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1.
Reumatol. clín. (Barc.) ; 15(1): 54-57, ene.-feb. 2019. tab, graf
Artigo em Espanhol | IBECS | ID: ibc-176077

RESUMO

Objetivo: Comparar la supervivencia de los anti-TNF subcutáneos utilizados durante el periodo 2008-2012 según práctica clínica. Material y métodos: Estudio observacional retrospectivo de todos los pacientes diagnosticados de AR que habían iniciado tratamiento con un anti-TNF subcutáneo y mantenido durante al menos 6 meses. Los datos fueron analizados mediante SPSS V17,0. Resultados: Cuarenta y nueve pacientes con AR iniciaron tratamiento con anti-TNF subcutáneo (32 con etanercept y 17 con adalimumab). La media de edad fue de 45,94 años (75,5% mujeres). La media de duración de la enfermedad previa al inicio del anti-TNF fue de 2,67 años. La media de edad al inicio del tratamiento fue de 51,84 años, índice de actividad de la enfermedad en 28 articulaciones medio de 4,93. La supervivencia media del tratamiento anti-TNF fue de 8,40 años, mostrando una mayor supervivencia etanercept. La principal razón de discontinuación fue por fallo secundario (90,9%). Conclusión: En la práctica clínica habitual, la supervivencia a largo plazo de los tratamientos anti-TNF subcutáneos fue elevada e independiente de que tuvieran o no tratamiento inmunosupresor concomitante


Objective:To compare the survival of subcutaneous anti-tumor necrosis factor (TNF) drugs used between 2008 and 2012 prescribed in accordance with clinical practice. Material and methods:Retrospective, observational study of the patients in our center diagnosed with rheumatoid arthritis (RA). We included patients who had received a subcutaneous anti-TNF agent for at least 6 months. The data were analyzed using the SPSS V17.0 statistical package. Results:Forty-nine RA patients started subcutaneous biological treatment with an anti-TNF agent (32 with etanercept and 17 with adalimumab). The mean age was 45.94 years (75.5% female). The mean disease duration prior to starting anti-TNF administration was 2.67 years. The mean age at the start of treatment was 51.84 years, and the average Disease Activity Score 28 was 4.93. The median survival of the anti-TNF treatment was 8.40 years; the survival of etanercept was the longer of the two. The main reason for discontinuation was secondary failure (90.9%). Conclusions:In routine clinical practice, the survival of subcutaneous anti-TNF treatment was extensive and was independent of whether or not the patients received concomitant immunosuppressive therapy


Assuntos
Humanos , Artrite Reumatoide/tratamento farmacológico , Terapia Biológica , Fatores de Necrose Tumoral/antagonistas & inibidores , Etanercepte/farmacocinética , Adalimumab/uso terapêutico , Injeções Subcutâneas , Resultado do Tratamento , Estudos Retrospectivos , Disponibilidade Biológica
2.
Arthritis Rheumatol ; 2018 Sep 24.
Artigo em Inglês | MEDLINE | ID: mdl-30251476

RESUMO

OBJECTIVE: A genome-wide association study (GWAS) was conducted to shed light into the genetic background influencing the development of cardiovascular (CV) disease in patients diagnosed with rheumatoid arthritis (RA). METHODS: After quality control and imputation, a total of 6,308,944 polymorphisms across the whole genome were analysed in 2,989 RA patients from European origin. Data on subclinical atherosclerosis, obtained by carotid ultrasonography through assessment of carotid intima-media thickness (cIMT) and presence/absence of carotid plaques, were available for 1,355 individuals. RESULTS: A genetic variant of the RARB gene (rs116199914) was associated with cIMT values at the genome-wide level of significance (minor allele (G): beta (ß) coefficient=0.142, P=1.86E-08). Interestingly, rs116199914 overlapped with regulatory elements in tissues related to CV pathophysiology and immune cells. In addition, biological pathway enrichment and predictive protein-protein relationship analyses, including suggestive GWAS signals of potential relevance, revealed a functional enrichment of the collagen biosynthesis network related to the presence/absence of carotid plaques (GO:0032964, PFDR =4.01E-03). Furthermore, our data suggest a potential influence of the previously described candidate CV risk loci NFKB1, MSRA and ZC3HC1 (P=8.12E-04, P=5.94E-04 and P=2.46E-04, respectively). CONCLUSION: Our study strongly suggests that genetic variation within RARB contributes to the development of subclinical atherosclerosis in patients with RA. This article is protected by copyright. All rights reserved.

3.
Sci Rep ; 7(1): 5088, 2017 Jul 11.
Artigo em Inglês | MEDLINE | ID: mdl-28698626

RESUMO

The genetic component of Immunoglobulin-A (IgA) vasculitis is still far to be elucidated. To increase the current knowledge on the genetic component of this vasculitis we performed the first genome-wide association study (GWAS) on this condition. 308 IgA vasculitis patients and 1,018 healthy controls from Spain were genotyped by Illumina HumanCore BeadChips. Imputation of GWAS data was performed using the 1000 Genomes Project Phase III dataset as reference panel. After quality control filters and GWAS imputation, 285 patients and 1,006 controls remained in the datasets and were included in further analysis. Additionally, the human leukocyte antigen (HLA) region was comprehensively studied by imputing classical alleles and polymorphic amino acid positions. A linkage disequilibrium block of polymorphisms located in the HLA class II region surpassed the genome-wide level of significance (OR = 0.56, 95% CI = 0.46-0.68). Although no polymorphic amino acid positions were associated at the genome-wide level of significance, P-values of potential relevance were observed for the positions 13 and 11 of HLA-DRB1 (P = 6.67E-05, P = 1.88E-05, respectively). Outside the HLA, potential associations were detected, but none of them were close to the statistical significance. In conclusion, our study suggests that IgA vasculitis is an archetypal HLA class II disease.

4.
Reumatol Clin ; 2017 May 25.
Artigo em Inglês, Espanhol | MEDLINE | ID: mdl-28551175

RESUMO

OBJECTIVE: To compare the survival of subcutaneous anti-tumor necrosis factor (TNF) drugs used between 2008 and 2012 prescribed in accordance with clinical practice. MATERIAL AND METHODS: Retrospective, observational study of the patients in our center diagnosed with rheumatoid arthritis (RA). We included patients who had received a subcutaneous anti-TNF agent for at least 6 months. The data were analyzed using the SPSS V17.0 statistical package. RESULTS: Forty-nine RA patients started subcutaneous biological treatment with an anti-TNF agent (32 with etanercept and 17 with adalimumab). The mean age was 45.94 years (75.5% female). The mean disease duration prior to starting anti-TNF administration was 2.67 years. The mean age at the start of treatment was 51.84 years, and the average Disease Activity Score 28 was 4.93. The median survival of the anti-TNF treatment was 8.40 years; the survival of etanercept was the longer of the two. The main reason for discontinuation was secondary failure (90.9%). CONCLUSIONS: In routine clinical practice, the survival of subcutaneous anti-TNF treatment was extensive and was independent of whether or not the patients received concomitant immunosuppressive therapy.

5.
Sci Rep ; 7: 40303, 2017 01 06.
Artigo em Inglês | MEDLINE | ID: mdl-28059143

RESUMO

A genetic component influences the development of atherosclerosis in the general population and also in rheumatoid arthritis (RA). However, genetic polymorphisms associated with atherosclerosis in the general population are not always involved in the development of cardiovascular disease (CVD) in RA. Accordingly, a study in North-American RA patients did not show the association reported in the general population of coronary artery disease with a series of relevant polymorphisms (TCF21, LPA, HHIPL1, RASD1-PEMT, MRPS6, CYP17A1-CNNM2-NT5C2, SMG6-SRR, PHACTR1, WDR12 and COL4A1-COL4A2). In the present study, we assessed the potential association of these polymorphisms with CVD in Southern European RA patients. We also assessed if polymorphisms implicated in the increased risk of subclinical atherosclerosis in non-rheumatic Caucasians (ZHX2, PINX1, SLC17A4, LRIG1 and LDLR) may influence the risk for CVD in RA. 2,609 Spanish patients were genotyped by TaqMan assays. Subclinical atherosclerosis was determined in 1,258 of them by carotid ultrasonography (assessment of carotid intima media thickness and presence/absence of carotid plaques). No statistically significant differences were found when each polymorphism was assessed according to the presence/absence of cardiovascular events and subclinical atherosclerosis, after adjustment for potential confounder factors. Our results do not show an association between these 15 polymorphisms and atherosclerosis in RA.


Assuntos
Artrite Reumatoide/genética , Aterosclerose/complicações , Aterosclerose/genética , Doença da Artéria Coronariana/complicações , Doença da Artéria Coronariana/genética , Predisposição Genética para Doença , Polimorfismo de Nucleotídeo Único/genética , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Fatores de Risco , Espanha
6.
Sci Rep ; 6: 31979, 2016 08 18.
Artigo em Inglês | MEDLINE | ID: mdl-27534721

RESUMO

Association between elevated C-reactive protein (CRP) serum levels and subclinical atherosclerosis and cardiovascular (CV) events was described in rheumatoid arthritis (RA). CRP, HNF1A, LEPR, GCKR, NLRP3, IL1F10, PPP1R3B, ASCL1, HNF4A and SALL1 exert an influence on elevated CRP serum levels in non-rheumatic Caucasians. Consequently, we evaluated the potential role of these genes in the development of CV events and subclinical atherosclerosis in RA patients. Three tag CRP polymorphisms and HNF1A, LEPR, GCKR, NLRP3, IL1F10, PPP1R3B, ASCL1, HNF4A and SALL1 were genotyped in 2,313 Spanish patients by TaqMan. Subclinical atherosclerosis was determined in 1,298 of them by carotid ultrasonography (by assessment of carotid intima-media thickness-cIMT-and presence/absence of carotid plaques). CRP serum levels at diagnosis and at the time of carotid ultrasonography were measured in 1,662 and 1,193 patients, respectively, by immunoturbidimetry. Interestingly, a relationship between CRP and CRP serum levels at diagnosis and at the time of the carotid ultrasonography was disclosed. However, no statistically significant differences were found when CRP, HNF1A, LEPR, GCKR, NLRP3, IL1F10, PPP1R3B, ASCL1, HNF4A and SALL1 were evaluated according to the presence/absence of CV events, carotid plaques and cIMT after adjustment. Our results do not confirm an association between these genes and CV disease in RA.


Assuntos
Artrite Reumatoide/sangue , Artrite Reumatoide/genética , Aterosclerose/sangue , Aterosclerose/genética , Proteína C-Reativa/genética , Doenças Cardiovasculares/sangue , Doenças Cardiovasculares/genética , Idoso , Artrite Reumatoide/epidemiologia , Aterosclerose/diagnóstico por imagem , Aterosclerose/epidemiologia , Doenças Cardiovasculares/diagnóstico por imagem , Doenças Cardiovasculares/epidemiologia , Grupo com Ancestrais do Continente Europeu , Feminino , Predisposição Genética para Doença , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo Genético , Fatores de Risco
7.
Clin Exp Rheumatol ; 34(3 Suppl 97): S84-8, 2016 May-Jun.
Artigo em Inglês | MEDLINE | ID: mdl-26842496

RESUMO

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.


Assuntos
Interleucina-1beta/genética , Nefropatias/etiologia , Polimorfismo de Nucleotídeo Único , Púrpura de Schoenlein-Henoch/genética , Adolescente , Criança , Pré-Escolar , Feminino , Marcadores Genéticos/genética , Genótipo , Humanos , Masculino , Púrpura de Schoenlein-Henoch/complicações
8.
PLoS One ; 10(11): e0143153, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26571131

RESUMO

OBJECTIVES: To determine whether the interleukin-33 (IL-33)-interleukin-1 receptor like 1 (IL-1RL1) signaling pathway is implicated in the risk of subclinical atherosclerosis in patients with rheumatoid arthritis (RA). METHODS: A total of 576 Spanish RA patients from Northern Spain were genotyped for 6 well-known IL33-IL1RL1 polymorphisms (IL33 rs3939286, IL33 rs7025417, IL33 rs7044343, IL1RL1 rs2058660, IL1RL1 rs2310173 and IL1RL1 rs13015714) by TaqMan genotyping assay. The presence of subclinical atherosclerosis was determined by the assessment of carotid intima-media thickness (cIMT) by carotid ultrasound (US). RESULTS: RA patients carrying the TT genotype of the IL33 rs3939286 polymorphism had lower cIMT values than those homozygous for the CC genotype (mean ± standard deviation (SD): 0.71 ± 0.14 mm versus 0.76 ± 0.16 mm, respectively) while patients carrying the CT genotype had intermediate cIMT values (mean ± SD: 0.73 ± 0.17 mm). Moreover, RA patients carrying the mutant allele T of the IL33 rs3939286 polymorphism exhibited significantly lower cIMT values than those carrying the wild allele C (mean ± SD: 0.72 ± 0.16 mm versus 0.75 ± 0.18 mm respectively; p = 0.04). The association of both genotype and allele frequencies of IL33 rs3939286 and cIMT levels remained statistically significant after adjustment for sex, age at the time of US study, follow-up and center (p = 0.006 and p = 0.0023, respectively), evidencing that the potential effect conferred by IL33 rs3939286 may be independent of confounder factors. No association with other IL33-IL1RL1 genetic variants was observed. CONCLUSIONS: In conclusion, our results may suggest a potential protective effect of the IL33 rs3939286 allele T in the risk of subclinical atherosclerosis in patients with RA.


Assuntos
Artrite Reumatoide/genética , Aterosclerose/genética , Interleucina-33/genética , Adulto , Idoso , Alelos , Artrite Reumatoide/complicações , Aterosclerose/etiologia , Artérias Carótidas/diagnóstico por imagem , Feminino , Seguimentos , Frequência do Gene , Genótipo , Humanos , Desequilíbrio de Ligação , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Receptores Tipo I de Interleucina-1/genética , Risco , Ultrassonografia
9.
Arthritis Res Ther ; 17: 286, 2015 Oct 13.
Artigo em Inglês | MEDLINE | ID: mdl-26458874

RESUMO

INTRODUCTION: To determine whether the PTPN22 (protein tyrosine phosphatase nonreceptor 22)/CSK (c-src tyrosine kinase) pathway is implicated in the susceptibility and clinical heterogeneity of Henoch-Schönlein purpura (HSP) in the largest series of Caucasian HSP patients ever assessed for genetic studies. METHODS: A set of 329 Spanish patients diagnosed with HSP fulfilling the American College of Rheumatology and the Michel et al. classification criteria and 515 sex and ethnically matched controls were recruited in this study. Two well-known CSK (CSK rs34933034 and CSK rs1378942) and two functional PTPN22 (PTPN22 rs2476601 (R620W) and PTPN22 rs33996649 (R263Q)) polymorphisms, previously associated with autoimmunity, were genotyped with TaqMan single nucleotide polymorphism (SNP) genotyping assays. RESULTS: No significant differences in the genotype and allele frequencies between HSP patients and controls were observed when the CSK rs34933034, CSK rs1378942, PTPN22 rs2476601 (R620W) and PTPN22 rs33996649 (R263Q) polymorphisms were analyzed independently. In keeping with this observation, no significant differences were found when we assessed these polymorphisms combined conforming haplotypes. In addition, there were no differences in the allele or genotype frequencies when HSP patients were stratified according the age at disease onset, sex, presence of arthralgia/arthritis, nephritis or gastrointestinal manifestations. CONCLUSIONS: Our results do not support association between PTPN22/CSK and HSP.


Assuntos
Predisposição Genética para Doença/genética , Polimorfismo de Nucleotídeo Único , Proteína Tirosina Fosfatase não Receptora Tipo 22/genética , Púrpura de Schoenlein-Henoch/genética , Quinases da Família src/genética , Adulto , Criança , Feminino , Frequência do Gene , Genótipo , Humanos , Masculino , Reação em Cadeia da Polimerase em Tempo Real , Espanha
10.
Rheumatol Int ; 35(12): 2069-78, 2015 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-26143161

RESUMO

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.


Assuntos
Antirreumáticos/farmacologia , Doenças Cardiovasculares/etiologia , Células Endoteliais/efeitos dos fármacos , Infliximab/farmacologia , Espondilite Anquilosante/tratamento farmacológico , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Antirreumáticos/uso terapêutico , Biomarcadores/sangue , Doenças Cardiovasculares/metabolismo , Quimiocina CCL2/sangue , Selectina E/sangue , Células Endoteliais/metabolismo , Endotélio Vascular/efeitos dos fármacos , Endotélio Vascular/metabolismo , Feminino , Humanos , Infliximab/uso terapêutico , Masculino , Espondilite Anquilosante/complicações , Espondilite Anquilosante/metabolismo , Molécula 1 de Adesão de Célula Vascular/sangue
11.
Arthritis Res Ther ; 17: 102, 2015 Apr 14.
Artigo em Inglês | MEDLINE | ID: mdl-25889603

RESUMO

INTRODUCTION: A study was conducted to determine whether the human leukocyte antigen (HLA) B alleles are implicated in the susceptibility to Henoch-Schönlein purpura (HSP) in the largest series of Caucasian HSP patients ever assessed for genetic studies. METHODS: The study population was composed of 349 Spanish patients diagnosed with HSP fulfilling the American College of Rheumatology and the Michel et al. classification criteria, and 335 sex and ethnically matched controls. HLA-B phenotypes were determined by sequencing-based typing (SBT) and analyzed by chi-square or Fisher exact test. RESULTS: A statistically significant increase of HLA-B*41:02 allele in HSP patients when compared with controls was found (8.3% versus 1.5% respectively; P = 0.0001; OR (odds ratio) =5.76 [2.15-19.3]). These results remained statistically significant after adjusting for Bonferroni correction (P = 0.0028). An internal validation also confirmed the susceptibility effect on HSP associated with HLA-B*41:02 (OR = 5.70 [1.98-16.44]). Since a former study described an association between HLA-DRB1*01:03 and HSP susceptibility, we also evaluated the implication of HLA-B*41:02 independently of HLA-DRB1*01:03. Interestingly, the association remained statistically significant (P = 0.0004, OR = 4.97 [1.8-16.9]). No HLA-B association with specific HSP clinical features was found. CONCLUSIONS: Our study indicates that HLA-B*41:02 is associated with the susceptibility to HSP in Spanish patients irrespective of HLA-DRB1 status.


Assuntos
Estudos de Associação Genética , Predisposição Genética para Doença/genética , Antígenos HLA-B/genética , Cadeias HLA-DRB1/genética , Púrpura de Schoenlein-Henoch/epidemiologia , Púrpura de Schoenlein-Henoch/genética , Adolescente , Criança , Pré-Escolar , Feminino , Seguimentos , Estudos de Associação Genética/métodos , Humanos , Masculino , Púrpura de Schoenlein-Henoch/diagnóstico , Espanha/epidemiologia , Adulto Jovem
12.
Am J Hum Genet ; 96(4): 565-80, 2015 Apr 02.
Artigo em Inglês | MEDLINE | ID: mdl-25817017

RESUMO

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.


Assuntos
Genes MHC da Classe II/genética , Arterite de Células Gigantes/genética , Herança Multifatorial/genética , Estudos de Coortes , Grupo com Ancestrais do Continente Europeu/genética , Estudos de Associação Genética , Genótipo , Humanos , Análise Multivariada , Razão de Chances
13.
Biomed Res Int ; 2015: 318364, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-25815310

RESUMO

Rheumatoid arthritis (RA) is a polygenic disease associated with accelerated atherosclerosis and increased cardiovascular (CV) mortality. JAK/STAT signalling pathway is involved in autoimmune diseases and in the atherosclerotic process. JAK3 is a highly promising target for immunomodulatory drugs and polymorphisms in JAK3 gene have been associated with CV events in incident dialysis patients. Therefore, the aim of this study was to assess the potential role of JAK3 polymorphisms in the development of CV disease in patients with RA. 2136 Spanish RA patients were genotyped for the rs3212780 and rs3212752 JAK3 gene polymorphisms by TaqMan assays. Subclinical atherosclerosis was evaluated in 539 of these patients by carotid ultrasonography (US). No statistically significant differences were found when each polymorphism was assessed according to carotid intima-media thickness 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 events after adjusting for potential confounders. In conclusion, our results do not confirm association between JAK3 polymorphisms and CV disease in RA.


Assuntos
Artrite Reumatoide/complicações , Artrite Reumatoide/genética , Doenças Cardiovasculares/genética , Estudos de Associação Genética , Predisposição Genética para Doença , Janus Quinase 3/genética , Polimorfismo de Nucleotídeo Único/genética , Artrite Reumatoide/enzimologia , Proteína C-Reativa/metabolismo , Doenças Cardiovasculares/complicações , Doenças Cardiovasculares/enzimologia , Espessura Intima-Media Carotídea , Demografia , Feminino , Frequência do Gene/genética , Humanos , Masculino , Pessoa de Meia-Idade , Peptídeos Cíclicos/metabolismo , Placa Aterosclerótica/complicações , Placa Aterosclerótica/enzimologia , Placa Aterosclerótica/genética
14.
Arthritis Rheumatol ; 67(3): 823-827, 2015 03.
Artigo em Inglês | MEDLINE | ID: mdl-25470797

RESUMO

Objective: Henoch-Schönlein purpura (HSP) is the most common vasculitis in children but it is not exceptional in adults. Increased familial occurrence supports a genetic predisposition for HSP. In this context, an association with the human leukocyte antigen-HLA-DRB1*01 phenotype has been suggested in Caucasian individuals with HSP. However, data on the potential association of HSP with HLA-DRB1*01 were based on small case series. To further investigate this issue, we performed HLA-DRB1 genotyping of the largest series of HSP patients ever assessed for genetic studies in Caucasians. Methods: 342 Spanish patients diagnosed with HSP fulfilling the American College of Rheumatology and the Michel et al classification criteria, and 303 sex and ethnically matched controls were assessed. HLA-DRB1 alleles were determined using a PCR-Sequence-Specific-Oligonucleotide Probe (PCR-SSOP) method. Results: A statistically significant increase of HLA-DRB1*01 in HSP patients when compared with controls was found (43% vs 7%, respectively; p<0.001; odds ratio-OR=2.03 [1.43-2.87]). It was due to the increased frequency of HLA-DRB1*0103 phenotype in HSP (14% vs 2%; p<0.001; OR=8.27 [3.46-23.9]). These results remained statistically significant after adjusting for Bonferroni correction. In contrast, a statistically significant decreased frequency of the HLA-DRB1*0301 phenotype was observed in patients compared to controls (5.6% vs 18.1%, respectively; p<0.001, OR=0.26 [0.14-0.47]), even after adjustment for Bonferroni correction. No HLA-DRB1 association with specific features of the disease was found. Conclusion: Our study confirms an association of HSP with HLA-DRB1*01 in Caucasians. Also, a protective effect against the development of HSP appears to exist in Caucasians carrying the HLA-DRB1*03 phenotype. This article is protected by copyright. All rights reserved.

15.
Biomed Res Int ; 2014: 671061, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-25295265

RESUMO

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.


Assuntos
Arginina/análogos & derivados , Inflamação/genética , Fator de Crescimento Insulin-Like I/metabolismo , Síndrome Metabólica/genética , Espondilite Anquilosante/genética , Adipocinas/genética , Anticorpos Monoclonais/administração & dosagem , Arginina/genética , Arginina/metabolismo , Feminino , Humanos , Inflamação/tratamento farmacológico , Inflamação/patologia , Infliximab , Proteína 3 de Ligação a Fator de Crescimento Semelhante à Insulina/genética , Fator de Crescimento Insulin-Like I/genética , Masculino , Síndrome Metabólica/complicações , Síndrome Metabólica/tratamento farmacológico , Síndrome Metabólica/patologia , Óxido Nítrico/metabolismo , Óxido Nítrico Sintase/antagonistas & inibidores , Osteopontina/metabolismo , Osteoporose/complicações , Osteoporose/genética , Osteoporose/patologia , Espondilite Anquilosante/complicações , Espondilite Anquilosante/tratamento farmacológico , Fator de Necrose Tumoral alfa/antagonistas & inibidores
16.
Clin Exp Rheumatol ; 32(5): 640-6, 2014 Sep-Oct.
Artigo em Inglês | MEDLINE | ID: mdl-25190453

RESUMO

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.


Assuntos
Anti-Inflamatórios/uso terapêutico , Anticorpos Monoclonais/uso terapêutico , Células Endoteliais/efeitos dos fármacos , Osteoprotegerina/sangue , Espondilite Anquilosante/tratamento farmacológico , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Adipocinas/sangue , Adulto , Idoso , Biomarcadores/sangue , Células Endoteliais/imunologia , Células Endoteliais/metabolismo , Feminino , Humanos , Mediadores da Inflamação/sangue , Infliximab , Masculino , Pessoa de Meia-Idade , Índice de Gravidade de Doença , Espondilite Anquilosante/sangue , Espondilite Anquilosante/diagnóstico , Espondilite Anquilosante/imunologia , Resultado do Tratamento
17.
PLoS One ; 9(9): e106823, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-25184828

RESUMO

INTRODUCTION: Rheumatoid arthritis is an inflammatory disease with high incidence of cardiovascular disease due to accelerated atherosclerosis. Osteoprotegerin (OPG) has been associated with increased risk of atherosclerotic disease in the general population. Several polymorphisms in the OPG gene with functional effects on cardiovascular disease in non-rheumatic individuals have been described. Therefore, we aimed to analyze the effect of three of these functional OPG polymorphisms on the risk of cardiovascular disease in a large and well-characterized cohort of Spanish patients with rheumatoid arthritis. METHODS: Three OPG gene variants (rs3134063, rs2073618 and rs3134069) were genotyped by TaqMan assays in 2027 Spanish patients with rheumatoid arthritis. Anti-cyclic citrullinated peptide (anti-CCP) antibody testing was positive in 997 of 1714 tested. Also, 18.3% of the whole series had experienced cardiovascular events, including 5.4% with cerebrovascular accidents. The relationship between OPG variants and cardiovascular events was assessed using Cox regression. RESULTS: No association between OPG gene variants and cardiovascular disease was observed in the whole group of rheumatoid arthritis patients or in anti-CCP positive patients. Nevertheless, a protective effect of CGA haplotype on the risk of cardiovascular disease in general, and specifically in the risk of cerebrovascular complications after adjusting for sex, age at disease diagnosis and traditional cardiovascular risk factors was disclosed in anti-CCP negative patients (HR = 0.54; 95%CI: 0.31-0.95; p = 0.032 and HR = 0.17; 95%CI: 0.04-0.78; p = 0.022, respectively). CONCLUSION: Our results indicate a protective effect of the OPG CGA haplotype on cardiovascular risk, mainly due to a protective effect against cerebrovascular events in anti-CCP negative rheumatoid arthritis patients.


Assuntos
Artrite Reumatoide , Autoanticorpos/sangue , Transtornos Cerebrovasculares , Haplótipos , Osteoprotegerina/genética , Polimorfismo de Nucleotídeo Único , Adulto , Idoso , Artrite Reumatoide/sangue , Artrite Reumatoide/complicações , Artrite Reumatoide/genética , Transtornos Cerebrovasculares/sangue , Transtornos Cerebrovasculares/etiologia , Transtornos Cerebrovasculares/genética , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Peptídeos Cíclicos/sangue , Espanha
18.
Mediators Inflamm ; 2014: 798060, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24976690

RESUMO

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.


Assuntos
Espondilite Anquilosante/sangue , Ligante Indutor de Apoptose Relacionado a TNF/sangue , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Adulto , Anticorpos Monoclonais/uso terapêutico , Antirreumáticos/uso terapêutico , Feminino , Humanos , Infliximab , Masculino , Pessoa de Meia-Idade
19.
Arthritis Res Ther ; 16(4): R146, 2014 Jul 10.
Artigo em Inglês | MEDLINE | ID: mdl-25011482

RESUMO

INTRODUCTION: Rheumatoid arthritis (RA) is a complex polygenic inflammatory disease associated with accelerated atherosclerosis and increased cardiovascular (CV) disease risk. Interferon regulatory factor 5 (IRF5) is a regulator of type I interferon induction. Recently, researchers have described an association between multiple single-nucleotide polymorphisms of the IRF5 gene and some rheumatic disorders. In this study, we aimed to evaluate whether three different haplotype blocks within the IRF5 locus which have been shown to alter the protein function are involved in the risk of CV events occurring in Spanish RA patients. METHODS: Three IRF5 polymorphisms (rs2004640, rs2070197 and rs10954213) representative of each haplotype group were genotyped by performing TaqMan assays using a 7900HT Fast Real-Time PCR System with tissue from a total of 2,137 Spanish patients diagnosed with RA. Among them, 390 (18.2%) had experienced CV events. The relationship of IRF5 genotypes and haplotypes to CV events was tested using Cox regression. RESULTS: Male sex, age at RA diagnosis and most traditional risk factors (hypertension, dyslipidemia and smoking habit) were associated with increased risk for CV events in the RA population. Interestingly, a protective effect of both IRF5 rs2004640 GG and IRF5 rs10954213 GG genotypes against the risk for CV events after adjusting the results for sex, age at RA diagnosis and traditional CV disease risk factors was observed (hazard ratio (HR) = 0.6, 95% confidence interval (CI) = 0.38 to 0.92, P = 0.02; and HR = 0.58, 95% CI = 0.36 to 0.95, P = 0.03, respectively). Moreover, we detected a protective effect of the GTG haplotype against the risk for CV events after adjusting the results for potential confounding factors (HR = 0.72, 95% CI = 0.56 to 0.93, P = 0.012). CONCLUSIONS: Our results reveal that IRF5 gene variants are associated with risk of CV events in patients with RA.


Assuntos
Artrite Reumatoide/complicações , Artrite Reumatoide/genética , Doenças Cardiovasculares/genética , Predisposição Genética para Doença/genética , Fatores Reguladores de Interferon/genética , Polimorfismo de Nucleotídeo Único , Feminino , Genótipo , Haplótipos , Humanos , Masculino , Pessoa de Meia-Idade , Reação em Cadeia da Polimerase em Tempo Real , Fatores de Risco
20.
Mediators Inflamm ; 2014: 756279, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24795506

RESUMO

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.


Assuntos
Artrite Reumatoide/metabolismo , Doenças Cardiovasculares/metabolismo , Espessura Intima-Media Carotídea , Sistema do Grupo Sanguíneo ABO/genética , Adulto , Idoso , Classe Ib de Fosfatidilinositol 3-Quinase/genética , Feminino , Frequência do Gene , Predisposição Genética para Doença/genética , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Fosfatidato Fosfatase/genética
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