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INTRODUCTION: The nature of the relationship between inflammation, cardiovascular (CV) risk factors and atherosclerosis in axial spondyloarthritis (axSpA) remains largely unknown and sex differences in this regard are yet to be assessed. METHODS: Study including 611 men and 302 women from the Spanish multicentre AtheSpAin cohort to assess CV disease in axSpA. Data on CV disease risk factors were collected both at disease diagnosis and at enrolment, and data on disease activity, functional indices and carotid ultrasonography only at enrolment. RESULTS: After a median disease duration of 9 years, patients of both sexes who at disease diagnosis had elevated acute phase reactants (APRs), more frequently had hypertension and obesity. The same occurred with dyslipidaemia in men and with diabetes mellitus in women. At enrolment, CV risk factors were independently associated with APR and with activity and functional indices, with various sex differences. C reactive protein (CRP) values were inversely associated with HDL-cholesterol in men (ß coefficient: -1.2 (95% CI: -0.3 to -0.07) mg/dL, p=0.001), while erythrocyte sedimentation rate values were positively associated with triglycerides in women (ß coefficient: 0.6 (95% CI: 0.04 to 1) mg/dL, p=0.035). Furthermore, only women showed an independent relationship between insulin resistance parameters and APR or disease activity. Both men and women with high-very high CV risk according to the Systematic Assessment of Coronary Risk Evaluation 2 and CRP levels higher than 3 mg/L at diagnosis of the disease presented carotid plaques significantly more frequently than those with normal CRP levels at disease diagnosis. CONCLUSION: Inflammation is associated with atherosclerosis and CV disease in axSpA. A gender-driven effect is observed in this relationship.
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Aterosclerose , Fatores de Risco de Doenças Cardíacas , Inflamação , Humanos , Masculino , Feminino , Aterosclerose/epidemiologia , Aterosclerose/etiologia , Aterosclerose/diagnóstico , Pessoa de Meia-Idade , Inflamação/complicações , Adulto , Fatores Sexuais , Espondiloartrite Axial/epidemiologia , Espondiloartrite Axial/complicações , Fatores de Risco , Biomarcadores , Doenças Cardiovasculares/etiologia , Doenças Cardiovasculares/epidemiologia , Doenças Cardiovasculares/diagnóstico , Proteína C-Reativa/análise , Proteína C-Reativa/metabolismoRESUMO
Osteopontin (OPN) is a glycoprotein involved in Th1 and Th17 differentiation, and inflammation and tissue remodeling. OPN is a biomarker of disease activity in patients with autoimmune inflammatory conditions. This study aimed to assess the diagnostic and prognostic value of OPN in interstitial lung diseases (ILDs). Between May 2016 and October 2019, 344 patients with ILD were recruited at the Hospital Universitario Marqués de Valdecilla (Spain) and were prospectively followed-up. This study involved the determination of OPN serum levels by ELISA and OPN RNA expression quantified using qPCR. Six genetic polymorphisms in OPN (rs28357094, rs2853749, rs2853750, rs11728697, rs7695531, and rs1126616) were genotyped using TaqMan assays. OPN serum levels were also assessed in 140 healthy controls. OPN serum levels (median [interquartile range]) were significantly higher in ILD patients than in controls (1.05 [0.75-1.51] ng/mL versus 0.81 [0.65-0.98] ng/mL in healthy controls; p < 0.01). OPN serum levels were inversely correlated with the forced vital capacity. OPN serum levels were also higher in ILD patients who died or underwent lung transplantation when compared with the remaining ILD patients (1.15 [0.80-1.72] ng/mL versus 0.99 [0.66-1.32] ng/mL; p = 0.05). Survival worsened in ILD patients with OPN > 1.03 ng/mL at 1, 3, and 5 years. No statistically significant differences in the genetic frequencies of OPN polymorphisms or the RNA expression were found among the different ILD groups. Elevated levels of OPN in the serum may be a useful indicator in identifying patients with ILD who are more likely to experience poor outcomes.
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The most critical forms of coronavirus disease 2019 (COVID-19) are associated with excessive activation of the inflammasome. Despite the COVID-19 impact on public health, we still do not fully understand the mechanisms by which the inflammatory response influences disease prognosis. Accordingly, we aimed to elucidate the role of polymorphisms in the key genes of the formation and signaling of the inflammasome as biomarkers of COVID-19 severity. For this purpose, a large and well-defined cohort of 377 COVID-19 patients with mild (n = 72), moderate (n = 84), severe (n = 100), and critical (n = 121) infections were included. A total of 24 polymorphisms located in inflammasome-related genes (NLRP3, NLRC4, NLRP1, CARD8, CASP1, IL1B, IL18, NFKB1, ATG16L1, and MIF) were genotyped in all of the patients and in the 192 healthy controls (HCs) (who were without COVID-19 at the time of and before the study) by RT-qPCR. Our results showed that patients with mild, moderate, severe, and critical COVID-19 presented similar allelic and genotypic distribution in all the variants studied. No statistically significant differences in the haplotypic distribution of NLRP3, NLRC4, NLRP1, CARD8, CASP1, IL1B, and ATG16L1 were observed between COVID-19 patients, who were stratified by disease severity. Each stratified group of patients presented a similar genetic distribution to the HCs. In conclusion, our results suggest that the inflammasome polymorphisms studied are not associated with the worsening of COVID-19.
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COVID-19 , Inflamassomos , Humanos , Inflamassomos/genética , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , COVID-19/genética , Biomarcadores , Caspase 1/genética , Polimorfismo Genético , Proteínas de Neoplasias , Proteínas Adaptadoras de Sinalização CARD/genéticaRESUMO
OBJECTIVES: To unveil biological milieus underlying low disease activity (LDA) and remission versus active systemic lupus erythematosus (SLE). METHODS: We determined differentially expressed pathways (DEPs) in SLE patients from the PRECISESADS project (NTC02890121) stratified into patients fulfilling and not fulfilling the criteria of (1) Lupus LDA State (LLDAS), (2) Definitions of Remission in SLE remission, and (3) LLDAS exclusive of remission. RESULTS: We analysed data from 321 patients; 40.8% were in LLDAS, and 17.4% in DORIS remission. After exclusion of patients in remission, 28.3% were in LLDAS. Overall, 604 pathways differed significantly in LLDAS versus non-LLDAS patients with an false-discovery rate-corrected p (q)<0.05 and a robust effect size (dr)≥0.36. Accordingly, 288 pathways differed significantly between DORIS remitters and non-remitters (q<0.05 and dr≥0.36). DEPs yielded distinct molecular clusters characterised by differential serological, musculoskeletal, and renal activity. Analysis of partially overlapping samples showed no DEPs between LLDAS and DORIS remission. Drug repurposing potentiality for treating SLE was unveiled, as were important pathways underlying active SLE whose modulation could aid attainment of LLDAS/remission, including toll-like receptor (TLR) cascades, Bruton tyrosine kinase (BTK) activity, the cytotoxic T lymphocyte antigen 4 (CTLA-4)-related inhibitory signalling, and the nucleotide-binding oligomerization domain leucine-rich repeat-containing protein 3 (NLRP3) inflammasome pathway. CONCLUSIONS: We demonstrated for the first time molecular signalling pathways distinguishing LLDAS/remission from active SLE. LLDAS/remission was associated with reversal of biological processes related to SLE pathogenesis and specific clinical manifestations. DEP clustering by remission better grouped patients compared with LLDAS, substantiating remission as the ultimate treatment goal in SLE; however, the lack of substantial pathway differentiation between the two states justifies LLDAS as an acceptable goal from a biological perspective.
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Lúpus Eritematoso Sistêmico , Indução de Remissão , Transcriptoma , Humanos , Lúpus Eritematoso Sistêmico/tratamento farmacológico , Lúpus Eritematoso Sistêmico/sangue , Lúpus Eritematoso Sistêmico/genética , Feminino , Adulto , Masculino , Pessoa de Meia-Idade , Índice de Gravidade de Doença , Estudos de CoortesRESUMO
Interstitial lung disease (ILD) constitutes the most critical comorbidity in autoimmune diseases (ADs) and its early diagnosis remains a challenge for clinicians. Accordingly, we evaluated whether E-selectin, ICAM-1, and ET-1, key molecules in endothelial damage, could be useful biomarkers for the detection of AD-ILD+. We recruited patients with rheumatoid arthritis (RA)-ILD+ (n = 21) and systemic sclerosis (SSc)-ILD+ (n = 21). We included comparison groups of patients: RA-ILD- (n = 25), SSc-ILD- (n = 20), and idiopathic pulmonary fibrosis (IPF) (n = 21). Serum levels of these proteins were determined by ELISA. E-selectin, ICAM-1, and ET-1 serum levels were increased in RA-ILD+ and IPF patients in comparison to RA-ILD- patients. Additionally, SSc-ILD+ and IPF patients exhibited higher ICAM-1 levels than those with SSc-ILD-. The ability of E-selectin, ICAM-1, and ET-1 to discriminate RA-ILD+ from RA-ILD- patients, and ICAM-1 to distinguish SSc-ILD+ from SSc-ILD- patients was confirmed using ROC curve analysis. Furthermore, elevated levels of ET-1 and E-selectin correlated with lung function decline in RA-ILD+ and SSc-ILD+ patients, respectively. In conclusion, our findings support the relevant role of E-selectin, ICAM-1, and ET-1 in RA-ILD+ patients as well as of ICAM-1 in SSc-ILD+ patients, constituting potential screening blood biomarkers of ILD in AD. Moreover, this study suggests ET-1 and E-selectin as possible indicators of worsening lung function in RA-ILD+ and SSc-ILD+ patients, respectively.
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Artrite Reumatoide , Doenças Autoimunes , Fibrose Pulmonar Idiopática , Doenças Pulmonares Intersticiais , Escleroderma Sistêmico , Humanos , Molécula 1 de Adesão Intercelular , Selectina E , Doenças Pulmonares Intersticiais/complicações , Doenças Pulmonares Intersticiais/diagnóstico , Fibrose Pulmonar Idiopática/complicações , Fibrose Pulmonar Idiopática/diagnóstico , Doenças Autoimunes/complicações , Doenças Autoimunes/diagnóstico , Artrite Reumatoide/complicações , Artrite Reumatoide/diagnóstico , Biomarcadores , Escleroderma Sistêmico/complicações , Escleroderma Sistêmico/diagnóstico , PulmãoRESUMO
INTRODUCTION AND OBJECTIVES: Patients with clinically evident coronary artery disease differ in their rate of progression, which impacts prognosis. We aimed to characterize serum and genetic markers in patients with rapid clinical progression (RCP) of coronary artery disease vs those with long standing stable (LSS) disease. METHODS: Retrospective study of cases (RCP) and controls (LSS) (1:2). Patients requiring ≥ 2 revascularizations due to atherosclerotic progression in the 10 years after a first angioplasty were considered to be RCP and those without events during the same period after the first angioplasty were considered to have LSS disease. After patient selection, we analyzed serum values, mRNA expression and genetic polymorphisms of inflammatory markers, including interleukin-6, C-reactive protein, and tumor necrosis factor (TNF)-a, and atherogenic markers consisted of proprotein convertase subtilisin/kexin type 9 (PCSK9), low-density lipoprotein receptor, sterol regulatory element binding transcription factor 2, and apolipoprotein-B. RESULTS: The study included 180 patients (58 RCP and 122 LSS). Demographic characteristics, classic risk factors and the extent of coronary disease were similar in the 2 groups. Patients with RCP showed higher serum levels of interleukin-6 and PCSK9 and higher TNF mRNA expression. Interleukin-6 rs180075C, TNF rs3093664 non-G and PCSK9 rs2483205 T alleles conferred a risk of RCP (P<.05 in all cases). Among patients with RCP, 51.7% had all 3 risk alleles vs 18% of those with LSS (P<.001). CONCLUSIONS: We suggest the existence of specific phenotypic and genotypic markers associated with RCP of coronary artery disease that could help to individualize the type and intensity of treatment.
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Aterosclerose , Doença da Artéria Coronariana , Humanos , Pró-Proteína Convertase 9 , Doença da Artéria Coronariana/diagnóstico , Doença da Artéria Coronariana/genética , Marcadores Genéticos , Estudos Retrospectivos , Interleucina-6/genética , Progressão da Doença , RNA MensageiroRESUMO
OBJECTIVES: To determine the potential impact of sex-specific disease-related characteristics on cardiovascular (CV) disease in axial spondyloarthritis (axSpA). METHODS: Cross-sectional study of the Spanish AtheSpAin cohort to study CV disease in axSpA. Data on carotid ultrasound and CV disease and disease-related features were collected. RESULTS: 611 men and 301 women were recruited. Classic CV risk factors were significantly less prevalent in women, who also showed a lower frequency of carotid plaques (p = 0.001), lower carotid intima-media thickness (IMT) values ââ(p<0.001) and CV events (p = 0.008). However, after adjustment for classic CV risk factors, only the differences with respect to carotid IMT remained statistically significant. Women showed higher ESR at diagnosis (p = 0.038), and more active disease (ASDAS, p = 0.012, and BASDAI, p<0.001). They had shorter disease duration (p<0.001), lower prevalence of psoriasis (p = 0.008), less structural damage (mSASSS, p<0.001), and less mobility limitation (BASMI, p = 0.033). To establish whether these findings could lead to sex differences in CV disease burden, we compared the prevalence of carotid plaques in men and women with the same level of CV risk stratified according to the Systematic Coronary Risk Evaluation (SCORE). Men included in the low-moderate CV risk SCORE category had more carotid plaques (p = 0.050), along with longer disease duration (p = 0.004), higher mSASSS (p = 0.001) and psoriasis (p = 0.023). In contrast, in the high-very high-risk SCORE category, carotid plaques were observed more frequently in women (p = 0.028), who were characterized as having worse BASFI (p = 0.011), BASDAI (p<0.001) and ASDAS (p = 0.027). CONCLUSION: Disease-related features may influence the expression of atherosclerosis in patients with axSpA. This may be especially applicable to women at high CV risk, characterized by greater disease severity and more severe subclinical atherosclerosis than men, suggesting a stronger interaction between disease activity and atherosclerosis in women with axSpA.
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Aterosclerose , Espondiloartrite Axial , Doenças Cardiovasculares , Placa Aterosclerótica , Psoríase , Humanos , Masculino , Feminino , Espessura Intima-Media Carotídea , Estudos Transversais , Caracteres Sexuais , Aterosclerose/epidemiologia , Doenças Cardiovasculares/epidemiologia , Doenças Cardiovasculares/etiologiaRESUMO
OBJECTIVES: Since interleukin-6 (IL-6) is a pivotal proinflammatory cytokine implicated in the pathogenesis of giant cell arteritis (GCA), we aimed to determine the potential association of the functional IL6 -174 G/C polymorphism with GCA as well as if the single base change variation at the promoter region in the human IL-6 gene may account for differences in the clinical spectrum of GCA between cranial and extracranial large vessel vasculitis (LVV)-GCA. METHODS: The IL6 -174 G/C polymorphism (rs1800795) was genotyped in 191 patients with biopsy-proven GCA who had typical cranial manifestations of the disease, 109 patients with extracranial LVV-GCA, without cranial ischaemic manifestations of GCA, and 877 ethnically matched unaffected controls. A comparative study was carried out between patients with cranial and extracranial LVV-GCA and controls. RESULTS: No significant differences in genotype and allele frequencies of IL6 -174 G/C polymorphism were found between the whole cohort of GCA patients and healthy controls. It was also the case when cranial and extracranial LVV-GCA were compared or when each of these subgroups was compared to controls. Moreover, no significant results in genotype and allele frequencies of IL6 -174 G/C polymorphism were disclosed when the whole cohort of GCA patients were stratified according to the presence of polymyalgia rheumatica, severe ischaemic manifestations, including permanent visual loss and peripheral arteriopathy, and HLA-DRB1*04:01 status. CONCLUSIONS: Our results show that the IL6 -174 G/C polymorphism does not influence the phenotypic expression of GCA.
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Arterite de Células Gigantes , Polimialgia Reumática , Humanos , Arterite de Células Gigantes/genética , Arterite de Células Gigantes/patologia , Interleucina-6/genética , Polimorfismo Genético , Frequência do Gene , Isquemia/genética , Predisposição Genética para DoençaRESUMO
The aim of this study was to determine the role of endothelin-1 (ET-1), a molecule involved in multiple vascular and fibrosing abnormalities, as a biomarker of interstitial lung disease (ILD), as well as its use for the differential diagnosis between idiopathic pulmonary fibrosis (IPF) and ILD associated with autoimmune diseases (AD-ILD), using a large and well-defined cohort of patients with ILD. A total of 112 patients with IPF, 91 patients with AD-ILD (28 rheumatoid arthritis (RA), 26 systemic sclerosis, 20 idiopathic inflammatory myositis and 17 interstitial pneumonia with autoimmune features) and 44 healthy controls were included. ET-1 serum levels were determined by enzyme-linked immunosorbent assay. A significant increase in ET-1 levels was found in patients with IPF compared to controls. Likewise, AD-ILD patients also showed higher ET-1 levels than controls when the whole cohort was stratified by the type of AD. Similar ET-1 levels were found in IPF and AD-ILD patients, regardless of the underlying AD. Interestingly, increased ET-1 levels were correlated with worse lung function in IPF and RA-ILD patients. Our study supports that serum ET-1 may be useful as a biomarker of ILD, although it could not help in the differential diagnosis between IPF and AD-ILD. Moreover, ET-1 levels may be associated with ILD severity.
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Artrite Reumatoide , Doenças Autoimunes , Fibrose Pulmonar Idiopática , Doenças Pulmonares Intersticiais , Humanos , Endotelina-1 , Doenças Pulmonares Intersticiais/complicações , Doenças Pulmonares Intersticiais/diagnóstico , Fibrose Pulmonar Idiopática/complicações , Fibrose Pulmonar Idiopática/diagnóstico , Doenças Autoimunes/complicações , Doenças Autoimunes/diagnóstico , Artrite Reumatoide/complicações , Artrite Reumatoide/diagnóstico , BiomarcadoresRESUMO
OBJECTIVES: To analyse the influence of adipokines on attaining the clinical outcomes in patients with axial spondyloarthritis (axSpA) treated with TNF inhibitors (TNFi), and then, to investigate the association of patients' characteristics and adipokine concentrations. METHODS: This was a longitudinal study including 110 patients with axSpA who were initiated at TNFi and were followed-up for 6 months (m). Disease activity was assessed by Ankylosing Spondylitis Disease Activity Score (ASDAS) at baseline and at 6 m of treatment. Clinical outcomes at 6 m of treatment were defined as remission (ASDAS <1.3) and the attainment of low disease activity (LDA; ASDAS<2.1). Leptin and adiponectin concentrations were measured in serum samples collected at baseline and after 6 m. RESULTS: Both leptin and adiponectin were constitutively elevated in female axSpA patients. At time of TNFi initiation, leptin concentrations were higher in patients with high body mass index (overweight or obese). On the contrary, adiponectin was higher in normalweight patients. After 6 m of TNFi treatment, 24% of patients attained remission. They had significant lower leptin concentration at baseline compared with patients who did not attain remission. Furthermore, this difference remained significant after 6 m of treatment meaning that TNFi did not modify adipokine concentration. Similar results were found considering LDA as the clinical outcome, obtained in 48% of the patients. CONCLUSIONS: The present study showed that low leptin concentrations were associated with attaining clinical outcomes in axSpA patients treated with TNFi. In addition, since leptin secretion by white adipocytes is enhanced during obesity and considering that TNFi do not seem to modulate its expression, obese patients should be encouraged to decrease BMI to attain a successful therapy.
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Espondilartrite , Espondilite Anquilosante , Humanos , Feminino , Inibidores do Fator de Necrose Tumoral/uso terapêutico , Estudos Longitudinais , Leptina , Adiponectina , Fator de Necrose Tumoral alfa , Resultado do Tratamento , Espondilite Anquilosante/tratamento farmacológico , Obesidade , Espondilartrite/tratamento farmacológico , Índice de Gravidade de DoençaRESUMO
OBJECTIVES: Two main different clinical phenotypes of giant cell arteritis (GCA) have been described, the classic cranial pattern and the extracranial large-vessel (LV) pattern. Since interferon gamma (IFNG) has shown to be a pivotal cytokine in the pathophysiology of GCA, our aim was to evaluate for the first time the influence of IFNG and IFNG receptor 1 (IFNGR1) polymorphisms in the different clinical phenotypes of GCA. METHODS: Two IFNG polymorphisms (rs2069718 G/A and rs1861493 A/G) and one polymorphism in IFNGR1 (rs1327474 G/A) were genotyped in 191 patients with biopsy-proven cranial GCA, 109 with extracranial LV-GCA and 490 healthy controls. A comparative study was conducted between patients with cranial and extracranial LV-GCA. RESULTS: No significant differences in genotype, allele, and haplotype frequencies of IFNG polymorphisms were found between GCA patients with the classic cranial pattern and the extracranial LV-GCA pattern. Similar results were found for genotype and allele frequencies of IFNGR1 polymorphism. It was also the case when patients with extracranial LV-GCA were compared with healthy controls. CONCLUSIONS: Our results show that IFNG and IFNGR1 polymorphisms do not influence the clinical phenotype of expression of GCA. Classic cranial GCA and extracranial LV-GCA seem to share a genetic pattern of IFNG pathway.
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Arterite de Células Gigantes , Humanos , Arterite de Células Gigantes/genética , Interferon gama/genética , Polimorfismo Genético , Frequência do Gene , Genótipo , Predisposição Genética para DoençaRESUMO
CD40, BLK and BANK1 genes involved in the development and signaling of B-cells are identified as susceptibility loci for numerous inflammatory diseases. Accordingly, we assessed the potential influence of CD40, BLK and BANK1 on the pathogenesis of immunoglobulin-A vasculitis (IgAV), predominantly a B-lymphocyte inflammatory condition. Three genetic variants within CD40 (rs1883832, rs1535045, rs4813003) and BLK (rs2254546, rs2736340, rs2618476) as well as two BANK1 polymorphisms (rs10516487, rs3733197), previously associated with inflammatory diseases, were genotyped in 382 Caucasian patients with IgAV and 955 sex- and ethnically matched healthy controls. No statistically significant differences were observed in the genotype and allele frequencies of CD40, BLK and BANK1 when IgAV patients and healthy controls were compared. Similar results were found when CD40, BLK and BANK1 genotypes or alleles frequencies were compared between patients with IgAV stratified according to the age at disease onset or to the presence/absence of gastrointestinal or renal manifestations. Moreover, no CD40, BLK and BANK1 haplotype differences were disclosed between patients with IgAV and healthy controls and between patients with IgAV stratified according to the clinical characteristics mentioned above. Our findings indicate that CD40, BLK and BANK1 do not contribute to the genetic background of IgAV.
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OBJECTIVES: To determine the potential impact of extra-articular manifestations (EAMs) on disease characteristics and cardiovascular (CV) risk in patients with axial spondylarthritis (axSpA). METHODS: This is a cross-sectional study from the AtheSpAin cohort, a Spanish multicenter cohort to study atherosclerosis in axSpA. Data on the history of CV events, subclinical carotid atherosclerosis, and disease-related features, including EAMs, were collected. RESULTS: 888 axSpA patients were recruited. Concomitant acute anterior uveitis (AAU), psoriasis (PSO), and inflammatory bowel disease (IBD) were present in 177 (19.9%), 96 (10.8%), and 57 (6.4%) patients, respectively. When compared with axSpA patients without EAMs, a significant increase in past CV events was observed in patients with PSO (9% versus 4%, p = 0.048) and in those with at least one EAM (7% versus 4%, p = 0.032) or with more than one EAM (11% versus 4%, p = 0.022). The frequency of carotid plaques and the values of cIMT were higher in patients with EAMs than in those without EAMs, although only the univariable analysis for carotid plaques in patients with PSO (39% versus 30%, p = 0.038) and for cIMT in patients with AAU (665 ± 156 µm versus 637 ± 139 µm, p = 0.042) and those with at least one EAM (661 ± 155 µm versus 637 ± 139 µm, p = 0.024) showed significant results. In addition, patients with PSO or IBD were found to have specific disease-related features, such as higher ESR at diagnosis, and more frequent use of glucocorticoids and TNF inhibitors than those without EAMs. Also, PSO patients had more commonly peripheral involvement and those with AAU more severe radiographic damage than those without EAMs. The frequency of HLA B27 was higher in patients with AAU and lower in those with PSO or IBD compared to those without EAMs. CONCLUSION: Patients with axSpA and EAMs, in addition to displaying their own disease-related features, are likely to have an increased CV risk that appears proportional to the number of EAMs and could be related to proatherogenic factors other than traditional CV risk factors, such as the inflammatory load and the use of glucocorticoids.
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Espondiloartrite Axial , Doenças Inflamatórias Intestinais , Psoríase , Espondilartrite , Espondilite Anquilosante , Uveíte Anterior , Humanos , Espondilartrite/complicações , Espondilartrite/diagnóstico , Estudos Transversais , Glucocorticoides , Uveíte Anterior/epidemiologia , Uveíte Anterior/etiologia , Espondilite Anquilosante/complicações , Psoríase/complicações , Doenças Inflamatórias Intestinais/complicações , Doença AgudaRESUMO
Introduction: Patients with axial spondyloarthritis (axSpA) have a high disease burden mainly due to the rheumatic disease itself, and also exhibit accelerated atherosclerosis, that leads to a higher incidence of cardiovascular (CV) disease. Accordingly, the identification of biomarkers of CV risk and inflammation in axSpA patients is clinically relevant. In this sense, given the beneficial functions exerted by the adipomyokine irisin in processes related to CV disease and inflammation, our aim was to assess, for the first time, the role of irisin as a genetic and serological biomarker of subclinical atherosclerosis, CV risk and disease severity in axSpA patients. Methods: A large cohort of 725 Spanish patients with axSpA was included. Subclinical atherosclerosis (presence of plaques and abnormal carotid intima-media thickness values) was evaluated by carotid ultrasound. Four irisin polymorphisms (rs16835198 G/T, rs3480 A/G, rs726344 G/A, and rs1570569 G/T) were genotyped by TaqMan probes. Additionally, serum irisin levels were determined by ELISA. Results: Low irisin levels were linked to the presence of plaques (p=0.002) and atherogenic index values ≥4 (p=0.01). Serum irisin were positively correlated with C-peptide levels (p<0.001) and negatively correlated with visual analogue scale and Bath Ankylosing Spondylitis Metrology Index (p<0.05 in all the cases). Moreover, lower irisin levels were observed in patients with sacroiliitis and in those with a negative HLA-B27 status (p<0.001 and p=0.006, respectively), as well as in those treated with non-steroidal anti-inflammatory drugs and conventional disease-modifying antirheumatic drugs (p<0.001 and p=0.002, respectively). Interestingly, the TT genotype and the T allele of rs16835198 were less frequent in axSpA patients with ASDAS >2.1 (Odds Ratio (OR): 0.48 [0.28-0.83] and OR: 0.73 [0.57-0.92], respectively, p=0.01 in both cases). Additionally, the frequency of rs1570569 T allele was higher in these patients (OR: 1.46 [1.08-1.97], p=0.01). Furthermore, the GGGT haplotype was more frequent in patients with ASDAS values >2.1 (OR: 1.73 [1.13-2.66], p=0.01). Conclusions: Our results indicate that low serum irisin levels could be indicators of the presence of subclinical atherosclerosis, high CV risk and more severe disease in axSpA patients. In addition, irisin may also constitute a genetic biomarker of disease activity in axSpA.
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Aterosclerose , Espondiloartrite Axial , Doenças Cardiovasculares , Espondilartrite , Aterosclerose/complicações , Aterosclerose/diagnóstico , Aterosclerose/genética , Doenças Cardiovasculares/diagnóstico , Doenças Cardiovasculares/etiologia , Espessura Intima-Media Carotídea , Fibronectinas/genética , Marcadores Genéticos , Fatores de Risco de Doenças Cardíacas , Humanos , Inflamação/complicações , Fatores de Risco , Espondilartrite/diagnóstico , Espondilartrite/genéticaRESUMO
OBJECTIVES: To identify disease-related factors associated with subclinical atherosclerosis and cardiovascular (CV) events in a large series of patients with axial spondyloarthritis (axSpA) and to identify possible differences in the effect of the potential pro-atherogenic factors between ankylosing spondylitis (AS) non-radiographic axSpA (nr-axSpA). METHODS: This is a cross-sectional observational study of the AtheSpAin cohort, a Spanish multicenter cohort to study atherosclerosis in axSpA. Subclinical atherosclerosis determined by carotid ultrasound included assessment of carotid intima-media thickness (cIMT) and plaque detection. RESULTS: 639 AS and 167 nr-axSpA patients were recruited. CV risk factors (CRF) and several disease-related factors showed a statistically significant association with subclinical atherosclerosis in the crude analysis. After adjustment for age, sex, and smoking (model 1), associations remained statistically significant for spinal mobility, inflammatory bowel disease, use of prednisone, and Disease-modifying antirheumatic drugs (DMARD) when assessing carotid plaques and for acute phase reactants (APR) at diagnosis, use of prednisone, DMARD, and TNF-inhibitors when measuring cIMT. In model 2, which also included classic CRF as confounding factors to identify axSpA features with a potential independent pro-atherogenic effect, the functional status was the only variable significantly associated with plaques and the use of prednisone and APR at diagnosis with cIMT. No association differences were found between both subtypes of patients. Besides, APR at diagnosis were also associated with subsequent development of CV events that had occurred in 33 patients. CONCLUSION: Apart from CRF, atherosclerotic disease in AxSpA is associated with disease-related factors such as inflammatory response and disease severity, with no differences between AS and nr-axSpA.
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Antirreumáticos , Aterosclerose , Espondiloartrite Axial , Espondiloartrite Axial não Radiográfica , Espondilartrite , Espondilite Anquilosante , Antirreumáticos/uso terapêutico , Aterosclerose/complicações , Aterosclerose/diagnóstico por imagem , Espessura Intima-Media Carotídea , Estudos Transversais , Humanos , Prednisona/uso terapêutico , Espondilartrite/complicações , Espondilartrite/diagnóstico por imagem , Espondilite Anquilosante/complicações , Espondilite Anquilosante/diagnóstico por imagemRESUMO
(1) Background: We explored, for the first time, the contribution of angiogenic T cells (TAng) in interstitial lung disease associated to autoimmune disease (AD-ILD+) as potential biomarkers of the disease, evaluating their role in the underlying vasculopathy and lung fibrosis. Additionally, the relationship of TAng with clinical manifestations and cellular and molecular endothelial dysfunction-related biomarkers was assessed. (2) Methods: We included 57 AD-ILD+ patients (21 with rheumatoid arthritis (RA)-ILD+, 21 with systemic sclerosis (SSc)-ILD+ and 15 with other AD-ILD+) and three comparative groups: 45 AD-ILD- patients (25 RA-ILD- and 20 SSc-ILD-); 21 idiopathic pulmonary fibrosis (IPF) patients; 21 healthy controls (HC). TAng were considered as CD3+CD184+CD31+ by flow cytometry. (3) Results: A similar TAng frequency was found between AD-ILD+ and IPF, being in both cases lower than that observed in AD-ILD- and HC. A lower TAng frequency was associated with negative Scl-70 status and lower FEV1/FVC ratio in SSc-ILD+, as well as with men in RA-ILD+ and non-specific interstitial pneumonia radiological pattern in other AD-ILD+. No relationship between TAng and endothelial progenitor cells, endothelial cells and vascular endothelial growth factor gene expression and protein levels was disclosed. (4) Conclusions: Our findings suggest TAng as potential biomarkers for the early diagnosis of ILD in AD.
RESUMO
OBJECTIVE: To characterize the demographic, genetic, clinical, and serological features of patients with anti-3hydroxy-3-methylglutaryl-CoA reductase (HMGCR) immune-mediated necrotizing myopathy (IMNM) in a region of northern Spain. METHODS: Study of all patients diagnosed with anti-HMGCR IMNM during a 5-year period at a reference hospital in northern Spain. Besides clinical and laboratory data, we analyzed the genetic influence of HLA genes and the rs4149056 (c.521T>C) single nucleotide polymorphism (SNP) in the SLCO1B1 gene. RESULTS: 8 patients (5 women, 3 men) with a mean ± SD age of 64.9 ± 7.3 years, fulfilled the criteria for anti-HMGCR IMNM. The incidence rate was 0.6 per 100.000 person-years and the prevalence 3 per 100.000 population. All patients had been exposed to statins. All of them had predominant lower limb proximal and symmetric muscle weakness that was severe in 2 and had elevated serum CK levels with a median [IQR] of 4488 [2538-9194] IU/L. Serum 25hydroxy vitamin D levels were decreased in all patients in whom it was determined. The 3 patients with a previous diagnosis of hypothyroidism had abnormal levels of TSH at the time of diagnosis. All patients experienced improvement with different schemes of immunosuppressive therapy. Noteworthy, 7 of 8 patients carried the HLA-DRB1*11 allele. The frequency of the rs4149056 C allele in the SLCO1B1 gene (12.5%) was similar to that of the general population. CONCLUSION: In northern Spain, anti-HMGCR IMNM preferentially affects people over 50 years of age who are carriers of the HLA-DRB1*11 allele and take statins. Both low vitamin D levels and hypothyroidism may play a potential predisposing role in the development of this disease.
Assuntos
Doenças Autoimunes , Inibidores de Hidroximetilglutaril-CoA Redutases , Hipotireoidismo , Doenças Musculares , Miosite , Idoso , Autoanticorpos , Feminino , Cadeias HLA-DRB1 , Humanos , Hidroximetilglutaril-CoA Redutases , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Transportador 1 de Ânion Orgânico Específico do Fígado , Masculino , Pessoa de Meia-Idade , Músculo Esquelético , Doenças Musculares/epidemiologia , Doenças Musculares/genética , Miosite/epidemiologia , Miosite/genética , Necrose , Vitamina DRESUMO
OBJECTIVES: To determine whether functional vascular endothelial growth factor (VEGF) polymorphisms influence the expression of the clinical phenotype of giant cell arteritis (GCA). We also evaluated whether VEGF polymorphism is associated with the development of severe ischaemic manifestations in patients with GCA regardless of the clinical phenotype, classic cranial GCA or predominantly extracranial GCA large vessel vasculitis (LVV). METHODS: VEGF rs833061 T/C, rs2010963 G/C and rs3025039 C/T polymorphisms were genotyped in 185 patients with biopsy-proven cranial GCA, 105 with extracranial LVV-GCA and 490 healthy controls. Allelic combinations (haplotypes) of VEGF were carried out. Comparisons were performed between patients with GCA and healthy controls as well as between patients with GCA stratified according to the clinical phenotype and the presence of severe ischaemic manifestations. RESULTS: No significant differences in genotype, allele, and haplotype frequencies of VEGF were found between patients with GCA and healthy controls as well as between GCA patients with the classic cranial pattern and the extracranial LVV-GCA pattern of the disease. However, the VEGF CGC haplotype (OR= 1.63 [1.05-2.53]) and the CGT haplotype (OR= 2.55 [1.10-5.91]) were significantly more frequent in GCA patients with severe ischaemic complications compared to those patients without these complications. CONCLUSIONS: VEGF haplotypes seem to play a role in the development of severe ischaemic manifestations in GCA patients, regardless of the clinical phenotype of expression of the disease.
Assuntos
Arterite de Células Gigantes , Fator A de Crescimento do Endotélio Vascular/metabolismo , Alelos , Predisposição Genética para Doença , Arterite de Células Gigantes/complicações , Arterite de Células Gigantes/genética , Haplótipos , Humanos , Isquemia/genética , Fenótipo , Fator A de Crescimento do Endotélio Vascular/genéticaRESUMO
OBJECTIVES: To analyse the role of body mass index (BMI) in the clinical response to biologic dis-ease-modifying anti-rheumatic drugs (bDMARDs) in patients with rheumatoid arthritis (RA). To per-form an in-depth analysis of the pathophysiology of obesity by assessing serum adipokine levels and their potential changes according to treatment. METHODS: This study involved 105 patients with RA starting tumour necrosis factor inhibitors (TNFi) or tocilizumab (TCZ). Patients were classified ac-cording to BMI as normal-weight and overweight/obesity. The clinical response to treatment was as-sessed by Clinical Disease Activity Index (CDAI) 6 months after initiation of bDMARDs. Serum adi-pokines (leptin and adiponectin) were determined using a commercial immunoassay kit in samples ob-tained before initiation of bDMARDs and after 6 months of treatment. RESULTS: A correlation was observed between BMI and disease activity and between BMI and serum adipokines. Sixty percent of patients achieved low disease activity (LDA)/remission: 45 patients in TNFi group (64.2%) and 18 (51.4%) in TCZ group. In TNFi group, patients who did not attain LDA/remission had a higher BMI (kg/m2) ([28.7±5.1] vs. [24.5±4.6], p=0.001) and baseline CDAI (26.3 [17.4-33.9] vs. 19.8 [14.0-28.8], p<0.03). However, no differences in BMI or baseline CDAI were observed between patients who achieved LDA after 6 months in TCZ group. CONCLUSIONS: Obesity influences the extent of LDA/remission in patients treated with TNFi, but not in patients treated with TCZ, probably because of underlying pathophysiological mechanisms intrinsic to the production of proinflammatory adi-pokines. Therefore, therapeutic strategies with a mechanism of action other than TNF inhibition would be more suitable for obese patients.