Impact of disease duration on proteomic bioprofile and prognosis in rheumatoid arthritis patients.

OBJECTIVES: Cardiovascular disease worsens the prognosis of rheumatoid arthritis (RA) and vice-versa. Inflammation may be a common pathway for both conditions. It is expected that a longer RA duration leads to a greater inflammatory cumulative exposure burden; however, studies on the association between RA disease duration and outcomes are scarce. Our aim is to compare the characteristics, biomarker expression and outcomes according to the duration of RA. METHODS: Prospective cohort study including 399 RA patients, with detailed clinical, echocardiographic, and proteomic phenotyping that were compared across tertiles of RA disease duration. Cox proportional models were used to study the association of disease duration with cardiovascular outcomes. RESULTS: RA duration tertiles were: tertile 1 with median of 3.2; tertile 2 with median of 8.8; and tertile 3 with median of 21.8 years. Compared to tertile 1, patients in tertile 3 were older, had more erosive disease, more frequent echocardiographic alterations, lower haemoglobin and walked a shorter distance on the 6MWT. Natriuretic peptides, cathepsin L1, galectin 9, matrix metalloproteinase-12, adrenomedullin and tumour necrosis factor receptor 11A were higher in patients with longer disease duration. Compared to patients in tertile 1, those in tertile 3 had higher risk of a subsequent cardiovascular hospitalisation or cardiovascular death (HR 2.71, 95%CI 1.06-6.92, p=0.04). CONCLUSIONS: RA patients with longer disease duration had more organ damage and worse outcomes than those with shorter disease duration. Biomarker expression suggested that patients with longer RA duration had activation of pathways related to inflammation, extracellular matrix organisation, fibrosis and congestion.

Clinical associations and prognostic implications of 6-minute walk test in rheumatoid arthritis.

The clinical associations and prognostic implications of the 6-minute walk test (6MWT) distance in patients with rheumatoid arthritis (RA) is yet to be explored. To identify the clinical features and prognostic implications associated with the 6MWT in patients with RA. Cohort study including 387 RA patients who underwent 6MWT. Regression models (linear and logistic) were built to identify independent predictors of shorter 6MWT distance. Cox proportional models were used to study the association of 6MWT distance with cardiovascular outcomes. Patients were subdivided according to 6MWT tertiles: 126 patients walked > 405 m, 129 walked 345-405 m, and 132 walked < 345 m. Older age (> 55 years), elevated waist circumference, NT-pro BNP > 125 pg/mL, anemia, C-reactive protein ≥ 3 mg/dL, and troponin T ≥ 14 pg/mL were independent predictors of walking shorter distances. Patients walking less than 345 m had higher risk of a subsequent cardiovascular hospitalization or cardiovascular death compared with patients walking 345 m or more (adjusted HR: 2.98, 95%CI: 1.37-6.51, p = 0.006). Older age, abdominal obesity, anemia, cardiac dysfunction, and inflammation were associated with walking shorter distances in patients with RA. Walking less than 345 m in the 6MWT was associated with a poor cardiovascular prognosis. The 6MWT is simple, reproducible, and inexpensive, easily performed in routine practice, and provides important information regarding the patients´ status and outcomes, enabling the monitorization of the therapeutic optimization of the various domains of the RA.

Sex differences in circulating proteins of patients with rheumatoid arthritis: A cohort study.

OBJECTIVES: Differences in proteomic profiles between men and women may provide insights into the biological pathways that contribute to known sex differences in rheumatoid arthritis (RA). Studies focusing on sex differences in circulating proteins in RA patients are scarce. Our objective was to investigate the sex differences in circulating proteins of RA patients. METHODS: Cohort study enrolling 399 RA patients. Ninety-four circulating protein-biomarkers (92CVDIIOlink®  + troponin-T + C-reactive protein) were measured. Clinical, demographic, and echocardiographic characteristics were compared between men and women. Sex differences in biomarker expression were assessed using regression modeling. RESULTS: In all, 306 (76.7%) patients were women. Compared with men, women had less visceral fat, smoked less, had diabetes and chronic obstructive pulmonary disease less frequently, and expressed more fatigue, anxiety, and depression. The association with cardiovascular outcomes did not differ between sexes. After adjusting for potential confounders, women expressed higher levels of circulating proteins related to adipokine signaling and vascular function (eg, leptin and vascular endothelial growth factor), whereas men expressed higher levels of circulating proteins related to extracellular matrix organization and inflammation (eg, matrix metalloproteinase-2 and C-reactive protein). These results were not found in patients without RA. CONCLUSION: Sex differences in circulating proteins reflect distinct pathways implicated in the pathogenesis of RA, including inflammation, adiposity, angiogenesis, and extracellular matrix organization. These findings may help further investigations into factors underlying sex-based differences and allow future studies focused on sex-specific personalized treatment approaches in RA. CLINICALTRIALS: gov ID: NCT03960515.

Circulating Biomarkers and Cardiac Structure and Function in Rheumatoid Arthritis.

Background: Rheumatoid arthritis (RA) increases the risk for abnormalities of the cardiac structure and function, which may lead to heart failure (HF). Studying the association between circulating biomarkers and echocardiographic parameters is important to screen patients with RA with a higher risk of cardiac dysfunction. Aim: To study the association between circulating biomarkers and echocardiographic parameters in patients with RA. Methods: Echocardiography was performed in 355 patients with RA from RA Porto cohort and the associations between echocardiographic characteristics and 94 circulating biomarkers were assessed. These associations were also assessed in the Metabolic Road to Diastolic Heart Failure (MEDIA-DHF) [392 patients with HF with preserved ejection fraction (HFpEF)] and the Suivi Temporaire Annuel Non-Invasif de la Santé des Lorrains Assurés Sociaux (STANISLAS) (1,672 healthy population) cohorts. Results: In the RA Porto cohort, mean age was 58 ± 13 years, 23% were males and mean RA duration was 12 ± 10 years. After adjustment and multiple testing correction, left ventricular mass index (LVMi), left atrial volume index (LAVi), and E/e' were independently associated with biomarkers reflecting inflammation [i.e., bone morphogenetic protein 9 (BMP9), pentraxin-related protein 3 (PTX3), tumor necrosis factor receptor superfamily member 11a (TNFRSF11A)], extracellular matrix remodeling [i.e., placental growth factor (PGF)], congestion [i.e., N-terminal pro-brain natriuretic peptide (NT-proBNP), adrenomedullin (ADM)], and myocardial injury (e.g., troponin). Greater LVMi [hazard ratio (HR) (95% CI) per 1 g/m2 = 1.03 (1.02-1.04), p < 0.001], LAVi [HR (95% CI) per 1 ml/m2 = 1.03 (1.01-1.06), p < 0.001], and E/e' [HR (95% CI) per 1 = 1.08 (1.04-1.13), p < 0.001] were associated with higher rates of cardiovascular events. These associations were externally replicated in patients with HFpEF and asymptomatic individuals. Conclusion: Circulating biomarkers reflecting inflammation, extracellular matrix remodeling, congestion, and myocardial injury were associated with underlying alterations of cardiac structure and function. Biomarkers might be used for the screening of cardiac alterations in patients with RA.

Prevalence, risk factors and proteomic bioprofiles associated with heart failure in rheumatoid arthritis: The RA-HF study.

BACKGROUND: Rheumatoid arthritis (RA) patients have high risk of heart failure (HF). AIMS: Identifying the risk factors and mechanistic pathways associated with HF in patients with RA. METHODS: Cohort study enrolling 355 RA patients. HF was defined according to the ESC criteria. 93 circulating protein-biomarkers (91CVDIIOlink®+troponin-T+c-reactive protein) were measured. Regression modeling (multivariate and multivariable) were built and network analyses were performed - based on the identified relevant protein biomarkers. RESULTS: 115 (32.4%) patients fulfilled the ESC criteria for HF, but only 24 (6.8%) had a prior HF diagnosis. Patients with HF were older (67 vs. 55yr), had a longer RA duration (10 vs. 14yr), had more frequently diabetes, hypertension, obesity, dyslipidemia, atrial fibrillation, and ischemic arterial disease. Several protein-biomarkers remained independently associated with HF, the top (FDR1%) were adrenomedullin, placenta-growth-factor, TNF-receptor-11A, and angiotensin-converting-enzyme-2. The networks underlying the expression of these biomarkers pointed towards congestion, apoptosis, inflammation, immune system signaling and RAAS activation as central determinants of HF in RA. Similar HF-associated biomarker-pathways were externally found in patients without RA. Having RA plus HF increased the risk of cardiovascular events compared to RA patients without RF; adjusted-HR (95%CI)=2.37 (1.07-5.30), p=0.034 CONCLUSION: Age, cardiovascular risk factors, and RA duration increase the HF odds in patients with RA. Few RA patients had a correct prior HF diagnosis, but the presence of HF increased the patients` risk. RA patients with HF largely share the mechanistic pathways of HF patients without RA. Randomized HF trials should include patients with RA. CLINICALTRIALS. GOV ID: NCT03960515.