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Background/Introduction Hydroxychloroquine (HCQ) is a widely used drug in Systemic Lupus Erythematosus (SLE). It may cause cardiac alterations which includes short term arrhythmic events (via QT interval prolongation) and medium-late term dose dependent cardiomyopathy1. The few research articles published on the medium-late term effects of HCQ in cardiac conduction disorder do not show relevant alterations. Purpose To assess the effect of HCQ in cardiac conduction in a consecutive SLE population. Methods Observational, single University hospital study of all consecutive SLE patients with an electrocardiogram (EKG) at HCQ onset and at least one EKG in follow-up, with a period of at least 3 months on HCQ treatment was performed. We assessed conduction alteration by electrocardiogram (EKG), defined as any degree of atrio-ventricular block or bundle branch block. The EKGs were gathered from the clinical history and interpreted at the beginning of the treatment and during the 15.2 years (CI95% 13.24–17.16) follow-up period. We defined cumulated HCQ (cHCQ) as the multiple of the mean annual dose of the sample. Results We studied 109 (96 women/ 13 men) SLE patients with a mean (±.SD) age of 61 ±. 2.78 years. A statistically significant association was observed between the cHCQ, and the development of cardiac conduction alterations [OR 1.1 CI95% 1.02–1.19; p=0.011] (Table & Figure). A total of 8 covariates were included. Among them, those that had the greatest influence on the development of the primary event were previous conduction alterations [OR 4.15 CI95% 6.39–624.54; p Conclusion According to our study, it seems to be an association between the cHCQ and development of cardiac conduction alterations regardless of other variables evaluated. Wider longitudinal studies are required with a protocolized EKG performance in successive visits to further analyze this association. Funding Acknowledgement Type of funding sources: None.

Background Once coronary atherosclerosis is clinically evident, it presents a very different rate of progression in each particular patient, being this progression one of the most important factors influencing on prognosis. Angiographic progression of lesions has been approached in some studies and certain driving factors have been identified. Nonetheless, clinical progression is more relevant but predictive factors remain less known. Purpose We aim to characterize a group of patients with accelerated clinical atherosclerosis (“fast progressors”, FP) and compare them to a stable group (“long standing stable”, LSS) both at baseline conditions, in order to explore potential markers or modulators that might have an impact on the prognosis. Methods We designed a case and control (1:2) study comparing the FP group (at least 3 different coronary revascularizations over the novo or previously non-significant lesions in a 10-year period of time), to a group of patients with LSS ischemic heart disease (those who have remained clinically stable during at least 10 years after a first coronary revascularization). We have analysed clinical, angiographic, social and environmental factors, as well as molecular substrates, the latter in baseline conditions. Results We identified 58 cases and compared them to 122 sex and age paired controls. Demographic characteristics and risk factors profile were similar in both groups. Clinical presentation at first event and coronary disease extent was also comparable in between groups. Figure 1 shows serum levels of patients during a stable phase of their disease. Creatinine was higher in the fast progressor group (FP) (p=0.03).Regarding the lipid profile LDLc and Apo B100 levels tended to be lower in the FP group most likely related to a more enhanced statin treatment in these group. Conversely, HDL and Apo A1 level were clearly lower in the FP group which could be explained due to an underlying higher risk condition. As to inflammatory determinants, CRP was found to be similar in both groups but IL-6 was significantly higher in the FP group. This could suggest that IL-6 levels might be a key marker of severity in the FP even at baseline condition. Of note, 10 patients showed IL-6 levels much higher than the mean. Moreover, we also assessed IL-6 genic expression, finding significant higher levels in the long standing stable group (LSS) (Figure 2). These findings suggest that the increase of IL-6 expression observed in the LSS group is not linked to a higher IL-6 production, therefore, the inflammatory state in those patients might be more controlled. Conclusion The main differential features at baseline of a clinically fast progressor patient compared to a long standing stable might reside in low HDL/Apo A1, along with a higher level of inflammation as estimated by IL-6 levels, but not CRP. Funding Acknowledgement Type of funding sources: Private grant(s) and/or Sponsorship. Main funding source(s): AMGEN Serum levels of both groupsIL-6 levels

Background Tofacitinib is anoral Janus kinase inhibitor for the treatment of rheumatoid arthritis (RA). Objectives This post hoc analysis aims to explore the efficacy of tofacitinib in patients (pts) with RA based on their baseline (BL) body mass index (BMI). Methods Data were analysed from six Phase 3 studies for pts who were methotrexate-naive (NCT01039688) or had an inadequate response to DMARDs (NCT00960440, NCT00847613, NCT00814307, NCT00856544, NCT00853385) and received ≥1 dose of tofacitinib 5 or 10 mg twice daily (BID) or placebo (PBO). Pts were stratified by BL BMI ( Results Overall, 1589, 1611 and 681 pts received tofacitinib 5 and 10 mg BID and PBO, respectively, with 1690, 1173 and 1017 pts in the BMI Conclusions Results of this post hoc analysis suggest that tofacitinib is associated with improvements in RA outcomes compared with PBO regardless of BL BMI category. In both tofacitinib and PBO groups, similar trends in improvements were seen in most endpoints regardless of BMI category, implying that the effect of BL BMI is not specific to tofacitinib. Further investigation is needed to assess the degree of impactof BMI on tofacitinib efficacy. Acknowledgements: Study sponsored by Pfizer Inc. Medical writing support was provided by C Viegelmann of CMC and funded by Pfizer Inc. Disclosure of Interest: A. DikranianGrant/research support from: AbbVie, Mallinckrodt, Pfizer Inc, Speakers bureau:AbbVie, Amgen, Celgene, Mallinckrodt, Pfizer Inc, M. Gonzalez-Gay Consultant for: Pfizer Inc, F. Wellborne Grant/research support from: AbbVie, BMS, EliLilly, Novartis, Pfizer Inc, Sanofi/Genzyme/Regeneron, Consultant for: AbbVie,BMS, Novartis, Pfizer Inc, Sanofi/Genzyme/Regeneron, Speakers bureau: AbbVie,BMS, Eli Lilly, Novartis, Pfizer Inc, Sanofi/Genzyme/Regeneron, J.Alvaro-Gracia Consultant for: Abbvie, BMS, Eli Lilly, MSD, Novartis, PfizerInc, Roche, Sanofi/Genzyme/Regeneron, Speakers bureau: Abbvie, BMS, Eli Lilly,MSD, Novartis, Pfizer Inc, Roche, Sanofi/Genzyme/Regeneron, L. Takiya Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, L. Stockert Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, D. Chapman Shareholder of: Pfizer Inc,Employee of: Pfizer Inc, S. Tatulych Shareholder of: Pfizer Inc, Employee of:Pfizer Inc, P. Dahl Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, J.Curtis Grant/research support from: Amgen, Corrona, Crescendo Bio, Pfizer Inc, Consultant for: AbbVie, Amgen, BMS, Corrona, Eli Lilly, Janssen, Myriad, Roche/Genentech,UCB

Contains fulltext : 88471.pdf (Publisher’s version ) (Closed access) OBJECTIVE: To investigate the possible association of the BANK1 gene with genetic susceptibility to systemic sclerosis (SSc) and its subphenotypes. METHODS: A large multicentre case-control association study including 2380 patients with SSc and 3270 healthy controls from six independent case-control sets of Caucasian ancestry (American, Spanish, Dutch, German, Swedish and Italian) was conducted. Three putative functional BANK1 polymorphisms (rs17266594 T/C, rs10516487 G/A, rs3733197 G/A) were selected as genetic markers and genotyped by Taqman 5 allelic discrimination assay. RESULTS: A significant association of the rs10516487 G and rs17266594 T alleles with SSc susceptibility was observed (pooled OR=1.12, 95% CI 1.03 to 1.22; p=0.01 and pooled OR=1.14, 95% CI 1.05 to 1.25; p=0.003, respectively), whereas the rs3733197 genetic variant showed no statistically significant deviation. Stratification for cutaneous SSc phenotype showed that the BANK1 rs10516487 G, rs17266594 T and rs3733197 G alleles were strongly associated with susceptibility to diffuse SSc (dcSSc) (pooled OR=1.20, 95% CI 1.05 to 1.37, p=0.005; pooled OR=1.23, 95% CI 1.08 to 1.41, p=0.001; pooled OR=1.15, 95% CI 1.02 to 1.31, p=0.02, respectively). Similarly, stratification for specific SSc autoantibodies showed that the association of BANK1 rs10516487, rs17266594 and rs3733197 polymorphisms was restricted to the subgroup of patients carrying anti-topoisomerase I antibodies (pooled OR=1.20, 95% CI 1.02 to 1.41, p=0.03; pooled OR=1.24, 95% CI 1.05 to 1.46, p=0.01; pooled OR=1.26, 95% CI 1.07 to 1.47, p=0.004, respectively). CONCLUSION: The results suggest that the BANK1 gene confers susceptibility to SSc in general, and specifically to the dcSSc and anti-topoisomerase I antibody subsets. 01 april 2010

Necrotizing histiocytic lymphadenopathy (Kikuchi's disease) is a rarely observed clinical entity characterized by fever, and solitary or multiple lymphadenopathy predominantly in the posterior cervical region. Kikuchi's disease has been reported to precede, coexist with or follow the diagnosis of systemic lupus erythematosus. In only rare instances has its association with cutaneous lupus erythematosus without systemic involvement been reported. We report a 45-year-old woman who presented characteristic systemic and cutaneous manifestations of Kikuchi's disease. Several months later, after sun exposure, she developed lesions of subacute cutaneous lupus erythematosus. The American Rheumatism Association criteria for systemic lupus erythematosus were not fulfilled. The possible pathogenic relationships between the two processes are discussed.

The aim of this study was to investigate whether polymorphisms in the tumor necrosis factor (TNF) and HLA-DRB1 gene regions are independently associated with rheumatoid arthritis (RA) in a population from Lugo region of northwestern Spain. RA patients (n=179) attending hospital outpatient clinics in Lugo, northwestern Spain and matched controls (n=145) were recruited. RA susceptibility in this population was predominantly associated with DRB1*0401, while erosive disease was associated with HLA-DRB1*0101 and DRB1*04. The increase in DRB1*04 was accounted for by an increase in DRB1*0404 and *0405 but not *0401 frequencies. In contrast, *0401 frequency was significantly increased in seropositive patients. The rheumatoid arthritis shared epitope (SE) was associated with increased risk for seropositive and erosive disease and this appeared to operate in a dose-dependent manner. Logistic regression analyses revealed that the TNF microsatellite markers TNFc1 and b3 were associated with RA independently of DRB1*04 and the SE. Carriage of a TNF c1 allele provided an increased risk of RA in SE-negative and SE-heterozygous individuals. TNFc1 and TNFb3 were not associated with erosive or seropositive disease. In contrast, TNF a2 was significantly associated with erosive disease which was independent of DRB1*04 and the SE. Further studies will be needed to establish why (TNFc1) polymorphism seemingly associated with low TNFalpha production, is a risk factor for RA.

BACKGROUND: Rheumatoid arthritis (RA) is an oligogenic disease for which only one susceptibility locus has been identified to date. Genes involved in T-cell regulation are potential candidates. Association to cytotoxic T-lymphocyte-associated-4 (CTLA-4) protein, a negative regulator of T-cell activation, has previously been described in a subset of German RA patients carrying the HLA DRB1*0401 subtype. Linkage and association with another oligogenic autoimmune disease, insulin-dependent diabetes mellitus, has also been described in a Spanish population. OBJECTIVE: To investigate the association of CTLA-4 with RA in Spanish and UK subjects. METHODS: Caucasoid UK RA patients (n=192), UK controls (n=96), Spanish RA patients (n=136) and Spanish controls (n=144) were typed for an A/G bi-allelic polymorphism in exon 1 of CTLA-4 using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) (enzyme). RESULTS: No significant differences in the frequency of the G allele or the GG genotype were found in either the UK or Spanish RA patients compared with controls. CONCLUSION: No significant evidence was found of an association between RA and CTLA-4

Contains fulltext : 107808.pdf (Publisher’s version ) (Closed access) There is increasing evidence that gene copy number (CN) variation influences clinical phenotype. The low-affinity Fc receptor 3B (FCGR3B) located in the FCGR gene cluster is a CN polymorphic gene involved in the recruitment of polymorphonuclear neutrophils to sites of inflammation and their activation. Given the genetic overlap between systemic lupus erythematosus and systemic sclerosis (SSc) and the strong evidence for FCGR3B CN in the pathology of SLE, we hypothesised that FCGR3B gene dosage influences susceptibility to SSc. We obtained FCGR3B deletion status in 777 European Caucasian cases and 1000 controls. There was an inverse relationship between FCGR3B CN and disease susceptibility. CN of /= 2. Although requiring replication, these results suggest that impaired immune complex clearance arising from FCGR3B deficiency contributes to the pathology of SSc, and FCGR3B CN variation is a common risk factor for systemic autoimmunity.

Objective To investigate whether polymorphisms in Toll-like receptor (TLR) genes, previously reported to be associated with immune-mediated diseases, are involved in systemic sclerosis (SSc). Methods We genotyped 14 polymorphisms in the genes for TLRs 2, 4, 7, 8, and 9 in a discovery cohort comprising 452 SSc patients and 537 controls and a replication cohort consisting of 1,170 SSc patients and 925 controls. In addition, we analyzed 15-year followup data on 964 patients to assess the potential association of TLR variants with the development of disease complications. We analyzed the functional impact of the associated polymorphism on monocyte-derived dendritic cells. Results In the discovery cohort, we observed that a rare functional polymorphism in TLR2 (Pro631His) was associated with antitopoisomerase (antitopo) positivity (odds ratio 2.24 [95% confidence interval 1.24-4.04], P = 0.003). This observation was validated in the replication cohort (odds ratio 2.73 [95% confidence interval 1.85-4.04], P = 0.0001). In addition, in the replication cohort the TLR2 variant was associated with the diffuse subtype of the disease (P = 0.02) and with the development of pulmonary arterial hypertension (PAH) (Cox proportional hazards ratio 5.61 [95% confidence interval 1.53-20.58], P = 0.003 by log rank test). Functional analysis revealed that monocyte-derived dendritic cells carrying the Pro63His variant produced increased levels of inflammatory mediators (tumor necrosis factor α and interleukin-6) upon TLR-2-mediated stimulation (both P < 0.0001). Conclusion Among patients with SSc, the rare TLR2 Pro631His variant is robustly associated with antitopoisomerase positivity, the diffuse form of the disease, and the development of PAH. In addition, this variant influences TLR-2-mediated cell responses. Further research is needed to elucidate the precise role of TLR-2 in the pathogenesis of SSc. © 2012 by the American College of Rheumatology.

To assess whether the polymorphism of the macrophage migration inhibitory factor (MIF) gene at the position -173 is implicated in the disease susceptibility, risk of cardiovascular (CV) events and presence of subclinical atherosclerosis in patients with rheumatoid arthritis (RA).A series of 293 unselected patients fulfilling the 1987 American College of Rheumatology classification criteria for RA seen at the rheumatology outpatient clinic of Hospital Xeral-Calde, Lugo, Spain and 526 matched controls were studied for differences in the MIF-173 G/C gene biallelic polymorphism. A total of 182 consecutive patients that had been periodically followed between March 1996 and September 1996 until patient's death or January 1, 2008 were assessed for the presence of CV events. Moreover, between March and December 2007, a subgroup of unselected RA patients with no history of CV events was studied for the presence of subclinical atherosclerosis by the assessment of the endothelial function (n=107) and the carotid artery intima-media thickness (IMT) (n=91) by ultrasonography studies. Patients and controls were genotyped for the MIF-173 G/C gene polymorphism using a PCR system with pre-developed TaqMan allelic discrimination assay.No significant differences in allele or genotype frequencies for the MIF-173 gene polymorphism between RA patients and controls were found. Forty-four of the 182 patients followed between 1996 and January 2008 experienced CV events. Although the frequency of MIF-173 GG homozygous was increased in those who had CV events (88.6%) compared to those who did not suffer these complication (73.2%), the difference was not statistically significant. It was also the case when we analyzed the potential influence of MIF-173 genotypes in the presence of endothelial dysfunction or increased carotid IMT of patients with RA.Our results do not show that MIF-173 gene polymorphism may infer a direct risk for disease susceptibility or CV disease in patients with RA.

Visfatin is an insulin-mimetic adipokine. In non-rheumatoid arthritis (RA) patients circulating levels of visfatin are correlated with the amount of visceral fat. Recent studies have disclosed an implication of visfatin in inflammation. Chronic systemic inflammation is of major importance in the development of atherosclerosis in RA. In the present study we investigated whether inflammation, obesity or metabolic syndrome are potential determinants of circulating visfatin concentrations in a group of RA patients on periodical treatment with the TNF-alpha blocker infliximab due to severe disease. We also assessed whether the infusion of infliximab may alter circulating visfatin concentrations in patients with severe RA.We investigated 33 non-diabetic patients with RA on periodical treatment with infliximab. Serum visfatin levels were determined immediately prior to and after infliximab infusion.There was no correlation between body mass index of RA patients and baseline serum level of visfatin. Also, no significant correlations between baseline visfatin levels and the age at the time of the study or at the onset of the disease, disease duration, ESR and CRP levels, DAS28, lipids, insulin sensitivity, resistin or the cumulative prednisone dose at the time of the study were found. Visfatin levels did not change upon infliximab infusion.In RA patients on TNF-alpha blocker treatment, circulating visfatin levels are unrelated to disease activity, adiposity or metabolic syndrome. The beneficial effect of anti-TNF-alpha therapy on cardiovascular mortality in RA does not seem to be mediated by changes in serum levels of visfatin.

To determine whether the interleukin (IL)6 -174 gene polymorphism may influence the development of subclinical atherosclerosis manifested by the presence of endothelial dysfunction in RA patients.311 patients (228 [73.3%] women; 243 [78.1%] rheumatoid factor positive) who fulfilled the 1987 ACR classification criteria for RA seen at the Rheumatology outpatient clinic of Hospital Xeral-Calde, Lugo between March 1996 and December 2006 and 226 matched controls were included in this study. Between March and December 2007, a subgroup of 98 patients randomly selected was assessed for the presence of endothelial dysfunction. Patients and controls were genotyped for a single biallelic (G/C) nucleotide polymorphism (rs1800795) in the promoter region at the position -174 of the IL6 gene using a TaqMan 5' allele discrimination assay.No significant differences in the IL6 -174 allele or genotype frequency between RA patients and controls were found. However, RA patients homozygous for the IL6 -174 GG genotype had more severe endothelial dysfunction (flow-mediated endothelium-dependent vasodilatation-FMD%: 4.2 + or - 6.6) than those carrying the IL6 -174 GC (FMD%: 6.3 + or - 8.1) or IL6 -174 CC (FMD%: 6.0 + or - 3.3) genotypes. In this regard, significant differences were observed when FMD% values in RA patients carrying the IL6 -174 GG genotype were compared with that observed in those carrying the IL6 -174 GC and the IL6 -174 CC genotypes (FMD%: 6.3 + or - 4.6) (p=0.02).Our results support a role of IL6 -174 gene polymorphism in the development of subclinical atherosclerosis in patients with RA.

TNF-alpha increases expression of inducible nitric oxide synthase (iNOS) in macrophages and vascular endothelial cells. Under normal conditions, iNOS activity is very low. However, iNOS activity is stimulated during inflammation by cytokines such as TNF-alpha and the amount of NO produced by iNOS may be a 1,000-fold greater than that produced by endothelial NOS. Since functional iNOS gene polymorphisms have been associated with susceptibility to rheumatoid arthritis (RA), drugs blocking TNF-alpha might decrease production of cytotoxic concentrations of NO leading to beneficial effect on RA or its complications. In the present study we investigated whether the infusion of the anti-TNF-alpha-infliximab may yield a short-term effect altering circulating NO oxidation products in patients with severe RA.We investigated 33 RA patients on periodical treatment with infliximab. Serum levels of nitrates, nitrites and NOx (nitrites+nitrates) were determined immediately prior to and after infliximab infusion. Correlation with clinical variables, laboratory markers of inflammation, metabolic syndrome features, adipokines and adhesion molecules was also assessed.Upon infliximab administration, serum NOx concentrations (microM) decreased significantly ([mean+/-SD: 15.0+/-8.8; median: 11.9; interquartile range: 9.2-18.5] before infliximab-time 0 (baseline) and [12.9+/-6.3; 10.9; 7.8-17.2] after infliximab infusion-time 120 minutes; p=0.03). It was also the case for nitrates (9.8+/- 8.3; 7.6; 5.5-10.2] before infliximab and [7.5+/-4.0; 6.6; 5.2-10.0] after infliximab infusion; p=0.008). There was a positive correlation between basal levels of nitrites and leptin concentration prior to infliximab administration. However, no significant correlations between NO oxidation products and clinical or other laboratory variables were found.Our results show, for the first time, a short-term effect of anti-TNF-alpha therapy on the levels of nitric oxide production.

The adipocytokine leptin regulates weight centrally and participates in the regulation of the immune and inflammatory responses. Chronic systemic inflammation is of major importance in the development of atherosclerosis in rheumatoid arthritis (RA). In the present study we investigated whether inflammation, obesity or both of these characteristics are potential determinants of circulating leptin concentrations in a group of RA patients on periodical treatment with the TNF-alpha-blocker-infliximab due to severe disease. We also assessed whether the infusion of infliximab may alter circulating leptin concentrations in patients with severe RA.We investigated 33 patients with RA on periodical treatment with infliximab. Serum leptin levels were determined immediately prior to and after infliximab infusion.There was a positive correlation between body mass index of RA patients and baseline serum level of leptin (rho=0.665, p0.001). Apart from a significant correlation with VCAM-1 (rho=0.349, p=0.04), no significant correlations between baseline leptin levels and the age at the time of the study or at the onset of the disease, disease duration, ESR and CRP levels, DAS28, lipids, insulin sensitivity, adhesion molecules, resistin, adiponectin, ghrelin or the cumulative prednisone dose at the time of the study were found. Leptin levels did not change upon infliximab infusion (p=0.48).In RA patients on TNF-alpha blocker treatment, circulating leptin levels are unrelated to disease activity but constitute a manifestation of adiposity. The beneficial effect of anti-TNF-alpha therapy on cardiovascular mortality in RA does not seem to be mediated by reduction in serum levels of leptin.

Complex interactions between environmental and genetic determinants in both the host immune system and the vasculature may operate modifying the vascular risk in rheumatoid arthritis (RA). An increased incidence of cardiovascular (CV) events in RA patients carrying HLA-DRB1 shared epitope alleles, in particular HLA-DRB1*0404, has recently been found. In the present study we have assessed the potential contribution of inducible and endothelial nitric oxide synthase (NOS2A and NOS3) gene polymorphisms to CV events in a cohort of patients with rheumatoid arthritis (RA). Also, interactions between NOS2A or NOS3 gene polymorphisms and HLA-DRB1 alleles for the risk of developing CV events were assessed.One hundred and eighty-two consecutive patients fulfilling the 1987 American College of Rheumatology classification criteria for RA seen at the Rheumatology outpatient clinic of Hospital Xeral Calde, Lugo, Northwest Spain, between March and September 1996 were included. Patients were genotyped by PCR based techniques for a multiallelic (CCTTT)n repeat in the promoter region of the NOS2A gene and for a T/C polymorphism at position -786 in the promoter region and a polymorphism in exon 7 (298Glu/Asp or 5557G/T) of the NOS3 gene. They were prospectively followed and clinical records were examined until patient's death or September 1, 2005. At the end of the study 39 (21%) patients had experienced CV events.No significant differences in allele or genotype frequencies for the NOS2A promoter CCTTT repeat microsatellite and NOS3 gene polymorphisms between RA patients with or without CV events were found. However, an increased frequency of CV events was observed in RA patients who carried the HLA-DRB1*0404 allele and were homozygous for the NOS3 (-786) TT genotype (OR: 9.06 [95% CI: 1.29-63.37]; p= 0.03) or for the presence of long NOS2A alleles (OR: 11.7 [95% CI: 1.53-88.4]); p= 0.02).Our results show that NOS2A or NOS3 gene polymorphisms do not infer a direct risk for CV events in RA. However, some interactions between NOS gene polymorphisms and HLA-DRB1 alleles confer and increased risk of developing CV events in patients with RA.

Contains fulltext : 81363.pdf (Publisher’s version ) (Closed access) The aim of this study was to investigate the possible role of STAT4 gene in the genetic predisposition to systemic sclerosis (SSc) susceptibility or clinical phenotype. A total of 1317 SSc patients [896 with limited cutaneous SSc (lcSSc) and 421 with diffuse cutaneous SSc (dcSSc)] and 3113 healthy controls, from an initial case-control set of Spanish Caucasian ancestry and five independent cohorts of European ancestry (The Netherlands, Germany, Sweden, Italy and USA), were included in the study. The rs7574865 polymorphism was selected as STAT4 genetic marker. We observed that the rs7574865 T allele was significantly associated with susceptibility to lcSSc in the Spanish population [P = 1.9 x 10(-5) odds ratio (OR) 1.61 95% confidence intervals (CI) 1.29-1.99], but not with dcSSc (P = 0.41 OR 0.84 95% CI 0.59-1.21). Additionally, a dosage effect was observed showing individuals with rs7574865 TT genotype higher risk for lcSSc (OR 3.34, P = 1.02 x 10(-7) 95% CI 2.11-5.31). The association of the rs7574865 T allele with lcSSc was confirmed in all the replication cohorts with different effect sizes (OR ranging between 1.15 and 1.86), as well as the lack of association of STAT4 with dcSSc. A meta-analysis to test the overall effect of the rs7574865 polymorphism showed a strong risk effect of the T allele for lcSSc susceptibility (pooled OR 1.54 95% CI 1.36-1.74; P < 0.0001). Our data show a strong and reproducible association of the STAT4 gene with the genetic predisposition to lcSSc suggesting that this gene seems to be one of the genetic markers influencing SSc phenotype.

Localized gastrointestinal vasculitis is a rare condition. It may be observed as an incidental unexpected pathologic finding at the time of biopsy of an abdominal mass or may present as unexplained abdominal pain with or without unexplained lower gastrointestinal bleeding. In this report we describe a new case of localized polyarteritis nodosa with involvement of peripancreatic middle-sized blood vessels. A literature review of cases of localized gastrointestinal vasculitis was also conducted. A major point of concern is whether a single organ vasculitis of the gastrointestinal tract is actually a localized gastrointestinal vasculitis or simply an initial manifestation of a more severe systemic vasculitis. Due to this, in cases of localized gastrointestinal vasculitis a complete evaluation of the patient to exclude the presence of a systemic a potentially threatening systemic vasculitis is required.

To assess the potential influence of the age in the clinical spectrum of giant cell arteritis (GCA).The case records of all patients diagnosed with biopsy-proven GCA at the Department of Medicine of the Hospital Xeral-Calde (Lugo, Northwest Spain) between 1981 and 2006 were reviewed.During the period of study, 273 Lugo residents were diagnosed with biopsy-proven GCA. The mean age +/- standard deviation at the time of disease diagnosis was 75.1+/-6.8 years (median: 75 years; interquartile range 71-80 years). A longer delay to the diagnosis was observed in patients younger than 70 years of age (13.2+/-12.8 weeks) compared to those 70 years and older (9.4+/-10.2 weeks) (p=0.03). Patients younger than 70 years presented more frequently polymyalgia rheumatica (p=0.02), cerebrovascular accidents (p=0.004), peripheral arteriopathy of recent onset due to large artery stenosis (p=0.03) and high alkaline phosphatase values (p=0.001) than those 70 years and older. Individuals 70-79 years of age at the time of disease diagnosis had ESR values (90.2+/-22.8 mm/1st hour) lower than those observed in patients younger than 70 years (98.3+/-22.2 mm/1st hour) or 80 years and older (99.5+/-20.6 mm/1st hour) (p=0.005). However, no significant differences in the frequency of visual ischemic complications according to the age at the time of disease diagnosis were observed.The results from this study display differences in the clinical spectrum of the disease according to the age of disease onset.

Granuloma annulare (Gan) and giant cell arteritis (GCA) share common histologic features. In Gan, a disease characterized by the presence of palisading granulomas usually in the dermis, the main alteration is the presence of elastic fiber degeneration and it strongly suggests that the primary target leading to the development of this disorder is the injury to the elastic tissue. On the other hand, in giant cell arteritis (GCA), a vasculitis involving large-and middle-sized blood vessels, the main histologic features are the disruption of the internal elastic lamina and the nonsuppurative granulomatous giant cell infiltrate, which seems to be focused around the disintegrated elastic fibers. Due to this, these two conditions appear to be related. However, to the best of our knowledge, only one case of association of generalized Gan and GCA is described in the literature. We herein report a new case of generalized Gan in a patient previously diagnosed with biopsy-proven GCA. Both diseases were successfully treated by oral prednisone. Although the etiology of generalized Gan and GCA remains still unknown, they seem to be immunologically mediated conditions showing predominance of T-cells in the inflammatory infiltrate.

The aim of this cross-sectional study was to establish the frequency, phenotype and characteristics of metabolic syndrome (MS), as defined by the Adult Treatment Panel III, in a cohort of patients with systemic lupus erythematosus (SLE) and its possible association with cardiovascular diseases (CVD). A total of 160 patients with SLE and 245 age, sex, educational level and ethnically matched controls were included. Association with cardiovascular risk factors, SLE features, treatment of SLE and history of CVD were assessed in patients with SLE and controls with and without MS. MS was non-significantly increased in patients with SLE (20%) compared with controls (13%; P = 0.083). It was more commonly observed in patients with SLE ≤40 years old (15.8%) than in controls of the same age group (4.2%; P

Chronic systemic inflammation plays a pivotal role in the development of atherosclerosis in rheumatoid arthritis (RA). In the present study, we investigated whether anti-TNF-alpha antagonist-monoclonal antibody-infliximab administration alters circulating levels of resistin, a proinflammatory adipokine. We further assessed associations of circulating resistin concentrations with CRP and ESR levels, platelet counts and metabolic syndrome and demographic characteristics in RA patients on periodical treatment with infliximab.We investigated 33 patients with RA on periodical treatment with infliximab. Serum resistin levels were determined immediately prior to and after infliximab infusion.Upon infliximab administration, mean (SD) serum resistin concentrations (ng/ml) decreased from 21.9 (9.9) to 17.4 (8.9) (p=0.005). Also, a significant association between the mean ESR (r=0.405; p=0.03) and CRP (r=0.571; p=0.0005) from disease diagnosis and ESR (r=0.486; p=0.004), CRP (r=0.599; p=0.0005) and platelet count (r=0.559; p=0.0007) at the time of the study and baseline resistin levels was found.The present study shows that anti-TNF-alpha therapy results in a rapid reduction of serum resistin levels in patients with RA. It also confirms a close association between laboratory markers of inflammation, particularly CRP and resistin levels. These observations support a potential role of resistin in the inflammatory cascade in RA.

To assess the possible association between the PTPN22 gene 1858C--T polymorphism and the susceptibility to Henoch-Schönlein purpura (HSP) and determine if this polymorphism is implicated in the severity of this systemic vasculitis.Fifty-seven unselected patients from Northwest Spain with primary systemic vasculitis, classified as HSP according to previously proposed criteria, with a follow-up of at least 2 years and 229 healthy controls, were included in this study. All the individuals were of Spanish Caucasian origin. Genotyping of the PTPN22 gene 1858C--T polymorphism was performed by real time PCR technology, using TaqMan 5' allelic discrimination assay.No significant differences in allele or genotype distribution frequencies for the PTPN22 gene polymorphism were observed between HSP patients and controls. It was also the case when HSP patients were stratified for the presence of severe gastrointestinal complications (n = 46), nephritis (n= 37) or permanent renal involvement (renal sequelae) (n = 12).Our results do not support a potential implication of the PTPN22 gene polymorphism in the susceptibility to and clinical expression of HSP.

To assess the potential in-fluence of endothelial nitric oxide synthase (eNOS) polymorphisms in the susceptibility to and clinical expression of a series of patients diagnosed with biopsy-proven erythema nodosum (EN).Ninety-seven unselected patients from Northwest Spain with biopsy-proven EN were studied. Patients and ethnically matched controls were genotyped by PCR based techniques for a variable number tandem repeat polymorphism in intron 4, a T/C polymorphism at position -786 in the promoter region and a polymorphism in exon 7 (298Glu/Asp or 5557G/T) of the eNOS gene.No differences in allele or genotype frequencies for any of the individual eNOS polymorphisms were observed between biopsy-proven patients with EN and controls. It was also the case when patients with EN secondary to sarcoidosis were compared with the remaining patients or controls. In the group of patients with EN, no linkage disequilibrium between these polymorphisms was found. Also, no significant differences in haplotype frequencies were observed between patients and controls.Our present results do not support a role for eNOS polymorphisms in the susceptibility to and clinical expression of EN.

OBJECTIVE: The aim of this study was to investigate the possible role of the caspase 7 (CASP7) in susceptibility to rheumatoid arthritis (RA). METHODS: Genotyping of three single nucleotide polymorphisms (SNPs) of the CASP7 gene: rs11593766 (G/ T), rs2227310 (C/G) and rs2227309 (G/A) was performed in a total of 906 RA patients and 528 matched healthy controls using TaqMan assays. All the subjects were of Spanish Caucasian origin. A relative quantification of mRNA encoding the non-functional variant of procaspase 7 (isoform beta) vs functional isoforms was performed in total RNA from 32 healthy individuals using real-time PCR. RESULTS: Only the rs2227309 SNP was found to be associated with susceptibility to RA. Frequency of the G allele was significantly higher among RA patients [overall frequency of the G allele 74.0% in cases vs 68.4% in controls, P = 0.001, Odds ratio (OR) = 1.32, 95% Confidence intervals (95% CI) 1.11-1.56] and a higher frequency of GG homozygous individuals was found in the RA patient group (overall frequency of GG genotype 56.0% in cases and 46.4% in controls, P = 0.0005, OR = 1.47, 95%CI 1.18-1.83). A statistically significant deviation was observed to compare the relative expression of the procaspase 7 isoform beta in samples from individuals stratified according their rs2227309 genotypes (AA + AG: 1.36 +/- 0.55, n = 19, vs GG: 2.35 +/- 0.74, n = 13; P = 0.0002). CONCLUSION: Our results support involvement of the CASP7 gene in the susceptibility to RA. The higher production of the no functional variant of CASP7 by individuals with a particular genotype could be the basis of this association.

To assess whether polymorphism of the interleukin (IL)-6 gene at the position -174 was implicated in the incidence of Henoch-Schönlein pur-pura (HSP). A further objective was to determine if any relationship existed with severe systemic complications of HSP, in particular with severe renal and gastrointestinal involvement.Unselected patients from Northwest Spain with primary cutaneous vasculitis classified as HSP according to proposed criteria were studied. All patients included in the present study were required to have had at least 2 year's follow-up. Patients and controls were genotyped for a single biallelic (G/C) nucleotide polymorphism in the promoter region at the position -174 of the IL-6 gene by a polymerase reaction chain-restriction fragment length polymorphism (PCR-RFLP) method.Forty-six Caucasian HSP patients and 124 healthy matched controls were studied. No allele or genotype differences between the whole group of HSP and controls were observed. This was also the case when HSP patients were stratified by the presence of gastrointestinal complications, nephritis, and permanent renal involvement (renal sequelae).The polymorphism in IL-6 gene promoter (-174 G/C) does not appear to be a genetic risk factor for HSP in Northwest Spain.

Secondary vasculitis resulting from unusual pathologic expressions of infections has been described and has important clinical significance. Infectious agents have also been implicated in the pathogenesis of different primary systemic necrotizing vasculitides. Infectious endocarditis is of particular importance in the differential diagnosis of a patient presenting with ANCA associated vasculitis. We report a well-documented case of a patient with recurrent Staphylococcus aureus bacteremia who developed bacterial endocarditis and also fulfilled the Chapel Hill Conference definitions for microscopic polyangiitis. To the best of our knowledge, it is the second case of bacterial endocarditis associated with both pANCA and anti-MPO specificity that fulfilled definitions for systemic necrotizing vasculitis. We emphasize the potential pathogenic role of infection as the trigger factor for the development of systemic vasculitis.

To assess whether polymorphism of the macrophage migration inhibitory factor (MIF) gene at position -173 was implicated in the incidence of Henoch-Schönlein purpura (HSP) and cutaneous leukocytoclastic angiitis (CLA). A further objective was to determine if any relationship existed with severe systemic complications of HSP, in particular with severe renal involvement and permanent renal dysfunction.Unselected patients from Northwest Spain with primary cutaneous vasculitis classified as HSP or hypersensitivity vasculitis (HV) according to proposed criteria were studied. Patients with HV were included in this study if they fulfilled the Chapel Hill Consensus Conference on the Nomenclature of Systemic Vasculitis definitions for CLA. Patients and controls were genotyped for a single nucleotide polymorphism (SNP) in the 5'-flanking region at position -173 of the MIF gene, using SNapshot ddNTP primer extension, followed by capillary electrophoresis (ABI 3100).Ninety-five Caucasian patients (57 classified as having HSP and 38 who fulfilled definitions for CLA) and 122 healthy controls were studied. No allele or genotype differences between the whole group of HSP or CLA patients and controls were observed. This was also the case when HSP patients were stratified by the presence of gastrointestinal complications, nephritis, and permanent renal involvement (renal sequelae).The polymorphism in MIF gene promoter (-173 G/C) does not appear to be genetic risk factors for cutaneous vasculitis in Northwest Spain.

Chronic systemic inflammation plays a pivotal role in the development of atherosclerosis in rheumatoid arthritis (RA). Soluble (s) adhesion molecules were found significantly increased in RA patients with active disease. Since increased levels of some adhesion molecules were closely linked to the development of endothelial dysfunction and atherosclerosis and administration of anti-TNF-alpha-infliximab resulted in a rapid and dramatic improvement of endothelial function in long-term infliximab treated RA patients, we assessed whether infusion of the chimeric anti-TNF-alpha infliximab might also yield a rapid and favorable effect on serum levels of soluble adhesion molecules in RA patients periodically treated with this drug because of severe disease.We recruited patients with RA refractory to conventional therapy seen over a period of 2 months at Hospital Xeral-Calde, Lugo, Spain, who were on periodical treatment with infliximab for at least 14 weeks. Blood samples for determination of sICAM-1, sICAM-3, sVCAM-1, sE-selectin, and sP-selectin levels by ELISA were taken immediately before and after infliximab infusion.Thirty-four RA patients (25 women; mean age: 55.4 years; mean DAS28: 4.27) fulfilled the inclusion criteria. Following infliximab infusion a reduction of the overall mean values of the five adhesion molecules was observed. However, when a Wilcoxon signed-rank test was used, only significant differences for sICAM-3 and sP-selectin were observed. In this regard, sICAM-3 and sP-selectin levels fell in 26 (77%) and 28 (82%) of the 34 patients.Our study confirms a rapid and beneficial effect of infliximab infusion on expression of some adhesion molecules in RA patients treated periodically with this anti-TNF-alpha monoclonal antibody because of severe disease.

Endothelial dysfunction has been found in patients with rheumatoid arthritis (RA). In this study we aimed to assess whether adalimumab, a fully human monoclonal antibody directed against TNF-alpha, was able to improve endothelial function in RA patients with long-standing disease refractory to infliximab.Eight RA patients (7 women; range: 24- 74 years) were studied. They had been treated with the chimeric monoclonal anti-TNF-alpha antibody-infliximab for at least 1 year and were switched to adalimumab therapy because of loss of efficacy following periodical treatment with infliximab. Endothelial dependent (EDV) and independent vasodilatation (EIV) were measured by brachial ultrasonography. Patients were assessed prior to (day 0) and at day 2, and weeks 2 and 12 after the onset of adalimumab therapy.Following adalimumab administration a rapid increase in the percentage (%) of EDV was found in all patients (mean +/- SD: 10.1 +/- 5.1% at day 2 compared to 5.8 +/- 4.1% at day 0). At weeks 2 and 12 the %EDV was also significantly increased compared to day 0. All patients showed decrease in the disease activity score 28 and C-reactive protein levels (P = 0.012). Moreover, at week 12 the atherogenic index was reduced in all patients (P = 0.012).Our study confirms that short-term adalimumab therapy yields an active and positive effect on endothelial function in long-standing RA patients with severe disease. This observation emphasizes the potential role of the TNF-alpha blockade in the mechanisms implicated in the development of atherogenesis in RA.

Systemic inflammation, insulin resistance, and endothelial dysfunction have been implicated in the development of cardiovascular disease in rheumatoid arthritis (RA). Since insulin resistance can promote endothelial dysfunction and anti-TNF-alpha blockade yield a rapid improvement of endothelial function, we have sought to assess whether TNF-alpha blockade may also result in a reduction of insulin serum levels and improvement of insulin resistance in RA patients who require this therapy because of severe and refractory disease.We recruited patients with RA seen over a period of 1 month at Hospital Xeral-Calde, Lugo, Spain, that were on treatment with anti-TNF-alpha monoclonal antibody-infliximab. Patients with diabetes mellitus or plasma glucose110 mg/dl were excluded. Fasting blood samples were taken for determination of plasma glucose and serum insulin levels immediately prior to and after infliximab infusion.Twenty-seven RA patients (21 women; mean age: 57.1 years; mean DAS28: 4.43) fulfilled the inclusion criteria. Dramatic reduction in the serum insulin levels and insulin/glucose index was observed following infliximab infusion. Also, a significant improvement of insulin resistance and insulin sensitivity was found.Our study confirms a rapid beneficial effect of infliximab on insulin resistance and insulin sensitivity in RA patients treated periodically with this drug. It may support the long-term use of drugs that act blocking TNF-alpha function to reduce the mechanisms implicated in the development of atherosclerosis in patients with RA.

To examine the frequency and predictors of cerebrovascular accidents (CVA) in giant cell arteritis (GCA) patients from a defined population.Retrospective study of biopsy-proven GCA patients diagnosed from 1981 through 2001 at the single hospital for the population of Lugo (Northwest Spain).Thirty (14.3%) of the 210 biopsy-proven GCA patients had CVA, 5 of them (16.7%) involving the vertebrobasilar territory. Five patients (4 of them involving the carotid territory) had CVA within the 2 years prior to the onset of GCA symptoms. Four patients had CVA within the first month after the diagnosis of the disease. Of these, 3 involved the vertebrobasilar territory. Another 5 patients suffered carotid stroke between the 4th and the 12th month after the disease diagnosis. The remaining 16 GCA patients had CVA (all but one involving the carotid territory) at least 1 year after the diagnosis of vasculitis. No differences in the clinical and laboratory features at the time of diagnosis between patients who had CVA and the rest of the biopsy-proven GCA patients were observed. However, hypertension and hyperlipidemia at the time of diagnosis of GCA were associated with the development of CVA (p0.05 for both). Also, anemia at the time of diagnosis (hemoglobin12 g/dL) [hazard ratio = 0.34 (95% CI 0.12 - 1.00; p = 0.05)] was negatively associated with CVA within the first 10 years after the diagnosis of the disease. Mortality in GCA patients with CVA was not significantly higher than that in patients without CVA (hazard ratio = 1.53; p = 0.14).The present study confirms that CVA may occur in GCA. Vertebrobasilar accidents are more common than carotid accidents at the time of diagnosis of the disease. Vascular risk factors should be carefully controlled in the follow-up of GCA patients.

A high erythrocyte sedimentation rate (ESR) is considered to be a hallmark of giant cell arteritis (GCA) and one of the 1990 American College of Rheumatology classification criteria. We studied 248 patients with GCA to assess the frequency and clinical features of patients with GCA and an ESR50 mm/h. Ten patients had a low ESR (43.1 +/- 4.9 mm/h) and in the remaining 238, the ESR wasor = 50 mm/h (96.4 +/-23.6). None of the patients with an ESR less than 50 had a completely normal ESR. The spectrum of the disease in both groups was very similar. Both groups required similar corticosteroid therapy and had a similar outcome. The ESR, analysed as a continuous variable, showed a significant positive correlation with other parameters reflecting the acute-phase response such as presence of anaemia, weight loss and fever. We suggest that in patients with a clinical picture compatible with GCA, the use of an ESRor = 30 mm/h as the main laboratory parameter to consider the possibility of GCA would be enough to arise the suspicion and prevent cases of GCA being missed.

A 38 year old female owner of a fashion shop presented at the rheumatology outpatient clinic because of intense pain and nodular lesions in her hands (fig 1A). She had a 1 year history of pain and multiple small intradermal deposits, with drainage of white chalky material. She had been initially considered to have an infection owing to the presence of a pyogenic pustule. Because of this, she had been treated with several courses of antibiotics (oral cloxacillin for 2 weeks and then oral amoxicillin plus clavulanic acid for another 2 weeks) draining a thick material, but not frank pus. At the outpatient clinic a needle aspiration obtained a thick white matter. Cultures were sterile and the material contained numerous monosodium urate crystals. She was diagnosed as having intradermal tophaceous …

Collagen-induced arthritis (CIA) is an animal model of auto-immune inflammatory polyarthritis which has features similar to rheumatoid arthritis (RA). Much like RA, susceptibility to mouse CIA is influenced by the major histocompatibility complex (MHC) and is restricted to the H2 haplotypes q and r. In previous experiments, we have found that the introduction of an H2-Ebd transgene in H2-Aq CIA-susceptible mice was able to protect these mice against disease development. More recently, we have proposed that the polymorphism of the first domain of the Ebeta molecule modulates this protection, and that the presentation of a peptide from the third hypervariable region of the Ebeta chain by the H2-Aq molecule plays an important role in this mechanism. In the present report, we investigated whether the H2-E-mediated protection is H2-Aq-specific and whether the source of collagen has any influence. While the source of collagen had no effect on the protection, our results showed that the H2-E molecule failed to protect B10.RIII (H2(r)) mice against CIA. Further, the H2 haplotype r exerted a negative effect on the Ebetad-mediated protection in H2-Aq-restricted disease. Our results provide additional proof that self-MHC-derived peptides, such as Ebeta peptides, may play an important role in the T-cell repertoire education and/or modulation of the T-cell response in the periphery.

Aim Pre-B cell colony-enhancing factor (PBEF) is intricately involved in inflammation and fibrosis, functional polymorphisms of PBEF have been previously shown to influence PBEF expression and pulmonary damage. Systemic sclerosis (SSc) is a disease in which inflammation, fibrosis and pulmonary deterioration are prominent hallmarks. Therefore the authors here investigate the role of the PBEF -1001T>G and PBEF -1543C>T polymorphisms in the genetic predisposition to SSc susceptibility and pulmonary involvement. Patients and methods The authors genotyped DNA from 2737 SSc patients and 1913 matched healthy controls, both from eight different ethnic populations. Genotyping was performed using custom Taqman 59 allelic discrimination assays. In addition, PBEF serum expression levels were measured by ELISA and correlated with genotypes. Results In two separate populations and in a meta-analysis, the combined PBEF -1543CC -1001TT genotype , hence carrying no minor alleles, was found associated with SSc susceptibility (p=0.009 OR 1.20 (95% CI 1.05 to 1.37)). In addition, these subjects showed an increased decline in forced vital capacity over 15 years follow-up (p=0.02) (HR 1.64, 95% CI 1.02 to 2.64) and a higher PBEF serum concentration (p PBEF -1001TT were at lower risk for PAH development within 15 years of disease onset compared to the carriers with genotypes PBEF -1001GG and PBEF -1001TG (p Conclusions This data identify PBEF as a novel candidate gene that influences SSc susceptibility, pulmonary function and the development of PAH.

To assess whether children with Henoch-Schonlein purpura (HSP) who had an upper respiratory tract infection (URTI) or received medication prior to the onset of the disease exhibited a different clinical spectrum of features and outcome from children without such a history.Retrospective study of children (or = 14 years old) with HSP diagnosed from 1980 through December 2001 at the single hospital for the Lugo region (Northwest Spain). Children with primary cutaneous vasculitis were classified as having HSP according to currently used criteria. Drugs or URTI were considered precipitating events if any new medication was taken or an URTI had occurred within a week prior to the onset of the vasculitis. A comparative analysis of clinical and laboratory features according to the presence or absence of URTI and drugs was conducted.Eighty-six children fulfilled the classification criteria for HSP. Eight of them were excluded from this analysis due to insufficient follow-up (less than 1 year post-diagnosis). An URTI and a history of drugs were reported to occur in 32/78 (41%) and 23/78 (30%) children respectively. No differences in the age at the onset of the disease, gender and seasonal incidence between children with or without URTI were observed. However, 23/32 (72%) children with URTI had hematuria with or without proteinuria, compared with only 18/46 (39%) children without history of URTI (p = 0.004). This higher incidence of renal manifestations in HSP with URTI was not associated with more severe nephritis or with a significantly higher frequency of renal sequelae or relapses of the disease. No statistically significant differences between children with or without a history of drugs were observed.Although in unselected children with HSP a history of URTI seems to be associated with a higher incidence of nephritis, it does not influence the outcome of the disease.