Impact of Immune Checkpoint Inhibitors on COVID-19 Severity in Patients with Cancer.

BACKGROUND: Amid continued uncertainty about the management of cancer patients during the pandemic, this study sought to obtain real-world data on the use of immune checkpoint inhibitors (ICIs) before COVID-19 diagnosis and its association with severity and survival outcomes in cancer patients who contracted COVID-19. METHODS: Cancer patients diagnosed with COVID-19 were identified from a large electronic health record database; those treated with ICIs before COVID-19+ diagnosis were matched in a 1:2 ratio to those not treated with ICIs, using a 2-step matching procedure. A descriptive analysis examined the difference in COVID-19 mortality (30-day and overall) and severity outcomes between the 2 cohorts, and overall survival was compared. RESULTS: Among 17 545 adults ≥18 years with cancer who tested positive for COVID-19 between February 20, 2020, and January 28, 2021, in the US, 228 ICI-treated patients were matched to 456 non-ICI-treated patients, comprising the 2 study cohorts. Clinical characteristics differed significantly between the 2 cohorts before matching, with metastatic disease, lung cancer, a history of smoking, and the presence of pulmonary comorbidities being more common in the ICI-treated cohort; after matching, the 2 cohorts were similar. There were no significant differences between the ICI-treated and non-ICI-treated cohorts for 30-day mortality (12.7% vs. 14.9%, P = .235), overall mortality (22.4% vs. 22.4%, P = 1.000), hospitalization (38.6% vs. 39.0%, P = .912), or emergency department visits (16.7% vs. 14.7%, P = .500). Overall survival was similar between the 2 cohorts. CONCLUSION: This analysis adds to the clinical evidence base that use of ICIs before SARS-CoV-2 infection does not affect COVID-19 severity or survival outcomes, supporting the continued use of ICIs in cancer patients during the pandemic.

Risk of serious infections in tocilizumab versus other biologic drugs in patients with rheumatoid arthritis: a multidatabase cohort study.

OBJECTIVE: To investigate the rate of serious bacterial, viral or opportunistic infection in patients with rheumatoid arthritis (RA) starting tocilizumab (TCZ) versus tumour necrosis factor inhibitors (TNFi) or abatacept. METHODS: Using claims data from US Medicare from 2010 to 2015, and IMS and MarketScan from 2011 to 2015, we identified adults with RA who initiated TCZ or TNFi (primary comparator)/abatacept (secondary comparator) with prior use of ≥1 different biologic drug or tofacitinib. The primary outcome was hospitalised serious infection (SI), including bacterial, viral or opportunistic infection. To control for >70 confounders, TCZ initiators were propensity score (PS)-matched to TNFi or abatacept initiators. Database-specific HRs were combined by a meta-analysis. RESULTS: The primary cohort included 16 074 TCZ PS-matched to 33 109 TNFi initiators. The risk of composite SI was not different between TCZ and TNFi initiators (combined HR 1.05, 95% CI 0.95 to 1.16). However, TCZ was associated with an increased risk of serious bacterial infection (HR 1.19, 95% CI 1.07 to 1.33), skin and soft tissue infections (HR 2.38, 95% CI 1.47 to 3.86), and diverticulitis (HR 2.34, 95% CI 1.64 to 3.34) versus TNFi. An increased risk of composite SI, serious bacterial infection, diverticulitis, pneumonia/upper respiratory tract infection and septicaemia/bacteraemia was observed in TCZ versus abatacept users. CONCLUSIONS: This large multidatabase cohort study found no difference in composite SI risk in patients with RA initiating TCZ versus TNFi after failing ≥1 biologic drug or tofacitinib. However, the risk of serious bacterial infection, skin and soft tissue infections, and diverticulitis was higher in TCZ versus TNFi initiators. The risk of composite SI was higher in TCZ initiators versus abatacept.

Comparative effectiveness of tocilizumab versus TNF inhibitors as monotherapy or in combination with conventional synthetic disease-modifying antirheumatic drugs in patients with rheumatoid arthritis after the use of at least one biologic disease-modifying antirheumatic drug: analyses from the pan-European TOCERRA register collaboration.

OBJECTIVE: To compare the effectiveness of tocilizumab (TCZ) and tumour necrosis factor (TNF) inhibitors (TNFi) as monotherapy or in combination with conventional synthetic disease-modifying antirheumatic drugs (DMARDs) in patients with rheumatoid arthritis (RA) after the use of at least one biologic DMARD (bDMARD). METHODS: We included patients with RA having used at least one bDMARD from 10 European registries. We compared drug retention using Kaplan-Meier and Cox models and Clinical Disease Activity Index (CDAI) change over time with mixed-effects models for longitudinal data. The proportions of CDAI remission and low disease activity (LDA) at 1 year were compared using LUNDEX correction. RESULTS: 771 patients on TCZ as monotherapy (TCZ mono), 1773 in combination therapy (TCZ combo), 1404 on TNFi as monotherapy (TNFi mono) and 4660 in combination therapy (TNFi combo) were retrieved. Crude median retention was higher for TCZ mono (2.31 years, 95% CI 2.07 to 2.61) and TCZ combo (1.98 years, 95% CI 1.83 to 2.11) than TNFi combo (1.37 years, 95% CI 1.30 to 1.45) and TNFi mono (1.31 years, 95% CI 1.18 to 1.47). In a country and year of treatment initiation-stratified, covariate-adjusted analysis, hazards of discontinuation were significantly lower among patients on TCZ mono or combo compared with patients on TNFi mono or combo, and TNFi combo compared with TNFi mono, but similar between TCZ mono and combo. Average adjusted CDAI change was similar between groups. CDAI remission and LDA rates were comparable between groups. CONCLUSION: With significantly longer drug retention and similar efficacy to TNFi combo, TCZ mono or combo are reasonable therapeutic options in patients with inadequate response to at least one bDMARD.

Diagnostic Pathways to Alzheimer Disease: Costs Incurred in a Medicare Population.

Despite its implications on the personal and policy level, little is currently known about the specific diagnostic pathways that patients with cognitive impairment (CI) pass through before being diagnosed with Alzheimer disease (AD). Four major diagnostic pathways were identified in the Medicare claims records for 2001 to 2006: AD as initial diagnosis, cognitive disturbance followed by AD; dementia with suspected etiologies followed by AD; dementia without known cause followed by AD; and 1 triple pathway, cognitive disturbance followed by dementia without known cause followed by AD. For all of these pathways, previously low medical costs peaked during patients' month of initial diagnosis and then declined to a level substantially higher than before. The 3 CI pathways that transition to AD included another peak in costs when a secondary AD diagnosis occurred. Each time, inpatient and skilled nursing facility services were major cost contributors. The primary diagnoses on Medicare claims for the AD event were usually comorbidities rather than CI. A linear regression model adjusting for demographic factors, selected comorbidities, and overall frailty found that the transitional CI diagnoses were significant independent cost determinants. They increased Medicare expenditures by an estimated $4600 to $14,200 relative to patients whose initial CI diagnosis was AD.

Depressive, functional status, and neuropsychiatric symptom trajectories before an Alzheimer's disease diagnosis.

OBJECTIVES: This short report relied on multiyear data from the National Alzheimer's Coordinating Center - Uniform Data Set (NACC-UDS) to examine whether significant changes occurred in functional status, neuropsychiatric symptoms, and depressive symptoms in the years before receiving an Alzheimer's disease (AD) diagnosis. METHOD: The secondary analysis used a retrospective cohort design. The NACC-UDS is a publicly accessible, longitudinal database that includes standardized data on neuropsychiatric symptoms, functional status, and depressive symptoms for Alzheimer's Disease Center (ADC) participants in the USA based on their annual visits from 2005 to 2011. ADC participants were considered diagnosed with AD if a follow-up data form indicated an affirmative response to whether the ADC participant had 'probable AD (National Institute of Neurological and Communicative Disorders and Stroke (NINCDS)/Alzheimer's Disease and Related Disorders Association (ADRDA))' or 'possible AD (NINCDS/ADRDA).' This yielded an analytic sample of 2478 individuals (139 with an eventual probable AD diagnosis, 109 individuals with an eventual possible AD diagnosis, and 2230 without any AD diagnosis) representing a total of 11,358 visits/points of data. RESULTS: Multilevel linear models revealed significant decreases (p < 0.05) in functional status prior to a probable or possible AD diagnosis and significant increases in depressive symptoms prior to a probable AD diagnosis. DISCUSSION: Changes in functional and depressive symptoms were partly independent of cognitive decline. The longitudinal results lend additional support to conceptual and empirical models of pre-diagnosis declines in AD.

Enhancing site selection strategies in clinical trial recruitment using real-world data modeling.

Slow patient enrollment or failing to enroll the required number of patients is a disruptor of clinical trial timelines. To meet the planned trial recruitment, site selection strategies are used during clinical trial planning to identify research sites that are most likely to recruit a sufficiently high number of subjects within trial timelines. We developed a machine learning approach that outperforms baseline methods to rank research sites based on their expected recruitment in future studies. Indication level historical recruitment and real-world data are used in the machine learning approach to predict patient enrollment at site level. We define covariates based on published recruitment hypotheses and examine the effect of these covariates in predicting patient enrollment. We compare model performance of a linear and a non-linear machine learning model with common industry baselines that are constructed from historical recruitment data. Performance of the methodology is evaluated and reported for two disease indications, inflammatory bowel disease and multiple myeloma, both of which are actively being pursued in clinical development. We validate recruitment hypotheses by reviewing the covariates relationship with patient recruitment. For both indications, the non-linear model significantly outperforms the baselines and the linear model on the test set. In this paper, we present a machine learning approach to site selection that incorporates site-level recruitment and real-world patient data. The model ranks research sites by predicting the number of recruited patients and our results suggest that the model can improve site ranking compared to common industry baselines.

Assessing ascertainment bias in atrial fibrillation across US minority groups.

The aim of this study is to define atrial fibrillation (AF) prevalence and incidence rates across minority groups in the United States (US), to aid in diversity enrollment target setting for randomized controlled trials. In AF, US minority groups have lower clinically detected prevalence compared to the non-Hispanic or Latino White (NHW) population. We assess the impact of ascertainment bias on AF prevalence estimates. We analyzed data from adults in Optum's de-identified Clinformatics® Data Mart Database from 2017-2020 in a cohort study. Presence of AF at baseline was identified from inpatient and/or outpatient encounters claims using validated ICD-10-CM diagnosis algorithms. AF incidence and prevalence rates were determined both in the overall population, as well as in a population with a recent stroke event, where monitoring for AF is assumed. Differences in prevalence across cohorts were assessed to determine if ascertainment bias contributes to the variation in AF prevalence across US minority groups. The period prevalence was respectively 4.9%, 3.2%, 2.1% and 5.9% in the Black or African American, Asian, Hispanic or Latino, and NHW population. In patients with recent ischemic stroke, the proportion with AF was 32.2%, 24.3%, 25%, and 24.5%, respectively. The prevalence of AF among the stroke population was approximately 7 to 10 times higher than the prevalence among the overall population for the Asian and Hispanic or Latino population, compared to approximately 5 times higher for NHW patients. The relative AF prevalence difference of the Asian and Hispanic or Latino population with the NHW population narrowed from respectively, -46% and -65%, to -22% and -24%. The study findings align with previous observational studies, revealing lower incidence and prevalence rates of AF in US minority groups. Prevalence estimates of the adult population, when routine clinical practice is assumed, exhibit higher prevalence differences compared to settings in which monitoring for AF is assumed, particularly among Asian and Hispanic or Latino subgroups.

Potential impact of amyloid imaging on diagnosis and intended management in patients with progressive cognitive decline.

Florbetapir F18 has been approved by the Food and Drug Administration for in vivo assessment of amyloid pathology in patients undergoing evaluation for Alzheimer disease (AD). The aim of this study was to determine the impact of amyloid imaging on the diagnoses and management of patients undergoing evaluation for cognitive decline. Patients were recruited to participate at 19 clinical sites. The site physician provided a provisional diagnosis, an estimate of their diagnostic confidence, and their plan for diagnostic evaluation and management both before and after receiving the results from amyloid imaging with florbetapir F18. Analyses compared the frequency of AD and non-AD diagnoses, plans for ancillary testing, and intended patient management before and after florbetapir imaging. A total of 229 patients participated in the trial (113 amyloid positive, 116 amyloid negative). After receiving the results of the florbetapir scan, diagnosis changed in 125/229, or 54.6% [95% confidence intervals (CI), 48.1%-60.9%], of cases, and diagnostic confidence increased by an average of 21.6% (95% CI, 18.3%-24.8%). A total of 199/229 or 86.9% (95% CI, 81.9%-90.7%) of cases had at least 1 change in their management plan. Intended cholinesterase inhibitor or memantine treatment increased by 17.7% (95% CI, 11.8%-25.8%) of all cases with positive scans and decreased by 23.3% (95% CI, 16.5%-31.8%) of all those with negative scans. Among subjects who had not yet undergone a completed work up, planned brain structural imaging (computed tomographic/magnetic resonance imaging) decreased by 24.4% (95% CI, 17.5%-32.8%) and planned neuropsychological testing decreased by 32.8% (95% CI, 25.0%-41.6%). In summary, amyloid imaging results altered physician's diagnostic thinking, intended testing, and management of patients undergoing evaluation for cognitive decline.

The role of the FcGRIIIa polymorphism in modifying the association between treatment and outcome in patients with rheumatoid arthritis treated with rituximab versus TNF-α antagonist therapies.

OBJECTIVES: There is an association between the FcGRIIIa polymorphism and the development of rheumatoid arthritis (RA). Studies in non-Hodgkin lymphoma demonstrated a relationship between the FcGRIIIa polymorphism and response to anti-CD20 therapies. However, there are currently no published studies evaluating the relationship between this polymorphism and therapeutic response to treatment with anti-CD20 agents such as rituximab in RA. We conducted a study to identify if the FcGRIIIa polymorphism is associated with rituximab efficacy in patients with RA. METHODS: Subjects with RA treated with rituximab (cases, n=158) or TNF-α antagonist (controls, n=390) were recruited from the Consortium of Rheumatology Researchers of North America. The FcGRIIIa variant was genotyped for all subjects and longitudinal patient outcomes were assessed using the clinical disease activity index (CDAI). We used a linear regression random effects model to estimate CDAI scores over time with multiple time points nested within patient. RESULTS: Similar changes in CDAI were observed across the three FcGRIIIa genotypes for the rituximab treated group (VV [4.56, SD 14.5]), VF (7.44, SD 14.9) and FF (4.75, SD 10.8) (p >0.05)] and the TNF-α antagonist therapy treated group [VV (5.12, SD 14.6), VF (6.77, SD 15.9), and FF (4.36, SD 18.2) (p >0.05). Overall, there were similar changes in CDAI at 6 months for rituximab (-5.91, SD 14.1) and anti-TNFs (-5.77, SD 15.5) (p >0.05). The FcGRIIIa genotype was not significantly associated (p=0.86) with treatment response in rituximab treated RA patients compared with TNF-α antagonist therapy treated patients. Baseline CDAI and number of prior biologics were significant predictors of clinical response over time. CONCLUSIONS: Our finding emphasises the idea that determinants of response to treatment are complex and may be dependent upon genetic and phenotypic interactions. Future studies should analyse the interaction between the FcGRIIIa gene, other neighbouring polymorphisms and other phenotypic and environmental factors.

Derivation of a brief measure of agitation and aggression in Alzheimer's disease.

OBJECTIVE: Neuropsychiatric symptoms, including agitation and aggression (A/A), are highly prevalent in Alzheimer's disease (AD) and are associated with increased disability, functional impairment, caregiver distress, and institutionalization. Previous psychometric work suggests that individual items of agitation, irritability, disinhibition, and aberrant motor behavior from the Neuropsychiatric Inventory (NPI) may be a valid measure of A/A in AD. We provide additional confirmation of this subscale, as well as preliminary validation of it as a measure of A/A (the NPI-4-A/A). METHODS: The sample included 641 individuals identified from the South Carolina Alzheimer's Disease Registry and assessed to be at a nursing home level of care. Demographic and medical data were extracted from the Registry, and phone interviews were conducted with caregivers to collect additional information not included in the Registry. The primary statistical analysis was confirmatory factor analysis of the NPI-12 factor structure. RESULTS: The standardized root mean residual and root mean square error of approximation (90% CI) values of 0.060 and 0.043 (0.030, 0.057), respectively suggest adequate model fit of the data, whereas the Tucker-Lewis index estimate of 0.779 is below the criteria for adequate model fit. All but two normalized residuals (NR) suggested adequate model fit of the data (|NR| < 2.58). NPI-4-A/A scores were higher in patients residing in nursing homes and were correlated with caregiver burden. CONCLUSIONS: The NPI-4-A/A is proposed as a measure of A/A in AD. The utility and validity of this measure should be explored further. Improved measurement and focus on subgroups of neuropsychiatric symptoms should be integrated into interventions for AD.

Factors predicting change in frequency of heavy drinking days among alcohol-dependent participants in the National Epidemiologic Survey on Alcohol and Related Conditions (NESARC).

AIMS: To discover the predictors of change in the frequency of heavy drinking (HD) over a 4-year period in alcohol dependent (AD)-individuals identified in the general population, namely, among participants of the US National Epidemiologic Survey on Alcohol and Related Conditions interviewed at Wave 1 (2001-2002) and at Wave 2 (2004-2005). METHODS: The study cohort included subjects meeting DSM-IV criteria for AD in the past year at Wave 1 (n = 1484), who were present at Wave 2 (n = 1172) and had complete data on factors of interest (n = 1123). Frequency of HD was defined as the number of HD days (HDD) (≥5 drinks per day for men and ≥4 for women). Change in frequency of HDD from baseline (Wave 1) to ~3 years later (Wave 2) was determined. An analysis of covariance model (ANCOVA), adjusting for baseline HDD, was used to examine individual factors associated with change in frequency of HDD, while a multivariable regression model was employed to assess factors associated with change in frequency of HDD simultaneously. RESULTS: Overall, there was a decrease in mean (SE) HDD [from 119.4 (1.8) at Wave 1 to 82.5 (2.1) at Wave 2, P < 0.0001]. Compared with smokers, non-smokers had a mean (SE) HDD reduction of 13.4 (6.7), P < 0.05. AD criteria of tolerance was significantly associated (P < 0.05) with less reduction in HDD. Change in depression/dysthymia status was associated with greater reduction in HDD in the ANCOVA model, but not the fully adjusted multivariable model. CONCLUSION: Findings from this study suggest that smoking and AD criteria of tolerance are important factors for long-term follow-up of AD patients and they should influence the selection of the kinds of interventions required for AD patients to achieve maximal therapeutic benefit.

Durability of Protection Post-Primary COVID-19 Vaccination in the United States.

The durability of immune responses after COVID-19 vaccination will drive long-term vaccine effectiveness across settings and may differ by vaccine type. To determine durability of protection of COVID-19 vaccines (BNT162b2, mRNA-1273, and Ad26.COV2.S) following primary vaccination in the United States, a matched case-control study was conducted in three cohorts between 1 January and 7 September 2021 using de-identified data from a database covering 168 million lives. Odds ratios (ORs) for developing outcomes of interest (breakthrough SARS-CoV-2 infection, hospitalization, or intensive care unit admission) were determined for each vaccine (no direct comparisons). In total, 17,017,435 individuals were identified. Relative to the baseline, stable protection was observed for Ad26.COV2.S against infections (OR [95% confidence interval (CI)], 1.31 [1.18-1.47]) and hospitalizations (OR [95% CI], 1.25 [0.86-1.80]). Relative to the baseline, protection waned over time against infections for BNT162b2 (OR [95% CI], 2.20 [2.01-2.40]) and mRNA-1273 (OR [95% CI], 2.07 [1.87-2.29]) and against hospitalizations for BNT162b2 (OR [95% CI], 2.38 [1.79-3.17]). Baseline protection remained stable for intensive care unit admissions for all three vaccines. Calculated baseline VE was consistent with published literature. This study suggests that the three vaccines in three separate populations may have different durability profiles.

Does caregiver burden mediate the effects of behavioral disturbances on nursing home admission?

OBJECTIVES: The primary objective of this study was to determine whether caregiving burden mediated the relationship between specific behavior disturbances and time to nursing home admission (NHA) for persons with dementia (i.e., Alzheimer disease or a related disorder). DESIGN: The study used secondary longitudinal data from the Medicare Alzheimer's Disease Demonstration, a Medicare-covered home care benefit and case management program for family caregivers of persons with dementia. Primary caregivers of persons with dementia were assessed via in-person and telephone interviews every 6 months over a 3-year period. SETTING: Dementia caregivers were recruited from eight catchment areas throughout the United States. PARTICIPANTS: The baseline sample included 5,831 dementia caregivers. Just more than 40% (43.9%; N = 2,556) of persons with dementia permanently entered a nursing home during the 3-year study period. MEASUREMENTS: Individual behavior problems were measured with the Memory and Behavior Problem Checklist. Caregiving burden was assessed with a short version of the Zarit Burden Inventory. Key covariates, including sociodemographic background, functional status, and service utilization, were also considered. RESULTS: Event history analyses revealed that time-varying measures of caregiver burden fully mediated the relationship between four behavioral disturbances (episodes of combativeness, property destruction, repetitive questions, and reliving the past) and NHA. CONCLUSIONS: The findings highlight the multifaceted, complex pathway to NHA for persons with dementia and their family caregivers. The results emphasize the need for comprehensive treatment approaches that incorporate the burden of caregivers and the behavioral/psychiatric symptoms of persons with dementia simultaneously.

Family socioeconomic status and child executive functions: the roles of language, home environment, and single parenthood.

The association between family socioeconomic status (SES) and child executive functions is well-documented. However, few studies have examined the role of potential mediators and moderators. We studied the independent and interactive associations between family SES and single parenthood to predict child executive functions of inhibitory control, cognitive flexibility, and working memory and examined child expressive language abilities and family home environment as potential mediators of these associations. Sixty families from diverse SES backgrounds with a school-age target child (mean [SD] age = 9.9 [0.96] years) were evaluated. Child executive functioning was measured using a brief battery. The quality of the home environment was evaluated using the Home Observation for the Measurement of the Environment inventory. Family SES predicted the three child executive functions under study. Single parent and family SES were interactively associated with children's inhibitory control and cognitive flexibility; such that children from low SES families who were living with one parent performed less well on executive function tests than children from similarly low SES who were living with two parents. Parental responsivity, enrichment activities and family companionship mediated the association between family SES and child inhibitory control and working memory. This study demonstrates that family SES inequalities are associated with inequalities in home environments and with inequalities in child executive functions. The impact of these disparities as they unfold in the lives of typically developing children merits further investigation and understanding.

Association of biological antirheumatic therapy with risk for type 2 diabetes: a retrospective cohort study in incident rheumatoid arthritis.

OBJECTIVE: To explore possible associations of treatment with biological disease-modifying antirheumatic drugs (bDMARDs), including T-cell-based and interleukin-6 inhibition (IL-6i)-based therapies, and the risk for type 2 diabetes mellitus (T2DM) in patients with rheumatoid arthritis (RA). STUDY DESIGN, SETTING AND PARTICIPANTS: Five treatment groups were selected from a United States Electronic Medical Records database of 283 756 patients with RA (mean follow-up, 5 years): never received bDMARD (No bDMARD, n=125 337), tumour necrosis factor inhibitors (TNFi, n=34 873), IL-6i (n=1884), T-cell inhibitors (n=5935) and IL-6i+T cell inhibitor abatacept (n=1213). Probability and risk for T2DM were estimated with adjustment for relevant confounders. RESULTS: In the cohort of 169 242 patients with a mean 4.5 years of follow-up and a mean 641 200 person years of follow-up, the adjusted probability of developing T2DM was significantly lower in the IL-6i (probability, 1%; 95% CI 0.6 to 2.0), T-cell inhibitor (probability, 3%; 95% CI 2.3 to 3.3) and IL-6i+T cell inhibitor (probability, 2%; 95% CI 0.1 to 2.9) groups than in the No bDMARD (probability, 5%; 95% CI 4.6 to 4.9) and TNFi (probability, 4%; 95% CI 3.7 to 4.7) groups. Compared with No bDMARD, the IL-6i and IL-6i+T cell inhibitor groups had 37% (95% CI of HR 0.42 to 0.96) and 34% (95% CI of HR 0.46 to 0.93) significantly lower risk for T2DM, respectively; there was no significant difference in risk in the TNFi (HR 0.99; 95% CI 0.93 to 1.06) and T-cell inhibitor (HR 0.96; 95% CI 0.82 to 1.12) groups. CONCLUSIONS: Treatment with IL-6i, with or without T-cell inhibitors, was associated with reduced risk for T2DM compared with TNFi or No bDMARDs; a less pronounced association was observed for the T-cell inhibitor abatacept.

The effects of incident and persistent behavioral problems on change in caregiver burden and nursing home admission of persons with dementia.

BACKGROUND: The individual contributions of behavior problems to key and related outcomes in dementia, such as nursing home admission (NHA) or caregiver burden, remain unclear. OBJECTIVES: This study sought to determine the ramifications of temporal change in individual behavior problems when accounting for increases in caregiver burden and time to NHA. Although burden is sometimes conceptualized as an antecedent to NHA, it has also emerged as a relevant outcome in dementia caregiving research. METHODS: A sample of 4545 dementia caregivers who participated in the Medicare Alzheimer disease Demonstration Evaluation was selected for this secondary analysis. Various patterns of change in individual behavior problems were considered as predictors of increases in caregiver burden and time to NHA over a 3-year period via mixed effects and Cox proportional hazards models, respectively. RESULTS: Caregivers who did not indicate a care recipient's dangerous behavior initially but did so subsequently (ie, an "incident" behavior problem) were more likely to experience increases in burden (P < 0.0026). Alternatively, the persistent occurrence of behavior disturbances (particularly memory problems) emerged as the strongest predictors of time to NHA. DISCUSSION: The findings of this study suggest the benefit of examining temporal patterns of individual behavioral disturbances, and that incident and persistent problems account for different dementia outcomes over time. Considering the temporal ramifications and potency of specific behavior problems can facilitate the targeted and timely delivery of effective clinical interventions.

Subtypes of sleep disturbance: associations among symptoms, comorbidities, treatment, and medical costs.

Medical claims and survey data were used to evaluate patients with sleep disturbance lasting 1 year or more, and to identify subtypes of sleep disturbance using latent class analysis. Four subtypes were identified from the 1,374 patients. Subtypes differed on the number of sleep disturbance symptoms, presence of non-restorative sleep and comorbidities, degree of daytime impairment, and insomnia severity. The results from this study suggest that patient-reported symptoms of sleep disturbance, the frequency of symptoms, functional impairment, and comorbid conditions are important elements in distinguishing among groups of patients with varying degrees of sleep problems. These data provide evidence that the Insomnia Severity Index (ISI) varies accordingly with the frequency and resulting impairment of symptoms captured in the 4 clusters.

Rituximab utilization for approved and off-label nononcology indications and patients' experiences with the Patient Alert Card.

This study used retrospective chart review and survey data to evaluate: (1) off-label use of rituximab (MabThera®/Rituxan®) in autoimmune conditions and (2) patients' receipt and knowledge of the Patient Alert Card (PAC), a risk minimization measure for progressive multifocal leukoencephalopathy (PML) and serious infections. Anonymized patient data were collected from infusion centers in Europe from December 2015 to July 2017. Adults receiving rituximab in the same centers were provided a self-administered survey. Outcomes included patterns of off-label rituximab use for nononcology indications, and evaluation of patients' receipt and knowledge of the PAC and its impact. Of 1012 patients in the retrospective chart review, 70.2% received rituximab for rheumatoid arthritis or granulomatosis with polyangiitis/microscopic polyangiitis, and 29.8% received rituximab off label. Among 524 survey participants, 32.8% reported receiving the PAC, 59.3% reported not receiving the PAC and 7.9% did not know whether they received the PAC. A total of 72.4% of patients reported that they were unaware that some patients receiving rituximab experience PML. A higher proportion of PAC recipients identified PML as a potential risk of rituximab than nonrecipients (37.8% vs 19.9%); 58.3% of PAC recipients had poor awareness of PML. Most PAC recipients (90.0%) and nonrecipients (85.5%) correctly answered that they should seek medical attention for infection symptoms. In conclusion, approximately 30% of patients received off-label rituximab. Most patients reported not receiving the PAC or having knowledge of PML but demonstrated understanding of the recommended action in the event of infection symptoms, regardless of PAC receipt.

Characterizing Disease Manifestations and Treatment Patterns Among Adults with Systemic Sclerosis: A Retrospective Analysis of a US Healthcare Claims Population.

INTRODUCTION: Real-world use of immunomodulating therapy (IMT) in patients with systemic sclerosis (SSc) was investigated for the first time in a descriptive, retrospective cohort analysis of claims made in a healthcare insurance database to characterize treatment patterns and their alignment with SSc disease manifestations. METHODS: Treatment patterns and disease manifestations, symptoms, complications, and comorbidities were assessed in patients with SSc enrolled in a US healthcare claims database who received treatment between January 2006 and December 2013 and for whom data were available 6 months before and 12 months after SSc diagnosis. RESULTS: Among 7812 eligible patients, 6852 received treatments of interest for SSc and 2404 (30.8%) received IMT during the first year after SSc diagnosis. In the first year after diagnosis, the most common claims were for antibiotics (61.7%), opioids (50.6%), glucocorticoids (46.5%), and proton pump inhibitors (35.4%); the most common organs involved with complications among patients with SSc were lung (30.5%), heart (17.4%), and gastrointestinal tract (22.4%); the most common signs or symptoms were musculoskeletal (16.1%) and fatigue (10.5%); 1035 patients (15.1%) had infections and 14 (0.2%) had malignancies. Among patients who received IMT, 43.8% received at least hydroxychloroquine and 21.1% received at least methotrexate; 460 patients switched to a second IMT, 23.0% to at least methotrexate and 22.8% to at least mycophenolate mofetil. The most common comorbidities reported with first IMT were in lung (11.8%), overlap syndrome (8.4%), heart (5.3%), and gastrointestinal (6.8%) categories. CONCLUSION: One-third of patients with SSc in the healthcare claims population received IMTs during the first year after diagnosis. However, patients who received IMTs had disease manifestations similar to those of the overall SSc healthcare claims population.

Risk of malignancy associated with use of tocilizumab versus other biologics in patients with rheumatoid arthritis: A multi-database cohort study.

OBJECTIVES: To examine the rate of incident malignancies excluding non-melanoma skin cancer (NMSC) in patients with rheumatoid arthritis (RA) newly treated with tocilizumab versus other biologic drugs. METHODS: We conducted a cohort study using data from 3 U.S. insurance claims databases - Medicare (2010-2015), 'IMS' PharMetrics Plus (2011-2015) and Truven 'MarketScan' (2011-2015). Adults with RA who newly started tocilizumab or a TNF inhibitor (TNFi) after failing a different TNFi, abatacept or tofacitinib were included. The primary outcome was development of any malignancies excluding NMSC. For confounding control, tocilizumab starters were propensity score (PS)-matched to TNFi starters with a variable ratio of 1:3 within each database. Hazard ratios (HR) from the 3 PS-matched cohorts were combined by an inverse variance-weighted, fixed-effects model. We conducted a secondary analysis where we compared tocilizumab initiators with abatacept initiators. RESULTS: We included 13,102 tocilizumab initiators PS-matched to 26,727 TNFi initiators in all three databases. The incidence rate of malignancies per 1,000 person-years ranged from 8.27 (IMS) to 23.18 (Medicare) in the tocilizumab group and from 9.64 (MarketScan) to 21.46 (Medicare) in the TNFi group. The risk of incident malignancies was similar between tocilizumab and TNFi initiators across all three databases, with a combined HR of 0.98 (95%CI 0.80-1.19) in tocilizumab versus TNFi. The secondary analysis comparing tocilizumab versus abatacept showed similar results (combined HR 0.97, 95%CI 0.74-1.27). CONCLUSIONS: This large multi-database cohort study found no difference in the risk of malignancies excluding NMSC in RA patients who newly started tocilizumab compared with TNFi or abatacept.