RESUMO
OBJECTIVES: (1) To evaluate clinical and molecular cardiovascular disease (CVD) signs and their relationship with psoriatic arthritis (PsA) features and (2) to identify a clinical patient profile susceptible to benefit from methotrexate (MTX) and/or apremilast regarding CVD risk. METHODS: This cross-sectional study included 100 patients with PsA and 100 age-matched healthy donors. In addition, an exploratory cohort of 45 biologically naïve patients treated for 6 months with apremilast, MTX or combined therapy according to routine clinical practice was recruited. Extensive clinical and metabolic profiles were obtained. Ninety-nine surrogate CVD-related molecules were analysed in plasma and peripheral blood mononuclear cells (PBMCs). Hard cluster analysis was performed to identify the clinical and molecular phenotypes. Mechanistic studies were performed on adipocytes. RESULTS: Cardiometabolic comorbidities were associated with disease activity and long-term inflammatory status. Thirty-five CVD-related proteins were altered in the plasma and PBMCs of PsA patients and were associated with the key clinical features of the disease. Plasma levels of some of the CVD-related molecules might distinguish insulin-resistant patients (MMP-3, CD163, FABP-4), high disease activity (GAL-3 and FABP-4) and poor therapy outcomes (CD-163, LTBR and CNTN-1). Hard cluster analysis identified two phenotypes of patients according to the rates of cardiometabolic comorbidities with distinctive clinical and molecular responses to each treatment. CONCLUSIONS: (1) Novel CVD-related proteins associated with clinical features could be emerging therapeutic targets in the context of PsA and (2) the pleiotropic action of apremilast could make it an excellent choice for the management of PsA patients with high CVD risk, targeting metabolic alterations and CVD-related molecules.
Assuntos
Antirreumáticos , Artrite Psoriásica , Doenças Cardiovasculares , Antirreumáticos/uso terapêutico , Artrite Psoriásica/diagnóstico , Artrite Psoriásica/tratamento farmacológico , Doenças Cardiovasculares/tratamento farmacológico , Estudos Transversais , Humanos , Leucócitos Mononucleares , Metotrexato/uso terapêutico , Talidomida/análogos & derivadosRESUMO
OBJECTIVES: To characterise splicing machinery (SM) alterations in leucocytes of patients with rheumatoid arthritis (RA), and to assess its influence on their clinical profile and therapeutic response. METHODS: Leucocyte subtypes from 129 patients with RA and 29 healthy donors (HD) were purified, and 45 selected SM elements (SME) were evaluated by quantitative PCR-array based on microfluidic technology (Fluidigm). Modulation by anti-tumour necrosis factor (TNF) therapy and underlying regulatory mechanisms were assessed. RESULTS: An altered expression of several SME was found in RA leucocytes. Eight elements (SNRNP70, SNRNP200, U2AF2, RNU4ATAC, RBM3, RBM17, KHDRBS1 and SRSF10) were equally altered in all leucocytes subtypes. Logistic regressions revealed that this signature might: discriminate RA and HD, and anti-citrullinated protein antibodies (ACPAs) positivity; classify high-disease activity (disease activity score-28 (DAS28) >5.1); recognise radiological involvement; and identify patients showing atheroma plaques. Furthermore, this signature was altered in RA synovial fluid and ankle joints of K/BxN-arthritic mice. An available RNA-seq data set enabled to validate data and identified distinctive splicing events and splicing variants among patients with RA expressing high and low SME levels. 3 and 6 months anti-TNF therapy reversed their expression in parallel to the reduction of the inflammatory profile. In vitro, ACPAs modulated SME, at least partially, by Fc Receptor (FcR)-dependent mechanisms. Key inflammatory cytokines further altered SME. Lastly, induced SNRNP70-overexpression and KHDRBS1-overexpression reversed inflammation in lymphocytes, NETosis in neutrophils and adhesion in RA monocytes and influenced activity of RA synovial fibroblasts. CONCLUSIONS: Overall, we have characterised for the first time a signature comprising eight dysregulated SME in RA leucocytes from both peripheral blood and synovial fluid, linked to disease pathophysiology, modulated by ACPAs and reversed by anti-TNF therapy.
Assuntos
Processamento Alternativo , Artrite Reumatoide/sangue , Artrite Reumatoide/genética , RNA/sangue , Spliceossomos , Proteínas Adaptadoras de Transdução de Sinal/genética , Adulto , Processamento Alternativo/efeitos dos fármacos , Animais , Anticorpos Antiproteína Citrulinada/farmacologia , Antirreumáticos/farmacologia , Artrite Reumatoide/tratamento farmacológico , Artrite Reumatoide/metabolismo , Estudos de Casos e Controles , Proteínas de Ciclo Celular/genética , Células Cultivadas , Citrulinação , Citocinas/farmacologia , Proteínas de Ligação a DNA/genética , Feminino , Expressão Gênica/efeitos dos fármacos , Humanos , Linfócitos , Masculino , Camundongos , Pessoa de Meia-Idade , Monócitos , Neutrófilos , RNA/metabolismo , Fatores de Processamento de RNA/genética , RNA Nuclear Pequeno/genética , Proteínas de Ligação a RNA/genética , Proteínas Repressoras/genética , Ribonucleoproteína Nuclear Pequena U1/genética , Ribonucleoproteínas Nucleares Pequenas/genética , Análise de Sequência de RNA , Fatores de Processamento de Serina-Arginina/genética , Fator de Processamento U2AF/genética , Líquido Sinovial/metabolismo , Fator de Necrose Tumoral alfa/antagonistas & inibidoresRESUMO
OBJECTIVE: Our aim was to characterize distinctive clinical antiphospholipid syndrome phenotypes and identify novel microRNA (miRNA)-mRNA-intracellular signaling regulatory networks in monocytes linked to cardiovascular disease. Approach and Results: Microarray analysis in antiphospholipid syndrome monocytes revealed 547 differentially expressed genes, mainly involved in inflammatory, cardiovascular, and reproductive disorders. Besides, this approach identified several genes related to inflammatory, renal, and dermatologic diseases. Functional analyses further demonstrated phosphorylation of intracellular kinases related to thrombosis and immune-mediated chronic inflammation. miRNA profiling showed altered expression of 22 miRNAs, enriched in pathways related to immune functions, cardiovascular disease, and autoimmune-associated pathologies. Unbiased integrated mRNA-miRNA analysis identified a signature of 9 miRNAs as potential modulators of 17 interconnected genes related to cardiovascular disease. The altered expression of that miRNA-mRNA signature was proven to be stable along time and distinctive of nonautoimmune thrombotic patients. Transfection studies and luciferase assays established the relationship between specific miRNAs and their identified target genes and proteins, along with their involvement in the regulation of monocytes procoagulant activity and cell adhesion. Correlation analyses showed relationship among altered miRNAs and their interconnected genes with aPL (antiphospholipid antibodies)-titers, along with microvascular endothelial dysfunction. In vitro studies demonstrated modulation in healthy monocytes by IgG-aPLs of several genes/miRNAs, which further intermediated downstream effects on endothelial function. The identified transcriptomic signature allowed the unsupervised division of three clusters of patients with antiphospholipid syndrome showing distinctive clinical profiles, mainly associated with their prothrombotic risk (thrombosis, autoantibody profile, cardiovascular risk factors, and atherosclerosis). CONCLUSIONS: Extensive molecular profiling of monocytes in patients with primary antiphospholipid syndrome might help to identify distinctive clinical phenotypes, thus enabling new patients' tailored treatments.
Assuntos
Síndrome Antifosfolipídica/genética , Perfilação da Expressão Gênica , MicroRNAs/genética , Monócitos/metabolismo , Trombose/genética , Transcriptoma , Aprendizado de Máquina não Supervisionado , Adulto , Síndrome Antifosfolipídica/sangue , Síndrome Antifosfolipídica/complicações , Estudos de Casos e Controles , Células Cultivadas , Análise por Conglomerados , Feminino , Regulação da Expressão Gênica , Redes Reguladoras de Genes , Humanos , Masculino , MicroRNAs/sangue , Pessoa de Meia-Idade , Análise de Sequência com Séries de Oligonucleotídeos , Mapas de Interação de Proteínas , Medição de Risco , Fatores de Risco , Transdução de Sinais , Trombose/sangue , Trombose/etiologiaRESUMO
Objective: Systemic lupus erythematosus (SLE) is associated to boosted atherosclerosis development and a higher cardiovascular disease risk. This study aimed to delineate the role of anti-double stranded DNA (anti-dsDNA) antibodies on the molecular profile and the activity of immune and vascular cells, as well as on their enhanced cardiovascular risk. Approach and Results: Eighty SLE patients were included. Extensive clinical/analytical evaluation was performed, including cardiovascular disease parameters (endothelial function, proatherogenic dyslipidemia, and carotid intima-media thickness). Gene and protein expression profiles were evaluated in monocytes from patients diagnosed positive or negative for anti-dsDNA antibodies by using NanoString and cytokine arrays, respectively. NETosis and circulating inflammatory profile was assessed in both neutrophils and plasma. Positivity and persistence of anti-dsDNA antibodies in SLE patients were associated to endothelial dysfunction, proatherogenic dyslipidemia, and accelerated atherosclerosis. In parallel, anti-dsDNA antibodies were linked to the aberrant activation of innate immune cells, so that anti-dsDNA(+) SLE monocytes showed distinctive gene and protein expression/activity profiles, and neutrophils were more prone to suffer NETosis in comparison with anti-dsDNA(−) patients. Anti-dsDNA(+) patients further displayed altered levels of numerous circulating mediators related to inflammation, NETosis, and cardiovascular risk. In vitro, Ig-dsDNA promoted NETosis on neutrophils, apoptosis on monocytes, modulated the expression of inflammation and thrombosis-related molecules, and induced endothelial activation, at least partially, by FcR (Fc receptor)-binding mechanisms. Conclusions: Anti-dsDNA antibodies increase the cardiovascular risk of SLE patients by altering key molecular processes that drive a distinctive and coordinated immune and vascular activation, representing a potential tool in the management of this comorbidity.
Assuntos
Anticorpos Antinucleares/sangue , Doenças Cardiovasculares/imunologia , DNA/imunologia , Células Endoteliais/imunologia , Imunoglobulina G/sangue , Leucócitos/imunologia , Lúpus Eritematoso Sistêmico/imunologia , Adulto , Apoptose , Biomarcadores/sangue , Doenças Cardiovasculares/sangue , Doenças Cardiovasculares/diagnóstico por imagem , Doenças Cardiovasculares/genética , Células Cultivadas , Técnicas de Cocultura , Estudos Transversais , Citocinas/genética , Citocinas/metabolismo , Células Endoteliais/metabolismo , Armadilhas Extracelulares/metabolismo , Feminino , Fatores de Risco de Doenças Cardíacas , Humanos , Leucócitos/metabolismo , Lipídeos/sangue , Lúpus Eritematoso Sistêmico/sangue , Lúpus Eritematoso Sistêmico/diagnóstico , Lúpus Eritematoso Sistêmico/genética , Masculino , Pessoa de Meia-Idade , Monócitos/imunologia , Monócitos/metabolismo , Neutrófilos/imunologia , Neutrófilos/metabolismo , Estresse Oxidativo , Estudos Retrospectivos , Medição de Risco , Transdução de SinaisRESUMO
OBJECTIVE: To evaluate whether the presence of psoriasis influences the clinical expression, disease activity and disease burden in both axial and peripheral phenotypes of spondyloarthritis (SpA). METHODS: Patients from the Spanish REGISPONSER registry classified as having SpA according to the ESSG criteria were included. Patients were classified as psoriatic or non-psoriatic depending on the presence of cutaneous or nail psoriasis; thereafter, they were classified as having either axial [presence of radiographic sacroiliitis OR inflammatory back pain (IBP)] or peripheral phenotype (absence of radiographic sacroiliitis AND absence of IBP AND presence of peripheral involvement). Pair-wise univariate and multivariate analyses among the four groups (psoriatic/non-psoriatic axial phenotypes and psoriatic/non-psoriatic peripheral phenotypes) were performed with adjustment for treatment intake. RESULTS: A total of 2296 patients were included in the analysis. Among patients with axial phenotype, psoriasis was independently associated (P < 0.05) with HLA-B27+ [odds ratio (OR) 0.27], uveitis (OR 0.46), synovitis (ever) (OR 2.59), dactylitis (OR 2.78) and the use of conventional synthetic DMARDs (csDMARDs) (OR 1.47) in comparison with non-psoriatic patients. Among patients with peripheral phenotype and adjusting for csDMARD intake, psoriasis was independently associated with higher age at disease onset (OR 1.05), HLA-B27+ (OR 0.14) and heel enthesitis (OR 0.22). Higher scores for patient-reported outcomes and greater use of treatment at the time of the study visit were observed in psoriatic patients with either axial or peripheral phenotype. CONCLUSION: These findings suggest that, among all patients with SpA, psoriasis is associated with differences in clinical expression of SpA, a greater disease burden and increased use of drugs.
Assuntos
Psoríase/epidemiologia , Espondilite Anquilosante/epidemiologia , Idade de Início , Antirreumáticos/uso terapêutico , Dor nas Costas/epidemiologia , Efeitos Psicossociais da Doença , Estudos Transversais , Feminino , Antígeno HLA-B27/sangue , Humanos , Masculino , Pessoa de Meia-Idade , Medidas de Resultados Relatados pelo Paciente , Fenótipo , Psoríase/tratamento farmacológico , Sistema de Registros , Sacroileíte/epidemiologia , Espanha/epidemiologia , Espondilite Anquilosante/tratamento farmacológico , Sinovite/epidemiologia , Uveíte/epidemiologiaRESUMO
Ankylosing spondylitis (AS) remains difficult to diagnose before irreversible damage to sacroiliac joint is noticeable. Circulating microRNAs have demonstrated to serve as diagnostic tools for several human diseases. Here, we analysed plasma microRNAs to identify potential AS biomarkers. Higher expression levels of microRNA (miR)-146a-5p, miR-125a-5p, miR-151a-3p and miR-22-3p, and lower expression of miR-150-5p, and miR-451a were found in AS versus healthy donors. Interestingly, higher miR-146a-5p, miR-125a-5p, miR-151a-3p, miR-22-3p and miR-451a expression was also observed in AS than psoriatic arthritis patients. The areas under the curve, generated to assess the accuracy of microRNAs as diagnostic biomarkers for AS, ranged from 0.614 to 0.781; the six-microRNA signature reached 0.957. Bioinformatics analysis revealed that microRNAs targeted inflammatory and bone remodeling genes, underlying their potential role in this pathology. Indeed, additional studies revealed an association between these six microRNAs and potential target proteins related to AS pathophysiology. Furthermore, miR-146a-5p, miR-125a-5p and miR-22-3p expression was increased in active versus non-active patients. Moreover, miR-125a-5p, miR-151a-3p, miR-150-5p and miR-451a expression was related to the presence of syndesmophytes in AS patients. Overall, this study identified a six-plasma microRNA signature that could be attractive candidates as non-invasive biomarkers for the AS diagnosis, and may help to elucidate the disease pathogenesis.
Assuntos
MicroRNA Circulante/sangue , Espondilite Anquilosante/genética , Adulto , Biomarcadores/sangue , Estudos de Casos e Controles , MicroRNA Circulante/metabolismo , Feminino , Perfilação da Expressão Gênica , Humanos , Interleucina-5/sangue , Masculino , MicroRNAs/sangue , Pessoa de Meia-Idade , Espondilite Anquilosante/sangue , Espondilite Anquilosante/diagnóstico , Fator de Necrose Tumoral alfa/sangueRESUMO
This translational multi-centre study explored early changes in serologic variables following B lymphocyte depletion by rituximab (RTX) treatment in systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA) patients and investigated in vitro effects on the activity of other immune cells and the vascular endothelium. Eighty-five SLE patients, seventy-five RA patients and ninety healthy donors were enrolled. Two additional cohorts of selected SLE and RA patients were treated with RTX for 3 months. Changes in circulating levels of inflammatory mediators, oxidative stress markers and NETosis-derived bioproducts were evaluated. Serum miRNomes were identified by next-generation sequencing, and RTX-induced changes were delineated. Mechanistic in vitro studies were performed to assess activity profiles. Altered inflammatory, oxidative and NETosis-derived biomolecules were found in SLE and RA patients, closely interconnected and associated to specific miRNA profiles. RTX treatment reduced SLE and RA patients' disease activity, linked to a prominent alteration in those biomolecules and the reversal of altered regulating miRNAs. In vitro studies showed inhibition of NETosis and decline of pro-inflammatory profiles of leucocytes and human umbilical vein endothelial cells (HUVECs) after B cell depletion. This study provides evidence supporting an early RTX-induced re-setting of the pro-inflammatory status in SLE and RA, involving a re-establishment of the homeostatic equilibrium in immune system and the vascular wall.
Assuntos
Artrite Reumatoide/imunologia , Linfócitos B/imunologia , Lúpus Eritematoso Sistêmico/imunologia , Adulto , Anticorpos Monoclonais Humanizados/imunologia , Anticorpos Monoclonais Humanizados/uso terapêutico , Artrite Reumatoide/tratamento farmacológico , Linfócitos B/efeitos dos fármacos , Linhagem Celular , Feminino , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Células Endoteliais da Veia Umbilical Humana/imunologia , Humanos , Lúpus Eritematoso Sistêmico/tratamento farmacológico , Masculino , MicroRNAs/imunologia , Pessoa de Meia-Idade , Fenótipo , Rituximab/imunologia , Rituximab/uso terapêuticoRESUMO
We aimed to identify the plasma miRNA profile of antiphospholipid syndrome (APS) patients and to investigate the potential role of specific circulating miRNAs as non-invasive disease biomarkers. Ninety APS patients and 42 healthy donors were recruited. Profiling of miRNAs by PCR-array in plasma of APS patients identified a set of miRNAs differentially expressed and collectively involved in clinical features. Logistic regression and ROC analysis identified a signature of 10 miRNA ratios as biomarkers of disease. In addition, miRNA signature was related to fetal loss, atherosclerosis, and type of thrombosis, and correlated with parameters linked to inflammation, thrombosis, and autoimmunity. Hard clustering analysis differentiated 3 clusters representing different thrombotic risk profile groups. Significant differences between groups for several miRNA ratios were found. Moreover, miRNA signature remained stable over time, demonstrated by their analysis three months after the first sample collection. Parallel analysis in two additional cohorts of patients, including thrombosis without autoimmune disease, and systemic lupus erythematosus without antiphospholipid antibodies, each displayed specific miRNA profiles that were distinct from those of APS patients. In vitro, antiphospholipid antibodies of IgG isotype promoted deregulation in selected miRNAs and their potential atherothrombotic protein targets in monocytes and endothelial cells. Taken together, differentially expressed circulating miRNAs in APS patients, modulated at least partially by antiphospholipid antibodies of IgG isotype, might have the potential to serve as novel biomarkers of disease features and to typify patients' atherothrombotic status, thus constituting a useful tool in the management of the disease.
Assuntos
Síndrome Antifosfolipídica/complicações , Aterosclerose/diagnóstico , Biomarcadores/análise , MicroRNA Circulante/genética , Regulação Neoplásica da Expressão Gênica , Trombose/diagnóstico , Adulto , Idoso , Síndrome Antifosfolipídica/fisiopatologia , Aterosclerose/etiologia , Aterosclerose/patologia , Estudos de Casos e Controles , Estudos de Coortes , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Trombose/etiologia , Trombose/patologia , Adulto JovemRESUMO
OBJECTIVE: Antiphospholipid syndrome (APS) leukocytes exhibit an oxidative perturbation, directly linked to alterations in mitochondrial dynamics and metabolism. This disturbance is related to the patients' prothrombotic status and can be prevented by in vitro treatment with coenzyme Q10. Our aim was to investigate short-term effects of in vivo ubiquinol (reduced coenzyme Q10 [Qred]) supplementation on markers related to inflammation and thrombosis in APS through a prospective, randomized, crossover, placebo-controlled trial. APPROACH AND RESULTS: Thirty-six patients with APS were randomized to receive Qred (200 mg/d) or placebo for 1 month. Thirty-three patients with APS completed the intervention, which increased plasma coenzyme Q10. Qred improved endothelial function and decreased monocyte expression of prothrombotic and proinflammatory mediators, inhibited phosphorylation of thrombosis-related protein kinases, and decreased peroxides and percentage of monocytes with depolarized mitochondria; mitochondrial size was increased, and mitochondrial biogenesis-related genes were upregulated. Qred ameliorated extruded neutrophil extracellular traps in neutrophils and downregulated peroxides, intracellular elastase, and myeloperoxidase. Nanostring microRNA profiling revealed 20 microRNAs reduced in APS monocytes, and 16 of them, with a preponderance of cardiovascular disease-related target mRNAs, were upregulated. Monocytes gene profiling showed differential expression of 29 atherosclerosis-related genes, 23 of them changed by Qred. Interaction networks of genes and microRNAs were identified. Correlation studies demonstrated co-ordinated effects of Qred on thrombosis and endothelial function-associated molecules. CONCLUSIONS: Our results highlight the potential of Qred to modulate the overexpression of inflammatory and thrombotic risk markers in APS. Because of the absence of clinically significant side effects and its potential therapeutic benefits, Qred might act as safe adjunct to standard therapies in APS. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT02218476.
Assuntos
Síndrome Antifosfolipídica/tratamento farmacológico , Síndrome Antifosfolipídica/fisiopatologia , Ubiquinona/análogos & derivados , Vitaminas/uso terapêutico , Estudos Cross-Over , Endotélio Vascular/fisiologia , Feminino , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases , Inflamação/fisiopatologia , Masculino , Pessoa de Meia-Idade , Mitocôndrias/fisiologia , Monócitos/patologia , Oxirredução , Estudos Prospectivos , Ubiquinona/uso terapêuticoAssuntos
Anticorpos Antifosfolipídeos/sangue , Síndrome Antifosfolipídica/sangue , Medição de Risco/estatística & dados numéricos , Trombose/imunologia , Adulto , Síndrome Antifosfolipídica/imunologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Reprodutibilidade dos Testes , Medição de Risco/métodosRESUMO
Psoriatic disease, encompassing both psoriasis (Pso) and psoriatic arthritis (PsA), is closely intertwined with a significantly elevated risk of developing cardiovascular diseases. This connection is further compounded by a higher prevalence of cardiometabolic comorbidities, including type 2 diabetes, obesity, insulin resistance, arterial hypertension, and dysregulated lipid profiles. These comorbidities exceed the rates seen in the general population and compound the potential for increased mortality among those living with this condition. Recognizing the heightened cardiometabolic risk inherent in psoriatic disease necessitates a fundamental shift in the treatment paradigm. It is no longer sufficient to focus solely on mitigating inflammation. Instead, there is an urgent need to address and effectively manage the metabolic parameters that have a substantial impact on cardiovascular health. Within this context, apremilast emerges as a pivotal treatment option for psoriatic disease. What sets apremilast apart is its dual-action potential, addressing not only inflammation but also the critical metabolic parameters. This comprehensive treatment approach opens up new opportunities to improve the well-being of people living with psoriatic disease. This review delves into the multifaceted aspects involved in the development of cardiovascular disease and its intricate association with psoriatic disease. We then provide an in-depth exploration of the pleiotropic effects of apremilast, highlighting its potential to simultaneously mitigate metabolic complications and inflammation in individuals affected by these conditions.
Assuntos
Anti-Inflamatórios não Esteroides , Doenças Cardiovasculares , Psoríase , Talidomida , Humanos , Talidomida/análogos & derivados , Talidomida/uso terapêutico , Doenças Cardiovasculares/tratamento farmacológico , Doenças Cardiovasculares/prevenção & controle , Psoríase/tratamento farmacológico , Psoríase/metabolismo , Anti-Inflamatórios não Esteroides/uso terapêutico , Artrite Psoriásica/tratamento farmacológico , AnimaisRESUMO
Introduction: RA patients are at higher risk of cardiovascular disease, influenced by therapies. Studying their cardiovascular and cardiometabolic proteome can unveil biomarkers and insights into related biological pathways. Methods: This study included two cohorts of RA patients: newly diagnosed individuals (n=25) and those with established RA (disease duration >25 years, n=25). Both cohorts were age and sex-matched with a control group (n=25). Additionally, a longitudinal investigation was conducted on a cohort of 25 RA patients treated with methotrexate and another cohort of 25 RA patients treated with tofacitinib for 6 months. Clinical and analytical variables were recorded, and serum profiling of 184 proteins was performed using the Olink technology platform. Results: RA patients exhibited elevated levels of 75 proteins that might be associated with cardiovascular disease. In addition, 24 proteins were increased in RA patients with established disease. Twenty proteins were commonly altered in both cohorts of RA patients. Among these, elevated levels of CTSL1, SORT1, SAA4, TNFRSF10A, ST6GAL1 and CCL18 discriminated RA patients and HDs with high specificity and sensitivity. Methotrexate treatment significantly reduced the levels of 13 proteins, while tofacitinib therapy modulated the expression of 10 proteins. These reductions were associated with a decrease in DAS28. Baseline levels of SAA4 and high levels of BNP were associated to the non-response to methotrexate. Changes in IL6 levels were specifically linked to the response to methotrexate. Regarding tofacitinib, differences in baseline levels of LOX1 and CNDP1 were noted between non-responder and responder RA patients. In addition, response to tofacitinib correlated with changes in SAA4 and TIMD4 levels. Conclusion: In summary, this study pinpoints molecular changes linked to cardiovascular disease in RA and proposes candidate protein biomarkers for distinguishing RA patients from healthy individuals. It also highlights how methotrexate and tofacitinib impact these proteins, with distinct alterations corresponding to each drug's response, identifying potential candidates, as SAA4, for the response to these therapies.
Assuntos
Antirreumáticos , Artrite Reumatoide , Doenças Cardiovasculares , Humanos , Metotrexato , Antirreumáticos/uso terapêutico , Proteoma , Doenças Cardiovasculares/diagnóstico , Doenças Cardiovasculares/tratamento farmacológico , Artrite Reumatoide/diagnóstico , Artrite Reumatoide/tratamento farmacológico , Artrite Reumatoide/induzido quimicamenteRESUMO
Objectives: 1) To characterize the inflammatory proteome of synovial fluid (SF) from patients with Psoriatic Arthritis (PsA) using a high-quality throughput proteomic platform, and 2) to evaluate its potential to stratify patients according to clinical features. Methods: Inflammatory proteome profile of SF from thirteen PsA patients with active knee arthritis were analyzed using proximity extension assay (PEA) technology (Olink Target 96 Inflammation panel). Four patients with OA were included as control group. Results: Seventy-nine inflammation-related proteins were detected in SF from PsA patients (SF-PsA). Unsupervised analyzes of the molecular proteome profile in SF-PsA identified two specific phenotypes characterized by higher or lower levels of inflammation-related proteins. Clinically, SF-PsA with higher levels of inflammatory proteins also showed increased systemic inflammation and altered glucose and lipid metabolisms. Besides, SF from PsA patients showed 39 out of 79 proteins significantly altered compared to SF-OA specifically related to cell migration and inflammatory response. Among these, molecules such as TNFα, IL-17A, IL-6, IL-10, IL-8, ENRAGE, CCL20, TNFSF-14, OSM, IFNγ, MCP-3, CXCL-11, MCP4, CASP-8, CXCL-6, CD-6, ADA, CXCL-10, TNFß and IL-7 showed the most significantly change. Conclusion: This is the first study that characterizes the inflammatory landscape of synovial fluid of PsA patients by analyzing a panel of 92 inflammatory proteins using PEA technology. Novel SF proteins have been described as potential pathogenic molecules involved in the pathogenesis of PsA. Despite the flare, inflammatory proteome could distinguish two different phenotypes related to systemic inflammation and lipid and glucose alterations.
Assuntos
Artrite Psoriásica , Líquido Sinovial , Líquido Sinovial/química , Artrite Psoriásica/imunologia , Artrite Psoriásica/metabolismo , Humanos , Masculino , Feminino , Adulto , Pessoa de Meia-Idade , Sinoviócitos/metabolismo , Citocinas/análise , Joelho/patologiaRESUMO
Liver disease is one of the most important causes of morbidity and mortality worldwide whose prevalence is dramatically increasing. The first sign of hepatic damage is inflammation which could be accompanied by the accumulation of fat called non-alcoholic fatty liver disease (NAFLD), causing damage in the hepatocytes. This stage can progress to fibrosis where the accumulation of fibrotic tissue replaces healthy tissue reducing liver function. The next stage is cirrhosis, a late phase of fibrosis where a high percentage of liver tissue has been replaced by fibrotic tissue and liver functionality is substantially impaired. There is a close interplay of cardiovascular disease (CVD) and hepatic alterations, where different mechanisms mediating this relation between the liver and systemic vasculature have been described. In chronic inflammatory diseases such as rheumatoid arthritis (RA) and psoriatic arthritis (PsA), in which the CVD risk is high, hepatic alterations seem to be more prevalent compared to the general population and other rheumatic disorders. The pathogenic mechanisms involved in the development of this comorbidity are still unraveled, although chronic inflammation, autoimmunity, treatments, and metabolic deregulation seem to have an important role. In this review, we will discuss the involvement of liver disease in the cardiovascular risk associated with inflammatory arthritis, the pathogenic mechanisms, and the recognized factors involved. Likewise, monitoring of the liver disease risk in routine clinical practice through both, classical and novel techniques and indexes will be exposed. Finally, we will examine the latest controversies that have been raised about the effects of the current therapies used to control the inflammation in RA and PsA, in the liver damage of those patients, such as methotrexate, leflunomide or biologics.
Assuntos
Artrite Psoriásica , Artrite Reumatoide , Produtos Biológicos , Doenças Cardiovasculares , Hepatopatia Gordurosa não Alcoólica , Artrite Psoriásica/complicações , Artrite Psoriásica/tratamento farmacológico , Artrite Reumatoide/complicações , Artrite Reumatoide/tratamento farmacológico , Artrite Reumatoide/epidemiologia , Produtos Biológicos/uso terapêutico , Doenças Cardiovasculares/complicações , Doenças Cardiovasculares/etiologia , Fatores de Risco de Doenças Cardíacas , Humanos , Inflamação/complicações , Leflunomida/uso terapêutico , Cirrose Hepática/complicações , Metotrexato/uso terapêutico , Hepatopatia Gordurosa não Alcoólica/patologia , Fatores de RiscoRESUMO
We aimed to evaluate the association between adipose tissue (AT) dysfunction, autoimmunity, and disease activity in rheumatoid arthritis (RA). A cross-sectional study including 150 RA patients and 50 healthy donors and longitudinal study with 122 RA patients treated with anti-tumor necrosis factor (TNF)-α, anti-interleukin 6 receptor (IL6R) or anti-CD20 therapies for 6 months were carried out. In vitro experiments with human AT and adipocyte and macrophage cell lines were performed. A collagen-induced arthritis mouse model was developed. The insulin resistance and the altered adipocytokine profile were associated with disease activity, the presence of anti-citrullinated proteins anti-bodies (ACPAs), and worse response to therapy in RA. AT in the context of arthritis is characterized by an inflammatory state alongside the infiltration of macrophages and B/plasmatic cells, where ACPAs can have a direct impact, inducing inflammation and insulin resistance in macrophages and promoting a defective adipocyte differentiation, partially restored by biologicals.
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Endothelial dysfunction (ED) is well known as a process that can lead to atherosclerosis and is frequently presented in radiographic axial spondyloarthritis (r-axSpA) patients. Here, we investigated cellular and molecular mechanisms underlying r-axSpA-related ED, and analyzed the potential effect of peripheral blood mononuclear cells (PBMCs) in promoting endothelial injury in r-axSpA. A total of 30 r-axSpA patients and 32 healthy donors (HDs) were evaluated. The endothelial function, inflammatory and atherogenic profile, and oxidative stress were quantified. In vitro studies were designed to evaluate the effect of PBMCs from r-axSpA patients on aberrant endothelial activation. Compared to HDs, our study found that, associated with ED and the plasma proatherogenic profile present in r-axSpA, PBMCs from these patients displayed a pro-oxidative, proinflammatory, and proatherogenic phenotype, with most molecular changes noticed in lymphocytes. Correlation studies revealed the relationship between this phenotype and the microvascular function. Additional in vitro studies confirmed that PBMCs from r-axSpA patients promoted endothelial injury. Altogether, this study suggests the relevance of r-axSpA itself as a strong and independent cardiovascular risk factor, contributing to a dysfunctional endothelium and atherogenic status by aberrant activation of PBMCs. Lymphocytes could be the main contributors in the development of ED and subsequent atherosclerosis in this pathology.
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Disease severity, progression and response to therapy might be worse in obese rheumatoid arthritis (RA) patients, but paradoxically, obesity also might protect from radiographic joint damage. Thus, the intricate relationship between obesity and RA needs urgent clarification. The aim of this study was to assess the influence of obesity on the onset and development of RA and to determine whether arthritis could modify the adipose tissue biology and whether conventional Disease Modifying Anti-Rheumatic Drugs (cDMARDs) can modulate these alterations. Two strategies were followed: (1) clinical profiling of two cohorts of RA: non-obese and obese patients; and (2) mechanistic studies carried out in both a collagen-induced arthritis (CIA) in an obese mouse model and 3T3-L1 adipocytes treated with cDMARDs (leflunomide, methotrexate, and hydroxychloroquine). In our cohort of RA patients with low-moderate disease activity, the presence of obesity was not related to a higher activity of the disease; actually, disease activity score 28-erythrocyte sedimentation rate (DAS28-ESR) was reduced in the obese RA patients. However, the induction of arthritis promoted transcriptomic changes in the adipose tissue under obesity condition in the obese CIA model. Treatment with hydroxychloroquine reduced weight and insulin resistance, accompanied by beneficial metabolic effects in the adipose tissue. These molecular changes in adipose tissue were also observed after methotrexate administration. In sum, arthritis might affect directly the inflammatory burden and metabolic alterations associated with obesity in adipose tissue. Clinicians should be cautious measuring the activity of the disease in obesity and managing the best therapeutic options for the metabolic comorbidities of these patients, where the combination of hydroxychloroquine and methotrexate should be considered to improve adipose tissue dysfunction in obese RA.
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Tecido Adiposo/metabolismo , Antirreumáticos/uso terapêutico , Artrite Reumatoide/complicações , Artrite Reumatoide/tratamento farmacológico , Obesidade/complicações , Tecido Adiposo/efeitos dos fármacos , Adulto , Animais , Estudos Transversais , Feminino , Humanos , Masculino , Camundongos , Pessoa de Meia-IdadeRESUMO
Background: This prospective multicenter study developed an integrative clinical and molecular longitudinal study in Rheumatoid Arthritis (RA) patients to explore changes in serologic parameters following anti-TNF therapy (TNF inhibitors, TNFi) and built on machine-learning algorithms aimed at the prediction of TNFi response, based on clinical and molecular profiles of RA patients. Methods: A total of 104 RA patients from two independent cohorts undergoing TNFi and 29 healthy donors (HD) were enrolled for the discovery and validation of prediction biomarkers. Serum samples were obtained at baseline and 6 months after treatment, and therapeutic efficacy was evaluated. Serum inflammatory profile, oxidative stress markers and NETosis-derived bioproducts were quantified and miRNomes were recognized by next-generation sequencing. Then, clinical and molecular changes induced by TNFi were delineated. Clinical and molecular signatures predictors of clinical response were assessed with supervised machine learning methods, using regularized logistic regressions. Results: Altered inflammatory, oxidative and NETosis-derived biomolecules were found in RA patients vs. HD, closely interconnected and associated with specific miRNA profiles. This altered molecular profile allowed the unsupervised division of three clusters of RA patients, showing distinctive clinical phenotypes, further linked to the TNFi effectiveness. Moreover, TNFi treatment reversed the molecular alterations in parallel to the clinical outcome. Machine-learning algorithms in the discovery cohort identified both, clinical and molecular signatures as potential predictors of response to TNFi treatment with high accuracy, which was further increased when both features were integrated in a mixed model (AUC: 0.91). These results were confirmed in the validation cohort. Conclusions: Our overall data suggest that: 1. RA patients undergoing anti-TNF-therapy conform distinctive clusters based on altered molecular profiles, which are directly linked to their clinical status at baseline. 2. Clinical effectiveness of anti-TNF therapy was divergent among these molecular clusters and associated with a specific modulation of the inflammatory response, the reestablishment of the altered oxidative status, the reduction of NETosis, and the reversion of related altered miRNAs. 3. The integrative analysis of the clinical and molecular profiles using machine learning allows the identification of novel signatures as potential predictors of therapeutic response to TNFi therapy.
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Antirreumáticos/uso terapêutico , Artrite Reumatoide/sangue , Artrite Reumatoide/tratamento farmacológico , Inibidores do Fator de Necrose Tumoral/uso terapêutico , Adulto , Artrite Reumatoide/classificação , Artrite Reumatoide/diagnóstico , Biomarcadores/sangue , Análise por Conglomerados , Armadilhas Extracelulares/metabolismo , Feminino , Humanos , Inflamação , Estudos Longitudinais , Aprendizado de Máquina , Masculino , MicroRNAs/sangue , Pessoa de Meia-Idade , Estresse Oxidativo , Fenótipo , Valor Preditivo dos Testes , Estudos Prospectivos , Resultado do TratamentoRESUMO
BACKGROUND: Juvenile Idiopathic Arthritis (JIA) is one of the most common chronic diseases of childhood that often persists into adulthood and can result in significant long-term morbidity. As a long lasting chronic inflammatory disease, concern has been raised regarding the risk of premature development of cardiovascular disease (CVD) in JIA. This study aims to determine whether adults with JIA in clinical remission display clinical and subclinical signs of CVD risk: inflammatory mediators, adipokines, endothelial dysfunction and oxidative stress markers. METHODS: This is a cross-sectional study including 25 patients diagnosed with JIA according to the International League of Associations for Rheumatology criteria (ILAR 2001) and 25 age- and sex-matched controls. Remission was determined by JADAS10 < 1 and according to Wallace criteria. The presence of traditional CVD risk factors was analyzed. An extensive clinical analysis including body mass index (BMI), lipid profile, homeostatic model assessment - insulin resistance (HOMA-IR) and arterial blood pressure was performed. Intima media thickness of the common carotid artery (CIMT) was measured as a marker of subclinical atherosclerosis. Several proinflammatory cytokines, molecules involved in the endothelial dysfunction, oxidative stress and adipokines were quantified on serum by ELISA and on peripheral blood mononuclear cells (PBMCs) by RT-PCR. In vitro studies were carried out in healthy PBMCs, adipocytes and endothelial cells which were treated with serum from JIA patients under sustained remission. RESULTS: Mean duration of the disease was 13.47 ± 5.47 years. Mean age was 25.11 ± 7.21. Time in remission was 3.52 ± 3.33 years. Patients were in remission with no treatment (40%) and with treatments (60%). CVD risk factors and CIMT were similar in JIA patients and controls. However, cholesterol levels were significantly elevated in JIA patients. Levels of adipocytokines, oxidative stress and endothelial activation markers were elevated in serum and PBMCs from JIA patients. Serum of those JIA patients induced the activation of adipocytes, endothelial cells and healthy PBMCs. CONCLUSIONS: JIA adult patients in remission have subclinical signs of inflammation and CVD risk, showed by an increase in the levels of inflammatory cytokines, endothelial activation and oxidative stress markers and adipokines, molecules closely involved in the alteration of the vascular system.
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Artrite Juvenil , Citocinas/sangue , Endotélio Vascular/metabolismo , Inflamação , Adulto , Idade de Início , Artrite Juvenil/sangue , Artrite Juvenil/diagnóstico , Artrite Juvenil/epidemiologia , Artrite Juvenil/fisiopatologia , Doenças Assintomáticas , Biomarcadores/sangue , Espessura Intima-Media Carotídea , Estudos Transversais , Feminino , Fatores de Risco de Doenças Cardíacas , Humanos , Inflamação/sangue , Inflamação/imunologia , Mediadores da Inflamação/sangue , Resistência à Insulina , Masculino , Estresse Oxidativo , Gravidade do Paciente , Espanha , TempoRESUMO
AIMS: To evaluate the association of estimated cardiovascular (CV) risk and subclinical atherosclerosis with radiographic structural damage in patients with axial spondyloarthritis (axSpA). METHODS: Cross-sectional study including 114 patients axSpA from the SpA registry of Córdoba (CASTRO) and 132 age- and sex-matched healthy controls (HCs). Disease activity and the presence of traditional CV risk factors were recorded. The presence of atherosclerotic plaques and carotid intima media thickness (cIMT) were evaluated through carotid ultrasound and the SCORE index was calculated. Radiographic damage was measured though modified Stoke Ankylosing Spondylitis Spinal Score (mSASSS). The association between mSASSS and SCORE was tested using generalized linear models (GLM), and an age-adjusted cluster analysis was performed to identify different phenotypes dependent on the subclinical CV risk. RESULTS: Increased traditional CV risk factors, SCORE, and the presence of carotid plaques were found in axSpA patients compared with HCs. The presence of atherosclerotic plaques and SCORE were associated with radiographic structural damage. The GLM showed that the total mSASSS was associated independently with the SCORE [ß coefficient 0.24; 95% confidence interval (CI) 0.10-0.38] adjusted for disease duration, age, tobacco, C-reactive protein, and non-steroidal anti-inflammatory drugs (NSAID) intake. Hard cluster analysis identified two phenotypes of patients. Patients from cluster 1, characterized by the presence of plaques and increased cIMT, had a higher prevalence of CV risk factors and SCORE, and more structural damage than cluster two patients. CONCLUSION: Radiographic structural damage is associated closely with increased estimated CV risk: higher SCORE levels in axSpA patients were found to be associated independently with mSASSS after adjusting for age, disease duration, CRP, tobacco and NSAID intake.