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1.  Obesity and Other Modifiable Factors for Physical Inactivity Measured by Accelerometer in Adults with Knee Osteoarthritis: Data from the Osteoarthritis Initiative (OAI) 
Arthritis care & research  2013;65(1):53-61.
Objective
To investigate the public health impact of obesity and other modifiable risk factors related to physical inactivity in adults with knee osteoarthritis (OA).
Methods
The frequency of inactivity as defined by the United States Department of Health and Human Services was assessed from objective accelerometer monitoring of 1089 participants with radiographic knee OA aged 49 to 84 years during the OAI 48 month visit (2008–2010). The relationship between modifiable factors (weight status, dietary fat, fiber, smoking, depressive symptoms, knee function, knee pain, knee confidence) with inactivity was assessed using odds ratios (OR) and attributable fractions (AF) controlling for descriptive factors (age, gender, race, education, live alone, employment, frequent knee symptoms, comorbidity).
Results
Almost half (48.9%) of participants with knee OA were inactive. Being overweight (OR=1.8, CI: 1.2, 2.5) or obese (OR=3.9, CI: 2.6, 5.7), inadequate dietary fiber intake (OR =1.6, 95% CI: 1.2, 2.2), severe knee dysfunction (OR=1.9, 95% CI: 1.3, 2.8), and severe pain (OR=1.7, 95% CI: 1.1, 2.5) were significantly related to inactivity, controlling for descriptive factors. Modifiable factors with significant average AFs were being overweight or obese (AF=23.8%, 95% CI: 10.5%, 38.6%) and inadequate dietary fiber (AF=12.1%, 95% CI: 0.1%, 24.5%) controlling for all factors.
Conclusion
Being obese or overweight, the quality of the diet, severe pain, and severe dysfunction are significantly associated with physical inactivity in adults with knee OA. All components should be considered in designing physical activity interventions that target arthritis populations with low activity levels.
doi:10.1002/acr.21754
PMCID: PMC3449019  PMID: 22674911
2.  Association of Vitamin D with Cardiometabolic Risk Factors in Rheumatoid Arthritis 
Arthritis care & research  2012;64(10):1497-1504.
Objectives
Individuals with rheumatoid arthritis (RA) are at a greater risk for cardiovascular disease (CVD). Vitamin D deficiency is a potential risk factor for CVD and metabolic syndrome. Since patients with RA have a high prevalence of vitamin D deficiency, we investigated the association of vitamin D levels with cardiometabolic risk factors in a cohort of RA patients with no prior history of CVD.
Methods
Serum 25(OH)D levels were measured among RA patients enrolled in a cohort study of subclinical CVD. The cross-sectional associations of 25(OH)D level with traditional CVD risk factors, such as insulin resistance [estimated using the Homeostatic Model Assessment (HOMA)], adiopokines, markers of systemic inflammation and endothelial activation were explored, adjusting for pertinent sociodemographic, lifestyle, and RA characteristics.
Results
Among 179 RA patients, 73 (41%) had a 25(OH)D level <30ng/mL. Only 23 patients (13%) had a 25(OH)D level ≥45ng/mL. After adjusting for demographics and BMI, 25(OH)D remained significantly associated with HDL and inversely associated with HOMA-IR, fibrinogen, E-selectin, and s-ICAM. Significant associations with HDL, E-selectin, and s-ICAM were maintained after adjusting for DAS28 and autoantibody status. These associations were similar between groups subdivided by gender, ethnicity, body mass index, DAS28 level and autoantibody status.
Conclusions
These data suggest that vitamin D deficiency is common in RA and may be independently associated with several cardiometabolic intermediates in this population.
doi:10.1002/acr.21715
PMCID: PMC3462271  PMID: 22555877
3.  Muscle Density in Rheumatoid Arthritis: Associations with Disease Features and Functional Outcomes 
Arthritis and rheumatism  2012;64(8):2438-2450.
OBJECTIVE
To explore the associations of thigh computed tomography (CT)-derived measures of body composition with functional outcomes in patients with rheumatoid arthritis (RA).
METHODS
Patients with RA underwent bilateral mid-femoral quantitative CT for measurement of thigh fat area (TFA), muscle area (TMA), and muscle density (TMD). The associations of thigh composition measures with disability and physical performance, measured with the Health Assessment Questionnaire (HAQ), Valued Life Activities (VLA) scale, and Short Physical Performance Battery (SPPB), were explored for the total cohort and by gender, controlling for pertinent demographic, lifestyle, and RA disease and treatment covariates.
RESULTS
A total of 152 RA patients were studied. Among potential determinants of TMD, higher age, higher duration of sedentary activity, longer RA duration, higher tender joint count, higher serum IL-6 levels, use of glucocorticoids, and non-use of hydroxychloroquine were all significantly associated with lower TMD in multivariable modeling. RA characteristics accounted for 77% of the explainable variability in TMD. When co-modeled, higher TFA and lower TMD, but not lower TMA, were significantly and independently associated with higher HAQ scores, lower SF-36 total physical scores, lower composite SPPB scores, and a greater proportion of affected obligatory VLAs.
CONCLUSIONS
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.
doi:10.1002/art.34464
PMCID: PMC3521589  PMID: 22391952
Body Composition; Disability; Muscle; Adipose
4.  Association of Body Fat With C-Reactive Protein in Rheumatoid Arthritis 
Arthritis and rheumatism  2008;58(9):2632-2641.
Objective
The serum C-reactive protein (CRP) concentration is commonly used in rheumatoid arthritis (RA) as a surrogate marker of systemic inflammation, presumably induced by synovitis. However, other tissues, such as adipose tissue, can induce CRP production. This study was undertaken to explore the associations between measures of adiposity and CRP levels in RA.
Methods
One hundred ninety-six men and women with RA underwent anthropometric assessment and total body dual-energy x-ray absorptiometry for measurement of total and regional body fat and lean mass. The associations between measures of fat and lean mass and serum levels of CRP and interleukin-6 (IL-6) were determined in analyses stratified by sex, with adjustment for pertinent demographic, lifestyle, and RA disease and treatment covariates as well as for the potential modifying effects of articular activity and biologic pharmacotherapeutic agents.
Results
All measures of adiposity were significantly associated with the level of CRP in women, but not in men. In women, the measure of adiposity that showed the strongest association with the CRP level was truncal fat, in which, in adjusted analyses, each kilogram increase was associated with a 0.101-unit increase in the logarithmically transformed CRP level (P < 0.001). Neither the level of articular activity nor the use of biologic agents significantly modified this association in women. However, in men, elevated articular involvement was associated with a decreasing CRP level as truncal fat increased. For all analyses, substitution of IL-6 for CRP produced similar findings.
Conclusion
Adiposity is independently associated with CRP levels in women with RA, and thus may confound the estimation of RA disease activity when serum CRP concentration is used as a surrogate for systemic inflammation.
doi:10.1002/art.23766
PMCID: PMC2671067  PMID: 18759279
5.  Association of Body Composition With Disability in Rheumatoid Arthritis: Impact of Appendicular Fat and Lean Tissue Mass 
Arthritis and rheumatism  2008;59(10):1407-1415.
Objective
To explore the association of measures of body composition with disability in patients with rheumatoid arthritis (RA).
Methods
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.
Results
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 (P < 0.001), and 0.81 units higher for subjects in the lowest versus the highest quartile of appendicular lean mass (P < 0.001). 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.
Conclusion
Body composition, particularly the amount of fat and lean mass located in the arms and legs, is strongly associated with disability in RA patients.
doi:10.1002/art.24109
PMCID: PMC2670990  PMID: 18821641
6.  Association of circulating adiponectin levels with progression of radiographic joint destruction in rheumatoid arthritis 
Annals of the rheumatic diseases  2011;70(9):1562-1568.
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 <30 kg/m2 and those receiving baseline biological disease-modifying antirheumatic drugs.
Conclusions
These prospective data provide evidence of temporality and dose-response in the relationship between circulating adiponectin and erosive joint destruction in RA, and highlight subgroups of patients at highest risk for adiponectin-associated radiographic progression.
doi:10.1136/ard.2011.150813
PMCID: PMC3543946  PMID: 21571734
7.  Prevalence of Traditional Modifiable Cardiovascular Risk Factors in Patients with Rheumatoid Arthritis: Comparison with Control Subjects from the Multi-Ethnic Study of Atherosclerosis 
Objective
Despite the recognized risk of accelerated atherosclerosis in patients with rheumatoid arthritis (RA), little is known about cardiovascular risk management in contemporary cohorts of these patients. We tested the hypotheses that major modifiable cardiovascular risk factors were more frequent and rates of treatment, detection, and control were lower in patients with RA than in non-RA controls.
Methods
The prevalence of hypertension, diabetes, elevated low-density lipoprotein (LDL) cholesterol, elevated body mass index, smoking, moderate-high 10-year cardiovascular risk and the rates of underdiagnosis, therapeutic treatment, and recommended management were compared in 197 RA patients and 274 frequency-matched control subjects, and their associations with clinical characteristics were examined.
Results
Eighty percent of RA patients and 81% of control subjects had at least 1 modifiable traditional cardiovascular risk factor. Hypertension was more prevalent in the RA group (57%) than in controls [42%, P =0.001]. There were no statistically significant differences in the frequency of diabetes, elevated body mass index, smoking, intermediate-high 10-year coronary heart disease risk, or elevated LDL in patients with RA versus controls. Rates of newly identified diabetes, hypertension, and hyperlipidemia were similar in RA patients versus controls. Rates of therapeutic interventions were low in both groups but their use was associated with well-controlled blood pressure (OR = 4.55, 95% CI: 1.70, 12.19) and lipid levels (OR = 9.90, 95% CI: 3.30, 29.67).
Conclusions
Hypertension is more common in RA than in controls. Other traditional cardiovascular risk factors are highly prevalent, underdiagnosed, and poorly controlled in patients with RA, as well as controls.
doi:10.1016/j.semarthrit.2011.07.004
PMCID: PMC3538033  PMID: 22340996
rheumatoid arthritis; cardiovascular risk; epidemiology
8.  Longitudinal Predictors of Progression of Carotid Atherosclerosis in Rheumatoid Arthritis 
Arthritis and rheumatism  2011;63(11):3216-3225.
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 two timepoints, separated by an average of 3.2 ± 0.3 years. The associations of baseline and average patient characteristics with the average yearly change in mean maximal intima-medial thickness (IMT) of the common (CCA) and internal carotid arteries (ICA), and with incident or progressive plaque in the ICA/carotid bulb, were explored.
Results
Among the 158 RA patients, maxCCA-IMT increased in 82% (median=16 μm/year; p<0.001) and maxICA-IMT increased in 70% (median=25 μm/year; p<0.001). Incident plaque was observed in 14% without baseline plaque [incidence rate=4.2/100 person-years (95% CI 1.61–6.82)]. Plaque progression was observed in 5% with baseline plaque. Among RA predictors, the adjusted average yearly change in maxCCA-IMT was significantly greater in patients with earlier RA vs. longer disease. Those prescribed TNF inhibitors at baseline had a 37% lower adjusted rate of maxCCA-IMT progression vs. non-users (14 vs. 22 μm/year; p=0.026). For maxICA-IMT, cumulative prednisone exposure was associated with progression [1.2 μm/year per gram (95% CI 0.1–2.4)] after adjustment, and was lower in patients prescribed statins concomitant with prednisone. Higher swollen joint count and higher average CRP were both associated with incident or progressive plaque, primarily in patients with elevated baseline CVD risk based on the Framingham score.
Conclusions
These prospective data provide evidence for inflammation as a contributor to subclinical atherosclerosis progression in RA, potentially modified favorably by TNF inhibitors and detrimentally by glucocorticoids.
doi:10.1002/art.30542
PMCID: PMC3205252  PMID: 21965129
Atherosclerosis; Inflammation; prediction; carotid ultrasound
9.  Objective physical activity measurement in the Osteoarthritis Initiative: Are guidelines being met? 
Arthritis and rheumatism  2011;63(11):3372-3382.
Objective
Osteoarthritis (OA) clinical practice guidelines identify a substantial therapeutic role for physical activity but objective information about the physical activity of this population is lacking. We objectively measured physical activity levels of adults with knee OA and report the prevalence of meeting public health physical activity guidelines.
Methods
Cross-sectional accelerometer data from 1111 adults with radiographic knee OA aged 49 to 84 years participating in Osteoarthritis Initiative accelerometer monitoring ancillary study were assessed for meeting the aerobic component of the 2008 Physical Activity Guidelines for Americans (≥150 minutes/week in episodes≥10 minutes). Quantile regression was used to test median gender differences in physical activity levels.
Results
Aerobic physical activity guidelines were met by 12.9% of men and 7.7% of women with knee OA. A substantial 40.1% of men and 56.5% of women were inactive, doing no moderate-to-vigorous (MV) activity over 7 days that lasted 10 minutes or more. Although men engaged in significantly more MV intensity activity (20.7 vs. 12.3 average daily minutes) they also spent more time in no or very light intensity activity (608.2 vs. 585.8 average daily minutes) than women.
Conclusion
Despite substantial health benefits from physical activity, adults with knee OA were particularly inactive based on objective accelerometer monitoring. The percentages of men and women who met public health physical activity guidelines were substantially less than previous reports based on self-reported activity in arthritis populations. These findings support intensified public health efforts to increase physical activity levels among persons with knee OA.
doi:10.1002/art.30562
PMCID: PMC3205278  PMID: 21792835
10.  Serum Protein Signatures Detect Early Radiographic Osteoarthritis 
Objective
To test the hypothesis that early knee and hand OA development is characterized by detectable changes in serum proteins relevant to inflammation, cell growth, activation, and metabolism several years before OA becomes radiographically evident.
Methods
Using microarray platforms that simultaneously test 169 proteins relevant to inflammation, cell growth, activation and metabolism, we conducted a case-control study nested within the Baltimore Longitudinal Study of Aging (BLSA). Subjects included 22 incident cases of osteoarthritis and 66 age, sex and BMI- matched controls. Serum samples tested were obtained at the time of radiographic classification as either case or control, and up to 10 years earlier at a time when all participants were free of radiographic OA. Proteins with mean signal intensities 4-fold higher than background were compared between cases and controls using multivariate techniques.
Results
Sixteen proteins were different between OA cases compared to controls. Four of these proteins (MMP-7, IL-15, PAI-1 and sVAP-1) were already different in samples obtained 10 years before radiographic classification and remained different at the time of diagnosis. Six additional proteins were only associated with subsequent OA development and not with established OA.
Conclusions
Changes in serum proteins implicated in matrix degradation, cell activation, inflammation and bone collagen degradation products accompany early OA development and can precede radiographic detection by several years.
doi:10.1016/j.joca.2008.05.004
PMCID: PMC2667202  PMID: 18571442
11.  Pain Sensitivity and Pain Reactivity in Osteoarthritis 
Arthritis care & research  2010;63(3):320-327.
Objective
In systemic inflammatory diseases such as rheumatoid arthritis, pain and inflammation exhibit reciprocal inter-relationships. However, the nature of the association between pain and inflammation in osteoarthritis (OA) is not clear. We assessed experimental pain sensitivity and compared the inflammatory response to pain in 26 OA patients and 33 age-and sex-matched controls from the general population.
Methods
Participants underwent psychophysical pain testing to assess pain sensitivity in response to heat, cold and mechanical stimuli. Blood samples were taken at baseline and four time points after testing to determine the effect of acute pain on C-reactive protein (CRP), interleukin 6 (IL-6), interleukin-1beta (IL-1β) and tumor necrosis factor-alpha (TNF-α).
Results
OA patients had lower pressure pain thresholds (P ≤ 0.003) and higher heat pain ratings (P ≤ 0.04) than controls across multiple body sites. OA patients had higher CRP levels than controls (P = 0.007). CRP levels did not change in response to pain testing. Although not statistically significant, OA patients tended to have higher IL-6 levels than controls (P = 0.12). IL-6 levels increased after pain testing in OA patients and controls (P < 0.0001), but the amount of increase was not different between the two groups. Among OA patients, heightened pain sensitivity was associated with elevated CRP and IL-6 (P ≤ 0.05).
Conclusions
Compared to controls, OA patients are more sensitive to experimental pain at multiple body sites. IL-6 levels in OA patients and controls exhibited reactivity to acute painful stimuli, increasing at similar rates after psychophysical pain testing.
doi:10.1002/acr.20373
PMCID: PMC3030930  PMID: 20957660
12.  Assessing Physical Activity in Persons with Knee Osteoarthritis Using Accelerometers: Data in the Osteoarthritis Initiative 
Arthritis care & research  2010;62(12):1724-1732.
Objective
Physical activity measured by accelerometers requires basic assumptions to translate the output into meaningful measures. We used accelerometer data from the Osteoarthritis Initiative to investigate in the context of knee osteoarthritis (OA) the following data processing assumptions derived from the general adult US population: non-wear (a period the monitor was removed) is based on zero activity exceeding 60 minutes; a valid day of monitoring is based on wear time evidence exceeding 10 hours.
Methods
We examined the influence of non-wear thresholds ranging from 20 to 300 minutes of zero activity on 1) mean daily activity minutes (counts>0), 2) mean daily activity counts, and 3) mean daily moderate to vigorous physical activity (MVPA) minutes. The effect of selecting minimums of 8, 10, or 12 wear hours to signify a valid day of monitoring on data retention was examined.
Results
Our sample of 3536 days’ accelerometer data from 519 persons with knee OA showed mean daily activity minutes increased with the non-wear threshold until stabilizing at 463 minutes per day, corresponding to the 90-minute non-wear threshold. Similar patterns were observed for mean daily activity counts. Varying the non-wear threshold had no effect on mean daily MVPA minutes. Choosing the 90-minute non-wear threshold and a minimum of 10 wear hours to constitute a valid day provided 94% data retention.
Conclusion
Data supported applying the 90-minute non-wear threshold to the knee OA population instead of the general population 60-minute threshold, while retaining the 10-hour valid day threshold.
doi:10.1002/acr.20305
PMCID: PMC2995807  PMID: 20806273
accelerometer; physical activity; non-wear time; valid day; osteoarthritis
13.  Abdominal Adiposity in Rheumatoid Arthritis: Association with Cardiometabolic Risk Factors and Disease Characteristics 
Arthritis and rheumatism  2010;62(11):3173-3182.
Background
Abdominal adiposity, especially visceral adiposity, is an emerging cardiometabolic risk factor. How abdominal fat is distributed in rheumatoid arthritis (RA) and its RA-related determinants have not been explored.
Methods
Men and women with RA were compared to non-RA controls from the Multi-Ethnic Study of Atherosclerosis. Participants underwent anthropometric measures and quantification of visceral and subcutaneous fat areas (VFA, 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 45cm2 higher (+51%) for RA vs. control men (p=0.005) but not significantly different by RA status in women. The adjusted mean SFA was 119cm2 higher (+68%) for RA vs. control women (p<0.001) but not significantly different by RA status in men. Elevated VFA (>75th percentile) was associated with a significantly higher adjusted probability of having an elevated fasting glucose, hypertension, or the composite definition of the metabolic syndrome for 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 scores were significantly associated with both VFA and SFA.
Conclusions
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.
doi:10.1002/art.27629
PMCID: PMC2962724  PMID: 20589684
14.  Left Ventricular Structure and Function by Cardiac Magnetic Resonance Imaging in Rheumatoid Arthritis 
Arthritis and rheumatism  2010;62(4):940-951.
Background
Heart failure is a major contributor to cardiovascular morbidity and mortality in rheumatoid arthritis. However, little is known about myocardial structure and function in this population.
Methods
Using cardiac magnetic resonance imaging, measures of myocardial structure and function were assessed in men and women with rheumatoid arthritis enrolled in ESCAPE RA, a cohort study of subclinical cardiovascular disease in rheumatoid arthritis, and compared with controls without rheumatoid arthritis enrolled in the Baltimore cohort of the Multi-Ethnic Study of Atherosclerosis.
Results
Myocardial measures were compared between 75 rheumatoid arthritis patients and 225 matched controls. After adjustment, mean left-ventricular mass was 26 grams lower for the RA group compared to controls (p<0.001), an 18% difference. After similar adjustment, mean left-ventricular ejection fraction, cardiac output, and stroke volume were modestly lower in the rheumatoid arthritis group vs. controls. Mean left-ventricular end-systolic and end-diastolic volumes did not differ by rheumatoid arthritis status. Within the rheumatoid arthritis group, higher levels of anti-CCP antibodies and current use of biologics, but not other disease activity or severity measures, were associated with significantly lower adjusted mean left-ventricular mass, end-diastolic volume, and stroke volume, but not ejection fraction. The combined associations of anti-CCP antibody level and biologic use on myocardial measures were additive, without evidence of interaction.
Conclusions
These findings suggest that the progression to heart failure in RA may occur through reduced myocardial mass rather than hypertrophy. Both modifiable and non-modifiable factors may contribute to lower levels of left-ventricular mass and volume.
doi:10.1002/art.27349
PMCID: PMC3008503  PMID: 20131277
myocardial dysfunction; heart failure; inflammation; cardiac imaging
15.  Adiponectin is a Mediator of the Association of Adiposity with Radiographic Damage in Rheumatoid Arthritis 
Arthritis and rheumatism  2009;61(9):1248-1256.
Objectives
Recent reports have suggested that increasing adiposity may protect against radiographic damage in rheumatoid arthritis. We explored the role of serum adipokines (adiponectin, resistin, leptin) in mediating this association.
Methods
RA patients underwent total-body dual-energy 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 Sharp-van der Heijde 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 Sharp score increasing 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 Sharp score, a proportion comparable to rheumatoid factor and greater than HLA-DRB1 shared epitope alleles or C-reactive protein. 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.
Conclusions
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.
doi:10.1002/art.24789
PMCID: PMC2759038  PMID: 19714593
adipose; body composition; erosion; rheumatoid arthritis; comorbidity
16.  Assessment of myocardial abnormalities in rheumatoid arthritis using a comprehensive cardiac magnetic resonance approach: a pilot study 
Arthritis Research & Therapy  2010;12(5):R171.
Introduction
Rheumatoid arthritis (RA) is a multi-organ inflammatory disorder associated with high cardiovascular morbidity and mortality. We sought to assess cardiac involvement using a comprehensive cardiac magnetic resonance imaging (cMRI) approach and to determine its association with disease characteristics in RA patients without symptomatic cardiac disease.
Methods
RA patients with no history and/or clinical findings of systemic or pulmonary hypertension, coronary artery disease, severe valvular heart disease, atrial fibrillation, diabetes mellitus, or echocardiographic abnormalities underwent contrast-enhanced cMRI on a 1.5T scanner. Adenosine triphosphate was used to assess perfusion defects due to microvascular impairment or ischemia, and delayed enhanced imaging was obtained for the assessment of myocardial inflammation/fibrosis. We explored the associations of cMRI abnormalities with RA disease activity and severity measures.
Results
Eighteen patients (78% female) with a mean age of 57 ± 10 years were studied. Eight patients (45%) demonstrated a myocardial abnormality. Perfusion defects under pharmacologic stress were seen in two patients (11%), one of whom had a circumferential subendocardial perfusion defect and one had a non-segmental subendocardial perfusion defect. Seven patients (39%) were found to have delayed enhancement, only one of whom also demonstrated a perfusion defect. Mean disease activity score (DAS)28 was significantly higher in the group with delayed enhancement compared to the group without by an average of 1.32 DAS28 units (4.77 vs. 3.44 units, respectively; P = 0.011). Corresponding trends to statistical significance were noted in systemic inflammatory markers, with both C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR) quantitatively higher in the group with delayed enhancement. Other RA characteristics, such as disease duration, autoantibody status, and current treatments were not significantly associated with cardiac involvement.
Conclusions
Myocardial abnormalities, as detected by cMRI, were frequent in RA patients without known cardiac disease. Abnormal cMRI findings were associated with higher RA disease activity, suggesting a role for inflammation in the pathogenesis of myocardial involvement in RA.
doi:10.1186/ar3131
PMCID: PMC2990998  PMID: 20836862
17.  Respiratory symptoms and disease characteristics as predictors of pulmonary function abnormalities in patients with rheumatoid arthritis: an observational cohort study 
Arthritis Research & Therapy  2010;12(3):R104.
Introduction
Lung involvement is a common extra-articular manifestation of rheumatoid arthritis (RA) that confers significant morbidity and mortality. The objective of the present study is to assess which respiratory symptoms and patient and disease characteristics are most highly associated with pulmonary function test (PFT) abnormalities in an RA patient cohort without clinical cardiovascular disease.
Methods
A total of 159 individuals with RA and without clinically evident cardiovascular disease were evaluated. Respiratory symptoms were assessed with the Lung Tissue Research Consortium questionnaire and all patients underwent evaluation with PFTs. Demographic, lifestyle, RA disease and treatment characteristics were collected. Subclinical coronary artery disease was assessed by cardiac computed tomography. Multivariable regression analysis was used to identify pulmonary symptoms and nonpulmonary parameters associated with PFT abnormalities. Areas under the receiver operating characteristic curves (AUC) were calculated to evaluate the discrimination of these variables for identifying patients with PFT abnormalities.
Results
Respiratory symptoms were reported by 42% of the patient population. Although only 6% carried a prior diagnosis of lung disease, PFT abnormalities were identified in 28% of the subjects. Symptoms combined with other patient and RA characteristics (body mass index, current smoking, anti-cyclic citrullinated peptide antibodies, and current prednisone use) performed satisfactorily in predicting the PFT abnormalities of obstruction (AUC = 0.91, 95% confidence interval = 0.78 to 0.98), restriction (AUC = 0.79, 95% confidence interval = 0.75 to 0.93) and impaired diffusion (AUC = 0.85, 95% confidence interval = 0.59 to 0.92). Co-morbid subclinical coronary artery disease did not modify these relationships.
Conclusions
Assessment of respiratory symptoms along with a limited number of clinical parameters may serve as a useful and inexpensive clinical tool for identifying RA patients in need of further pulmonary investigation.
doi:10.1186/ar3037
PMCID: PMC2911894  PMID: 20507627
18.  Association of Autoimmunity to Peptidyl Arginine Deiminase Type 4 With Genotype and Disease Severity in Rheumatoid Arthritis 
Arthritis and rheumatism  2008;58(7):1958-1967.
Objective
Protein citrullination is an important posttranslational modification recognized by rheumatoid arthritis (RA)–specific autoantibodies. One of the citrullinating enzymes, peptidyl arginine deiminase type 4 (PAD-4), is genetically associated with development of RA in some populations, although the mechanism(s) mediating this effect are not yet clear. There have been descriptions of anti–PAD-4 autoantibodies in different rheumatic diseases. This study was undertaken to investigate whether anti–PAD-4 antibodies are specific to RA, are associated with disease phenotype or severity, and whether PAD-4 polymorphisms influence the anti–PAD-4 autoantibody response.
Methods
Sera from patients with established RA, patients with other rheumatic diseases, and healthy adults were assayed for anti–PAD-4 autoantibodies by immunoprecipitation of in vitro–translated PAD-4. The epitope(s) recognized by PAD-4 autoantibodies were mapped using various PAD-4 truncations. PAD-4 genotyping was performed on RA patients with the TaqMan assay. Joint erosions were scored from hand and foot radiographs using the Sharp/van der Heijde method.
Results
PAD-4 autoantibodies were found in 36–42% of RA patients, and were very infrequent in controls. Recognition by anti–PAD-4 autoantibodies required the 119 N-terminal amino acids, which encompass the 3 nonsynonymous polymorphisms associated with disease susceptibility. Strikingly, the anti–PAD-4 immune response was associated with the RA susceptibility haplotype of PADI4. Anti–PAD-4 antibodies were associated with more severe joint destruction in RA.
Conclusion
Our findings indicate that anti–PAD-4 antibodies are specific markers of RA, independently associated with more severe disease, suggesting that an anti–PAD-4 immune response may be involved in pathways of joint damage in this disease. Polymorphisms in the PADI4 gene influence the immune response to the PAD-4 protein, potentially contributing to disease propagation.
doi:10.1002/art.23596
PMCID: PMC2692635  PMID: 18576335
19.  Abnormal Body Composition Phenotypes in Older Rheumatoid Arthritis Patients: Association With Disease Characteristics and Pharmacotherapies 
Arthritis and rheumatism  2008;59(6):807-815.
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 (<25 kg/m2). Among RA characteristics, increasing joint deformity, self-reported disability scores, C-reactive protein levels, rheumatoid factor seropositivity, and a lack of current treatment with disease-modifying antirheumatic drugs were significantly associated with abnormal body composition.
Conclusion
Abnormal body composition phenotypes are overrepresented in patients with RA, particularly in those in the normal weight BMI range. RA-associated disease and treatment characteristics contribute to this increase in abnormal body composition.
doi:10.1002/art.23719
PMCID: PMC2670994  PMID: 18512711
20.  Myocardial dysfunction in rheumatoid arthritis: epidemiology and pathogenesis 
Arthritis Research & Therapy  2005;7(5):195-207.
Data from population- and clinic-based epidemiologic studies of rheumatoid arthritis patients suggest that individuals with rheumatoid arthritis are at risk for developing clinically evident congestive heart failure. Many established risk factors for congestive heart failure are over-represented in rheumatoid arthritis and likely account for some of the increased risk observed. In particular, data from animal models of cytokine-induced congestive heart failure have implicated the same inflammatory cytokines produced in abundance by rheumatoid synovium as the driving force behind maladaptive processes in the myocardium leading to congestive heart failure. At present, however, the direct effects of inflammatory cytokines (and rheumatoid arthritis therapies) on the myocardia of rheumatoid arthritis patients are incompletely understood.
doi:10.1186/ar1814
PMCID: PMC1257451  PMID: 16207349
21.  Progression of coronary artery atherosclerosis in rheumatoid arthritis: comparison with participants from the Multi-Ethnic Study of Atherosclerosis 
Arthritis Research & Therapy  2013;15(5):R134.
Introduction
In cross-sectional studies, patients with rheumatoid arthritis (RA) have higher coronary artery calcium (CAC) than controls. However, their rate of progression of CAC and the predictors of CAC progression have heretofore remained unknown.
Methods
Incidence and progression of CAC were compared in 155 patients with RA and 835 control participants. The association of demographic characteristics, traditional cardiovascular risk factors, RA disease characteristics and selected inflammatory markers with incidence and progression of CAC were evaluated.
Results
The incidence rate of newly detected CAC was 8.2/100 person-years in RA and 7.3/100 person-years in non-RA control subjects [IRR 1.1 (0.7-1.8)]. RA patients who developed newly detectable CAC were older (59±7 vs. 55±6 years old, p=0.03), had higher triglyceride levels (137±86 vs. 97±60 mg/dL, p=0.03), and higher systolic blood pressure (129±17 vs. 117±15 mm Hg, p=0.01) compared to those who did not develop incident CAC. Differences in blood pressure and triglyceride levels remained significant after adjustment for age (p<=0.05). RA patients with any CAC at baseline had a median rate of yearly progression of 21 (7–62) compared to 21 (5–70) Agatston units in controls. No statistical differences between RA progressors and RA non-progressors were observed for inflammatory markers or for RA disease characteristics.
Conclusions
The incidence and progression of CAC did not differ between RA and non-RA participants. In patients with RA, incident CAC was associated with older age, higher triglyceride levels, and higher blood pressure, but not with inflammatory markers or RA disease characteristics.
doi:10.1186/ar4314
PMCID: PMC3978773  PMID: 24286380
22.  Myocardial citrullination in rheumatoid arthritis: a correlative histopathologic study 
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.
doi:10.1186/ar3752
PMCID: PMC3392839  PMID: 22364592
23.  Coronary arterial calcification in rheumatoid arthritis: comparison with the Multi-Ethnic Study of Atherosclerosis 
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.
doi:10.1186/ar2641
PMCID: PMC2688181  PMID: 19284547

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