Mechanical thrombectomy versus catheter directed thrombolysis in patients with pulmonary embolism: A multicenter experience.

OBJECTIVES: Compare in-hospital outcomes of patients treated with either mechanical thrombectomy (MT) or catheter directed lysis (CDL) in treatment of acute pulmonary embolism (PE). METHODS: This is a multicenter, retrospective cohort study of patients undergoing MT or CDL for acute PE between 2014 and 2021. The primary outcome was the composite of in-hospital death, significant bleed, vascular complication, or need for mechanical support post-procedure. Secondary outcomes included the individual components of the composite outcome in addition to blood transfusions, invasive hemodynamics, echocardiographic data, and intensive care unit (ICU) utilization. RESULTS: 458 patients were treated for PE with 266 patients in the CDL arm and 192 patients in the MT arm. The primary composite endpoint was not significantly different between the two groups with CDL 12% versus MT 11% (p = 0.5). There was a significant difference in total length of ICU time required with more in the CDL group versus MT (3.8 ± 2.0 vs. 2.8 ± 3.0 days, p = 0.009). All other secondary end points showed no significant difference between the groups. CONCLUSIONS: In patients undergoing catheter directed treatment of PE, there was no difference between MT and CDL in terms of in-hospital mortality, bleeds, catheter-related complications, and hemodynamics.

Integrated safety studies of the urate reabsorption inhibitor lesinurad in treatment of gout.

Objective: Lesinurad (LESU) is a selective urate reabsorption inhibitor approved at 200 mg daily for use with a xanthine oxidase inhibitor (XOI) to treat hyperuricaemia in gout patients failing to achieve target serum urate on XOI. The aim of the study was to investigate the long-term safety of LESU + XOI therapy. Methods: Safety data were pooled from three 12-month phase III (core) trials evaluating LESU 200 and 400 mg/day combined with an XOI (LESU200+XOI and LESU400+XOI), and two 12-month extension studies using descriptive statistics. To adjust for treatment duration, treatment-emergent adverse events (TEAEs) were expressed as exposure-adjusted incidence rates (patients with events per 100 person-years). Results: In the core studies, exposure-adjusted incidence rates for total and total renal-related TEAEs were comparable for XOI alone and LESU200+XOI but higher with LESU400+XOI. Exposure-adjusted incidence rates for serum creatinine (sCr) elevations ⩾1.5×baseline were 2.9, 7.3 and 18.7, respectively. Resolution (sCr ⩽1.2×baseline) occurred in 75-90% of all events, with 66-75% occurring without any study medication interruption. Major adverse cardiovascular events were 3, 4 and 9 with XOI, LESU200+XOI and LESU400+XOI, respectively. Longer exposure in core+extension studies did not increase rates for any safety signals. Conclusion: At the approved dose of 200 mg once-daily combined with an XOI, LESU did not increase renal, cardiovascular or other adverse events compared with XOI alone, except for sCr elevations. With extended exposure in the core+extension studies, the safety profile was consistent with that observed in the core studies, and no new safety concerns were identified.

Safety and efficacy of verinurad, a selective URAT1 inhibitor, for the treatment of patients with gout and/or asymptomatic hyperuricemia in the United States and Japan: Findings from two phase II trials.

Objective: Evaluate efficacy/safety of verinurad monotherapy in patients with gout (Japan/US) or asymptomatic hyperuricemia (Japan).Methods: Two randomized, placebo-controlled, phase II studies were conducted (NCT01927198/NCT02078219). Patients were randomized to once-daily doses of placebo or escalating doses of verinurad (study 1: 5-12.5 mg; study 2: 2.5-15 mg). Primary endpoint was percentage change from baseline in serum urate (sUA) at week 12 (study 1)/week 16 (study 2). Safety was also assessed.Results: Most patients in study 1 (n = 171) were white (74.9%); all patients were Japanese in study 2 (n = 204). Least squares means (±SE) estimate of percentage change in sUA levels from baseline in study 1 was 1.2 ± 2.9 for placebo, and -17.5 ± 2.8, -29.1 ± 2.8, -34.4 ± 2.9 for verinurad 5, 10, 12.5 mg, respectively. In study 2, results were -2.4 ± 2.5 and -31.7 ± 2.5, -51.7 ± 2.6,-55.8 ± 2.5, respectively. Difference from placebo was significant for each verinurad dose (p<.0001). The proportion of patients with treatment-emergent adverse events (TEAEs) was similar across all groups. Renal-related TEAEs were more common with verinurad than placebo.Conclusion: Verinurad monotherapy resulted in sustained reductions in sUA in Japanese/US patients but renal AEs occurred, so verinurad alone is not recommended for treatment of hyperuricemia or gout. The renal consequences of excessive uric acid excretion deserve study.

Presence of monosodium urate crystal deposition by dual-energy CT in patients with gout treated with allopurinol.

OBJECTIVE: Dual-energy CT (DECT) detects and quantifies monosodium urate (MSU) crystal deposition with high precision. This DECT study assessed crystal deposition in patients with gout treated with stable-dose allopurinol, and investigated potential clinical determinants for crystal deposition. METHODS: Patients with gout treated with allopurinol ≥300 mg daily for at least 3 months were prospectively recruited from the USA and New Zealand, using monitored enrolment to include approximately 25% patients with palpable tophi and approximately 50% with serum urate (sUA) levels <6.0 mg/dL (<357µmol/L). MSU crystal deposition was measured in the hands/wrists, feet/ankles/Achilles and knees bilaterally. The presence and total volume of crystals were assessed by DECT and analysed according to sUA levels and gout characteristics. RESULTS: Among 152 patients receiving allopurinol ≥300 mg/day for 5.1 years on average, 69.1% had crystal deposition on DECT, with a median total crystal volume of 0.16 cm3 (range: 0.01-19.53 cm3). The prevalence of crystal deposition ranged from 46.9% among patients with sUA <6.0 mg/dL and no palpable tophi to 90.0% among those with sUA ≥6.0 mg/dL and tophi. Total volume of crystal deposition was positively associated with sUA ≥6.0 mg/dL, gout flares within the past 3 months and tophi. Total volume of crystal deposition correlated positively with Patient Global Impression of Disease Activity scores. CONCLUSION: A substantial proportion of patients without palpable tophi have MSU crystal deposition, despite receiving allopurinol doses ≥300 mg/day for a considerable duration. Patients with higher sUA and clinical features of severe disease have a higher frequency and greater volume of MSU crystal deposition.

Lesinurad in combination with allopurinol: a randomised, double-blind, placebo-controlled study in patients with gout with inadequate response to standard of care (the multinational CLEAR 2 study).

OBJECTIVES: Determine the efficacy and safety of daily lesinurad (200 or 400 mg orally) added to allopurinol in patients with serum uric acid (sUA) above target in a 12-month, randomised, phase III trial. METHODS: Patients on allopurinol ≥300 mg (≥200 mg in moderate renal impairment) had sUA level of ≥6.5 mg/dL (≥387 µmol/L) at screening and two or more gout flares in the prior year. Primary end point was the proportion of patients achieving sUA level of <6.0 mg/dL (<357 µmol/L) (month 6). Key secondary end points were mean gout flare rate requiring treatment (months 7 through 12) and proportions of patients with complete resolution of one or more target tophi (month 12). Safety assessments included adverse events and laboratory data. RESULTS: Patients (n=610) were predominantly male, with mean (±SD) age 51.2±10.90 years, gout duration 11.5±9.26 years and baseline sUA of 6.9±1.2 mg/dL (410±71 µmol/L). Lesinurad at 200 and 400 mg doses, added to allopurinol, significantly increased proportions of patients achieving sUA target versus allopurinol-alone therapy by month 6 (55.4%, 66.5% and 23.3%, respectively, p<0.0001 both lesinurad+allopurinol groups). In key secondary end points, there were no statistically significant treatment-group differences favouring lesinurad. Lesinurad was generally well tolerated; the 200 mg dose had a safety profile comparable with allopurinol-alone therapy. Renal-related adverse events occurred in 5.9% of lesinurad 200 mg+allopurinol, 15.0% of lesinurad 400 mg+allopurinol and 4.9% of allopurinol-alone groups, with serum creatinine elevation of ≥1.5× baseline in 5.9%, 15.0% and 3.4%, respectively. Serious treatment-emergent adverse events occurred in 4.4% of lesinurad 200 mg+allopurinol, in 9.5% of lesinurad 400 mg+allopurinol and in 3.9% of allopurinol-alone groups, respectively. CONCLUSION: Lesinurad added to allopurinol demonstrated superior sUA lowering versus allopurinol-alone therapy and lesinurad 200 mg was generally well tolerated in patients with gout warranting additional therapy. TRIAL REGISTRATION NUMBER: NCT01493531.

Lesinurad monotherapy in gout patients intolerant to a xanthine oxidase inhibitor: a 6 month phase 3 clinical trial and extension study.

Objective: To investigate the efficacy and safety of lesinurad, a selective uric acid reabsorption inhibitor, in a 6 month, phase 3 clinical trial and extension study. Methods: Patients with gout who cannot take a xanthine oxidase inhibitor (XOI) and have serum uric acid (sUA) ⩾6.5 mg/dl were randomized to receive oral lesinurad (400 mg daily) or placebo. The primary endpoint was the proportion of patients with sUA <6.0 mg/dl at month 6. Safety assessments included treatment-emergent adverse events (TEAEs) and laboratory data. Patients who completed the study were eligible for an open-label, uncontrolled extension study of lesinurad 400 mg monotherapy. Results: Patients (n = 214) were primarily white males (mean age 54.4 years; gout duration 11.2 years). Significantly more patients achieved the primary endpoint with lesinurad than placebo (29.9 vs 1.9%; P < 0.0001). Overall TEAE rates were higher with lesinurad (77.6 vs 65.4%); renal-related TEAEs (17.8%), renal-related serious TEAEs (4.7%) and serum creatinine elevations (1.5 times baseline, 24.3%) occurred only with lesinurad. A total of 143 patients (65 lesinurad, 78 placebo) enrolled in the extension study. Treatment with lesinurad 400 mg resulted in rapid and sustained sUA lowering that persisted for up to 18 months before the study was terminated prematurely. No new safety findings were observed in the extension. Conclusion: In patients with gout and intolerance/contraindication to XOIs, lesinurad 400 mg monotherapy demonstrated superior sUA lowering compared with placebo, with sustained effects for up to 18 months. Due to a high incidence of serum creatinine elevations and renal-related adverse events, including serious adverse events with lesinurad 400 mg, lesinurad should not be used as monotherapy. Trial registration: ClinicalTrials.gov (http://clinincaltrials.gov), NCT01508702.

Brodalumab, an anti-interleukin-17-receptor antibody for psoriasis.

BACKGROUND: In this phase 2, randomized, double-blind, placebo-controlled, dose-ranging study, we assessed the efficacy and safety of brodalumab (AMG 827), a human anti-interleukin-17-receptor monoclonal antibody, for the treatment of moderate-to-severe plaque psoriasis. METHODS: We randomly assigned patients with a score of 12 or higher on the psoriasis area-and-severity index (PASI, on which scores range from 0 to 72, with higher scores indicating more severe disease) and with 10% or more of their body-surface area affected by psoriasis to receive brodalumab (70 mg, 140 mg, or 210 mg at day 1 and weeks 1, 2, 4, 6, 8, and 10 or 280 mg monthly) or placebo. The primary end point was the percentage improvement from baseline in the PASI score at week 12. Secondary end points included improvement of at least 75% and at least 90% in the PASI score and the score on the static physician's global assessment at week 12. RESULTS: A total of 198 patients underwent randomization. At week 12, the mean percentage improvements in the PASI score were 45.0% among patients receiving 70 mg of brodalumab, 85.9% among those receiving 140 mg, 86.3% among those receiving 210 mg, 76.0% among those receiving 280 mg, and 16.0% among those receiving placebo (P<0.001 for all comparisons with placebo). An improvement of at least 75% and at least 90% in the PASI score at week 12 was seen in 77% and 72%, respectively, of the patients in the 140-mg brodalumab group and in 82% and 75%, respectively, of the patients in the 210-mg group, as compared with 0% in the placebo group (P<0.001 for all comparisons). The percentage of patients with a static physician's global assessment of clear or minimal disease was 26%, 85%, 80%, and 69% with the 70-mg, 140-mg, 210-mg, and 280-mg doses, respectively, of brodalumab, as compared with 3% with placebo (P<0.01 for all comparisons with placebo). Two cases of grade 3 neutropenia were reported in the 210-mg brodalumab group. The most commonly reported adverse events in the combined brodalumab groups were nasopharyngitis (8%), upper respiratory tract infection (8%), and injection-site erythema (6%). CONCLUSIONS: Brodalumab significantly improved plaque psoriasis in this 12-week, phase 2 study. (Funded by Amgen; ClinicalTrials.gov number, NCT00975637.).

Pharmacodynamic, pharmacokinetic and tolerability evaluation of concomitant administration of lesinurad and febuxostat in gout patients with hyperuricaemia.

OBJECTIVE: The aim of this study was to evaluate the pharmacodynamics (PDs), pharmacokinetics (PKs) and safety of lesinurad (selective uric acid reabsorption inhibitor) in combination with febuxostat (xanthine oxidase inhibitor) in patients with gout. METHODS: This study was a phase IB, multicentre, open-label, multiple-dose study of gout patients with serum uric acid (sUA) >8 mg/dl following washout of urate-lowering therapy with colchicine flare prophylaxis. Febuxostat 40 or 80 mg/day was administered on days 1-21, lesinurad 400 mg/day was added on days 8-14 and then lesinurad was increased to 600 mg/day on days 15-21. sUA, urine uric acid and PK profiles were evaluated at the end of each week. Safety was assessed by adverse events, laboratory tests and physical examinations. RESULTS: Initial treatment with febuxostat 40 or 80 mg/day monotherapy resulted in 67% and 56% of subjects, respectively, achieving a sUA level <6 mg/dl. Febuxostat 40 or 80 mg/day plus lesinurad 400 or 600 mg/day resulted in 100% of subjects achieving sUA <6 mg/dl and up to 100% achieving sUA <5 mg/dl. No clinically relevant changes in the PKs of either drug were noted. The combination was well tolerated. CONCLUSION: The clinically important targets of sUA <6 mg/dl and <5 mg/dl are achievable in 100% of patients when combining lesinurad and febuxostat.

Delay in prior authorization of biologic therapy: Another possible cause of healthcare disparity in IBD patients.

BACKGROUND: Biologics, a mainstay in inflammatory bowel disease (IBD) treatment, typically require prior authorization from insurance companies. Multiple studies show that African Americans are less likely to be prescribed biologics. The prior authorization process may perpetuate disparities in healthcare. This study evaluated the approval time for biologics in IBD. METHODS: A chart review of IBD patients seen in a university gastroenterology clinic over 5 years was performed. Patient gender, race, IBD subtype, biologic use, and insurance type were recorded. Insurance type was classified as private or public (Medicaid or Medicare). Biologic agents evaluated included infliximab, adalimumab, vedolizumab and ustekinumab. Length of time to approval (TTA) and length of time to first infusion or administration (TFI) were recorded. Analysis was performed using t-testing, Fisher's exact testing, and ANOVA with significance set at p<0.05. The study was IRB approved. RESULTS: 458 charts were analyzed. 66 patients were being treated with a biologic. 42 had private insurance, 16 Medicaid and 8 Medicare. 37 patients had ulcerative colitis, 27 Crohn's disease, and 2 indeterminate colitis. There were 38 men and 28 women. 32 patients were white, 26 African American, 1 Asian, 5 other, and 2 declined identification. Average TTA was 30.5 days (range 1-145) and average TFI was 45.3 days (range 2-166). African Americans were more often on public insurance compared to whites (p=0.0001). Crohn's disease compared to ulcerative colitis patients were more often on public insurance (p=0.017). Significantly more private compared to public insurance patients were on infliximab (p=0.001). Medicaid and Medicare patients had significantly longer mean TTAs than private insurance patients (49.1 and 52.7 vs 19.4 days, p=0.007). African Americans had significantly longer mean TTA compared to whites (45.9 vs 24.8 days, p=0.044). Crohn's disease compared to ulcerative colitis patients had significantly longer mean TTA (39.7 vs 21.8 days, p=0.050). DISCUSSION: This study shows that prior authorization for biologic therapy was longer for African Americans. Patients on public insurance also tend to have a longer TTA, and more African Americans were on public insurance compared to White patients in this study which may explain the difference in biologic access for African Americans.

Predictors of Patient and Physician Assessments of Gout Control.

OBJECTIVE: To understand the clinical variables that contribute to the patient and physician assessments of gout control and which variables predict discordant assessments. METHODS: Patients (n = 223) with gout taking allopurinol ≥300 mg daily attended a standardized gout assessment visit. Participants and physicians completed questionnaires rating their assessment of current gout control using a numerical rating scale (0 = not at all controlled, 10 = fully controlled). Discordance between patients' and physicians' scores was defined as an absolute difference of >2 units. RESULTS: The mean ± SD patient gout control score was 8.09 ± 2.24, and the physician gout control score was 7.38 ± 2.63 (P < 0.001 for comparison). Absence of gout flares in the last 12 months and in the last 3 months and serum urate at the treatment target (<6 mg/dl) were associated with higher patient and physician gout control scores. Absence of tophus also predicted higher physician, but not patient, gout control scores. Discordant scores for gout control were present in 50 participants (22.3%), mostly due to lower assessment of disease control by physicians. Gout flare in the preceding 3 months (odds ratio [OR] 5.9, P < 0.001) and tophus (OR 3.1, P = 0.007) predicted discordant disease-control assessments in which physicians scored lower gout control than patients. CONCLUSION: For both patients and physicians, absence of gout flares and serum urate levels at the treatment target predict assessment of gout control. However, discordance between patients and physicians in their assessment of disease control is not uncommon, with recent gout flares and tophus predicting lower scores by physicians than patients.

Safety of Catheter Ablation Therapy for Atrial Fibrillation in Cardiac Amyloidosis.

Background Despite the high burden of atrial fibrillation in cardiac amyloidosis (CA), the safety of catheter ablation therapy in CA is not well established. We sought to examine short-term safety outcomes following atrial fibrillation ablation in patients with CA compared with matched patients with dilated cardiomyopathy (DCM). Methods and Results Using data from the National Inpatient Sample, we identified all hospitalizations for atrial fibrillation ablation from the fourth quarter of 2015 through 2019. Admissions for CA and DCM were matched in a 1:5 ratio using propensity scores based on the following sociodemographics: age, sex, race or ethnicity, payor, median income, comorbidities, and hospital characteristics. We compared in-hospital outcomes between both cardiomyopathies. We identified 1395 unweighted hospitalizations (representing 6750 national hospitalizations) for atrial fibrillation ablation, out of which 45 (3.2%) were admissions for CA. Compared with DCM, patients with CA were older (72.9 versus 65.1 years), had a higher burden of prior stroke (20.0% versus 8.6%) and chronic kidney disease (53.3% versus 33.6%), and were less likely to have a prior implantable cardioverter-defibrillator (4.4% versus 23.0%). We successfully matched 42 CAs to 210 DCM hospitalizations. After matching, there was no difference in total complications (14.3% versus 10.5%, P=0.60), length-of-stay (3.1 versus 2.1 days, P=0.23), home disposition (97.6% versus 96.2%, P=0.65), and total charges ($137 250 versus $133 910, P=0.24). Conclusions In this nationally representative study of atrial fibrillation catheter ablation in CA, short-term safety outcomes and complication rates were similar to a propensity score-matched cohort of DCM. Further studies exploring long-term safety outcomes are needed.

Integrated safety analysis: short- and long-term safety profiles of etanercept in patients with psoriasis.

BACKGROUND: Multiple trials demonstrate the tolerability and safety of etanercept. However, there are limited data on etanercept tolerability in large populations of patients with psoriasis or with extended therapy. OBJECTIVES: We sought to determine whether there is an increased safety risk associated with higher etanercept doses or with extended exposure in patients with psoriasis. METHODS: Integrated adverse event (AE) data from etanercept psoriasis trials were used to evaluate short-term (up to 12 weeks from controlled studies) and long-term (up to 144 weeks from uncontrolled extension studies) safety of etanercept (25 mg once weekly to 50 mg twice weekly). Long-term data were stratified by treatment regimens. Rates of noninfectious and infectious AE and standardized incidence ratios for malignancies were determined. RESULTS: In short-term analyses, rates of noninfectious and infectious AE and serious noninfectious and infectious AE were comparable between placebo and etanercept groups. In both short- and long-term analyses, there were no dose-related increases in these events. Cumulative event rates for serious infections were not significantly different across dose groups and over time. The standardized incidence ratios for malignancies excluding nonmelanoma skin cancers did not achieve statistical significance. There was no increase in overall malignancies with etanercept therapy compared with the psoriasis population. Lymphoma (n = 2 patients), demyelination (n = 2), congestive heart failure (n = 7), and opportunistic infection (n = 1) were rare. LIMITATIONS: Study limitations include the rarity of some events and the resultant broad 95% confidence intervals. CONCLUSIONS: In this integrated analysis, etanercept was well tolerated, and there were no signs of dose-related or cumulative toxicity over time.

Health-related quality of life of pediatric patients with moderate to severe plaque psoriasis: comparisons to four common chronic diseases.

Health-related quality of life (HRQOL) is an important indicator of the burden of illness in moderate-to-severe plaque psoriasis. This study evaluated self-reported generic HRQOL among pediatric patients with moderate-to-severe plaque psoriasis based on pooled baseline clinical trial data and compared them to four common chronic diseases and to a healthy sample. The Pediatric Quality of Life Inventory Version 4.0 (PedsQL™ 4.0) Generic Core Scales was administered to 208 patients ages 4 to 17 years with stable, moderate-to-severe plaque psoriasis. Patients with moderate-to-severe plaque psoriasis were compared using one-sample t-tests to published PedsQL™ ( http://www.pedsql.org ) data on healthy children and pediatric patients with arthritis, psychiatric disorders, asthma, and diabetes. Pediatric patients with moderate-to-severe plaque psoriasis demonstrated significantly impaired physical, emotional, social, and school functioning in comparison to healthy children. The PedsQL™ Emotional and School Functioning Scales demonstrated the largest mean difference between the two groups (12.1, 11.1 points, respectively). In general, patients with plaque psoriasis demonstrated significantly more impaired generic HRQOL compared to patients with diabetes, comparable HRQOL to arthritis and asthma, and better HRQOL than psychiatric patients. In conclusion, the findings indicate that pediatric patients with moderate-to-severe plaque psoriasis have significantly impaired generic HRQOL in comparison to healthy children, and HRQOL generally comparable to other serious chronic diseases. These results demonstrate the significant negative impact of plaque psoriasis on the daily lives of these children from the patients' perspective.

Effects of long-term etanercept treatment on growth in children with selected categories of juvenile idiopathic arthritis.

OBJECTIVE: To evaluate the effects of long-term etanercept treatment, with or without methotrexate, on growth in children with selected categories of juvenile idiopathic arthritis (JIA). METHODS: We conducted a 3-year, open-label, nonrandomized registry of 594 patients with polyarticular or systemic JIA treated with etanercept only, etanercept plus methotrexate, or methotrexate only. Height, weight, and body mass index (BMI) were assessed at baseline and at years 1, 2, and 3, using percentiles derived from US Centers for Disease Control and Prevention standardized growth charts. RESULTS: Statistically significant increases in the mean height percentiles from baseline were observed in etanercept-treated patients at year 3 (4.8 percentile points) and in patients treated with etanercept plus methotrexate at years 1, 2, and 3 (2.4, 3.3, and 5.6 percentile points, respectively). Statistically significant increases from baseline in the mean weight percentiles were observed at years 1, 2, and 3 in both the etanercept group (7.4, 10.0, and 13.0 percentile points) and the etanercept-plus-methotrexate group (2.9, 6.9, and 8.4 percentile points, respectively). Statistically significant increases from baseline in the mean BMI percentiles were observed in both the etanercept group (range 9.6-13.8 percentile points) and the etanercept-plus-methotrexate group (range 2.1-5.2 percentile points). The mean height, weight, and BMI percentiles did not change significantly in patients in the methotrexate-only group. CONCLUSION: Etanercept treatment, with or without methotrexate, may contribute to the restoration of normal growth in children with JIA.

Clinical trial safety and mortality analyses in patients receiving etanercept across approved indications.

OBJECTIVES: Assessment of associations between etanercept treatment and rare adverse events has been limited by the size of clinical trial populations. The authors examined the collective safety of etanercept in clinical trials across approved indications. PATIENTS AND METHODS: Forty-nine U.S. and non-U.S. trials of etanercept, involving up to 13,977 patients for approved indications, with final trial reports as of May 2006, were selected from the Amgen Inc. clinical trials database. Exposure-adjusted rates of serious infections, opportunistic infections, malignancies, and deaths were reported by trial, indication, and dosage. RESULTS: Rates of serious infections were generally similar between etanercept and controls. Overall rates of opportunistic infections and tuberculosis were low. The standardized incidence ratio (SIR) (95% CI) for malignancy was 1.00 (0.83-1.19) for all etanercept patients across all indications. The SIR for lymphoma for patients with rheumatoid arthritis was 3.45 (1.83-5.89); all other indications reported SIRs similar to those observed in the general population. The SIRs for cutaneous squamous cell carcinoma in patients with psoriasis relative to the general population with high or low sun exposure were 2.09 (1.27-3.22) and 4.96 (3.03-7.66), respectively. SIRs were less than 1.0 for all other indications regardless of sun exposure. Rates of melanoma and basal cell carcinoma were not significantly different from those in the general population. There was no increase in mortality associated with etanercept use relative to control populations. CONCLUSION: These data support the overall tolerability of etanercept across approved indications.

The Enhanced Brief Structured Observation Model: Efficiently Assess Trainee Competence and Provide Feedback.

Introduction: The regular observation of trainees is essential to ascertain trainee proficiency in competency-based assessments. Unfortunately, observation of residents is not frequent enough to facilitate entrustment decisions, and the busy clinician-educator may not have the tools or time to conduct effective and efficient observations. Methods: We created a hands-on faculty development workshop utilizing an enhanced variation of the brief structured observation (BSO) technique to train both primary care and subspecialty pediatric faculty on how to effectively and efficiently observe trainees. The workshop has provided faculty a practical approach to observing trainees in a focused fashion and providing effective feedback on clinical skills based on their observation. In the workshop, faculty had an opportunity to observe residents taking an unrehearsed history from a medical student simulating an acutely ill patient, culminating in feedback on the residents' performance using the subjective, objective, assessment, and plan (SOAP) format. Results: This faculty development workshop has been presented to more than 100 faculty both locally and nationally, and feedback has been uniformly positive, with three institutions incorporating this model into their programs to date. Discussion: This enhanced BSO workshop promotes a model that streamlines the observations of trainees and provides faculty with the tools to encourage more observations.

A Randomized, Double-Blind, Placebo-Controlled, Phase 2a Study to Evaluate the Efficacy and Safety of RIST4721 in Subjects with Palmoplantar Pustulosis.

INTRODUCTION: Palmoplantar pustulosis (PPP) is a chronic inflammatory skin condition with neutrophilic infiltration of the epidermis. RIST4721 antagonizes CXC chemokine receptor type 2, which is important in neutrophil recruitment and migration. In this study, the efficacy and safety of RIST4721 versus placebo were assessed in adult subjects with moderate to severe PPP. METHODS: This phase 2a, multicenter, randomized, double-blind, placebo-controlled study investigated RIST4721 versus placebo in subjects with moderate to severe PPP. Key eligibility criteria included: Palmoplantar Pustulosis Area and Severity Index (PPPASI) ≥ 8 and Palmoplantar Pustulosis Physician Global Assessment ≥ 3. Subjects were randomized 1:1 to RIST4721 300 mg or placebo once daily for 28 days. The primary efficacy endpoints were relative change from baseline in fresh and total pustule count at day 28. RESULTS: Fifteen subjects received RIST4721 and 19 subjects received placebo. Treatment with RIST4721 was found to be generally well tolerated. At day 28, the mean ± standard deviation (SD) relative change from baseline in fresh pustule count was 0.86 ± 0.692 and 0.53 ± 0.561 (P = 0.240) and in total pustule count was 0.99 ± 0.667 and 0.96 ± 0.672 (P = 0.804) for RIST4721 and placebo groups, respectively. Subgroup analysis of subjects with progressing disease demonstrated that subjects with a PPPASI-50 at day 28 was significantly higher for subjects treated with RIST4721 (71%) than placebo (15%) (P = 0.022). CONCLUSION: Preliminary data suggest RIST4721 is well tolerated and may be a potential therapy for patients with PPP. TRIAL REGISTRATION: RIST4721-201 was registered in June 2019 at clinicaltrials.gov: NCT03988335.

Risk of elevated liver enzymes associated with TNF inhibitor utilisation in patients with rheumatoid arthritis.

OBJECTIVE: Liver function test (LFT) elevations are reported with the use of tumour necrosis factor inhibitors (TNF-Is). The aim of this study was to compare LFT elevations in patients with rheumatoid arthritis receiving adalimumab (ADA), etanercept (ETN) or infliximab (INF) enrolled in the Consortium of Rheumatology Researchers of North America from October 2001 to March 2007. METHODS: Alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) levels >1x upper limit of normal (ULN) were considered elevations and ALT/AST levels >2x ULN were considered abnormalities. Treatments included TNF-Is, methotrexate (MTX), leflunomide and other disease-modifying antirheumatic agents (DMARDs). Patients were censored after their first LFT elevation. Three analytical models were evaluated: (1) individual TNF-I vs non-biological DMARDs (primary model); (2) individual TNF-I plus MTX vs MTX monotherapy; and (3) limited to new users of individual TNF-I vs non-biological DMARDs. ORs for LFT elevations were estimated using generalised estimating equation logistic regression. RESULTS: 6861 patients (ADA: 849; ETN: 1383; INF: 1449) with 22 522 determinations were analysed. LFT elevations >1x ULN with TNF-I use were seen in 5.9% of AST/ALT determinations and abnormalities >2x ULN in 0.77%. In the primary model the adjusted ORs for LFT elevations >1x ULN were ADA 1.35 (95% CI 1.09 to 1.66), ETN 1.00 (95% CI 0.83 to 1.21) and INF 1.58 (95% CI 1.35 to 1.86). For 2x ULN, adjusted ORs were ADA 1.72 (95% CI 0.99 to 3.01), ETN 1.10 (95% CI 0.64 to 1.88) and INF 2.40 (95% CI 1.53 to 3.76). Similar results were obtained in other models. CONCLUSION: The overall incidence of LFT elevations >1x ULN with TNF-I use was uncommon and abnormalities >2x ULN were rarely observed. Significant differences were most consistently observed with INF, less commonly with ADA and were not observed with ETN compared with comparator DMARDs.

Radiologic evidence of symmetric and polyarticular monosodium urate crystal deposition in gout - A cluster pattern analysis of dual-energy CT.

OBJECTIVES: To determine the clustering patterns of monosodium urate (MSU) crystal deposition and bone erosions among patients with gout requiring urate-lowering therapy (ULT) using dual-energy CT (DECT). METHODS: DECT scans of bilateral hands/wrists, feet/ankles, and knees were obtained on 153 patients with gout on allopurinol ≥300 mg daily for ≥3 months. Two radiologists assessed the images at pre-specified sites (15 in the hands/wrists, 12 in the feet/ankles, 4 in the knees). Clustering patterns of MSU crystal deposition and bone erosions were evaluated. RESULTS: Among 153 patients with gout (mean duration, 15 years) on allopurinol (mean duration, 5 years), MSU crystal deposition (67%) affected multiple sites in the hands/wrists, feet/ankles, and knees more often than would be expected by chance (p<0.001 for all 3 regions). In the feet/ankles, bone erosions were also observed in a clustered manner (p<0.001). Presence of MSU crystal deposition at a particular joint was most strongly associated with symmetric involvement of the same joint of the opposite extremity in the hands/wrists, feet/ankles, and knees (adjusted odds ratio (OR) 26.1, 46.9, and 9.9, respectively). Similarly, presence of erosions in the feet/ankles was highly symmetric (adjusted OR 91.4). Erosions were 8-fold more likely to be present in sites with MSU crystal deposition compared to those without. CONCLUSION: Among patients with longstanding gout on ULT, MSU crystal deposition and bone erosions affect multiple joints within the hands/wrists, feet/ankles, and knees in a highly symmetric manner. These radiologic data support the notion of MSU crystal deposition in gout as a symmetric polyarthropathy.

The economic burden of uncontrolled gout: how controlling gout reduces cost.

AIM: To evaluate the burden of uncontrolled gout by examining estimated costs and cost drivers. MATERIALS AND METHODS: Data from the 2012 and 2013 US National Health and Wellness Survey (NHWS; 2012 NHWS, n = 71,157 and 2013 NHWS, n = 75,000) were utilized in this study. Based on self-reported gout diagnosis and gout symptoms, respondents were categorized into three groups: controlled gout (n = 344), uncontrolled gout (n = 2,215), and non-gout controls (n = 126,360). Chi-square tests and one-way analysis of variance (ANOVAs) were used to assess group differences on work productivity loss, healthcare resource utilization, and costs. Zero-inflated negative binomial regressions were used to assess the burden of uncontrolled gout on total costs after controlling for covariates. RESULTS: Patients with uncontrolled gout had higher presenteeism, overall work impairment, activity impairment, and number of emergency department visits than those with controlled gout or controls. Overall, uncontrolled gout patients had both higher indirect and total costs compared to patients with controlled gout. After controlling for confounders, those with uncontrolled gout had higher total costs than controlled gout respondents and non-gout controls; there was no significant difference in total costs between patients with controlled gout and non-gout controls. LIMITATIONS: Results were based on cross-sectional, self-reported data, making causal inferences more uncertain. Additionally, sample size was small for controlled-gout respondents. Lastly, sampling weights were not used, thus potentially limiting generalizability. CONCLUSION: Gout can be an expensive condition, particularly if it is not properly controlled. This study provides support that controlling symptoms (e.g. flares) can reduce the economic and societal burden of gout. Therefore, more attention needs to be paid to effective management of gout symptoms.