Inflammatory and Noninflammatory Thyroid Eye Disease: Comparison of Disease Signs, Symptoms, and Quality of Life in Patients in the United States.

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.

Characteristics of Diabetic and Nondiabetic Patients With Thyroid Eye Disease in the United States: A Claims-Based Analysis.

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.

Intensive urate-lowering with pegloticase plus methotrexate co-therapy in uncontrolled gout patients with and without chronic kidney disease: A retrospective case series.

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 ±â€…11.3 mL/min/1.73 m2; SU: 8.6 ±â€…2.2 mg/dL), 27 non-CKD (eGFR: 82.9 ±â€…19.0 mL/min/1.73 m2; SU: 9.5 ±â€…1.7 mg/dL) patients were included. Comorbidity profiles were similar, but CKD patients were older (72.0 ±â€…9.9 vs 52.3 ±â€…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 ±â€…8.1 [CKD] vs 14.1 ±â€…7.1 [non-CKD] pegloticase infusions. However, CKD patients had lower MTX dose (14.8 ±â€…5.8 vs 19.3 ±â€…4.9 mg/week). Urate-lowering response was similar (92% vs 86%). eGFR increased during treatment in 60% of CKD (+11.5 ±â€…20.9 mL/min/1.73 m2, 87% stable/improved CKD-stage) and 44% of non-CKD (+4.2 ±â€…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.

Monosodium urate crystal depletion and bone erosion remodeling during pegloticase treatment in patients with uncontrolled gout: Exploratory dual-energy computed tomography findings from MIRROR RCT.

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 (VMSU)<0.5cm3 were excluded to minimize artifact contributions. VMSU 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, VMSU 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 VMSU depletion during pegloticase therapy was observed with concomitant bone remodeling within 1year. Following pegloticase discontinuation, VMSU reduction slowed or stopped even when SU was maintained<6mg/dL with oral ULT. CLINICAL TRIAL REGISTRATION: NCT03994731.

Projected Health and Economic Burden of Comorbid Gout and Chronic Kidney Disease in a Virtual US Population: A Microsimulation Study.

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.

Urate-lowering therapy, serum urate, inflammatory biomarkers, and renal function in patients with gout following pegloticase discontinuation.

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.

Comparison Between Early-Onset and Common Gout: A Systematic Literature Review.

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.

Gout, an inflammatory arthritis caused by high urate levels in the blood (SU), is associated with medical issues, including heart disease, high blood pressure, type 2 diabetes, and kidney disease. Millions of Americans have gout, with some having early-onset gout (EOG), generally the first gout attack at or before 40 years of age. Little information on EOG has been published; this literature review provides insight. More recent articles and major rheumatology meeting presentations (2016 to August 2022) on EOG were reviewed. Publications that were duplicates, not in English, on a single patient, or were not relevant/did contain enough information were excluded. The age at gout diagnosis determined if patients had common gout (CG) or EOG. Of the 283 publications identified, 17 were included in this review. Gout-associated medical issues (heart, metabolic, and kidney-related) were less common in EOG than CG patients and occurred after gout diagnosis in EOG patients. Compared to CG patients, EOG patients more often had severe gout (more gout attacks and affected joints), higher SU, and worse response to oral SU-lowering medications. Genetics-focused publications showed that mutations affecting how urate is removed from the body are more common in EOG patients. Overall, the literature suggests that EOG may be difficult to treat, has a genetic component, and has a heavy disease burden. Therefore, early rheumatology referral and gout management may benefit EOG patients due to a potential "window of opportunity" where proper SU control may prevent gout-related suffering and health burden in young EOG patients who will live with gout and its consequences for decades.

A Randomized, Double-Blind, Placebo-Controlled Multicenter Efficacy and Safety Study of Methotrexate to Increase Response Rates in Patients With Uncontrolled Gout Receiving Pegloticase: 12-Month Findings.

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.

Pilot study for the detection of early exudative age-related macular degeneration with optical coherence tomography.

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.

Enhancing the Response Rate to Recombinant Uricases in Patients with Gout.

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.

Effect of Leflunomide on Pegloticase Response Rate in Patients with Uncontrolled Gout: A Retrospective Study.

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.

Community Practice Experiences with a Variety of Immunomodulatory Agents Co-Administered with Pegloticase for the Treatment of Uncontrolled Gout.

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 m2 (41% eGFR < 60 ml/min/1.73 m2). 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 m2), 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.

Patients with gout that does not respond to oral urate-lowering therapies have heavy disease burden and few treatment options. Pegloticase lowers serum urate levels (SU) and resolves tophi, but anti-drug antibodies can limit urate-lowering efficacy duration. Evidence increasingly supports co-administering an immunomodulator with pegloticase to increase the proportion of patients with sustained urate-lowering response. However, there are few published cases from real-world clinical practice. This study examined treatment with pegloticase + immunomodulation at two community rheumatology practices. Patients who began treatment with pegloticase and an immunomodulator in 2017 or later were included. The proportion of patients with sustained urate-lowering response (≥ 12 infusions received, SU < 6 mg/dl at infusion 12) was investigated. Renal function before and after therapy was also examined. Thirty-four patients were included. Before treatment, SU averaged 9.1 mg/dl and most-reported comorbidities were hypertension (76%), obesity (71%), osteoarthritis (68%), and chronic kidney disease (47%). All patients began using an immunomodulator before or at first pegloticase infusion (subcutaneous methotrexate [20 patients], oral methotrexate [9 patients], mycophenolate mofetil [3 patients], and azathioprine [2 patients]). On average, 14.6 infusions were administered over 28.5 weeks and overall response rate was 89%. Response rate varied among different immunomodulators: subcutaneous methotrexate: 93%, oral methotrexate: 89%, mycophenolate mofetil: 100%, azathioprine: 50%. On average, kidney function improved, with chronic kidney disease stage stability/improvement in 85% of patients. Nineteen patients (56%) experienced gout flares. No infusion reactions or infections were noted and no new safety concerns were identified. These real-world findings provide further support for administering immunomodulation as co-therapy to pegloticase.

Quality of Life in Patients with Chronic Thyroid Eye Disease in the United States.

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.

Thyroid eye disease (TED) occurs when loss of immune tolerance results in orbital and retro-orbital inflammation. Fat and muscle tissue can swell severely, causing debilitating symptoms, including pain around/behind the eyes, eye movement abnormalities, bulging eyes (proptosis), and double vision (diplopia), manifesting in appearance and vision quality of life (QOL) changes. Some improvement can occur as inflammation quiets and TED becomes chronic/inactive. However, appearance and visual changes often remain due to persistent proptosis and eye muscle and eyelid changes. This study examined TED symptoms and QOL in 100 chronic TED patients. They answered questions about symptoms, how TED affected them, and their medical care. The average duration of TED was 6 years (3 years inactive), patients had an average of 20 TED-related doctor visits/year, and nearly one-half (42%) of patients reported having anxiety and/or depression. Prior TED treatments included steroids (25% when TED-related inflammation was present), orbital radiation (5%), and surgery (25%). Disease-specific QOL scores (average score: 60.5 of 100) indicated that these chronic patients reported similar QOL impact as those with moderate-to-severe, active disease. Compared with the least impacted group, the most impacted patients reported higher rates of hypothyroidism (18% vs. 0%), anxiety (48% vs. 17%), disability/unemployment (21% vs.3%), number of doctor visits (40 vs. 5 visits/person/year), pain (39% vs. 13%), blurry vision (30% vs. 17%), diplopia (27% vs. 3%), and surgical treatment for TED (45% vs. 10%). This study demonstrates that QOL continues to be severely impacted by TED long after TED-related inflammation has quieted.

Characteristics, Comorbidities, and Potential Consequences of Uncontrolled Gout: An Insurance-Claims Database Study.

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.

The effect of immunomodulators on the efficacy and tolerability of pegloticase: a systematic review.

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.

Physician-Perceived Impact of Thyroid Eye Disease on Patient Quality of Life in the United States.

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.

Little is known on how thyroid eye disease (TED) affects patient quality of life (QOL) in the USA. Patient QOL can affect how TED is treated; consequently, it is important to understand how physicians perceive QOL in patients with TED. We evaluated 714 patients, as reported by physicians, with this rare condition to better understand QOL in US patients with TED. The medical records of 612 patients with moderate TED and 102 patients with severe TED were examined. QOL impact was rated from 1 to 7, with 1 being "not at all impaired" and 7 being "extremely impaired." Overall QOL, as assessed by treating physicians, is heavily impacted by both moderate and severe TED in US patients, with these patients also reported to have a higher frequency of mental health diagnoses than reported in the general US adult population. Higher levels of inflammation on and around the eye and more severe disease led to a higher QOL impairment. More specifically, pain, visual disturbances (including double vision), and changes to the face and tissues around the eye all negatively affected QOL.

Trends in Treatment of Active, Moderate-to-Severe Thyroid Eye Disease in the United States.

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 ±â€…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.

Genetic study of familial uveal melanoma: association of uveal and cutaneous melanoma with cutaneous and ocular nevi.

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.

The electroretinogram components in Abyssinian cats with hereditary retinal degeneration.

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.