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Introduction: Relative to the general population, patients with schizophrenia or schizoaffective disorder have higher rates of suicide attempts and mortality from COVID-19 infection. Therefore, determining whether a history of suicide attempt is associated with COVID-19 in patients with schizophrenia or schizoaffective disorder has implications for COVID-19 vulnerability stratification in this patient population. Methods: We carried out cross-sectional analyses of electronic health records of veterans with a diagnosis of schizophrenia or schizoaffective disorder that received treatment at any United States Veterans Affairs Medical Center between January 1, 2020, and January 31, 2021. We used logistic regression to estimate unadjusted and adjusted (including age, sex, race, marital status, body mass index (BMI), and a medical comorbidity score) odds ratios (ORs) for COVID-19 positivity in suicide attempters relative to nonattempters. Results: A total of 101,032 veterans (mean age 56.67 ± 13.13 years; males 91,715 [90.8%]) were included in the analyses. There were 2,703 (2.7%) suicide attempters and 719 (0.7%) patients were positive for COVID-19. The association between history of suicide attempt and COVID-19 positivity was modified by age and BMI, such that the relationship was only significant in patients younger than 59 years, and in obese (BMI ≥30) patients (adjusted OR 3.42, 95% CI 2.02–5.79 and OR 2.85, 95% CI 1.65–4.94, respectively). Conclusions: Higher rates of COVID-19 in young or obese suicide attempters with a diagnosis of schizophrenia or schizoaffective disorder might be due to the elevated risk for the infection in this subgroup of patients.

ObjectiveTo determine the joint role of ideal cardiovascular health (CVH) and genetic risk on risk of dementia.MethodsWe categorized CVH on the basis of the American Heart Association Ideal CVH Index and genetic risk through a genetic risk score (GRS) of common genetic variants and the APOE ε4 genotype in 1,211 Framingham Heart Study (FHS) offspring cohort participants. We used multivariable Cox proportional hazards regression models to examine the association between CVH, genetic risk, and incident all-cause dementia with up to 10 years of follow-up (mean 8.4 years, 96 incident dementia cases), adjusting for age, sex, and education.ResultsWe observed that a high GRS (>80th percentile) was associated with a 2.6-fold risk of dementia (95% confidence interval [CI] of hazard ratio [HR] 1.23–5.29; p = 0.012) compared with having a low GRS (APOE ε4 allele was associated with a 2.3-fold risk of dementia compared with not carrying an APOE ε4 allele (95% CI of HR 1.49–3.53; p = 0.0002), and having a favorable CVH showed a 0.45-fold lower risk of dementia (95% CI of HR 0.20–1.01; p = 0.0527) compared to having an unfavorable CVH when all 3 components were included in the model. We did not observe an interaction between CVH and GRS (p = 0.99) or APOE ε4 (p = 0.16).ConclusionsWe observed that both genetic risk and CVH contribute additively to dementia risk.

Background: Publications suggest immunomodulation co-therapy improves responder rates in uncontrolled/refractory gout patients undergoing pegloticase treatment. The MIRROR open-label trial showed a 6-month pegloticase+methotrexate co-therapy responder rate of 79%, compared to an established 42% pegloticase monotherapy responder rate. Longer-term efficacy/safety data are presented here.Methods: Uncontrolled gout patients (serum urate [SU]≥6 mg/dL and SU≥6 mg/dL despite urate-lowering therapy [ULT], ULT intolerance, or functionally-limiting tophi) were included. Patients with immunocompromised status, G6PD deficiency, severe kidney disease, or methotrexate contraindication were excluded. Oral methotrexate (15 mg/week) and folic acid (1 mg/day) were administered 4-weeks before and during pegloticase therapy. Twelve-month responder rate (SUResults: Fourteen patients were included (all male, 49.3 ± 8.7 years, 13.8 ± 7.4 year gout history, pre-therapy SU: 9.2 ± 2.5 mg/dL). Three patients were non-responders and discontinued study treatment before 24-weeks, one patient exited the study per-protocol at 24-weeks (enrolled prior to treatment extension amendment), and 10 remained in study through Week 52. Of the 10, 8 completed 52-weeks of pegloticase+methotrexate and were 12-month responders. The remaining two discontinued pegloticase+methotrexate at Week 24 (met treatment goals) and stayed in study under observation (allopurinol prescribed at physicians’ discretion); one remained a responder at 12-months. At 52-weeks, change from baseline in SU was -8.2 ± 4.1 mg/dL (SU: 1.1 ± 2.4 mg/dL, n=10). Gout flares were common early in treatment but progressively decreased while on therapy (Weeks 1-12: 13/14 [92.9%], Weeks 36-52: 2/8 [25.0%]). One patient recovered from sepsis (serious AE). Two non-responders developed high ADA titres; fewer patients had trough concentrations (Cmin) below quantitation limit (BQL) and median Cmin was higher (1.03 mg/mL vs. BQL) than in pegloticase monotherapy trials.Conclusions: Methotrexate+pegloticase co-therapy was well-tolerated over 12-months, with sustained SU lowering, progressive gout flare reduction, and no new safety concerns. Antibody/PK findings suggest methotrexate attenuates ADA formation, coincident with higher treatment response rates.Trial registration: ClinicalTrials.gov: NCT03635957, registered 17 August 2018, https://clinicaltrials.gov/ct2/show/NCT03635957

ImportanceAs patients with schizophrenia or schizoaffective disorder have a high risk of suicide, and a history of suicide attempt is a strong predictor of suicide, determining whether history of suicide attempt is associated with COVID-19 in patients with schizophrenia or schizoaffective disorder has implications for suicide prevention in this patient population.ObjectiveTo determine whether a history of suicide attempt is associated with COVID-19 in Veterans with schizophrenia or schizoaffective disorder.DesignCross-sectional analyses of nation-wide electronic health records (EHR).SettingUnited States Veterans Health Administration.ParticipantsVeterans with a diagnosis of schizophrenia or schizoaffective disorder that received treatment at any United States Veterans Affairs Medical Center from January 1, 2020 to January 31, 2021.ExposureHistory of suicide attempt.Main OutcomeAdjusted and unadjusted odds ratios (ORs) for COVID-19 positivity in suicide attempters relative to non-attempters. Adjusted analyses included age, sex, race, marital status, BMI, and a medical comorbidity score.ResultsA total of 101,032 Veterans [mean age 56.67 ± 13.13 years; males 91,715 (90.8%)] were included in the analyses. There were 2,703 (2.7%) suicide attempters and 719 (0.7%) patients were positive for COVID-19. There was effect modification by age and BMI in the association of history of suicide attempt with COVID-19 positivity such that the association was only significant in obese (BMI ≥ 30) patients and patients younger than 59 years respectively. In the entire sample, the unadjusted OR for COVID-19 positivity in attempters was 1.42 (95% CI 0.97 to 2.10) and the adjusted odds ratio was 1.90 (95% CI 1.28 to 2.80). In patients younger than 59 years, and in the obese patients respectively, history of suicide attempt was associated with COVID-positive status in unadjusted analyses [OR 3.53 (95% CI 2.10 to 5.94); OR 2.22 (95% CI 1.29 to 3.81)] and adjusted analyses [OR 3.42 (95% CI 2.02 to 5.79); OR 2.85 (95% CI 1.65 to 4.94)].Conclusions and RelevanceYoung or obese suicide attempters with a diagnosis of schizophrenia or schizoaffective disorders have higher rates of COVID-19 diagnosis; due to possible long-term neuropsychiatric sequelae of infection with SARS-CoV-2, such patients should be monitored closely.

Background:Familial sitosterolemia is a rare Mendelian disorder characterized by hyperabsorption and decreased biliary excretion of dietary sterols. Affected individuals typically have complete genetic deficiency—homozygous loss-of-function (LoF) variants—in theABCG5orABCG8genes and have substantially elevated plasma sitosterol and LDL (low-density lipoprotein) cholesterol (LDL-C) levels. The impact of partial genetic deficiency ofABCG5orABCG8—as occurs in heterozygous carriers of LoF variants—on LDL-C and risk of coronary artery disease (CAD) has remained uncertain.Methods:We first recruited 9 sitosterolemia families, identified causative LoF variants inABCG5orABCG8, and evaluated the associations of theseABCG5orABCG8LoF variants with plasma phytosterols and lipid levels. We next assessed for LoF variants inABCG5orABCG8in CAD cases (n=29 321) versus controls (n=357 326). We tested the association of rare LoF variants inABCG5orABCG8with blood lipids and risk for CAD. Rare LoF variants were defined as protein-truncating variants with minor allele frequency ABCG5orABCG8.Results:In sitosterolemia families, 7 pedigrees harbored causative LoF variants inABCG5and 2 pedigrees inABCG8. Homozygous LoF variants in eitherABCG5orABCG8led to marked elevations in sitosterol and LDL-C. Of those sitosterolemia families, heterozygous carriers ofABCG5LoF variants exhibited increased sitosterol and LDL-C levels compared with noncarriers. Within large-scale CAD case-control cohorts, prevalence of rare LoF variants inABCG5and inABCG8was ≈0.1% each.ABCG5heterozygous LoF variant carriers had significantly elevated LDL-C levels (25 mg/dL [95% CI, 14–35];P=1.1×10−6) and were at 2-fold increased risk of CAD (odds ratio, 2.06 [95% CI, 1.27–3.35];P=0.004). By contrast,ABCG8heterozygous LoF carrier status was not associated with increased LDL-C or risk of CAD.Conclusions:Although familial sitosterolemia is traditionally considered as a recessive disorder, we observed that heterozygous carriers of an LoF variant inABCG5had significantly increased sitosterol and LDL-C levels and a 2-fold increase in risk of CAD.

ObjectiveTo examine the efficacy and safety of pegloticase in combination with methotrexate (MTX) in patients with uncontrolled gout in an exploratory, open-label clinical trial (ClinicalTrials.gov: NCT03635957) prior to a randomized, controlled trial.MethodsA multicenter, open-label efficacy and safety study of pegloticase with MTX co-treatment was conducted in patients with uncontrolled gout. Patients were administered oral MTX (15 mg/week) and folic acid (1 mg/day) 4 weeks prior to and throughout pegloticase treatment. The primary study outcome was the proportion of responders, defined as serum uric acid (sUA) < 6 mg/dL for ≥ 80% of the time during Month 6 (Weeks 20, 22, and 24). All analyses were performed on a modified intent-to-treat population, defined as patients who received ≥ 1 pegloticase infusion.ResultsSeventeen patients were screened and 14 patients (all men, average age 49.3 ± 8.7 years) were enrolled. On Day 1, mean sUA was 9.2 ± 2.5 mg/dL, and 12 of the 14 patients had visible tophi. At the 6-month timepoint, 11/14 (78.6%, 95% CI 49.2–95.3%) met the responder definition, with 3 patients discontinuing after meeting protocol-defined treatment discontinuation rules (preinfusion sUA values > 6 mg/dL at 2 consecutive scheduled visits). All patients tolerated MTX. No new safety concerns were identified.ConclusionIn this study, an increased proportion of patients maintained therapeutic response at 6 months when treated concomitantly with MTX and pegloticase as compared to the previously reported 42% using pegloticase alone. These results support the need for a randomized study of MTX or placebo with pegloticase to validate these open-label findings.

Autosomal genetic analyses of blood lipids have yielded key insights for coronary heart disease (CHD). However, X chromosome genetic variation is understudied for blood lipids in large sample sizes. We now analyze genetic and blood lipid data in a high-coverage whole X chromosome sequencing study of 65,322 multi-ancestry participants and perform replication among 456,893 European participants. Common alleles on chromosome Xq23 are strongly associated with reduced total cholesterol, LDL cholesterol, and triglycerides (min P = 8.5 × 10−72), with similar effects for males and females. Chromosome Xq23 lipid-lowering alleles are associated with reduced odds for CHD among 42,545 cases and 591,247 controls (P = 1.7 × 10−4), and reduced odds for diabetes mellitus type 2 among 54,095 cases and 573,885 controls (P = 1.4 × 10−5). Although we observe an association with increased BMI, waist-to-hip ratio adjusted for BMI is reduced, bioimpedance analyses indicate increased gluteofemoral fat, and abdominal MRI analyses indicate reduced visceral adiposity. Co-localization analyses strongly correlate increased CHRDL1 gene expression, particularly in adipose tissue, with reduced concentrations of blood lipids., The influence of X chromosome genetic variation on blood lipids and coronary heart disease (CHD) is not well understood. Here, the authors analyse X chromosome sequencing data across 65,322 multi-ancestry individuals, identifying associations of the Xq23 locus with lipid changes and reduced risk of CHD and diabetes mellitus.

Epidemiological and genetic studies have pointed to the role of cholesterol in Alzheimer's disease (AD). We explored the interaction of a genetic risk score (GRS) of AD risk alleles with mid-life plasma lipid levels (LDL-C, HDL-C, and triglycerides) on risk for AD in the Framingham Heart Study (FHS). Mid-life (between the ages of 40-60 years old) lipid levels were obtained from individuals in the FHS Original and Offspring cohorts (157 cases and 2,882 controls) with genetic data and AD status available. Cox proportional hazards regression was performed to test the interaction between mid-life lipid levels and an AD GRS, as well as the individual contributing SNPs, on risk of incident AD adjusting for age, sex, and cohort. We found a significant interaction between a GRS of AD loci and log triglyceride levels on risk of clinical AD (p = 0.006), but no interaction of the GRS with HDL-C (p = 0.458) or LDL-C (p = 0.366). We then tested the interaction between the individual SNPs contributing to the GRS and log triglycerides. We found two SNPs that had interactions with triglycerides on AD risk that reached a p-value < 0.05 (rs11218343 and APOEɛ4). The association between some AD SNPs and risk of AD may be modified by triglyceride levels. Furthermore, sequential testing of a GRS with a set of traits on disease followed by testing individual SNPs for interaction provides a framework for narrowing the associations that need to be tested for interaction analyses. Replication is needed to confirm these findings.

OBJECTIVE To investigate the safety and efficacy of ABT-122, a tumor necrosis factor (TNF)- and interleukin-17A (IL-17A)-targeted dual variable domain immunoglobulin, in patients with active psoriatic arthritis (PsA) who have experienced an inadequate response to methotrexate. METHODS Patients (n = 240) were randomized to receive ABT-122 (120 or 240 mg every week), adalimumab (40 mg every other week), or placebo in a 12-week double-blind, parallel-group study. The primary efficacy end point was the proportion of patients achieving ≥20% improvement in disease activity according to the American College of Rheumatology response criteria (ACR20) at week 12. Secondary and exploratory 12-week end points included 50% improvement (ACR50) and 70% improvement (ACR70) response rates, and proportion of patients meeting the Psoriasis Area and Severity Index (PASI) response criteria for ≥75% (PASI75) and ≥90% (PASI90) improvement in skin scores among those with ≥3% of their body surface area affected by psoriasis. RESULTS In both ABT-122 dose groups, ACR20 response rates at week 12 (64.8-75.3%) were superior to that in patients receiving placebo (25.0%) (P < 0.001) but similar to that in patients receiving adalimumab (68.1%). ACR50 and ACR70 response rates were also superior in both ABT-122 dose groups (36.6-53.4% and 22.5-31.5%, respectively) compared to the placebo group (12.5% and 4.2%, respectively) (P < 0.05). Among eligible patients in the placebo, adalimumab, ABT-122 120 mg every week, and ABT-122 240 mg every week treatment groups, PASI75 responses were achieved in 27.3%, 57.6%, 74.4%, and 77.6% of patients, respectively, whereas PASI90 responses were achieved in 18.2%, 45.5%, 48.8%, and 46.9% of patients, respectively. Frequencies of treatment-emergent adverse events, including infections, were similar across all treatment groups, causing no discontinuations. No serious infections or systemic hypersensitivity reactions were reported with ABT-122. CONCLUSION Dual neutralization of TNF and IL-17A with ABT-122 had efficacy and safety that was similar to, and not broadly differentiated from, that of adalimumab over a 12-week treatment course in patients with PsA.

The dual-variable domain immunoglobulin ABBV-257 binds tumor necrosis factor-α and interleukin 17A. Following single ascending doses ( 0.3, 1.0, and 3.0 mg/kg intravenously; 0.3 and 3.0 mg/kg subcutaneously) in a randomized, double-blind, placebo-controlled study in healthy subjects (n = 40; n = 29 evaluated for pharmacokinetics), maximum observed serum concentration (Cmax ) increased dose-proportionally, whereas area under the serum concentration-versus-time curve trended to more than dose-proportional increase. Absolute subcutaneous bioavailability was ∼80%, and the time to Cmax (tmax ) occurred 6 to 8 days after subcutaneous administration. The terminal-phase harmonic mean elimination half-life (t½ ) ranged from 5.5 to 11 days following intravenous and subcutaneous administration. In another randomized, placebo-controlled study, rheumatoid arthritis (RA) patients (n = 8) received ABBV-257 30 mg/kg subcutaneously every other week for 8 weeks. Following the fourth dose, Cmax was 7.69 μg/mL, and tmax occurred ∼4 days after dosing; t½ was ∼16 days. Most individuals (single-dose study, 97%; multiple-dose study, 83%) developed antidrug antibodies (ADAs). Generally, subjects with higher ADA titers had shorter ABBV-257 t½ and lower exposure. One serious adverse event (cerebral ischemia, considered unrelated to treatment, resolved with interventions) occurred in an RA patient who received ABBV-257. Because of the high incidence of ADA-mediated drug clearance, ABBV-257 is no longer being developed.

Thiazide diuretics, commonly used antihypertensives, may cause QT interval (QT) prolongation, a risk factor for highly fatal and difficult to predict ventricular arrhythmias. We examined whether common single-nucleotide polymorphisms (SNPs) modified the association between thiazide use and QT or its component parts (QRS interval, JT interval) by performing ancestry-specific, transethnic and cross-phenotype genome-wide analyses of European (66%), African American (15%) and Hispanic (19%) populations (N = 78 199), leveraging longitudinal data, incorporating corrected standard errors to account for underestimation of interaction estimate variances and evaluating evidence for pathway enrichment. Although no loci achieved genome-wide significance (P

Background Limited data are available on the prospective relationship between beverage consumption and plasma lipid and lipoprotein concentrations. Two major sources of sugar in the US diet are sugar‐sweetened beverages ( SSBs ) and 100% fruit juices. Low‐calorie sweetened beverages are common replacements. Methods and Results Fasting plasma lipoprotein concentrations were measured in the FOS (Framingham Offspring Study) (1991–2014; N=3146) and Generation Three (2002–2001; N=3584) cohorts. Beverage intakes were estimated from food frequency questionnaires and grouped into 5 intake categories. Mixed‐effect linear regression models were used to examine 4‐year changes in lipoprotein measures, and Cox proportional hazard models were used to estimate hazard ratios for incident dyslipidemia, adjusting for potential confounding factors. We found that regular (>1 serving per day) versus low (SSB consumption was associated with a greater mean decrease in high‐density lipoprotein cholesterol (β±standard error −1.6±0.4 mg/dL; P trend P trend =0.003) concentrations. Long‐term regular SSB consumers also had a higher incidence of high triglyceride (hazard ratio, 1.52; 95% CI, 1.03–2.25) compared with low consumers. Although recent regular low‐calorie sweetened beverage consumers had a higher incidence of high non–high‐density lipoprotein cholesterol (hazard ratio, 1.40; 95% CI , 1.17–1.69) and low‐density lipoprotein cholesterol (hazard ratio, 1.27; 95% CI, 1.05–1.53) concentrations compared with low consumers, cumulative average intakes of low‐calorie sweetened beverages were not associated with changes in non–high‐density lipoprotein cholesterol, low‐density lipoprotein cholesterol concentrations, or incident dyslipidemias. Conclusions SSB intake was associated with adverse changes in high‐density lipoprotein cholesterol and triglyceride concentrations, along with a higher risk of incident dyslipidemia, suggesting that increased SSB consumption may contribute to the development of dyslipidemia.

BackgroundFamilial sitosterolemia is a rare, recessive Mendelian disorder characterized by hyperabsorption and decreased biliary excretion of dietary sterols. Affected individuals typically have complete genetic deficiency – homozygous loss-of-function (LoF) variants — in the ATP-binding cassette transporter G5 (ABCG5) or G8 (ABCG8) genes, and have substantially elevated plasma sitosterol and low-density lipoprotein cholesterol (LDL-C) levels. The impact of partial genetic deficiency ofABCG5orABCG8, as occurs in heterozygous carriers of LoF variants, on LDL-C and risk of coronary artery disease (CAD) has remained uncertain.MethodsWe first recruited nine sitosterolemia families, identified causative LoF variants inABCG5orABCG8, and evaluated the associations of theseABCG5orABCG8LoF variants with plasma phytosterols and lipid levels. We next assessed for LoF variants inABCG5orABCG8in CAD cases (n=29,361) versus controls (n=357,326). We tested the association of rare LoF variants inABCG5orABCG8with blood lipids and risk for CAD. Rare LoF variants were defined as protein-truncating variants with minor allele frequency less than 0.1% inABCG5orABCG8.ResultsIn sitosterolemia families, seven pedigrees harbored causative LoF variants inABCG5and two pedigrees inABCG8. Homozygous LoF variants in eitherABCG5orABCG8led to marked elevations in sitosterol and LDL-C. Of those sitosterolemia families, heterozygous carriers ofABCG5LoF variants exhibited increased sitosterol and LDL-C levels compared to non-carriers. Within the large-scale CAD case-control cohorts, prevalence of rare LoF variants inABCG5and inABCG8were approximately 0.1% each.ABCG5heterozygous LoF variant carriers had significantly elevated LDL-C levels (24.7 mg/dL; 95% confidence interval [CI] 14 to 35; P=1.1×10−6), and were at two-fold increased risk of CAD (odds ratio 2.06, 95% CI 1.27 to 3.35; P=0.004). By contrast,ABCG8heterozygous LoF carrier status was not associated with increased LDL-C or risk of CAD.ConclusionsAlthough familial sitosterolemia is traditionally considered as a recessive disorder, we observed that heterozygous carriers of a LoF variant inABCG5had significantly increased sitosterol and LDL-C levels and a two-fold increase in risk of CAD.

History of a hypertensive disorder of pregnancy (HDP) among women may be useful to refine atherosclerotic cardiovascular disease risk assessments. However, future risk of diverse cardiovascular conditions in asymptomatic middle-aged women with prior HDP remains unknown.The purpose of this study was to examine the long-term incidence of diverse cardiovascular conditions among middle-aged women with and without prior HDP.Women in the prospective, observational UK Biobank age 40 to 69 years who reported ≥1 live birth were included. Noninvasive arterial stiffness measurement was performed in a subset of women. Cox models were fitted to associate HDP with incident cardiovascular diseases. Causal mediation analyses estimated the contribution of conventional risk factors to observed associations.Of 220,024 women included, 2,808 (1.3%) had prior HDP. The mean age at baseline was 57.4 ± 7.8 years, and women were followed for median 7 years (interquartile range: 6.3 to 7.7 years). Women with HDP had elevated arterial stiffness indexes and greater prevalence of chronic hypertension compared with women without HDP. Overall, 7.0 versus 5.3 age-adjusted incident cardiovascular conditions occurred per 1,000 women-years for women with versus without prior HDP, respectively (p = 0.001). In analysis of time-to-first incident cardiovascular diagnosis, prior HDP was associated with a hazard ratio (HR) of 1.3 (95% CI: 1.04 to 1.60; p = 0.02). HDP was associated with greater incidence of CAD (HR: 1.8; 95% CI: 1.3 to 2.6; p 0.001), heart failure (HR: 1.7; 95% CI: 1.04 to 2.60; p = 0.03), aortic stenosis (HR: 2.9; 95% CI: 1.5 to 5.4; p 0.001), and mitral regurgitation (HR: 5.0; 95% CI: 1.5 to 17.1; p = 0.01). In causal mediation analyses, chronic hypertension explained 64% of HDP's association with CAD and 49% of HDP's association with heart failure.Hypertensive disorders of pregnancy are associated with accelerated cardiovascular aging and more diverse cardiovascular conditions than previously appreciated, including valvular heart disease. Cardiovascular risk after HDP is largely but incompletely mediated by development of chronic hypertension.

OBJECTIVES: Limited data are available on the prospective relationship between beverage consumption and plasma lipid and lipoprotein concentrations in population-based studies. Two major sources of sugar in the US diet are sugar-sweetened beverages (SSB; sodas and fruit drinks) and 100% fruit juices (FJ). Low-calorie sweetened beverages (LCSB) are common replacements for SSB and FJ. METHODS: Fasting plasma triglyceride (TG), low-density lipoprotein cholesterol (LDL-C), and high-density lipoprotein cholesterol (HDL-C) concentrations were measured at up to 5 exams in the Framingham Heart Study offspring and up to 2 exams in generation 3 cohorts (1998–2005; N = 6730). Consumption of SSB, FJ, and LCSB were estimated from food frequency questionnaires and intakes were categorized. Mixed-effect linear regression models were used to examine changes in lipid concentrations, and Cox proportional hazard models were used to estimate hazard ratios (HR) for incident dyslipidemia, adjusting for potential confounding factors. Results were statistically significant at a Bonferroni-corrected P-value 1 serving/day) vs. low intake category (

Background Familial hypobetalipoproteinemia is a genetic disorder caused by rare protein-truncating variants (PTV) in the gene encoding APOB (apolipoprotein B), the major protein component of LDL (low-density lipoprotein) and triglyceride-rich lipoprotein particles. Whether heterozygous APOB deficiency is associated with decreased risk for coronary heart disease (CHD) is uncertain. We combined family-based and large scale gene-sequencing to characterize the association of rare PTVs in APOB with circulating LDL-C (LDL cholesterol), triglycerides, and risk for CHD. Methods We sequenced the APOB gene in 29 Japanese hypobetalipoproteinemia families, as well as 57 973 individuals derived from 12 CHD case-control studies-18 442 with early-onset CHD and 39 531 controls. We defined PTVs as variants that lead to a premature stop, disrupt canonical splice-sites, or lead to insertions/deletions that shift reading frame. We tested the association of rare APOB PTV carrier status with blood lipid levels and CHD. Results Among 29 familial hypobetalipoproteinemia families, 8 families harbored APOB PTVs. Carrying 1 APOB PTV was associated with 55 mg/dL lower LDL-C ( P=3×10-5) and 53% lower triglyceride level ( P=2×10-4). Among 12 case-control studies, an APOB PTV was present in 0.038% of CHD cases as compared to 0.092% of controls. APOB PTV carrier status was associated with a 43 mg/dL lower LDL-C ( P=2×10-7), a 30% decrease in triglycerides ( P=5×10-4), and a 72% lower risk for CHD (odds ratio, 0.28; 95% CI, 0.12-0.64; P=0.002). Conclusions Rare PTV mutations in APOB which are associated with lower LDL-C and reduced triglycerides also confer protection against CHD. Dr Peloso is supported by the National Heart, Lung, and Blood Institute (NHLBI) of the National Institutes of Health under Award Number K01HL125751. Dr Nomura was supported by the Yoshida Scholarship Foundation. Dr Khera is supported by an institutional grant from the Broad Institute of Massachusetts Institute of Technology (MIT) and Harvard (BroadIgnite), a K08 from the National Human Genome Research Institute (K08HG010155), and a Junior Faculty Award from the National Lipid Association. Dr Kathiresan is supported by a research scholar award from the Massachusetts General Hospital, the Donovan Family Foundation, and grant R01 HL127564 from the NHLBI. Funding for the EOMI study (Exome Sequencing Project Early-Onset Myocardial Infarction) was provided by grants RC2 HL103010 (HeartGO, Heart Grand Opportunity), RC2 HL102923 (LungGO, Lung Grand Opportunity), and RC2 HL102924 (WHISP) from the NHLBI. Exome sequencing was performed through grants RC2 HL102925 (BroadGO, Broad Grand Opportunity) and RC2 HL102926 (SeattleGO, Seattle Grand Opportunity) from the NHLBI. Exome sequencing in ATVB (Italian Atherosclerosis, Thrombosis, and Vascular Biology), the PROCARDIS study (Precocious Coronary Artery Disease), the OHS (Ottawa Heart Study), PROMIS (Pakistan Risk of Myocardial Infarction Study), South German MI study (South German Myocardial Infarction), and the JHS (Jackson Heart Study) was supported by grant 5U54HG003067 from the National Institutes of Health. Fieldwork, genotyping, and standard clinical chemistry assays in PROMIS were principally supported by grants awarded to the University of Cambridge from the British Heart Foundation, UK Medical Research Council, Wellcome Trust, European Union (EU) Framework 6–funded Bloodomics Integrated Project, Pfizer, Novartis, and Merck. Additional support for PROMIS was provided by the UK Medical Research Council (MR/L003120/1), British Heart Foundation (RG/13/13/30194), UK National Institute for Health Research Cambridge Biomedical Research Centre, European Research Council (268834), and European Commission Framework Programme 7 (HEALTH-F2-2012–279233). The Jackson Heart Study is supported by contracts HHSN268201300046C, HHSN268201300047C, HHSN268201300048C, HHSN268201300049C, and HHSN268201300050C from the NHLBI and the National Institute on Minority Health and Health Disparities. Dr Wilson is supported by U54GM115428 from the National Institute of General Medical Sciences. REGICOR study (Registre Gironí del COR [Gerona Heart Registry]) was supported by the Spanish Ministry of Economy and Innovation through the Carlos III Health Institute (Red Investigación Cardiovascular RD12/0042, PI09/90506), European Funds for Development (ERDF-FEDER), and by the Catalan Research and Technology Innovation Interdepartmental Commission (2014SGR240). Samples for the Leicester (Leicester Myocardial Infarction) cohort were collected as part of projects funded by the British Heart Foundation (British Heart Foundation Family Heart Study, RG2000010; UK Aneurysm Growth Study, CS/14/2/30841) and the National Institute for Health Research (NIHR Leicester Cardiovascular Biomedical Research Unit Biomedical Research Informatics Centre for Cardiovascular Science, IS_BRU_0211_20033). The South MI Study is supported by the German Federal Ministry of Education and Research (BMBF) in the context of the e:Med program (e:AtheroSysMed) and the FP7 European Union project CVgenes@target (261123). Additional grants were received from the Fondation Leducq (CADgenomics: Understanding Coronary Artery Disease Genes, 12CVD02). This study was also supported through the Deutsche Forschungsgemeinschaft cluster of excellence Inflammation at Interfaces and SFB 1123. The ATVB study was supported by a grant from RFPS-2007-3-644382 and Programma di ricerca Regione-Università 2010–2012 Area 1–Strategic Programmes–Regione Emilia-Romagna. The authors would like to thank the MyCode Community Health Initiative participants for their permission to utilize their health and genomics information in the DiscovEHR (DiscovEHR partnership of the Regeneron Genetics Center and Geisinger Health System) collaboration. The DiscovEHR study was funded, in part, by the Regeneron Genetics Center.

Background:Dual Energy CT Scan (DECT) can detect monosodium urate crystal deposits in multiple tissues. EULAR gout guidelines (Richette, 2020) recognized the value of DECT in making a clinical diagnosis when joint aspiration is difficult. DECT shows crystal deposits in almost 50% of gout patients without tophi (Dalbeth, 2017). Tophi are known to predict all-cause and cardiovascular mortality (Vincent 2017, Perez-Ruiz 2013) and it is plausible that DECT could as well. A prognostic measure should be reliable and valid. DECT validity would be evident for death, disability and distress.Objectives:This study used a best evidence synthesis approach to synthesize the evidence for DECT as a prognostic measure in gout.Methods:PUBMED and EMBASE were searched from initiation to December 2019; keywords (Dual Energy Computed Tomography OR DECT, gout, tophaceous gout, chronic gout, monosodium urate crystals OR monosodium urate burden OR tophi OR monosodium urate volume OR flares OR pain OR distress OR death OR disability OR function). Human studies in English were considered. Titles, abstracts and full articles were reviewed. A manual search of secondary sources was conducted. Key gaps identified were considered throughout 2020 when reviewing emerging articles and presentations. Data extraction was conducted by both authors; data presented represents consensus.Results:Of 344 articles, 81 titles/abstracts met screening inclusion criteria (24%) in the 2019 search; review of the full manuscript led to 41 articles selected (51%). Additionally, 3 key papers and 2 ACR 2020 presentations were identified through 2020. DECT is highly reliable with inter-class correlation coefficients >0.9. DECT has content validity. Dalbeth (2015) showed DECT and X-Rays findings correlated in tophaceous patients, r=0.70, p2=0.59, p=0.024 (Dalbeth 2007). Dalbeth (2017) showed DECT associated with greater flares at 3 and 12 months (p3, p=0.05) versus those not flaring. Dalbeth (2017) showed abnormal DECT scans occurred in 47% of patients with normal uric acid (3 at feet and ankles, including Pascart 2020.Conclusion:DECT imaging is highly reliable, has evidence for content validity and is highly sensitive to change. DECT appears to predict future gout flares, cardiovascular risk factor prevalence and mortality. Minimum important DECT volume approximates 1.0 cm3. DECT requires further study but appears to be a relevant outcome for clinical trials and staging gout patients.References:AuthorsJournal, Volume, IssueYearAraujo, E. G., Bayat, S., et al.RMD Open2015Dalbeth, N., Nicolaou, S., et al.Ann Rheum Dis, 77(3)2017Dalbeth, N., Aati, O., et al.Ann Rheum Dis, 74(6)2015Dalbeth, N., Collis, J., et al.Rheumatology, 46(12)2007Gamala, M., Linn-Rasker, S. P., et al.Clinical Rheumatol, 37(7)2018Lee, K., Ryu, S., et al.Clinical Rheumatol, 372017Marty-Ané, A., Norberciak, L., et al.Arthritis Rheumatol 72 (supp 10) [abstract #0954] ACR 2020.2020Pascart, T., Ramon, A., et al.J Clin Med, 9(5)2020Pascart, T., Capon, B., et al.Arthritis Res and Therapy, 20(1)2018Perez-Ruiz, F., Martínez-Indart, L., et al.Ann Rheum Dis, 73(1)2013Richette, P., Doherty, M., et al.Ann Rheum Dis, 79(1)2020Vincent, Z., Gamble, G., et al.J Rheumatol, 44 (3)2017Disclosure of Interests:Sally Stauder: None declared, Paul M. Peloso Shareholder of: Horizon Therapeutics plc, Employee of: Horizon Therapeutics plc.

Background:The prevalence of gout is high in kidney transplant (KT) recipients (up to 13%), largely because of decreased kidney function and calcineurin inhibitor use.1 Residual chronic kidney disease (CKD) leading to decreased urate lowering therapy clearance and drug interactions make managing gout in KT recipients challenging. Studies show that successful treatment with pegloticase, a pegylated uricase, leads to marked reductions in serum uric acid (sUA)2 and a subsequent decrease in overall urate load and tophi burden.3 However, pegloticase use in solid organ transplant recipients has not been systematically studied or well-characterized in the literature.4,5Objectives:To examine the safety and efficacy of pegloticase in KT recipients with uncontrolled gout.Methods:This ongoing multicenter, open-label, efficacy and safety study of pegloticase in KT recipients (NCT04087720) included patients with uncontrolled gout sUA ≥7 mg/dL, urate lowering therapy [ULT] contraindication/inefficacy, and with either visible tophi, chronic gouty arthritis, or ≥2 flares in past year, who were KT recipients (KT >1 year prior), had a functioning graft (estimated glomerular filtration rate [eGFR] ≥15 ml/min/1.73m2), and were on a stable immunosuppressant regimen. Pegloticase (8 mg infusion) was administered biweekly for 24 weeks (12 infusions) followed by a safety visit 30 days after the last infusion and 3-month post-treatment follow up visit. The primary endpoint was proportion of patients who were serum uric acid responders during Month 6 (sUA Results:Preliminary findings of this study included 15 patients (12 male, 53.5±11.0 years of age) with uncontrolled gout (6.2±6.0 years since diagnosis) who had received a donor kidney 15.1±6.6 years earlier. At the time of analysis, 5 patients had completed the 24-week treatment period and 8 remained on therapy (last visit sUA 2, BL: 40.9±14.4 ml/min/1.73 m2; n=5). Urine albumin-to-creatinine ratio showed improvement at 24 weeks (CFB: -223±405 mg/g, BL: 664±870 mg/g; n=5). 80% of patients experienced an AE, and 4 SAEs (duodenal ulcer, cellulitis, dyspnea, skin bacterial infection) deemed unrelated to pegloticase were reported. AEs that occurred in >1 patient included gout flare, pyrexia, arthralgia, and nasal congestion. No anaphylaxis or infusion reactions occurred.Conclusion:Initial findings suggest that pegloticase therapy is effective at reducing sUA in most KT recipients while preserving renal function. Results suggest that in the setting of profound urate lowering with pegloticase in KT patients, eGFR remains stable and patients experience clinically beneficial reductions in pain and disability with an absence of unexpected safety findings.References:[1]Clive DM. J Am Soc Nephrol 2000;May11(5):974-9.[2]Sundy JS, et al. JAMA 2011;306:711-720.[3]Mandell BF, et al. Arthritis Res Ther 2018;20:286.[4]Freyne B. Transplant Proc 2018;50:4099-101.[5]Hershfield MS, et al. Arthritis Res Ther 2014;16:R63.Disclosure of Interests:Abdul Abdellatif Speakers bureau: Horizon Therapeutics plc, Consultant of: Horizon Therapeutics plc, Lin Zhao Shareholder of: Horizon Therapeutics plc, Employee of: Horizon Therapeutics plc, Paul M. Peloso Shareholder of: Horizon Therapeutics plc, Employee of: Horizon Therapeutics plc, Katya Cherny Shareholder of: Horizon Therapeutics plc, Employee of: Horizon Therapeutics plc, Brad Marder Shareholder of: Horizon Therapeutics plc, Employee of: Horizon Therapeutics plc, John Scandling Consultant of: Horizon Therapeutics plc, Kenneth Saag Consultant of: Arthrosi, Atom Bioscience, Horizon, LG Pharma, Mallinkrodt, SOBI, Takeda, Grant/research support from: Horizon, SOBI, Shanton.

Background:Gout development follows persistent serum uric acid (sUA) elevation. Patients who are refractory to or cannot tolerate oral urate lowering therapies (ULTs) have limited treatment options. Pegloticase is effective in treating refractory gout, but many patients develop anti-drug antibodies (ADAs), which are associated with loss of urate-lowering efficacy1-3 and infusion reactions (IRs).1,2 In phase 3 trials, the pooled pegloticase responder rate during Months 3 and 6 combined was 42% (8 mg infusion every 2 weeks), with high-titer ADA positive patients losing efficacy prior to 6 months.1 The 6-month results from the MIRROR open-label trial (79% response rate [11/14], 95%CI 49-95%)4 suggest that methotrexate (MTX) administered in conjunction with pegloticase increases treatment responder rate.Objectives:To examine longer-term (12-month) exploratory endpoints from the MIRROR open-label trial, including joint, overall health, and gout global assessments. Serial dual-energy computed tomography (DECT) images were also examined when available.Methods:Adult patients with uncontrolled gout (sUA ≥6 mg/dL with ≥1 of the following: sUA ≥6 mg/dL despite ULT use, intolerance to ULT, or functionally limiting tophaceous deposits) were included. Patients with immunocompromised status, G6PD deficiency, severe renal impairment, or MTX contraindication were excluded. Patients were administered oral MTX (15 mg/week) and folic acid (1 mg/day) 4 weeks prior to and throughout pegloticase therapy (8 mg biweekly infusion for up to 52 weeks). Exploratory outcomes included mean change from baseline (CFB) in number of affected joints (tophi, swollen, tender), Health Assessment Questionnaire (HAQ) scores (Disability Index [DI; score 0−3], Pain [score 0−100], Health [score 0−100]), and Gout Global Assessments (Patient, Physician; score 0−10). A decrease in these measures reflects clinical/patient-reported health improvement. Change in urate deposition volume, as measured on DECT imaging, was also examined as available. Analyses were performed on the modified intent-to-treat (mITT) population (≥1 pegloticase infusion received).Results:14 patients (all male, mean±SD age: 49.3±8.7 years) made up the mITT population. Mean±SD sUA prior to pegloticase treatment was 9.2±2.5 mg/dL and 13 patients had visible tophi. 3 patients discontinued due to 2 consecutive sUA levels >6 mg/dL and 1 patient completed the study at week 24 (pre-protocol amendment extending treatment from 24 to 52 weeks). 10 patients completed the 52-week study. Of these, 8 patients received 26 infusions and 2 patients received 12 infusions, discontinued pegloticase after meeting their treatment goal at 24 weeks, and started allopurinol while remaining in study under observation. At week 52 (n=10, sUA=1.1±2.5 mg/dL), the number of affected joints improved, along with HAQ measures (Figure 1). Global Assessments of Gout also improved (Physician: CFB=-5.7±2.6, Patient CFB=-4.6±2.1) and majority of subjects had a score of 0 or 1 (0=“excellent health”) at week 52 (Physician: 0.3±0.5, Patient: 1.1±1.3). Two patients had available DECT imaging. One received pegloticase/methotrexate co-therapy thru week 52 and had a marked reduction in total urate volume (baseline: 128.76 cm3, week 52: 1.33 cm3). The other received only 5 pegloticase infusions, but also showed total urate volume reduction (baseline: 59.20 cm3, week 10: 25.07 cm3). Both patients displayed improvement in bone erosion healing.Conclusion:These 12-month exploratory endpoints of the MIRROR open-label trial suggest that MTX/pegloticase co-therapy results in meaningful changes in clinical evaluations (tophaceous, tender, and swollen joint counts), and patient-reported outcomes (pain, disability) in patients with uncontrolled gout.References:[1]Sundy JS et al. JAMA 2011;306:711-20[2]Baraf HS et al. J Clin Rheumatol 2014;20:427-32[3]Lipsky PE et al. Arthritis Res Ther 2014, 16:R60[4]Botson JK et al. J Rheum 2020 [Epub ahead of print]Disclosure of Interests:John Botson Speakers bureau: Horizon Therapeutics, Celgene, Novartis, and AbbVie, Consultant of: Horizon Therapeutics, Celgene, Novartis, and AbbVie, Grant/research support from: Horizon Therapeutics and Radius Health, Paul M. Peloso Shareholder of: Horizon Therapeutics plc, Employee of: Horizon Therapeutics plc, Katie Obermeyer Shareholder of: Horizon Therapeutics plc, Employee of: Horizon Therapeutics plc, Brian LaMoreaux Shareholder of: Horizon Therapeutics plc, Employee of: Horizon Therapeutics plc, Lin Zhao Shareholder of: Horizon Therapeutics plc, Employee of: Horizon Therapeutics plc, Michael E. Weinblatt Shareholder of: Lycera, Can-Fite BioPharma, Scipher Medicine, Inmedix, and Vorso, Consultant of: Bristol Myers Squibb, Corona, Lilly, AbbVie, Amgen, Arena, GlaxoSmithKline, Gilead Sciences, Horizon Therapeutics, Lycera, Novartis, Pfizer, Roche, Samsung, Scipher Medicine, and Set Point, Grant/research support from: Amgen, Bristol-Myers Squibb, Crescendo Bioscience, Lilly and Sanofi, Jeff Peterson Speakers bureau: Horizon Therapeutics plc, Grant/research support from: Horizon Therapeutics plc.

Background:In an open-label, single-arm trial in adult patients with uncontrolled gout (MIRROR open-label [OL] trial) evaluating pegloticase co-treatment with methotrexate (MTX); 78.6% patients were responders, defined as maintenance of serum uric acid 1. MTX co-treatment is shown to improve the pharmacokinetics (PK) of biologics by attenuating the formation of anti-drug antibodies2.Objectives:To determine the systemic exposures of pegloticase and methotrexate polyglutamate(s) (MTX-PGs) in uncontrolled gout patients receiving pegloticase and MTX; to evaluate the effect of MTX on the PK of pegloticase in comparison to historical pegloticase monotherapy trials (C0405 and C0406)3, 4; and to evaluate the immunogenicity of pegloticase in co-treatment with MTX.Methods:In the MIRROR OL trial, MTX (15 mg/week) was given orally 4 weeks prior to the first pegloticase dose and continued weekly, in combination with pegloticase 8 mg given intravenously every 2 weeks, for a treatment duration of up to 52 weeks. Pre-infusion samples were collected to measure MTX-PGs in red blood cells. Pre- and post-infusion blood samples were obtained to measure the peak (Cmax) and trough (Cmin) concentrations of pegloticase at multiple visits. Anti-drug antibody blood samples were collected at multiple visits. The impact of MTX on pegloticase PK was evaluated by comparing pegloticase exposures with MTX from this trial to historical monotherapy data (C0405 and C0406)3, 4. The observed pegloticase concentrations with MTX were also overlaid with the 90% prediction interval based on the population PK model5 from C0405 and C0406.Results:Pegloticase and MTX-PG levels were determined in 14 patients. The 11 responders were generally associated with higher pegloticase exposures than the non-responders, especially Cmin (Figure 1). Concomitant treatment of MTX resulted in fewer patients with Cmin below quantitation limit (BQL) (5/14 [36%] with MTX vs 63/82 [77%] without MTX), and higher overall Cmin (median: 1.03 µg/ml with MTX vs BQL without MTX); Cmax was slightly higher (median [Q1, Q3]: 2.11 [1.65, 2.59] µg/mL with MTX vs 1.51 [BQL, 2.48] µg/mL without MTX). Pegloticase co-treatment with MTX resulted in more concentrations above the predicted median value of pegloticase, compared to monotherapy. ADA data is consistent with pegloticase PK and efficacy. Significant increase in ADA titers were only observed in 2 subjects (both were non-responders) at time corresponding to the loss of pegloticase exposure and increases in sUA levels. Concentrations of MTX-PGs were maintained during the treatment course, suggesting compliance of MTX administration. There was no apparent difference in concentrations of MTX-PGs between responders and non-responders.Conclusion:Pegloticase 8 mg IV every 2 weeks co-treatment with MTX 15 mg weekly resulted in fewer patients with pegloticase Cmin below the quantification limit (BQL) and gave higher overall trough concentrations (Cmin) compared to pegloticase monotherapy in the phase 3 studies.Pegloticase 8 mg IV every 2 weeks co-treatment with MTX 15 mg weekly was associated with an improved response rate for pegloticase in association with improved drug levels in these patients with uncontrolled gout compared to pegloticase monotherapy in the phase 3 studies.References:[1]Botson J., et al. J Rheumatol. 2020; doi: 10.3899/jrheum.200460[2]Goss S. L., et al. Clin Ther;2018, 40 (2).[3]Lipsky P. E., et al. Arthritis Res Ther;2014, 16 (2).[4]Sundy J. S., et al. JAMA;2011, 306 (7).[5]Yue C. S., et al. ASCPT, Atlanta, 2010.Disclosure of Interests:Yang Song Shareholder of: Horizon Therapeutics plc, Employee of: Horizon Therapeutics plc, Yan Xin Shareholder of: Horizon Therapeutics plc, Employee of: Horizon Therapeutics plc, Michael E. Weinblatt Shareholder of: Canfite, Inmedix, Lycera, Vorso, Scipher, Grant/research support from: Crescendo Bioscience, Bristol Myers Squibb, Sanofi, Eli Lilly, Amgen, Jason Chamberlain Shareholder of: Horizon Therapeutics plc, Employee of: Horizon Therapeutics plc, Katie Obermeyer Shareholder of: Horizon Therapeutics plc, Employee of: Horizon Therapeutics plc, Lin Zhao Shareholder of: Horizon Therapeutics plc, Employee of: Horizon Therapeutics plc, Colleen Canavan Shareholder of: Horizon Therapeutics plc, Employee of: Horizon Therapeutics plc, Paul M. Peloso Shareholder of: Horizon Therapeutics plc, Employee of: Horizon Therapeutics plc, Srini Ramanathan Shareholder of: Horizon Therapeutics plc, Employee of: Horizon Therapeutics plc.

Background:Gout is a painful inflammatory arthritis caused by persistently elevated serum uric acid (sUA) levels. Pegloticase, an infused recombinant PEGylated uricase, rapidly lowers sUA levels by converting uric acid to allantoin, a water-soluble molecule that is readily excreted by the kidneys. In the phase 3 clinical trials, 42% of patients1dosed with pegloticase every two weeks maintained sUA levels below 6.0 mg/dL during months 3 and 6 of pegloticase treatment. The loss of pegloticase efficacy has been attributed to the development of anti-drug antibodies (ADAs)1-3and these ADAs have been associated with infusion reactions (IRs).1,2Case reports4and prospective case series5, 6indicate that methotrexate (MTX) may allow patients to attain more complete therapeutic benefits, presumably through attenuation of pegloticase immunogenicity. The current study prospectively examines the efficacy and safety of MTX-pegloticase co-therapy in patients with uncontrolled gout.Objectives:To assess efficacy and safety of concomitant pegloticase and MTX therapy in patients with uncontrolled gout.Methods:Adult patients with uncontrolled gout who were beginning pegloticase therapy were considered for enrollment in this ongoing multicenter, open-label, efficacy and safety study of pegloticase with MTX co-treatment (NCT03635957). Patients were administered oral MTX (15 mg/week) and folate (1 mg/day) 4 weeks prior to the first pegloticase infusion (Day 1) and throughout the pegloticase treatment period. Blood was drawn prior to each infusion to measure sUA level, monitor clinical parameters, and examine for ADA development. All patients followed typical IR prophylaxis protocols (fexofenadine one day before and the morning of each infusion and acetaminophen and IV corticosteroid the morning of each infusion). Patients also received gout flare prophylaxis with either NSAIDs, colchicine or prednisone initiated at least 1 week prior to Day 1. The primary study outcome was the proportion of responders, defined as sUA Results:A total of 17 patients were screened and 14 patients (all men, average age: 49.3 ± 8.7 years) were enrolled. On Day 1, mean sUA was 9.2 ± 2.5 mg/dL and 12 of the 14 patients had visible tophi. At the 6 months timepoint, 11/14 (78.6%, 95%CI 49.2-95.3%) met the responder definition, with 3 patients discontinuing after meeting stopping rules (pre-infusion sUA values greater than 6 mg/dL at 2 consecutive scheduled visits). All patients tolerated MTX. One serious AE of bacterial sepsis occurred (resolved). AEs that occurred in >1 patient during the co-treatment period were: diarrhea and upper respiratory tract infection in 3 patients each, sinusitis, muscle strain, and hypertension in 2 patients each. Gout flares occurred in 12/14 (85.7%) patients. No new safety concerns were identified.Conclusion:An increased proportion of patients maintained therapeutic response at 6 months when treated concomitantly with MTX and pegloticase (78.6%) when compared to the previously reported 42% using pegloticase alone.1These results support and reflect the improved response rates demonstrated in two prior case series.5,6A definitive randomized double-blinded trial evaluating pegloticase with MTX vs. pegloticase with placebo is ongoing.References:[1]Sundy JS et al.JAMA2011;306:711-20.[2]Baraf HS et al.J Clin Rheumatol2014;20:427-32.[3]Lipsky PE et al.Arthritis Res Ther2014;16:R60.[4]Bessen SY et al.Semin Arthritis Rheum2019;49:56-61.[5]Botson J, Peterson J.Ann Rheum Dis2019;78:A1289.[6]Albert JA et al.Arthritis & Rheumatology2019;71(S10):A1236.Disclosure of Interests: :John Botson Grant/research support from: Horizon Therapeutics (PI and study site), Radius Health (study site), Consultant of: Horizon Therapeutics, Speakers bureau: Celgene, Eli Lilly, Horizon Therapeutics, Mallinckrodt, Novartis, Pfizer, Paul M. Peloso Shareholder of: Horizon Therapeutics, Employee of: Horizon Therapeutics, Katie Obermeyer Shareholder of: Horizon Therapeutics, Employee of: Horizon Therapeutics, Brian LaMoreaux Shareholder of: Horizon Therapeutics, Employee of: Horizon Therapeutics, Michael E. Weinblatt Grant/research support from: BMS, Amgen, Lilly, Crescendo and Sonofi-Regeneron, Consultant of: Horizon Therapeutics, Bristol-Myers Squibb, Amgen, Abbvie, Crescendo, Lilly, Pfizer, Roche, Gilead, Jeff Peterson Grant/research support from: Abbvie, UCB, Smith Klein, Horizon Therapeutics, Consultant of: Lilly, Norvartis, Horizon Therapeutics, Speakers bureau: Lilly, Novartis, Horizon Therapeutics, Abbvie, Genentech

To evaluate the efficacy and safety of elagolix, an oral, nonpeptide gonadotropin-releasing hormone antagonist, over 12 months in women with endometriosis-associated pain.Elaris Endometriosis (EM)-III and -IV were extension studies that evaluated an additional 6 months of treatment after two 6-month, double-blind, placebo-controlled phase 3 trials (12 continuous treatment months) with two elagolix doses (150 mg once daily and 200 mg twice daily). Coprimary efficacy endpoints were the proportion of responders (clinically meaningful pain reduction and stable or decreased rescue analgesic use) based on average monthly dysmenorrhea and nonmenstrual pelvic pain scores. Safety assessments included adverse events, clinical laboratory tests, and endometrial and bone mineral density assessments. The power of Elaris EM-III and -IV was based on the comparison to placebo in Elaris EM-I and -II with an expected 25% dropout rate.Between December 28, 2012, and October 31, 2014 (Elaris EM-III), and between May 27, 2014, and January 6, 2016 (Elaris EM-IV), 569 participants were enrolled. After 12 months of treatment, Elaris EM-III responder rates for dysmenorrhea were 52.1% at 150 mg once daily (Elaris EM-IV 550.8%) and 78.2% at 200 mg twice daily (Elaris EMIV 575.9%). Elaris EM-III nonmenstrual pelvic pain responder rates were 67.5% at 150 mg once daily (Elaris EM-IV 566.4%) and 69.1% at 200 mg twice daily (Elaris EM-IV 567.2%).”After 12 months of treatment, Elaris EM-III dyspareunia responder rates were 45.2% at 150 mg once daily (Elaris EM-IV=45.9%) and 60.0% at 200 mg twice daily (Elaris EM-IV=58.1%). Hot flush was the most common adverse event. Decreases from baseline in bone mineral density and increases from baseline in lipids were observed after 12 months of treatment. There were no adverse endometrial findings.Long-term elagolix treatment provided sustained reductions in dysmenorrhea, nonmenstrual pelvic pain, and dyspareunia. The safety was consistent with reduced estrogen levels and no new safety concerns were associated with long-term elagolix use.ClinicalTrials.gov, NCT01760954 and NCT02143713.

Objectives ABT-122 is a dual-variable-domain immunoglobulin that neutralizes both TNF-α and IL-17A. The objective of this work was to characterize exposure-response relationships for ABT-122 relative to adalimumab (TNF-α inhibitor) using ABT-122 phase 2 trials in patients with RA or PsA. Methods Patients received subcutaneous doses of ABT-122 ranging from 60 mg every other week (EOW) to 240 mg every week, adalimumab 40 mg EOW, or placebo (PsA patients only) for 12 weeks. Relationships between ABT-122 or adalimumab serum concentrations and time course of ACR20, ACR50 and ACR70 and PASI50, PASI75 and PASI90 responses were characterized using a non-linear mixed-effects Markov modelling approach. Results A total of 221 RA patients and 240 PsA patients were included in the analyses. At comparable molar exposures, there was no differentiation of efficacy between ABT-122 and adalimumab and there were no consistent differences between ABT-122 and adalimumab in the potency estimates for different efficacy endpoints based on the Markov models. Plateau of ABT-122 efficacy was achieved at exposures associated with the 120 mg EOW dose in patients with RA, which were comparable to molar exposures of adalimumab 40 mg EOW, and at the lowest dose of 120 mg every week in patients with PsA. Conclusion The exposure-response relationships for ABT-122 were not distinguishably different from those of adalimumab in patients with RA or PsA. Overall, there was no clear evidence that inhibition of the IL-17 pathway provided incremental benefit in the presence of TNF-α inhibition. Trial registration ClinicalTrials.gov, NCT02433340, NCT02349451.

It is unknown if lifelong exposure to increased hemodynamic stress from an elevated resting heart rate (HR) may contribute to aortic valve calcium (AVC). We performed multivariate regression analyses using data from 1,266 Framingham Heart Study (FHS) Offspring cohort participants and 6,764 Multi-Ethnic Study of Atherosclerosis (MESA) participants. We constructed a genetic risk score (GRS) for HR using summary-level data in the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) AVC Consortium to investigate if there was evidence in favor of a causal relation. AVC was present in 39% of FHS Offspring cohort participants and in 13% of MESA cohort participants. In multivariate adjusted models, participants in the highest resting HR quartiles had significantly greater prevalence of AVC, with a prevalence ratio of 1.19 (95% confidence interval [CI] 0.99 to 1.44) for the FHS Offspring cohort and 1.32 (95% CI 1.12 to 1.63) for the MESA cohort, compared with those in the lowest quartile. There was a similar increase in the prevalence of AVC per standard deviation increase in resting HR in both FHS Offspring (prevalence ratio 1.08, 95% CI 1.01 to 1.15) and MESA (1.10, 95% CI 1.03 to 1.17). In contrast with these observational findings, a HR associated GRS was not significantly associated with AVC. Although our observational analysis indicates that a higher resting HR is associated with AVC, our genetic results do not support a causal relation. Unmeasured environmental and/or lifestyle factors associated with both increased resting HR and AVC that are not fully explained by covariates in our observational models may account for the association between resting HR and AVC.

Background— The burden of subclinical atherosclerosis in asymptomatic individuals is heritable and associated with elevated risk of developing clinical coronary heart disease. We sought to identify genetic variants in protein-coding regions associated with subclinical atherosclerosis and the risk of subsequent coronary heart disease. Methods and Results— We studied a total of 25 109 European ancestry and African ancestry participants with coronary artery calcification (CAC) measured by cardiac computed tomography and 52 869 participants with common carotid intima–media thickness measured by ultrasonography within the CHARGE Consortium (Cohorts for Heart and Aging Research in Genomic Epidemiology). Participants were genotyped for 247 870 DNA sequence variants (231 539 in exons) across the genome. A meta-analysis of exome-wide association studies was performed across cohorts for CAC and carotid intima–media thickness. APOB p.Arg3527Gln was associated with 4-fold excess CAC ( P =3×10 − 10 ). The APOE ε2 allele (p.Arg176Cys) was associated with both 22.3% reduced CAC ( P =1×10 − 12 ) and 1.4% reduced carotid intima–media thickness ( P =4×10 − 14 ) in carriers compared with noncarriers. In secondary analyses conditioning on low-density lipoprotein cholesterol concentration, the ε2 protective association with CAC, although attenuated, remained strongly significant. Additionally, the presence of ε2 was associated with reduced risk for coronary heart disease (odds ratio 0.77; P =1×10 − 11 ). Conclusions— Exome-wide association meta-analysis demonstrates that protein-coding variants in APOB and APOE associate with subclinical atherosclerosis. APOE ε2 represents the first significant association for multiple subclinical atherosclerosis traits across multiple ethnicities, as well as clinical coronary heart disease.

Background: Approximately 7% of American adults have severe hypercholesterolemia (untreated low-density lipoprotein [LDL] cholesterol ≥190 mg/dl), which may be due to familial hypercholeste...

Enriched enrolment, randomised withdrawal (EERW) pain trials select, before randomisation, patients who respond by demonstrating a predetermined degree of pain relief and acceptance of adverse events. There is uncertainty over the value of this design. We report a systematic review of EERW trials in chronic noncancer pain together with a critical appraisal of methods and potential biases in the methods used and recommendations for the design and reporting of future EERW trials. Electronic and other searches found 25 EERW trials published between 1995 and June 2014, involving 5669 patients in a randomised withdrawal phase comparing drug with placebo; 13 (median, 107 patients) had a randomised withdrawal phase of 6 weeks or less, and 12 (median, 334) lasted 12 to 26 weeks. Risks of bias included short duration, inadequate outcome definition, incomplete outcome data reporting, small size, and inadequate dose tapering on randomisation to placebo. Active treatment was usually better than placebo (22/25 trials). This review reduces the uncertainty around the value of EERW trials in pain. If properly designed, conducted, and reported, they are feasible and useful for making decisions about pain therapies. Shorter, small studies can be explanatory; longer, larger studies can inform practice. Current evidence is inadequate for valid comparisons in outcome between EERW and classical trials, although no gross differences were found. This systematic review provides a framework for assessing potential biases and the value of the EERW trials, and for the design of future studies by making recommendations for the conduct and reporting of EERW trials.

Introduction There is conflicting evidence whether high-density lipoprotein cholesterol (HDL-C) is a risk factor for Alzheimer's disease (AD) and dementia. Genetic variation in the cholesteryl ester transfer protein (CETP) locus is associated with altered HDL-C. We aimed to assess AD risk by genetically predicted HDL-C. Methods Ten single nucleotide polymorphisms within the CETP locus predicting HDL-C were applied to the International Genomics of Alzheimer's Project (IGAP) exome chip stage 1 results in up 16,097 late onset AD cases and 18,077 cognitively normal elderly controls. We performed instrumental variables analysis using inverse variance weighting, weighted median, and MR-Egger. Results Based on 10 single nucleotide polymorphisms distinctly predicting HDL-C in the CETP locus, we found that HDL-C was not associated with risk of AD (P > .7). Discussion Our study does not support the role of HDL-C on risk of AD through HDL-C altered by CETP. This study does not rule out other mechanisms by which HDL-C affects risk of AD., Highlights • CETP SNPs were not associated with AD in a large sample of AD cases/controls. • Genetically predicted HDL-C through CETP does not associate with AD.

Objectives To evaluate the safety and maintenance of efficacy with ABT-122, a bi-specific monoclonal antibody targeting TNF and IL-17A, in patients with RA or PsA in open-label, 24-week extensions [open-label extensions (OLEs)] of 12-week, randomized, double-blind studies. Methods All patients received ABT-122 (RA, 120 mg; PsA, 240 mg) subcutaneously every other week on background MTX. Safety assessments included adverse events (AEs) and laboratory parameters. Efficacy was evaluated with ACR responses, 28-joint DAS using high-sensitivity CRP [DAS28 (hsCRP)], and Psoriasis Area and Severity Index (PsA study). Results The RA OLE study enrolled 158 patients; the PsA OLE study enrolled 168 patients. In the RA OLE study, the incidence of treatment emergent AEs (TEAEs; 41%) appeared similar to the double-blind study (36-43%). In the PsA OLE study, 57% of patients reported ⩾1 TEAE (double-blind study, 42-53%). Most TEAEs were mild or moderate in severity. There were no neutrophil abnormalities greater than grade 2. Grade 3 and/or 4 laboratory abnormalities were reported for lymphocytes, alanine aminotransferase, aspartate aminotransferase, bilirubin and haemoglobin; the number of these severe laboratory values was low (0.6-3.0%), except grade 3 lymphocyte count decreased (11.5%) in the RA study. In both OLE studies, efficacy assessed by ACR responses and other disease activity scores was maintained over the 24 weeks. Conclusion ABT-122 demonstrated acceptable tolerability and maintenance of efficacy for up to 36 weeks in patients with RA or PsA receiving background MTX. Trial registration ClinicalTrials.gov, http://clinicaltrials.gov, NCT02433340 and NCT02429895.

Objective Tumor necrosis factor (TNF) and interleukin-17A (IL-17A) may independently contribute to the pathophysiology of rheumatoid arthritis (RA). This study sought to evaluate the safety and efficacy of ABT-122, a novel dual variable domain immunoglobulin targeting human TNF and IL-17A, in patients with RA who have experienced an inadequate response to methotrexate. Methods Patients with active RA who were receiving treatment with methotrexate and had no prior exposure to biologic agents (n = 222) were enrolled in a 12-week phase II randomized, double-blind, active-controlled, parallel-group study. Patients were randomized to receive either ABT-122 at dosages of 60 mg every other week, 120 mg every other week, or 120 mg every week or adalimumab at 40 mg every other week, administered subcutaneously. The primary efficacy end point was the proportion of patients achieving a ≥20% improvement response based on the American College of Rheumatology criteria for 20% improvement (ACR20) at week 12. Results Treatment-emergent adverse events were similar across all treatment groups, with no serious infections or systemic hypersensitivity reactions reported with ABT-122. ACR20 response rates at week 12 were 62%, 75%, and 80% with ABT-122 60 mg every other week, 120 mg every other week, and 120 mg every week, respectively, compared with an ACR20 response rate of 68% with 40 mg adalimumab every other week. The corresponding response rates for ACR50 and ACR70 improvement in the ABT-122 dose groups and adalimumab group were 35%, 46%, 47%, and 48%, respectively, and 22%, 18%, 36%, and 21%, respectively. Conclusion Over the 12-week study period, dual inhibition of TNF and IL-17A with ABT-122 produced a safety profile consistent with that of adalimumb used for inhibition of TNF alone. The efficacy of ABT-122 over 12 weeks at dosages of 120 mg every other week or 120 mg every week was not meaningfully differentiated from that of adalimumab at a dosage of 40 mg every other week in patients with RA receiving concomitant methotrexate.

Background Mitral annular calcium (MAC), commonly identified by cardiac imaging, is associated with cardiovascular events and predisposes to the development of clinically important mitral valve regurgitation and mitral valve stenosis. However, its biological determinants remain largely unknown. Objectives The authors sought to evaluate whether a genetic predisposition to elevations in plasma lipids is associated with the presence of MAC. Methods The authors used 3 separate Mendelian randomization techniques to evaluate the associations of lipid genetic risk scores (GRS) with MAC in 3 large patient cohorts: the Framingham Health Study, MESA (Multiethnic European Study of Atherosclerosis), and the AGE-RS (Age, Gene/Environment Susceptibility-Reykjavik Study). The authors provided cross-ethnicity replication in the MESA Hispanic-American participants. Results MAC was present in 1,149 participants (20.4%). In pooled analyses across all 3 cohorts, a triglyceride GRS was significantly associated with the presence of MAC (odds ratio [OR] per triglyceride GRS unit: 1.73; 95% confidence interval [CI]: 1.24 to 2.41; p = 0.0013). Neither low- nor high-density lipoprotein cholesterol GRS was significantly associated with MAC. Results were consistent in cross-ethnicity analyses among the MESA Hispanic-Americans cohort (OR per triglyceride GRS unit: 2.04; 95% CI: 1.03 to 4.03; p = 0.04). In joint meta-analysis across all included cohorts, the triglyceride GRS was associated with MAC (OR per triglyceride GRS unit: 1.79; 95% CI: 1.32 to 2.41; p = 0.0001). The results were robust to several sensitivity analyses that limit both known and unknown forms of genetic pleiotropy. Conclusions Genetic predisposition to elevated triglyceride levels was associated with the presence of MAC, a risk factor for clinically significant mitral valve disease, suggesting a causal association. Whether reducing triglyceride levels can lower the incidence of clinically significant mitral valve disease requires further study.

Objectives: The objective was to evaluate the effects of elagolix on dyspareunia in women with endometriosis-associated pain. Methods: Data were pooled from two similar, randomized, double-blind, placebo-controlled, 6-month phase 3 studies (Elaris Endometriosis-I and Elaris Endometriosis-II) of elagolix at two doses (150 mg QD and 200 mg BID) in women with endometriosis-associated pain. In this post hoc analysis, dyspareunia responders were defined as having a clinically meaningful decrease from baseline in the dyspareunia score and decreased or stable use of rescue analgesic agents, as recorded in a daily electronic diary. Sexual relationship was assessed using the 30-item Endometriosis Health Profile questionnaire sexual relationship module. Results: A total of 1384 women reported ⩾1 day of sexual activity at baseline (35 days prior to and including day 1 of treatment). Of these 1384 women, 1297 (94%) reported ⩾1 day of any dyspareunia (mild, moderate, or severe), of which 51% reported ⩾1 day of severe dyspareunia. Among sexually active women who reported any dyspareunia at baseline, both elagolix doses led to improvements in dyspareunia. Women in the 200-mg BID group showed more months at which the dyspareunia response rates were statistically significantly greater than placebo, particularly in a subgroup of women with severe dyspareunia at baseline. Compared to placebo, both elagolix doses led to statistically significantly greater improvements in the mean 30-item Endometriosis Health Profile sexual relationship module score. Conclusion: Up to 6 months of elagolix treatment improved dyspareunia in women with endometriosis-associated pain in a dose-dependent manner, with 200-mg BID dose showing the most significant improvements in dyspareunia and quality of sexual relationships compared with placebo.

Objectives: To conduct an overview (review-of-reviews) on pharmacological interventions for neck pain. Search Strategy: Computerized databases and grey literature were searched from 2006 to 2012. Selection Criteria: Systematic reviews of randomized controlled trials (RCT) in adults with acute to chronic neck pain reporting effects of pharmacological interventions including injections on pain, function/disability, global perceived effect, quality of life and patient satisfaction. Data Collection & Analysis: Two independent authors selected articles, assessed risk of bias and extracted data The GRADE tool was used to evaluate the body of evidence and an external panel provided critical review. Main Results: We found 26 reviews reporting on 47 RCTs. Most pharmacological interventions had low to very low quality methodologic evidence with three exceptions. For chronic neck pain, there was evidence of: 1) a small immediate benefit for eperison hydrochloride (moderate GRADE, 1 trial, 157 participants); 2) no short-term pain relieving benefit for botulinum toxin-A compared to saline (strong GRADE; 5 trial meta-analysis, 258 participants) nor for subacute/chronic whiplash (moderate GRADE; 4 trial meta-analysis, 183 participants) including reduced pain, disability or global perceived effect; and 3) no long-term benefit for medial branch block of facet joints with steroids (moderate GRADE; 1 trial, 120 participants) over placebo to reduce pain or disability; Reviewers' Conclusions: While in general there is a lack of evidence for most pharmacological interventions, current evidence is against botulinum toxin-A for chronic neck pain or subacute/chronic whiplash; against medial branch block with steroids for chronic facet joint pain; but in favour of the muscle relaxant eperison hydrochloride for chronic neck pain.

Background: Controversy persists regarding medicinal injections for mechanical neck disorders (MNDs). Objectives: To determine the effectiveness of physician-delivered injections on pain, function/disability, quality of life, global perceived effect and patient satisfaction for adults with MNDs. Search Methods: We updated our previous searches of CENTRAL, MEDLINE and EMBASE from December 2006 through to March 2012. Selection Criteria: We included randomized controlled trials of adults with neck disorders treated by physician-delivered injection therapies. Data Collection and Analysis: Two authors independently selected articles, abstracted data and assessed methodological quality. When clinical heterogeneity was absent, we combined studies using random-effects models. Results: We included 12 trials (667 participants). No high or moderate quality studies were found with evidence of benefit over control. Moderate quality evidence suggests little or no difference in pain or function/disability between nerve block injection of steroid and bupivacaine vs bupivacaine alone at short, intermediate and long-term for chronic neck pain. We found limited very low quality evidence of an effect on pain with intramuscular lidocaine vs control for chronic myofascial neck pain. Two low quality studies showed an effect on pain with anaesthetic nerve block vs saline immediately post treatment and in the short-term. All other studies were of low or very low quality with no evidence of benefit over controls. Authors' Conclusions: Current evidence does not confirm the effectiveness of IM-lidocaine injection for chronic mechanical neck pain nor anaesthetic nerve block for cervicogenic headache. There is moderate evidence of no benefit for steroid blocks vs controls for mechanical neck pain.

We describe patterns of treatment of rheumatoid arthritis with biologics in the United States during 2000–2010 using longitudinal data in the IMS LifeLink™ health plan claims database. Rheumatoid arthritis prevalent and incident cases were identified by ICD-9 diagnostic codes. The proportion of prevalent rheumatoid arthritis cases using biologics increased from 18.7% in 2005 to 26.3% in 2010. Tumor necrosis factor α antagonists constituted 99.1% of biologics in 2005 and 84.4% in 2010. During 2000–2010, 58.1% of incident cases were treated with 1st-line non-steroidal anti-inflammatory drugs and/or corticosteroids and 36.5% were treated with 1st-line synthetic disease-modifying anti-rheumatic drugs. Biologics constituted 5.4% of 1st-line therapies for incident rheumatoid arthritis cases and 30.9%–56.3% of 2nd-to-≥5th line therapies. For those who started on 1st-line non-steroidal anti-inflammatory drugs/corticosteroids, the duration of pharmacotherapy before switching to biologics was 7.2 years for those st...

Importance The activity of lipoprotein lipase (LPL) is the rate-determining step in clearing triglyceride-rich lipoproteins from the circulation. Mutations that damage the LPL gene ( LPL ) lead to lifelong deficiency in enzymatic activity and can provide insight into the relationship of LPL to human disease. Objective To determine whether rare and/or common variants in LPL are associated with early-onset coronary artery disease (CAD). Design, Setting, and Participants In a cross-sectional study, LPL was sequenced in 10 CAD case-control cohorts of the multinational Myocardial Infarction Genetics Consortium and a nested CAD case-control cohort of the Geisinger Health System DiscovEHR cohort between 2010 and 2015. Common variants were genotyped in up to 305 699 individuals of the Global Lipids Genetics Consortium and up to 120 600 individuals of the CARDIoGRAM Exome Consortium between 2012 and 2014. Study-specific estimates were pooled via meta-analysis. Exposures Rare damaging mutations in LPL included loss-of-function variants and missense variants annotated as pathogenic in a human genetics database or predicted to be damaging by computer prediction algorithms trained to identify mutations that impair protein function. Common variants in the LPL gene region included those independently associated with circulating triglyceride levels. Main Outcomes and Measures Circulating lipid levels and CAD. Results Among 46 891 individuals with LPL gene sequencing data available, the mean (SD) age was 50 (12.6) years and 51% were female. A total of 188 participants (0.40%; 95% CI, 0.35%-0.46%) carried a damaging mutation in LPL , including 105 of 32 646 control participants (0.32%) and 83 of 14 245 participants with early-onset CAD (0.58%). Compared with 46 703 noncarriers, the 188 heterozygous carriers of an LPL damaging mutation displayed higher plasma triglyceride levels (19.6 mg/dL; 95% CI, 4.6-34.6 mg/dL) and higher odds of CAD (odds ratio = 1.84; 95% CI, 1.35-2.51; P LPL variants resulted in an odds ratio for CAD of 1.51 (95% CI, 1.39-1.64; P = 1.1 × 10 −22 ) per 1-SD increase in triglycerides. Conclusions and Relevance The presence of rare damaging mutations in LPL was significantly associated with higher triglyceride levels and presence of coronary artery disease. However, further research is needed to assess whether there are causal mechanisms by which heterozygous lipoprotein lipase deficiency could lead to coronary artery disease.

Introduction: In observational studies, higher plasma high-density lipoprotein cholesterol (HDL-C) has been associated with increased risk of spontaneous intracerebral hemorrhage (ICH). Common DNA sequence variants within the cholesteryl ester transfer protein ( CETP ) gene decrease CETP protein activity and increase plasma HDL-C; as such, medicines that inhibit CETP and raise HDL-C are in clinical development to combat coronary artery disease. Hypothesis: Common CETP DNA sequence variants associated with higher HDL-C also increase risk for ICH. Methods: We performed a two-stage case-control genetic association study in Caucasians. The discovery phase utilized data on 12 independent loci within CETP (+/- 50 kilobases) from 3 genome-wide association studies of ICH. Replication involved direct genotyping in 5 additional studies. We also constructed a genetic risk score with 7 independent CETP variants and tested it for association with HDL-C and ICH risk. We used principal component analysis to account for population structure and a Bonferroni-adjusted p Results: The discovery phase included 1149 ICH cases (43% lobar hemorrhages) and 1238 controls. Twelve variants were nominally associated (p-4 ) and no heterogeneity across studies (I 2 =0%). This association was replicated in 1625 cases (43% lobar hemorrhages) and 1845 controls (OR 1.12, 95%CI 1.02-1.24; p=0.03). A genetic score of independent CETP variants known to increase HDL-C by ~2.85 mg/dL was strongly associated with ICH risk (OR 1.86, 95%CI 1.44-2.40; p=1.4x10 -6 ). Conclusion: Genetic variants in CETP associated with increased HDL-C raise the risk of ICH. Given ongoing therapeutic development in CETP inhibition and other HDL-raising strategies, further exploration of potential adverse cerebrovascular outcomes is warranted.

Background— 9p21.3 is among the most strongly replicated regions for cardiovascular disease. There are few reports of sequencing the associated 9p21.3 interval. We set out to sequence the 9p21.3 region followed by a comprehensive study of genetic associations with clinical and subclinical cardiovascular disease and its risk factors, as well as with copy number variation and gene expression, in the Framingham Heart Study (FHS). Methods and Results— We sequenced 281 individuals (94 with myocardial infarction, 94 with high coronary artery calcium levels, and 93 control subjects free of elevated coronary artery calcium or myocardial infarction), followed by genotyping and association in >7000 additional FHS individuals. We assessed genetic associations with clinical and subclinical cardiovascular disease, risk factor phenotypes, and gene expression levels of the protein-coding genes CDKN2A and CDKN2B and the noncoding gene ANRIL in freshly harvested leukocytes and platelets. Within this large sample, we found strong associations of 9p21.3 variants with increased risk for myocardial infarction, higher coronary artery calcium levels, and larger abdominal aorta diameters and no evidence for association with traditional cardiovascular disease risk factors. No common protein-coding variation, variants in splice donor or acceptor sites, or copy number variation events were observed. By contrast, strong associations were observed between genetic variants and gene expression, particularly for a short isoform of ANRIL and for CDKN2B . Conclusions— Our thorough genomic characterization of 9p21.3 suggests common variants likely account for observed disease associations and provides further support for the hypothesis that complex regulatory variation affecting ANRIL and CDKN2B gene expression may contribute to increased risk for clinically apparent and subclinical coronary artery disease and aortic disease.

Background Treatment with non-steroidal anti-inflammatory drugs (NSAID) is a common component of treatment regimens for rheumatoid arthritis (RA). Etoricoxib is a COX-2 selective NSAID that has demonstrated efficacy in the treatment of RA at a dose of 90 mg. The current study further evaluated the efficacy of etoricoxib 60 mg and 90 mg in RA patients with active disease. Methods This was a 2-part, double-blind, placebo-controlled study in RA (NCT01208181). Patients were required to have a diagnosis of RA (according to ARA 1987 revised classification criteria) and were to demonstrate symptom flare upon discontinuation of previous NSAID treatment prior to randomization. Part I was a 6-week, placebo-controlled period to assess the efficacy of etoricoxib 90 mg and etoricoxib 60 mg, each compared to placebo, as well as to each other. Part II was a 6-week period to evaluate the potential benefit of dose escalation from etoricoxib 60 mg to etoricoxib 90 mg after 6 weeks exposure to etoricoxib 60 mg in Part I compared to maintaining a steady dose of etoricoxib 60 mg throughout Parts I and II. Primary endpoints were Disease Activity Score evaluating 28 joints and C reactive protein level (DAS28-CRP) index and Patient Global Assessment of Pain (Pain) score (0–100 mm VAS) after 6 weeks of treatment in Part I. Adverse events were monitored throughout the study. Results In total, 1404 patients were randomized in a 2:7:7:8 ratio; 1228 patients completed Part I and 713 patients continued to Part II. Both etoricoxib doses were superior to placebo on both primary efficacy endpoints (p = 0.004 for 60 mg and p = 0.034 for 90 mg for DAS28-CRP; p

OBJECTIVE: To estimate the prevalence of inadequate pain relief (IPR) among patients with symptomatic knee OA prescribed analgesic therapy and to characterize patients with IPR. METHODS: Patients ≥50 years old with physician-diagnosed knee OA who had taken topical or oral pain medication for at least 14 days were recruited for this prospective non-interventional study in six European countries. Pain and function were assessed using the Brief Pain Inventory (BPI) and the WOMAC; quality of life (QoL) was assessed using the 12-item short form. IPR was defined as an average pain score of >4 out of 10 on BPI question 5. RESULTS: Of 1187 patients enrolled, 68% were female and the mean age was 68 years (s.d. 9); 639 (54%) met the definition of IPR. Patient responses for the BPI average pain question were well correlated with responses on the WOMAC pain subscale (Spearman r = 0.64, P < 0.001). In multivariate logistic regression, patients with IPR had greater odds of being female [adjusted odds ratio (adjOR) 1.90 (95% CI 1.46, 2.48)] and having OA in both knees [adjOR 1.48 (95% CI 1.15, 1.90)], higher BMI, longer OA duration, depression or diabetes. Patients with IPR (vs non-IPR) were more likely to have worse QoL, greater function loss and greater pain interference. CONCLUSION: IPR is common among patients with knee OA requiring analgesics and is associated with large functional loss and impaired QoL. Patients at particular risk of IPR, as characterized in this study, may require greater attention towards their analgesic treatment options. Trial registration: https://clinicaltrials.gov/ (NCT01294696).

s / Osteoarthritis and Cartilage 20 (2012) S54–S296 S178 JSN scores, medially or laterally. Progression was compartment specific for the various clusters. Medial progression occurred only in clusters 1, 2 and 4, most dramatically so in cluster 4 (48%). Cluster 3 again only showed lateral progression (61%). Conclusions: We found clear differences between the various clusters. Cluster 1 could be described as amild type of OA,with nodenuded bone and limited OA progression. Cluster 3 and 4weremore severe and erosive types of OA, showing strong increases in area of denudedbonewith increasingOA severity, and a high prevalence of progression. Interestingly, cluster 3 was purely a lateral type of OA, while cluster 4was purelymedial in all respects. The causes that led to differences between the clusters remain speculative. The higher prevalence of reported trauma in cluster 3 and 4, the more aggressive OA types might suggest a difference in OA initiation. Wekept the complexityof themodels lowtoreduce the riskofoverfittingand increase the likelihood that our findings are generalizable to other cohorts. The fact that clusters also differed on data not included in cluster finding (trauma and progression) indicates that the found clusters are meaningful. In conclusion, latent class cluster analysis confirmed the suspected existence of distinct subtypes of knee OA.