***TASK*** the task is to summarize an input biomedical literature in six sentences 
    ***INPUT*** the input is a biomedical literature 
    ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences 
    ***DOCUMENTATION*** 
    ***EXAMPLES*** 
    Input: Coronary endothelial function is impaired in hypertension ; however , the severity of this impairment varies among patients . We aim ed to identify the predictors of coronary endothelial dysfunction among clinical variables related to hypertension and atherosclerosis . Twenty-seven untreated , uncomplicated essential hypertensive patients and 10 age-matched healthy controls were studied prospect ively . Myocardial blood flow ( MBF ) was measured by using 15O-water positron emission tomography ( PET ) at rest and during a cold pressor test ( CPT ) .  Coronary vascular resistance ( CVR ) during CPT was used as a marker of coronary endothelial function . Serum low density lipoprotein ( LDL ) cholesterol , high density lipoprotein ( HDL ) cholesterol , triglycerides , malondialdehyde-LDL , homeostasis model assessment , high-sensitivity C-reactive protein ( hs-CRP ) , and plasma interleukin-6 ( IL-6 ) and tumor necrosis factor (TNF)-α were also measured . CVR during CPT  was significantly higher in hypertensive patients than in healthy controls ( 114±26 vs. 94±12 mmHg/[mL/g/min ] ; p<0.05 ) . By univariate analysis , CVR during CPT  was correlated with LDL cholesterol ( r=0.38 , p<0.05 ) , IL-6 ( r=0.46 , p<0.02 ) , and TNF-α ( r=0.39 , p<0.05 ) in hypertensive patients . By multivariate analysis , IL-6 and TNF-α were significant independent predictors of CVR during CPT . Elevated plasma IL-6 and TNF-α levels were independent predictors of coronary endothelial dysfunction in hypertensive patients . These results suggest that plasma IL-6 and TNF-α might be useful for identifying the high risk subgroup of hypertensive patients with coronary endothelial dysfunction and provide an important clue to link systemic inflammation to the development of coronary atherosclerosis OBJECTIVE This study investigated whether efficacious methotrexate ( MTX ) treatment has an impact on mortality of patients with severe rheumatoid arthritis ( RA ) . METHODS In this prospect i ve , observational , one-center study , patients with severe RA refractory to other disease-modifying antirheumatic drugs started MTX treatment between 1980 and 1987 . Patients were divided into 4 different groups according to their response to MTX treatment after 1 year ( > 50 % improvement [ n = 99 ] , 20 - 50 % improvement [ n = 70 ] , no improvement [ n = 52 ] , and discontinued treatment [ n = 35 ] ) . After a followup of 7.5 - 15.3 years ( mean 10 years ) , the numbers of deaths were assessed in the different groups . St and ardized mortality ratios ( SMR ) were calculated by comparing the number of observed deaths in the study with the number of expected deaths in an age- and sex-matched sample of the general population . RESULTS Two hundred seventy-one patients entered the study between 1980 and 1987 . In 1995/1996 , outcomes for 256 patients ( 94.5 % ) could be documented ; 88 patients ( 34.4 % ) had died . In patients with > 50 % improvement after 1 year , the SMR was 1.47 , while in patients with 20 - 50 % improvement , the SMR was 1.85 . In both groups combined , the SMR was 1.64 ( 95 % confidence interval [ 95 % CI ] 1.11 - 2.17 ) , compared with 4.11 ( 95 % CI 2.56 - 5.66 ) in patients without improvement . Patients who had discontinued MTX treatment during the first year had an SMR of 5.56 ( 95 % CI 3.29 - 7.83 ) . CONCLUSION Patients with severe RA who do not respond to MTX treatment have a poor prognosis , with > 4-fold increased mortality compared with the general population , while RA patients who respond to MTX treatment have only a moderately increased mortality rate Background Atherosclerosis is a chronic inflammatory disease , with interleukin 6 ( IL‐6 ) as a major player in inflammation cascade . IL‐6 blockade may reduce cardiovascular risk , but current treatments to block IL‐6 also induce dyslipidemia , a finding with an uncertain prognosis . Methods and Results We aim ed to determine the endothelial function responses to the IL‐6–blocking agent tocilizumab , anti – tumor necrosis factor α , and synthetic disease‐modifying antirheumatic drug therapies in patients with rheumatoid arthritis in a 16‐week prospect i ve study . Sixty consecutive patients with rheumatoid arthritis were enrolled .  Tocilizumab and anti – tumor necrosis factor α therapy were started in 18 patients each while 24 patients were treated with synthetic disease‐modifying antirheumatic drugs . Forty patients completed the 16‐week follow‐up period . The main outcome was flow‐mediated dilation percentage variation before and after therapy . In the tocilizumab  group , flow‐mediated dilation percentage variation increased statistically significantly from a pre‐treatment mean of ( 3.43 % [ 95 % CI , 1.28–5.58 ] to 5.96 % [ 95 % CI , 3.95–7.97 ] ; P=0.03 ) . Corresponding changes were 4.78 % ( 95 % CI , 2.13–7.42 ) to 6.75 % ( 95 % CI , 4.10–9.39 ) ( P=0.09 ) and 2.87 % ( 95 % CI , −2.17 to 7.91 ) to 4.84 % ( 95 % CI , 2.61–7.07 ) ( P=0.21 ) in the anti – tumor necrosis factor α and the synthetic disease‐modifying antirheumatic drug groups , respectively ( both not statistically significant ) . Total cholesterol increased significantly in the tocilizumab group from 197.5 ( 95 % CI , 177.59–217.36 ) to 232.3 ( 201.62–263.09 ) ( P=0.003 ) and in the synthetic disease‐modifying antirheumatic drug group from 185.8 ( 95 % CI , 169.76–201.81 ) to 202.8 ( 95 % CI , 176.81–228.76 ) ( P=0.04 ) , but not in the  anti  – tumor necrosis factor α group . High‐density lipoprotein did not change significantly in any group . Conclusions Endothelial function is improved by tocilizumab in a high‐risk population , even as it increases total cholesterol and low‐density lipoprotein levels BACKGROUND Methotrexate is the most frequent choice of disease-modifying antirheumatic therapy for rheumatoid arthritis . Although results of studies have shown the efficacy of such drugs , including methotrexate , on rheumatoid arthritis morbidity measures , their effect on mortality in patients with the disease remains unknown . Our aim was to prospect ively assess the effect on mortality of methotrexate in a cohort of patients with rheumatoid arthritis . METHODS Our cohort included 1240 patients with rheumatoid arthritis seen at the Wichita Arthritis Center , an outpatient rheumatology facility . Patients ' details were entered into a computerised data base at the time of their first clinic visit . We also obtained and recorded demographic , clinical , laboratory , and self-reported data at each follow-up visit ( average interval 3.5 months ) . We estimated the mortality hazard ratio of methotrexate with a marginal structural Cox proportional hazards model . FINDINGS 191 individuals  died during follow-up . Patients who began treatment with  methotrexate ( n=588 ) had worse prognostic factors for mortality . After adjustment for this confounding by indication , the mortality hazard ratio for methotrexate use compared with no methotrexate use was 0.4 ( 95 % CI 0.2 - 0.8 ) . Other conventional disease-modifying antirheumatic drugs did not have a significant effect on mortality . The hazard ratio of methotrexate use for cardiovascular death was 0.3 ( 0.2 - 0.7 ) , whereas that for non-cardiovascular deaths was 0.6 ( 0.2 - 1.2 ) . INTERPRETATION Our data indicate that methotrexate may provide a substantial survival benefit , largely by reducing cardiovascular mortality . This survival benefit of methotrexate would set a st and ard against which new disease-modifying antirheumatic drugs could be compared OBJECTIVES Rheumatoid arthritis ( RA ) imposes substantial social costs , including an increased risk of work-related disability and accelerated cardiovascular diseases . The aim of the study is to determine the risk of acute myocardial infa rct ion ( AMI ) associated with RA in a nationwide retrospective cohort study . METHODS Using the catastrophic illness registry of the Taiwan National Health Insurance Research Data base ( NHIRD ) , we identified patients with RA from 1998 to 2010 . We also r and omly selected non-RA controls frequency-matched by age , sex , and index year from the general population free of RA . The risk of AMI was analyzed using Cox proportional hazards regression models including sex , age , and comorbidities . RESULTS From a total of 23.74 million people in the cohort , 29,260 RA patients and 117,040 controls were followed for 193,987 and 792,254 person-years , respectively . The incidence density rate increased in all groups of RA patients than those of the controls . RA patients had a 1.33-fold higher overall incidence of AMI than controls , with an adjusted hazard ration of 1.38 . Although the overall adjusted hazard ratio of AMI increased with age , the age-specific RA patients to controls incidence rate ratio was higher for younger RA patients . Subjects with comorbidities of hypertension , diabetes hyperlipidemia , CVA , COPD , or ESRD had increased risk of AMI .  Subjects with ESRD had the highest hazard of AMI . CONCLUSION This nationwide retrospective cohort study indicates that AMI risk increased by 38 % in RA patients compared to the general population . Comorbidities increase the AMI risk independently BACKGROUND Inflammation plays a fundamental role in atherothrombosis . Yet , whether direct inhibition of inflammation will reduce the occurrence of adverse cardiovascular outcomes is not known . DESIGN The Cardiovascular Inflammation Reduction Trial ( CIRT ) ( Clinical Trials.govNCT01594333 ) will r and omly allocate 7,000 patients with prior myocardial infa rct ion ( MI ) and either type 2 diabetes or the metabolic syndrome to low-dose methotrexate ( target dose 15 - 20 mg/wk ) or placebo over an average follow-up period of 3 to 5 years . Low-dose methotrexate is a commonly used anti-inflammatory regimen for the treatment of rheumatoid arthritis and lacks significant effects on lipid levels , blood pressure , or platelet function . Both observational and mechanistic studies suggest that low-dose methotrexate has clinical ly relevant antiatherothrombotic effects . The CIRT primary end point is a composite of nonfatal MI , nonfatal stroke , and cardiovascular death . Secondary end points are all-cause mortality , coronary revascularization plus the primary end point , hospitalization for congestive heart failure plus the primary end point , all-cause mortality plus coronary revascularization plus congestive heart failure plus the primary end point , incident type 2 diabetes , and net clinical benefit or harm . CIRT will use st and ardized central methodology design ed to ensure consistent performance of all dose adjustments and safety interventions at each clinical site in a manner that protects the blinding to treatment but maintains safety for enrolled participants . SUMMARY CIRT aims to test the inflammatory hypothesis of atherothrombosis in patients with prior MI and either type 2 diabetes or metabolic syndrome , conditions associated with persistent inflammation . If low-dose methotrexate reduces cardiovascular events , CIRT would provide a novel therapeutic approach for the secondary prevention of heart attack , stroke , and cardiovascular death OBJECTIVE While medications used to treat rheumatoid arthritis ( RA ) may affect survival in RA , few studies take into account the propensity for medication use , which may reflect selection bias in treatment allocation in survival models . We undertook this study to examine the relationship between methotrexate ( MTX ) use and mortality in RA , after controlling for individual propensity scores for MTX use . METHODS We studied 5,626 RA patients prospect ively for 25 years to determine the risk of death associated with MTX use , modeled in time-varying Cox regression models . We used the r 
    Output:
    
Recent systematic review s and meta-analyses have shown that treatment with methotrexate , a first-line disease-modifying antirheumatic drug ( DMARD ) , is associated with a significant reduction in atherosclerosis-mediated cardiovascular events , such as myocardial infa rct ion and stroke , and mortality , when compared to other DMARDs .
This suggests that methotrexate might exert specific protective effects against vascular inflammation and atherosclerosis in the context of autoimmune rheumatic disease .