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Rheumatoid arthritis (RA) is associated with a heightened risk of cardiovascular disease (CVD) events, presumably related to a greater burden of atherosclerosis, as well as atherosclerotic plaques that tend to be inflamed and rupture prone. Many of the inflammatory pathways underlying the pathobiology of RA are also recognized contributors to atherosclerosis. Immunomodulation is the mainstay for RA therapy, and a variety of biologic and non-biologic pharmacotherapies are used either singly or in combination to control articular and systemic inflammation and prevent joint destruction. Almost all of these agents have theoretical potential to favorably affect atherogenesis and atherothrombosis, but mechanisms by which they exert effects have been incompletely studied, to date. However, whether clinical control of RA disease activity is associated with a reduction in CVD events regardless of agent used or whether the potency of anti-atherogenic effects varies between disease-modifying anti-rheumatic drugs (DMARDs) is an area of current interest in RA research. More broadly, RA immunotherapies are currently being tested in high-CVD-risk patients in proof-of-concept clinical trials that could alter the paradigm for CVD treatment and prevention in the general population. In this review, we will summarize the current evidence ascribing atheroprotective effects to RA pharmacotherapies.

To explore the associations between measures of body composition derived from computed tomography (CT) of the thigh and functional outcomes in patients with rheumatoid arthritis (RA).Patients with RA underwent bilateral midfemoral quantitative CT for measurement of thigh fat area (TFA), thigh muscle area (TMA), and thigh muscle density (TMD). The associations of thigh-composition measures with disability and physical performance, as measured with the Health Assessment Questionnaire (HAQ), the Valued Life Activities (VLAs), and the Short Physical Performance Battery (SPPB) instruments, were explored in the total cohort and in the cohort subgrouped by sex, controlling for pertinent demographic, lifestyle, and RA disease and treatment covariates.A total of 152 RA patients were studied. Among the potential determinants of TMD, older age, longer duration of sedentary activity, longer duration of RA, higher tender joint count, higher serum interleukin-6 levels, use of glucocorticoids, and nonuse of hydroxychloroquine were all significantly associated with lower TMD in multivariable models. RA characteristics accounted for 63% of the explainable variability in TMD. When comodeled, higher TFA and lower TMD, but not lower TMA, were significantly and independently associated with higher HAQ scores, lower Short Form 36 health survey physical functioning scores, lower composite SPPB scores, and a greater proportion of affected obligatory VLAs.Thigh CT-derived measures of body composition, particularly fat area and muscle density, were strongly associated with disability and physical performance in RA patients, with RA disease features as potential determinants. Efforts to reduce fat and improve muscle quality may reduce disability in this population with impaired physical functioning.

That individuals with rheumatoid arthritis (RA) have, on average, higher rates of events related to atherosclerotic vascular disease is now well documented and accepted. However, optimal ways to identify RA patients with atherosclerosis, and treat them to mitigate cardiovascular disease (CVD) risk have not been rigorously established. As such, current guidelines for CVD screening and prevention lack an evidence base. In the context of the current understanding of the determinants of atherosclerosis in RA and the current guidelines that have been published, this review focuses on strategies for identifying RA patients at risk of CVD events, and the possible primary and secondary prevention strategies that may be effective.

ObjectiveTo define the relationship between autoantigen citrullination and different peptidylarginine deiminase (PAD) enzymes in rheumatoid arthritis (RA).MethodsCitrullinated autoantigens were identified by immunoblotting control and ionomycin-activated human primary neutrophil lysate with RA sera. Autoantigen identity and citrullination sites were defined by mass spectrometry. PAD isoenzyme expression in human neutrophils was determined by immunoblotting. PAD substrate specificity was addressed in HL-60 cell lysates co-incubated with human recombinant PAD2, PAD3 and PAD4.ResultsAlthough prominent protein citrullination is observed in ionomycin-activated neutrophils, RA sera only recognised a limited number of these citrullinated molecules. Among these, the authors identified that β and γ-actins are citrullinated on at least 10 arginine residues, generating a novel 47 kDa species that is frequently recognised by RA autoantibodies. Interestingly, the authors showed that the PAD enzymes expressed in human neutrophils (ie, PAD2, PAD3 and PAD4) have unique substrate specificities, independent of their subcellular distribution. Thus, only PAD2 was able to citrullinate native β/γ-actin, while histone H3 was only citrullinated by PAD4.ConclusionThese studies identified β and γ-actins as novel citrullinated autoantigens in RA, allowing enzyme specificity against intracellular substrates to be addressed. The studies provide evidence that PAD enzymes have the intrinsic capacity to select unique protein targets. The authors propose that unique PAD specificity may play a role in autoantigen selection in RA.

To the Editor: In patients with rheumatoid arthritis (RA), cardiac involvement such as myocarditis and myocardial infarction is common. This cardiac involvement may have serious consequences and can contribute to worsening of a patient’s cardiac-related morbidity and mortality1,2. Importantly, myocardial disease is typically clinically silent3, only manifesting as myocardial dysfunction after an extended preclinical phase. Cardiovascular magnetic resonance (CMR) is a sensitive noninvasive diagnostic technique that can identify subclinical myocardial structural and functional abnormalities. No systematic studies of left ventricular (LV) regional function by CMR have been conducted in patients with RA. We sought to use a CMR approach to detect LV regional dysfunction in RA patients without cardiac symptoms compared to healthy volunteers. Further, we compared LV regional function between patients with RA who were treated with methotrexate (MTX) plus biologics compared to those treated only with MTX. Consecutive patients with RA as defined by the American College of Rheumatology classification criteria were recruited from the outpatient rheumatology clinic at Itabashi Chuo Medical Center between September 2009 and December 2012. Healthy volunteers were also included in the study. Because the regional myocardial function is related to age, we have included only subjects less than 70 years old. All patients with RA received either MTX or MTX plus the biologics infliximab (IFX) or tocilizumab (TCZ). All patients and volunteers underwent nonenhanced CMR with steady-state free-precession (SSFP) cine magnetic resonance imaging (MRI) on a 1.5 Tesla MRI scanner. … Address correspondence to Dr. Y. Kobayashi, Department of Radiology, St. Marianna University School of Medicine, 2-16-1 Sugao, Miyamae-ku, Kawasaki, Kanagawa, 216-8511, Japan. E-mail: yasukoba2{at}gmail.com

Objective.Validated imaging outcome tools to assess response to therapies in a single joint are required. Our aim was to review the published literature to ascertain the responsiveness of novel imaging techniques as outcome measures in interventional therapeutic studies of knee arthritis.Methods.An Ovid Medline search was performed for original articles in English that used imaging techniques to assess response at the knee joint to therapy in osteoarthritis, rheumatoid arthritis, and psoriatic arthritis. Changes in response to therapy were assessed with regard to both internal and external responsiveness.Results.In the studies that presented appropriate statistical data to allow responsiveness to be assessed, MRI was generally found to be internally responsive to pathologies imaged, and externally responsive, referenced against both other imaging modalities and biochemical biomarkers of arthritis. Ultrasonography was found to demonstrate internal responsiveness with regard to synovial thickness, effusion size, and popliteal cyst size. External responsiveness was demonstrated against several referenced health status measures. Scintigraphy was found to be externally responsive in the majority of studies, with internal responsiveness demonstrated in 1 study.Conclusion.While the imaging techniques appear to be responsive from the data we present, further inspection reveals that interpreting the responsiveness of imaging techniques was difficult, largely because of a lack of standardization of image acquisition, definitions of pathology, and scoring systems. Refined pathological definitions and scoring systems are required to enable the development of valid and responsive tools for interventional clinical trials.

Author(s): Hughes-Austin, Jan M; Deane, Kevin D; Giles, Jon T; Derber, Lezlie A; Zerbe, Gary O; Dabelea, Dana M; Sokolove, Jeremy; Robinson, William H; Holers, V Michael; Norris, Jill M | Abstract: BACKGROUND:Extra-articular manifestations of rheumatoid arthritis (RA), potentially due to systemic inflammation, include cardiovascular disease and sarcopenic obesity. Adiponectin, an adipose-derived cytokine, has been implicated in inflammatory processes in RA, but little is known regarding its association with inflammation in a pre-clinical period. Therefore, we investigated whether adiponectin was associated with inflammatory markers in individuals at risk for RA, and whether RA-related autoimmunity modifies these associations. METHODS:We analyzed samples from 144 first-degree relatives (FDRs) of RA probands, of whom 23 were positive for anti-cyclic citrullinated peptide antibody and/or ≥ 2 rheumatoid factor isotypes (IgM, IgG or IgA). We called this phenotype the 'high risk autoantibody profile (HRP)' as it has been shown in prior work to be g96% specific for future RA. We measured adiponectin, cytokines, and high-sensitivity C-reactive protein (hsCRP). Using linear mixed effects models, we evaluated interaction between HRP positivity and adiponectin on inflammatory markers, adjusting for age, sex, ethnicity, body mass index, pack-years smoking, and use of cholesterol-lowering medications. RESULTS:In everyone, adiponectin concentration was inversely associated with hsCRP and IL-1β in adjusted models, where a 1% higher adiponectin was associated with a 26% lower hsCRP (p = 0.04) and a 26% lower IL-1β (p = 0.04). Significant interactions between HRP and adiponectin for associations with GM-CSF, IL-6, and IL-9 were detected in fully adjusted models (p = 0.0006, p = 0.006, p = 0.01, respectively). In HRP positive FDRs but not HRP negative FDRs, a 1% higher adiponectin was associated with 97% higher GM-CSF, 73% higher IL-6, and 54% higher IL-9 concentrations. CONCLUSIONS:Adiponectin associates with inflammatory markers, and these associations differ in individuals with a high-risk autoantibody profile compared with those without. The interaction between adiponectin and autoimmunity warrants further investigation into the potential systemic effects of RA-related autoantibodies and adiponectin on inflammation in the absence of clinically apparent RA.

Objective Abdominal adiposity, especially visceral adiposity, is emerging as a recognized cardiometabolic risk factor. This study was undertaken to investigate how abdominal fat is distributed in rheumatoid arthritis (RA), and its RA-related determinants. Methods Men and women with RA were compared with non-RA controls from the Multi-Ethnic Study of Atherosclerosis. Participants underwent anthropometric studies and quantification of visceral and subcutaneous fat areas (VFA and SFA) using abdominal computed tomography. Results A total of 131 RA patients were compared with 121 controls. Despite similar body mass index and waist circumference between the RA and control groups, the adjusted mean VFA was 45 cm2 higher (+51%) in male RA patients versus male controls (P = 0.005), but did not significantly differ by RA status in women. The adjusted mean SFA was 119 cm2 higher (+68%) in female RA patients versus female controls (P < 0.001), but did not significantly differ by RA status in men. Elevated VFA (≥75th percentile) was associated with a significantly higher adjusted probability of having an elevated fasting glucose level, hypertension, or meeting the composite definition of the metabolic syndrome in the RA group compared with controls. Within the RA group, rheumatoid factor seropositivity and higher cumulative prednisone exposure were significantly associated with a higher mean adjusted VFA. Higher C-reactive protein levels and lower Sharp/van der Heijde scores were significantly associated with both VFA and SFA. Conclusion The distribution of abdominal fat differs significantly by RA status. Higher VFA in men with RA, and the more potent association of VFA with cardiometabolic risk factors in men and women with RA, may contribute to cardiovascular risk in RA populations.

Objectives. Pain is among the most frequently reported, bothersome, and disabling symptoms described by patients with rheumatoid arthritis (RA), and the experience of pain is partially shaped by catastrophizing, a set of cognitive and emotional pain-related processes. However, other variables may moderate catastrophizing's influence on the experience of pain. In this study, we investigated a variety of factors that might buffer or magnify catastrophizing's deleterious consequences among patients with RA. Methods. A total of 185 RA patients were surveyed to determine levels of catastrophizing, pain, general psychological distress, and physical functioning. Results. Catastrophizing was associated with increased pain severity and psychological distress, and with poorer physical functioning. Some of these relationships were significantly moderated by education and social functioning; among RA patients with above-average social functioning and a college education, minimal relationships of catastrophizing with pain and distress symptoms were observed, while these associations were highly significant ( P s < 0.001) among patients with lower levels of education or social functioning. Conclusions. Collectively, educational achievement and positive social interactions may protect against some of the deleterious effects of catastrophizing. The design of future interventions to reduce catastrophizing or ameliorate its impact on pain outcomes may benefit from further study of these subgroups of patients.

Objective.Cardiovascular (CV) morbidity and mortality are increased in rheumatoid arthritis (RA). Prior investigations of the association of RA with measures of carotid atherosclerosis have yielded conflicting results. We compared carotid intima-media thickness (IMT) of both the common carotid (CCA) and proximal internal carotid (bulb-ICA) arteries, and plaque prevalence, between RA and non-RA participants.Methods.Subjects with RA were participants in a cohort study of subclinical CV disease in RA. Non-RA controls were selected from the Multi-Ethnic Study of Atherosclerosis. Both groups underwent B-mode ultrasonography of the right and left CCA and bulb-ICA. Linear regression was used to model the association of RA status with CCA and bulb-ICA-IMT, and logistic regression for the association of RA status with plaque.Results.We compared 195 RA patients to 198 non-RA controls. CV risk factors were similarly distributed, except for a higher prevalence of hypertension in the RA group. Mean adjusted bulb-ICA-IMT was higher in RA patients than controls (1.16 vs 1.02 mm, respectively; p < 0.001), while mean adjusted CCA-IMT did not differ significantly. After adjusting for CV risk factors, the odds of plaque were significantly increased in RA participants compared to controls (OR 2.41, 95% CI 1.26–4.61). The association of gender, age, smoking, and hypertension with bulb-ICA-IMT and plaque did not significantly differ by RA status. Interleukin 6 was strongly associated with bulb-ICA-IMT and plaque in controls but not in RA patients. In the RA group, shared epitope was associated with an increased prevalence of plaque.Conclusion.Compared to controls, RA was associated with a higher prevalence and higher severity of atherosclerosis in the bulb-ICA but not the CCA. Our data suggest that future studies in RA that utilize carotid artery measurements should include assessment of the bulb-ICA.

To evaluate the effect of antitumor necrosis factor-alpha monoclonal antibody infliximab treatment on anemia in patients with rheumatoid arthritis (RA).Data from patients with RA who received infliximab or placebo in the multicenter, placebo-controlled, double-blind, randomized ATTRACT, ASPIRE, and START studies were included in this post-hoc, pooled analysis. Infliximab (3 to 10 mg/kg) was administered every 4 or 8 weeks, and all patients received stable doses of methotrexate (MTX). We determined the percentage of anemic patients (baseline hemoglobin level12 g/dL) who had an increase from baseline in hemoglobin level greater than or equal to 1 or 2 g/dL or achieved normal hemoglobin level at week 22. The association of improvement in anemia with improvement in clinical parameters was also evaluated.Among patients with anemia at baseline, infliximab plus MTX treatment produced a significantly greater mean (standard deviation) increase in hemoglobin level from baseline to week 22 (0.74 [1.12], P0.0001) than placebo plus MTX (0.30 [0.92]). Significantly (P0.001) greater proportions of anemic patients treated with infliximab plus MTX had either at least a 1 g/dL (40%) or at least a 2 g/dL (12%) increase in hemoglobin level from baseline to week 22 or achieved normal hemoglobin level (43%) when compared with placebo plus MTX (19, 5, and 28%, respectively). Greater improvement in hemoglobin level among infliximab plus MTX-treated patients was consistently observed across subgroups and in patients without clinical response (American College of Rheumatology 20% response criteria) at week 22. Multiple regression analysis indicated that the effect of infliximab plus MTX on anemia was independent of improvement in disease activity.Treatment with infliximab plus MTX significantly improved hemoglobin level among anemic RA patients when compared with treatment with placebo plus MTX, even after adjusting for improvement in disease activity.

Objective Recent reports have suggested that increasing adiposity may protect against radiographic damage in rheumatoid arthritis (RA). We explored the role of serum adipokines (adiponectin, resistin, and leptin) in mediating this association. Methods Patients with RA underwent total-body dual x-ray absorptiometry for measurement of total and regional body fat and lean mass, abdominal computed tomography for measurement of visceral fat area, and radiographs of the hands and feet scored according to the modified Sharp/van der Heijde (SHS) method. Serum levels of adipokines were measured and cross-sectional associations with radiographic damage were explored, adjusting for pertinent confounders. The associations of measures of adiposity with radiographic damage were explored with the introduction of adipokines into multivariable modeling as potential mediators. Results Among the 197 patients studied, adiponectin demonstrated a strong association with radiographic damage, with the log SHS score increasing by 0.40 units for each log unit increase in adiponectin (P = 0.001) after adjusting for pertinent predictors of radiographic damage. Adiponectin independently accounted for 6.1% of the explainable variability in SHS score, a proportion comparable with rheumatoid factor, and greater than HLA–DRB1 shared epitope alleles or C-reactive protein levels. Resistin and leptin were not associated with radiographic damage in adjusted models. An inverse association between visceral fat area and radiographic damage was attenuated when adiponectin was modeled as a mediator. The association of adiponectin with radiographic damage was stronger in patients with longer disease duration. Conclusion Adiponectin may represent a mechanistic link between low adiposity and increased radiographic damage in RA. Adiponectin modulation may represent a novel strategy for attenuating articular damage.

The need to develop validated outcome measures to assess response to therapies in single joints has been recognized. In 2004, a task force was established to assess established and novel outcome measures in accordance with the OMERACT filter (truth, discrimination, and feasibility) for single joint assessment. This report describes the proceedings of the single joint assessment special interest group (SIG) at OMERACT 9, including an updated literature review of imaging of the knee joints, with a focus on the extent to which these modalities fulfill the OMERACT filter. A series of studies are reported that examine patient reported, clinical examination, and imaging outcomes in therapeutic studies in knee arthritis. A summary of discussions from the meeting are presented that raise many of the ongoing challenges in establishing appropriate domains to evaluate a range of conditions and potential therapeutic interventions. Because of emerging drug candidates and modalities targeting individual joints, the ongoing work of this SIG is providing the evidence base that can be used to establish a core domain set to incorporate as outcomes in future studies.

To explore the association of measures of body composition with disability in patients with rheumatoid arthritis (RA).Patients with RA underwent total body dual-energy x-ray absorptiometry for measurement of total and regional body fat and lean mass. The associations of measures of fat and lean mass with disability, measured with the Health Assessment Questionnaire (HAQ), were explored for the total cohort and by sex, controlling for pertinent demographic, lifestyle, and RA disease and treatment covariates.We studied 197 subjects (118 women, 79 men). Median (interquartile range) HAQ score was 0.625 (0.125-1.25) and was significantly higher, indicating worse physical function, in women than in men. HAQ score was strongly correlated with depression, pain, RA duration, duration of morning stiffness, Disease Activity Score in 28 joints, radiographic damage scores, levels of physical and sedentary activities, and body composition, with increasing fat and decreasing lean mass associated with higher HAQ scores. Appendicular fat and lean mass demonstrated the strongest association per kilogram with HAQ. Mean HAQ score was 0.52 units higher for subjects in the highest versus the lowest quartile of appendicular fat mass (P0.001), and 0.81 units higher for subjects in the lowest versus the highest quartile of appendicular lean mass (P0.001). Adjusting for demographic and RA characteristics partially attenuated these associations. The joint associations of appendicular fat and lean mass on HAQ were additive without significant interaction.Body composition, particularly the amount of fat and lean mass located in the arms and legs, is strongly associated with disability in RA patients.

Patients with rheumatoid arthritis and other inflammatory arthritides treated with tumor necrosis factor inhibitors frequently undergo orthopedic procedures. These patients may be at risk for serious postoperative infections as antitumor necrosis factor agents may be associated with impaired immunity against usual and opportunistic pathogens.Information regarding the influence of tumor necrosis factor inhibitors on the risk for postoperative orthopedic complications is limited, contradictory and solely based on retrospective studies. Basic science derived data seem to only add to the confusion.The practitioner is at a loss whenever a decision regarding the perioperative handling of antitumor necrosis factor agents has to be made. An attempt to combine, reconcile, and expand the knowledge available in the current literature will be made.

Rheumatoid arthritis (RA), a systemic auto-immune disease affecting 0.5–1% of the population worldwide, is characterized by chronic joint inflammation and, in severe cases, joint erosions (1). Although the mechanisms of initiation and propagation of RA remain incompletely defined, autoimmunity and inflammatory effector pathways appear to play important pathogenetic roles. The notable efficacy of tumor necrosis factor (TNF) inhibitors has established that TNFα plays a central role in RA, and the therapeutic effects of rituximab and abatacept strongly indicate roles for B cells and T cells, respectively (2,3). Although the specific autoantigens that drive B cells and T cells in RA remained elusive for decades, recent advances have identified protein citrullination as a primary focus of the RA-specific autoantibody response (4). Citrulline is generated posttranslationally by the deimination of arginine, and autoantibodies in RA recognize various naturally citrullinated proteins (including fibrin, vimentin, and filaggrin), as well as cyclic citrullinated peptides (CCPs) derived from them (5-7). Together with the extraordinary specificity (90–99%) of anti-CCP antibodies in RA (8,9), the observation that anti-CCP antibodies are frequently present early in the disease process and often precede development of the diagnostic phenotype (10-13) strongly suggests that these antibodies are markers of the specific events that initiate autoimmunity in RA. The citrullination reaction is catalyzed by a family of enzymes known as peptidyl arginine deiminases (PADs). There are 5 isoforms (14), differentially expressed in various cells. PAD type 4 (PAD-4) has received particular attention in RA, since it is expressed in myelomonocytes, can be detected in inflamed RA synovium (14,15), and has recently been genetically associated with RA. The first group to describe the genetic association of PADI4 variants with RA defined 2 common haplotypes of the PADI4 gene segregated by 4 exonic single-nucleotide polymorphisms (SNPs) in linkage disequilibrium. These 2 haplotypes were designated “susceptible (haplotype 2)” or “nonsusceptible (haplo-type 1)” based on their relative frequency in a group of Japanese patients with RA versus controls (16). The odds ratio (OR) for association of the susceptibility haplotype with RA was 1.4. In several other populations, similar associations of PADI4 susceptibility haplotypes with RA were observed, although the magnitude of the effect was lower (17-20). In some studies, no association of PADI4 genotype with RA was observed (21-23). Suzuki et al showed a modest increase in RNA stability for the susceptibility haplotype, and proposed that the genetic effect of PADI4 is mediated through increased PAD-4 levels and activity, with enhanced citrullination and increased levels of anti-CCP antibodies (16). Significant direct support for this model is still lacking, prompting us to explore whether additional mechanisms might mediate some of the genetic effect of PADI4. We demonstrate here that autoantibodies against PAD-4 protein are a highly specific marker of RA. In a cross-sectional cohort of RA patients, these antibodies were independently associated with a more severe RA phenotype, characterized by worse joint damage and erosions. Notably, anti–PAD-4 autoantibodies were associated with the PADI4 susceptibility haplotype (OR 2.59), particularly with the heterozygous diplotype (OR 4.02). Interestingly, the epitopes recognized by anti–PAD-4 antibodies include the N-terminal region of PAD-4 containing the polymorphisms associated with RA susceptibility. Taken together, the specificity of the antibody response for the polymorphic N-terminal region of PAD-4, the magnitude of the association of autoantibody with susceptibility genotype, and the association of the strongest anti–PAD-4 autoantibody responses with RA severity are striking. They implicate unique PAD-4 structure and/or function in the generation of a PAD-4–specific immune response and, potentially, the downstream augmentation of joint damage in RA.

Rheumatoid arthritis (RA) is associated with an elevated risk of cardiovascular disease (CVD) events and subclinical atherosclerosis, but the reasons for the excess risk are unclear. We explored whether psychosocial comorbidities, which may be associated with CVD in the general population, are differentially associated with subclinical atherosclerosis in RA compared to controls.Data were from a longitudinal cohort study of 195 RA patients and 1,073 non-RA controls. Using validated scales, heterogeneity in the associations of psychosocial measures (depression, stress, anxiety/anger, support, discrimination/hassles) with measures of subclinical atherosclerosis (coronary artery calcium [CAC] and carotid intima-media thickness [IMT]/plaque) were compared in RA and non-RA groups using multivariable generalized linear models. Computed tomography and ultrasound were used to identify CAC and IMT/plaque, respectively. CAC100 units was used to define moderate/severe CAC.In RA, per-unit higher anxiety scores (odds ratio [OR] 1.10, P = 0.029), anger scores (OR 1.14, P = 0.037), depressive symptoms (OR 3.41, P = 0.032), and caregiver stress (OR 2.86, P = 0.014) were associated with increased odds of CAC100 units after adjustment for relevant covariates. These findings persisted despite adjustment for markers of inflammation (C-reactive protein and interleukin-6 levels) and were seen only in RA, not in controls (adjusted multiplicative interaction P = 0.001-0.077). In RA, job stress was associated with an increased risk of carotid plaque (adjusted OR = 3.21, P = 0.019), and increasing social support was associated with lower internal carotid IMT (adjusted P = 0.024).Depressive symptoms, stress, anger/anxiety, and social support may preferentially affect CVD risk in RA, and screening/treatment for psychosocial morbidities in RA may help ameliorate the additional CVD burden.

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).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.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.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.

This review focuses on the genetic features of psoriatic arthritis (PsA) and their relationship to phenotypic heterogeneity in the disease, and addresses three questions: what do the recent studies on human leukocyte antigen (HLA) tell us about the genetic relationship between cutaneous psoriasis (PsO) and PsA - that is, is PsO a unitary phenotype; is PsA a genetically heterogeneous or homogeneous entity; and do the genetic factors implicated in determining susceptibility to PsA predict clinical phenotype? We first discuss the results from comparing the HLA typing of two PsO cohorts: one cohort providing the dermatologic perspective, consisting of patients with PsO without evidence of arthritic disease; and the second cohort providing the rheumatologic perspective, consisting of patients with PsA. We show that these two cohorts differ considerably in their predominant HLA alleles, indicating the heterogeneity of the overall PsO phenotype. Moreover, the genotype of patients in the PsA cohort was shown to be heterogeneous with significant elevations in the frequency of haplotypes containing HLA-B*08, HLA-C*06:02, HLA-B*27, HLA-B*38 and HLA-B*39. Because different genetic susceptibility genes imply different disease mechanisms, and possibly different clinical courses and therapeutic responses, we then review the evidence for a phenotypic difference among patients with PsA who have inherited different HLA alleles. We provide evidence that different alleles and, more importantly, different haplotypes implicated in determining PsA susceptibility are associated with different phenotypic characteristics that appear to be subphenotypes. The implication of these findings for the overall pathophysiologic mechanisms involved in PsA is discussed with specific reference to their bearing on the discussion of whether PsA is conceptualised as an autoimmune process or one that is based on entheseal responses.

The risk of cardiovascular disease is increased in patients with rheumatoid arthritis, as discussed in this Review. Joan M Bathon and colleagues outline some preliminary recommendations for how these complications can be prevented and managed by aggressive control of both synovitis and conventional cardiovascular risk factors. Chronic low-grade inflammation was recognized during the past decade as an important risk factor for the development of atherosclerosis and, more recently, for the development of heart failure. Patients with rheumatoid arthritis (RA) are at increased risk of morbidity and mortality from ischemic cardiovascular events and heart failure. Epidemiologic and clinical studies indicate that RA is an independent risk factor for cardiovascular disease, which suggests that chronic exposure to high levels of inflammatory mediators contributes to this enhanced risk. The relative contribution of conventional risk factors to the acceleration of cardiovascular disease does not seem to be increased in patients with RA compared with control populations. Nonetheless, some preclinical laboratory measures of risk factors (e.g. insulin sensitivity) are adversely modulated in the context of the highly inflammatory rheumatoid microenvironment. Discerning the net effect of RA therapies on cardiovascular disease is also challenging because, theoretically, their biologic effects could either promote or attenuate atherosclerosis and ventricular dysfunction; however, available data suggest a beneficial effect on cardiovascular morbidity and mortality in patients with RA. This review provides an overview of the potential influence of RA and its treatment on the development and progression of cardiovascular disease, and outlines some preliminary recommendations for prevention and management of this complication in patients with RA.

Introduction Postoperative infections, such as periprosthetic septic arthritis, postoperative osteomyelitis, and deep-wound infection, are a particularly devastating complication of orthopedic surgery. They incur significant morbidity in terms of patient suffering and disability, prolonged hospitalization, frequent need for additional surgical procedures, and delay in rehabilitation. Moreover, there is a 3-fold increase in mortality in orthopedic procedures complicated by joint sepsis or osteomyelitis (1). The use of aggressive aseptic operating conditions, including laminar flow and perioperative antibiotic administration, has decreased the overall incidence of postoperative orthopedic infections to 1–2% (2). Despite these advances, rheumatoid arthritis (RA) remains an independent risk factor for postoperative orthopedic infection, with infection rates 2–4 times higher than those reported in patients without RA (3,4). The recent development of tumor necrosis factor (TNF ) inhibitors has revolutionized the care of patients with RA. TNF , a highly inflammatory macrophage-derived cytokine, plays a critical role in the joint destruction of patients with RA (5). Treatment of patients with RA using TNF inhibitors provides symptomatic and functional improvement and slows radiographic progression of disease (6). However, TNF inhibitors also enhance the risk of infection with mycobacteria and other opportunistic microorganisms in humans (7). Less is known about the effect of TNF inhibitors on susceptibility to common bacterial infections, in particular those associated with postoperative infections. To address this clinically important issue, we investigated the association of TNF-inhibitor therapy with serious postoperative infection in patients with RA who underwent orthopedic surgery.

Dyslipidemia is highly prevalent in rheumatoid arthritis (RA) and appears to be present very early in the RA disease process, in some studies even before a diagnosis of clinical RA has been made. The association between lipid measures and the risk of cardiovascular disease (CVD) in RA appears to be paradoxical, whereby lower levels of total cholesterol (TC), low-density lipoprotein (LDL-C), and atherogenic ratios are associated with higher CVD risk. This may be due to the lipid-lowering effects of RA-related systemic inflammation. Therefore, standard CVD risk calculators have been shown to underperform in RA. Data also suggest that lipoprotein particle sizes and the apolipoprotein cargo of lipoproteins skew toward atherogenic dyslipidemia in RA and may contribute to the initiation and progression of atherosclerosis. Inflammatory burden in RA may also alter the anti-inflammatory and atheroprotective roles associated with high-density lipoprotein cholesterol (HDL-C). Adipose tissue is quantitatively increased in RA patients compared with matched non-RA controls and may be more inflamed and metabolically dysfunctional compared with an otherwise similar non-RA patient. In vitro, animal, and a handful of non-RA human, studies suggest that inflamed, metabolically dysfunctional adipose tissue contributes directly to lower HDL-C levels. In turn, lower HDL-C that has been altered functionally by inflammation may lead to expanded adipose mass and further adipose dysfunction and inflammation. In the last part of this review, we speculate how the RA disease state may recapitulate these processes.

Objective Current disease activity measures for systemic lupus erythematosus (SLE) are difficult to score or interpret and problematic for use in clinical practice. Lupus Foundation of America (LFA)-Rapid Evaluation of Activity in Lupus (REAL) is a pilot application composed of anchored visual analogue scores (0–100 mm each) for each organ affected by lupus. This study evaluated the use of LFA-REAL in capturing SLE disease activity. Methods In a preliminary test of LFA-REAL, this simplified, organ-based system was compared with the most widely used outcome measures in clinical trials, the British Isles Lupus Assessment Group 2004 Index (BILAG), the SLE Disease Activity Index (SLEDAI) and the Safety of Estrogens in Lupus Erythematosus National Assessment (SELENA) SLEDAI Physician's Global Assessment (SS-PGA). The level of agreement was analysed using Spearman rank correlations. Results 91 patients with SLE with mild to severe disease activity were evaluated, their median SLEDAI score was 4.0 (range 0–28) and BILAG score 8.0 (0–32). The median SS-PGA was 38 mm (4–92) versus the total REAL 50 mm (0–268), which expands in range by additive organ scores. Thirty-three patients had moderate to severe disease activity (≥1.5 on SS-PGA landmarks). The median SS-PGA score of this group was 66 mm (50–92) versus median REAL score of 100 mm (59–268), confirming ability to detect a wider distribution of scores at higher disease activity. Total REAL correlated with SLEDAI, BILAG and SS-PGA (correlation coefficient=0.816, 0.933 and 0.903, respectively; p

Understanding how immune cells interact with adipocytes to induce the downstream consequences of obesity (i.e., insulin resistance, hepatic steatosis, atherosclerosis, just to name a few) is among the most active areas of current interest among obesity researchers. In fact, that white adipose tissue has secretory capacity is a relatively recent concept. In the early 1990s it was recognized that tumor necrosis factor-α (TNF-α) and leptin are expressed by adipocytes in proportion to adipose tissue mass and that they possess diverse autocrine and paracrine functions relating to energy metabolism and the neurohormonal regulation of feeding impulses1,2. Since then, dozens of secreted adipocyte products have been identified3. That many proteins termed “adipokines” overlap those considered central to the inflammatory pathobiology of rheumatoid arthritis (RA) is of particular interest to RA researchers. Adipocytes secrete inflammatory cytokines [TNF-α, interleukin 1β (IL-1β), IL-6], chemokines (monocyte chemoattractant protein-1), acute-phase reactants (serum amyloid A), and others that parallel the expression profiles of inflamed synovium4. Adipokine expression is potentiated through activated macrophages and T lymphocytes within adipose tissue, and represents an additional parallel to the processes occurring in RA synovitis. Interestingly, many obesity-related complications are also present in patients with RA, even among those who are not obese. Cardiovascular disease (CVD) event … Address correspondence to Dr. Giles; E-mail: jtg2122{at}columbia.edu

To investigate the association between oral calcium supplementation and coronary artery calcification among rheumatoid arthritis (RA) patients without known cardiovascular disease (CVD).This study was conducted as a nested, prospective cohort study of RA patients without known CVD. The daily supplemental calcium dose was ascertained from each patients' list of prescription and over-the-counter medications at baseline and at visit 2 (median 20 months postbaseline). The coronary artery calcium (CAC) score, a measure of coronary atherosclerosis, was assessed by cardiac multidetector row computed tomography at baseline and at visit 3 (median 39 months postbaseline). The association between calcium supplementation and CAC was explored.Among the 145 RA patients studied, 42 (28%) were taking ≥1,000 mg/day of supplemental calcium at baseline. A CAC score of100 units was seen in 44 patients (30%) at baseline and 50 patients (34%) at followup. Baseline CAC scores of100 units were significantly less frequent in patients receiving the higher dosage (≥1,000 mg/day) of supplemental calcium than in those receiving the lower dosage (1,000 mg/day) (odds ratio [OR] 0.28, 95% confidence interval [95% CI] 0.11-0.74); this association remained significant after adjustment for relevant confounders (adjusted OR 0.30, 95% CI 0.09-0.93). Similarly, at the third study visit, CAC scores of100 units were less frequent in the higher supplemental calcium dose group compared to the lower dose group (OR 0.41, 95% CI 0.18-0.95); however, after adjustment for relevant confounders, the statistical significance of this association was lost (adjusted OR 0.39, 95% CI 0.14-1.12). No effect of sex heterogeneity was seen in the association of calcium supplementation with coronary artery calcification, and no change in the CAC score over time was observed.Higher levels of oral calcium supplementation were not associated with an increased risk of coronary atherosclerosis, as measured by the CAC score, in this RA cohort.

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.

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

Objective:\ud To evaluate associations between lipid levels, inflammation, and rheumatoid arthritis (RA) disease activity, at baseline and during treatment, with the risk of major adverse cardiovascular events (MACE) in tocilizumab‐treated patients with RA.\ud \ud Methods:\ud In retrospective post hoc analyses, data were pooled for 3,986 adult patients with moderate to severe RA who received ≥1 dose of tocilizumab (4 mg/kg or 8 mg/kg) intravenously every 4 weeks in randomized controlled trials and extension studies. Cox proportional hazards modeling was used to evaluate associations between baseline characteristics and posttreatment changes in laboratory and disease characteristics (week 24) and change in disease activity and laboratory values from baseline to week 24 with the risk of future MACE during extended followup.\ud \ud Results:\ud We identified 50 independently adjudicated cases of MACE during 14,683 patient‐years of followup (0.34 MACE cases/100 patient‐years). At baseline, age, a history of cardiac disorders, the Disease Activity Score in 28 joints (DAS28), and the total cholesterol:high‐density lipoprotein cholesterol ratio were independently associated with MACE in multivariable models (P < 0.05 for all). During treatment, a higher DAS28 and higher swollen and tender joint counts at week 24 were associated with future MACE. In separate models, greater reductions in the DAS28 and joint counts from baseline to week 24 were inversely associated with future MACE; changes in lipid parameters were not statistically significantly associated with the risk of MACE.\ud \ud Conclusion:\ud In this population of patients treated with tocilizumab, an association was observed between the baseline total cholesterol:high‐density lipoprotein cholesterol ratio and an increased risk of MACE. The risk of MACE while receiving treatment, however, was associated with control of disease activity but not lipid changes. Larger studies are needed to confirm these findings.

Interstitial lung disease (ILD) is associated with high morbidity and mortality in rheumatoid arthritis (RA). Citrullinated proteins are observed in RA lung tissues; however, the association of specific anticitrullinated peptide antibodies (ACPA) with ILD in RA is unknown.RA patients underwent multidetector CT (MDCT) of the chest, from which ILD features and a semiquantitative ILD Score (ILDS; range 0-32) were assessed. Anti-CCP (CCP2) and levels of a panel of antibodies against 17 citrullinated and four non-citrullinated peptides were assessed from concurrent serum samples using a custom Bio-Plex bead array. High level ACPA was defined as ≥the group 75th percentile.Among the 177 RA patients studied, median levels of CCP2 and all specific ACPAs were 46-273% higher among RA patients with versus those without ILD (all p values0.05), and higher levels correlated with higher ILDS. In contrast, levels of non-citrullinated protein antibodies were not higher in those with ILD. RA patients had a median of 2 high level ACPA reactivities (range 0-16), with each high level ACPA associated, on average, with a 0.10 unit higher ILDS (p=0.001). This association remained significant after adjusting for characteristics associated with ILD (age, gender, current and former smoking, Disease Activity Score for 28 joints, current prednisone and leflunomide use). More high level ACPA were observed in those with versus without pulmonary function restriction or impaired diffusion.Our findings of a broader ACPA repertoire in RA ILD suggest a possible role for ACPA in the pathogenesis of ILD.

Peptidylarginine deiminases (PADs) play a critical role in generating autoantigens in rheumatoid arthritis (RA), but the mechanisms underlying their dysregulation in this disease remain unknown. Although PADs require supraphysiologic concentrations of calcium for activity in vitro, the enzymes are clearly active in vivo (e.g. in RA synovial fluid) where calcium concentrations are much lower. In this study, we have discovered a novel subset of anti-PAD4 autoantibodies (identified by their cross-reactivity with PAD3) which strikingly increase the catalytic efficiency of PAD4 by decreasing the enzyme’s requirement for calcium into the physiologic range. Patients with these novel PAD3/PAD4 cross-reactive autoantibodies had higher baseline radiographic damage scores and a higher likelihood of radiographic progression compared to individuals negative for these antibodies. The ability of autoantibodies to activate an enzyme that itself generates citrullinated autoantigens identifies an important feed-forward loop which may drive the erosive outcome observed in RA patients with these autoantibodies. PAD3 autoantibodies may therefore identify RA patients who would benefit from early aggressive treatment or addition of PAD-inhibitor therapy.

Rheumatoid arthritis (RA) is a systemic inflammatory arthritis associated with increased morbidity and mortality, primarily related to greater atherosclerotic burden. Compared to non-RA controls, patients with RA are at a 1.5–3 fold increased risk of cardiovascular events (1, 2). The risk factors contributing to this increased propensity towards atherosclerosis in RA are poorly understood and have been a focus of expanding research. RA specific risk factors, such as chronic systemic inflammation (3), altered lipid function (4) and change in body composition (5) have been identified as few of the possible mechanisms driving the increased cardiovascular risk. Thus, identification of these and other risk factors is critical as their modification may result in improved long term outcomes in the RA population. Vitamin D deficiency has been associated with atherosclerosis and cardiometabolic risk factors, such as insulin resistance (6) hypertension (7) metabolic syndrome (8) and cardiovascular events (9, 10) in cross-sectional analyses of non-RA populations. In a meta-analysis of 28 studies, the highest levels of serum 25(OH)D were associated with a 43% reduction in cardiometabolic disorders, (ie CVD, DM and metabolic syndrome) [OR 0.57, 95% CI 0.48–0.68] (11). However, not all studies have confirmed these associations (12). Vitamin D is a pleiotropic steroid molecule and exerts its physiological effects through the ubiquitous vitamin D receptor, a nuclear hormone receptor (13). Activated vitamin D is now implicated in regulating several genes with diverse biological functions (14, 15) which may explain its possible epidemiological associations with diverse chronic diseases, such as common cancers, cardiovascular disease (CVD) and autoimmune disorders (16, 17). Vitamin D also has known immunomodulatory effects (18) and its possible role in initiation and exacerbation of autoimmune diseases is an area of ongoing scientific study. Low levels of vitamin D are noted to be common in RA, with several studies indicating greater than 50% prevalence of suboptimal vitamin D levels in this population (19, 20). Our data suggest that up to 60% of RA patients have suboptimal vitamin D levels in the mid-Atlantic region (21). It is plausible that vitamin D deficiency in RA may pose an independent risk of cardiometabolic disease and thus may provide a modifiable target to potentially reduce cardiovascular disease burden in this population. However, any possible link between vitamin D deficiency and cardiometabolic risk factors in RA has not been evaluated. We thus investigated the relationship of vitamin D levels with cardiometabolic risk factors in a cohort of RA patients without established CVD and hypothesized that low vitamin D levels would be associated with greater cardiometabolic burden this population.

Introduction The aim of this study was to explore the presence and localization of myocardial citrullination in samples from rheumatoid arthritis (RA) patients compared to rheumatic and non-rheumatic disease control groups. Methods Archived myocardial samples obtained during autopsy from 1995 to 2009 were assembled into four groups: RA; scleroderma; fatal myocarditis; and non-rheumatic disease controls. Samples were examined by immunohistochemistry (IHC) for the presence and localization of citrullination and peptidyl arginine deiminase enzymes (PADs) by a single cardiovascular pathologist blinded to disease group and clinical characteristics. Results Myocardial samples from seventeen RA patients were compared with those from fourteen controls, five fatal myocarditis patients, and ten scleroderma patients. Strong citrullination staining was detected exclusively in the myocardial interstitium in each of the groups. However, average and peak anti-citrulline staining was 59% and 44% higher, respectively, for the RA group compared to the combined non-RA groups (P < 0.05 for both comparisons). Myocardial fibrosis did not differ between the groups. In contrast to citrullination, PADs 1 to 3 and 6 were detected in cardiomyocytes (primarily PADs 1 and 3), resident inflammatory cells (primarily PADs 2 and 4), and, to a smaller extent, in endothelial cells and vascular smooth muscle cells. PAD staining did not co-localize with anti-citrulline staining in the interstitium and did not vary by disease state. Conclusions Staining for citrullination was higher in the myocardial interstitium of RA compared to other disease states, a finding that could link autoimmunity to the known increase in myocardial dysfunction and heart failure in RA.

Objective The purpose of this study was to explore whether nontraditional risk factors, such as apolipoprotein C-III (Apo C-III) and its corresponding Apo B lipoprotein (Lp) subclasses, contribute to the risk of cardiovascular disease in rheumatoid arthritis (RA) patients. Methods Apolipoprotein and lipoproteins were measured in 152 RA patients by immunoturbidimetric procedures, electroimmunoassay, and immunoprecipitation. Patients had a coronary artery calcium (CAC) score assessed at baseline and at year 3. Differences in the CAC scores between baseline and year 3 were calculated and dichotomized at 0, where patients with a difference score >0 were denoted as progressors and the rest were denoted as nonprogressors. Differences between means were tested with a 2-sided independent Student's t-test with Satterthwaite's adjustment. Proportion differences were tested with a chi-square test. Multiple logistic regression was performed to assess the relationship between apolipoprotein and lipoprotein levels and the dichotomized CAC score. Results Progressors accounted for almost 60% of the cohort. Progressors had significantly higher levels of triglycerides, very low-density lipoprotein (VLDL) cholesterol, total cholesterol/high-density lipoprotein (HDL), triglycerides/HDL, Apo B, LpA-II:B:C:D:E, LpB:C, Apo B/Apo A-I, Apo C-III, and Apo C-III–heparin precipitate than the nonprogressors. After adjusting for age, sex, statin use (yes/no), and hypertension (yes/no), significant risk factors of progressors were total cholesterol, triglycerides, VLDL cholesterol, LDL cholesterol, Apo B, LpB:C, Apo C-III, and Apo B/Apo A-I. Conclusion Apo C-III–containing Apo B lipoprotein subclasses were found to be significantly elevated in progressors compared to nonprogressors. Many of these same lipoproteins were found to be associated with an increase in CAC scores among progressors. These lipoproteins may be considered new risk factors for progression of atherosclerosis in RA patients.

Objective To explore predictors of change in measures of carotid atherosclerosis among rheumatoid arthritis (RA) patients without known cardiovascular disease (CVD) at baseline. Methods RA patients underwent carotid ultrasonography at 2 time points separated by a mean ± SD of 3.2 ± 0.3 years. The associations of baseline and average patient characteristics with the average yearly change in the mean maximal intima-media thickness (IMT) of the common carotid artery (CCA) and the internal carotid artery (ICAs) and with incident or progressive plaque in the ICA/carotid bulb, were explored. Results Among the 158 RA patients, the maximal CCA-IMT increased in 82% (median 16 μm/year; P < 0.001) and the maximal ICA-IMT increased in 70% (median 25 μm/year; P < 0.001). Incident plaque was observed in 14% of those without plaque at baseline (incidence rate 4.2 per 100 person-years [95% confidence interval 1.6, 6.8]). Plaque progression was observed in 5% of those with plaque at baseline. Among RA predictors, the adjusted average yearly change in the maximal CCA-IMT was significantly greater in patients with earlier RA than in those with disease of longer duration. Those taking tumor necrosis factor (TNF) inhibitors at baseline had a 37% lower adjusted rate of progression in the maximal CCA-IMT compared with nonusers (14 μm/year versus 22 μm/year; P = 0.026). For the maximal ICA-IMT, cumulative prednisone exposure was associated with progression after adjustment (1.2 μm/year per gm [95% confidence interval 0.1, 2.4]) and was lower in patients who were prescribed statins concomitant with prednisone. Higher swollen joint counts and higher average C-reactive protein levels were both associated with incident or progressive plaque, primarily in patients with elevated CVD risk at baseline based on the Framingham Risk Score. Conclusion These prospective data provide evidence that inflammation is a contributor to the progression of subclinical atherosclerosis in RA and that it is potentially modified favorably by TNF inhibitors and detrimentally by glucocorticoids.

Background Adipokines have inflammatory and immunomodulatory properties that may contribute to erosive joint damage. The association of serum adipokine levels with progression of radiographic joint damage in patients with rheumatoid arthritis (RA) was prospectively explored. Methods Patients with RA underwent serum adipokine assessment (adiponectin, resistin, leptin) at three timepoints and hand/feet x-rays, scored using the Sharp-van der Heijde Score (SHS), at baseline and the third study visit, separated by an average of 39 +/- 4 months. The associations of baseline and average adipokine levels with change in SHS were explored, adjusting for pertinent confounders. Results Of the 152 patients studied, 85 (56%) showed an increase in SHS (defined as >0 SHS units). Among the adipokines studied, only adiponectin was significantly associated with radiographic progression, with average adiponectin levels more strongly associated than baseline levels. After adjusting for average C reactive protein and baseline SHS, patients in the highest quartile of average adiponectin had a SHS progression rate more than double the lowest quartile (1.00 vs 0.48 units/year; p=0.008). Similarly, those in the highest quartile of adiponectin had a more than fivefold greater odds of any radiographic progression compared with the lowest quartile (OR 5.75; p=0.002). The magnitude of the association of average adiponectin levels with radiographic progression was greater in women, those with body mass index

Objective Heart failure is a major contributor to cardiovascular morbidity and mortality in patients with rheumatoid arthritis (RA), but little is known about myocardial structure and function in this population. This study was undertaken to assess the factors associated with progression to heart failure in patients with RA. Methods With the use of cardiac magnetic resonance imaging, measures of myocardial structure and function were assessed in men and women with RA enrolled in the Evaluation of Subclinical Cardiovascular Disease and Predictors of Events in Rheumatoid Arthritis study, a cohort study of subclinical cardiovascular disease in patients with RA, in comparison with non-RA control subjects from a cohort enrolled in the Baltimore Multi-Ethnic Study of Atherosclerosis. Results Measures of myocardial structure and function were compared between 75 patients with RA and 225 frequency-matched controls. After adjustment for confounders, the mean left ventricular mass was found to be 26 gm lower in patients with RA compared with controls (P < 0.001), an 18% difference. In addition, the mean left ventricular ejection fraction, cardiac output, and stroke volume were modestly lower in the RA group compared with controls. The mean left ventricular end systolic and end diastolic volumes did not differ between the groups. In patients with RA, higher levels of anti–cyclic citrullinated peptide (anti-CCP) antibodies and current use of biologic agents, but not other measures of disease activity or severity, were associated with significantly lower adjusted mean values for the left ventricular mass, end diastolic volume, and stroke volume, but not with ejection fraction. The combined associations of anti-CCP antibody level and biologic agent use with myocardial measures were additive, without evidence of interaction. Conclusion These findings suggest that the progression to heart failure in RA may occur through reduced myocardial mass rather than hypertrophy. Both modifiable and nonmodifiable factors may contribute to lower levels of left ventricular mass and volume.

(2010). Cardiac magnetic resonance imaging abnormalities in patients with systemic lupus erythematosus: a preliminary report. Modern Rheumatology: Vol. 20, No. 3, pp. 319-323.

Introduction Although cardiovascular morbidity and mortality are increased in rheumatoid arthritis, little is known about the burden of subclinical coronary atherosclerosis in these patients. Methods Using computed tomography, coronary artery calcification was measured in 195 men and women with rheumatoid arthritis aged 45 to 84 years without clinical cardiovascular disease and compared with 1,073 controls without rheumatoid arthritis enrolled in the Baltimore cohort of the Multi-Ethnic Study of Atherosclerosis. Results The prevalence of coronary calcification (Agatston score > 0) was significantly higher in men, but not women, with rheumatoid arthritis after adjusting for sociodemographic and cardiovascular risk factors (prevalence ratio = 1.19; P = 0.012). Among participants with prevalent calcification, those with rheumatoid arthritis had adjusted mean Agatston scores 53 units higher than controls (P = 0.002); a difference greater for men than women (P for interaction = 0.017). In all analyses, serum IL-6 attenuated the association between rheumatoid arthritis and coronary calcification, suggesting its role as a potential mediator of enhanced atherosclerosis. Notably, increasing severity of rheumatoid arthritis was associated with a higher prevalence and extent of coronary calcification among both men and women with rheumatoid arthritis, and for all age categories. The largest percentage difference in coronary arterial calcification between rheumatoid arthritis patients and their nonrheumatoid arthritis counterparts was observed in the youngest age category. Conclusions Increasing rheumatoid arthritis disease severity was associated with a higher prevalence and greater extent of coronary artery calcification, potentially mediated through an atherogenic effect of chronic systemic inflammation. Gender and age differences in association with coronary calcification suggest that preventive measures should be emphasized in men with rheumatoid arthritis, and considered even in younger rheumatoid arthritis patients with low levels of traditional cardiovascular risk factors.

The introduction of aromatase inhibitor (AI) therapy for the adjuvant treatment of postmenopausal women with hormone receptor-positive breast cancer has led to a significant change in the management of the disease. AIs are slightly more efficacious and initially appeared to have a better toxicity profile compared to the previous gold standard, tamoxifen. However, increased use of AIs in the community setting has led to the recognition that the clinical impact of the musculoskeletal side effects is substantial. This review will describe the variety of AI-associated musculoskeletal symptoms (AIMSS), potential mechanisms underlying the development of the toxicity, and available treatment options for these side effects. Increased knowledge about the etiology and management of this clinically important toxicity could potentially improve patient adherence to AI therapy, thereby leading to a reduction in breast cancer recurrence and death.

Objective.To assess cardiac involvement in asymptomatic patients with systemic sclerosis (SSc) by cardiac magnetic resonance imaging (MRI).Methods.Ten asymptomatic patients with SSc (all female; mean age 59.5 ± 9.4 yrs) underwent contrast enhanced cardiac MRI on a 1.5 T MRI device. Adenosine triphosphate was used for stress and rest perfusion to assess perfusion defects due to microvascular impairment or ischemia, and delayed enhanced (DE) imaging was obtained for the assessment of myocardial necrosis and fibrosis. We evaluated the pathophysiological associations of stress perfusion combined with DE imaging with SSc disease severity measures.Results.Stress perfusion defects were seen in 5 out of 9 patients (56%): 4 had nonsegmental subendocardial perfusion defects and one had a segmental subendocardial perfusion defect. Three patients were found to have DE. DE was not observed in any patient without perfusion defect; and among the 5 patients with perfusion defects, 3 (60%) had DE. Two of the 3 had DE in segments not matching the region of nonsegmental perfusion defects. The remaining one had a segmental subendocardial DE matching the region of a segmental perfusion defect. Perfusion defects were seen in 75% of patients with a history of digital ulceration compared to only 20% of those without history of ulceration.Conclusion.Subclinical myocardial involvement, as detected by cardiac MRI, was frequent in asymptomatic patients with SSc. Cardiac MRI may aid in understanding the pathophysiological mechanism of SSc.

Over the last few decades, the serum C-reactive protein (CRP) concentration has been widely adopted as a marker of systemic inflammation. In rheumatoid arthritis (RA), the level of CRP is frequently used in conjunction with assessments of articular swelling and tenderness to estimate the level of disease activity and, in addition to the erythrocyte sedimentation rate, is a component of the American College of Rheumatology core set for measuring clinical response in RA trials (1), is a component of the Disease Activity Score in 28 joints (DAS28) (2), and has been proposed as a biomarker of structural damage in RA trials (3). CRP is a pentamer of 23-kd subunits that is synthesized and secreted by hepatocytes when stimulated by a variety of inflammatory cytokines, including tumor necrosis factor α (TNFα), interleukin-1 (IL-1), and especially IL-6 (4). Under these conditions, serum CRP levels can rise ≥100-fold over baseline levels (4). In addition to being a sensitive surrogate marker of the acute-phase response, an increasing level of CRP may also have direct downstream proinflammatory effects, including activation of complement and induction of tissue factor (5). In RA, inflamed synovium and circulating monocytes are sources of the cytokines that induce CRP production. However, other tissues are known sources of these cytokines. Adipose tissue is a potent source of inflammatory cytokines, including TNFα and IL-6, that induce hepatic production of CRP. In studies of the general population, an association between body fat mass and circulating CRP levels has been confirmed (6). In particular, visceral adipose tissue, distributed within the intraabdominal cavity and surrounding the mesentery and omentum, has been shown to be the adipose depot with the greatest contribution to systemic inflammation (7). Interventions that reduce adipose tissue mass (e.g., weight loss) are associated with a decline in CRP production (8). To investigate the potential contribution of adiposity to CRP levels in RA, we compared the relative contributions of anthropometric and dual-energy x-ray absorptiometry (DXA)–derived measures of body fat, along with RA disease characteristics, demographic and lifestyle factors, and cardiovascular risk factors, to the serum CRP concentration in men and women with RA. We also investigated whether the levels of articular swelling and tenderness modified the association between body fat and CRP.

Objective To compare measures of body fat and lean mass and the prevalence of abnormal body composition phenotypes (sarcopenia, overfat, and sarcopenic obesity) in men and women with rheumatoid arthritis (RA) versus matched controls, and to explore the disease-related predictors of abnormal body composition in patients with RA. Methods A total of 189 men and women with RA and 189 age-, sex-, and race-matched non-RA controls underwent dual-energy x-ray absorptiometry for measurement of total and regional body fat and lean mass. Continuous and categorical measures of body composition were compared between RA and control subjects by sex and according to categories of body mass index (BMI). Within the group of RA patients, demographic, lifestyle, and RA disease and treatment characteristics were compared for RA patients with healthy body composition versus those with abnormal body composition phenotypes. Results Compared with non-RA controls, RA status was significantly associated with greater odds of sarcopenia, overfat, and sarcopenic obesity in women, but not in men. Relative differences in body composition phenotypes between RA and control subjects were greatest for patients in the normal weight BMI category (