You will be presented with a collection of medical randomized controlled trial (RCT) reports addressing a shared clinical question -- for instance, the efficacy of a medical intervention on a disease or condition. Given the titles and abstracts of these reports, your task is to generate the conclusion of the systematic review article synthesizing the key findings. Your conclusion should be a few sentences long. In your response, include only the conclusion and no other text. The RCT reports are below.



Title 1:
Genetic variations in the alanine–glyoxylate aminotransferase 2 (AGXT2) gene and dimethylarginines levels in rheumatoid arthritis
Abstract 1:
Rheumatoid arthritis ( RA ) is associated with high rates of cardiovascular events mainly due to coronary and cerebrovascular atherosclerotic disease . Asymmetric ( ADMA ) and symmetric ( SDMA ) dimethylarginines are endogenous inhibitors of nitric oxide synthase and have been repeatedly linked with adverse cardiovascular outcomes in the general population and various disease setting s. Alanine – glyoxylate aminotransferase 2 ( AGTX2 ) is considered an alternative metabolic pathway contributing to the clearance of dimethylarginines in humans . The aim of the current study was to investigate the effect of specific AGXT-2 gene polymorphisms on circulating levels of ADMA or SDMA in patients with RA .  Serum ADMA and SDMA levels were measured in 201 individuals with RA [ median age : 67 years ( IQR : 59–73 ) , 155 females ] . Two single nucleotide polymorphisms ( SNPs ) in the AGXT-2 gene — rs37369 and rs28305—were genotyped . Distributions of SDMA and ADMA were skewed , hence comparisons across the gene polymorphisms were performed using Kruskal – Wallis tests , and summarized using medians and interquartile ranges . Univariable analysis did not demonstrate a significant difference in the levels of SDMA or ADMA amongst the different genotypic groups of either rs37369AGXT2 ( p = 0.800 , 0.977 ) or rs28305AGXT2 ( p = 0.463 , 0.634 ) . In multivariable analyses , ADMA levels were found to be significantly associated with erythrocyte sedimentation rate and estimated glomerular filtration rate , whilst SDMA levels were significantly associated with estimated glomerular filtration rate and quantitative insulin sensitivity check index . After adjustments for these factors , the relationship between the AGXT2 gene variants and both ADMA and SDMA remained non-significant . Our study in a well-characterized RA population did not show an association between serum concentrations of dimethylarginines and genetic variants of the AGXT2 gene


Title 2:
Disparate effects of anti-TNF-α therapies on measures of disease activity and mediators of endothelial damage in ankylosing spondylitis.
Abstract 2:
BACKGROUND  Asymmetric dimethylarginine ( ADMA ) is associated with endothelial injury . Increased ADMA levels are found in rheumatoid arthritis ( RA ) and ankylosing spondylitis ( AS ) . We set out to assess the  ADMA and symmetric dimethylarginine ( SDMA ) levels in AS , RA , and healthy controls , and in the anti-TNF treated patients with active AS . METHODS In 78AS patients and 29 RA patients who were anti-TNF treatment naive at baseline , along with 23 healthy control subjects , we assessed erythrocyte sedimentation rate ( ESR ) , high-sensitivity C-reactive protein ( hsCRP ) , ADMA , and SDMA . For AS patients , the Bath Ankylosing Spondylitis Disease Activity Index ( BASDAI ) , back pain VAS and patient 's global activity of disease were calculated . After 6 months , we repeated the assessment in 30 out of the 78 AS patients in whom the anti-TNF treatment was initiated . RESULTS The baseline mean ( SD ) plasma ADMA concentration of AS patients was 0.64 ( 0.19 ) μmol/l and did not differ from controls ( 0.65 [ 0.19 ] μmol/l , p > 0.05 ) . In the RA group , ADMA concentration was higher than in controls ( 0.77 vs. 0.65 μmol/l , p < 0.05 ) . Both at baseline and at follow-up , ADMA levels correlated positively with BASDAI ( R = 0.52 , p = 0.02 , and R = 0.47 , p = 0.04 , baseline and follow-up , respectively ) . Six months of anti-TNF treatment did not influence ADMA concentration ( 0.51 [ 0.12 ] vs. 0.51 [ 0.11 ] μmol/l , p = 0.70 ) . CONCLUSION An absence of changes in plasma ADMA levels in the anti-TNF treated AS group despite the improvement in disease activity ( BASDAI ) and inflammation ( ESR , CRP ) may suggest either a lack of effect , or , even if such an effect were to take place , it needs not imply measurable changes in blood ADMA


Title 3:
Role of Asymmetrical Dimethylarginine in Inflammation-Induced Endothelial Dysfunction in Human Atherosclerosis
Abstract 3:
We explored the role of asymmetrical dimethylarginine ( ADMA ) as a cause of endothelial dysfunction induced by systemic inflammation . In vitro data suggest that ADMA bioavailability is regulated by proinflammatory stimuli , but it is unclear whether ADMA is a link between inflammation and endothelial dysfunction in humans . In study 1 we recruited 351 patients with coronary artery disease ( CAD ) and 87 healthy controls . In study 2 we recruited 69 CAD , 69 healthy , and 10 patients with rheumatoid arthritis , whereas in study 3 , 22 healthy and 70 CAD subjects were r and omly assigned to Salmonella typhii vaccination ( n=11 healthy and n=60 CAD ) or placebo ( n=11 healthy and n=10 CAD ) . Circulating interleukin 6/ADMA and flow-mediated dilation ( FMD ) were measured at 0 and 8 hours . In study 1 , ADMA was inversely correlated with FMD in healthy individuals and CAD patients ( P<0.0001 for both ) . However , interleukin 6 was inversely correlated with FMD ( P<0.0001 ) in healthy subjects but not in CAD patients . The positive correlation between ADMA and interleukin 6 was stronger in healthy ( r=0.515 ; P<0.0001 ) compared with CAD ( r=0.289 ; P=0.0001 ) subjects . In study 2 , both patients with rheumatoid arthritis and CAD had higher interleukin 6 ( P<0.0001 ) and ADMA ( P=0.004 ) but lower FMD ( P=0.001 ) versus healthy subjects . In study 3 , vaccination increased interleukin 6 in healthy ( P<0.001 ) and CAD ( P<0.001 ) subjects . FMD was reduced in healthy subjects ( P<0.05 ) , but its reduction in CAD was borderline . Vaccination increased ADMA only in healthy subjects ( P<0.001 ) . Systemic , low- grade inflammation leads to increased ADMA that may induce endothelial dysfunction . This study demonstrated that ADMA may be a link between inflammation and endothelial dysfunction in humans


Title 4:
Cumulative inflammation associates with asymmetric dimethylarginine in rheumatoid arthritis: a 6 year follow-up study.
Abstract 4:
OBJECTIVE The aim of the present study was to investigate the associations of cumulative inflammatory burden ( assessed by serial measurements of inflammatory markers ) and classical cardiovascular disease ( CVD ) risk factors with  asymmetric dimethylarginine ( ADMA )  in a large prospect i ve cohort of patients with established RA . METHODS Two hundred and one RA patients [ 155 females , median age 67 years ( range 59 - 73 ) ] were assessed at baseline ( 2006 ) for the presence of classical CVD risk factors and determination of systemic inflammation by CRP and ESR . Global CVD risk was identified by the Framingham Risk Score and the Reynolds Risk Score . At follow-up ( 2012 ) ,  ADMA levels were measured by ELISA . A quarterly measurement of CRP and ESR for each year the patient was in the study was used to produce an average area under the curve ( AAUC ) for ESR and CRP . RESULTS Regression analysis revealed that baseline ESR in 2006 and the AAUC of ESR and CRP all had significant positive relationships with current ADMA ( P = 0.004 , P < 0.001 and P = 0.002 , respectively ) . Baseline CRP in 2006 was not a significant predictor of ADMA ( P = 0.093 ) , although this relationship was in the same direction as the other factors . These results remained consistent after adjustment for classical CVD risk factors . CONCLUSION Cumulative inflammatory burden is positively associated with  ADMA levels , suggesting a potential pathogenic mechanism through which chronic systemic inflammation exerts deleterious effects on nitric oxide metabolism and endothelial homeostasis . This association is independent of classical CVD risk factors


Title 5:
Dietary L-arginine supplementation normalizes platelet aggregation in hypercholesterolemic humans.
Abstract 5:
OBJECTIVES The present study was design ed to test the hypothesis that long-term dietary supplementation with the nitric oxide precursor L-arginine would enhance vascular or platelet-derived nitric oxide activity , or both , and thereby inhibit platelet reactivity in hypercholesterolemic humans . BACKGROUND We have shown that reduced vascular activity of nitric oxide in hypercholesterolemic rabbits can be restored by L-arginine supplementation . The improvement in nitric oxide activity is associated with an inhibition of platelet aggregation ex vivo . This effect is most likely due to increased elaboration of endothelium- or platelet-derived nitric oxide , or both , because the inhibition of platelet reactivity was associated with elevation of intraplatelet cyclic guanosine monophosphate and was reversed by the nitric oxide synthase antagonist N-methyl-arginine . METHODS In a double-blinded , r and omized , placebo-controlled trial , hypercholesterolemic patients were assigned to L-arginine hydrochloride , 8.4 g/day orally , or placebo for 2 weeks . Platelet-rich plasma was obtained for aggregometry induced by collagen ( 1 to 10 micrograms/ml ) at four points : baseline , after 2 weeks of treatment , after a 2-week washout and after a long-term washout of 16 weeks on average . Aggregation was quantified by light transmittance and expressed as a percent transmittance observed with platelet-poor plasma . RESULTS Compared with normocholesterolemic control subjects , platelets from hypercholesterolemic subjects stimulated with 5 micrograms/ml of collagen showed increased aggregability ( 68.6 % in hypercholesterolemic patients vs. 54.5 % in normocholesterolemic control subjects , p < or = 0.02 ) . After 2 weeks of treatment with L-arginine ( but not placebo ) , platelet reactivity was modestly reduced ; this effect persisted for 2 weeks after discontinuation of arginine ( 52.6 % in arginine-treated patients vs. 65.1 % in normocholesterolemic control subjects , p = 0.07 ) . After 18 weeks ( i.e. , 16 weeks after discontinuing arginine treatment ) , the platelets of hypercholesterolemic patients once again became hyperaggregable , and the extent of platelet aggregation was significantly increased compared with the 4-week point ( 73.6 % after vs. 52.6 % during arginine treatment , p < 0.01 ) . No significant change in platelet reactivity was seen in placebo-treated hypercholesterolemic patients throughout the study . L-Arginine treatment was well tolerated without side effects . CONCLUSIONS This double-blinded , placebo-controlled study demonstrates that dietary supplementation with L-arginine can modestly attenuate the increased platelet reactivity seen in hypercholesterolemic patients . The data are consistent with our previous studies in hypercholesterolemic animals , demonstrating that L-arginine restores endogenous nitric oxide activity and inhibits platelet aggregation . Enhancement of endogenous nitric oxide activity is a potential novel therapeutic strategy worthy of further study


Title 6:
Serum Levels of Asymmetric Dimethylarginine and Apelin as Potential Markers of Vascular Endothelial Dysfunction in Early Rheumatoid Arthritis
Abstract 6:
Objectives . Impaired endothelial function represents the early stage of atherosclerosis , which is typically associated with systemic inflammatory diseases like rheumatoid arthritis ( RA ) . As modulators of endothelial nitric oxide synthase expression , asymmetric-dimethylarginine ( ADMA ) and apelin might be measured in the blood of RA patients to detect early atherosclerotic changes . We conducted a prospect i ve , case-control study to investigate serum ADMA and apelin profiles of patients with early-stage RA ( ERA ) before and after disease-modifying antirheumatic drug ( DMARD ) therapy . Methods . We enrolled 20 consecutively diagnosed , treatment-naïve patients with ERA and 20 matched healthy controls .  Serum ADMA and apelin levels and the 28-joint disease activity scores ( DAS28 ) were assessed before and after 12 months of DMARDs treatment . All patients underwent ultrasonographic assessment for intima-media tickness ( IMT ) evaluation . Results . In the ERA group , ADMA serum levels were significantly higher than controls at baseline ( P = 0.007 ) and significantly decreased after treatment ( P = 0.012 versus controls ) . Baseline serum apelin levels were significantly decreased in this group ( P = 0.0001 versus controls ) , but they were not significantly altered by treatment . IMT did not show significant changes . Conclusions . ERA is associated with alterations of serum ADMA and apelin levels , which might be used as biomarkers to detect early endothelial dysfunction in these patients


Title 7:
Decrease of asymmetric dimethyl arginine after anti-TNF therapy in patients with rheumatoid arthritis.
Abstract 7:
Chronic inflammatory diseases such as rheumatoid arthritis ( RA ) are associated with accelerated atherosclerosis and increased morbidity and mortality for cardiovascular events . Asymmetric dimethyl arginine ( ADMA ) , an endogenous inhibitor of nitric oxide synthase , contributes to the impairment of endothelial function , the earlier and reversible stage of atherosclerotic plaque formation . Since tumor necrosis factor ( TNF ) inhibits enzymatic degradation of ADMA , anti-TNF agents could restore its physiological level . The aim of this study was to investigate the effect of  TNF inhibitors on ADMA serum levels in patients with RA . Our results suggest a possible effect of anti-TNF drugs on ADMA serum levels ; longer studies would be necessary to confirm the role ADMA in assessing cardiovascular risk in RA
Circulating ADMA levels are higher in RA patients compared with healthy controls .
In addition , ADMA levels are influenced by age , disease duration and disease activity