Medication Nonadherence Is Associated With Increased Subsequent Acute Care Utilization Among Medicaid Beneficiaries With Systemic Lupus Erythematosus.
ABSTRACT: We examined whether nonadherence to hydroxychloroquine (HCQ) or immunosuppressive medications (ISMs) was associated with higher subsequent acute care utilization among Medicaid beneficiaries with systemic lupus erythematosus (SLE).We utilized US Medicaid data from 2000-2006 to identify adults ages 18-64 years with SLE who were new users of HCQ or ISMs. We defined the index date as receipt of HCQ or ISMs without use in the prior 6 months. We measured adherence using the medication possession ratio (MPR), the proportion of days covered by total days' supply dispensed, for the 1-year post-index date. Our outcomes were all-cause and SLE-related emergency department (ED) visits and hospitalizations in the subsequent year. We used multivariable Poisson regression models to examine the association between nonadherence (MPR <80%) and acute care utilization, adjusting for sociodemographics and comorbidities.We identified 9,600 HCQ new users and 3,829 ISM new users with SLE. The mean?±?SD MPR for HCQ was 47.8%?± 30.3% and for ISMs was 42.7%?±?30.7%. Seventy-nine percent of HCQ users and 83% of ISM users were nonadherent (MPR <80%). In multivariable models, among HCQ users, the incidence rate ratio (IRR) of ED visits was 1.55 (95% confidence interval [95% CI] 1.43-1.69) and the IRR of hospitalizations was 1.37 (95% CI 1.25-1.50), comparing nonadherers to adherers. For ISM users, the IRR of ED visits was 1.64 (95% CI 1.42-1.89) and of hospitalizations was 1.67 (95% CI 1.41-1.96) for nonadherers versus adherers.In this cohort, nonadherence to HCQ and ISMs was common and was associated with significantly higher subsequent acute care utilization.
Project description:BACKGROUND:Hydroxychloroquine (HCQ) is the standard of care medication for most SLE patients, however nonadherence is common. We investigated longitudinal patterns and predictors of nonadherence to HCQ in a U.S. SLE cohort of HCQ initiators. METHODS:We used Medicaid data from 28 states to identify adults 18-65 years with prevalent SLE. We included HCQ initiators following ?6 months without use, and required ?1 year of follow-up after first dispensing (index date). We used the proportion of days covered (PDC) to describe overall HCQ adherence (<80% = nonadherent) and novel group-based trajectory models (GBTM) to examine monthly patterns (<80% of days/month covered = nonadherent), during the first year of use. Multivariable multinomial logistic regression models were used to examine predictors of nonadherence. RESULTS:We identified 10,406 HCQ initiators with SLE. Mean age was 38 (±12) years, 94% were female, 42% black, 31% white; 85% had a mean PDC < 80%. In our 4-group GBTM, 17% were persistent adherers, 36% persistent nonadherers, and 47% formed two dynamic patterns of partial adherence. Adherence declined for most patients over the first year. Compared to persistent adherers, the odds of nonadherence were increased for blacks and Hispanics vs. whites and for younger ages vs. older; increased SLE-related comorbidities were associated with reduced odds of nonadherence for persistent nonadherers (0.95, 95% CI: 0.91-0.99). CONCLUSIONS:Among HCQ initiators with SLE, we observed poor adherence which declined for most over the first year of use. HCQ adherence is a dynamic behavior and further studies of associated predictors, outcomes, and interventions should reflect this.
Project description:OBJECTIVE:Azathioprine (AZA) and mycophenolate mofetil (MMF) are immunosuppressants frequently used in the treatment of moderate-to-severe systemic lupus erythematosus (SLE). We studied longitudinal patterns and predictors of adherence to AZA and MMF in a nationwide US SLE cohort. METHODS:In the Medicaid Analytic eXtract (2000-2010) database, we identified patients with SLE who initiated AZA or MMF (no use in the prior 6 months) with ?12 months of continuous follow-up. We dichotomized adherence at 80%, with ?24 of 30 days per month considered adherent. We used group-based trajectory models to estimate monthly adherence patterns and multivariable multinomial logistic regression to determine the association between demographic, SLE and utilization-related predictors, and the odds ratios (OR) of belonging to a nonadherent versus the adherent trajectory, separately for AZA and MMF. RESULTS:We identified 2,309 AZA initiators and 2,070 MMF initiators with SLE. Four-group trajectory models classified 17% of AZA and 21% of MMF initiators as adherent. AZA and MMF nonadherers followed similar trajectory patterns. African American race (OR 1.67 [95% confidence interval (95% CI) 1.20-2.31]) and Hispanic ethnicity (OR 1.58 [95% CI 1.06-2.35]) increased odds of AZA nonadherence; there were no significant associations between race/ethnicity and MMF nonadherence. Male sex and polypharmacy were associated with lower odds of nonadherence to both medications; lupus nephritis was associated with lower odds of nonadherence to MMF (OR 0.74 [95% CI 0.55-0.99]). CONCLUSION:Adherence to AZA or MMF over the first year of use was rare. Race, sex, and lupus nephritis were modestly associated with adherence, but the magnitude, direction, and significance of predictors differed by medication, suggesting the complexity of predicting adherence behavior.
Project description:<h4>Objective</h4>Adherence to hydroxychloroquine (HCQ) treatment in patients with systemic lupus erythematous (SLE) is suboptimal. Although individual-level factors, including younger age and non-white race/ethnicity, have been implicated, contextual factors have not been explored. The aim of this study was to investigate the effect of contextual factors, including racial composition, socioeconomic status, and the concentration of health care resources, on adherence to HCQ among SLE patients enrolled in Medicaid.<h4>Methods</h4>We identified SLE patients from 28 states in the US who enrolled in Medicaid (2000-2010) and in whom HCQ treatment was newly initiated (no use for ?6 months). We required 12 months of continuous enrollment with complete drug dispensing data and measured adherence using the proportion of days covered (PDC). We identified individual-level variables from Medicaid, zip code-level, county-level and state-level sociodemographic variables from the American Community Survey, and health resources from Area Health Resources Files. We used 4-level hierarchical multivariable logistic regression models to examine the odds ratios (ORs) and 95% credible intervals (95% CrIs) of adherence (PDC ?80%) versus nonadherence.<h4>Results</h4>Among 10,268 patients with SLE in whom HCQ treatment was initiated, 15% were adherent to treatment. After we adjusted for individual-level characteristics, we observed lower odds of adherence among patients living in zip code areas with a higher percentage of black individuals (highest tertile OR 0.81 [95% CrI 0.69-0.96] versus lowest tertile). This association persisted after controlling for area-level educational attainment, percent below federal poverty level (FPL), urbanicity, and health care resources. We did not observe statistically significant associations with zip code-level percent Hispanic, percent white, education, or percent below FPL. The odds of adherence were higher in counties with more hospitals (OR 1.30 [95% CrI 1.07-1.58]).<h4>Conclusion</h4>Among Medicaid beneficiaries with SLE, we observed significant effects of racial composition and hospital concentration on HCQ adherence. Interventions that acknowledge and address contextual factors should be considered in order to reduce high rates of nonadherence in vulnerable populations.
Project description:We propose an efficient framework for genetic subtyping of SARS-CoV-2, the novel coronavirus that causes the COVID-19 pandemic. Efficient viral subtyping enables visualization and modeling of the geographic distribution and temporal dynamics of disease spread. Subtyping thereby advances the development of effective containment strategies and, potentially, therapeutic and vaccine strategies. However, identifying viral subtypes in real-time is challenging: SARS-CoV-2 is a novel virus, and the pandemic is rapidly expanding. Viral subtypes may be difficult to detect due to rapid evolution; founder effects are more significant than selection pressure; and the clustering threshold for subtyping is not standardized. We propose to identify mutational signatures of available SARS-CoV-2 sequences using a population-based approach: an entropy measure followed by frequency analysis. These signatures, Informative Subtype Markers (ISMs), define a compact set of nucleotide sites that characterize the most variable (and thus most informative) positions in the viral genomes sequenced from different individuals. Through ISM compression, we find that certain distant nucleotide variants covary, including non-coding and ORF1ab sites covarying with the D614G spike protein mutation which has become increasingly prevalent as the pandemic has spread. ISMs are also useful for downstream analyses, such as spatiotemporal visualization of viral dynamics. By analyzing sequence data available in the GISAID database, we validate the utility of ISM-based subtyping by comparing spatiotemporal analyses using ISMs to epidemiological studies of viral transmission in Asia, Europe, and the United States. In addition, we show the relationship of ISMs to phylogenetic reconstructions of SARS-CoV-2 evolution, and therefore, ISMs can play an important complementary role to phylogenetic tree-based analysis, such as is done in the Nextstrain project. The developed pipeline dynamically generates ISMs for newly added SARS-CoV-2 sequences and updates the visualization of pandemic spatiotemporal dynamics, and is available on Github at https://github.com/EESI/ISM (Jupyter notebook), https://github.com/EESI/ncov_ism (command line tool) and via an interactive website at https://covid19-ism.coe.drexel.edu/.
Project description:Recombinant virus-like nanoparticles (VLPs) are a promising nanoparticle platform to develop safe vaccines for many viruses. Herein, we describe a novel and rapid protein transfer process to enhance the potency of enveloped VLPs by decorating influenza VLPs with exogenously added glycosylphosphatidylinositol-anchored immunostimulatory molecules (GPI-ISMs). With protein transfer, the level of GPI-ISM incorporation onto VLPs is controllable by varying incubation time and concentration of GPI-ISMs added. ISM incorporation was dependent upon the presence of a GPI-anchor and incorporated proteins were stable and functional for at least 4weeks when stored at 4°C. Vaccinating mice with GPI-granulocyte macrophage colony-stimulating factor (GM-CSF)-incorporated-VLPs induced stronger antibody responses and better protection against a heterologous influenza virus challenge than unmodified VLPs. Thus, VLPs can be enriched with ISMs by protein transfer to increase the potency and breadth of the immune response, which has implications in developing effective nanoparticle-based vaccines against a broad spectrum of enveloped viruses.The inherent problem with current influenza vaccines is that they do not generate effective cross-protection against heterologous viral strains. In this article, the authors described the development of virus-like nanoparticles (VLPs) as influenza vaccines with enhanced efficacy for cross-protection, due to an easy protein transfer modification process.
Project description:OBJECTIVE:Baseline retinal examinations have long been recommended for patients beginning treatment with hydroxychloroquine (HCQ), but it is unknown how well this guideline is followed. We investigated baseline eye examinations among US SLE patients enrolled in Medicaid in whom HCQ treatment was newly initiated. METHODS:Using billing codes, we identified SLE patients ages 18-65 years who were enrolled in Medicaid and residing in the 29 most populated US states, from 2000 to 2010. New users of HCQ were identified by filled prescriptions, with none filled in the preceding 12 months. Retinal examinations that were performed within 30 days before to 1 year after the index prescription were identified. We examined the proportions of patients receiving retinal examinations over the study years and compared the characteristics of those who did and those who did not receive examinations, using bivariable and multivariable logistic regression models. RESULTS:Among 12,755 SLE patients newly starting HCQ treatment, 32.5% received baseline dilated eye examinations. The proportions of patients receiving baseline eye examinations did not significantly change from 2000 to 2010 (31.0-34.4%; P for linear trend = 0.12). Factors associated with an increased likelihood of having an examination included female sex, Asian versus white race, and a higher number of laboratory tests performed during the preceding year. Compared with white patients, lower proportions of black and Native American patients with SLE had baseline retinal examinations. CONCLUSION:Only one-third of patients with SLE enrolled in Medicaid and in whom HCQ was newly initiated received the recommended baseline retinal examinations, and this proportion did not significantly increase from 2000 to 2010. The sociodemographic variation in this recommended care has been observed for other recommended medical care in SLE and requires both further investigation and interventions to address it.
Project description:The interferon (IFN) signature (IS) in patients with systemic lupus erythematosus (SLE) includes over 100 genes induced by type I IFN pathway activation. We developed a method to quantify the IS using three genes-the IS metric (ISM)-and characterised the clinical characteristics of patients with SLE with different ISM status from multiple clinical trials.Blood microarray expression data from a training cohort of patients with SLE confirmed the presence of the IS and identified surrogate genes. We assayed these genes in a quantitative PCR (qPCR) assay, yielding an ISM from the IS. The association of ISM status with clinical disease characteristics was assessed in patients with extrarenal lupus and lupus nephritis from four clinical trials.Three genes, HERC5, EPSTI and CMPK2, correlated well with the IS (p>0.96), and composed the ISM qPCR assay. Using the 95th centile for healthy control data, patients with SLE from different studies were classified into two ISM subsets-ISM-Low and ISM-High-that are longitudinally stable over 36?weeks. Significant associations were identified between ISM-High status and higher titres of anti-dsDNA antibodies, presence of anti extractable nuclear antigen autoantibodies, elevated serum B cell activating factor of the tumour necrosis factor family (BAFF) levels, and hypocomplementaemia. However, measures of overall clinical disease activity were similar for ISM-High and ISM-Low groups.The ISM is an IS biomarker that divides patients with SLE into two subpopulations-ISM-High and ISM-Low-with differing serological manifestations. The ISM does not distinguish between high and low disease activity, but may have utility in identifying patients more likely to respond to treatment(s) targeting IFN-?.NCT00962832.
Project description:Designed peptides derived from the islet amyloid polypeptide (IAPP) cross-amyloid interaction surface with A? (termed interaction surface mimics or ISMs) have been shown to be highly potent inhibitors of A? amyloid self-assembly. However, the molecular mechanism of their function is not well understood. Using solution-state and solid-state NMR spectroscopy in combination with ensemble-averaged dynamics simulations and other biophysical methods including TEM, fluorescence spectroscopy and microscopy, and DLS, we characterize ISM structural preferences and interactions. We find that the ISM peptide R3-GI is highly dynamic, can adopt a ?-like structure, and oligomerizes into colloid-like assemblies in a process that is reminiscent of liquid-liquid phase separation (LLPS). Our results suggest that such assemblies yield multivalent surfaces for interactions with A?40. Sequestration of substrates into these colloid-like structures provides a mechanistic basis for ISM function and the design of novel potent anti-amyloid molecules.
Project description:Immune Thrombocytopenia (ITP) is an autoimmune disease in which platelet destruction causes thrombocytopenia. Due to the known steroid toxicities, alternative agents have been evaluated for the treatment of these patients. We aimed to review the literature and find evidences regarding the potential benefits of hydroxychloroquine (HCQ) as a steroid-sparing agent in the treatment of ITP. We searched English language articles within Web of Science, PubMed, and Scopus. Cohorts, clinical trials, case reports, conference papers, and letters were included. We excluded papers which either focused on administration of HCQ for non-ITP conditions or studies on other treatment modalities for ITP. In total, 54 ITP cases with either primary or systemic lupus erythematosus (SLE)-associated ITP were included in four studies (SLE-associated ITP; n = 23). All patients have received corticosteroids previously and >90% received other agents with HCQ concomitantly. Overall response was achieved in more than 60% of patients. Sustained response in 18 (33.3%) patients was associated with no treatment or HCQ alone. One of the studies reported a significantly better response in patients with definite SLE compared to those with positive antinuclear antibody and no definite SLE. Similarly, another study found a nonsignificant trend toward better long-term response in patients with definite SLE compared to incomplete SLE. The included articles reported the efficacy of the HCQ with acceptable safety. Available data regarding the use of HCQ for this indication are spare and more studies are needed in ITP with different severity. It seems that HCQ can be considered as an option in the treatment of SLE-associated ITP, and although promising, currently, the place of HCQ in the treatment of ITP continues to evolve.
Project description:Lapatinib is an oral small molecule dual tyrosine kinase inhibitor that has been shown to improve time to progression versus capecitabine in women with HER2+ metastatic breast cancer (MBC) previously treated with trastuzumab. To describe extent, predictors, and consequences of nonadherence with lapatinib in women with MBC who were previously treated with trastuzumab. This was a retrospective observational study using data from a large health insurance claims databases spanning January 2000 to March 2010. Measures of lapatinib adherence included medication possession ratio (MPR), time to discontinuation (end of supply), time to first treatment interruption (gap during treatment of 30 days without supply), and duration of continuous therapy (time to gap of 30 days without supply or end of supply). Predictors of nonadherence to lapatinib and the association between nonadherence and outcomes, utilization, and costs were examined using multiple regression analysis. A total of 666 patients met all inclusion criteria. Mean initial lapatinib dosage was 1161 mg daily; 63% received index lapatinib in combination with capecitabine. Mean MPR was 87%; 22% of patients had MPR < 80%. Median time to lapatinib discontinuation was 9.1 months (95% confidence interval = 8.0-10.2). Twenty-seven percent of patients had one or more treatment interruptions during follow-up. Median duration of continuous therapy was 5.9 months (95% confidence interval = 5.1-6.1). Concomitant therapy with a taxane was a predictor of nonadherence (odds ratio for MPR < 80% = 10.30; < .001). There was a statistically significant association between nonadherence to lapatinib and greater number of outpatient visits ( = .028). In women with MBC who were previously treated with trastuzumab, mean adherence to lapatinib in typical clinical practice is relatively high overall, although there is a small group of patients with high nonadherence. Targeted efforts to improve adherence to lapatinib in this subgroup may be warranted.