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Rheumatoid arthritis (RA) is associated with a wide variety of extra-articular manifestations and comorbidities, several of which can be organ- or even life-threatening. These extra-articular manifestations and comorbidities can also contribute to the physical disability and psychological morbidity of RA that lead to reduced quality of life, higher direct and indirect costs, and societal burden of the disease. Although the expansion of RA treatment options and adoption of treat-to-target approaches has reduced the incidence and severity of several nonarticular manifestations of RA, such as rheumatoid vasculitis and cardiovascular disease events, this does not seem to be shared by all RA comorbidities. Moreover, a number of highly prevalent and impactful RA-driven comorbidities, such as accelerated atherosclerosis, interstitial lung disease, and sarcopenia, can present clinically in the years before the manifestation of joint pain or observable synovitis. A larger proportion of patients with RA have atherosclerosis, myocardial dysfunction, interstitial lung disease, and sarcopenia that is subclinical in the preclinical and earliest clinical phases of RA, emphasizing the importance of targeting the pre-RA phase for the prevention of comorbidities that are often poorly responsive to treatment once they develop. Herein, we review the potential impact of pre-RA prevention on the incidence and burden of extra-articular manifestations and nonarticular comorbidities.

Rheumatoid arthritis (RA) patients have a 1.5- to twofold higher risk of developing heart failure (HF) and a twofold increased risk of HF-associated mortality compared to those without RA. HF is preceded subclinically by left ventricular (LV) remodeling in the general population. There is a relative absence of prospective studies following RA patients from pre-clinical to clinical HF as well as prospective studies of LV remodeling in RA without clinical HF. In our study, 158 RA patients without clinical HF were enrolled and underwent transthoracic echocardiography (TTE) at baseline and on follow-up between 4 and 6 years. Extensive characterization of RA disease activity and cardiovascular risk factors were performed. LV remodeling was prevalent at 40% at baseline and increased to 60% over time. Higher levels of interleukin-6 (IL 6) were associated with concentric LV remodeling on follow-up. The use of tocilizumab was also significantly associated with baseline LV remodeling (relative wall thickness). These findings suggest a role for IL-6 as a biomarker for LV remodeling in RA patients without clinical HF. Future research should focus on prospective follow-up of LV remodeling and the effects of IL-6 inhibition on LV remodeling in RA patients.

Purpose Rheumatoid cachexia has been described as a process of concurrent muscle loss and gain of adipose tissue. We evaluated longitudinal changes in body composition in patients with rheumatoid arthritis (RA) to evaluate the changes in adiposity that accompany loss of lean mass. Methods We combined and assessed three independent longitudinal RA cohorts that included assessments of body composition. Whole body DXA was performed in all participants to quantify appendicular lean mass index (ALMI, kg/m2) and fat mass index (FMI, kg/m2). Independent associations between loss of ALMI during follow‐up and FMI over the same time‐period were assessed adjusting for age, sex, race, baseline body composition and study using mixed‐effects regression to account for clustering by study. Changes in adipokines (adiponectin and leptin) were also assessed over time in similar models. Visceral fat area was determined from DXA (cm2) in one of the cohorts and was also assessed. Results Among 451 patients with a mean (SD) age of 58.3 (10.5), the mean (SD) ALMI was 6.97 (1.41) kg/m2. Longitudinal analyses were conducted in 361 participants with follow‐up data [average follow‐up 2.65 (0.71) years]. Of these, 195 lost lean mass (experienced a negative change in ALMI during follow‐up), while 166 gained lean mass. Participants that lost lean mass had greater reductions in BMI [−0.77 (95% CI: −1.21, −0.33) v. +1.07 (95% CI: 0.56, 1.59)], greater reductions in FMI [−0.17 (95% CI: −0.48, 0.14) v. +0.46 (95% CI: 0.08, 0.83) p = 0.07] and a greater odds of having a reduction in FMI [OR: 2.30 (1.31, 4.05) p = 0.004], and had declining leptin levels and visceral fat area. Associations were strongest among those with high FMI at baseline. Conclusions In RA, loss of lean mass tends to occur in the context of a loss of weight and a loss of both total and visceral adiposity. These observations help to inform our understanding of the mechanisms leading to loss of muscle and rheumatoid cachexia in RA as well as to inform potential screening practices.

Background Hydroxychloroquine (HCQ) is a cornerstone therapy for systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA). However, reports of its use and subsequent fatal arrhythmias in patients with coronavirus disease 19 (COVID-19) have raised concern regarding its cardiovascular (CV) safety. Therefore, we examined the relationship between HCQ use and corrected QT (QTc) length in SLE and RA patients without clinical CV disease (CVD). Methods SLE patients from the Columbia University Lupus Cohort registry ( n = 352) and two RA cohorts ( n = 178; ESCAPE-RA and RHYTHM-RA) with electrocardiograms (ECGs) collected as part of study data were analyzed. RA cohort participants were recruited from tertiary referral centers with additional referrals from community rheumatologists, while SLE subjects originated from the Columbia University Lupus Cohort. All patients met American College of Rheumatology (ACR) classification criteria for SLE or RA and lacked known CVD. The exposure of interest was HCQ use and main outcome measure was QTc length [continuous or categorical (≥ 440 ms and ≥ 500 ms)]. Results Of the combined SLE and RA cohorts ( n = 530), 70% were HCQ users and 44% had a QTc ≥ 440 ms. The adjusted mean QTc length was comparable between HCQ users vs non-users (438 ms vs 437 ms). In multivariable logistic models, HCQ use was not a significant predictor of a QTc ≥ 440 ms for the entire cohort (OR 0.77; 95% CI 0.48–1.23; p = 0.27). Importantly, a QTc ≥ 500 ms was inversely associated with HCQ use and not associated with arrhythmias or deaths. A significant interaction was found between HCQ use and use of anti-psychotics. Ultimately, the use of HCQ combined with any QTc prolonging medication as a group was associated with a QTc length (434 ms; 95% CI 430, 439) which was comparable to that of use of HCQ alone (433 ms; 95% CI 429-437). Conclusion In a combined cohort of SLE and RA patients without clinical CVD, adjusted QTc length was comparable between HCQ and non-HCQ users, supporting its CV safety in patients with rheumatic diseases.

A subset of rheumatoid arthritis (RA) patients have detectable antibodies directed against the peptidyl-arginine deiminase (PAD) enzyme isoforms 3 and 4. Anti-PAD3/4 cross-reactive antibodies (anti-PAD3/4XR) have been shown to lower the calcium threshold required for PAD4 activation, an effect potentially relevant to the pathogenesis of RA-associated interstitial lung disease (ILD). RA patients underwent multi-detector computed tomography (MDCT) of the chest with interpretation by a pulmonary radiologist for ILD features. A semi-quantitative ILD Score (range 0-32) was calculated. Concurrent serum samples were assessed for antibodies against PAD by immunoprecipitation with radiolabeled PAD3 and PAD4. Among the 176 RA patients studied, any ILD was observed in 58 (33%) and anti-PAD3/4XR was detected in 19 (11%). The frequency of any ILD among those with anti-PAD3/4XR was 68% vs. 29% among those with no anti-PAD (crude OR = 5.39; p = 0.002) and vs. 27% among those with anti-PAD4 that was not cross-reactive with PAD3 (crude OR = 5.74; p = 0.001). Both associations were stronger after adjustment for relevant confounders (adjusted ORs = 7.22 and 6.61, respectively; both p-values<0.01). Among ever smokers with anti-PAD3/4XR, the adjusted frequency of any ILD was 93% vs. 17% for never smokers without the antibody (adjusted OR = 61.4; p = 0.001, p-value for the interaction of smoking with anti-PAD3/4XR<0.05). The prevalence and extent of ILD was markedly higher among RA patients with anti-PAD3/4 cross-reactive antibodies, even after accounting for relevant confounders, particularly among ever smokers. These findings may suggest etiopathologic mechanisms of RA-ILD, and their clinical utility for predicting ILD warrants additional study.

Background Diastolic dysfunction (DD) is more prevalent in patients with rheumatoid arthritis (RA) compared to the general population. However, its evolution over time and its significant clinical predictors remain uncharacterized. We report on baseline and prospective changes in diastolic function and its associated RA and cardiovascular (CV) predictors. Methods In this study, 158 RA patients without clinical CV disease (CVD) were enrolled and followed up at 4 to 6 years, undergoing baseline and follow-up echocardiography to assess for DD, as well as extensive characterization of RA disease activity and CV risk factors. Novel measures of myocardial inflammation and perfusion were obtained at baseline only. Using baseline and follow-up composite DD (E/e′, Left Atrial Volume Index (LAVI) or peak tricuspid regurgitation (TR) velocity; ≥ 1 in top 25%) as the outcome, multivariable regression models were constructed to identify predictors of DD. Results DD was prevalent in RA patients without clinical heart failure (HF) (40.7% at baseline) and significantly progressed on follow-up (to 57.9%). Baseline composite DD was associated with baseline RA disease activity (Clinical Disease Activity Index; CDAI) (OR 1.39; 95% CI 1.02–1.90; p =0.034). Several individual diastolic parameters (baseline E/e′ and LAVI) were associated with troponin-I and brain natriuretic peptide (BNP). Baseline and follow-up composite DD, however, were not associated with myocardial inflammation, myocardial microvascular dysfunction, or subclinical atherosclerosis. Conclusions DD is prevalent in RA patients without clinical HF and increases to >50% over time. Higher RA disease activity at baseline predicted baseline composite DD. Future longitudinal studies should explore whether adverse changes in diastolic function lead to clinical HF and are attenuated by disease-modifying antirheumatic drugs (DMARDs).

Background Cardiovascular (CV) risk estimation calculators for the general population underperform in patients with rheumatoid arthritis (RA). The purpose of this study was to identify relevant protein biomarkers that could be added to traditional CV risk calculators to improve the capacity of coronary artery calcification (CAC) prediction in individuals with RA. In a second step, we quantify the improvement of this prediction of CAC when these circulating biomarkers are added to standard risk scores. Methods A panel of 141 serum and plasma proteins, which represent a broad base of both CV and RA biology, were evaluated and prioritized as candidate biomarkers. Of these, 39 proteins were selected and measured by commercial ELISA or quantitative mass spectroscopy in 561 individuals with RA in whom a measure of CAC and frozen sera were available. The patients were randomly split 50:50 into a training/validation cohort. Discrimination (using area under the receiver operator characteristic curves) and re-classification (through net reclassification improvement and integrated discrimination improvement calculation) analyses were performed first in the training cohort and replicated in the validation cohort, to estimate the increase in prediction accuracy for CAC using the ACA/AHA (American College of Cardiology and the American Heart Association) score with, compared to without, addition of these circulating biomarkers. Results The model containing ACC/AHA score plus cytokines (osteopontin, cartilage glycoprotein-39, cystatin C, and chemokine (C–C motif) ligand 18) and plus quantitative mass spectroscopy biomarkers (serpin D1, paraoxonase, and clusterin) had a statistically significant positive net reclassifications index and integrated discrimination improvement for the prediction of CAC, using ACC/AHA score without any biomarkers as the reference category. These results were confirmed in the validation cohort. Conclusion In this exploratory analysis, the addition of several circulating CV and RA biomarkers to a standard CV risk calculator yielded significant improvements in discrimination and reclassification for the presence of CAC in individuals with RA.

The association between chronic inflammation and increased risk of cardiovascular disease in rheumatoid arthritis (RA) is well established. In the general population, inflammation is an established independent risk factor for cardiovascular disease, and much interest is placed on controlling inflammation to reduce cardiovascular events. As inflammation encompasses numerous pathways, the development of targeted therapies in RA provides an opportunity to understand the downstream effect of inhibiting specific pathways on cardiovascular risk. Data from these studies can inform cardiovascular risk management in patients with RA, and in the general population. This Review focuses on pro-inflammatory pathways targeted by existing therapies in RA and with mechanistic data from the general population on cardiovascular risk. Specifically, the discussions include the IL-1, IL-6 and TNF pathways, as well as the Janus kinase (JAK)–signal transducer and activator of transcription (STAT) signalling pathway, and the role of these pathways in RA pathogenesis in the joint alongside the development of atherosclerotic cardiovascular disease. Overall, some robust data support inhibition of IL-1 and IL-6 in decreasing the risk of cardiovascular disease, with growing data supporting IL-6 inhibition in both patients with RA and the general population to reduce the risk of cardiovascular disease.Rheumatoid arthritis is associated with an excess risk of atherosclerotic cardiovascular disease. This Review summarizes shared inflammatory pathways between rheumatoid arthritis and atherosclerotic cardiovascular disease that are targeted by existing therapies, and lessons learnt from clinical trials of these drugs.

Peptidylarginine deiminases (PAD) 2 and 4 are key enzymes in rheumatoid arthritis (RA) pathogenesis due to their ability to generate the protein targets of anti-citrullinated protein antibodies (ACPA). Anti-PAD4 antibodies that cross-react with PAD3 (anti-PAD3/4) have been identified and are associated with severe joint and lung disease. Here, we examined whether anti-PAD2 antibodies were present in patients with RA and defined their clinical significance. A PAD2 ELISA was established to screen for anti-PAD2 IgG in sera from RA patients from a prospective observational cohort study ( = 184) and healthy controls ( = 100). RA patient characteristics were compared according to anti-PAD2 antibody status. Multivariable models were constructed to explore the independent associations of anti-PAD2 antibodies with clinical variables. Anti-PAD2 antibodies were found in 18.5% of RA patients and 3% of healthy controls ( < 0.001). Among RA patients, anti-PAD2 antibodies were not associated with traditional genetic or serologic RA risk factors, including HLA-DRβ1 shared epitope alleles, ACPA, rheumatoid factor (RF), or anti-PAD3/4 antibodies. In addition, antibodies to PAD2 were associated with fewer swollen joints, a lower prevalence of interstitial lung disease, and less progression of joint damage. In subset analyses in which patients were stratified by the baseline presence of ACPA/RF or anti-PAD3/4 antibodies, anti-PAD2 antibodies provided additional value in identifying patients with the least progressive joint disease. Anti-PAD2 antibodies represent a novel serologic marker in RA that identifies a genetically and clinically unique subset of patients with less severe joint and lung disease.

A population-based cohort showed an association between cigarette smoking and subclinical parenchymal lung disease defined as regions of increased computed tomography (CT) lung densitometry. This technique has not been applied to the rheumatoid arthritis (RA) population where associated ILD is highly prevalent. The association between cumulative cigarette smoking and volume of areas of high attenuation (HAA: >-600 and <-250 Hounsfield Units) on full inspiratory CT was compared in 172 RA participants and 3,969 controls in a general population sample. Multivariable regression models were used to adjust for demography, anthropometrics, percent emphysema, and CT parameters. The mean cumulative cigarette smoking exposure was 25 (IQR 10-42) and 15(IQR 5-31) pack-years for the RA and non-RA cohorts, respectively. Mean HAA was 153(±57) cm.sup.3 and 129(±50) cm.sup.3 in the RA and non-RA cohorts, respectively. Each 10 cigarette pack-year increment was associated with a higher HAA by 0.03% (95% CI, 0.007-0.05%) in RA patients and by 0.008% (95% CI, 0.003-0.01%) in those without RA (interaction p = 0.001). Cigarette smoking was associated with higher lung attenuation; with a magnitude of association more pronounced in those with RA than in the general population. These data suggest that cigarette smoking may be a more potent ILD risk factor for RA patients than in the general population.