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1.  GUEPARD treat-to-target strategy is significantly more efficacious than ESPOIR routine care in early rheumatoid arthritis according to patient-reported outcomes and physician global estimate 
Rheumatology (Oxford, England)  2013;52(10):1890-1897.
Objective. To analyse seven RA Core Data Set measures and three indices for their capacity to distinguish treatment results in early RA in the GUEPARD treat-to-target clinical trial vs ESPOIR routine care.
Methods. Post hoc analyses compared 65 GUEPARD and 130 matched control ESPOIR patients over 6 and 12 months for mean changes in measures, relative efficiencies and standardized response means (SRM). Three indices—28-joint disease activity score (DAS28), clinical disease activity index (CDAI) and routine assessment of patient index data (RAPID3)—were compared for mean changes and numbers of patients with high, moderate or low activity or remission using κ values.
Results. Greater improvement was seen for GUEPARD vs ESPOIR, statistically significant for physician and patient global estimates and pain and health assessment questionnaire physical function (HAQ-FN), but not joint counts and laboratory tests. Relative efficiencies with tender joint count as the referent measure indicated that pain (2.57) and global estimates by patient (3.13) and physician (2.31) were most efficient in distinguishing GUEPARD from ESPOIR. Mean improvements in GUEPARD vs ESPOIR were −3.4 vs −2.6 for DAS28 (0–10) (24%), −29.8 vs −23.1 for CDAI (0–76) (23%) and −13.0 vs −7.8 for RAPID3 (0–30) (40%) (all P < 0.01); agreement was moderate between CDAI vs DAS28 (κ = 0.56) and vs RAPID3 (κ = 0.48), and fair between DAS28 vs RAPID3 (κ = 0.26).
Conclusion. Patient and global measures indicate greater efficacy than joint counts or laboratory measures in detecting difference between GUEPARD treat-to-target and ESPOIR routine care. A RAPID3 of only patient measures may help guide treat-to-target in busy clinical settings.
PMCID: PMC3775294  PMID: 23864169
treat-to-target; patient-reported outcomes; assessment; rheumatoid arthritis; patient questionnaires
2.  The 2010 American College of Rheumatology/European League Against Rheumatism Classification Criteria for Rheumatoid Arthritis 
Arthritis and rheumatism  2010;62(9):2582-2591.
The American College of Rheumatology and the European League Against Rheumatism have developed new classification criteria for rheumatoid arthritis (RA). The aim of Phase 2 of the development process was to achieve expert consensus on the clinical and laboratory variables that should contribute to the final criteria set.
Twenty-four expert RA clinicians (12 from Europe and 12 from North America) participated in Phase 2. A consensus-based decision analysis approach was used to identify factors (and their relative weights) that influence the probability of “developing RA,” complemented by data from the Phase 1 study. Patient case scenarios were used to identify and reach consensus on factors important in determining the probability of RA development. Decision analytic software was used to derive the relative weights for each of the factors and their categories, using choice-based conjoint analysis.
The expert panel agreed that the new classification criteria should be applied to individuals with undifferentiated inflammatory arthritis in whom at least 1 joint is deemed by an expert assessor to be swollen, indicating definite synovitis. In this clinical setting, they identified 4 additional criteria as being important: number of joints involved and site of involvement, serologic abnormality, acute-phase response, and duration of symptoms in the involved joints. These criteria were consistent with those identified in the Phase 1 data-driven approach.
The consensus-based, decision analysis approach used in Phase 2 complemented the Phase 1 efforts. The 4 criteria and their relative weights form the basis of the final criteria set.
PMCID: PMC3077961  PMID: 20872596
3.  Lipoprotein Subclasses Determined by Nuclear Magnetic Resonance Spectroscopy and Coronary Atherosclerosis in Patients with Rheumatoid Arthritis 
The Journal of rheumatology  2010;37(8):1633-1638.
Patients with rheumatoid arthritis (RA) are at increased risk of atherosclerosis, but routine lipid measurements differ little from those of people without RA. We examined the hypothesis that lipid subclasses determined by nuclear magnetic resonance spectroscopy (NMR) differed in patients with RA compared to controls and are associated with disease activity and the presence of coronary-artery atherosclerosis.
We measured lipoprotein subclasses by NMR in 139 patients with RA and 75 control subjects. Lipoproteins were classified as large LDL (diameter range: 21.2-27.0 nm), small LDL (18.0-21.2 nm), large HDL (8.2-13.0 nm), small HDL (7.3-8.2 nm), and total VLDL (≥27 nm). All subjects underwent an interview and physical examination; disease activity was quantified by the 28 joint disease activity score (DAS28) and coronary artery calcification (CAC) was measured with electron beam computed tomography.
Concentrations of small HDL particles were lower in patients with RA (18.2±5.4 nmol/L) than controls (20.0±4.4 nmol/L), P=0.003. In patients with RA, small HDL concentrations were inversely associated with DAS28 (rho=-0.18, P=0.04) and CRP (rho=-0.25, P=0.004). Concentrations of small HDL were lower in patients with coronary calcification (17.4±4.8 nmol/L) than in those without (19.0±5.8 nmol/L), P=0.03. This relationship remained significant after adjustment for the Framingham risk score and DAS28 (P=0.025). Concentrations of small LDL particles were lower in patients with RA (1390±722 nmol/L) than in control subjects (1518±654 nmol/L), P=0.05, but did not correlate with DAS28 or CAC.
Low concentrations of small HDL particles may contribute to increased coronary atherosclerosis in patients with RA.
PMCID: PMC2914215  PMID: 20516025
4.  Poor physical function, pain and limited exercise: risk factors for premature mortality in the range of smoking or hypertension, identified on a simple patient self-report questionnaire for usual care 
BMJ Open  2011;1(1):e000070.
To analyse poor physical function, pain, limited exercise and smoking, assessed in a patient-friendly self-report questionnaire format that has been completed by every patient at every visit over 20–30 years in the authors’ and other usual care settings, to predict 5-year mortality in a general older population.
An extended version of a Multidimensional Health Assessment Questionnaire was mailed to 2000 subjects in Finland, identified as a randomly selected control cohort for a rheumatoid arthritis cohort. The questionnaire included queries concerning baseline physical function, pain, exercise and smoking status, identical to the clinic version, as well as age and 25 medical conditions. Five-year survival was analysed according to descriptive statistics, Kaplan–Meier curves and Cox regressions.
The questionnaire was returned by 1523 subjects (76%). Five-year survival was 94% in all subjects, 98% in subjects with no disease or no acutely life-threatening disease, and 17% in subjects with an acutely life-threatening disease. Hazard ratios (HRs) for 5-year mortality were 3.5 for poor physical function, 2.2 for pain, 5.2 for limited exercise and 4.6 for smoking (p<0.01); 5-year survivals were 93%, 97%, 93% and 95%, respectively, compared with 91% for hypertension. Each of the four patient history variables predicted mortality at higher levels in subjects who reported no versus one or more acutely life-threatening conditions.
Poor physical function, pain, limited exercise and smoking can be assessed systematically on a simple standard Multidimensional Health Assessment Questionnaire, to identify potentially modifiable risk factors for premature mortality in the infrastructure of usual medical care and health maintenance.
Article summary
Article focus
A simple, one-page patient self-report questionnaire to assess systematically physical function, pain, limited exercise and smoking has been completed by all patients at all visits in 5–10 min in routine care in several rheumatology clinical settings for 20–30 years, including those of the authors.
Responses on this questionnaire indicating poor physical function, pain and limited exercise have been documented as significant prognostic markers for premature mortality in patients with rheumatoid arthritis, with greater significance than radiographs or laboratory tests.
Questionnaire responses in an older cohort from the general population, identified from a population register as a control cohort for a rheumatoid arthritis cohort, indicated that poor physical function, pain and limited exercise also predicted 5-year mortality significantly, in the range of smoking and hypertension.
Key messages
Poor physical function, pain and limited exercise are potentially modifiable risk factors for premature mortality in the general population, in a similar range to that of smoking and hypertension.
A systematic assessment of these patient history variables is not included at most medical visits, in contrast to blood pressure or serum cholesterol, in part as most available questionnaire formats appear to add to the burden of care for patients and doctors.
Scores in a simple format on a questionnaire completed by patient self-report in 5–10 min provide quantitative data concerning physical function, pain, exercise status and smoking as significant risk factors for mortality, with virtually no additional work on the part of a health professional, to ensure that data are available for clinical review.
Poor physical function, pain and limited exercise are more significant in prognosis of death over 5 years in individuals who do not versus do report one or more potentially acutely life-threatening diseases.
Strengths and limitations of this study
Population-based subjects? Survey returned by 1523 of 2000 subjects (76%).
Questionnaire easily completed by patient self-report in 5–10 min in any clinical or research setting, or even at home.
No laboratory tests were available—it would be of interest to compare medical history variables with laboratory tests, such as serum cholesterol, in the prognosis of mortality, and whether a component of the risk according to the laboratory test may be ‘explained’ in part by a patient history measure.
All subjects were from Finland, although most data suggest that mortality experience in Finland is similar to that found in most Western countries, and reports from other countries have indicated that poor physical function, pain and limited exercise are prognostic of premature mortality. Furthermore, a response rate of >75% from the general population might be unlikely in most countries, and may be unique to Finland.
Diagnoses were available only from self-report, which can be inaccurate for certain diagnoses. However, the excess risk according to poor physical function, pain and limited exercise was greater in subjects who reported no versus any acutely life-threatening diseases.
Actual survey includes more queries and is not identical to that used in clinical settings, although actual queries about four risk factors are identical in clinical and study format.
PMCID: PMC3191419  PMID: 22021748
5.  Inflammatory Mediators and Premature Coronary Atherosclerosis in Rheumatoid Arthritis 
Arthritis and rheumatism  2009;61(11):1580-1585.
Rheumatoid arthritis (RA) is an inflammatory disease associated with premature atherosclerosis. We examined the hypothesis that mediators of inflammation associated with atherosclerosis in other populations IL-6, TNF-α, SAA, VEGF, neutrophil count, IL-1α, E-selectin, ICAM-1, MPO, MMP-9, and VCAM-1 were increased and associated with the severity of coronary atherosclerosis in patients with RA.
Clinical variables, concentrations of inflammatory mediators and coronary artery calcification were measured in 169 patients with RA and 92 control subjects. Differences in concentrations of inflammatory mediators were compared using median quantile regression. The relationship of inflammatory mediators with the severity of coronary calcification in RA and control subjects was examined using proportional odds logistic regression allowing for interaction with disease status. Models were adjusted for traditional cardiovascular risk factors.
Median serum concentrations of IL-6, SAA, ICAM-1, E-selectin, TNF-α, and MPO and peripheral blood neutrophil count were higher in patients with RA than controls (all p<0.05) independent of Framingham risk score and diabetes. IL-6 (main effect OR 1.72, 95%CI 1.12–2.66) and TNF-α concentrations (main effect OR 1.49, 95%CI 1.16–1.90) were significantly associated with higher amounts of coronary calcium independent of Framingham risk score and diabetes, and such main effects significantly differed from controls (p-value for interaction=0.001 and 0.03, respectively).
TNF-α and IL-6 are significantly associated with the severity of subclinical atherosclerosis independent of Framingham risk score in RA.
PMCID: PMC2828265  PMID: 19877084
Rheumatoid arthritis; Atherosclerosis; Cytokine; Inflammation; TNF-α; IL-6; Coronary Calcium
6.  QUEST‐RA: quantitative clinical assessment of patients with rheumatoid arthritis seen in standard rheumatology care in 15 countries 
Annals of the Rheumatic Diseases  2007;66(11):1491-1496.
To conduct a cross‐sectional review of non‐selected consecutive outpatients with rheumatoid arthritis (RA) as part of standard clinical care in 15 countries for an overview of the characteristics of patients with RA.
The review included current disease activity using data from clinical assessment and a patient self‐report questionnaire, which was translated into each language. Data on demographic, disease and treatment‐related variables were collected and analysed using descriptive statistics. Variation in disease activity on DAS28 (disease activity score on 28‐joint count) within and between countries was graphically analysed. A median regression model was applied to analyse differences in disease activity between countries.
Between January 2005 and October 2006, the QUEST‐RA (Quantitative Patient Questionnaires in Standard Monitoring of Patients with Rheumatoid Arthritis) project included 4363 patients from 48 sites in 15 countries; 78% were female, >90% Caucasian, mean age was 57 years and mean disease duration was 11.5 years. More than 80% of patients had been treated with methotrexate in all but three countries. Overall, patients had an active disease with a median DAS28 of 4.0, with a significant variation between countries (p<0.001). Among 42 sites with >50 patients included, low disease activity of DAS28 ⩽3.2 was found in the majority of patients in seven sites in five countries; in eight sites in five other countries, >50% of patients had high disease activity of DAS28 >5.1.
This international multicentre cross‐sectional database provides an overview of clinical status and treatments of patients with RA in standard clinical care in 2005–6 including countries that are infrequently involved in clinical research projects.
PMCID: PMC2111618  PMID: 17412740
7.  Assessing dyspnea and its impact on patients with connective tissue disease-related interstitial lung disease 
Respiratory medicine  2010;104(9):1350-1355.
Dyspnea is the cardinal symptom in patients with any type of interstitial lung disease (ILD); however, there are limited data on dyspnea among patients with connective tissue disease-related ILD (i.e., CTD-ILD).
To explore the utility of two dyspnea instruments (the University of California San Diego Shortness of Breath Questionnaire [UCSD] and the Dyspnea-12 [D-12]) and use their scores to examine the impact of dyspnea on the lives of patients with CTD-ILD.
Subjects were enrolled from the Autoimmune Lung Database (ALD) at National Jewish Health. Chronbach’s alpha was used to assess the internal consistency reliability of the two dyspnea questionnaires. We used the Multi-Dimensional Health Assessment Questionnaire [MDHAQ] as a measure of health status and examined associations between health status and dyspnea by using Pearson product-moment correlation and linear regression.
The internal consistency reliability of each of the two dyspnea questionnaires was excellent (alpha=0.9 for each). There were significant correlations between either of the two dyspnea measures and MDHAQ components. While controlling for ILD severity, dyspnea as assessed by the UCSD, was a significant predictor of physical function (p=0.04), psychological well-being (p=0.005), and fatigue (p=0.02); dyspnea as assessed the D-12, was a significant predictor of psychological well-being (p=0.01) and global status (p=0.03).
Dyspnea significantly affects day-to-day functioning and global well-being in patients with CTD-ILD. The UCSD and D-12 yield meaningful information about these patients that measures of pulmonary physiology can not. Future studies should examine other performance characteristics of these self-report measures in patients with CTD-ILD.
PMCID: PMC2914213  PMID: 20471238
interstitial lung disease; connective tissue disease; dyspnea; patient-assessed outcomes
8.  Adipocytokines Are Associated with Radiographic Joint Damage in Rheumatoid Arthritis 
Arthritis and rheumatism  2009;60(7):1906-1914.
Obesity protects against radiographic joint damage in rheumatoid arthritis (RA) through poorly defined mechanisms. Adipocytokines are produced in adipose tissue and modulate inflammatory responses and joint damage in animal models. We examined the hypothesis that adipocytokines modulate inflammation and joint damage in patients with RA.
We compared serum concentrations of leptin, resistin, adiponectin and visfatin in 167 patients with RA and 91 control subjects. The independent association between adipocytokines and body mass index (BMI), measures of inflammation (C-reactive protein (CRP), interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α)) and radiographic damage (Larsen score, n=93) was examined in patients with RA with multivariable regression analysis first controlling for age, race and sex, and then obesity (BMI) and inflammation (TNF-α, IL-6 and CRP).
Concentrations of all adipocytokines were significantly higher in RA than controls (all p<0.01); for visfatin (p<0.001) and adiponectin (p<0.05) this association remained significant after adjusting for BMI, inflammation, or both. Visfatin concentrations were associated with higher Larsen score and this remained significant after adjustment for age, race, sex, disease duration, BMI and inflammation (OR=2.38, 95%CI: 1.32–4.29, p=0.004). Leptin concentrations were associated positively with BMI (rho=0.58, p<0.01) and negatively with Larsen score after adjustment for inflammation (OR=0.32, 95%CI: 0.17–0.61, p<0.001) but not after adjustment for BMI (OR 0.86, 95%CI: 0.42–1.73, p=0.67).
Concentrations of adipocytokines are increased in patients with RA and may modulate radiographic joint damage. Visfatin is associated with increased, and leptin with reduced radiographic joint damage.
PMCID: PMC2894567  PMID: 19565493
Rheumatoid Arthritis; Adipocytokine; Visfatin; Leptin; Resistin; Adiponectin; Larsen Score; Obesity
9.  Work disability remains a major problem in rheumatoid arthritis in the 2000s: data from 32 countries in the QUEST-RA Study 
Work disability is a major consequence of rheumatoid arthritis (RA), associated not only with traditional disease activity variables, but also more significantly with demographic, functional, occupational, and societal variables. Recent reports suggest that the use of biologic agents offers potential for reduced work disability rates, but the conclusions are based on surrogate disease activity measures derived from studies primarily from Western countries.
The Quantitative Standard Monitoring of Patients with RA (QUEST-RA) multinational database of 8,039 patients in 86 sites in 32 countries, 16 with high gross domestic product (GDP) (>24K US dollars (USD) per capita) and 16 low-GDP countries (<11K USD), was analyzed for work and disability status at onset and over the course of RA and clinical status of patients who continued working or had stopped working in high-GDP versus low-GDP countries according to all RA Core Data Set measures. Associations of work disability status with RA Core Data Set variables and indices were analyzed using descriptive statistics and regression analyses.
At the time of first symptoms, 86% of men (range 57%-100% among countries) and 64% (19%-87%) of women <65 years were working. More than one third (37%) of these patients reported subsequent work disability because of RA. Among 1,756 patients whose symptoms had begun during the 2000s, the probabilities of continuing to work were 80% (95% confidence interval (CI) 78%-82%) at 2 years and 68% (95% CI 65%-71%) at 5 years, with similar patterns in high-GDP and low-GDP countries. Patients who continued working versus stopped working had significantly better clinical status for all clinical status measures and patient self-report scores, with similar patterns in high-GDP and low-GDP countries. However, patients who had stopped working in high-GDP countries had better clinical status than patients who continued working in low-GDP countries. The most significant identifier of work disability in all subgroups was Health Assessment Questionnaire (HAQ) functional disability score.
Work disability rates remain high among people with RA during this millennium. In low-GDP countries, people remain working with high levels of disability and disease activity. Cultural and economic differences between societies affect work disability as an outcome measure for RA.
PMCID: PMC2888189  PMID: 20226018
10.  Inflammation-Associated Insulin Resistance: Differential Effects in Rheumatoid Arthritis and Systemic Lupus Erythematosus Define Potential Mechanisms 
Arthritis and rheumatism  2008;58(7):2105-2112.
Insulin resistance is increased by inflammation, but the mechanisms are unclear. The present study was undertaken to test the hypothesis that decreased insulin sensitivity is differentially associated with mediators of inflammation by studying 2 chronic inflammatory diseases of different pathogenesis, systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA).
We measured fasting insulin, glucose, and lipid levels, erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), interleukin-6 (IL-6), tumor necrosis factor α (TNFα), and coronary artery calcification in 103 patients with SLE and in 124 patients with RA. Insulin sensitivity was measured using the homeostasis model assessment (HOMA) index.
The HOMA value was higher in RA patients (median 2.05 [interquartile range (IQR) 1.05–3.54]) than in SLE patients (1.40 [0.78–2.59]) (P = 0.007). CRP and ESR did not differ significantly in RA and SLE patients. Body mass index (BMI) was significantly correlated with the HOMA index in both RA (ρ = 0.20) and SLE (ρ = 0.54), independently of age, sex, race, and current use of corticosteroids. In RA patients, the HOMA index was also significantly positively correlated with IL-6 (ρ = 0.63), TNFα (ρ = 0.50), CRP (ρ = 0.29), ESR (ρ = 0.26), coronary calcification (ρ = 0.26), and Disease Activity Score in 28 joints (ρ = 0.21); associations adjusted for age, sex, race, BMI, and current use of corticosteroids remained significant (P < 0.05). In SLE patients, the HOMA index was also significantly correlated with ESR (ρ = 0.35) and CRP (ρ = 0.25), but not with other variables. The association between the ESR and the HOMA value in patients with SLE remained significant after adjustment for confounding covariates (P = 0.008). In multivariable models, the major contributing factors to the HOMA index were the BMI in SLE patients, and IL-6 and TNFα levels in RA patients.
The pathogenesis of insulin resistance and its contribution to atherogenesis varies in different inflammatory settings.
PMCID: PMC2755593  PMID: 18576352
11.  Amino-Terminal Fragment of the Prohormone Brain-type Natriuretic Peptide (NT-proBNP) in Rheumatoid Arthritis 
Arthritis and rheumatism  2008;58(9):2662-2669.
Increased concentrations of amino-terminal prohormone brain-type natriuretic peptide (NT-proBNP) are associated with cardiovascular morbidity and mortality, but little is known about their relationship to chronic inflammation. Patients with rheumatoid arthritis (RA) have chronic inflammation, increased arterial stiffness and accelerated coronary atherosclerosis. We tested the hypothesis that NT-proBNP concentrations are elevated in patients with RA, and are associated with coronary artery calcification and markers of inflammation.
In 159 subjects with RA (90 patients with early RA and 69 patients with longstanding RA) without heart failure and 88 control subjects, we measured serum concentrations of NT-proBNP, interleukin (IL)-6, and tumor necrosis factor-α (TNF-α), and coronary calcification.
NT-proBNP concentrations were elevated in patients with long-standing RA [median (IQR): 142.8 (54.8–270.5) pg/mL] and those with early RA [58.1 (19.4–157.6) pg/mL] compared to controls [18.1 (3.2–46.0) pg/mL, P<0.001]. In patients with RA, NT-proBNP concentrations were associated with age (ρ=0.35, P<0.001), IL-6 (ρ=0.33, P<0.001), TNF-α (ρ=0.23, P=0.003), CRP (ρ=0.21, P=0.01), coronary calcium score (ρ=0.30, P<0.001), systolic blood pressure (ρ=0.30, p<0.001), and disease activity (ρ=0.29, P<0.001). After adjustment for age, race and sex the associations between NT-proBNP concentrations and disease activity (P<0.001), TNF-α (P<0.001), IL-6 (P=0.04) and CRP concentrations (P=0.02) remained significant, but those with systolic blood pressure (P=0.10) and coronary calcium score (P=0.27) were attenuated.
NT-proBNP concentrations are increased in patients with RA without clinical heart failure and may indicate subclinical cardiovascular disease and a chronic inflammatory state.
PMCID: PMC2587412  PMID: 18759301
rheumatoid arthritis; inflammation; atherosclerosis; B-type natriuretic peptide; NT-proBNP
12.  Women, men, and rheumatoid arthritis: analyses of disease activity, disease characteristics, and treatments in the QUEST-RA Study 
Gender as a predictor of outcomes of rheumatoid arthritis (RA) has evoked considerable interest over the decades. Historically, there is no consensus whether RA is worse in females or males. Recent reports suggest that females are less likely than males to achieve remission. Therefore, we aimed to study possible associations of gender and disease activity, disease characteristics, and treatments of RA in a large multinational cross-sectional cohort of patients with RA called Quantitative Standard Monitoring of Patients with RA (QUEST-RA).
The cohort includes clinical and questionnaire data from patients who were seen in usual care, including 6,004 patients at 70 sites in 25 countries as of April 2008. Gender differences were analyzed for American College of Rheumatology Core Data Set measures of disease activity, DAS28 (disease activity score using 28 joint counts), fatigue, the presence of rheumatoid factor, nodules and erosions, and the current use of prednisone, methotrexate, and biologic agents.
Women had poorer scores than men in all Core Data Set measures. The mean values for females and males were swollen joint count-28 (SJC28) of 4.5 versus 3.8, tender joint count-28 of 6.9 versus 5.4, erythrocyte sedimentation rate of 30 versus 26, Health Assessment Questionnaire of 1.1 versus 0.8, visual analog scales for physician global estimate of 3.0 versus 2.5, pain of 4.3 versus 3.6, patient global status of 4.2 versus 3.7, DAS28 of 4.3 versus 3.8, and fatigue of 4.6 versus 3.7 (P < 0.001). However, effect sizes were small-medium and smallest (0.13) for SJC28. Among patients who had no or minimal disease activity (0 to 1) on SJC28, women had statistically significantly higher mean values compared with men in all other disease activity measures (P < 0.001) and met DAS28 remission less often than men. Rheumatoid factor was equally prevalent among genders. Men had nodules more often than women. Women had erosions more often than men, but the statistical significance was marginal. Similar proportions of females and males were taking different therapies.
In this large multinational cohort, RA disease activity measures appear to be worse in women than in men. However, most of the gender differences in RA disease activity may originate from the measures of disease activity rather than from RA disease activity itself.
PMCID: PMC2688237  PMID: 19144159
13.  Serum Osteoprotegerin is Increased and Independently Associated with Coronary-Artery Atherosclerosis in Patients with Rheumatoid Arthritis 
Atherosclerosis  2007;195(2):e135-e141.
Osteoprotegerin (OPG), a soluble decoy receptor for receptor activator of nuclear factor B ligand, is implicated in the pathogenesis of atherosclerosis. Patients with rheumatoid arthritis (RA) have inflammation and increased atherosclerosis. We examined the hypothesis that OPG concentrations are increased in patients with RA and are associated with coronary-artery atherosclerosis. Serum OPG concentrations were measured by ELISA and coronary-artery calcification by electron beam computer tomography in 157 patients with RA and 87 control subjects. OPG concentrations were higher in patients with long-standing RA (n=67) [median (interquartile range)]: [1895 (1337–2847) pg/mL, and early RA (n=90): [1340 (1021–1652) pg/mL, than controls 1068 (692–1434) pg/ml; (P<0.001)]. In patients with RA, OPG concentrations were associated with erythrocyte sedimentation rate (p<0.001), homocysteine (p=0.001), disease duration (p=0.02), coronary calcium score (p=0.03), and cumulative dose of corticosteroids (p=0.04) after adjustment for age and sex. In patients with long-standing RA, OPG was associated with coronary artery calcification independently of cardiovascular risk factors and disease activity [OR for every increase in 500 pg/mL of OPG = 2.22 (1.43–3.34), p<0.001]. In conclusion, OPG concentrations are increased in patients with RA and are associated with inflammation. In patients with long-standing disease, OPG is independently associated with coronary-artery calcification.
PMCID: PMC2174431  PMID: 17570371
rheumatoid arthritis; osteoprotegerin; atherosclerosis; coronary calcification; cardiovascular disease
14.  Treatment of rheumatoid arthritis: a global perspective on the use of antirheumatic drugs 
Modern Rheumatology  2008;18(3):228-239.
Modern therapy for rheumatoid arthritis (RA) is based on knowledge of the severity of the natural history of the disease. RA patients are approached with early and aggressive treatment strategies, methotrexate as an anchor drug, biological targeted therapies in those with inadequate response to methotrexate, and “tight control,” aiming for remission and low disease activity according to quantitative monitoring. This chapter presents a rationale for current treatment strategies for RA with antirheumatic drugs, a review of published reports concerning treatments in clinical cohorts outside of clinical trials, and current treatments at 61 sites in 21 countries in the QUEST-RA database.
PMCID: PMC2668379  PMID: 18437286
Rheumatoid arthritis; DMARDs; Methotrexate
15.  Cardiovascular disease in patients with rheumatoid arthritis: results from the QUEST-RA study 
We analyzed the prevalence of cardiovascular (CV) disease in patients with rheumatoid arthritis (RA) and its association with traditional CV risk factors, clinical features of RA, and the use of disease-modifying antirheumatic drugs (DMARDs) in a multinational cross-sectional cohort of nonselected consecutive outpatients with RA (The Questionnaires in Standard Monitoring of Patients with Rheumatoid Arthritis Program, or QUEST-RA) who were receiving regular clinical care.
The study involved a clinical assessment by a rheumatologist and a self-report questionnaire by patients. The clinical assessment included a review of clinical features of RA and exposure to DMARDs over the course of RA. Comorbidities were recorded; CV morbidity included myocardial infarction, angina, coronary disease, coronary bypass surgery, and stroke. Traditional risk factors recorded were hypertension, hyperlipidemia, diabetes mellitus, smoking, physical inactivity, and body mass index. Unadjusted and adjusted hazard ratios (HRs) (95% confidence interval [CI]) for CV morbidity were calculated using Cox proportional hazard regression models.
Between January 2005 and October 2006, the QUEST-RA project included 4,363 patients from 48 sites in 15 countries; 78% were female, more than 90% were Caucasian, and the mean age was 57 years. The prevalence for lifetime CV events in the entire sample was 3.2% for myocardial infarction, 1.9% for stroke, and 9.3% for any CV event. The prevalence for CV risk factors was 32% for hypertension, 14% for hyperlipidemia, 8% for diabetes, 43% for ever-smoking, 73% for physical inactivity, and 18% for obesity. Traditional risk factors except obesity and physical inactivity were significantly associated with CV morbidity. There was an association between any CV event and age and male gender and between extra-articular disease and myocardial infarction. Prolonged exposure to methotrexate (HR 0.85; 95% CI 0.81 to 0.89), leflunomide (HR 0.59; 95% CI 0.43 to 0.79), sulfasalazine (HR 0.92; 95% CI 0.87 to 0.98), glucocorticoids (HR 0.95; 95% CI 0.92 to 0.98), and biologic agents (HR 0.42; 95% CI 0.21 to 0.81; P < 0.05) was associated with a reduction of the risk of CV morbidity; analyses were adjusted for traditional risk factors and countries.
In conclusion, prolonged use of treatments such as methotrexate, sulfasalazine, leflunomide, glucocorticoids, and tumor necrosis factor-alpha blockers appears to be associated with a reduced risk of CV disease. In addition to traditional risk factors, extra-articular disease was associated with the occurrence of myocardial infarction in patients with RA.
PMCID: PMC2453774  PMID: 18325087
16.  Utility of the Framingham risk score to predict the presence of coronary atherosclerosis in patients with rheumatoid arthritis 
The prevalence of ischemic heart disease and atherosclerosis is increased in patients with rheumatoid arthritis (RA). In the general population, but not in patients with systemic lupus erythematosus, the Framingham risk score identifies patients at increased cardiovascular risk and helps determine the need for preventive interventions. We examined the hypothesis that the Framingham score is increased and associated with coronary-artery atherosclerosis in patients with RA. The Framingham score and the 10-year cardiovascular risk were compared among 155 patients with RA (89 with early disease, 66 with long-standing disease) and 85 control subjects. The presence of coronary-artery calcification was determined by electron-beam computed tomography. The Framingham score was compared in patients with RA and control subjects, and the association between the risk score and coronary-artery calcification was examined in patients. Patients with long-standing RA had a higher Framingham score (14 [11 to 18]) (median [interquartile range]) compared to patients with early RA (11 [8 to 14]) or control subjects (12 [7 to 14], P < 0.001). This remained significant after adjustment for age and gender (P = 0.015). Seventy-six patients with RA had coronary calcification; their Framingham risk score was higher (14 [12 to 17]) than that of 79 patients without calcification (10 [5 to 14]) (P < 0.001). Furthermore, a higher Framingham score was associated with a higher calcium score (odds ratio [OR] = 1.20, 95% confidence interval [CI] 1.12 to 1.29, P < 0.001), and the association remained significant after adjustment for age and gender (OR = 1.15, 95% CI 1.02 to 1.29, P = 0.03). In conclusion, a higher Framingham risk score is independently associated with the presence of coronary calcification in patients with RA.
PMCID: PMC1794532  PMID: 17169159
Quantitative studies were made of the organ distribution of murine leukemia virus in AKR mice of various ages. Infectious virus first appeared shortly before or after birth and was continuously present in all mice thereafter. Highest infectivity titers were found in uterus and bone, with spleen slightly lower. Virus titers in normal thymus were relatively low, but increased significantly with the development of thymic lymphoma. The level of viremia decreased after the 1st month of life, but increased sharply in lymphomatous mice.
PMCID: PMC2180520  PMID: 4334098
The Journal of Experimental Medicine  1971;133(6):1219-1233.
Previous studies have indicated that all naturally occurring murine leukemia viruses propagate significantly more efficiently on embryo cells of either NIH Swiss or BALB/c mice. Studies of the plaquing efficiency of representative viruses on embryo cells of various inbred and hybrid mice indicate that the pattern of sensitivity of the cells is genetically determined. All of 23 strains tested were found to resemble either NIH Swiss (N-type) or BALB/c (B-type) with respect to plaquing efficiency of these viruses. Virus growth on embryo cells derived from (N-type x B-type)F1 hybrids indicated dominance of resistance to both types of viruses. Backcross hybrid studies indicated that a single locus is the primary determinant of the host-range patterns observed. This locus has no effect on growth of certain laboratory-passaged leukemia viruses which propagate equally well on embryo cells of all mouse strains, F1, and backcross hybrids. Though other genetic and nongenetic factors influence viral growth or expression in vitro and in vivo, the genetic locus described appears of major significance in the biology of murine leukemia.
PMCID: PMC2138932  PMID: 4325132
The Journal of Experimental Medicine  1971;133(6):1234-1241.
The N-B locus affecting tissue culture infectivity with naturally occurring murine leukemia viruses appears to be identical to the Fv-1 locus described for sensitivity to Friend leukemia virus. Results of tissue culture studies were parallel to results of studies in vivo and indicate that the F-S virus is N-tropic and the F-B virus is NB-tropic. Inbred and partially congenic mouse strains sensitive at Fv-1 show N-type sensitivity; strains resistant at Fv-1 show B-type sensitivity. The Fv-2 locus does not appear to exert significant effect in tissue culture. Knowledge of N-B type has been useful in predicting Fv-1 sensitivity.
PMCID: PMC2138931  PMID: 4325133
20.  Subcellular Localization of Salmonella enteritidis Endotoxin in Liver and Spleen of Mice and Rats 
Infection and Immunity  1970;1(5):440-445.
Salmonella enteritidis14C-endotoxin was recovered predominantly from the nuclear and mitochondrial subcellular fractions of livers and spleens of mice and rats, 3.5 hr and 3 days after intravenous administration. Of the recovered radioactivity, 10 to 20% was present in the liver mitochondrial fraction as high-molecular-weight, biologically active material, suggesting the presence of intact endotoxin. Autoradiographic studies demonstrated nuclear and cytoplasmic labeling in the liver and at least nuclear label in spleen cells. The resistance of rats, as compared to mice, to the induction of amyloidosis does not appear to be based on a difference in subcellular localization of endotoxin within the reticuloendothelial system.
PMCID: PMC415921  PMID: 16557755
Three of 16 rabbits injected (intravenously) daily with crystalline bovine serum albumin (BSA) for periods in excess of 10 wk developed chronic glomerulonephritis. In vivo, animals with chronic proteinuria formed variable quantities of soluble complex after injection of antigen while animals without proteinuria exhibited rapid removal of the injected BSA. In vitro studies demonstrated that a major part of the antibodies produced by rabbits with chronic nephritis lacked precipitating properties. Interpretations of these observations were presented in the discussion. It is suggested that, in addition to quantity, quality of antibody plays an important role in the development of chronic serum sickness. Complexes formed with nonprecipitating antibody, which are less rapidly removed from circulation, would have a greater opportunity to deposit in glomeruli and induce inflammation.
PMCID: PMC2138470  PMID: 4171055

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