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PURPOSE OF REVIEW: Rheumatoid arthritis (RA) patients remain at higher cardiovascular (CV) risk compared to non-RA patients, driven by accelerated atherosclerosis, leading to plaque rupture and acute CV events (CVE), including heart failure (HF). It has been hypothesized that chronic inflammation is the main driving force behind such outcomes. We summarize the current evidence supporting this hypothesis, focusing on arterial disease and myocardial disease. RECENT FINDINGS: RA patients demonstrate higher prevalence of subclinical atherosclerosis (high risk plaque and arterial inflammation) compared to non-RA patients, with RA disease activity correlating independently with CVE and death. Nonischemic HF with preserved ejection fraction (HFpEF) is more common in RA compared to non-RA, with subclinical myocardial structural and functional alterations also more prevalent in RA. HFpEF and myocardial remodeling and dysfunction bear a strong and independent association with inflammatory correlates. SUMMARY: All of this suggests that inflammation contributes to enhanced risk of CVE in RA. A more accurate and specific CV risk stratification tool for RA, incorporating biomarkers or imaging, is needed. Likewise, more prospective studies outlining the trajectory from preclinical to clinical HF, incorporating biomarkers and imaging, are also needed.
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Artrite Reumatoide , Aterosclerose , Doenças Cardiovasculares , Insuficiência Cardíaca , Placa Aterosclerótica , Humanos , Fatores de Risco , Insuficiência Cardíaca/etiologia , Insuficiência Cardíaca/complicações , Estudos Prospectivos , Volume Sistólico , Artrite Reumatoide/complicações , Artrite Reumatoide/epidemiologia , Inflamação/complicações , Aterosclerose/complicações , Placa Aterosclerótica/complicações , Biomarcadores , Doenças Cardiovasculares/epidemiologia , Doenças Cardiovasculares/etiologiaRESUMO
Rheumatoid arthritis is a chronic, systemic, autoimmune inflammatory disease that mainly affects the joints and periarticular soft tissues. In this Seminar, we provide an overview of the main aspects of rheumatoid arthritis. Epidemiology and advances in the understanding of rheumatoid arthritis pathogenesis will be reviewed. We will discuss the clinical manifestations of rheumatoid arthritis, classification criteria, and the value of imaging in the diagnosis of the disease. The advent of new medications and the accumulated scientific evidence demand continuous updating regarding the diagnosis and management, including therapy, of rheumatoid arthritis. An increasing number of patients are now able to reach disease remission. This major improvement in the outcome of patients with rheumatoid arthritis has been determined by a combination of different factors (eg, early diagnosis, window of opportunity, treat-to-target strategy, advent of targeted disease-modifying antirheumatic drugs, and combination therapy). We will discuss the updated recommendations of the two most influential societies for rheumatology worldwide (ie, the American College of Rheumatology and European Alliance of Associations for Rheumatology) for the management of rheumatoid arthritis. Furthermore, controversies (ie, the role of glucocorticoids in the management of rheumatoid arthritis and safety profile of Janus kinase inhibitors) and outstanding research questions, including precision medicine approach, prevention, and cure of rheumatoid arthritis will be highlighted.
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Antirreumáticos , Artrite Reumatoide , Inibidores de Janus Quinases , Reumatologia , Humanos , Artrite Reumatoide/diagnóstico , Artrite Reumatoide/tratamento farmacológico , Antirreumáticos/uso terapêutico , Glucocorticoides/uso terapêutico , Inibidores de Janus Quinases/uso terapêuticoRESUMO
OBJECTIVES: Rheumatoid arthritis (RA) and atherosclerosis share many common inflammatory pathways. We studied whether a multi-biomarker panel for RA disease activity (MBDA) would associate with changes in arterial inflammation in an interventional trial. METHODS: In the TARGET Trial, RA patients with active disease despite methotrexate were randomly assigned to the addition of either a TNF inhibitor or sulfasalazine+hydroxychloroquine (triple therapy). Baseline and 24-week follow-up 18F-fluorodeoxyglucose (FDG) positron emission tomography/computed tomography scans were assessed for change in arterial inflammation measured as the maximal arterial target-to-blood background ratio of FDG uptake in the most diseased segment of the carotid arteries or aorta (MDS-TBRmax). The MBDA test, measured at baseline and weeks 6, 18, and 24, was assessed for its association with the change in MDS-TBRmax. RESULTS: Interpretable scans were available at baseline and week 24 for n = 112 patients. The MBDA score at week 24 was significantly correlated with the change in MDR-TBRmax (Spearman's rho = 0.239; p= 0.011) and remained significantly associated after adjustment for relevant confounders. Those with low MBDA at week 24 had a statistically significant adjusted reduction in arterial inflammation of 0.35 units vs no significant reduction in those who did not achieve low MBDA. Neither DAS28-CRP nor CRP predicted change in arterial inflammation. The MBDA component with the strongest association with change in arterial inflammation was serum amyloid A (SAA). CONCLUSIONS: Among treated RA patients, achieved MBDA predicts of changes in arterial inflammation. Achieving low MBDA at 24 weeks was associated with clinically meaningful reductions in arterial inflammation, regardless of treatment.
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OBJECTIVES: Galectin-3 is a beta-galactoside-binding lectin and is a marker of cardiovascular disease (CVD) in the general population. It may also play a role in joint inflammation. We asked whether serum galectin-3 is a useful marker of subclinical vascular disease in patients with rheumatoid arthritis (RA). METHODS: RA patients without clinical CVD underwent assessment of coronary artery calcium (CAC) score, aortic inflammation (using 18Fluorodeoxyglucose positron emission-computed tomography [FDG PET/CT]), and myocardial flow reserve (MFR). Aorta FDG uptake was measured as standardized uptake values (SUV). Generalized linear models were constructed to explore the associations of galectin-3 levels with CAC score, aortic SUV, and MFR. RESULTS: A total of 124 RA patients (mean age 57; 82 % women, 45 % Hispanic; median RA duration 6.8 years; 75 % seropositive; median CDAI 16; 33 % on prednisone; 89 % on DMARDs; median CAC score 0; median aorta SUV 2.59; mean MFR 2.86; median galectin-3 level 8.54 ng/mL) were analyzed. In univariable analysis, higher galectin-3 levels were associated with higher aortic SUV (p = 0.007) but CAC score and MFR were not. In multivariable analysis, higher galectin-3 level remained significantly associated with higher aortic SUV (ß Coefficient=0.1786, p value=0.002). CONCLUSION: In our cohort of RA patients without clinical CVD, higher serum galectin-3 levels were independently associated with higher levels of aortic inflammation, but not CAC score or MFR. This suggests that galectin-3 may be a biomarker for an inflammatory and potentially reversible stage, but not a later (calcified) stage, of atherosclerosis in patients with RA.
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Artrite Reumatoide , Aterosclerose , Doenças Cardiovasculares , Humanos , Feminino , Pessoa de Meia-Idade , Masculino , Galectina 3 , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Fluordesoxiglucose F18 , Artrite Reumatoide/complicações , Artrite Reumatoide/diagnóstico por imagem , Artrite Reumatoide/epidemiologia , Inflamação , Doenças Cardiovasculares/complicações , Aterosclerose/complicaçõesRESUMO
Cardiovascular disease remains an important comorbidity in patients with rheumatoid arthritis (RA), but traditional models do not accurately predict cardiovascular risk in patients with RA. The addition of biomarkers could improve prediction. METHODS AND RESULTS: The TARGET (Treatments Against RA and Effect on FDG PET/CT) trial assessed whether different treatment strategies in RA differentially impact cardiovascular risk as measured by the change in arterial inflammation on arterial target to background ratio on fluorodeoxyglucose positron emission tomography/computed tomography scans conducted 24 weeks apart. A group of 24 candidate biomarkers supported by prior literature was assessed at baseline and 24 weeks later. Longitudinal analyses examined the association between baseline biomarker values, measured in plasma EDTA, and the change in arterial inflammation target to background ratio. Model fit was assessed for the candidate biomarkers only, clinical variables only, and models combining both. One hundred nine patients with median (interquartile range) age 58 years (53-65 years), RA duration 1.4 years (0.5-6.6 years), and 82% women had biomarkers assessed at baseline and follow-up. Because the main trial analyses demonstrated significant target to background ratio decreases with both treatment strategies but no difference across treatment groups, we analyzed all patients together. Baseline values of serum amyloid A, C-reactive protein, soluble tumor necrosis factor receptor 1, adiponectin, YKL-40, and osteoprotegerin were associated with significant change in target to background ratio. When selected candidate biomarkers were added to the clinical variables, the adjusted R2 improved from 0.20 to 0.33 (likelihood ratio P=0.0005). CONCLUSIONS: A candidate biomarker approach identified several promising biomarkers that associate with baseline and treatment-associated changes in arterial inflammation in patients with RA. These will now be tested in an external validation cohort.
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Arterite , Artrite Reumatoide , Doenças Cardiovasculares , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Arterite/complicações , Artrite Reumatoide/complicações , Artrite Reumatoide/diagnóstico , Artrite Reumatoide/tratamento farmacológico , Biomarcadores , Doenças Cardiovasculares/diagnóstico , Doenças Cardiovasculares/epidemiologia , Doenças Cardiovasculares/etiologia , Fatores de Risco de Doenças Cardíacas , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada/métodos , Fatores de Risco , IdosoRESUMO
BACKGROUND: Treatments for rheumatoid arthritis (RA) are associated with complex changes in lipids and lipoproteins that may impact cardiovascular (CV) risk. The objective of this study was to examine lipid and lipoprotein changes associated with two common RA treatment strategies, triple therapy or tumor necrosis factor inhibitor (TNFi), and association with CV risk. METHODS: In this secondary data analysis of the TARGET trial, methotrexate (MTX) inadequate responders with RA were randomized to either add sulfasalazine and hydroxychloroquine (triple therapy), or TNFi for 24-weeks. The primary trial outcome was the change in arterial inflammation measured in the carotid arteries or aorta by FDG-PET/CT at baseline and 24-weeks; this change was described as the target-to-background ratio (TBR) in the most diseased segment (MDS). Routine lipids and advanced lipoproteins were measured at baseline and 24-weeks; subjects on statin therapy at baseline were excluded. Comparisons between baseline and follow-up lipid measurements were performed within and across treatment arms, as well as change in lipids and change in MDS-TBR. RESULTS: We studied 122 participants, 61 in each treatment arm, with median age 57 years, 76% female, and 1.5 year median RA disease duration. When comparing treatment arms, triple therapy had on average a larger reduction in triglycerides (15.9 mg/dL, p = 0.01), total cholesterol to HDL-C ratio (0.29, p-value = 0.01), and LDL particle number (111.2, p = 0.02) compared to TNFi. TNFi had on average a larger increase in HDL particle number (1.6umol/L, p = 0.006). We observed no correlation between change in lipid measurements and change in MDS-TBR within and across treatment arms. CONCLUSIONS: Both treatment strategies were associated with improved lipid profiles via changes in different lipids and lipoproteins. These effects had no correlation with change in CV risk as measured by vascular inflammation by FDG-PET/CT. TRIAL REGISTRATION: ClinicalTrials.gov ID NCT02374021.
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Antirreumáticos , Artrite Reumatoide , Quimioterapia Combinada , Hidroxicloroquina , Lipídeos , Metotrexato , Humanos , Artrite Reumatoide/tratamento farmacológico , Artrite Reumatoide/sangue , Feminino , Pessoa de Meia-Idade , Masculino , Antirreumáticos/uso terapêutico , Hidroxicloroquina/uso terapêutico , Lipídeos/sangue , Metotrexato/uso terapêutico , Idoso , Sulfassalazina/uso terapêutico , Adulto , Inibidores do Fator de Necrose Tumoral/uso terapêutico , Resultado do Tratamento , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada/métodos , Vasculite/tratamento farmacológico , Vasculite/sangueRESUMO
Knee osteoarthritis (OA), characterized by multiple joint tissue degenerations, remains a significant clinical challenge. Recent evidence suggests that crosstalk within the osteochondral unit may drive OA progression. Although structural-biomechanical properties of bone and cartilage have been studied, potential interaction within the osteochondral unit in the context of OA has yet to be investigated. We performed comprehensive structural and biomechanical quantification of the cartilage, subchondral bone plate (SBP), and subchondral trabecular bone (STB) using 101 osteochondral cores collected from tibial plateaus of 12 control human cadavers (CT, 5 male/7 female) and 19 patients undergoing total knee replacement (OA, 6 male/13 female). For each sample, we quantified SBP microstructure, plate-and-rod morphological properties of the STB using individual trabecula segmentation, and morphological and compositional properties of the articular cartilage. We also performed indentation testing on each compartment of the osteochondral unit to extract the respective structural-mechanical properties. Cartilage thickness was lower in moderate and severe OA regions, while Osteoarthritis Research Society International score was higher only in severe OA regions. GAG content did not change in any OA region. Aggregate and shear moduli were lower only in severe OA regions, while permeability was lower only in moderate OA regions. In the SBP, thickness and tissue mineral density were higher in moderate and severe OA regions. Tissue modulus of STB was lower in moderate OA regions despite a thicker and more mineralized SBP; this deterioration was not observed in severe OA regions. Regression analysis revealed strong correlations between cartilage and STB properties in CT; these correlations were also found in moderate OA regions but were not observed in severe OA regions. In summary, our findings comprehensively characterize the human OA osteochondral unit. Importantly, uncoupling cartilage and subchondral bone structural-mechanical properties may be a hallmark of OA.
Knee osteoarthritis (OA) is a complex condition involving the degradation of joint tissues. To better understand OA progression, we investigated the interplay between different components of the joint. Our study focused on how cartilage, subchondral bone plate (SBP), and subchondral trabecular bone (STB) interact in human knee OA samples. We observed distinct changes in these tissues in moderate and severe OA regions compared with healthy joints. In moderate to severe OA, we found that cartilage thickness decreased, while the SBP thickened. Interestingly, the strength of the STB decreased only in moderate OA regions, not in severe OA. Moreover, our analysis revealed strong correlations between cartilage and STB properties in healthy joints and moderate OA regions. However, these correlations were absent in severe OA regions, indicating a disruption in the usual relationship between these tissues. Overall, our findings shed light on the structural and biomechanical changes occurring within the knee joint in OA. Understanding these changes may offer insights into potential therapeutic strategies for managing OA.
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Cartilagem Articular , Osteoartrite do Joelho , Humanos , Cartilagem Articular/patologia , Cartilagem Articular/diagnóstico por imagem , Cartilagem Articular/fisiopatologia , Masculino , Feminino , Osteoartrite do Joelho/patologia , Osteoartrite do Joelho/fisiopatologia , Idoso , Fenômenos Biomecânicos , Pessoa de Meia-Idade , Idoso de 80 Anos ou mais , Osso Esponjoso/patologia , Osso Esponjoso/diagnóstico por imagem , Osso Esponjoso/fisiopatologiaRESUMO
Objective: Leveraging the Manhattan Lupus Surveillance Program (MLSP), a population-based registry of cases of systemic lupus erythematosus (SLE) and related diseases, we investigated the proportion of SLE with concomitant rheumatic diseases, including Sjögren's disease (SjD), antiphospholipid syndrome (APLS), and fibromyalgia (FM), as well as the prevalence of autoantibodies in SLE by sex and race/ethnicity. Methods: Prevalent SLE cases fulfilled one of three sets of classification criteria. Additional rheumatic diseases were defined using modified criteria based on data available in the MLSP: SjD (anti-SSA/Ro positive and evidence of keratoconjunctivitis sicca and/or xerostomia), APLS (antiphospholipid antibody positive and evidence of a blood clot), and FM (diagnosis in the chart). Results: 1,342 patients fulfilled SLE classification criteria. Of these, SjD was identified in 147 (11.0%, 95% CI 9.2-12.7%) patients with women and non-Latino Asian patients being the most highly represented. APLS was diagnosed in 119 (8.9%, 95% CI 7.3-10.5%) patients with the highest frequency in Latino patients. FM was present in 120 (8.9%, 95% CI 7.3-10.5) patients with non-Latino White and Latino patients having the highest frequency. Anti-dsDNA antibodies were most prevalent in non-Latino Asian, Black, and Latino patients while anti-Sm antibodies showed the highest proportion in non-Latino Black and Asian patients. Anti-SSA/Ro and anti-SSB/La antibodies were most prevalent in non-Latino Asian patients and least prevalent in non-Latino White patients. Men were more likely to be anti-Sm positive. Conclusion: Data from the MLSP revealed differences among patients classified as SLE in the prevalence of concomitant rheumatic diseases and autoantibody profiles by sex and race/ethnicity underscoring comorbidities associated with SLE.