Dupilumab treatment in adults with moderate-to-severe atopic dermatitis.

BACKGROUND: Dupilumab, a fully human monoclonal antibody that blocks interleukin-4 and interleukin-13, has shown efficacy in patients with asthma and elevated eosinophil levels. The blockade by dupilumab of these key drivers of type 2 helper T-cell (Th2)-mediated inflammation could help in the treatment of related diseases, including atopic dermatitis. METHODS: We performed randomized, double-blind, placebo-controlled trials involving adults who had moderate-to-severe atopic dermatitis despite treatment with topical glucocorticoids and calcineurin inhibitors. Dupilumab was evaluated as monotherapy in two 4-week trials and in one 12-week trial and in combination with topical glucocorticoids in another 4-week study. End points included the Eczema Area and Severity Index (EASI) score, the investigator's global assessment score, pruritus, safety assessments, serum biomarker levels, and disease transcriptome. RESULTS: In the 4-week monotherapy studies, dupilumab resulted in rapid and dose-dependent improvements in clinical indexes, biomarker levels, and the transcriptome. The results of the 12-week study of dupilumab monotherapy reproduced and extended the 4-week findings: 85% of patients in the dupilumab group, as compared with 35% of those in the placebo group, had a 50% reduction in the EASI score (EASI-50, with higher scores in the EASI indicating greater severity of eczema) (P<0.001); 40% of patients in the dupilumab group, as compared with 7% in the placebo group, had a score of 0 to 1 (indicating clearing or near-clearing of skin lesions) on the investigator's global assessment (P<0.001); and pruritus scores decreased (indicating a reduction in itch) by 55.7% in the dupilumab group versus 15.1% in the placebo group (P<0.001). In the combination study, 100% of the patients in the dupilumab group, as compared with 50% of those who received topical glucocorticoids with placebo injection, met the criterion for EASI-50 (P=0.002), despite the fact that patients who received dupilumab plus glucocorticoids used less than half the amount of topical glucocorticoids used by those who received placebo plus the topical medication (P=0.16). Adverse events, such as skin infection, occurred more frequently with placebo; nasopharyngitis and headache were the most frequent adverse events with dupilumab. CONCLUSIONS: Patients treated with dupilumab had marked and rapid improvement in all the evaluated measures of atopic dermatitis disease activity. Side-effect profiles were not dose-limiting. (Funded by Regeneron Pharmaceuticals and Sanofi; ClinicalTrials.gov numbers, NCT01259323, NCT01385657, NCT01639040, and NCT01548404.).

Osteocalcin protects pancreatic beta cell function and survival under high glucose conditions.

Diabetes is characterized by progressive beta cell dysfunction and loss due in part to oxidative stress that occurs from gluco/lipotoxicity. Treatments that directly protect beta cell function and survival in the diabetic milieu are of particular interest. A growing body of evidence suggests that osteocalcin, an abundant non-collagenous protein of bone, supports beta cell function and proliferation. Based on previous gene expression data by microarray, we hypothesized that osteocalcin protects beta cells from glucose-induced oxidative stress. To test our hypothesis we cultured isolated rat islets and INS-1E cells in the presence of normal, high, or high glucose ± osteocalcin for up to 72 h. Oxidative stress and viability/mitochondrial function were measured by H2O2 assay and Alamar Blue assay, respectively. Caspase 3/7 activity was also measured as a marker of apoptosis. A functional test, glucose stimulated insulin release, was conducted and expression of genes/protein was measured by qRT-PCR/western blot/ELISA. Osteocalcin treatment significantly reduced high glucose-induced H2O2 levels while maintaining viability/mitochondrial function. Osteocalcin also significantly improved glucose stimulated insulin secretion and insulin content in rat islets after 48 h of high glucose exposure compared to untreated islets. As expected sustained high glucose down-regulated gene/protein expression of INS1 and BCL2 while increasing TXNIP expression. Interestingly, osteocalcin treatment reversed the effects of high glucose on gene/protein expression. We conclude that osteocalcin can protect beta cells from the negative effects of glucose-induced oxidative stress, in part, by reducing TXNIP expression, thereby preserving beta cell function and survival.

Incorporating Medicare Advantage Admissions Into the CMS Hospital-Wide Readmission Measure.

Importance: Medicare Advantage (MA) enrollment is rapidly expanding, yet Centers for Medicare & Medicaid Services (CMS) claims-based hospital outcome measures, including readmission rates, have historically included only fee-for-service (FFS) beneficiaries. Objective: To assess the outcomes of incorporating MA data into the CMS claims-based FFS Hospital-Wide All-Cause Unplanned Readmission (HWR) measure. Design, Setting, and Participants: This cohort study assessed differences in 30-day unadjusted readmission rates and demographic and risk adjustment variables for MA vs FFS admissions. Inpatient FFS and MA administrative claims data were extracted from the Integrated Data Repository for all admissions for Medicare beneficiaries from July 1, 2018, to June 30, 2019. Measure reliability and risk-standardized readmission rates were calculated for the FFS and MA cohort vs the FFS-only cohort, overall and within specialty subgroups (cardiorespiratory, cardiovascular, medicine, surgery, neurology), then changes in hospital performance quintiles were assessed after adding MA admissions. Main Outcome and Measure: Risk-standardized readmission rates. Results: The cohort included 11 029 470 admissions (4 077 633 [37.0%] MA; 6 044 060 [54.8%] female; mean [SD] age, 77.7 [8.2] years). Unadjusted readmission rates were slightly higher for MA vs FFS admissions (15.7% vs 15.4%), yet comorbidities were generally lower among MA beneficiaries. Test-retest reliability for the FFS and MA cohort was higher than for the FFS-only cohort (0.78 vs 0.73) and signal-to-noise reliability increased in each specialty subgroup. Mean hospital risk-standardized readmission rates were similar for the FFS and MA cohort and FFS-only cohorts (15.5% vs 15.3%); this trend was consistent across the 5 specialty subgroups. After adding MA admissions to the FFS-only HWR measure, 1489 hospitals (33.1%) had their performance quintile ranking changed. As their proportion of MA admissions increased, more hospitals experienced a change in their performance quintile ranking (147 hospitals [16.3%] in the lowest quintile of percentage MA admissions; 408 [45.3%] in the highest). The combined cohort added 63 hospitals eligible for public reporting and more than 4 million admissions to the measure. Conclusions and Relevance: In this cohort study, adding MA admissions to the HWR measure was associated with improved measure reliability and precision and enabled the inclusion of more hospitals and beneficiaries. After MA admissions were included, 1 in 3 hospitals had their performance quintile changed, with the greatest shifts among hospitals with a high percentage of MA admissions.

Processing and validation of inpatient Medicare Advantage data for use in hospital outcome measures.

OBJECTIVE: To determine the feasibility of integrating Medicare Advantage (MA) admissions into the Centers for Medicare & Medicaid Services (CMS) hospital outcome measures through combining Medicare Advantage Organization (MAO) encounter- and hospital-submitted inpatient claims. DATA SOURCES AND STUDY SETTING: Beneficiary enrollment data and inpatient claims from the Integrated Data Repository for 2018 Medicare discharges. STUDY DESIGN: We examined timeliness of MA claims, compared diagnosis and procedure codes for admissions with claims submitted both by the hospital and the MAO (overlapping claims), and compared demographic characteristics and principal diagnosis codes for admissions with overlapping claims versus admissions with a single claim. DATA COLLECTION/EXTRACTION METHODS: We combined hospital- and MAO-submitted claims to capture MA admissions from all hospitals and identified overlapping claims. For admissions with only an MAO-submitted claim, we used provider history data to match the National Provider Identifier on the claim to the CMS Certification Number used for reporting purposes in CMS outcome measures. PRINCIPAL FINDINGS: After removing void and duplicate claims, identifying overlapped claims between the hospital- and MAO-submitted datasets, restricting claims to acute care and critical access hospitals, and bundling same admission claims, we identified 5,078,611 MA admissions. Of these, 76.1% were submitted by both the hospital and MAO, 14.2% were submitted only by MAOs, and 9.7% were submitted only by hospitals. Nearly all (96.6%) hospital-submitted claims were submitted within 3 months after a one-year performance period, versus 85.2% of MAO-submitted claims. Among the 3,864,524 admissions with overlapping claims, 98.9% shared the same principal diagnosis code between the two datasets, and 97.5% shared the same first procedure code. CONCLUSIONS: Inpatient MA data are feasible for use in CMS claims-based hospital outcome measures. We recommend prioritizing hospital-submitted over MAO-submitted claims for analyses. Monitoring, data audits, and ongoing policies to improve the quality of MA data are important approaches to address potential missing data and errors.

Assessing the accuracy of race-and-ethnicity data in the Outcome and Assessment Information Set.

BACKGROUND: Limitations in the quality of race-and-ethnicity information in Medicare's data systems constrain efforts to assess disparities in care among older Americans. Using demographic information from standardized patient assessments may be an efficient way to enhance the accuracy and completeness of race-and-ethnicity information in Medicare's data systems, but it is critical to first establish the accuracy of these data as they may be prone to inaccurate observer-reported or third-party-based information. This study evaluates the accuracy of patient-level race-and-ethnicity information included in the Outcome and Assessment Information Set (OASIS) submitted by home health agencies. METHODS: We compared 2017-2022 OASIS-D race-and-ethnicity data to gold-standard self-reported information from the Medicare Consumer Assessment of Healthcare Providers and Systems® survey in a matched sample of 304,804 people with Medicare coverage. We also compared OASIS data to indirect estimates of race-and-ethnicity generated using the Medicare Bayesian Improved Surname and Geocoding (MBISG) 2.1.1 method and to existing Centers for Medicare & Medicaid Services (CMS) administrative records. RESULTS: Compared with existing CMS administrative data, OASIS data are far more accurate for Hispanic, Asian American and Native Hawaiian or other Pacific Islander, and White race-and-ethnicity; slightly less accurate for American Indian or Alaska Native race-and-ethnicity; and similarly accurate for Black race-and-ethnicity. However, MBISG 2.1.1 accuracy exceeds that of both OASIS and CMS administrative data for every racial-and-ethnic category. Patterns of inconsistent reporting of racial-and-ethnic information among people for whom there were multiple observations in the OASIS and Consumer Assessment of Healthcare Providers and Systems (CAHPS) datasets suggest that some of the inaccuracies in OASIS data may result from observation-based reporting that lessens correspondence with self-reported data. CONCLUSIONS: When health record data on race-and-ethnicity includes observer-reported information, it can be less accurate than both true self-report and a high-performing imputation approach. Efforts are needed to encourage collection of true self-reported data and explicit record-level data on the source of race-and-ethnicity information.

Predictors of Lamotrigine-associated rash.

PURPOSE: To determine the predictors of lamotrigine-associated rash (LTG-rash) and the incidence of serious and benign LTG-rash to individualize risk assessment in a given patient. METHODS: We reviewed the charts of all 988 outpatients seen at the Columbia Comprehensive Epilepsy Center between January 1, 2000, and December 31, 2003, who received LTG. Charts were reviewed for documentation of rash developing from any medication, including antiepileptic drugs (AEDs) and non-AEDs, and including remote histories of drug-related rashes. Demographics, medical history, and medication variables were tested as potential predictors of LTG-rash. RESULTS: Fifty-six (5.7%) of 988 patients experienced rash attributed to LTG, and 39 (3.9%) discontinued LTG because of rash. No patients experienced toxic epidermal necrolysis or required hospitalization because of LTG-rash. One case of mild probable Stevens-Johnson syndrome occurred. In multivariate analysis, a history of rash after another AED was the strongest predictor of LTG-rash (13.9% vs. 4.6%; OR = 3.62; p < 0.001), with children younger than 13 years also experiencing significantly more LTG-rash (10.7% vs. 4.3%; OR = 2.77; p < 0.001). In children with a rash attributed to another AED, 18.2% experienced LTG-rash, whereas in adults without a rash from another AED, 3% experienced LTG-rash. CONCLUSIONS: Based on this retrospective analysis, a history of another AED-related rash is the greatest risk factor for developing rash to LTG; age younger than 13 years is also a risk factor. Severe rash is rare when using the currently recommended titration rate.