEGylated uricase, can lead to loss of urate-lowering response, increased risk of infusion reactions, and subsequent treatment failure. However, co-therapy with an immunomodulator can attenuate antidrug antibody development, potentially increasing the likelihood of sustained urate lowering, therapy course completion, and successful treatment outcomes. This review summarizes evidence surrounding the use of immunomodulation as co-therapy with recombinant uricases., (© 2022. The Author(s).)

Objective: Thyroid eye disease (TED) is a debilitating autoimmune disease characterized by ocular and periorbital tissue inflammation, proptosis, and visual impairment. The known risk factors for TED include radioactive iodine therapy, female sex, and smoking. The risk factors for severe TED include hyperthyroidism, male sex, smoking, and diabetes; however, little is known about how diabetes mellitus (DM) influences TED. This claims-based analysis examined TED characteristics in patients with and without diabetes., Methods: Symphony database (2010-2015 U.S. claims) was mined for patients with ≥1 Graves' disease diagnosis code and ≥1 TED-associated eye code, including proptosis, strabismus, diplopia, lid retraction, exposure keratoconjunctivitis, and optic neuropathy (ON). DM status was determined based on type 1 or type 2 diabetes coding. Sight-threatening TED was defined as ≥1 ON or exposure keratoconjunctivitis code., Results: A total of 51 220 patients were identified. Of them, 2618 (5.1%) and 12 846 (25.1%) had type 1 and type 2 DM, respectively. Patients with and without DM had similar characteristics, but patients with DM were more often men (type 1: 30.3%, type 2: 28.7% vs no DM: 20.5%; both P < .001) and older at the first TED code. In patients with DM, strabismus (25.4%, 22.6% vs 19.9%) and diplopia (38.6%, 37.9% vs 29.9%) occurred more often but proptosis occurred less often (42.3%, 46.3% vs 58.5%; all P < .001). Sight-threatening TED occurred more often in patients with DM because of higher ON rates., Conclusion: Patients with TED and DM may have more extraocular muscle involvement. Furthermore, the higher prevalence of severe TED stemmed from higher ON rates, possibly associated with diabetes-related vasculopathies. These hypothesis-generating data warrant further exploration., (Copyright © 2021 AACE. Published by Elsevier Inc. All rights reserved.)

Introduction: Thyroid eye disease (TED) is an autoimmune condition producing ocular pain, dysmotility, and ocular structure and function changes. As disease activity changes, redness, swelling, and pain can improve, but eye comfort, appearance, and motility alterations often persist. There are limited data on chronic TED patient-reported outcomes. This study examined chronic US TED patient-reported symptoms and quality of life (QOL)., Methods: Existing data from an online survey regarding chronic TED signs/symptoms and patient QOL were retrospectively examined. The Graves' Ophthalmopathy QOL instrument (GO-QOL; 0-100, 100 = highest QOL) evaluated overall, appearance, and vision-related QOL. Influencing factors were examined by stratifying patients into low (overall QOL ≤ 50), moderate (> 50 and < 75), and high (≥ 75) QOL categories., Results: One hundred patients (47 women, 81 Caucasian, 45.2 ± 7.6 years) were included. The duration of inactive TED was 3.0 ± 4.6 years and total duration of TED was 5.8 ± 5.9 years. Patients reported an average of 20 doctor visits/year and high prevalence of anxiety (34%) and depression (28%). Prior TED treatments for the polled population included systemic corticosteroids during active TED (25%), orbital radiation (5%), and surgery (25%). The overall GO-QOL score was 60.5 ± 21.8 (vision-related: 58.6 ± 24.0, appearance-related: 62.3 ± 25.1). Patients with low QOL more frequently reported hypothyroidism, anxiety, and a larger number of chronic TED signs/symptoms (average: 4.2). Compared to high QOL patients, low QOL patients had more pain (39% vs. 13%), blurry vision (30% vs. 17%), and diplopia (27% vs. 3%, all p ≤ 0.025). Additionally, the low QOL group more often had TED-specific surgical history (45% vs. 10%, p = 0.002), more often reported disability/unemployment (21% vs. 3%, p = 0.055), and had a higher number of doctor visits (40 vs. 5 visits/person/year, p < 0.001)., Conclusion: TED severely impacts patient QOL, despite becoming stable and chronic. Patients reported vision and appearance impairment and psychosocial impact long after acute TED had subsided., (© 2021. The Author(s).)

Introduction: Pegloticase is a recombinant PEGylated uricase that converts relatively insoluble urate to highly water-soluble allantoin, which is readily excreted by the kidneys. It is the first and only biologic treatment indicated for refractory or uncontrolled gout. Clinical trials showed a 6-month pegloticase responder rate of 42%, with the non-responder rate largely being attributed to the development of high-titer anti-drug antibodies (ADAs) against pegloticase. Immunomodulation attenuates ADA formation to biologics in a number of autoimmune conditions, but their use with pegloticase for uncontrolled gout is less established. This systematic review examined published cases of refractory gout patients treated with immunomodulation in combination with pegloticase., Methods: Published cases of immunomodulation with pegloticase were identified in a PubMed search and in abstract databases of major rheumatology society meetings (2012-2020). Duplicate and review articles were excluded, as were those that did not include cases of pegloticase use with immunomodulation. Cases with off-label pegloticase administration schedules were also excluded. Pegloticase response was defined according to each study's specified standard., Results: Ten publications describing 82 cases of pegloticase use in the setting of immunomodulation were identified. Overall pegloticase response rate was 82.9%. Patients co-treated with an individual immunomodulator had the following response rates: methotrexate: 87.5% (35 of 40 patients), mycophenolate mofetil: 86.4% (19 of 22 patients vs. pegloticase monotherapy [placebo]: 40% [4 of 10 patients]), azathioprine: 63.6% (7 of 11 patients), and leflunomide: 66.7% (4 of 6 patients). A single patient was co-treated with cyclosporin and was a responder. The two patients treated with more than one immunomodulator were both responders., Conclusion: Published reports suggest that immunomodulation co-therapy has the potential to markedly improve pegloticase responder rates in patients with uncontrolled gout., Competing Interests: Declarations of Competing Interest RTK has been or is a consultant with Horizon, Selecta Biosciences, Atom Biosciences, Dyve Biosciences, and Sobi; is an advisory board member for Horizon; and has received research support from Sobi and Selecta Biosciences. JKB has received research support from Horizon and Radius Health as a study site and principal investigator and has received consulting/speaker fees from Horizon, Celgene, Novartis, and AbbVie. KRM has received consulting/speaker fees and holds stock in Horizon. LP-S and BL are employees of and hold stock in Horizon. JAA is a consultant with Horizon. MHP has received consulting fees from Horizon and Sobi and investigator-initiated grants from Horizon and Hikma., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Introduction: Gout is a common, progressive, systemic inflammatory arthritis caused by hyperuricemia. Current guidelines recommend that serum uric acid (sUA) levels be maintained below 6.0 mg/dl to minimize acute gout attacks, tophi development, and long-term joint and organ damage. This study examined the influence of uncontrolled gout on post-diagnosis comorbidities and medication use., Methods: The Humana Research Database (2007-2016, commercial insurance and Medicare) was searched (PearlDiver tool) for patients who had a gout diagnosis code, claims data for at least 6 months before and after diagnosis, and at least 90 days of continuous urate-lowering therapy within 1 year of diagnosis. Patients with controlled (all sUA measurements < 6.0 mg/dl) and uncontrolled (all sUA measurements ≥ 8.0 mg/dl) gout were further examined and compared to better understand the influence of uncontrolled gout on post-diagnosis comorbidities, medication use, and reasons for seeking medical care., Results: A total of 5473 and 1358 patients met inclusion and classification criteria for the controlled and uncontrolled groups, respectively. Identified comorbidities in both groups included hypertension, hyperlipidemia, diabetes, cardiovascular disease, and chronic kidney disease (CKD). However, the uncontrolled group was more likely to have diabetes, CKD, and cardiovascular disease (including heart failure and atrial fibrillation). Additionally, CKD tended to be more advanced in the uncontrolled gout population (Stage 4-5: 34.6 vs. 22.2%). Overall opioid use was higher in uncontrolled patients., Conclusions: The current study identified differences between controlled and uncontrolled gout patients, including usage of medication, severity of CKD, and prevalence of CKD, diabetes, and heart disease.

Introduction: Thyroid eye disease (TED) is an autoimmune disease that causes retro-orbital inflammation and subsequent proptosis, corneal exposure, strabismus, and variable vision changes. European studies have shown that TED can severely impact quality of life (QOL), but little is known about the QOL of patients with TED in the USA. Given that patient QOL influences TED severity classifications and subsequent treatment, understanding physician-perceived patient QOL is extremely important., Methods: This retrospective chart review (conducted in 2018) examined QOL in US patients with moderate-to-severe TED, as reported by treating physicians who regularly manage patients with TED (≥ 5 patients in prior 12 months). The physicians graded patients' overall QOL (7-point Likert scale; 1 = "not at all impaired", 7 = "extremely impaired"), assessing mental health, vision changes, and ocular structural signs/symptoms. Patient demographics and clinical findings were examined to understand the impact of disease presentation on physician-perceived QOL., Results: Medical record data of 714 US patients with moderate-to-severe TED were provided by 181 physicians (73 endocrinologists, 108 ophthalmologists). Patients had a mean age of 49.4 (standard deviation [SD] 13.6) years, and 102 cases (14%) were severe. Anxiety and/or depression was reported in 36% of patients (an increase from the 18.9% prevalence reported for the USA in 2017 by the US National Institute of Mental Health; P < 0.001). The mean physician-reported QOL impact score was 4.1 (SD 1.5). Furthermore, 62 and 89% of patients with moderate and severe TED, respectively, had a high physician-perceived QOL impact (≥ 4). The higher QOL impact group had significantly higher rates of pain symptoms, visual disturbances (including diplopia), and orbito-facial structural changes. Higher disease activity and severity were associated with lower physician-perceived QOL., Conclusion: Patients' QOL, as evaluated by US physicians, is highly impacted by the activity and severity of TED. Additionally, mental health issues were more frequently reported by patients with TED than in the general US population. Ocular pain, strabismus, and diplopia appear to be main drivers of physician-perceived QOL impairment in this sample of US patients with TED.

Introduction: Limited data exist on US referral/management patterns for moderate-to-severe thyroid eye disease (TED), a disabling condition., Methods: US ophthalmologists and endocrinologists experienced in treating TED provided medical record data of moderate-to-severe TED patients and information on referral/treatment practices. Data on signs/symptoms, medical/surgical treatments, treatment response, and referral history were collected. Moderate and severe cases were stratified to interrogate treatment/practice differences., Results: A total of 181 physicians provided data on 714 patients (49.4 ± 13.6 years old, 65% women, 14% severe disease). Reporting physicians diagnosed 55% of patients themselves and solely managed 37% of cases, with similar referral/comanagement patterns between moderate and severe cases. Topical therapies included lubricating (79%) and glucocorticoid (39%) eye drops. Systemic therapies included oral glucocorticoids (36%), IV glucocorticoids (15%), and rituximab and/or tocilizumab (12%). Few patients underwent orbital radiation (4%) or surgical intervention (4%). IV glucocorticoids (33% vs. 12%), biologics (26% vs. 10%), orbital radiation (11% vs. 3%), and ocular surgery (12% vs. 3%) were used more often in severe versus moderate cases (all P  < 0.001). However, severe disease was less responsive to therapy (very responsive to therapy: 28% vs. 49%, P  < 0.001)., Conclusions: Participating physicians were primarily responsible for just over one-half of TED diagnoses, but solely treated <40% of patients. Severe TED was treated more often with surgery and systemic immunologic therapies than moderate disease, but was less likely to respond to treatment. These results reinforce that moderate-to-severe TED is difficult to treat with an unmet medical need in the United States., (© The Author(s) 2020. Published by Oxford University Press on behalf of the Endocrine Society.)

Purpose: To evaluate presumed iatrogenic graft failure (PIGF) in Descemet stripping automated endothelial keratoplasty (DSAEK)., Methods: Deidentified data were collected retrospectively from the Illinois Eye Bank between April 2007 and May 2010. PIGF was defined as cases in which a repeat corneal transplant was performed <8 weeks after an initial DSAEK. Data collected for each case included days between initial DSAEK and regraft, regraft type (DSAEK vs. penetrating keratoplasty), precut versus surgeon-cut tissue, and number of DSAEKs distributed to individual surgeons. Ninety-three cases of PIGF were identified for a group of 46 surgeons who received 2504 corneas. Nine PIGF cases from 4 surgeons in cornea fellowships were analyzed separately. Individual surgeon failure rate and overall failure rate were calculated. Analysis of the overall failure rate was conducted without cases performed by surgeons who train fellows. Effect of surgical experience on PIGF was analyzed., Results: Overall presumed iatrogenic DSAEK failure rate was 3.66% (84 PIGF cases divided by 2294 corneas). Within the group of 4 surgeons that trained fellows, the failure rate was 4.29% (9 cases PIGF divided by 210 corneas). Average time to regraft was 27.5 ± 17.4 days. Initial diagnoses included Fuchs dystrophy, pseudophakic bullous keratopathy, edema, and other disease states. Average donor and recipient ages were 54.3 ± 13.0 and 71.7 ± 11.3 years, respectively. Use of precut versus surgeon-cut tissue did not affect overall failure rates. Failure rates of less experienced surgeons (21.8% ± 10.8%) were higher than more experienced surgeons (1.5% ± 1.4%)., Conclusions: Overall, DSAEK failure rates improve as surgeons gain experience. Failure rates in cornea fellowship programs are not excessive.

Background: Optical coherence tomography (OCT) provides microscopic retinal images. Optical coherence tomography is noninvasive, using light waves to produce detailed retinal images. Here, we investigate the ability of OCT to detect early choroidal neovascularization in age-related macular degeneration., Methods: Seventy-nine patients, diagnosed with nonexudative macular degeneration in one eye and exudative macular degeneration in the other were enrolled in this prospective, observational, nonrandomized study. Participants underwent examination (visual acuity, intraocular pressure, biomicroscopy, and ophthalmoscopy) followed by OCT in the study eye (nonexudative macular degeneration eye) every 3 months for 2 years. If examination did not show choroidal neovascularization, but OCT images raised suspicion, patients were reexamined in 4 weeks to 6 weeks and/or fluorescein angiography was performed. Visual acuity, OCT anomaly detected, and time between OCT and fluorescein angiography detection were examined., Results: Fifteen (19%) patients developed exudative macular degeneration, as confirmed by fluorescein angiography, in the study eye. Four additional patients showed potential exudative macular degeneration on OCT only. Of the 15 patients who developed exudative macular degeneration, 13 had disease progression identified on OCT before examination and/or fluorescein angiography showed changes. Subretinal pigment epithelium fluid was the most common OCT anomaly, with development of sub-/intraretinal fluid also visible., Conclusion: Optical coherence tomography could be a powerful screening tool for patients with age-related macular degeneration at high risk for developing choroidal neovascularization.

Purpose: To assess surgeon satisfaction with precut corneal tissue from 1 eye bank for Descemet stripping automated endothelial keratoplasty (DSAEK). Surgical techniques and predictors of procedural success were also examined., Methods: A 19-question survey was completed by 53 surgeons around the United States for 197 DSAEK cases using prepared corneal allograft tissue from the Iowa Lions Eye Bank. Surgeries were performed between April 1 and December 31, 2006; surveys were completed retrospectively within a few weeks of surgery., Results: Tissue was found to be acceptable in 98% of DSAEK cases reported. Difficulties with precut tissue (eg, lack of anterior cap adherence to the posterior lamella, not visible or decentered central dot, anterior edge undermining) were reported in approximately 10% of cases. A rebubbling procedure was performed in 23% of cases for donor dislocations. The donor lenticule adhered, with resulting corneal deturgescence, in 86% of cases. Surgeons declared a successful procedure in 92% of cases. Of the 14 unsuccessful cases, donor tissue quality was the underlying etiology in only 1 case. Procedural success rates were related to surgeon experience (P = 0.002), lenticule adherence after only 1 anterior chamber air bubble (P = 0.005), no small perforations to release fluid (P = 0.005), and the presence of corneal deturgescence (P = 0.002)., Conclusions: The use of precut tissue for DSAEK is not associated with increased risk of complications related to tissue preparation. With standardization of precutting donor tissue, safety of DSAEK surgery may be improved while increasing surgeon efficiency.

Purpose: To evaluate a kindred with familial uveal and cutaneous melanoma and to identify potential genetic and environmental factors that may predispose individuals to develop uveal melanoma., Design: Family-based case report with detailed clinical and genetic evaluation., Participants: Ten siblings in a single nuclear family., Methods: Evaluation of a large sibship via family history, complete eye and skin examinations, environmental risk factor questionnaire, and genetic testing, as well as a MEDLINE search of familial uveal melanoma kindreds., Main Outcome Measures: Cutaneous and ocular nevi, benign and malignant neoplasms of skin and other sites, brief skin cancer risk assessment tool risk classification for cutaneous melanoma, DNA sequencing of p16INK4a and p14ARF genes, and citations on familial uveal melanoma., Results: The proband and his mother had uveal melanoma, 3 cutaneous melanomas occurred among 2 siblings, and 2 other siblings had basal cell carcinomas. No germline mutations were detected in the melanoma-associated tumor suppressor genes p16INK4a and p14ARF. Seven out of 10 siblings had a history of cutaneous and/or ocular nevi. Of the 3 subjects without nevi, 2 had histories of eye or skin malignancies (1 uveal melanoma, 1 basal cell carcinoma). Three of the 10 siblings had relevant ocular findings (2 choroidal nevi, 1 uveal melanoma). Six were also found to be in the "high-risk" classification for cutaneous malignancies based on scores from a previously validated risk assessment tool. This family, combined with the 91 previously reported familial uveal melanoma kindreds, brings to 92 the total number thus far recorded., Conclusions: Our results strengthen the association between uveal melanoma, atypical nevi, and cutaneous melanoma. This relationship supports the recommendation that individuals with a personal or family history of uveal melanoma, particularly in combination with atypical nevi, should be regularly screened for uveal and cutaneous melanoma.

Purpose: To examine phototransduction using the a-wave and other aspects of retinal function with the intraretinal b- and c-waves at different stages of an inherited photoreceptor degeneration in Abyssinian cats., Methods: Vitreal and intraretinal ERGs were recorded from eight dark-adapted, anesthetized Abyssinian cats. Brief bright flashes were used to elicit vitreal a- and b-waves. Longer, weaker flashes were used to elicit intraretinal b- and c-waves. Stages 1 through 4 of the disease were characterized ophthalmoscopically. Parameters of the Lamb and Pugh a-wave model (a(max), A, and t(eff)) for the Abyssinian cats were compared with those for normal cats. Light microscopy was used to count photoreceptor nuclei., Results: The maximum a-wave amplitude, a(max), was significantly smaller in stage 1, and continued to decrease (stage 1: 50% of normal, stage 2: 28%, stage 3: 27%; and stage 4: unrecordable). There was a small, but not significant, decrease in the amplification constant A from 0.24 +/- 0.11 s(-2) in normal cats to 0.16 +/- 0.08 s(-2) in Abyssinian cats. The intraretinal b- and c-wave amplitudes decreased most dramatically during the early stage of the disease. Affected animals had fewer photoreceptors than unaffected Abyssinians or control animals. The number of photoreceptors declined most rapidly in the inferior periphery., Conclusions: The amplitudes of all ERG components were already reduced significantly by stage 1 and progressively declined. The lack of major changes in a-wave model parameters indicates that the degeneration is probably not due to a mutation in transduction proteins. Losses of photoreceptor function were larger than losses of photoreceptor nuclei.

Purpose: To investigate the effects of a hereditary retinal degeneration on retinal oxygenation and determine whether it is responsible for the severe attenuation of retinal circulation in hereditary photoreceptor degenerations., Methods: Seven adult Abyssinian cats affected by hereditary retinal degeneration were studied. Oxygen microelectrodes were used to collect spatial profiles of retinal oxygenation in anesthetized animals. A one-dimensional model of oxygen diffusion was fitted to the data to quantify photoreceptor oxygen utilization (Qo(2))., Results: Photoreceptor Qo(2) progressively decreased until it reached zero in the end stage of the disease. Average inner retinal oxygen tension remained within normal limits at all disease stages, despite the observed progressive retinal vessel attenuation. Light affected photoreceptors normally, decreasing Qo(2) by approximately 50% at all stages of the disease., Conclusions: Loss of photoreceptor metabolism allows choroidal oxygen to reach the inner retina, attenuating the retinal circulation in this animal model of retinitis pigmentosa (RP) and probably also in human RP. As the degeneration progresses, there is a strong relationship between changes in the a-wave of the ERG and changes in rod oxidative metabolism, indicating that these two functional measures change together.

Purpose: To evaluate and compare the visual outcomes and accommodative amplitude in cataract patients after implantation of the Crystalens intraocular lens (IOL) (Eyeonics) versus standard monofocal IOLs., Setting: Ten clinics in a nationwide multicenter study in the United States., Methods: A multicenter comparative interventional case series with masked randomized postoperative examination of 224 eyes of 112 patients was performed by a single observer. Patients were divided into 2 groups (56 patients; 112 eyes each) depending on which IOL was implanted (Crystalens or monofocal). Accommodation was measured using 1 objective (dynamic retinoscopy) and 2 subjective methods (defocus and near point of accommodation). Visual acuity measurements were performed under the same conditions with standard visual acuity charts., Results: Uncorrected monocular near vision was significantly better in the Crystalens group than in the standard monofocal group, with 101 of 112 eyes (90%) and 17 of 112 (15%), respectfully, reading J3 or better postoperatively. All 56 Crystalens patients had a binocular uncorrected near visual acuity of J3 or better compared with 16 of 56 (29%) standard monofocal patients. The mean postoperative monocular (0.85 +/- 0.30 [SD] versus 0.70 +/- 0.19, P<.01) and binocular (1.16 +/- 0.17 versus 1.01 +/- 0.14, P<.01) distance uncorrected visual acuities were also better in the Crystalens group than in the control group. All patients in the study achieved a corrected distance visual acuity of 20/20 or better. Measures of accommodation were significantly higher in Crystalens patients than in the monofocal IOL patients (dynamic retinoscopy 2.42 +/- 0.39 diopters [D] versus 0.91 +/- 0.24 D, P<.01; monocular defocus 1.74 +/- 0.48 D versus 0.75 +/- 0.25 D, P<.01; monocular near point of accommodation 9.5 +/- 3.1 inches versus 34.7 +/- 9.8 inches, P<.01). Perceived accommodation (5.79 D) was significantly greater than the measured accommodation (1.96 to 2.42 D) in Crystalens patients (paired t test, P<.01)., Conclusions: The Crystalens IOL provided better uncorrected near and distance visual outcomes than standard monofocal IOLs in all analyses performed. Patients perceived a greater accommodation than measured. Understanding why this occurred could lead to valuable advances in accommodating IOL technology.

Objective: To examine the effects of acute hypoxemia and hyperglycemia on retinal pH to understand hyperglycemia-induced changes in the normal intact cat retina., Methods: Spatial profiles of extracellular hydrogen ion (H+) concentration were obtained from the cat retina, in vivo, using pH-sensitive microelectrodes during normoxia (arterial partial pressure of oxygen [PaO2] = 114.5 +/- 7.9 mm Hg), normoglycemia (plasma glucose concentration, 117 +/- 19 mg/dL), acute hypoxemia (PaO2 = 29.5 +/- 2.2 mm Hg), and acute hyperglycemia (plasma glucose concentration, 303 +/- 67 mg/dL). An H+ diffusion model was fitted to the outer retinal data to quantify photoreceptor H+ production. The inner retinal pH was also examined., Results: Hypoxemia induced a mean acute panretinal acidification of 0.16 pH units that originated from a 2.55-fold increase in net photoreceptor H+ production. Hyperglycemia induced an acute panretinal acidification of 0.12 pH units; however, photoreceptor H+ production levels remained unchanged. Retinal pH changes followed the course of arterial PaO2 and blood glucose changes., Conclusions: The increase in photoreceptor H+ production during hypoxemia confirms the importance of glycolysis in the retina. Hyperglycemia-induced pH changes resulted from either increased inner retinal H+ production or decreased H+ clearance/neutralization. Clinical Relevance The hyperglycemia-induced acidification that originates in the inner retina suggests that retinal acidosis may contribute to the development of diabetic retinal disease.

Purpose: To examine intraretinal extracellular H+ concentration([H+]o) in diabetic cats., Methods: Double-barreled H+-selective microelectrodes were used to measure [H+]o as a function of retinal depth ([H+]o profiles) in four cats with different stages of diabetic retinopathy. Profiles from "normal"and "damaged" areas of the retina were compared to profiles previously obtained from healthy cats., Results: In the healthy retina, [H+]o is generally highest in the middle of the retina and decreases toward the choroid and the vitreous. In 48 % of the profiles from diabetic animals with visible retinopathy, the inner retinal gradient was reversed so that the vitreous was more acidic than the middle of the retina. The profiles with reversed inner retinal gradients were classified as damaged. On the average, the inner retina tended to be 0.07-0.08 pH units more acidic in diabetic animals than in healthy normoglycemic animals, but of similar acidity to healthy hyperglycemic animals. In areas with damaged inner retinal gradients, net H+ production in the outer retina was also impaired., Conclusions: While the number of animals is small, we conclude that the [H+](O) distribution varied from normal to damaged in the same retina. Diabetes seems to lead to an acidification of the inner retina that appears to be at least partly related to hyperglycemia and which may be important in the progression of retinopathy.

Purpose: The Crabtree effect is the phenomenon of inhibition of respiration by glycolysis, as a result of elevated glucose levels. It is not certain whether the Crabtree effect occurs in the retina, which has a high glycolytic capacity. In the current study, in vivo photoreceptor oxygen consumption was examined during the normo- and hyperglycemic states in the dark-adapted cat retina to determine whether the Crabtree effect occurs in the outer retina., Methods: Spatial profiles of oxygen tension were obtained in the cat retina, in vivo, with the use of oxygen microelectrodes during control conditions and acute (5.19 +/- 0.83 hour) episodes of hyperglycemia (blood glucose, >350 mg/dL). The outer retinal portions of the profiles were fitted to a model of oxygen diffusion to quantify photoreceptor oxygen consumption., Results: Photoreceptor oxygen consumption did not significantly change during hyperglycemia compared with control conditions. Choroidal PO(2) decreased during hyperglycemia by an average of 5.8 +/- 7.4 mm Hg. This led to an increase in the fraction of O(2) used by the photoreceptors that was derived from the inner retina. Choroidal PO(2) did not recover when blood glucose levels were returned to normal. Average inner retinal PO(2) was not affected by the episodes of hyperglycemia., Conclusions: The Crabtree effect does not occur to any significant degree in the outer retina, because hyperglycemia did not affect photoreceptor oxygen consumption. Choroidal PO(2) decreased during hyperglycemia, and the oxygen deficit was made up by the retinal circulation.

We examined intraretinal [H+] in the intact retina of anesthetized cats using H+-sensitive microelectrodes to obtain spatial profiles of extracellular [H+]. One H+ is produced when an anaerobically generated ATP is utilized. We theorized that H+ production directly reflects anaerobic glucose consumption. From the choroid (pH approximately 7.40), [H+]o steadily increased to a maximum concentration in the proximal portion of the outer nuclear layer (pH approximately 7.20). The shape of the profile was always concave down, indicating that a net production of H+ occurred across the avascular outer retina. A three-layer diffusion model of the outer retina was developed and fitted to the data to quantify photoreceptor H+ extrusion into the extracellular space (Q(OR-H+)). It was determined that the outer segment (OS) layer had negligible H+ extrusion. The data were then refitted to a special three-layer model in which the OS layer Q(H+) was set equal to zero, but in which the inner segments and outer nuclear layer produced H+. The resulting Q(OR-H+) was several orders of magnitude lower than previous measurements of Q(OR-lactate), which were based on choroidal mass balances of lactate. Stoichiometrically, one H+ is produced for each lactate produced, so we concluded that Q(OR-H+) is a measure of net rather than total H+ production. Because retinal acid production is so high, the retina must contain efficient H+ clearance and/or neutralization mechanisms that prevent severe acidosis. The effect of light on retinal extracellular [H+] and Q(OR-H+) was also examined. As expected, light adaptation caused a retinal alkalinization that resulted from a 52% reduction in Q(OR-H+). This is in agreement with previous studies that have shown that both oxidative (e.g. Haugh et al., 1990) and glycolytic metabolism (Wang et al., 1997a,c) in the photoreceptor are decreased by a factor of 2 during light adaptation. Although we could not obtain absolute values for outer retinal glycolysis, changes in Q(OR-H+) appear to directly reflect changes in glycolytic metabolism.

Purpose: This article assesses the hypothesis that the high blood flow rate and low O(2) extraction associated with the choroidal circulation are metabolically necessary and explores the implications of the spatial relationship between the choroid and the photoreceptors for metabolism in the normal and detached retina., Methods: The O(2) distribution across the retinal layers was previously measured with O(2)-sensitive microelectrodes in cat. Profiles were fitted to a diffusion model to obtain parameters characterizing photoreceptor O(2) demand. This was a study of simulations based on those parameters., Results: Photoreceptor inner segments have a high O(2) demand (QO(2)), and they are far (20 to 30 microm) from the choroid. These unusual conditions require a large O(2) flux to the inner segments, which in turn requires high choroidal oxygen tension (PO(2)), high choroidal venous saturation (ScvO(2)), low choroidal O(2) oxygen extraction per unit volume of blood, and a choroidal blood flow (ChBF) of at least 500 ml/100 g-min. Movement of the inner segments further from the choroid, which occurs in a retinal detachment, severely reduces the ability of the inner segments to obtain O(2), even for detachment heights as small as 100 microm. Depending on detachment height and assumptions about choroidal and inner retinal PO(2) during elevation of inspired O(2) (hyperoxia), hyperoxia is predicted to partially or fully restore photoreceptor QO(2) during a detachment., Conclusions: The choroid is not overperfused, but requires a high flow rate to satisfy the normal metabolic demand of the retina. Because the oxygenation of the photoreceptors is barely adequate under normal conditions, detachment has serious metabolic consequences. Hyperoxia is predicted to have clinical benefit during detachment.