Cranial and extracranial giant cell arteritis do not exhibit differences in the IL6 -174 G/C gene polymorphism.

OBJECTIVES: Since interleukin-6 (IL-6) is a pivotal proinflammatory cytokine implicated in the pathogenesis of giant cell arteritis (GCA), we aimed to determine the potential association of the functional IL6 -174 G/C polymorphism with GCA as well as if the single base change variation at the promoter region in the human IL-6 gene may account for differences in the clinical spectrum of GCA between cranial and extracranial large vessel vasculitis (LVV)-GCA. METHODS: The IL6 -174 G/C polymorphism (rs1800795) was genotyped in 191 patients with biopsy-proven GCA who had typical cranial manifestations of the disease, 109 patients with extracranial LVV-GCA, without cranial ischaemic manifestations of GCA, and 877 ethnically matched unaffected controls. A comparative study was carried out between patients with cranial and extracranial LVV-GCA and controls. RESULTS: No significant differences in genotype and allele frequencies of IL6 -174 G/C polymorphism were found between the whole cohort of GCA patients and healthy controls. It was also the case when cranial and extracranial LVV-GCA were compared or when each of these subgroups was compared to controls. Moreover, no significant results in genotype and allele frequencies of IL6 -174 G/C polymorphism were disclosed when the whole cohort of GCA patients were stratified according to the presence of polymyalgia rheumatica, severe ischaemic manifestations, including permanent visual loss and peripheral arteriopathy, and HLA-DRB1*04:01 status. CONCLUSIONS: Our results show that the IL6 -174 G/C polymorphism does not influence the phenotypic expression of GCA.

Cranial and extracranial large-vessel giant cell arteritis share a genetic pattern of interferon-gamma pathway.

OBJECTIVES: Two main different clinical phenotypes of giant cell arteritis (GCA) have been described, the classic cranial pattern and the extracranial large-vessel (LV) pattern. Since interferon gamma (IFNG) has shown to be a pivotal cytokine in the pathophysiology of GCA, our aim was to evaluate for the first time the influence of IFNG and IFNG receptor 1 (IFNGR1) polymorphisms in the different clinical phenotypes of GCA. METHODS: Two IFNG polymorphisms (rs2069718 G/A and rs1861493 A/G) and one polymorphism in IFNGR1 (rs1327474 G/A) were genotyped in 191 patients with biopsy-proven cranial GCA, 109 with extracranial LV-GCA and 490 healthy controls. A comparative study was conducted between patients with cranial and extracranial LV-GCA. RESULTS: No significant differences in genotype, allele, and haplotype frequencies of IFNG polymorphisms were found between GCA patients with the classic cranial pattern and the extracranial LV-GCA pattern. Similar results were found for genotype and allele frequencies of IFNGR1 polymorphism. It was also the case when patients with extracranial LV-GCA were compared with healthy controls. CONCLUSIONS: Our results show that IFNG and IFNGR1 polymorphisms do not influence the clinical phenotype of expression of GCA. Classic cranial GCA and extracranial LV-GCA seem to share a genetic pattern of IFNG pathway.

Vascular endothelial growth factor haplotypes are associated with severe ischaemic complications in giant cell arteritis regardless of the disease phenotype.

OBJECTIVES: To determine whether functional vascular endothelial growth factor (VEGF) polymorphisms influence the expression of the clinical phenotype of giant cell arteritis (GCA). We also evaluated whether VEGF polymorphism is associated with the development of severe ischaemic manifestations in patients with GCA regardless of the clinical phenotype, classic cranial GCA or predominantly extracranial GCA large vessel vasculitis (LVV). METHODS: VEGF rs833061 T/C, rs2010963 G/C and rs3025039 C/T polymorphisms were genotyped in 185 patients with biopsy-proven cranial GCA, 105 with extracranial LVV-GCA and 490 healthy controls. Allelic combinations (haplotypes) of VEGF were carried out. Comparisons were performed between patients with GCA and healthy controls as well as between patients with GCA stratified according to the clinical phenotype and the presence of severe ischaemic manifestations. RESULTS: No significant differences in genotype, allele, and haplotype frequencies of VEGF were found between patients with GCA and healthy controls as well as between GCA patients with the classic cranial pattern and the extracranial LVV-GCA pattern of the disease. However, the VEGF CGC haplotype (OR= 1.63 [1.05-2.53]) and the CGT haplotype (OR= 2.55 [1.10-5.91]) were significantly more frequent in GCA patients with severe ischaemic complications compared to those patients without these complications. CONCLUSIONS: VEGF haplotypes seem to play a role in the development of severe ischaemic manifestations in GCA patients, regardless of the clinical phenotype of expression of the disease.

The presence of both HLA-DRB1*04:01 and HLA-B*15:01 increases the susceptibility to cranial and extracranial giant cell arteritis.

OBJECTIVES: To determine if patients with the predominant extracranial large-vessel-vasculitis (LVV) pattern of giant cell arteritis (GCA) have a distinctive HLA-B association, different from that reported in biopsy-proven cranial GCA patients. In a further step we assessed if the combination of HLA-B and HLA-DRB1 alleles confers an increased risk for GCA susceptibility, either for the cranial and extracranial LVV phenotypes. METHODS: A total of 184 patients with biopsy-proven cranial GCA, 105 with LVV-GCA and 486 healthy controls were included in our study. We compared HLA-B phenotype frequencies between the three groups. RESULTS: HLA-B*15 phenotype was significantly increased in patients with classic cranial GCA compared to controls (14.7% versus 5.8%, respectively; p<0.01; OR [95% CI] =2.81 [1.54-5.11]). It was mainly due to the HLA-B*15:01 allele (12.5% versus 4.0%, respectively; p<0.01; OR [95% CI] =3.51 [1.77-6.99]) and remained statistically significant after Bonferroni correction. Similar HLA-B*15 association was observed in patients with the LVV-GCA (11.4% versus 5.8%, p=0.04, OR [95% CI] =2.11 [1.04-4.30]). This association was also mainly due to the HLA-B*15:01 allele (10.5% versus 4.0%, respectively; p=0.0054; OR [95% CI] =2.88 [1.19-6.59]). Noteworthy, the presence of HLA-B*15:01 together with HLA-DRB1*04:01 led to an increased risk of developing both cranial and extracranial LVV-GCA. CONCLUSIONS: Susceptibility to GCA is strongly related to the HLA region, regardless of the clinical phenotype of expression of the disease.

Role of IRF5 in the pathogenesis of immunoglobulin-A vasculitis.

OBJECTIVES: Interferon regulatory factor 5 (IRF5) is a major regulator of type I interferon induction and is also critical to produce pro-inflammatory cytokines. An influence of IRF5 genetic variants on the increased risk of immune-mediated diseases has been described. Accordingly, we aimed to evaluate the implication of IRF5 in the pathogenesis of Immunoglobulin-A vasculitis (IgAV), an inflammatory vascular pathology. METHODS: Three tag genetic variants (rs2004640, rs2070197 and rs10954213), representative of 3 different haplotype blocks within IRF5, were genotyped in 372 Caucasian patients with IgAV and 876 sex and ethnically matched healthy controls by TaqMan assays. RESULTS: No significant differences in the genotype and allele frequencies between patients with IgAV and healthy controls were observed when each IRF5 polymorphism was evaluated independently. Likewise, no significant differences between patients with IgAV and healthy controls were found when we assessed the three IRF5 polymorphisms combined, conforming haplotypes. In addition, there were no significant differences in genotype, allele and haplotype frequencies of IRF5 when patients with IgAV were stratified according to the age at disease onset or to the presence/absence of gastrointestinal or renal manifestations. CONCLUSIONS: Our results do not support an influence of IRF5 on the pathogenesis of IgAV.

Influence of IL17A gene on the pathogenesis of immunoglobulin-A vasculitis.

OBJECTIVES: Cytokines signaling pathway genes represent a key component of the genetic network implicated in the pathogenesis of immunoglobulin-A vasculitis (IgAV), an inflammatory vascular pathology. Interleukin (IL)17A is described as a genetic risk locus for some autoimmune diseases, such as giant cell arteritis and spondyloarthritis. Accordingly, we aimed to determine the potential influence of IL17A on the pathogenesis of IgAV. METHODS: Five IL17A tag polymorphisms (rs4711998, rs8193036, rs3819024, rs2275913 and rs7747909), which cover the major variability of this gene, were genotyped in 360 Caucasian patients with IgAV and 1,003 sex and ethnically matched healthy controls using TaqMan probes. RESULTS: No statistically significant differences between patients with IgAV and healthy controls were observed when each IL17A genetic variant was analysed independently. Similarly, no statistically significant differences between patients with IgAV and healthy controls were found when the five IL17A polymorphisms were evaluated combined conforming haplotypes. In addition, there were no statistically significant differences in genotype, allele and haplotype frequencies of IL17A when patients with IgAV were stratified according to the age at disease onset or to the presence/absence of gastrointestinal or renal manifestations. CONCLUSIONS: Our results do not support an influence of IL17A on the pathogenesis of IgAV.

A large-scale genetic analysis reveals a strong contribution of the HLA class II region to giant cell arteritis susceptibility.

We conducted a large-scale genetic analysis on giant cell arteritis (GCA), a polygenic immune-mediated vasculitis. A case-control cohort, comprising 1,651 case subjects with GCA and 15,306 unrelated control subjects from six different countries of European ancestry, was genotyped by the Immunochip array. We also imputed HLA data with a previously validated imputation method to perform a more comprehensive analysis of this genomic region. The strongest association signals were observed in the HLA region, with rs477515 representing the highest peak (p = 4.05 × 10(-40), OR = 1.73). A multivariate model including class II amino acids of HLA-DRß1 and HLA-DQα1 and one class I amino acid of HLA-B explained most of the HLA association with GCA, consistent with previously reported associations of classical HLA alleles like HLA-DRB1(∗)04. An omnibus test on polymorphic amino acid positions highlighted DRß1 13 (p = 4.08 × 10(-43)) and HLA-DQα1 47 (p = 4.02 × 10(-46)), 56, and 76 (both p = 1.84 × 10(-45)) as relevant positions for disease susceptibility. Outside the HLA region, the most significant loci included PTPN22 (rs2476601, p = 1.73 × 10(-6), OR = 1.38), LRRC32 (rs10160518, p = 4.39 × 10(-6), OR = 1.20), and REL (rs115674477, p = 1.10 × 10(-5), OR = 1.63). Our study provides evidence of a strong contribution of HLA class I and II molecules to susceptibility to GCA. In the non-HLA region, we confirmed a key role for the functional PTPN22 rs2476601 variant and proposed other putative risk loci for GCA involved in Th1, Th17, and Treg cell function.

Interleukin 1 beta (IL1ß) rs16944 genetic variant as a genetic marker of severe renal manifestations and renal sequelae in Henoch-Schönlein purpura.

OBJECTIVES: Data from a small series suggested that the Interleukin 1 beta (IL1ß) rs16944 polymorphism may be associated with severe renal involvement and persistent renal damage (renal sequelae) in Henoch-Schönlein purpura (HSP). To confirm this association, we assessed the largest cohort of Caucasian HSP patients ever considered for genetic studies. METHODS: 338 Spanish HSP patients and 635 sex and ethnically matched controls were recruited in this study. All patients were required to have had at least 6 months' follow-up. Patients and controls were genotyped for IL1ß rs16944 by TaqMan genotyping assay. RESULTS: No differences between IL1ß rs16944 genotype or allele frequencies were found either in the case/control study or when HSP patients were stratified according to the age at disease onset, presence of nephritis or gastrointestinal manifestations. Nevertheless, 4 (25%) of the 16 HSP patients who developed severe renal manifestations carried the TT genotype versus 29 (9%) of 322 who did not develop this complication (p=0.01, OR=5.48, 95% CI: 1.01-28.10). Accordingly, patients carrying the mutant T allele had an increased risk of developing severe nephropathy (p=0.016, OR=2.35, 95% CI: 1.09-5.07). Additionally, a significant increase of the TT genotype was observed in patients with persistent renal damage when compared with those patients without this complication (25% versus 8.6%, respectively; p=0.0035, OR=4.90, 95% CI: 1.26- 18.51). Moreover, renal sequelae were more common in patients carrying the mutant T allele (p=0.0076, OR=2.20, 95% CI: 1.17-4.14). CONCLUSIONS: Our results support that the IL1ß rs16944 polymorphism may be a potential marker of severe renal manifestations and renal sequelae in HSP.

Anti-TNF-α therapy reduces endothelial cell activation in non-diabetic ankylosing spondylitis patients.

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.

Osteoprotegerin correlates with disease activity and endothelial activation in non-diabetic ankylosing spondylitis patients undergoing TNF-α antagonist therapy.

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.

Analysis of two autoimmunity genes, IRAK1 and MECP2, in giant cell arteritis.

OBJECTIVES: The Xq28 region, containing IRAK and MECP2, represent a common susceptibility locus for a high number of autoimmune diseases. Our aim in the present study was to evaluate the influence of the IRAK1 and MECP2 autoimmunity-associated genetic variants in the giant cell arteritis (GCA) susceptibility and its clinical subphenotypes. METHODS: We analysed a total of 627 female biopsy-proven GCA patients and 1,520 female healthy controls of Spanish Caucasian origin. Two polymorphisms, rs1059702 and rs17345, located at IRAK1 and MECP2, respectively, were genotyped using TaqMan® allelic discrimination assays. RESULTS: No association with any of the analysed polymorphisms was evident when genotype and allele frequencies were compared between GCA patients and controls (rs1059702: allelic p-value=0.699, OR=0.96, CI 95% 0.80-1.17; rs17435: allelic p-value=0.994, OR=1.00, CI 95% 0.84-1.19). Likewise, the subphenotype analysis yield similar negative results. CONCLUSIONS: We have assessed for the first time the possible role of IRAK1 and MECP2 autoimmune disease-associated polymorphisms in GCA. Our data suggest that IRAK1 rs1059702 and MECP2 rs17435 genetic variants do not play a significant role in GCA susceptibility or severity.

Sex differences in patients with systemic lupus erythematosus from Northwest Spain.

To further establish potential differences according to sex in systemic lupus erythematosus (SLE) patients from Southern Europe. We assessed clinical and epidemiological data of patients diagnosed with SLE according to the 1982 American College of Rheumatology classification criteria at the single hospital for a well-defined population of Northwest Spain, between 1987 and 2006. Prevalence in December 2006 and age-standardized incidence rates in the whole period were estimated. Kaplan-Meier method was used in order to estimate the probability of survivorship. Women outnumbered men [127 (84.7%) vs. 23 (15.3%)]. The median age at the time of disease diagnosis in men was 54 years versus 43 in women (p < 0.001). Annual incidence rates were higher in women [5.9 (95% confidence interval--CI 4.9-7.0) per 100,000 population] than in men [1.1 (95% CI 0.7-1.7) per 100,000 population; p < 0.001]. Raynaud's phenomenon was more common in women (40.9 vs. 3.0%; p = 0.01). While the frequency of secondary Sjögren's syndrome was increased in women (p = 0.02), renal disease at the time of diagnosis (39.1 vs. 15.0%; p < 0.01) and over the course of the disease was more common in men (43.5 vs. 24.4%; p = 0.06). Higher frequency of thrombocytopenia (39.1 vs. 16.5%; p = 0.01) and lower frequency of anti-SSA (13.0 vs. 31.5%; p = 0.08) and anti-SSB (0 vs. 17.7%; p = 0.03) were observed in men. The 5- and 10-year survival probabilities were nonsignificantly reduced in men (91.3 and 78.3 3% vs. 94.6 and 89.2% in women). The frequency of some clinical manifestations is different in men and women with SLE. Higher awareness of these peculiarities may help to establish appropriate diagnosis and management of SLE in men.

Patients with ankylosing spondylitis and low disease activity because of anti-TNF-alpha therapy have higher TRAIL levels than controls: a potential compensatory effect.

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.

Lack of association between ABO, PPAP2B, ADAMST7, PIK3CG, and EDNRA and carotid intima-media thickness, carotid plaques, and cardiovascular disease in patients with rheumatoid arthritis.

INTRODUCTION: Rheumatoid arthritis (RA) is a polygenic disease associated with accelerated atherosclerosis and increased cardiovascular (CV) mortality. Recent studies have identified the ABO rs579459, PPAP2B rs17114036, and ADAMTS7 rs3825807 polymorphisms as genetic variants associated with coronary artery disease and the PIK3CG rs17398575 and EDNRA rs1878406 polymorphisms as the most significant signals related to the presence of carotid plaque in nonrheumatic Caucasian individuals. Accordingly, we evaluated the potential relationship between these 5 polymorphisms and subclinical atherosclerosis (assessed by carotid intima-media thickness (cIMT) and presence/absence of carotid plaques) and CV disease in RA. MATERIAL AND METHODS: 2140 Spanish RA patients were genotyped for the 5 polymorphisms by TaqMan assays. Subclinical atherosclerosis was evaluated in 620 of these patients by carotid ultrasonography technology. RESULTS: No statistically significant differences were found when each polymorphism was assessed according to cIMT values and presence/absence of carotid plaques in RA, after adjusting the results for potential confounders. Moreover, no significant differences were obtained when RA patients were stratified according to the presence/absence of CV disease after adjusting for potential confounders. CONCLUSION: Our results do not confirm association between ABO rs579459, PPAP2B rs17114036, ADAMTS7 rs3825807, PIK3CG rs17398575, and EDNRA rs1878406 and subclinical atherosclerosis and CV disease in RA.

Adiponectin and resistin serum levels in non-diabetic ankylosing spondylitis patients undergoing TNF-α antagonist therapy.

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.

Correlation between insulin resistance and serum ghrelin in non-diabetic ankylosing spondylitis patients undergoing anti-TNF-α therapy.

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.

Apelin serum levels in non-diabetic ankylosing spondylitis patients undergoing TNF-α antagonist therapy.

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.

Asymmetric dimethylarginine serum levels in non-diabetic ankylosing spondylitis patients undergoing TNF-α antagonist therapy.

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.

Leptin and visfatin serum levels in non-diabetic ankylosing spondylitis patients undergoing TNF-α antagonist therapy.

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.

TNF-alpha antagonist therapy improves insulin sensitivity in non-diabetic ankylosing spondylitis patients.

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.