Pathway for Development and Validation of Multi-domain Endpoints for Amyloid Light Chain (AL) Amyloidosis.

Immunoglobin light chain (AL) amyloidosis is a rare disease in which a plasma cell dyscrasia leads to deposition of insoluble amyloid fibrils in multiple organs. To facilitate development of new therapies for this heterogenous disease, a public-private partnership was formed between the nonprofit Amyloidosis Research Consortium and the US Food and Drug Administration Center for Drug Evaluation and Research. In 2020, the Amyloidosis Forum launched an initiative to identify clinical trial endpoints and analytic strategies across affected organ systems and life impacts via specialized working groups. This review summarizes the proceedings of the Statistical Group and proposes a pathway for development and validation of multi-domain endpoints (MDEs) for potential use in AL amyloidosis clinical trials. Specifically, drawing on candidate domain-specific endpoints recommended by each organ-specific working group, different approaches to constructing MDEs were considered. Future studies were identified to assess the validity, meaningfulness and performance of MDEs through use of natural history and clinical trial data. Ultimately, for drug development, the context of use in a regulatory evaluation, the specific patient population, and the investigational therapeutic mechanism should drive selection of appropriate endpoints. MDEs for AL amyloidosis, once developed and validated, will provide important options for advancing patient-focused drug development in this multi-system disease.

Incidence of pneumococcal disease in children ≤48 months old in the United States: 1998-2019.

BACKGROUND: Pneumococcal disease (PD) is a major cause of morbidity and mortality among children, particularly in the youngest age groups. This study aimed to assess the incidence of PD over time by age group in young children with commercial or Medicaid coverage in the US. METHODS: Episodes of invasive pneumococcal disease (IPD), all-cause pneumonia (ACP), and acute otitis media (AOM) were identified in the MarketScan® Commercial and Medicaid claims databases using diagnosis codes among children aged ≤ 48 months with confirmed date of birth (DoB), at any time during the study period (1998-2019). DoB was assigned using diagnosis codes for birth or delivery using the child's or mother's medical claims to ensure accurate age determination. Annual incidence rates (IRs) were calculated as number of disease episodes/100,000 person-years (PY) for IPD and ACP and episodes/1,000 PY for AOM, for children aged 0-6, 7-12, 12-24, and 25-48 months. RESULTS: Annual IPD IRs declined from 53 to 7 episodes/100,000 PY between 1998 and 2019 in commercially-insured and 58 to 9 episodes/100,000 PY between 2001 and 2019 in Medicaid-insured children. Annual ACP IRs declined from 5,600 to 3,952 episodes/100,000 PY, and from 6,706 to 4,521 episodes/100,000 PY, respectively, over these periods. In both populations, children aged 0-6 months had the highest incidence of IPD and inpatient ACP. Annual AOM IRs declined from 1,177 to 738 episodes/1,000 PY (commercially-insured) and 633 to 624 episodes/1,000 PY (Medicaid-insured), over these periods. IRs were higher in rural vs. urban areas for all disease manifestations. CONCLUSIONS: Incidence rates of IPD, ACP, and AOM decreased in children with commercial insurance and Medicaid coverage from 1998 to 2019. However, burden of disease remained substantial, with higher annual IRs for IPD and ACP for Medicaid-insured vs. commercially-insured children. IPD and inpatient ACP were most common in the youngest children 0-6 months old, followed by the 7-12-month age group.

Survival among patients receiving eteplirsen for up to 8 years for the treatment of Duchenne muscular dystrophy and contextualization with natural history controls.

INTRODUCTION/AIMS: Eteplirsen, approved in the US for patients with Duchenne muscular dystrophy (DMD) with exon 51 skip-amenable variants, is associated with attenuated ambulatory/pulmonary decline versus DMD natural history (NH). We report overall survival in a US cohort receiving eteplirsen and contextualize these outcomes versus DMD NH. METHODS: US patients with DMD receiving eteplirsen were followed through a patient support program, with data collected on ages at eteplirsen initiation and death/end of follow-up. Individual DMD NH data were extracted by digitizing Kaplan-Meier (KM) curves from published systematic and targeted literature reviews. Overall survival age was analyzed using KM curves and contextualized with DMD NH survival curves; subanalyses considered age groups and duration of eteplirsen exposure. Overall survival time from treatment initiation was also evaluated. RESULTS: A total of 579 eteplirsen-treated patients were included. During a total follow-up of 2119 person-years, median survival age was 32.8 years. DMD NH survival curves extracted from four publications (follow-up for 1224 DMD NH controls) showed overall pooled median survival age of 27.4 years. Eteplirsen-treated patients had significantly longer survival from treatment initiation versus age-matched controls (age-adjusted hazard ratio [HR], 0.65; 95% confidence interval [CI], 0.44-0.98; p < .05). Longer treatment exposure was associated with improved survival (HR, 0.15; 95% CI, 0.05-0.41; p < .001). Comparisons using different DMD NH cohorts to address common risks of bias yielded consistent findings. DISCUSSION: Data suggest eteplirsen may prolong survival in patients with DMD across a wide age range. As more data become available, the impact of eteplirsen on survival will be further elucidated.

Real-World Treatment Patterns among Patients with Alopecia Areata in the USA: A Retrospective Claims Analysis.

Alopecia areata is an autoimmune disorder characterized by hair loss, for which there are few treatment options. This claims-based study characterized recent real-world treatment patterns among patients in the USA with alopecia areata, including the subtypes alopecia totalis and alopecia universalis, in the first year after diagnosis of an episode of alopecia areata. Approximately 5% of all patients (adults (age ≥ 18 years), n = 7,703; adolescents (age 12-17 years), n = 595) had alopecia totalis or alopecia universalis. Corticosteroids were the most common first-line (1L) and second-line (2L) treatments. The mean time from diagnosis of alopecia areata to initiation of 1L treatment was 2.2 days for adults and 2.6 days for adolescents; mean 1L duration was 76.9 and 64.3 days, respectively. For adults (57.5%) and adolescents (59.7%) with 2L therapy, the mean time from 1L discontinuation to 2L initiation was 57.2 and 53.6 days, respectively; the mean duration of 2L treatment was 55.5 and 50.1 days, respectively. More patients with vs without alopecia totalis or alopecia universalis initiated 2L therapy (adults: 71.9% vs 56.8%; adolescents: 71.4% vs 58.9%). The proportion of days covered during the first year post-diagnosis was 36.7% (adults) and 34.1% (adolescents). These results highlight the substantial disease burden of alopecia areata and a need for more effective treatments.

Incidence of non-invasive all-cause pneumonia in children in the United States before and after the introduction of pneumococcal conjugate vaccines: a retrospective claims database analysis.

BACKGROUND: Pneumonia is the most serious form of acute respiratory infection and Streptococcus pneumoniae is a leading cause of pediatric bacterial pneumonia. Pneumococcal conjugate vaccines were introduced in the United States (US) in 2000 (7-valent [PCV7]) and 2010 (13-valent [PCV13]). This study estimated annual incidence rates (IRs) of all-cause pneumonia (ACP) among US children aged < 18 years before and after the introduction of PCV7 and PCV13. METHODS: ACP episodes were identified in the IBM MarketScan Commercial and Medicaid Databases using diagnosis codes. Annual IRs were calculated overall and by inpatient and outpatient settings as the number of episodes per 100,000 person-years (PY) for all children aged < 18 years and by age group (< 2, 2-4, and 5-17 years). National estimates of annual pneumonia IRs were extrapolated using Census Bureau data. Interrupted time series (ITS) analyses were used to assess immediate and gradual changes in monthly pneumonia IRs, adjusting for seasonality. RESULTS: In the commercially-insured population, ACP IRs declined between the pre-PCV7 period (1998-1999) and late PCV13 period (2014-2018) from 5,322 to 3,471 episodes per 100,000 PY for children aged < 2 years, from 4,012 to 3,794 episodes per 100,000 PY in children aged 2-4 years but increased slightly from 1,383 to 1,475 episodes per 100,000 PY in children aged 5-17 years. The ITS analyses indicated significant decreases in monthly ACP IRs in the early PCV7 period (2001-2005) among younger children and in the early PCV13 period (2011-2013) among all children. Increases were observed in the late PCV7 period (2006-2009) among all age groups, but were only significant among older children. IRs of inpatient ACP decreased across all age groups, but outpatient pneumonia IRs remained stable during the study timeframe, even increasing slightly in children aged 5-17 years. More prominent declines were observed for Medicaid-insured children across all age groups; however, Medicaid IRs were higher than IRs of commercially-insured children during the entire study timeframe. CONCLUSIONS: ACP disease burden remains high in US children of all ages despite overall reductions in incidence rates during 1998-2018 following the introduction of PCV7 and PCV13.

Economic burden of acute otitis media, pneumonia, and invasive pneumococcal disease in children in the United States after the introduction of 13-valent pneumococcal conjugate vaccines during 2014-2018.

BACKGROUND: Streptococcus pneumoniae remains a leading cause of morbidity, mortality, and healthcare resource utilization (HRU) among children. This study quantified HRU and cost of acute otitis media (AOM), pneumonia, and invasive pneumococcal disease (IPD). METHODS: The IBM MarketScan® Commercial Claims and Encounters and Multi-State Medicaid databases from 2014 to 2018 were analyzed. Children with AOM, all-cause pneumonia, or IPD episodes were identified using diagnosis codes in inpatient and outpatient claims. HRU and costs were described for each condition in the commercial and Medicaid-insured populations. National estimates of the number of episodes and total cost ($US 2019 for each condition were extrapolated using data from the US Census Bureau. RESULTS: Approximately 6.2 and 5.6 million AOM episodes were identified in commercial and Medicaid-insured children, respectively, during the study period. Mean cost per AOM episode was $329 (SD $1505) for commercial and $184 (SD $1524) for Medicaid-insured children. A total of 619,876 and 531,095 all-cause pneumonia cases were identified among commercial and Medicaid-insured children, respectively. Mean cost per all-cause pneumonia episode was $2304 (SD $32,309) in the commercial and $1682 (SD $19,282) in the Medicaid-insured population. A total of 858 and 1130 IPD episodes were identified among commercial and Medicaid-insured children, respectively. Mean cost per IPD episode was $53,213 (SD $159,904) for commercial and $23,482 (SD $86,209) for the Medicaid-insured population. Nationally, there were over 15.8 million cases of AOM annually, with total estimated cost of $4.3 billion, over 1.5 million cases of pneumonia annually, with total cost of $3.6 billion, and about 2200 IPD episodes annually, for a cost of $98 million. CONCLUSIONS: The economic burden of AOM, pneumonia, and IPD among US children remains substantial. IPD and its manifestations were associated with higher HRU and costs per episode, compared to AOM and all-cause pneumonia. However, owing to their higher frequencies, AOM and all-cause pneumonia were the main contributors to the economic burden of pneumococcal disease nationally. Additional interventions, such as the development of pneumococcal conjugate vaccinees with sustained protection of existing vaccine type serotypes as well as broader inclusion of additional serotypes, are necessary to further reduce the burden of disease caused by these manifestations.

Trends in Prevalence and Incidence of Alopecia Areata, Alopecia Totalis, and Alopecia Universalis Among Adults and Children in a US Employer-Sponsored Insured Population.

Importance: Alopecia areata (AA) is characterized by nonscarring hair loss of the scalp, face, and/or body. Alopecia totalis (AT) and alopecia universalis (AU) involve complete loss of the scalp and body hair, respectively. The epidemiology of AA in the US remains unclear, having previously been extrapolated from older studies that were limited to specific geographic areas or clinical settings, or from self-reported data. Objective: To estimate the annual prevalence and incidence of AA and AT and/or AU (AT/AU) in the US. Design, Setting, and Participants: This retrospective, population-based cohort study was conducted from January 2016 to December 2019 and included enrollees in the IBM MarketScan Commercial Claims and Encounters and Medicare Supplemental databases and their dependents, with plan enrollment during each study calendar year and the year prior. Exposures: Prevalent cases were identified by 1 or more claims for AA or AT/AU (International Statistical Classification of Diseases, Tenth Revision, Clinical Modification [ICD-10-CM] codes L63.x, L63.0, L63.1) during each year of interest or the year prior. Incident cases were identified by 1 or more claims for AA or AT/AU during a specific year and no diagnosis the year prior. Main Outcomes and Measures: Annual incidence and prevalence rates were calculated and stratified by age, sex, and region. National employer-sponsored insurance population estimates were obtained using population-based weights. Results: Among eligible patients (2016: n = 18 368 [mean (SD) age, 40.6 (17.9) years; 12 295 women (66.9%)]; 2017: n = 14 372 [mean (SD) age, 39.6 (17.7) years; 9195 women (64.0%)]; 2018: n = 14 231 [mean (SD) age, 38.9 (17.3) years; 8998 women (63.2%)]; 2019: n = 13 455 [mean (SD) age, 39.1 (17.4) years; 8322 women (61.9%)]), AA prevalence increased from 0.199% (95% CI, 0.198%-0.200%) in 2016 to 0.222% (95% CI, 0.221%-0.223%) in 2019. Roughly 5% to 10% of prevalent and incident cases of AA were AT/AU. The prevalence of AT/AU increased from 0.012% (95% CI, 0.012%-0.013%) to 0.019% (95% CI, 0.018%-0.019%) from 2016 to 2019. Incidence of AA per 100 000 person-years ranged from 87.39 (95% CI, 86.84-87.96) in 2017 to 92.90 (95% CI, 92.35-93.45) in 2019. Incidence of AT/AU ranged from 7.09 (95% CI, 6.94-7.25) in 2017 to 8.92 (95% CI, 8.75-9.09) in 2016. Prevalence and incidence of AA and AT/AU were higher among female vs male individuals, adults vs children and adolescents, and in the Northeast vs other regions. Conclusions and Relevance: The results of this cohort study suggest that these recent AA prevalence and incidence estimates could help improve current understanding of the disease burden. Further research is warranted to elucidate subpopulation differences and trends in AA in the broader US population.

Patient characteristics associated with all-cause healthcare costs of alopecia areata in the United States.

Evidence on the factors of medical costs involved in the care of people with alopecia areata (AA) is limited, but mounting evidence points to significant variation in financial impact for patients with AA in the absence of effective treatments. This study explored drivers of medical costs among privately insured adults and adolescents with AA in the United States. The study found that patients of middle age (45­64 years), located in the Northeast region, with comprehensive health insurance, with greater extent of hair loss, or with other health disorders face greater all-cause medical costs. Adult females of young (18­44 years) and older (65+ years) age also faced greater costs on average. This research confirms high variability in the burden of AA, pointing to population subgroups that may be more affected by the disease and its commonly associated disorders.

Incidence of invasive pneumococcal disease in children with commercial insurance or Medicaid coverage in the United States before and after the introduction of 7- and 13-valent pneumococcal conjugate vaccines during 1998-2018.

BACKGROUND: Invasive pneumococcal disease (IPD) is a major cause of pediatric morbidity and mortality. Pneumococcal conjugate vaccines (PCVs) were introduced in the US in 2000 (PCV7) and 2010 (PCV13). This study estimated the annual incidence rates (IRs) and time trends of IPD to quantify the burden of disease in children before and after the introduction of PCV7 and PCV13 in the US. METHODS: IPD episodes were identified in the IBM MarketScan Commercial and Medicaid Databases using claims with International Classification of Diseases 9/10th Revision, Clinical Modification codes. Annual IRs were calculated as the number of IPD episodes/100,000 person-years (PYs) for children < 18 years and by age group (< 2, 2-4, and 5-17 years). National estimates of annual IPD IRs were extrapolated using Census Bureau data. Interrupted time series (ITS) analyses were conducted to assess immediate and gradual changes in IPD IRs before and after introduction of PCV7 and PCV13. RESULTS: In commercially insured children, IPD IRs decreased from 9.4 to 2.8 episodes/100,000 PY between the pre-PCV7 (1998-1999) and late PCV13 period (2014-2018) overall, and from 65.6 to 11.6 episodes/100,000 PY in children < 2 years. In the Medicaid population, IPD IRs decreased from 11.3 to 4.2 episodes/100,000 PY between the early PCV7 (2001-2005) and late PCV13 period overall, and from 42.6 to 12.8 episodes/100,000 PY in children < 2 years. The trends of IRs for meningitis, bacteremia, and bacteremic pneumonia followed the patterns of overall IPD episodes. The ITS analyses indicated significant decreases in the early PCV7 period, increases in the late PCV7 and decreases in the early PCV13 period in commercially insured children overall. However, increases were also observed in the late PCV13 period in children < 2 years. The percentage of cases with underlying risk factors increased in both populations. CONCLUSIONS: IRs of IPD decreased from 1998 to 2018, following introduction of PCV7 and PCV13, with larger declines during the early PCV7 and early PCV13 periods, and among younger children. However, the residual burden of IPD remains substantial. The impact of future PCVs on IPD IRs will depend on the proportion of vaccine-type serotypes and vaccine effectiveness in children with underlying conditions.

Healthcare Utilization and Costs Among US Adolescents With Alopecia Areata.

Background: Alopecia areata (AA) is an autoimmune disease of hair loss affecting people of all ages. Alopecia totalis (AT) and universalis (AU) involve scalp and total body hair loss, respectively. AA significantly affects quality of life, but evidence on the economic burden in adolescents is limited. Objectives: To assess healthcare resource utilization (HCRU) and all-cause direct healthcare costs, including out-of-pocket (OOP) costs, of US adolescents with AA. Methods: IBM MarketScan® Commercial and Medicare databases were used to identify patients aged 12-17 years with ≥2 claims with AA/AT/AU diagnosis (prevalent cases), from October 1, 2015, to March 31, 2018, enrolled for ≥12 months before and after the first AA diagnosis (index). Patients were matched 1:3 to non-AA controls on index year, demographics, plan type, and Charlson Comorbidity Index. Per patient per year HCRU and costs were compared post-index. Results: Patients comprised 130 AT/AU adolescents and 1105 non-AT/AU adolescents (53.8% female; mean age, 14.6 years). Post-index, AT/AU vs controls had more outpatient (14.5 vs 7.1) and dermatologist (3.6 vs 0.3) visits, higher mean plan costs ($9397 vs $2267), including medical ($7480 vs $1780) and pharmacy ($1918 vs $487) costs, and higher OOP costs ($2081 vs $751) (all P<.001). The non-AT/AU cohort vs controls had more outpatient (11.6 vs 8.0) and dermatologist (3.4 vs 0.4) visits, higher mean plan costs ($7587 vs $4496), and higher OOP costs ($1579 vs $805) (all P<.001). Discussion: This large-sample, real-world analysis found that adolescents with prevalent AA had significantly higher HCRU and all-cause costs than matched controls. The greater burden was driven by more frequent outpatient visits, and higher payer medical and pharmacy costs in comparison with controls. Oral corticosteroid use was higher among patients with AT/AU; topical and injectable corticosteroid use was higher for non-AT/AU. Although the data preclude the identification of AA-attributable costs, the matched-control design allows an estimation of incremental all-cause costs associated with AA. Conclusions: Adolescents with AA incurred substantial incremental healthcare costs, with greater costs incurred among those with AT/AU. Study findings suggest that AA incurs costs as a medical condition with a high burden on adolescent patients and health plans.

Long-term treatment effects of inotersen on health-related quality of life in patients with hATTR amyloidosis with polyneuropathy: Analysis of the open-label extension of the NEURO-TTR trial.

INTRODUCTION/AIMS: Hereditary transthyretin-mediated amyloidosis with polyneuropathy (hATTR-PN) progressively affects patients' functionality and compromises health-related quality of life (HRQL). The aim of this study was to quantify the projected long-term treatment effects of inotersen vs placebo on HRQL measures. METHODS: The inotersen phase 2/3 randomized, double-blind, placebo-controlled trial NEURO-TTR (NCT01737398, 65 weeks) and its subsequent open-label extension (OLE; NCT02175004, 104 weeks) included 172 (112 inotersen and 60 placebo) patients. Placebo double-blind period and overall inotersen-inotersen (double-blind/OLE) treatment period (170 weeks) data were used to extrapolate the long-term placebo-placebo effect using mixed-effects models with repeated measures. Changes from baseline in the Norfolk Quality of Life-Diabetic Neuropathy (QoL-DN) and 36-Item Short Form Health Survey version 2 (SF-36v2) in hATTR-PN were estimated. Differences in changes were compared between the inotersen-inotersen and extrapolated placebo-placebo arms. RESULTS: Inotersen-inotersen patients maintained their HRQL with an observed change ranging from 10.3% improvement (Norfolk QoL-DN item "Pain kept you awake at night") to 11.6% deterioration (SF-36v2 Activities of Daily Living subdomain). The extrapolated placebo-placebo results suggest greater deterioration over time compared with inotersen-inotersen treatment on Norfolk QoL-DN total score (23.6; 95% confidence interval [CI], 8.9-38.3; P < .01), Activities of Daily Living (4.6; 95% CI, 2.0-7.3; P < .001), and "Pain kept you awake at night" (1.2; 95% CI, 0.4-1.9; P < .01). Similarly, greater deterioration was expected for the SF-36v2 Physical Component Summary (8.0; 95% CI, 3.2-12.8, P < .01), Bodily Pain (7.8; 95% CI, 2.0-13.5; P < .01), and Physical Functioning (10.6; 95% CI, 5.5-15.6; P < .0001). DISCUSSION: Long-term (>3 years) inotersen treatment was associated with slowing and, in some domains, halting of deterioration in key HRQL outcome measures, particularly physical functioning and pain.

Factors associated with increased health-related quality-of-life benefits in hereditary transthyretin amyloidosis polyneuropathy patients treated with inotersen.

INTRODUCTION/AIMS: Hereditary transthyretin amyloidosis with polyneuropathy (ATTRv-PN) is a genetic condition associated with significant morbidity and mortality. In this study we aimed to identify patient subgroups exhibiting the greatest health-related quality of life (HRQL) benefit from inotersen treatment. METHODS: We examined data from the inotersen phase 2/3 randomized, controlled trial for ATTRv-PN, NEURO-TTR (NCT01737398, 66 weeks). LASSO regression models predicted changes in Norfolk QoL-DN total score (TQoL, range -4 to 136; higher scores indicate poorer HRQL) from baseline in the inotersen and placebo arm, respectively. Individualized efficacy scores (ES) were calculated as differences between predicted change scores had patients received inotersen vs placebo. Patients were ranked by ES to define the greatest-benefit subpopulation (top 50%). Characteristics of the top 50% and bottom 50% of patients were compared. RESULTS: The overall mean ± standard deviation TQoL change was -0.20 ± 19.13 for inotersen (indicating no change) and 10.77 ± 21.13 for placebo (indicating deterioration). Within the highest-benefit patients, mean TQoL change was -11.03 ± 17.06 (improvement) for inotersen and 11.24 ± 22.97 (deterioration) for placebo (P < .001). Compared with the overall population, patients in the greatest-benefit subpopulation were younger, more likely to have polyneuropathy disability (PND) scores 1 or 2, less likely to have received prior tafamidis or diflunisal treatment, and more likely to have Val30Met mutations and higher (worse) baseline TQoL. CONCLUSIONS: Patients who were younger and/or at earlier polyneuropathy stages experienced greater HRQL benefits from inotersen over 66 weeks. These findings underscore the need for early diagnosis and treatment initiation, especially among more severely affected patients in early stages of ATTRv-PN.

Real-world and natural history data for drug evaluation in Duchenne muscular dystrophy: suitability of the North Star Ambulatory Assessment for comparisons with external controls.

Using external controls based on real-world or natural history data (RWD/NHD) for drug evaluations in Duchenne muscular dystrophy (DMD) is appealing given the challenges of enrolling placebo-controlled trials, especially for multi-year trials. Comparisons to external controls, however, face risks of bias due to differences in outcomes between trial and RWD/NHD settings. To assess this bias empirically, we conducted a multi-institution study comparing mean 48-week changes in North Star Ambulatory Assessment (NSAA) total score between trial placebo arms and RWD/NHD sources, with and without adjustment for baseline prognostic factors. Analyses used data from three placebo arms (235 48-week intervals, N = 235 patients) and three RWD/NHD sources (348 intervals, N = 202 patients). Differences in mean ΔNSAA between placebo arms and RWD/NHD sources were small before adjustment (-1.2 units, 95% CI: [-2.0 -0.5]) and were attenuated and no longer statistically significant after adjustment (0.1 units (95% CI: [-0.6, 0.8]). Results were similar whether adjusting using multivariable regression or propensity score matching. This consistency in ΔNSAA between trial placebo arms and RWD/NHD sources accords with prior findings for the six-minute walk distance, provides a well-validated framework for baseline adjustment of prognostic factors, and supports the suitability of RWD/NHD external controls for drug evaluations in ambulatory DMD.

All-cause health care resource utilization and costs among adults with alopecia areata: A retrospective claims database study in the United States.

BACKGROUND: Alopecia areata (AA) is an autoimmune disorder characterized by hair loss. Patients may present with hair loss of the scalp, eyelashes, eyebrows, and/or body. Alopecia totalis (AT), total scalp hair loss, or alopecia universalis (AU), total body hair loss, are extensive forms. Although the impact of AA on quality of life is understood, evidence of its economic burden is limited. A better understanding of the all-cause health care costs for health plans and patients with AA is critical to comprehend disease burden. OBJECTIVE: To evaluate all-cause health care resource utilization and direct health care costs in US adults with AA with or without AT or AU, vs matched control subjects. METHODS: Patients (≥ 18 years) with AA with no less than 2 claims of AA at diagnosis (October 31, 2015, to March 3, 2018) were identified in the IBM MarketScan Commercial Claims and Encounters and Medicare Supplemental databases. Patients were enrolled no less than 12 months before and after first diagnosis (index). Patients were grouped according to AT or AU status (AT/AU group) or AA without AT/AU (non-AT/AU group) and matched 1:3 to control subjects without AA/AT/AU. Summary statistics were calculated for demographic and clinical characteristics at baseline and follow-up. RESULTS: At baseline, there were 14,972 adult patients with AA and 44,916 control subjects. Of patients with AA, 1,250 and 13,722 were in the AT/AU and non-AT/AU groups, respectively. A significantly greater proportion of patients with AA had atopic and autoimmune comorbidities vs control subjects. After index, patients with AA used significantly more corticosteroid treatments (injectable/oral/topical) than control subjects. A greater mean number of annual outpatient and dermatologist visits was observed for both AA groups vs control subjects (outpatient visits: AT/AU group: 17.8 vs 11.8; non-AT/AU group: 15.4 vs 11.2; dermatologist visits: AT/AU group: 3.4 vs 0.4; non-AT/AU group: 3.4 vs 0.4; P < 0.001 for all). Mean total all-cause medical and pharmacy costs (2018 US$) were higher in both AA groups vs control subjects (AT/AU group: $18,988 vs $11,030; non-AT/AU group: $13,686 vs $9,336; P < 0.001 for both). Patient out-of-pocket costs were higher for AA vs control subjects (AT/AU group: $2,685 vs $1,457; non-AT/AU group: $2,223 vs $1,341; P < 0.001 for both). CONCLUSIONS: Compared with control subjects, patients with AA are more likely to have atopic and autoimmune comorbidities, to use corticosteroids, and to make outpatient visits. Patients with AA have greater all-cause medical (including pharmacy) and out-of-pocket costs. The difference in total medical costs for patients with AT/AU vs control subjects is higher than the difference for patients with non-AT/AU vs control subjects. DISCLOSURES: This study was sponsored by Pfizer Inc. Pfizer Inc was involved in the study design; collection, analysis, and interpretation of data; writing of the report; and the decision to submit this report for publication. A. Mostaghimi reports consulting fees from Pfizer Inc, Concert, Lilly, AbbVie, hims, and Digital Diagnostics; reports equity from Lucid and hims; and is an associate editor at JAMA Dermatology. K. Gandhi, M. Ray, and V. Sikirica are former employees of Pfizer Inc and held stock and/or stock options with Pfizer Inc at the time of writing. N. Done, W. Gao, C. Carley, T. Wang, and E. Swallow are employees of Analysis Group, Inc, a consultancy that received payment from Pfizer Inc for participation in this analysis.

Incidence of acute otitis media in children in the United States before and after the introduction of 7- and 13-valent pneumococcal conjugate vaccines during 1998-2018.

BACKGROUND: Acute otitis media (AOM) is a leading cause of office visits and antibiotic prescriptions in children. Pneumococcal conjugate vaccines were introduced in the USA in 2000 (7-valent, PCV7) and 2010 (13-valent, PCV13). Expanded valency PCVs are currently under development. To describe the impact of PCVs and quantify the residual burden of AOM, this study estimated annual incidence rates (IRs) of AOM and AOM-related complications and surgical procedures in children < 18 years in the USA before and after the introduction of PCV7 and PCV13. METHODS: AOM episodes were identified in the IBM MarketScan® Commercial and Medicaid databases using diagnosis codes (ICD-9-CM: 382.x; ICD-10-CM: H66.xx and H67.xx). Annual IRs were calculated as the number of episodes per 1000 person-years (PYs) for all children < 18 years and by age group (< 2, 2-4, and 5-17 years). National estimates of annual AOM IRs were extrapolated using Census Bureau data. Interrupted time series analyses were used to assess immediate and gradual changes in monthly AOM IRs, controlling for seasonality. RESULTS: In the commercially insured population, AOM IRs declined between the pre-PCV7 period (1998-1999) and the late PCV13 period (2014-2018) from 1170.1 to 768.8 episodes per 1000 PY for children < 2 years, from 547.4 to 410.3 episodes per 1000 PY in children 2-4 years, and from 115.6 to 91.8 episodes per 1000 PY in children 5-17 years. The interrupted time series analyses indicated significant immediate or gradual decreases in the early PCV7 period (2001-2005), and gradual increases in the late PCV7 period (2006-2009) in children < 2 years; however, crude IRs trended downward in all time periods. In older children, IRs decreased in the early PCV7 and early PCV13 period (2011-2013), but gradually increased in the late PCV7 period. IRs of AOM-related surgical procedures decreased, and IRs of AOM-related complications increased during the study timeframe. CONCLUSIONS: AOM disease burden remains high in children of all ages despite overall reductions in AOM IRs during 1998-2018 following the introduction of PCV7 and PCV13. The impact of investigational PCVs on the disease burden of AOM will likely depend on AOM etiology and circulating pneumococcal serotypes.

Comparing total medical expenditure between patients receiving direct oral anticoagulants vs warfarin for the treatment of atrial fibrillation: evidence from VA-Medicare dual enrollees.

BACKGROUND: Direct oral anticoagulants (DOACs) are an alternative to warfarin for treatment of atrial fibrillation (AF). Evidence demonstrating the efficacy and safety of DOACs has primarily been from clinical trial settings. The real-world effectiveness of DOACs in specific nontrial populations that differ in age, comorbidity burden, and socioeconomic status is unclear. OBJECTIVE: To compare total downstream medical expenditure between AF patients treated with warfarin and DOACs dually enrolled in the Veterans Affairs (VA) Healthcare System and fee-for-service Medicare. METHODS: This was an exploratory treatment effectiveness study that analyzed VA administrative data and Medicare claims. We examined patients with an incident diagnosis for AF and initiated warfarin or DOAC treatment between 2012 and 2015. The primary outcome was total medical expenditure over 3 years following treatment initiation. To address potential informative censoring, we applied a multipart estimator that extends traditional 2-part models to separate differences between groups due to survival and cost accumulation effects. Inverse probability weighting was applied to address potential treatment selection bias. RESULTS: We identified 31,276 and 17,021 patients receiving warfarin and DOACs, respectively. Mean unadjusted (SD) expenditure was higher for warfarin ($56,265 [$96,666]) compared with DOAC patients ($32,736 [$52,470]). Compared with patients receiving DOACs, adjusted 3-year expenditure was $25,688 (P < 0.001) higher for patients receiving warfarin. CONCLUSIONS: VA patients with AF initiating warfarin incurred markedly higher downstream expenditure compared with similar patients receiving DOACs. The benefits of DOACs found in previous clinical trials were present in this population, suggesting that these DOACs may be the preferred option for treatment of AF in older VA patients. DISCLOSURES: This study was funded by a VA Health Services Research and Development Investigator Initiated Research Award (IIR 15-139). Support for VA/CMS data was provided by the Department of Veterans Affairs, Veterans Health Administration, Office of Research and Development, Health Services Research and Development, VA Information Resource Center (Project Numbers SDR 02-237 and 98-004). The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. The views expressed in this article are those of the authors and do not necessarily reflect the position or policy of the Department of Veterans Affairs, the University of Washington, Northeastern University, and Boston University. The authors declare no conflicts of interest. This research includes data obtained from the VHA Office of Performance Measurement (17API2), which resides within the Office of Analytics and Performance Integration (API), under the Office of Quality and Patient Safety (QPS; formerly known as RAPID). An oral presentation documenting a subset of the findings from this study was presented at the 2020 AcademyHealth Annual Research Meeting, delivered virtually on July 29, 2020.

Deterioration of Health-Related Quality of Life After Withdrawal of Risankizumab Treatment in Patients with Moderate-to-Severe Plaque Psoriasis: A Machine Learning Predictive Model.

INTRODUCTION: Risankizumab has demonstrated efficacy in treating moderate-to-severe psoriasis. The phase-3 IMMhance trial (NCT02672852) examined the effect of continuing versus withdrawing from risankizumab treatment on psoriasis severity, including the Psoriasis Area and Severity Index (PASI) and static Physician Global Assessment (sPGA). However, the effect of withdrawal on health-related quality of life (HRQL) was not assessed. Therefore, this study was conducted to evaluate the impact of risankizumab withdrawal on HRQL measured by the Dermatology Life Quality Index (DLQI). Because DLQI was not measured beyond week 16 in IMMhance, a machine learning predictive model for DLQI was developed. METHODS: A machine learning model for DLQI was fitted using repeated measures data from three phase-3 trials (NCT02684370, NCT02684357, NCT02694523) (pooled N = 1602). An elastic-net algorithm performed automated variable selection among candidate predictors including concurrent PASI and sPGA, demographics, and interaction terms. The machine learning model was used to predict DLQI at weeks 28-104 of IMMhance among patients re-randomized to continue (N = 111) or withdraw from (N = 225) risankizumab after achieving response (sPGA = 0/1) at week 28. RESULTS: The machine learning predictive model demonstrated good statistical fit during tenfold cross-validation and external validation against observed DLQI at weeks 0-16 of IMMhance (N = 507). Predicted improvements in DLQI from baseline were lower in the withdrawal versus the continuation cohort (mean DLQI change at week 104, -5.9 versus -11.5, difference [95% CI] = 5.6 [4.1, 7.3]). Predicted DLQI deteriorated more extensively than PASI (49.7% versus 36.4%) after treatment withdrawal. CONCLUSIONS: The predicted DLQI score deteriorated more rapidly after risankizumab withdrawal than the PASI score, an objective measure of disease. These findings suggest that the deterioration in HRQL reflects more substantial impacts after risankizumab discontinuation than those measured by PASI only.

The Relationship Between Follow-up Appointments and Access to Primary Care.

BACKGROUND: Health care operations managers need to balance scheduling frequent follow-ups for patients with chronic conditions and fitting in patients requiring care for new complaints. OBJECTIVE: We quantify how frequency of follow-up visits corresponds with access to care for patients receiving care from the Department of Veterans Affairs (VA). DESIGN: We use patient data collected between October 2013 and June 2016 by the Survey of Healthcare Experiences of Patients (SHEP). Our sample is comprised of 94,496 patients. We estimate logistic models with 1-month lagged facility-level predictors. MAIN MEASURES: We calculate monthly measures characterizing facility-level service provision, including the average time between successive primary care visits, the average primary care visit length, the percentage of primary care appointments that are overbooked, the percent of visits that are unscheduled (i.e., walk-ins), and the ratio of patients to providers. We control for economic factors that are associated with health care supply and demand, including median household income, veteran priority status, the Zillow Housing Price Index, and veteran unemployment rates. We also control for patient demographics. PATIENTS: We restrict the data to patients with at least one in-person primary care visit who have provided information on their ability to access urgent and routine care. KEY RESULTS: We find that shorter average follow-up times are associated with better access for patients needing urgent or routine care. A 1-month increase in the average time between successive primary care visits is associated with 10% (p < 0.001) lower odds of reporting being able to access urgent care within 1 day and 13% (p < 0.001) lower odds of reporting usually or always being able to access routine care when needed. CONCLUSION: Facilities with higher average follow-up times are more likely to have patients report that they are unable to quickly access urgent or routine primary care.

Lifetime Job Demands and Later Life Disability.

Occupational characteristics may improve or harm health later in life. Previous research, largely based on limited exposure periods, reached mixed conclusions. We use Health and Retirement Study data linked to the Department of Labor's O*Net job classification system to examine the relationship between lifetime exposure to occupational demands and disability later in life. We consistently find an association between non-routine cognitive demands and lower rates of Social Security Disability Insurance (SSDI) receipt and work-limiting health conditions. Routine manual demands are associated with moderately worse health and increased SSDI receipt in most lifetime specifications. These results are robust to various specifications of occupational demand measures and controlling for transitions between jobs of different levels of occupational intensity. We show that failure to account for job characteristic exposure early in a worker's tenure obscures the relationship between physical job demands and disability later in life. While characteristics of jobs worked at ages 30 and 55 are both predictive of later-life health outcomes, early-life job characteristics frequently dominate in models containing early and late exposures.