Missed opportunities for treatment of inflammatory arthritis and factors associated with non-treatment: An observational cohort study in United States Veterans with rheumatoid arthritis, psoriatic arthritis, or ankylosing spondylitis.

OBJECTIVE: To identify factors associated with non-treatment with biologic and non-biologic disease modifying anti-rheumatic drugs (DMARDs) during the 12 months after initial inflammatory arthritis (IA) diagnosis. METHODS: We identified Veterans with incident IA diagnosed in 2007-2019. We assessed time to treatment with Kaplan-Meier curves. We identified associations between non-treatment and factors relating to patients, providers, and the health system with multivariate Generalized Estimation Equation (GEE) log-Poisson. Subgroup analyses included IA subtypes (rheumatoid arthritis [RA], psoriatic arthritis [PsA], and ankylosing spondylitis [AS]) and timeframes of the initial IA diagnosis (2007-11, 2012-15, and 2016-19). RESULTS: Of 18,318 study patients, 40.7 % did not receive treatment within 12 months after diagnosis. In all patients, factors associated with non-treatment included Black race (hazard ratio, 95 % confidence interval: 1.13, 1.08-1.19), Hispanic ethnicity (1.14, 1.07-1.22), Charlson Comorbidity Index ≥2, (1.15, 1.11-1.20), and opiate use (1.09, 1.05-1.13). Factors associated with higher frequency of DMARD treatment included married status (0.86, 0.81-0.91); erosion in joint imaging report (HR: 0.86, 0.81-0.91); female diagnosing provider (0.90, CI: 0.85-0.96), gender concordance between patient and provider (0.91, CI: 0.86-0.97), and diagnosing provider specialty of rheumatology (0.53, CI: 0.49-0.56). CONCLUSION: A high proportion of Veterans with IA were not treated with a biologic or non-biologic DMARD within one year after their initial diagnosis. A wide range of factors were associated with non-treatment of IA that may represent missed opportunities for improving the quality of care through early initiation of DMARDs.

Identifying Patients With Axial Spondyloarthritis in Large Datasets: Expanding Possibilities for Observational Research.

OBJECTIVE: Observational research of axial spondyloarthritis (axSpA) is limited by a lack of methods for identifying diverse axSpA phenotypes in large datasets. Algorithms were previously designed to identify a broad spectrum of patients with axSpA, including patients not identifiable with diagnosis codes. The study objective was to estimate the performance of axSpA identification methods in the general Veterans Affairs (VA) population. METHODS: A patient sample with known axSpA status (n = 300) was established with chart review. For feasibility, this sample was enriched with veterans with axSpA risk factors. Algorithm performance outcomes included sensitivities, positive predictive values (PPV), and F1 scores (an overall performance metric combining sensitivity and PPV). Performance was estimated with unweighted outcomes for the axSpA-enriched sample and inverse probability weighted (IPW) outcomes for the general VA population. These outcomes were also assessed for traditional identification methods using diagnosis codes for the ankylosing spondylitis (AS) subtype of axSpA. RESULTS: The mean age was 54.7 and 92% were male. Unweighted F1 scores (0.59-0.74) were higher than IPW F1 scores (0.48-0.65). The full algorithm had the best overall performance (F1IPW 0.65). The Early Algorithm was the most inclusive (sensitivityIPW 0.90, PPVIPW 0.38). The traditional method using ≥ 2 AS diagnosis codes from rheumatology had the highest PPV (PPVIPW 0.84, sensitivityIPW 0.34). CONCLUSION: The axSpA identification methods demonstrated a range of performance attributes in the general VA population that may be appropriate for various types of studies. The novel identification algorithms may expand the scope of research by enabling identification of more diverse axSpA populations.

Identification of Axial Spondyloarthritis Patients in a Large Dataset: The Development and Validation of Novel Methods.

OBJECTIVE: Observational axial spondyloarthritis (axSpA) research in large datasets has been limited by a lack of adequate methods for identifying patients with axSpA, because there are no billing codes in the United States for most subtypes of axSpA. The objective of this study was to develop methods to accurately identify patients with axSpA in a large dataset. METHODS: The study population included 600 chart-reviewed veterans, with and without axSpA, in the Veterans Health Administration between January 1, 2005, and June 30, 2015. AxSpA identification algorithms were developed with variables anticipated by clinical experts to be predictive of an axSpA diagnosis [demographics, billing codes, healthcare use, medications, laboratory results, and natural language processing (NLP) for key SpA features]. Random Forest and 5-fold cross validation were used for algorithm development and testing in the training subset (n = 451). The algorithms were additionally tested in an independent testing subset (n = 149). RESULTS: Three algorithms were developed: Full algorithm, High Feasibility algorithm, and Spond NLP algorithm. In the testing subset, the areas under the curve with the receiver-operating characteristic analysis were 0.96, 0.94, and 0.86, for the Full algorithm, High Feasibility algorithm, and Spond NLP algorithm, respectively. Algorithm sensitivities ranged from 85.0% to 95.0%, specificities from 78.0% to 93.6%, and accuracies from 82.6% to 91.3%. CONCLUSION: Novel axSpA identification algorithms performed well in classifying patients with axSpA. These algorithms offer a range of performance and feasibility attributes that may be appropriate for a broad array of axSpA studies. Additional research is required to validate the algorithms in other cohorts.

Treatment Patterns with Disease-Modifying Antirheumatic Drugs in U.S. Veterans with Newly Diagnosed Rheumatoid Arthritis, Psoriatic Arthritis, or Ankylosing Spondylitis.

BACKGROUND: Delays in treatment for inflammatory arthritis (IA) are associated with unfavorable outcomes, including impaired quality of life, irreversible joint damage, and disability. OBJECTIVE: To characterize treatment initiation patterns in veterans with newly diagnosed rheumatoid arthritis (RA), psoriatic arthritis (PsA), or ankylosing spondylitis (AS). METHODS: ICD-9/10-CM codes and natural language processing were used to identify incident cases of RA, PsA, or AS between January 1, 2007, and December 31, 2015, in patients enrolled in the Veterans Health Administration. Patterns of treatment initiation and nontreatment with disease-modifying antirheumatic drugs (DMARDs) were assessed in the 12-month follow-up period after the incident diagnosis. Outcomes included the percentage of veterans treated with a DMARD, the mean time to the initial DMARD after diagnosis, and the percentage of veterans who accessed rheumatology care before DMARD initiation. To assess outcomes over time, veterans were grouped by year of initial IA diagnosis. Additionally, outcomes were compared between nonbiologic and biologic DMARDs and among IA subtypes (RA, PsA, and AS). Groups were statistically compared with 95% confidence intervals. RESULTS: The population consisted of 12,118 IA veterans (9,711 RA, 1,472 PsA, and 935 AS), with 91.3% males and a mean age of 63.7 years. The percentage of veterans treated with ≥ 1 DMARD (nonbiologic or biologic) during the 12-month follow-up period increased from 48.8% in 2007 to 66.4% in 2015. In veterans diagnosed with IA in 2015, DMARD treatment was more common for PsA patients (72.9%) and RA patients (68.6%) than for AS patients (28.9%). In the subset treated with a DMARD within 12 months after diagnosis, the mean time to the initial DMARD after diagnosis did not change throughout the observation period (35.5 days for RA, 43.9 days for PsA, and 59.5 days for AS). Rheumatology specialty care was accessed by 87.4% of veterans treated with a nonbiologic DMARD and 92.2% of veterans treated with a biologic DMARD, in patients diagnosed in 2015. CONCLUSIONS: DMARD treatment rates during the initial 12 months after diagnosis increased between 2007 and 2015, but nontreatment remained common, particularly in veterans with AS. The time to treatment after diagnosis was stable over time; it was shortest for RA, intermediate for PsA, and longest for AS. DMARD treatment was uncommon in veterans who did not access rheumatology specialty care. DISCLOSURES: AbbVie Pharmaceuticals and Marriott Daughters Foundation funded this study via investigator-initiated grants. Data analyses were completed by investigators independent of AbbVie and Marriott Daughters Foundation. Walker, Clewell, and Douglas are employed by, and stockholders in, Abbvie. Halwani reports grants from BMS, Kyowa Hakko Kirin, Seattle Genetics, Roche-Genentech, Miragen, Immunedesign, Takeda, Amgen, Pharmacyclics, and Abbvie. The other authors have nothing to disclose.

Cohort identification of axial spondyloarthritis in a large healthcare dataset: current and future methods.

BACKGROUND: Big data research is important for studying uncommon diseases in real-world settings. Most big data studies in axial spondyloarthritis (axSpA) have been limited to populations identified with billing codes for ankylosing spondylitis (AS). axSpA is a more inclusive concept, and reliance on AS codes does not produce a comprehensive axSpA study population. The first objective was to describe our process for establishing an appropriate sample of patients with and without axSpA for developing accurate axSpA identification methods. The second objective was to determine the classification performance of AS billing codes against the chart-reviewed axSpA reference standard. METHODS: Veteran Health Affairs clinical and administrative data, between January 2005 and June 2015, were used to randomly select patients with clinical phenotypes that represented high, moderate, and low likelihoods of an axSpA diagnosis. With chart review, the sampled patients were classified as Yes axSpA, No axSpA or Uncertain axSpA, and these classification assignments were used as the reference standard for determining the positive predictive value (PPV) and sensitivity of AS ICD-9 codes for axSpA. RESULTS: Six hundred patients were classified as Yes axSpA (26.8%), No axSpA (68.3%), or Uncertain axSpA (4.8%). The PPV and sensitivity of an AS ICD-9 code for axSpA were 83.3% and 57.3%, respectively. CONCLUSIONS: Standard methods of identifying axSpA patients in a large dataset lacked sensitivity. An appropriate sample of patients with and without axSpA was established and characterized for developing novel axSpA identification methods that are anticipated to enable previously impractical big data research.

Use of Disease-modifying Antirheumatic Drugs for Inflammatory Arthritis in US Veterans: Effect of Specialty Care and Geographic Distance.

OBJECTIVE: To evaluate the effect of access to and distance from rheumatology care on the use of disease-modifying antirheumatic drugs (DMARD) in US veterans with inflammatory arthritis (IA). METHODS: Provider encounters and DMARD dispensations for IA (rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis) were evaluated in national Veterans Affairs (VA) datasets between January 1, 2015, and December 31, 2015. RESULTS: Among 12,589 veterans with IA, 23.5% saw a rheumatology provider. In the general IA population, 25.3% and 13.6% of veterans were exposed to a synthetic DMARD (sDMARD) and biologic DMARD (bDMARD), respectively. DMARD exposure was 2.6- to 3.4-fold higher in the subpopulation using rheumatology providers, compared to the general IA population. The distance between veterans' homes and the closest VA rheumatology site was < 40 miles (Near) for 55.9%, 40-99 miles (Intermediate) for 31.7%, and ≥ 100 miles (Far) for 12.4%. Veterans in the Intermediate and Far groups were less likely to see a rheumatology provider than veterans in the Near group (RR = 0.72 and RR = 0.49, respectively). Exposure to bDMARD was 34% less frequent in the Far group than the Near group. In the subpopulation who used rheumatology care, the bDMARD exposure discrepancy did not persist between distance groups. CONCLUSION: Use of rheumatology care and DMARD was low for veterans with IA. DMARD exposure was strongly associated with rheumatology care use. Veterans in the general IA population living far from rheumatology sites accessed rheumatology care and bDMARD less frequently than veterans living close to rheumatology sites.

Adipocyte-Specific Deletion of Manganese Superoxide Dismutase Protects From Diet-Induced Obesity Through Increased Mitochondrial Uncoupling and Biogenesis.

Obesity and insulin resistance are associated with oxidative stress (OS). The causal role of adipose OS in the pathogenesis of these conditions is unknown. To address this issue, we generated mice with an adipocyte-selective deletion of manganese superoxide dismutase (MnSOD). When fed a high-fat diet (HFD), the AdSod2 knockout (KO) mice exhibited less adiposity, reduced adipocyte hypertrophy, and decreased circulating leptin. The resistance to diet-induced adiposity was the result of an increased metabolic rate and energy expenditure. Furthermore, palmitate oxidation was elevated in the white adipose tissue (WAT) and brown adipose tissue of AdSod2 KO mice fed an HFD, and the expression of key fatty acid oxidation genes was increased. To gain mechanistic insight into the increased fat oxidation in HFD-fed AdSod2 KO mice, we quantified the mitochondrial function and mitochondrial content in WAT and found that MnSOD deletion increased mitochondrial oxygen consumption and induced mitochondrial biogenesis. This effect was preserved in cultured adipocytes from AdSod2 KO mice in vitro. As expected from the enhanced fat oxidation, circulating levels of free fatty acids were reduced in the HFD-fed AdSod2 KO mice. Finally, HFD-fed AdSod2 KO mice were protected from hepatic steatosis, adipose tissue inflammation, and glucose and insulin intolerance. Taken together, these results demonstrate that MnSOD deletion in adipocytes triggered an adaptive stress response that activated mitochondrial biogenesis and enhanced mitochondrial fatty acid oxidation, thereby preventing diet-induced obesity and insulin resistance.

Insulin suppresses ischemic preconditioning-mediated cardioprotection through Akt-dependent mechanisms.

It is believed that the diabetic myocardium is refractory to cardioprotection by ischemic preconditioning (IPC) mainly because of impaired insulin signaling to phosphatidylinositol 3-kinase (PI3K) and protein kinase B (PKB or Akt). However, human as well as animal studies have clearly showed that the hearts of type 2 diabetic humans and animals may exhibit increased signaling through PI3K-Akt but yet are resistant to cardioprotection by IPC or ischemic post-conditioning. Therefore, this study was designed to determine whether activation of insulin signaling prior to IPC is detrimental for cardioprotection and to assess the role of insulin receptors (IRs) and Akt in mediating this effect. Wild-type (WT) hearts, hearts lacking IRs or hearts expressing an active form of Akt (myrAkt1) were perfused ex vivo using a Langendorff preparation and were subjected to IPC (3cycles of 5min ischemia followed by 5min reflow before 30min no flow ischemia and then by 45min reperfusion) in the presence or absence of 1nmol/L insulin. Interestingly, whereas insulin was protective against I/R (30min no flow ischemia and 45min reperfusion), it completely abolished cardioprotection by IPC in WT hearts but not in mice lacking insulin receptors (IRs) in cardiomyocytes (CIRKO) or in all cardiac cells (TIRKO). The suppression of IPC-mediated cardioprotection was mediated through downstream signaling to Akt and Gsk3ß. In addition, transgenic induction of Akt in the heart was sufficient to abrogate IPC even when insulin was absent, further confirming the involvement of Akt in insulin's suppression of cardioprotection by IPC. These data provide evidence that excessive insulin signaling to Akt is detrimental for cardioprotection by IPC and could explain the failure of the diabetic myocardium to precondition.

UCP3 regulates cardiac efficiency and mitochondrial coupling in high fat-fed mice but not in leptin-deficient mice.

These studies investigate the role of uncoupling protein 3 (UCP3) in cardiac energy metabolism, cardiac O(2) consumption (MVO(2)), cardiac efficiency (CE), and mitochondrial uncoupling in high fat (HF)-fed or leptin-deficient mice. UCP3KO and wild-type (WT) mice were fed normal chow or HF diets for 10 weeks. Substrate utilization rates, MVO(2), CE, and mitochondrial uncoupling were measured in perfused working hearts and saponin-permeabilized cardiac fibers, respectively. Similar analyses were performed in hearts of ob/ob mice lacking UCP3 (U3OB mice). HF increased cardiac UCP3 protein. However, fatty acid (FA) oxidation rates were similarly increased by HF diet in WT and UCP3KO mice. By contrast, MVO(2) increased in WT, but not in UCP3KO with HF, leading to increased CE in UCP3KO mice. Consistent with increased CE, mitochondrial coupling was increased in the hearts of HF-fed UCP3KO mice. Unexpectedly, UCP3 deletion in ob/ob mice reduced FA oxidation but had no effect on MVO(2) or CE. In addition, FA-induced mitochondrial uncoupling was similarly enhanced in U3OB compared with ob/ob hearts and was associated with elevated mitochondrial thioesterase-1 protein content. These studies show that although UCP3 may mediate mitochondrial uncoupling and reduced CE after HF feeding, it does not mediate uncoupling in leptin-deficient states.

Inhibition of the replication of hepatitis B virus in vitro by pu-erh tea extracts.

Hepatitis B virus (HBV) is one of the most widespread viral infections in the world and poses a significant global public health problem. The implementation of effective vaccination programs has resulted in a significant decrease in the incidence of acute hepatitis B. Nevertheless, there is still a need for as many effective anti-HBV drugs as possible. In this study, the role of pu-erh tea extracts (PTE) against HBV was analyzed in vitro by using a stably HBV-transfected cell line HepG2 2.2.15. The MTT assay showed that PTE and its active components (tea polyphenols, theaflavins, and theanine) presented low cytotoxicity. ELISA analysis revealed that PTE effectively reduced the secretion of HBeAg, but any one of the active components alone showed weaker efficacy, suggesting that the anti-HBV activity of PTE might be a synergetic effect of different components. RT-PCR and luciferase assay showed that PTE suppressed HBV mRNA expression while leaving four HBV promoter transcriptional activities unchanged. Fluorescence quantitative PCR results demonstrated that PTE dramatically diminished HBV DNA produced in cell supernatants as well as encapsidated DNA in intracellular core particles. Finally, PTE significantly reduced intracellular reactive oxygen species (ROS) level. This study is the first to demonstrate that PTE possesses anti-HBV ability and could be used as a potential treatment against HBV infection with an additional merit of low cytotoxicity.

Increasing M2 epitope density enhances systemic and mucosal immune responses to influenza A virus.

Recombinant proteins bearing one (sM2) or three (3sM2) copies of M2 epitope from influenza virus were expressed in Escherichia coli. Mice were administrated with these two proteins and systemic and mucosal immune responses were analyzed. Compared with sM2, 3sM2 induced M2-specific serum IgG and mucosal IgA antibodies with neutralizing activity more efficiently in the whole immune course and the later mucosal immunization improved this advantage. MDCK cells pretreated with 3sM2 antisera showed less pathogenic morphological changes compared with that of pretreated with sM2. Together, our results demonstrated that high epitope density in one recombinant protein can enhance humoral immune responses in both systemic and mucosal immunization, and combination of systemic and mucosal immunization enhances this advantage.