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Endothelial dysfunction can be detected by the presence of elevated levels of biomarkers of endothelial cell activation. In this study, we aimed to establish whether correlations of these biomarkers with characteristics of patients with ankylosing spondylitis (AS) exist. We also studied the effect of anti-TNF-α therapy on these biomarkers. Serum sE-selectin, MCP-1 and sVCAM-1 levels were measured by ELISA in 30 non-diabetic AS patients undergoing anti-TNF-α therapy, immediately before and after an infusion of infliximab. Correlations of these biomarkers with clinical features, systemic inflammation, metabolic syndrome and other serum and plasma biomarkers of cardiovascular risk were studied. Potential changes in the concentration of these biomarkers following an infliximab infusion were also assessed. sE-selectin showed a positive correlation with CRP (p = 0.02) and with other endothelial cell activation biomarkers such as sVCAM-1 (p = 0.019) and apelin (p = 0.008). sVCAM-1 negatively correlated with BMI (p = 0.018), diastolic blood pressure (p = 0.008) and serum glucose (p = 0.04). sVCAM-1 also showed a positive correlation with VAS spinal pain (p = 0.014) and apelin (p < 0.001). MCP-1 had a negative correlation with LDL cholesterol (p = 0.026) and ESR (p = 0.017). Patients with hip involvement and synovitis and/or enthesitis in other peripheral joints showed higher levels of MCP-1 (p = 0.004 and 0.02, respectively). A single infliximab infusion led to a significant reduction in sE-selectin (p = 0.0015) and sVCAM-1 (p = 0.04). Endothelial dysfunction correlates with inflammation and metabolic syndrome features in patients with AS. A beneficial effect of the anti-TNF-α blockade on endothelial dysfunction, manifested by a reduction in levels of biomarkers of endothelial cell activation, was observed.

Objectives: Osteoprotegerin (OPG) has been associated with increased risk and severity of atherosclerotic disease in the general population. Since ankylosing spondylitis (AS) is a chronic inflammatory disease associated with accelerated atherosclerosis, we aimed to assess whether OPG levels correlate with disease activity, systemic inflammation, metabolic syndrome, adipokines and biomarkers of endothelial cell activation in patients with AS undergoing TNF-α antagonist therapy., Methods: We assessed OPG plasma concentration in 30 non-diabetic AS patients without cardiovascular disease undergoing TNF-α antagonist-infliximab therapy. OPG levels were measured immediately before and after an infliximab infusion. Correlations of OPG levels with disease activity, clinical characteristics, systemic inflammation, metabolic syndrome features, adipokines and biomarkers of endothelial activation were assessed. Changes in OPG concentration following an infusion of anti-TNF-α monoclonal antibody-infliximab were also analysed., Results: We found a positive correlation between OPG levels and markers of disease activity such as BASDAI and VAS spinal pain (r=0.497, p=0.01; r=0.390; p=0.04, respectively). No differences in OPG levels according to specific clinical features of the disease were seen. An inverse correlation between OPG levels and total cholesterol and LDL-cholesterol was also found (r=-0.451; p=0.02 and r=-0.411; p=0.03, respectively). A correlation between OPG and asymmetric dimethylarginine, a biomarker of endothelial cell activation, was also disclosed (r=0.533; p=0.01). No correlation between OPG level and insulin resistance was observed. An infliximab infusion did not lead to a significant reduction in OPG levels., Conclusions: OPG shows a correlation with markers of disease activity and endothelial activation in non-diabetic ankylosing spondylitis patients undergoing TNF-α antagonist therapy.

Objectives: To determine whether circulating gelsolin (GSN) levels in patients with ankylosing spondylitis (AS) undergoing TNF-α antagonist-infliximab-therapy are altered compared with controls and to establish whether disease activity, systemic inflammation and metabolic syndrome are potential determinants of circulating GSN levels in these patients., Methods: We assessed GSN serum concentrations in a series of 30 non-diabetic AS patients without cardiovascular (CV) disease undergoing TNF-α antagonist-infliximab therapy and 48 matched controls. GSN levels were measured immediately before and after an infliximab infusion. Correlations of GSN serum levels with disease activity, systemic inflammation and metabolic syndrome were assessed. Potential changes in GSN concentration following an infusion of anti-TNF-α monoclonal antibody-infliximab were also analysed., Results: Although at the time of the study AS patients undergoing anti-TNF-α therapy had adequate control of the disease (mean BASDAI 2.94), they showed lower GSN serum levels than healthy controls (mean±SD: 38660.42±23624.6 ng/ml versus 68975.43±31246.79 ng/ml; p<0.0001). When AS patients were stratified according to sex, we observed that GSN levels were significantly lower in men than in women (p=0.032). However, no differences in GSN levels according to the specific clinical features of the disease were seen. No association was found between GSN concentration and adipokines or biomarkers of endothelial cell activation. However, correlation between basal GSN levels and insulin resistance was observed. A single infliximab infusion did not lead to significant changes in GSN levels., Conclusions: GSN concentration is reduced in AS patients undergoing periodical anti-TNF-α therapy and low disease activity. Potential association with some metabolic syndrome features seems to exist.

Objectives: To determine whether circulating osteopontin (OPN) levels in patients with ankylosing spondylitis (AS) undergoing TNF-α antagonist-infliximab-therapy are increased compared with controls and to establish whether disease activity, systemic inflammation, metabolic syndrome, adipokines and biomarkers of atherosclerosis are potential determinants of circulating OPN levels in these patients., Methods: We assessed OPN serum concentrations in a series of 30 non-diabetic AS patients without cardiovascular disease undergoing TNF-α antagonist-infliximab therapy and 48 matched controls. OPN levels were measured immediately before and after an infliximab infusion, at time 0 and at time 120 minutes respectively. Correlations of OPN serum levels with clinical features, disease activity, systemic inflammation, metabolic syndrome and several biomarkers of atherosclerosis were assessed. Potential changes in OPN concentration following an infusion of anti-TNF-α monoclonal antibody-infliximab were also analysed., Results: At the time of the study AS patients undergoing anti-TNF-α therapy had low disease activity (mean BASDAI 2.94) and they showed similar OPN serum levels to healthy controls. No differences in OPN levels according to the specific clinical features of the disease were seen. Also, no correlation between OPN concentration and insulin resistance and adipokines was observed. However, a positive correlation between OPN and angiopoietin-2 (Angpt-2) serum levels was found (r=0.397; p=0.04). In addition, a single infliximab infusion led to a marginal statistically significant reduction in OPN levels (24112.19±14608.73 pg/ml at time 0 versus 21806.62±11390.83 pg/ml at time 120'; p=0.05)., Conclusions: OPN and Angpt-2 serum levels are correlated in non-diabetic AS patients undergoing TNF-α antagonist therapy.

Objective: TRAIL is a potential biomarker of cardiovascular (CV) disease. Ankylosing spondylitis (AS) is a chronic inflammatory disease associated with metabolic syndrome (MeS) and accelerated atherosclerosis. We assessed whether disease activity, systemic inflammation, and MeS features were associated with circulating TRAIL levels in AS patients undergoing TNF-α antagonist infliximab therapy and if infliximab infusion modified TRAIL levels., Methods: We measured TRAIL serum levels in 30 nondiabetic AS patients without CV disease undergoing anti-TNF-α therapy, immediately before and after an infliximab infusion, and in 48 matched controls. Correlations of TRAIL levels with disease activity, systemic inflammation and MeS features, adipokines, and biomarkers of endothelial activation were evaluated. Changes in TRAIL levels following anti-TNF-α infusion were analyzed., Results: TRAIL levels were higher in AS patients than controls. TRAIL levels displayed an inverse correlation with total and LDL cholesterol. We observed an inverse correlation with QUICKI and a marginal association with HOMA-IR. We also found an inverse correlation with resistin and a marginal association with apelin and OPN. Anti-TNF-α infusion did not change TRAIL levels after 120'., Conclusion: Elevated TRAIL levels in AS patients may be the result of a compensatory mechanism to reduce CV risk in these patients.

Like rheumatoid arthritis, ankylosing spondylitis (AS) is also an inflammatory disease associated with accelerated atherosclerosis and the presence of metabolic syndrome (MeS) features. AS patients often display osteoporosis as well as new bone formation. Insulin-like growth factor 1 (IGF-1) is a protein involved in both inflammation and bone metabolism. In the present study we assessed whether disease activity, systemic inflammation, MeS features, adipokines, and biomarkers of endothelial activation were associated with IGF-1 and insulin-like growth factor binding protein-3 (IGFBP-3) levels in a series of 30 nondiabetic AS patients without CV disease undergoing TNF-α antagonist-infliximab therapy. All determinations were made in the fasting state, immediately before an infliximab infusion. Although no association of IGF-1 and IGFBP-3 levels with angiopoietin-2 or osteopontin was found, an inverse correlation between IGF-1 levels and asymmetric dimethylarginine (ADMA), an endogenous endothelial nitric oxide synthase inhibitor that impairs nitric oxide production and secretion promoting endothelial dysfunction, was found (r=-0.397; P=0.04). However, no significant association was found between IGF-1 and IGFBP-3 levels and disease activity, systemic inflammation, metabolic syndrome features, or adipokines. In conclusion, in nondiabetic patients with AS undergoing periodic anti-TNF-α therapy, IGF-1 and ADMA are inversely correlated.

Ankylosing spondylitis (AS) is a chronic inflammatory rheumatic disease associated with accelerated atherosclerosis and increased risk of cardiovascular (CV) disease. AS patients also display a high prevalence of features clustered under the name of metabolic syndrome (MeS). Anti-TNF- α therapy was found to be effective to treat AS patients by suppressing inflammation and also improving endothelial function. Previously, it was demonstrated that a short infusion of anti-TNF- α monoclonal antibodyinfliximab induced a rapid and dramatic reduction in serum insulin levels and insulin resistance along with a rapid improvement of insulin sensitivity in nondiabetic AS patients. The role of adipokines, MeS-related biomarkers and biomarkers of endothelial cell activation and inflammation seem to be relevant in different chronic inflammatory diseases. However, its implication in AS has not been fully established. Therefore, in this review we summarize the recent advances in the study of the involvement of these molecules in CV disease or MeS in AS. The assessment of adipokines and biomarkers of endothelial cell activation and MeS may be of potential relevance in the stratification of the CV risk of patients with AS.

Objectives: To evaluate whether anti-TNF-α therapy (infliximab) administration alters circulating levels of ghrelin, an anti-inflammatory gastric peptide. We also assessed possible associations of circulating ghrelin concentrations with CRP and ESR levels, metabolic syndrome, demographic characteristics and other adipokines in ankylosing spondylitis (AS) patients., Methods: We studied 30 consecutive non-diabetic AS patients, without history of cardiovascular (CV) events, on periodical treatment with infliximab. Serum ghrelin levels were determined immediately prior to and after an infliximab infusion. Correlations of ghrelin serum levels with disease activity, systemic inflammation and metabolic syndrome were assessed. Potential changes in ghrelin concentration following an infusion of infliximab were analysed., Results: We observed a negative correlation between ghrelin concentration and insulin resistance (HOMA-IR immediately before infliximab infusion- at time 0 and at the end of infliximab infusion- at time 120') (r=-0.496; p=0.01 at time 0; r=-0.393; p=0.047 at time 120', respectively). We also found a positive correlation with insulin sensitivity (QUICKI) (r=0.415; p=0.035 at time 0; r=0.465; p=0.017 at time 120'). A correlation was found between ghrelin and resistin prior to infliximab infusion (r=0.429; p=0.046), and a negative correlation between serum ghrelin levels at time 0 and triglycerides (r=-0.416; p=0.035). No differences in ghrelin levels according to specific clinical features of the disease were seen. A single infliximab infusion led to mild but not significant increase in ghrelin serum concentration., Conclusions: In AS patients undergoing periodical treatment with anti-TNF-α monoclonal antibody-infliximab a link between insulin resistance and serum ghrelin concentration was observed.

Objectives: This paper aims to determine whether disease activity, systemic inflammation and metabolic syndrome are potential determinants of circulating asymmetric dimethylarginine (ADMA) in ankylosing spondylitis (AS) patients undergoing TNF-α antagonist-infliximab-therapy., Methods: We investigated ADMA serum concentrations in a series of 30 non-diabetic AS patients without history of cardiovascular (CV) events that were treated with the TNF-α antagonist infliximab, immediately prior to an infliximab infusion. Correlations of ADMA serum levels with disease activity, systemic inflammation and metabolic syndrome were assessed. Also, potential changes in ADMA concentration following an infusion of the anti-TNF-α monoclonal antibody-infliximab were analysed., Results: A higher concentrations of ADMA in men (p=0.012) and patients with hypertension was found (p=0.001). There was also a marginally positive correlation of ADMA serum levels with C-reactive protein levels (p=0.08). Moreover, a significant negative correlation between ADMA levels and total cholesterol and LDL-cholesterol was observed (p= 0.05). No differences in ADMA levels according to the specific clinical features of the disease were seen. A single infliximab infusion did not lead to significant changes in ADMA serum levels., Conclusions: In AS patients undergoing periodical treatment with the anti-TNF-α monoclonal antibody-infliximab a link between some features of metabolic syndrome and ADMA concentrations was observed.

Objectives: To determine whether disease activity, systemic inflammation and metabolic syndrome are potential determinants of circulating apelin in ankylosing spondylitis (AS) patients undergoing TNF-α antagonist-infliximab therapy., Methods: We investigated apelin serum concentrations in a series of 30 non-diabetic AS patients without history of cardiovascular (CV) events that were treated with the TNF-α antagonist infliximab, immediately prior to an infliximab infusion. Correlations of apelin serum levels with disease activity, systemic inflammation and metabolic syndrome were assessed. Also, potential changes in apelin concentration following an infusion of the anti-TNF-α monoclonal antibody-infliximab were analysed., Results: No significant correlation between apelin concentration and demographic features, inflammation, adiposity and metabolic syndrome features was seen. Neither differences were seen in basal apelin in different categorical variables associated to AS. Following infliximab infusion, a reduction of apelin serum levels was observed. In this regard, the median (interquartile range) values of apelin decreased from 0.99 (0.74-1.25) ng/ml immediately prior to infliximab infusion to 0.92 (0.72-1.39) ng/ml at the end of the infusion (time 120 minutes). However, the reduction in apelin serum levels following administration of the drug did not achieve statistical significance., Conclusions: The present study shows that in non-diabetic patients with AS on treatment with infliximab apelin serum levels do not correlate with disease activity or metabolic syndrome. A single infusion of infliximab does not yield a significant change of apelin serum levels in AS patients.

Objectives: This paper aims to determine whether disease activity, systemic inflammation and metabolic syndrome are potential determinants of circulating leptin and visfatin levels in ankylosing spondylitis (AS) patients undergoing TNF-α antagonist therapy. We also assessed whether the infusion of infliximab may alter circulating leptin and visfatin concentrations in these patients., Methods: We investigated leptin and visfatin serum concentrations in a series of 30 non-diabetic AS patients without history of cardiovascular (CV) events that were treated with the TNF-α antagonist infliximab, immediately prior to an infliximab infusion. Leptin and visfatin levels were also determined immediately after administration of an infliximab dose., Results: Significant differences in leptin concentrations between men (8.85±5.31 ng/ml) and women (18.96±9.72 ng/ml) were observed (p=0.001). A significant correlation between visfatin concentrations and insulin resistance (HOMA at the time of the study) was found (r= 0.493; p=0.009). Circulating leptin and visfatin concentrations did not correlate with disease duration, erythrocyte sedimentation rate, C-reactive protein, BASDAI and VAS at the time of the study and adiponectin and resistin levels prior to infliximab infusion. Likewise, no differences in leptin and visfatin concentrations were observed when patients with a history of anterior uveitis or presence of syndesmophytes were compared with the remaining patients who did not exhibit these features. Leptin and visfatin levels did not change upon infliximab administration., Conclusions: The present study indicates that in non-diabetic patients with AS on treatment with infliximab leptin and visfatin serum levels do not correlate with disease activity or systemic inflammation. Nevertheless, visfatin concentration correlates with insulin resistance.

Objectives: The objective of this paper is to assess if disease activity, systemic inflammation and metabolic syndrome are potential determinants of circulating adiponectin and resistin levels in ankylosing spondylitis (AS) patients undergoing TNF-α antagonist therapy., Methods: We investigated adiponectin and resistin serum concentrations in a series of 29 non-diabetic AS patients without history of cardiovascular (CV) events that were treated with the TNF-α antagonist infliximab, immediately prior to an infliximab infusion. Adipokine levels were also determined immediately after administration of an infliximab dose., Results: A significant correlation between adiponectin concentrations and insulin sensitivity (QUICKI at the time of the study) was seen (r=0.384; p=0.05). Also, a marginally significant negative correlation between adiponectin serum levels and the body mass index was observed (r=-0.367; p=0.07). Circulating adiponectin and resistin concentrations did not correlate with disease duration, erythrocyte sedimentation rate, C-reactive protein, BASDAI or VAS at the time of the study. However, AS patients with hip involvement or synovitis and/or enthesitis in other peripheral joints had higher adiponectin concentrations than those who did not have these complications (p-value for both comparisons =0.01). Adiponectin and resistin levels did not change upon infliximab administration., Conclusions: The present study shows that in non-diabetic patients with AS on treatment with infliximab adiponectin and resistin serum levels do not correlate with disease activity. Nevertheless, adiponectin concentration correlates with insulin sensitivity. This finding raises the possibility that low circulating adiponectin concentrations may be involved in the pathogenesis of the CV disease in AS.

Objectives: Since insulin resistance can promote endothelial dysfunction, and anti-TNF-α treatment improves endothelial function in ankylosing spondylitis (AS) patients, in the present study we sought to assess whether an infusion of the anti-TNF-α monoclonal antibody-infliximab may improve insulin sensitivity in non-diabetic AS patients., Methods: We assessed a series of 30 non-diabetic patients with AS attending hospital outpatient clinics who fulfilled the modified New York diagnostic criteria for AS. In all cases, the drug was given as an intravenous infusion in a saline solution over 120 minutes. Fasting blood samples were taken for determination of plasma glucose and serum insulin levels immediately before (time 0) and after infliximab infusion (time 120)., Results: At the time of the study only 8 (26.7%) of the 30 patients fulfilled definitions for insulin resistance as HOMA index was in most cases less than 2.29. Nevertheless, a statistically significant reduction in the HOMA values was observed when results found at time 0 (mean±SD: 1.72±1.22) were compared with those observed immediately after infliximab infusion (1.18±0.94) (p<0.001). The reduction in HOMA values was more important in those patients with the higher values of HOMA before infliximab infusion. Also, a significant improvement of insulin sensitivity was observed in most patients when QUICKI values before (0.37±0.04) and after infusion (0.39±0.04) were compared (p=0.004)., Conclusions: The present study shows that non-diabetic patients with AS on treatment with infliximab experience a rapid improvement of insulin sensitivity following administration of this drug.

Megestrol acetate is a synthetic progestin that has been used since the 1970s for the treatment of advanced cancer and subsequently to treat anorexia, cachexia and weight loss in AIDS patients. It has been shown that high doses or prolonged treatment with this drug may cause Cushing's syndrome, new-onset diabetes and suppression of plasma ACTH and cortisol levels. Megestrol acetate may cause suppression of the pituitary-adrenal axis due to the affinity of this compound for the glucocorticoid receptor. Recognising the glucocorticoid-like activity of megestrol and its effects at the axis level is important for the diagnosis of sub-clinical adrenal insufficiency. We present the case of a 74-year-old woman with infiltrating ductal breast carcinoma refractory to prolonged hormonal treatment with megestrol acetate, presenting with adrenal insufficiency.