Grape seed extract proanthocyanidin antagonizes aristolochic acid I-induced liver injury in rats by activating PI3K-AKT pathway.

Aristolochic acid is internationally recognized as a carcinogen. It has been shown that the main toxic mechanism of aristolochic acid on the liver and kidney is the induction of ROS-induced oxidative stress damage. To investigate whether proanthocyanidins (GSPE), a natural antioxidant product from grape seed extract, could antagonize AA-I-induced liver injury. Thirty-two SD rats were selected and divided into aristolochic acid exposure group (AA-I), normal control group, GSPE group and GSPE intervention group. The protective effects of GSPE on AA-I liver injury were evaluated by examining the body weight, liver index, liver function and liver pathological sections of rats. The results of body weight, liver index, liver function and liver pathological sections of rats showed that GSPE had antagonistic effects on AA-I-induced liver injury. antioxidant enzyme activity in the GSPE intervention group was significantly higher than that in the aristolochic acid group, apoptotic cells were significantly lower than that in the aristolochic acid group, protein and mRNA expression of PI3K-AKT and BCL-2 were significantly higher than that in the aristolochic acid group, BAX, The protein and mRNA expression of BAX, CASPAES-3, CASPAES-9 were significantly lower than those of the aristolochic acid group. GSPE can antagonize aristolochic acid-induced hepatotoxicity, and its mechanism of action is to antagonize aristolochic acid I-induced liver injury by inhibiting PI3K-AKT pathway-mediated hepatocyte apoptosis.

Predictors of Treatment Change Among Patients with Rheumatoid Arthritis Treated with TNF Inhibitors as First-Line Biologic Agent in the USA: A Cohort Study from Longitudinal Electronic Health Records.

BACKGROUND: Previous observational studies utilizing administrative claims data have largely been unable to consider clinical factors that may be related to patterns of drug use among patients with rheumatoid arthritis (RA). OBJECTIVE: To understand predictors of treatment changes following initiation of a tumor necrosis factor inhibitor (TNFi) using nation-wide electronic health record (EHR) data in the USA. METHODS: The Optum Immunology Condition EHR data (01/01/2011-09/30/2019) was used to identify a population of adult patients with RA initiating a TNFi as the first line biologic disease-modifying anti-rheumatic drug (DMARD). The primary outcome was any treatment change during the 1-year post-index period defined as cycling to a different TNFi or switching to non-TNFi biologic or targeted synthetic DMARDs. Secondary outcomes were the individual components of TNFi cycling and switching, examined separately. To identify predictors of DMARD treatment changes, we used a least absolute shrinkage and selection operator (LASSO) regression model. Model c-statistics and odds ratios (ORs, 95% confidence intervals (CIs)) of predictors were reported. RESULTS: We identified 24,871 patients with RA who initiated a TNFi. The mean age was 55.5 (± 13.7) years and 77.2% were female. Among the TNFi initiators, 22.2% experienced TNFi cycling or switching during the 1-year follow-up time. Predictors that are associated with higher likelihood of TNFi cycling or switching included female gender (OR: 1.26, 95% CI: 1.16-1.36) and glucocorticoid use (OR: 1.30, 95% CI: 1.21-1.40). In contrast, inflammatory bowel disease (OR: 0.62, 95% CI: 0.48-0.78), psoriasis (OR: 0.82, 95% CI: 0.70-0.95), recent use of methotrexate (OR: 0.89, 95% CI: 0.81-0.97), and vitamin D intake (OR: 0.92, 95% CI: 0.85-0.99) were negatively associated with TNFi cycling or switch. CONCLUSIONS: Gender, glucocorticoid use, inflammatory bowel disease, psoriasis, and vitamin D intake were identified as significant predictors of TNFi cycling or switching for TNFi initiators in the RA population. Predicting treatment change remains challenging even with large detailed EHR data. This study aimed to identify key determinants of treatment changes among patients with rheumatoid arthritis (RA) initiating a tumor necrosis factor inhibitor (TNFi) as their first-line biologic disease-modifying antirheumatic drug (DMARD) in routine care settings using a US nation-wide longitudinal electronic health record (EHR). Among 24,871 patients with RA who initiated a TNFi, 22.2% experienced TNFi cycling or switching during the 1-year follow-up time. Female patients and those who used glucocorticoids were more likely to experience TNFi cycling or switching, whereas inflammatory bowel disease, psoriasis, recent methotrexate use, and vitamin D intake were negatively associated with the outcome. However, predicting treatment change remains challenging even with larger detailed EHR data potentially due to unmeasured factors such as prescriber's preference or patient's belief in the medication.

Occurrence of inflammatory bowel disease in patients with chronic inflammatory skin diseases: a cohort study: Classification: Epidemiology.

BACKGROUND: Several studies have linked various chronic inflammatory skin diseases (CISDs) with inflammatory bowel disease (IBD) in a range of data sources with mixed conclusions. OBJECTIVES: We compared the incidence of IBD - ulcerative colitis (UC) and Crohn disease (CD) - in patients with a CISD vs. similar persons without a CISD. METHODS: In this cohort study using nationwide, longitudinal, commercial insurance claims data from the USA, we identified adults and children who were seen by a dermatologist between 2004 and 2020, and diagnosed with either psoriasis, atopic dermatitis, alopecia areata, vitiligo or hidradenitis suppurativa. Comparator patients were identified through risk-set sampling; they were eligible if they were seen by a dermatologist at least twice and not diagnosed with a CISD. Patient follow-up lasted until either IBD diagnosis, death, disenrolment or end of data stream, whichever came first. IBD events, UC or CD, were identified via validated algorithms: hospitalization or diagnosis with endoscopic confirmation. Incidence rates were computed before and after adjustment via propensity-score decile stratification to account for IBD risk factors. Hazard ratios (HR) and 95% confidence intervals (CIs) were estimated to compare the incidence of IBD in CISD vs. non-CISD. RESULTS: We identified patients with atopic dermatitis (n = 123 614), psoriasis (n = 83 049), alopecia areata (n = 18 135), vitiligo (n = 9003) or hidradenitis suppurativa (n = 6806), and comparator patients without a CISD (n = 2 376 120). During a median follow-up time of 718 days, and after applying propensity-score adjustment for IBD risk factors, we observed increased risk of both UC (HRUC 2·30, 95% CI 1·61-3·28) and CD (HRCD 2·70, 1·69-4·32) in patients with hidradenitis suppurativa, an increased risk of CD (HRCD 1·23, 1·03-1·46) but not UC (HRUC 1·01, 0·89-1·14) in psoriasis, and no increased risk of IBD in atopic dermatitis (HRUC 1·02, 0·92-1·12; HRCD 1·08, 0·94-1·23), alopecia areata (HRUC 1·18, 0·89-1·56; HRCD 1·26, 0·86-1·86) or vitiligo (HRUC 1·14, 0·77-1·68; HRCD 1·45, 0·87-2·41). CONCLUSIONS: IBD was increased in patients with hidradenitis suppurativa. CD alone was increased in patients with psoriasis. Neither UC nor CD was increased in patients with atopic dermatitis, alopecia areata or vitiligo. What is already known about this topic? Several studies have linked various chronic inflammatory skin diseases (CISDs) with inflammatory bowel disease (IBD) utilizing a range of data sources, with mixed conclusions. What does this study add? This large-scale, claims-based cohort study expands current knowledge by providing background rates for IBD across multiple CISDs using consistent methods and within a single, nationally representative patient population. We observed a relative increased risk of IBD in patients with hidradenitis suppurativa, but the overall incidence rate difference of IBD was generally low. Crohn disease alone was significantly increased in patients with psoriasis, and neither ulcerative colitis nor Crohn disease was increased in patients with atopic dermatitis, vitiligo or alopecia areata.

Rotenone induces hepatotoxicity in rats by activating the mitochondrial pathway of apoptosis.

As a pesticide extracted from plants, rotenone is widely used to control plant pests. In order to explore the safety of rotenone in the environment, we took 60 healthy male SD rats and randomly divided them into rotenone low-dose group, rotenone medium-dose group, rotenone high-dose group, dimethyl sulfoxide group (DMSO), and control group. After 28 days of oral administration, the rat liver tissue ultrastructure, liver function, oxidative stress indexs, mitochondrial function, and apoptosis-related factors were tested to evaluate the hepatotoxicity and toxicological mechanism of rotenone. The results showed that rotenone significantly increased the hepatic index of rats and the activity of aspartate aminotransferase (AST) and alanine aminotransferase (ALT) in serum. Rotenone can reduce the number of endoplasmic reticulum of hepatocyte, concentrate chromatin and make the hepatocyte nuclears irregular. Rotenone weakened the ATP synthesis ability in mitochondria, decreased the activity of ATP enzyme in mitochondria, and increased the mitochondrial membrane potential in the high-dose group. And it induced oxidative stress damage to the mitochondria of rat liver cells. Rotenone can upregulate the expression of pro-apoptotic factors and downregulate the expression of anti-apoptotic factors. These results indicate that oral rotenone in rats induced hepatotoxicity in a dose-dependent manner. The mechanism of rotenone poisoning is that oxidative stress damages organelles of hepatocyte such as mitochondria and endoplasmic reticulum, resulting in their function being weakened or lost, leading to hepatocyte apoptosis.

Risk of Hospitalization for Serious Infection After Initiation of Ustekinumab or Other Biologics in Patients With Psoriasis or Psoriatic Arthritis.

OBJECTIVE: To compare the risk of serious infections requiring hospitalization in patients with psoriasis (PsO) or psoriatic arthritis (PsA) initiating ustekinumab versus other biologics or apremilast. METHODS: In this multi-database cohort study, we identified patients with PsO/PsA who initiated therapy with adalimumab, apremilast, certolizumab, etanercept, golimumab, ixekizumab, secukinumab, or ustekinumab between 2009 and 2018. The primary outcome measure was hospitalizations due to serious infections, which included bacterial, viral, or opportunistic infections. We estimated hazard ratios (HRs) comparing each study drug to ustekinumab after applying propensity score fine stratification weights for confounding control in each database. Database-specific weighted HRs were combined by meta-analysis. RESULTS: We identified 123,383 patients with PsO/PsA who initiated one of the study drugs. During a total of 117,744 person-years of follow-up, 1,514 serious infections occurred with a crude incidence of 1.29 per 100 person-years. After propensity score fine stratification and weighting, the incidence rates of serious infection among ustekinumab initiators ranged from 0.59 to 0.95 per 100 person-years. Compared with ustekinumab, the combined weighted HRs (95% confidence interval [95% CI]) for serious infections were 1.66 (95% CI 1.34-2.06) for adalimumab, 1.42 (95% CI 1.02-1.96) for apremilast, 1.09 (95% CI 0.68-1.75) for certolizumab, 1.39 (95% CI 1.01-1.90) for etanercept, 1.74 (95% CI 1.00-3.03) for golimumab, 2.92 (95% CI 1.80-4.72) for infliximab, 2.98 (95% CI 1.20-7.41) for ixekizumab, and 1.84 (95% CI 1.24-2.72) for secukinumab. CONCLUSION: Other biologics and apremilast were associated with a 1.4- to 3-times higher risk of hospitalization for serious infections in PsO/PsA patients when compared to ustekinumab; this finding should be considered in the safety profile of these therapies when selecting appropriate treatment regimens in patients with PsO/PsA.

Patient characteristics associated with use of TNF vs interleukin inhibitors as first-line biologic treatment for psoriatic arthritis.

BACKGROUND: Previous studies have examined treatment patterns among patients who use tumor necrosis factor (TNF) inhibitors for psoriatic arthritis (PsA). However, little data exist for a comparison between the TNF inhibitor treatment pattern and that of newly available biologics such as interleukin (IL)-12/23 or 17 inhibitors in the United States. OBJECTIVES: To (a) examine patient characteristics and their association with initiation of TNF inhibitors vs IL-12/23 or 17 inhibitors among PsA patients and (2) compare treatment persistence of PsA patients who initiated TNF inhibitors vs IL-12/23 or 17 inhibitors as first-line biologic treatment in a real-world setting in the United States. METHODS: Using claims data from MarketScan (2013-2017), we identified a cohort of PsA patients who initiated TNF inhibitors or IL-12/23 or 17 inhibitors. The primary outcome was treatment persistence, defined as continuous use of the index drug at 1 year, regardless of refill gaps. The secondary outcome was treatment persistence with high adherence at 1 year (ie, refill gaps ≤ 30 days). Multivariable logistic regression was used to assess the association between patient characteristics and treatment initiation and persistent use of TNF inhibitors vs IL-12/23 or 17 inhibitors. RESULTS: We identified 3,180 TNF inhibitor initiators and 214 IL-12/23 or 17 inhibitor initiators. Initiators of IL-12/23 or 17 inhibitors had more comorbidities than TNF inhibitor initiators. The proportion of patients with treatment persistence was 53.0% in TNF inhibitor initiators and 53.7% in IL-12/23 or 17 inhibitor initiators; 37.1% of TNF inhibitor users and 24.8% of IL-12/23 or 17 inhibitor users were treatment persistent with high adherence. There was no difference in 1-year treatment persistence between the 2 groups after adjusting for baseline characteristics (adjusted odds ratio [aOR] for TNF inhibitors vs IL-12/23 or 17 inhibitors: 0.86, 95% CI = 0.63-1.15). However, use of TNF inhibitors was associated with a greater treatment persistence with high adherence compared with use of IL-12/23 or 17 inhibitors (aOR = 1.61, 95% CI = 1.15-2.26). CONCLUSIONS: PsA patients who initiated an IL 12/23 or 17 inhibitor had a greater comorbidity burden compared with those who initiated TNF inhibitors. Treatment persistence was similar between the 2 groups, whereas medication adherence was higher with TNF inhibitors than with IL 12/23 or 17 inhibitors during the first year of treatment. DISCLOSURES: This study was funded by an investigator-initiated research grant from Pfizer, Inc (grant number: WI235988). The content is solely the responsibility of the authors. The sponsor was given the opportunity to make nonbinding comments on a draft of the manuscript. Publication of the manuscript was not contingent on approval by the sponsor. Kim has received research grants to the Brigham and Women's Hospital from Roche, AbbVie, and Bristol-Myers Squibb for unrelated topics. Merola is a consultant and/or investigator for BMS, AbbVie, Dermavant, Lilly, Novartis, Janssen, UCB, Sun Pharma, and Pfizer. Jin, Chen, Lee, and Landon have nothing to disclose.

Prevalence, incidence and cause-specific mortality of rheumatoid arthritis-associated interstitial lung disease among older rheumatoid arthritis patients.

OBJECTIVE: We aimed to investigate the prevalence, incidence and cause-specific mortality of RA-associated interstitial lung disease (RA-ILD) among older US patients with RA. METHODS: We performed a nationwide cohort study using Medicare claims data (parts A, B and D for 2008-2017). RA was identified with a validated algorithm using RA diagnosis codes and DMARD prescription. RA-ILD was identified with a validated algorithm using ILD diagnosis codes by a rheumatologist/pulmonologist. RA-ILD was categorized as prevalent or incident relative to the initial RA observation (baseline/index date). We compared the total mortality of RA-ILD to RA without ILD using multivariable Cox regression, adjusting for baseline covariates. For cause-specific mortality, Fine and Gray subdistribution hazard ratios (sdHRs) were estimated to handle competing risks of alternative mortality causes. RESULTS: Among 509 787 RA patients (mean age 72.6 years, 76.2% female), 10 306 (2.0%) had prevalent RA-ILD at baseline. After baseline, 13 372 (2.6%) developed RA-ILD during 1 873 127 person-years of follow-up (median 3.0 years/person). During follow-up, 38.7% of RA-ILD patients died compared with 20.7% of RA patients without ILD. After multivariable adjustment, RA-ILD had an HR of 1.66 (95% CI 1.60, 1.72) for total mortality. Accounting for competing risk of other causes of death, RA-ILD had an sdHR of 4.39 (95% CI 4.13, 4.67) for respiratory mortality and an sdHR of 1.56 (95% CI 1.43, 1.71) for cancer mortality compared with RA without ILD. CONCLUSIONS: RA-ILD was present or developed in nearly 5% of patients in this nationwide study of older patients with RA. Compared with RA without ILD, RA-ILD was associated with excess total, respiratory and cancer mortality that was not explained by measured factors.

Risk of Incident Type 2 Diabetes Mellitus Among Patients With Rheumatoid Arthritis: A Population-Based Cohort Study.

OBJECTIVE: To examine the risk of incident type 2 diabetes mellitus (DM) among patients with rheumatoid arthritis (RA) versus the risk among 4 different comparison cohorts. METHODS: Using a large US commercial insurance database, Optum Clinformatics Data Mart (2005-2017), we identified patients with RA based on ≥2 diagnoses for RA and use of ≥1 disease-modifying antirheumatic drug. We selected 4 comparison cohorts with ≥2 disease-specific diagnoses and ≥1 dispensing of disease-specific drugs: 1) general non-RA patients, 2) patients with hypertension, 3) patients with osteoarthritis (OA), and 4) patients with psoriatic arthritis (PsA). The index date was the disease-specific drug dispensing date. Patients with RA were matched to the comparator cohorts (except PsA) for age as of the index date, sex, and index date. The primary outcome was incident type 2 DM, defined as a new diagnosis of type 2 DM plus a new dispensing of antidiabetic drugs. A multivariable Cox proportional hazards model estimated hazard ratios of incident type 2 DM among RA versus each of the comparison cohorts, accounting for >40 baseline covariates. RESULTS: A total of 449,327 RA, general non-RA, hypertension, OA, or PsA patients were selected. During the median of 1.6 (range 0.6-3.3) years of follow-up, the incidence rate of type 2 DM was the lowest in the RA cohort (7.0 per 1,000 person-years) and highest (12.3 per 1,000 person-years) in the hypertension cohort. After adjusting for >40 baseline covariates, we found that RA was associated with a 24-35% lower risk of incident type 2 DM compared to 4 comparison groups. CONCLUSION: In this large population-based cohort study, patients with RA had a lower rate of incident type 2 DM compared to the general non-RA, hypertension, OA, and PsA cohorts.

Validation of claims-based algorithms to identify interstitial lung disease in patients with rheumatoid arthritis.

OBJECTIVE: To develop and validate claims-based algorithms to identify interstitial lung disease (ILD) in patients with rheumatoid arthritis (RA) METHODS: Using Medicare claims data linked with the electronic medical records (2012-2014), we first selected RA patients based on ≥2 diagnostic codes for RA and ≥1 disease-modifying antirheumatic drugs.Then, to identify ILD in RA, we developed eight claims-based algorithms using a combination of ICD-9 diagnosis codes and procedure codes related to the diagnosis or management of ILD. We assessed the positive predictive value (PPV) for each of the eight algorithms relative to confirmed ILD cases using chest computerized tomography or lung biopsy as the gold standard. RESULTS: A total of 5,214 RA patients were included in the study, and the ILD cases identified by each algorithm ranged from 181 to 993. The PPV of the diagnosis code-based algorithms ranged from 43.4% (≥1 diagnosis code by any physician) to 52.0% (≥2 diagnosis codes by any physician). When the algorithms further required ≥1 procedure code (e.g., imaging, bronchoscopy), the PPV did not improve. However, the algorithms that required ILD diagnosis codes by specialists (i.e., pulmonologist or rheumatologist) had PPVs of 61.5% with ≥1 code; 72.4% with ≥2 codes. CONCLUSIONS: In a cohort of RA patients, our algorithm that required ≥2 ILD diagnosis codes by specialists demonstrated a PPV of 72.4% in ascertaining ILD. Our results support the utility of the claims-based algorithm to identify a population-based cohort of RA patients with ILD using large administrative claims data.

Risk of Cataract Surgery and Age-Related Macular Degeneration After Initiation of Denosumab vs Zoledronic Acid for Osteoporosis: A Multi-Database Cohort Study.

BACKGROUND AND OBJECTIVE: There is a relative lack of head-to-head comparisons of denosumab against other osteoporosis drugs on safety. We aimed to explore ocular outcomes in patients with osteoporosis initiating denosumab vs zoledronic acid. METHODS: We conducted a cohort study using claims data (2010-15) from two large US commercial insurance databases including patients with osteoporosis who were aged 50 years or older and initiators of denosumab or zoledronic acid. The primary outcomes were (1) receipt of cataract surgery and development of (2) wet age-related macular degeneration and (3) dry age-related macular degeneration within 365 days after initiation of denosumab vs zoledronic acid. Propensity score fine stratification and weighting were used to control for potential confounding, and we calculated the incidence rate and hazard ratio for each outcome in the cohorts. The estimates from the two databases were combined with a fixed-effects model meta-analysis. RESULTS: The study cohort included 50,821 denosumab and 67,471 zoledronic acid initiators. In the propensity score-weighted analysis, compared to zoledronic acid use, denosumab was associated with a modestly decreased risk of undergoing cataract surgery (hazard ratio 0.91; 95% confidence interval 0.85-0.98) but not with the risk of wet age-related macular degeneration (hazard ratio 1.29; 95% confidence interval 0.99-1.70) or dry age-related macular degeneration (hazard ratio 1.03; 95% confidence interval 0.98-1.09). CONCLUSIONS: In this large population-based cohort study of 118,292 patients with osteoporosis, initiation of denosumab was associated with a modestly decreased risk of cataract surgery vs zoledronic acid. The risk of age-related macular degeneration was similar between the two drugs.

Clinical isolates of Tritrichomonas foetus in bulls in Wyoming, South Dakota and Montana, USA.

BACKGROUND: Several Tritrichomonas species have been found in mammalian hosts. Among these trichomonads T. foetus is often found in the urogenital tract of cattle and the gastrointestinal tract of the domestic cat, resulting in sexually transmitted bovine trichomonosis and fecal-orally transmitted feline trichomonosis, respectively. The aims of the current study were to molecularly characterize clinical isolates of T. foetus in cattle populations in Wyoming, South Dakota, and Montana of the United States of America and to phylogenetically analyze Tritrichomonas species of mammalian hosts. RESULTS: DNA sequencing of rRNA genes showed over 99% identity of the newly described isolates to other bovine isolates. Further, T. foetus isolates of various mammalian hosts originated in different geographic regions worldwide were clustered into two well-defined clades by phylogenetic analysis of rRNA and cysteine protease 2 genes. Clade I consisted of isolates originated from cattle, pig, and human whereas clade II contained isolates of cat and dog. CONCLUSION: It is concluded that all mammalian Tritrichomonas spp. apparently belong to T. foetus. Analysis of more sequences is warranted to support this conclusion.

Risk of Serious Infection Among Initiators of Tumor Necrosis Factor Inhibitors Plus Methotrexate Versus Triple Therapy for Rheumatoid Arthritis: A Cohort Study.

OBJECTIVE: To compare the risk of serious infections between the use of tumor necrosis factor inhibitors (TNFi) plus methotrexate (MTX) versus triple therapy among rheumatoid arthritis (RA) patients in a real-world setting. METHODS: Using claims data from Truven MarketScan (2003-2014), we conducted a cohort study to compare RA patients receiving MTX who added a TNFi (TNFi plus MTX group) versus MTX plus hydroxychloroquine and sulfasalazine (triple therapy group). The primary outcome was any serious infection (i.e., a composite end point of hospitalized bacterial and opportunistic infections or herpes zoster). Secondary outcomes were individual components of the composite end point. To adjust for baseline confounding, we used propensity score (PS)-based fine stratification and weighting. A weighted Cox proportional hazards model estimated the hazard ratio (HR) and 95% confidence interval (95% CI) of the outcomes. RESULTS: After PS stratification (PSS) and weighting, we included a total of 45,208 TNFi plus MTX initiators and 1,387 triple therapy initiators. Mean age was 53 years and 70% were female. The incidence rate of any serious infection per 100 person-years was 2.46 in the TNFi plus MTX group and 2.03 in the triple therapy group. The PSS-weighted HR for any serious infection comparing TNFi plus MTX versus triple therapy was 1.23 (95% CI 0.87-1.74). For the secondary outcomes, the PSS-weighted HR was 1.41 (95% CI 0.85-2.34) for bacterial infection and 0.80 (95% CI 0.55-1.18) for herpes zoster. CONCLUSION: In this real-world cohort of RA patients, we noted no substantially different risk of any serious infection, bacterial infection, or herpes zoster after initiating TNFi plus MTX versus triple therapy, although CIs were wide.

Risk of exacerbation of pulmonary comorbidities in patients with rheumatoid arthritis after initiation of abatacept versus TNF inhibitors: A cohort study.

BACKGROUND: Biologic agents may pose a potential risk for exacerbations of pulmonary comorbidities in rheumatoid arthritis (RA) patients. METHODS: Using U.S. Medicare and Truven MarketScan databases, we identified three cohorts of RA patients with interstitial lung disease (ILD), chronic obstructive pulmonary disease (COPD), or asthma who initiated abatacept or a TNF inhibitor (TNFi). The primary outcome was a composite exacerbation of individual pulmonary comorbidities based on inpatient or emergency department (ED) visits due to exacerbation of the given pulmonary comorbidity. To adjust for >60 baseline confounders, we used propensity-score fine stratification (PSS) and weighting. Negative binomial regression model estimated a cohort-specific incidence rate ratio (IRR) and 95% confidence interval (CI) of the primary outcome per database, comparing abatacept versus TNFi. Database-specific IRRs were combined using a random-effects meta-analysis. RESULTS: We identified 3,295 ILD, 7,161 COPD, and 5,613 asthma patients with RA who initiated either abatacept or a TNFi. IR of composite exacerbation was high in all three pulmonary cohorts but highest in COPD cohort (3.59-11.80 per 100 person-years in ILD, 20.68-34.97 in COPD, and 4.66-13.78 in asthma). After PSS weighting, the combined IRR (95%CI) in abatacept initiators versus TNFi initiators was 0.44 (0.18-1.09) for ILD exacerbation, 0.91 (0.80-1.03) for COPD exacerbation, and 0.81 (0.54-1.22) for asthma exacerbation. CONCLUSION: Among patients with RA and pulmonary comorbidities, exacerbations requiring inpatient or ED visits occurred frequently after initiating abatacept or TNFi. Overall, we found no significant difference in the risk of ILD, COPD or asthma exacerbation between abatacept and TNFi initiators, but precision of our estimates is limited.

Validation of claims-based algorithms for psoriatic arthritis.

PURPOSE: An increasing number of new medications are being developed and approved for psoriatic arthritis (PsA). To generate real-world evidence on comparative safety and effectiveness of these drugs, a claims-based algorithm that can accurately identify PsA is greatly needed. METHODS: To identify patients with PsA, we developed seven claims-based algorithms based on a combination of diagnosis codes and medication dispensing using the claims data from Medicare parts A/B/D linked to electronic medical records (2012-2014). Two physicians independently conducted a chart review using the treating physician's diagnosis of PsA as the gold standard. We calculated the positive predictive value (PPV) and 95% confidence intervals of each algorithm. RESULTS: Of the total 2157 records identified by the seven algorithms, 45% of the records had relevant clinical data to determine the presence of PsA. The PPV of the algorithms ranged from 75.2% (algorithm 1: ≥2 diagnosis codes for PsA and ≥1 diagnosis code for psoriasis) to 88.6% (algorithm 7: ≥2 diagnosis codes for PsA with ≥1 code by rheumatologist and ≥1 dispensing for PsA medication). Having ≥2 diagnosis codes and ≥1 dispensing for PsA medications (algorithm 6) also had PPV of 82.4%. CONCLUSIONS: All seven claims-based algorithms demonstrated a moderately high PPV of 75% to 89% in identifying PsA. The use of ≥2 diagnosis codes plus ≥1 prescription claim for PsA appears to be a valid and efficient tool in identifying PsA patients in the claims data, while broader algorithms based on diagnoses without a prescription claim also have reasonably good PPVs.

Association of Ustekinumab vs TNF Inhibitor Therapy With Risk of Atrial Fibrillation and Cardiovascular Events in Patients With Psoriasis or Psoriatic Arthritis.

Importance: Accumulating evidence indicates that there is an increased risk of cardiovascular disease among patients with psoriatic disease. Although an emerging concern that the risk of atrial fibrillation (AF) may also be higher in this patient population adds to the growing support of initiating early interventions to control systemic inflammation, evidence on the comparative cardiovascular safety of current biologic treatments remains limited. Objective: To evaluate the risk of AF and major adverse cardiovascular events (MACE) associated with use of ustekinumab vs tumor necrosis factor inhibitors (TNFi) in patients with psoriasis or psoriatic arthritis. Design, Setting, and Participants: This cohort study included data from a nationwide sample of 78 162 commercially insured patients in 2 US commercial insurance databases (Optum and MarketScan) from September 25, 2009, through September 30, 2015. Patients were included if they were 18 years or older, had psoriasis or psoriatic arthritis, and initiated ustekinumab or a TNFi therapy. Exclusion criteria included history of AF or receipt of antiarrhythmic or anticoagulant therapy during the baseline period. Exposures: Initiation of ustekinumab vs TNFi therapy. Main Outcomes and Measures: Incident AF and MACE, including myocardial infarction, stroke, or coronary revascularization. Results: A total of 60 028 patients with psoriasis or psoriatic arthritis (9071 ustekinumab initiators and 50 957 TNFi initiators) were included in the analyses. The mean (SD) age was 46 (13) years in Optum and 47 (13) in MarketScan, and 29 495 (49.1%) were male. Overall crude incidence rates (reported per 1000 person-years) for AF were 5.0 (95% CI, 3.8-6.5) for ustekinumab initiators and 4.7 (95% CI, 4.2-5.2) for TNFi initiators, and for MACE were 6.2 (95% CI, 4.9-7.8) for ustekinumab initiators and 6.1 (95% CI, 5.5-6.7) for TNFi initiators. The combined adjusted hazard ratio for incident AF among ustekinumab initiators was 1.08 (95% CI, 0.76-1.54) and for MACE among ustekinumab initiators was 1.10 (95% CI, 0.80-1.52) compared with TNFi initiators. Conclusions and Relevance: No substantially different risk of incident AF or MACE after initiation of ustekinumab vs TNFi was observed in this study. This information may be helpful when weighing the risks and benefits of various systemic treatment strategies for psoriatic disease.

Association of Geography and Access to Health Care Providers With Long-Term Prescription Opioid Use in Medicare Patients With Severe Osteoarthritis: A Cohort Study.

OBJECTIVE: To evaluate the variation in long-term opioid use in osteoarthritis (OA) patients according to geography and health care access. METHODS: We designed an observational cohort study among OA patients undergoing total joint replacement (TJR) in the Medicare program (2010 through 2014). The independent variables of interest were the state of residence and health care access, which was quantified at the primary care service area (PCSA) level as categories of number of practicing primary care providers (PCPs) and categories of rheumatologists per 1,000 Medicare beneficiaries. The percentage of OA patients taking long-term opioids (≥90 days in the 360-day period immediately preceding TJR) within each PCSA was the outcome variable in a multilevel, generalized linear regression model, adjusting for case-mix at the PCSA level and for policies, including rigor of prescription drug monitoring programs and legalized medical marijuana, at the state level. RESULTS: A total of 358,121 patients with advanced OA, with a mean age of 74 years, were included from 4,080 PCSAs. The unadjusted mean percentage of long-term opioid users varied widely across states, ranging from 8.9% (Minnesota) to 26.4% (Alabama), and this variation persisted in the adjusted models. Access to PCPs was only modestly associated with rates of long-term opioid use between PCSAs with highest (>8.6) versus lowest (<3.6) concentration of PCPs (adjusted mean difference 1.4% [95% confidence interval 0.8%, 2.0%]), while access to rheumatologists was not associated with long-term opioid use. CONCLUSION: We note a substantial statewide variation in rates of long-term treatment with opioids in OA, which is not fully explained by the differences in access to health care providers, varying case-mix, or state-level policies.

Cardiovascular (CV) Risk after Initiation of Abatacept versus TNF Inhibitors in Rheumatoid Arthritis Patients with and without Baseline CV Disease.

OBJECTIVE: To evaluate the cardiovascular safety of abatacept (ABA) versus tumor necrosis factor inhibitors (TNFi) in rheumatoid arthritis (RA) patients with and without underlying cardiovascular disease (CVD). METHODS: We identified RA patients with and without baseline CVD who initiated ABA or TNFi by using data from 2 large US insurance claims databases: Medicare (2008-2013) and Truven MarketScan (2006-2015). After stratifying by baseline CVD, ABA initiators were 1:1 propensity score (PS) matched to TNFi initiators to control for > 60 baseline covariates. Cox proportional hazards regression estimated the HR and 95% CI for a composite endpoint of CVD including myocardial infarction, stroke/transient ischemic stroke, or coronary revascularization in the PS-matched cohorts. HR from 2 databases were combined through an inverse variance-weighted fixed-effects model. RESULTS: We included 6102 PS-matched pairs of ABA and TNFi initiators from Medicare and 6934 pairs from MarketScan. Of these, 35.3% in Medicare and 14.0% in MarketScan had baseline CVD. HR (95% CI) for composite CVD in the overall ABA group versus TNFi was 0.67 (0.55-0.81) in Medicare and 1.08 (0.83-1.41) in MarketScan with the combined HR of 0.79 (0.67-0.92). Among patients with baseline CVD, the HR (95% CI) was 0.71 (0.55-0.92) in Medicare and 1.02 (0.68-1.51) in MarketScan, with the combined HR of 0.79 (0.64-0.98). CONCLUSION: In this large cohort of publicly or privately insured patients with RA in the United States, ABA was associated with a 20% reduced risk of CVD versus TNFi. While this observational study is subject to potential residual confounding, our results were consistent in patients with baseline CVD.

Highly Specific near-Infrared Fluorescent Probe for the Real-Time Detection of ß-Glucuronidase in Various Living Cells and Animals.

ß-Glucuronidase (GLU) is an important biomarker for primary cancers and intestinal metabolism of drugs or endogenous substances; however, an effective optical probe for near-infrared (NIR) monitoring in vivo is still lacking. Herein, we design an enzyme-activated off-on NIR fluorescent probe, HC-glu, based on a hemicyanine keleton, which is conjugated with a d-glucuronic acid residue via a glycosidic bond, for the fluorescent quantification and trapping of endogenous GLU activity in vitro and in vivo. The newly developed NIR probe exhibited prominent features including prominent selectivity, high sensitivity, and ultrahigh imaging resolution. It has been successfully used to detect and image endogenous GLU in various hepatoma carcinoma cells, tumor tissues, and tumor-bearing mouse models, for cancer diagnosis and therapy. Moreover, it could detect the in vivo activity of GLU in the intestinal tracts of animals including mice and zebrafish, where GLU performs a vital biological function and is mainly distributed. It could also evaluate real intestinal distribution and real-time variations of GLU in development and growth, all of which are very helpful to guide rational drug use in the clinic. Our results fully demonstrated that HC-glu may serve as a promising tool for evaluating the biological function and process of GLU in living systems.

Comparative Cardiovascular Risk of Abatacept and Tumor Necrosis Factor Inhibitors in Patients With Rheumatoid Arthritis With and Without Diabetes Mellitus: A Multidatabase Cohort Study.

BACKGROUND: We examined the cardiovascular risk of abatacept compared with tumor necrosis factor (TNF) inhibitors in patients with rheumatoid arthritis with and without diabetes mellitus (DM). METHODS AND RESULTS: We conducted a cohort study of patients with rheumatoid arthritis who newly started abatacept or TNF inhibitors using claims data from Medicare and MarketScan. The primary outcome was a composite cardiovascular end point of myocardial infarction (MI), stroke/transient ischemic attack, and coronary revascularization. To account for >60 baseline characteristics, abatacept initiators were 1:1 propensity score (PS) matched to TNF initiators in each database. Cox proportional hazards models estimated hazard ratio (HR) and 95% confidence interval (CI) in the PS-matched cohort per database. A fixed-effects meta-analysis pooled database-specific HRs. We included a total of 13 039 PS-matched pairs of abatacept and TNF inhibitor initiators (6103 pairs in Medicare and 6936 pairs in MarketScan). A total of 34.7% in Medicare and 19.8% in MarketScan had baseline DM. The HR (95% CI) for the primary outcome associated with abatacept use versus TNF inhibitor was 0.81 (0.66-0.99) in Medicare and 0.95 (0.74-1.23) in MarketScan, with a pooled HR of 0.86 (95% CI, 0.73-1.01; P=0.3 for heterogeneity). The risk of the primary outcome was lower in abatacept initiators versus TNF inhibitors in the DM subgroup, with a pooled HR of 0.74 (95% CI, 0.57-0.96; P=0.7 for heterogeneity), but not in the non-DM subgroup, with a pooled HR of 0.94 (95% CI, 0.77-1.14; P=0.4 for heterogeneity). CONCLUSIONS: In this large population-based cohort of patients with rheumatoid arthritis, abatacept use appeared to be associated with a modestly reduced cardiovascular risk when compared with TNF inhibitor use, particularly in patients with DM.