This study aimed to determine the prevalence of rheumatoid arthritis in the United States (US) adult insured population from 2004 to 2014. This was an observational, retrospective, cross-sectional study based on US administrative health insurance claims databases (Truven Health MarketScan Research database and IMS PharMetrics Plus database). Trends in RA prevalence focusing on the 10-year period covering January 1, 2004-December 31, 2014 were analyzed using a validated algorithm for the identification of RA. Prevalence rates in the databases were determined and age- and gender-adjusted rates were projected to the US population in 2014. Analysis of data from the two databases indicated that the RA prevalence rate in commercially insured adult US population ranged from 0.41 to 0.54% from 2004 to 2014. The prevalence varied substantially by gender and age in each year and increased gradually across the years for most subgroups. In 2014, out of 31,316,902 adult patients with continuous enrollment in the Truven Health MarketScan Research database, 157,634 (0.50%) patients met our criteria for RA. Similarly, out of 35,083,356 adult patients in the IMS PharMetrics Plus database, 139,300 (0.50%) patients met our criteria for RA. In 2014, the overall age-adjusted prevalence of RA ranged from 0.53 to 0.55% (0.29-0.31% for males and 0.73-0.78% for females). The prevalence of RA in the US appeared to increase during the period from 2004 to 2014, affecting a conservative estimate of 1.28-1.36 million adults in 2014.

Objective To characterize baseline gene expression and pharmacodynamically induced changes in whole blood gene expression in 1,760 systemic lupus erythematosus (SLE) patients from 2 phase III, 52‐week, randomized, placebo‐controlled, double‐blind studies in which patients were treated with the BAFF‐blocking IgG4 monoclonal antibody tabalumab. Methods Patient samples were obtained from SLE patients from the ILLUMINATE‐1 and ILLUMINATE‐2 studies, and control samples were obtained from healthy donors. Blood was collected in Tempus tubes at baseline, week 16, and week 52. RNA was analyzed using Affymetrix Human Transcriptome Array 2.0 and NanoString. Results At baseline, expression of the interferon (IFN) response gene was elevated in patients compared with controls, with 75% of patients being positive for this IFN response gene signature. There was, however, substantial heterogeneity of IFN response gene expression and complex relationships among gene networks. The IFN response gene signature was a predictor of time to disease flare, independent of anti–double‐stranded DNA (anti‐dsDNA) antibody and C3 and C4 levels, and overall disease activity. Pharmacodynamically induced changes in gene expression following tabalumab treatment were extensive, occurring predominantly in B cell–related and immunoglobulin genes, and were consistent with other pharmacodynamic changes including anti‐dsDNA antibody, C3, and immunoglobulin levels. Conclusion SLE patients demonstrated increased expression of an IFN response gene signature (75% of patients had an elevated IFN response gene signature) at baseline in ILLUMINATE‐1 and ILLUMINATE‐2. Substantial heterogeneity of gene expression was detected among individual patients and in gene networks. The IFN response gene signature was an independent risk factor for future disease flares. Pharmacodynamic changes in gene expression were consistent with the mechanism of BAFF blockade by tabalumab.

modulating the levels of LDL receptor (LDLR) (11)(12)(13)(14). PCSK9 binds to the LDLR and directs it into a lysosomal degradation pathway rather than the recycling pathway (15)(16)(17)(18). This activity of PCSK9 on the LDLR is independent of its catalytic activity ( 18 ). The synthesis of PCSK9 and LDLR is induced by HMG-CoA reductase inhibitors, such as statins, under the control of the sterol-regulated transcription factor, SREBP2 (19)(20). Treatment with statins increases both hepatic LDLR content and circulating levels of PCSK9 (21)(22). Therefore, increased PCSK9 appears to limit both statin-induced increases in LDLR content and the resulting reduction of plasma LDL-C in humans.PCSK9 is initially synthesized as a ‫ف‬ 74 kDa proprotein, from which proteolytic cleavage of the ‫ف‬ 14 kDa N-terminal prodomain results in the ‫ف‬ 60 kDa mature form consisting of the N-terminal catalytic domain and the C-terminal domain ( 13 ). PCSK9 is expressed in multiple tissues, including liver, intestine, kidney, and cerebellum, of which the liver appears to be the major source of the circulating protein ( 23-25 ). The liver is also the major site of regulation of plasma LDL-C by PCSK9 ( 24,(26)(27)(28). Clearance of PCSK9 from the circulation is thought to be rapid, based on the 5 min half-life of the recombinant human protein injected into mice ( 26,28 ). The clearance is presumed to be mediated primarily by the LDLR, as the half-life of recombinant PCSK9 is prolonged when injected into LDLR-defi cient mice ( 26 ). Decreased half-life of a mutant form of PCSK9 (D374Y) that has higher LDLR degradation activity also supports this notion ( 26 ).The proteolytic cleavage of PCSK9 may represent a second mechanism of its clearance. A truncated form of PCSK9 with a molecular mass of 52-55 kDa has been observed and represents up to 40% of the total circulating PCSK9 in human serum ( 29,30 ). Studies in mice with Abstract Proprotein convertase subtilisin-kexin type 9 (PCSK9) is a secreted protein which regulates serum LDL cholesterol. It circulates in human and rodent serum in an intact form and a major truncated form. Previous in vitro studies involving the expression of human PCSK9 genetic variants and in vivo studies of furin knockout mice suggest that the truncated form is a furin cleavage product. However, the circulating truncated form of PCSK9 has not been isolated and characterized. Utilizing antibodies which bind to either the catalytic domain or the C-terminal domain of PCSK9, the truncated PCSK9 was isolated from serum. MS was used to determine that this form of PCSK9 is a product of in vivo cleavage at Arg218 resulting in pyroglutamic acid formation of the nascent N terminus corresponding to Gln219 of intact PCSK9. We also determined that the trun- Proprotein convertase subtilisin-kexin type 9 (PCSK9) is a secreted serine protease which regulates plasma LDL cholesterol (LDL-C) ( 1-3 ). Rare gain-of-function mutations cause autosomal dominant hypercholesterolemia, a disorder characterized by LDL-C >300 mg/dl and prematu...

Background There has been much variation between epidemiological studies that report the prevalence of ankylosing spondylitis (AS). This study aimed to analyze the diagnostic prevalence rates and treatment patterns of male and female AS patients in the United States adult insured population from 2006 to 2016. Methods Trends in AS prevalence were calculated for the 11-year period covering January 1, 2006 to December 31, 2016. Adult (18+ years old) AS patients were included in this retrospective analysis of medical and pharmacy claims data from the IBM Marketscan Commercial, Medicaid and Medicare-Supplemental Claims database. Prevalence was determined as having ≥1 AS diagnostic codes (ICD-9:720.0; ICD-10:M45.x). Trends in treatment patterns were also analyzed and stratified by gender. Results The AS prevalence increased from 0.04 to 0.09% from 2006 to 2016. The mean age between 2006 and 2016 ranged from 49.52–50.00 years. In 2006, approximately 40% of AS patients were female, while in 2016 over 47% of AS patients were female. Rates of use of TNF inhibitors and oral glucocorticoids increased, while NSAIDs and non-biologic DMARDs (sulfasalazine & methotrexate) rates decreased. Opioid use rates were stable. In 2016, males were more likely to be prescribed biologics, while females were more likely to be prescribed methotrexate, sulfasalazine, NSAIDs, muscle relaxants, anticonvulsants, opioids, and glucocorticoids. Conclusions The prevalence of AS diagnosis codes more than doubled between 2006 and 2016, but the very low prevalence suggests that AS continues to be underdiagnosed and under-addressed in routine clinical practice. Despite the increase in female AS patients, females were less likely to be prescribed biologics compared to male AS patients.

Eli Lilly and Company was the sole sponsor and funder for this study and was responsible for the study design, data collection, data analysis, interpretation of data, and decision to publish the findings. All authors are employees and minor stockholders of Eli Lilly and Company. Nyhuis was employed by Eli Lilly and Company at the time of this study. The findings of this study were presented in part at the 18th Congress of the International Headache Society; September 7-10, 2017; Vancouver, Canada.