Association of anti-citrullinated protein or peptide antibodies with left ventricular structure and function in rheumatoid arthritis.

Objective: High levels of ACPAs in RA are associated with more severe arthritis and worse prognosis. However, the role of ACPAs in mediating the increased risk of heart failure in RA remains undefined. We examined whether specific ACPAs were associated with subclinical left ventricular (LV) phenotypes that presage heart failure. Methods: Sera from RA patients without clinical cardiovascular disease were assayed for specific ACPAs using a custom Bio-Plex bead assay, and their cross-sectional associations with cardiac magnetic resonance-derived LV measures were evaluated. High ACPA level was defined as ⩾ 75th percentile. Findings were assessed in a second independent RA cohort with an expanded panel of ACPAs and LV measures assessed by 3D-echocardiography. Results: In cohort 1 (n = 76), higher levels of anti-citrullinated fibrinogen 41-60 and anti-citrullinated vimentin antibodies were associated with a 10 and 6% higher adjusted mean LV mass index (LVMI), respectively, compared with lower antibody levels (P < 0.05). In contrast, higher levels of anti-citrullinated biglycan 247-266 were associated with a 13% lower adjusted mean LVMI compared with lower levels (P < 0.001). In cohort 2 (n = 74), the association between ACPAs targeting citrullinated fibrinogen and citrullinated vimentin peptides or protein and LVMI was confirmed: higher anti-citrullinated fibrinogen 556-575 and anti-citrullinated vimentin 58-77 antibody levels were associated with a higher adjusted mean LVMI (19 and 15%, respectively; P < 0.05), but no association with biglycan was found. Conclusion: Higher levels of antibodies targeting citrullinated fibrinogen and vimentin peptides or protein were associated with a higher mean LVMI in both RA cohorts, potentially implicating autoimmune targeting of citrullinated proteins in myocardial remodelling in RA.

Exploring the Lipid Paradox Theory in Rheumatoid Arthritis: Associations of Low Circulating Low-Density Lipoprotein Concentration With Subclinical Coronary Atherosclerosis.

OBJECTIVE: Rheumatoid arthritis (RA) patients with the lowest circulating low-density lipoprotein (LDL) concentrations are at heightened risk of cardiovascular events. However, the atherosclerosis burden within this subgroup is unknown. METHODS: RA patients pooled from 4 cohort studies of cardiovascular disease (CVD; n = 546) were compared with non-RA controls from the Multi-Ethnic Study of Atherosclerosis (n = 5,279). Those taking lipid-lowering medications were excluded. Differences in cardiac computed tomography-derived Agatston coronary artery calcium (CAC) scores between the RA and control groups were compared across strata of LDL concentration. RESULTS: Among those with low LDL concentrations (<70 mg/dl), mean adjusted CAC scores were >4-fold higher for RA patients than for controls (18.6 versus 4.6 Agatston units, respectively; P < 0.001), a difference significantly greater than that in any other LDL concentration stratum except LDL concentration ≥160 mg/dl. Similarly, 32% of the RA patients with low LDL concentration had a CAC score of ≥100 Agatston units compared with only 7% of controls in the same LDL concentration stratum (odds ratio 5.97; P < 0.001), a difference significantly greater than that in all of the other LDL concentration strata. Low LDL concentration was most strongly associated with higher CAC score among RA patients who were white, had ever smoked, or were not obese. Other than a higher frequency of current smokers, RA patients with low LDL concentrations did not have more CVD risk factors or higher measures of RA disease activity or severity than RA patients with higher LDL concentrations. CONCLUSION: RA patients with low LDL concentration may represent a group for whom heightened screening and prevention of atherosclerotic CVD is appropriate.

Myocardial Inflammation, Measured Using 18-Fluorodeoxyglucose Positron Emission Tomography With Computed Tomography, Is Associated With Disease Activity in Rheumatoid Arthritis.

OBJECTIVE: To determine the prevalence and correlates of subclinical myocardial inflammation in patients with rheumatoid arthritis (RA). METHODS: RA patients (n = 119) without known cardiovascular disease underwent cardiac 18-fluorodeoxyglucose (FDG) positron emission tomography with computed tomography (PET-CT). Myocardial FDG uptake was assessed visually and measured quantitatively as the standardized uptake value (SUV). Multivariable linear regression was used to assess the associations of patient characteristics with myocardial SUVs. A subset of RA patients who had to escalate their disease-modifying antirheumatic drug (DMARD) therapy (n = 8) underwent a second FDG PET-CT scan after 6 months, to assess treatment-associated changes in myocardial FDG uptake. RESULTS: Visually assessed FDG uptake was observed in 46 (39%) of the 119 RA patients, and 21 patients (18%) had abnormal quantitatively assessed myocardial FDG uptake (i.e., mean of the mean SUV [SUVmean ] ≥3.10 units; defined as 2 SD above the value in a reference group of 27 non-RA subjects). The SUVmean was 31% higher in patients with a Clinical Disease Activity Index (CDAI) score of ≥10 (moderate-to-high disease activity) as compared with those with lower CDAI scores (low disease activity or remission) (P = 0.005), after adjustment for potential confounders. The adjusted SUVmean was 26% lower among those treated with a non-tumor necrosis factor-targeted biologic agent compared with those treated with conventional (nonbiologic) DMARDs (P = 0.029). In the longitudinal substudy, the myocardial SUVmean decreased from 4.50 units to 2.30 units over 6 months, which paralleled the decrease in the mean CDAI from a score of 23 to a score of 12. CONCLUSION: Subclinical myocardial inflammation is frequent in patients with RA, is associated with RA disease activity, and may decrease with RA therapy. Future longitudinal studies will be required to assess whether reduction in myocardial inflammation will reduce heart failure risk in RA.

Myocarditis in systemic lupus erythematosus diagnosed by 18F-fluorodeoxyglucose positron emission tomography.

OBJECTIVES: Cardiovascular diseaseand heart failure (CHF) are leading causes of death in systemic lupus erythematosus (SLE). The underlying mechanisms for increased CHF in SLE are unclear but myocardial inflammation and lupus myocarditis (LM) may play a role. We propose that 18F-fluorodeoxyglucose-positron emission tomography (18F-FDG-PET)/CT can help diagnose LM. METHODS: This report describes eight patients with presumed LM; five patients were evaluated due to active cardiorespiratory symptoms and three patients were participating in a pilot study to determine the prevalence of subclinical myocarditis in SLE. Clinical characteristics, laboratory and cardiac testing including electrocardiography (ECG), transthoracic echocardiogram (TTE), coronary artery evaluation as well as 18F-FDG-PET/CT imaging are discussed. RESULTS: Four patients were African American and the others were Hispanic. Half presented with chest pain; 37% had dyspnoea and 25% were asymptomatic. The median SLE Disease Activity Index (SLEDAI-2K) was 5 (2-18) and SLICC Damage Index (SDI) 0.5 (0-5). The median troponin level was 0.08 ng/mL (0-0.9). The most common ECG findings were non-specific ST-T wave abnormalities (n=5). Fifty per cent of the patients had a decreased ejection fraction on TTE and all patients had diffuse myocardial FDG uptake on 18F-FDG-PET/CT consistent with myocardial inflammation. CONCLUSION: This case series is the first to describe the use of 18F-FDG-PET/CT in the diagnosis of LM and discuss the clinical characteristics and cardiac findings of eight patients with LM supporting the role for cardiac 18F-FDG-PET/CT in its diagnosis.

Adipose Tissue Macrophages in Rheumatoid Arthritis: Prevalence, Disease-Related Indicators, and Associations With Cardiometabolic Risk Factors.

OBJECTIVE: Adipose tissue macrophages (ATMs) are a potent source of inflammatory cytokines, with profound effects on adipose tissue function, yet their potential role in rheumatoid arthritis (RA) pathobiology is largely unstudied. METHODS: Periumbilical subcutaneous adipose tissue was obtained from 36 RA patients and 22 non-RA controls frequency matched on demographics and body mass index. Samples were stained for the macrophage marker CD68, and the average proportions of ATMs, crown-like structures (periadipocyte aggregates of 3 or more ATMs), and fibrosis were compared between groups. RESULTS: The adjusted proportion of ATMs among all nucleated cells was 76% higher in RA than in non-RA samples (37.7 versus 21.3%, respectively; P < 0.001), and the adjusted average number of crown-like structures was more than 1.5-fold higher in the RA group than in controls (0.58 versus 0.23 crown-like structure/high-power field, respectively; P = 0.001). ATMs were significantly more abundant in early RA and in those with anti-cyclic citrullinated peptide seropositivity. Users of methotrexate, leflunomide, and tumor necrosis factor inhibitors had a significantly lower proportion of ATMs compared with nonusers. Crown-like structures were significantly higher in patients with rheumatoid factor seropositivity and in those with C-reactive protein levels ≥10 mg/liter, and significantly lower among those treated with statins. Linear ATMs were significantly associated with whole-body insulin resistance, but not with serum lipids. CONCLUSIONS: ATMs and crown-like structures were more abundant in RA patients and were associated with systemic inflammation, autoimmunity, and whole-body insulin resistance, suggesting possible contributions to the RA disease process. Lower levels of ATMs and crown-like structures associated with specific RA treatments suggest that adipose tissue inflammation may be ameliorated by immunomodulation.

Arterial Inflammation Detected With 18 F-Fluorodeoxyglucose-Positron Emission Tomography in Rheumatoid Arthritis.

OBJECTIVE: In addition to traditional risk factors, excess cardiovascular disease (CVD) in rheumatoid arthritis (RA) is attributed to enhanced vascular and/or systemic inflammation. In several small studies using 18 F-fluorodeoxyglucose-positron emission tomography/computed tomography (18 F-FDG-PET/CT) to directly assess vascular inflammation, FDG uptake was higher in RA patients than in controls. Using a substantially larger sample of RA patients, we sought to identify RA disease characteristics independently associated with vascular FDG uptake. METHODS: RA patients underwent cardiac FDG-PET/CT, with aortic inflammation assessed by quantification of FDG uptake in the ascending aorta, calculated as the mean and maximum (max) standardized uptake value (SUV) of the entire ascending aorta and of its most diseased segment (SUV MDS). Univariate and multivariable regression models were constructed to model the associations of patient characteristics with aortic FDG uptake. RESULTS: Ninety-one RA patients were scanned. In multivariable models, in addition to the independent associations of hypertension and body mass index with increased aortic FDG uptake, the prevalence of rheumatoid nodules correlated with the SUV mean and SUV MDS mean measures, while anti-cyclic citrullinated peptide (anti-CCP) antibodies correlated inversely with these measures and with the SUV max and SUV MDS max (P < 0.05). A significant association of RA disease activity with aortic FDG uptake was observed but was restricted to anti-CCP seropositivity. CONCLUSION: Traditional CV risk factors and RA disease characteristics (rheumatoid nodules and the Disease Activity Score in 28 joints using the C-reactive protein level in anti-CCP antibody-positive individuals) were independently associated with ascending aortic FDG uptake in RA patients without clinical CVD.

Association of Anti-Citrullinated Peptide Antibodies With Coronary Artery Calcification in Rheumatoid Arthritis.

OBJECTIVE: Citrullinated proteins have been found within atherosclerotic plaque. However, studies evaluating the association between anti-citrullinated protein antibodies (ACPAs) and imaging measures of atherosclerosis in patients with rheumatoid arthritis (RA) have been limited to seroreactive citrullinated fibrinogen or citrullinated vimentin and have rendered contradictory results. Therefore, our objective was to evaluate this association using an extended panel of ACPAs in a larger sample of RA patients without clinical cardiovascular disease (CVD). METHODS: ACPAs were identified using a custom Bio-Plex bead assay in 270 patients from 2 independent RA cohorts without clinical CVD, with the first one consisting of 195 patients and the other of 75 patients. Coronary artery calcium (CAC) was assessed by computed tomography as a measure of coronary artery disease. RESULTS: High levels of anti-citrullinated histone H2B antibodies were strongly associated with higher CAC scores, compared with lower antibody levels (P = 0.001); this remained significant after adjustment for traditional CV and RA-specific risk factors (P = 0.03). No association between levels of ACPAs and CAC progression at 3 years was seen (P = 0.09); however, the number of progressors was small (n = 92). CONCLUSION: Higher levels of ACPAs targeting Cit-histone H2B were associated with higher CAC scores when compared to lower antibody levels, suggesting a potential role for histone citrullination seroreactivity in atherosclerosis.

ECG non-specific ST-T and QTc abnormalities in patients with systemic lupus erythematosus compared with rheumatoid arthritis.

OBJECTIVES: Cardiovascular disease (CVD) is a leading cause of death in systemic lupus erythematosus (SLE) and in rheumatoid arthritis (RA). Although only explored in one study, ECG non-specific ST-T abnormalities, in addition to corrected QT-interval (QTc) prolongation, were recently reported in an SLE inception cohort. Importantly, these ECG abnormalities are known predictors of CVD mortality in the general population, yet their prevalence in patients with established SLE has not been evaluated. METHODS: We cross-sectionally investigated the presence of non-specific ST-T and QTc abnormalities in 50 patients with SLE, predominantly Hispanic and black, without CVD or SLE-related cardiac involvement and compared them with 139 patients with RA without CVD. Demographics, disease-specific characteristics and CVD risk factors were ascertained and adjusted for. RESULTS: Patients with SLE (mean age 36±13 years, 92% women, 6 years median disease duration, 96% Hispanics and blacks) had a 3.3-fold higher adjusted prevalence of non-specific ST-T abnormalities (56% vs 17%; p <0.0001) compared with RA, despite the older age and higher percentage of men in the RA group. The QTc was 26 ms longer in SLE compared with RA (p=0.002) in the setting of a higher percentage of women, blacks, Hispanics and higher C reactive protein levels in the SLE group. CONCLUSIONS: This study demonstrates a high prevalence of ECG abnormalities in predominantly Hispanic and black patients with SLE. Longitudinal evaluation of the progression to potentially life-threatening arrhythmias and/or cardiovascular events is warranted.

Association of Elevations of Specific T Cell and Monocyte Subpopulations in Rheumatoid Arthritis With Subclinical Coronary Artery Atherosclerosis.

OBJECTIVE: Coronary artery disease (CAD) is the leading cause of excess deaths in rheumatoid arthritis (RA). However, identification of features denoting patients with a risk of developing CAD is lacking. The composition of circulating peripheral blood mononuclear cell (PBMC) subsets in RA patients differs markedly from that in healthy controls with regard to the extent of T cell activation, with clonal expansion and differentiation to effector memory status, and presence of inflammatory monocytes. In this study, we sought to evaluate whether elevations in these PBMC subpopulations in RA patients could denote those with an increased risk of subclinical CAD, as determined by the presence of coronary artery calcification (CAC). METHODS: The study cohort comprised 72 patients with RA who underwent cardiac computed tomography to assess CAC. PBMC subsets were determined by multiparameter flow cytometry. Multivariable logistic regression was used to determine the associations between PBMC subpopulations and the presence of CAC. RESULTS: Among the 72 patients with RA, 33% had CAC and exhibited significant increases in the levels of circulating CD4 T cell subsets denoting activation and differentiation to the effector memory phenotypes. Analogous increases in the levels of CD8 T cell subsets, as well as in the CD14(high)CD16+ intermediate monocyte subset, were also present in these patients, as compared to those without CAC. The increases in the CD4 and CD8 T cell subsets were highly intercorrelated, whereas the increases in CD14(high)CD16+ monocytes were independent of elevations in the CD4 T cell subsets. After adjustments for relevant confounders, the levels of CD4+CD56+CD57+ T cells and CD14(high)CD16+ monocytes remained associated with the presence of CAC. CONCLUSION: These findings indicate that PBMC subsets are markers for the presence of CAC and suggest that mechanisms of atherogenesis in RA may operate in part through the elevations in these subsets, raising further questions about the mechanisms underlying the presence of such alterations in cell composition in patients with RA and the potential for shared etiologic pathways between RA and cardiovascular disease.