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1.  Patient’s global assessment of disease activity and patient’s assessment of general health for rheumatoid arthritis activity assessment: are they equivalent? 
Annals of the rheumatic diseases  2012;71(12):1942-1949.
To assess (A) determinants of patient’s global assessment of disease activity (PTGL) and patient’s assessment of general health (GH) scores of rheumatoid arthritis (RA) patients; (B) whether they are equivalent as individual variables; and (C) whether they may be used interchangeably in calculating common RA activity assessment composite indices.
Data of 7023 patients from 30 countries in the Quantitative Standard Monitoring of Patients with RA (QUEST-RA) was analysed. PTGL and GH determinants were assessed by mixed-effects analyses of covariance models. PTGL and GH equivalence was determined by Bland-Altman 95% limits of agreement (BALOA) and Lin’s coefficient of concordance (LCC). Concordance between PTGL and GH based Disease Activity Score 28 (DAS28), Clinical Disease Activity Index (CDAI) and Routine Assessment of Patient Index Data 3 (RAPID3) indices were calculated using LCC, and the level of agreement in classifying RA activity in four states (remission, low, moderate, high) using κ statistics.
Significant differences in relative and absolute contribution of RA and non-RA related variables in PTGL and GH ratings were noted. LCC of 0.64 and BALOA of −4.41 to 4.54 showed that PTGL and GH are not equivalent. There was excellent concordance (LCC 0.95–0.99) for PTGL and GH based DAS28, CDAI and RAPID3 indices, and >80% absolute agreement (κ statistics 0.75–0.84) in RA activity state classification for all three indices.
PTGL and GH ratings differ in their determinants. Although they are individually not equivalent, they may be used interchangeably for calculating composite indices for RA activity assessment.
PMCID: PMC3731741  PMID: 22532638
2.  Determinants of Discordance in Patients’ and Physicians’ Rating of Rheumatoid Arthritis Disease Activity 
Arthritis care & research  2012;64(2):206-214.
To assess the determinants of patients’ (PTGL) and physicians’ (MDGL) global assessment of rheumatoid arthritis (RA) activity and factors associated with discordance among them.
A total of 7,028 patients in the Quantitative Standard Monitoring of Patients with RA study had PTGL and MDGL assessed at the same clinic visit on a 0–10-cm visual analog scale (VAS). Three patient groups were defined: concordant rating group (PTGL and MDGL within ±2 cm), higher patient rating group (PTGL exceeding MDGL by >2 cm), and lower patient rating group (PTGL less than MDGL by >2 cm). Multivariable regression analysis was used to identify determinants of PTGL and MDGL and their discordance.
The mean ± SD VAS scores for PTGL and MDGL were 4.01 ± 2.70 and 2.91 ± 2.37, respectively. Pain was overwhelmingly the single most important determinant of PTGL, followed by fatigue. In contrast, MDGL was most influenced by swollen joint count (SJC), followed by erythrocyte sedimentation rate (ESR) and tender joint count (TJC). A total of 4,454 (63.4%), 2,106 (30%), and 468 (6.6%) patients were in the concordant, higher, and lower patient rating groups, respectively. Odds of higher patient rating increased with higher pain, fatigue, psychological distress, age, and morning stiffness, and decreased with higher SJC, TJC, and ESR. Lower patient rating odds increased with higher SJC, TJC, and ESR, and decreased with lower fatigue levels.
Nearly 36% of patients had discordance in RA activity assessment from their physicians. Sensitivity to the “disease experience” of patients, particularly pain and fatigue, is warranted for effective care of RA.
PMCID: PMC3703925  PMID: 22052672
3.  Declining needs for total joint replacements for rheumatoid arthritis 
This millennium brings new views to rheumatology. Total joint replacement surgery is needed less often as active treatment strategies combined with availability of new medications has led to more effective rheumatoid arthritis control. This was beautifully shown in a recent issue of Arthritis Research & Therapy by a Swedish study that uses data from national registers and compares incidence rates for total hip and knee arthroplasties before and after the establishment of biologic agents use for rheumatoid arthritis
PMCID: PMC3308092  PMID: 22040689
4.  American College of Rheumatology/European League against Rheumatism Preliminary Definition of Remission in Rheumatoid Arthritis for Clinical Trials 
Arthritis and rheumatism  2011;63(3):573-586.
With remission in rheumatoid arthritis (RA) an increasingly attainable goal, there is no widely used definition of remission that is stringent but achievable and could be applied uniformly as an outcome in clinical trials.
A committee consisting of members of the American College of Rheumatology, the European League Against Rheumatism and the Outcome Measures in Rheumatology Initiative (OMERACT) met to guide the process and review prespecified analyses from clinical trials of patients with RA. The committee requested a stringent definition (little, if any, active disease) and decided to use core set measures to define remission including at least joint counts and an acute phase reactant. Members were surveyed to select the level of each core set measure consistent with remission. Candidate definitions of remission were tested including those that constituted a number of individual measures in remission (Boolean approach) as well as definitions using disease activity indexes. To select a definition of remission, trial data were analyzed to examine the added contribution of patient reported outcomes and the ability of candidate measures to predict later good x-ray and functional outcomes.
Survey results for the definition of remission pointed to indexes at published thresholds and to a count of core set measures with each measure scored as 1 or less (e.g. tender and swollen joint counts, CRP and global assessments on 0-10 scale). Analyses suggested the need to include a patient reported measure. Examination of 2 year follow-up data suggested that many candidate definitions performed comparably in terms of predicting later good x-ray and functional outcomes, although DAS28 based measures of remission did not predict good radiographic outcomes as well as did the other candidate definitions. Given these and other considerations, we propose that a patient be defined as in remission based on one of two definitions : 1: When their scores on the following measures are all <1: tender joint count, swollen joint count, CRP (in mg/dL) and patient global assessment (0-10 scale), OR 2: when their score on the SDAI is < 3.3.
We propose two new definitions of remission both of which can be uniformly applied and widely used in RA clinical trials. We recommend that one of these be selected in each trial as an outcome and that the results on both be reported in each trial.
PMCID: PMC3115717  PMID: 21294106
5.  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
6.  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
7.  Remission makes its way to rheumatology 
Remission was a rare event, even in the most advanced rheumatology clinics, until recent times. However, in the early 1990s, it was chosen as the treatment goal and the primary outcome measure for the Finnish Rheumatoid Arthritis Combination Therapy (FIN-RACo) trial, which can be considered the beginning of remission's way to rheumatology. In addition to remission in patients with rheumatoid arthritis, remission in patients with psoriatic arthritis is now being studied, although remission criteria for psoriatic arthritis have yet to be defined. Better treatment results with more active treatment strategies and availability of biologic agents motivate rheumatologists to monitor their patients as part of usual rheumatology care.
PMCID: PMC2945015  PMID: 20642867
8.  Gender, body mass index and rheumatoid arthritis disease activity: results from the QUEST-RA study 
To investigate whether body mass index (BMI), as a proxy for body fat, influences rheumatoid arthritis (RA) disease activity in a gender-specific manner.
Consecutive patients with RA were enrolled from 25 countries into the QUEST-RA program between 2005 and 2008. Clinical and demographic data were collected by treating rheumatologists and by patient self-report. Distributions of Disease Activity Scores (DAS28), BMI, age, and disease duration were assessed for each country and for the entire dataset; mean values between genders were compared using Student’s t-tests. An association between BMI and DAS28 was investigated using linear regression, adjusting for age, disease duration and country.
A total of 5,161 RA patients (4,082 women and 1,079 men) were included in the analyses. Overall, women were younger, had longer disease duration, and higher DAS28 scores than men, but BMI was similar between genders. The mean DAS28 scores increased with increasing BMI from normal to overweight and obese, among women, whereas the opposite trend was observed among men. Regression results showed BMI (continuous or categorical) to be associated with DAS28. Compared to the normal BMI range, being obese was associated with a larger difference in mean DAS28 (0.23, 95% CI: 0.11, 0.34) than being overweight (0.12, 95% CI: 0.03, 0.21); being underweight was not associated with disease activity. These associations were more pronounced among women, and were not explained by any single component of the DAS28.
BMI appears to be associated with RA disease activity in women, but not in men.
PMCID: PMC3012645  PMID: 20810033
Rheumatoid arthritis; gender; BMI; disease activity
9.  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
10.  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
11.  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
12.  EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs 
Annals of the Rheumatic Diseases  2010;69(6):964-975.
Treatment of rheumatoid arthritis (RA) may differ among rheumatologists and currently, clear and consensual international recommendations on RA treatment are not available. In this paper recommendations for the treatment of RA with synthetic and biological disease-modifying antirheumatic drugs (DMARDs) and glucocorticoids (GCs) that also account for strategic algorithms and deal with economic aspects, are described. The recommendations are based on evidence from five systematic literature reviews (SLRs) performed for synthetic DMARDs, biological DMARDs, GCs, treatment strategies and economic issues. The SLR-derived evidence was discussed and summarised as an expert opinion in the course of a Delphi-like process. Levels of evidence, strength of recommendations and levels of agreement were derived. Fifteen recommendations were developed covering an area from general aspects such as remission/low disease activity as treatment aim via the preference for methotrexate monotherapy with or without GCs vis-à-vis combination of synthetic DMARDs to the use of biological agents mainly in patients for whom synthetic DMARDs and tumour necrosis factor inhibitors had failed. Cost effectiveness of the treatments was additionally examined. These recommendations are intended to inform rheumatologists, patients and other stakeholders about a European consensus on the management of RA with DMARDs and GCs as well as strategies to reach optimal outcomes of RA, based on evidence and expert opinion.
PMCID: PMC2935329  PMID: 20444750
13.  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
14.  Stable occurrence of knee and hip total joint replacement in Central Finland between 1986 and 2003: an indication of improved long‐term outcomes of rheumatoid arthritis 
Annals of the Rheumatic Diseases  2006;66(3):341-344.
Total joint replacement (TJR) surgery is an important severe long‐term outcome of rheumatoid arthritis, but relatively little is known about changes of its incidence in patients with rheumatoid arthritis over the past two decades.
A population‐based, retrospective, incidence case review was conducted to analyse the frequency of primary TJR surgery of the knee and hip in all patients, and specifically in patients with rheumatoid arthritis in Central Finland between 1986 and 2003. Patients with TJR surgery of the knee and hip were identified in hospital databases over the 18‐year period. Age‐standardised incidence rate ratios for the primary TJR of the knee and hip were calculated, stratified to sex and diagnosis, with 1986 as the reference value.
In patients without rheumatoid arthritis the age‐adjusted incidence rate ratios (with 95% CI) for TJR of the knee increased 9.8‐fold from 1986 to 2003 in women and men, and for TJR of the hip 1.8‐fold in women and 2‐fold in men. By contrast, no meaningful change was seen over this period, in age‐adjusted incidence rate ratios for TJR of the knee or hip in patients with rheumatoid arthritis, ranging from 0.7 to 1.2 in 2003 compared with 1986.
The prevalence of TJR surgery has increased 2–10‐fold in patients without rheumatoid arthritis patients, associated with an ageing population, but has not increased in patients with rheumatoid arthritis between 1986 and 2003. These data are consistent with emerging evidence that long‐term outcomes of rheumatoid arthritis have improved substantially, even before the availability of biological agents.
PMCID: PMC1855996  PMID: 17068067
16.  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
17.  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
18.  Prediction of Disease Severity in Patients with Early Rheumatoid Arthritis by Gene Expression Profiling 
In order to test the ability of peripheral blood gene expression profiles to predict future disease severity in patients with early rheumatoid arthritis (RA), a group of 17 patients (1 ± 0.2 years disease duration) was evaluated at baseline for gene expression profiles. Disease status was evaluated after a mean of 5 years using an index combining pain, global and recoded MHAQ scores. Unsupervised and supervised algorithms identified “predictor genes” whose combined expression levels correlated with follow-up disease severity scores. Unsupervised clustering algorithms separated patients into two branches. The only significant difference between these two groups was the disease severity score; demographic variables and medication usage were not different. Supervised T-Test analysis identified 19 “predictor genes” of future disease severity. Results were validated in an independent cohort of subjects of established RA with using Support Vector Machines and K-Nearest-Neighbor Classification. Our study demonstrates that peripheral blood gene expression profiles may be a useful tool to predict future disease severity in patients with early and established RA.
PMCID: PMC2950309  PMID: 20948566
19.  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
20.  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
21.  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
22.  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
23.  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
24.  Smoking–gender interaction and risk for rheumatoid arthritis 
Arthritis Research & Therapy  2003;5(3):R158-R162.
The present case–control study was conducted to investigate the relationship between smoking and rheumatoid arthritis, and to investigate formally the interaction between sex, smoking, and risk for developing rheumatoid arthritis. The study was performed in the Central District of Finland. Cases were patients with rheumatoid arthritis and the control group was a random sample of the general population. Logistic regression models were used to evaluate the effect of smoking on risk for rheumatoid arthritis, after adjusting for the effects of age, education, body mass index, and indices of general health and pain. Overall, 1095 patients with rheumatoid arthritis and 1530 control individuals were included. Patients were older, less well educated, more disabled, and had poorer levels of general health as compared with control individuals (all P < 0.01). Preliminary analyses revealed the presence of substantial statistical interaction between smoking and sex (P < 0.001). In separate multivariable analyses, past history of smoking was associated with increased risk for rheumatoid arthritis overall in men (odds ratio 2.0, 95% confidence interval 1.2–3.2) but not in women. Among men, this effect was seen only for rheumatoid factor-positive rheumatoid arthritis. There were significant interactions between smoking and age among women but not among men. We conclude that sex is a biologic effect modifier in the association between smoking and rheumatoid arthritis. The role of menopause in the etiology of rheumatoid arthritis merits further research.
PMCID: PMC165046  PMID: 12723987
etiology; interaction; risk; rheumatoid arthritis; sex; smoking

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