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1.  Relationships Among Changes in C-Reactive Protein and Cardiovascular Disease Risk Factors With Lifestyle Interventions 
Background and Aims
Inflammation plays a role in the development of cardiovascular disease (CVD). Elevated levels of the inflammatory marker, C-reactive protein (CRP), are cross-sectionally associated with traditional CVD risk factors and are being considered as an emerging CVD risk factor. In a secondary data analysis, we examined changes in CRP and several CVD risk factors after one-year diet and exercise interventions to assess whether CRP changed concurrently with other risk factors, or was independent of the traditional risk factors.
Methods and Results
Data were analyzed from 143 men and 133 women with dyslipidemia who were randomized to one-year interventions of low-fat diet only, physical activity only, diet plus physical activity, or control. Plasma high-sensitivity CRP, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, triglycerides (TG), fasting and 2-hr blood glucose and insulin, blood pressure (BP), and waist circumference were obtained at baseline and follow-up. Multiple linear regression models were used to predict CRP change based on other risk factor changes, controlling for age, race, alcohol intake, and hormone replacement therapy. Treatment groups were combined for analysis. Baseline mean (SD) CRP levels were 1.3±1.3 (men) and 1.9±1.8 mg/L (women), with mean changes of -0.11±1.3 and -0.17±1.5 mg/L, respectively. Plasma CRP change was negatively associated with TG change in men (p=0.003) and women (p=0.05), positively associated with change in systolic BP in men (p=0.01), but was not associated with changes in the other risk factors.
Conclusion
Dietary and/or physical activity induced changes in CRP may be largely independent of traditional CVD risk factors in persons with dyslipidemia.
doi:10.1016/j.numecd.2012.05.003
PMCID: PMC3502629  PMID: 22831953
C-reactive protein; cardiovascular disease risk; physical activity; low-fat diet; interventions
2.  Disease-modifying antirheumatic drugs are associated with a reduced risk for cardiovascular disease in patients with rheumatoid arthritis: a case control study 
Rheumatoid arthritis (RA) is characterized by inflammation and an increased risk for cardiovascular disease (CVD). This study investigates possible associations between CVD and the use of conventional disease-modifying antirheumatic drugs (DMARDs) in RA. Using a case control design, 613 RA patients (5,649 patient-years) were studied, 72 with CVD and 541 without CVD. Data on RA, CVD and drug treatment were evaluated from time of RA diagnosis up to the first cardiovascular event or the end of the follow-up period. The dataset was categorized according to DMARD use: sulfasalazine (SSZ), hydroxychloroquine (HCQ) or methotrexate (MTX). Odds ratios (ORs) for CVD, corrected for age, gender, smoking and RA duration, were calculated per DMARD group. Patients who never used SSZ, HCQ or MTX were used as a reference group. MTX treatment was associated with a significant CVD risk reduction, with ORs (95% CI): 'MTX only', 0.16 (0.04 to 0.66); 'MTX and SSZ ever', 0.20 (0.08 to 0.51); and 'MTX, SSZ and HCQ ever', 0.20 (0.08 to 0.54). The risk reductions remained significant after additional correction for the presence of rheumatoid factor and erosions. After correction for hypertension, diabetes and hypercholesterolemia, 'MTX or SSZ ever' and 'MTX, SSZ and HCQ ever' showed significant CVD risk reduction. Rheumatoid factor positivity and erosions both increased CVD risk, with ORs of 2.04 (1.02 to 4.07) and 2.36 (0.92 to 6.08), respectively. MTX and, to a lesser extent, SSZ were associated with significantly lower CVD risk compared to RA patients who never used SSZ, HCQ or MTX. We hypothesize that DMARD use, in particular MTX use, results in powerful suppression of inflammation, thereby reducing the development of atherosclerosis and subsequently clinically overt CVD.
doi:10.1186/ar2045
PMCID: PMC1779436  PMID: 16984661
3.  Chronic Ingestion of Flavan-3-ols and Isoflavones Improves Insulin Sensitivity and Lipoprotein Status and Attenuates Estimated 10-Year CVD Risk in Medicated Postmenopausal Women With Type 2 Diabetes 
Diabetes Care  2012;35(2):226-232.
OBJECTIVE
To assess the effect of dietary flavonoids on cardiovascular disease (CVD) risk in postmenopausal women with type 2 diabetes on established statin and hypoglycemic therapy.
RESEARCH DESIGN AND METHODS
Despite being medicated, patients with type 2 diabetes have elevated CVD risk, particularly postmenopausal women. Although dietary flavonoids have been shown to reduce CVD risk factors in healthy participants, no long-term trials have examined the additional benefits of flavonoids to CVD risk in medicated postmenopausal women with type 2 diabetes. We conducted a parallel-design, placebo-controlled trial with type 2 diabetic patients randomized to consume 27 g/day (split dose) flavonoid-enriched chocolate (containing 850 mg flavan-3-ols [90 mg epicatechin] and 100 mg isoflavones [aglycone equivalents)]/day) or matched placebo for 1 year.
RESULTS
Ninety-three patients completed the trial, and adherence was high (flavonoid 91.3%; placebo 91.6%). Compared with the placebo group, the combined flavonoid intervention resulted in a significant reduction in estimated peripheral insulin resistance (homeostasis model assessment of insulin resistance [HOMA-IR] −0.3 ± 0.2; P = 0.004) and improvement in insulin sensitivity (quantitative insulin sensitivity index [QUICKI] 0.003 ± 0.00; P = 0.04) as a result of a significant decrease in insulin levels (−0.8 ± 0.5 mU/L; P = 0.02). Significant reductions in total cholesterol:HDL-cholesterol (HDL-C) ratio (−0.2 ± 0.1; P = 0.01) and LDL-cholesterol (LDL-C) (−0.1 ± 0.1 mmol/L; P = 0.04) were also observed. Estimated 10-year total coronary heart disease risk (derived from UK Prospective Diabetes Study algorithm) was attenuated after flavonoid intervention (flavonoid +0.1 ± 0.3 vs. placebo 1.1 ± 0.3; P = 0.02). No effect on blood pressure, HbA1c, or glucose was observed.
CONCLUSIONS
One-year intervention with flavan-3-ols and isoflavones improved biomarkers of CVD risk, highlighting the additional benefit of flavonoids to standard drug therapy in managing CVD risk in postmenopausal type 2 diabetic patients.
doi:10.2337/dc11-1443
PMCID: PMC3263874  PMID: 22250063
4.  Methotrexate therapy associates with reduced prevalence of the metabolic syndrome in rheumatoid arthritis patients over the age of 60- more than just an anti-inflammatory effect? A cross sectional study 
Arthritis Research & Therapy  2009;11(4):R110.
Introduction
The metabolic syndrome (MetS) may contribute to the excess cardiovascular burden observed in rheumatoid arthritis (RA). The prevalence and associations of the MetS in RA remain uncertain: systemic inflammation and anti-rheumatic therapy may contribute. Methotrexate (MTX) use has recently been linked to a reduced presence of MetS, via an assumed generic anti-inflammatory mechanism. We aimed to: assess the prevalence of the MetS in RA; identify factors that associate with its presence; and assess their interaction with the potential influence of MTX.
Methods
MetS prevalence was assessed cross-sectionally in 400 RA patients, using five MetS definitions (National Cholesterol Education Programme 2004 and 2001, International Diabetes Federation, World Health Organisation and European Group for Study of Insulin Resistance). Logistic regression was used to identify independent predictors of the MetS. Further analysis established the nature of the association between MTX and the MetS.
Results
MetS prevalence rates varied from 12.1% to 45.3% in RA according to the definition used. Older age and higher HAQ scores associated with the presence of the MetS. MTX use, but not other disease modifying anti-rheumatic drugs (DMARDs) or glucocorticoids, associated with significantly reduced chance of having the MetS in RA (OR = 0.517, CI 0.33–0.81, P = 0.004).
Conclusions
The prevalence of the MetS in RA varies according to the definition used. MTX therapy, unlike other DMARDs or glucocorticoids, independently associates with a reduced propensity to MetS, suggesting a drug-specific mechanism, and makes MTX a good first-line DMARD in RA patients at high risk of developing the MetS, particularly those aged over 60 years.
doi:10.1186/ar2765
PMCID: PMC2745792  PMID: 19607680
5.  Reduced Glomerular Filtration Rate and Its Association with Clinical Outcome in Older Patients at Risk of Vascular Events: Secondary Analysis 
PLoS Medicine  2009;6(1):e1000016.
Background
Reduced glomerular filtration rate (GFR) is associated with increased cardiovascular risk in young and middle aged individuals. Associations with cardiovascular disease and mortality in older people are less clearly established. We aimed to determine the predictive value of the GFR for mortality and morbidity using data from the 5,804 participants randomized in the Prospective Study of Pravastatin in the Elderly at Risk (PROSPER).
Methods and Findings
Glomerular filtration rate was estimated (eGFR) using the Modification of Diet in Renal Disease equation and was categorized in the ranges ([20–40], [40–50], [50–60]) ≥ 60 ml/min/1.73 m2. Baseline risk factors were analysed by category of eGFR, with and without adjustment for other risk factors. The associations between baseline eGFR and morbidity and mortality outcomes, accrued after an average of 3.2 y, were investigated using Cox proportional hazard models adjusting for traditional risk factors. We tested for evidence of an interaction between the benefit of statin treatment and baseline eGFR status. Age, low-density lipoprotein (LDL) and high-density lipoprotein (HDL) cholesterol, C-reactive protein (CRP), body mass index, fasting glucose, female sex, histories of hypertension and vascular disease were associated with eGFR (p = 0.001 or less) after adjustment for other risk factors. Low eGFR was independently associated with risk of all cause mortality, vascular mortality, and other noncancer mortality and with fatal and nonfatal coronary and heart failure events (hazard ratios adjusted for CRP and other risk factors (95% confidence intervals [CIs]) for eGFR < 40 ml/min/1.73m2 relative to eGFR ≥ 60 ml/min/1.73m2 respectively 2.04 (1.48–2.80), 2.37 (1.53–3.67), 3.52 (1.78–6.96), 1.64 (1.18–2.27), 3.31 (2.03–5.41). There were no nominally statistically significant interactions (p < 0.05) between randomized treatment allocation and eGFR for clinical outcomes, with the exception of the outcome of coronary heart disease death or nonfatal myocardial infarction (p = 0.021), with the interaction suggesting increased benefit of statin treatment in subjects with impaired GFRs.
Conclusions
We have established that, in an elderly population over the age of 70 y, impaired GFR is associated with female sex, with presence of vascular disease, and with levels of other risk factors that would be associated with increased risk of vascular disease. Further, impaired GFR is independently associated with significant levels of increased risk of all cause mortality and fatal vascular events and with composite fatal and nonfatal coronary and heart failure outcomes. Our analyses of the benefits of statin treatment in relation to baseline GFR suggest that there is no reason to exclude elderly patients with impaired renal function from treatment with a statin.
Using data from the PROSPER trial, Ian Ford and colleagues investigate whether reduced glomerular filtration rate is associated with cardiovascular and mortality risk among elderly people.
Editors' Summary
Background.
Cardiovascular disease (CVD)—disease that affects the heart and/or the blood vessels—is a common cause of death in developed countries. In the USA, for example, the single leading cause of death is coronary heart disease, a CVD in which narrowing of the heart's blood vessels slows or stops the blood supply to the heart and eventually causes a heart attack. Other types of CVD include stroke (in which narrowing of the blood vessels interrupts the brain's blood supply) and heart failure (a condition in which the heart can no longer pump enough blood to the rest of the body). Many factors increase the risk of developing CVD, including high blood pressure (hypertension), high blood cholesterol, having diabetes, smoking, and being overweight. Tools such as the “Framingham risk calculator” assess an individual's overall CVD risk by taking these and other risk factors into account. CVD risk can be minimized by taking drugs to reduce blood pressure or cholesterol levels (for example, pravastatin) and by making lifestyle changes.
Why Was This Study Done?
Another potential risk factor for CVD is impaired kidney (renal) function. In healthy people, the kidneys filter waste products and excess fluid out of the blood. A reduced “estimated glomerular filtration rate” (eGFR), which indicates impaired renal function, is associated with increased CVD in young and middle-aged people and increased all-cause and cardiovascular death in people who have vascular disease. But is reduced eGFR also associated with CVD and death in older people? If it is, it would be worth encouraging elderly people with reduced eGFR to avoid other CVD risk factors. In this study, the researchers determine the predictive value of eGFR for all-cause and vascular mortality (deaths caused by CVD) and for incident vascular events (a first heart attack, stroke, or heart failure) using data from the Prospective Study of Pravastatin in the Elderly at Risk (PROSPER). This clinical trial examined pravastatin's effects on CVD development among 70–82 year olds with pre-existing vascular disease or an increased risk of CVD because of smoking, hypertension, or diabetes.
What Did the Researchers Do and Find?
The trial participants were divided into four groups based on their eGFR at the start of the study. The researchers then investigated the association between baseline CVD risk factors and baseline eGFR and between baseline eGFR and vascular events and deaths that occurred during the 3-year study. Several established CVD risk factors were associated with a reduced eGFR after allowing for other risk factors. In addition, people with a low eGFR (between 20 and 40 units) were twice as likely to die from any cause as people with an eGFR above 60 units (the normal eGFR for a young person is 100 units; eGFR decreases with age) and more than three times as likely to have nonfatal coronary heart disease or heart failure. A low eGFR also increased the risk of vascular mortality, other noncancer deaths, and fatal coronary heart disease and heart failure. Finally, pravastatin treatment reduced coronary heart disease deaths and nonfatal heart attacks most effectively among participants with the greatest degree of eGFR impairment.
What Do These Findings Mean?
These findings suggest that, in elderly people, impaired renal function is associated with levels of established CVD risk factors that increase the risk of vascular disease. They also suggest that impaired kidney function increases the risk of all-cause mortality, fatal vascular events, and fatal and nonfatal coronary heat disease and heart failure. Because the study participants were carefully chosen for inclusion in PROSPER, these findings may not be generalizable to all elderly people with vascular disease or vascular disease risk factors. Nevertheless, increased efforts should probably be made to encourage elderly people with reduced eGFR and other vascular risk factors to make lifestyle changes to reduce their overall CVD risk. Finally, although the effect of statins in elderly patients with renal dysfunction needs to be examined further, these findings suggest that this group of patients should benefit at least as much from statins as elderly patients with healthy kidneys.
Additional Information.
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1000016.
The MedlinePlus Encyclopedia has pages on coronary heart disease, stroke, and heart failure (in English and Spanish)
MedlinePlus provides links to many other sources of information on heart disease, vascular disease, and stroke (in English and Spanish)
The US National Institute of Diabetes and Digestive and Kidney Diseases provides information on how the kidneys work and what can go wrong with them, including a list of links to further information about kidney disease
The American Heart Association provides information on all aspects of cardiovascular disease for patients, caregivers, and professionals (in several languages)
More information about PROSPER is available on the Web site of the Vascular Biochemistry Department of the University of Glasgow
doi:10.1371/journal.pmed.1000016
PMCID: PMC2628400  PMID: 19166266
6.  Personalized Prediction of Lifetime Benefits with Statin Therapy for Asymptomatic Individuals: A Modeling Study 
PLoS Medicine  2012;9(12):e1001361.
In a modeling study conducted by Myriam Hunink and colleagues, a population-based cohort from Rotterdam is used to predict the possible lifetime benefits of statin therapy, on a personalized basis.
Background
Physicians need to inform asymptomatic individuals about personalized outcomes of statin therapy for primary prevention of cardiovascular disease (CVD). However, current prediction models focus on short-term outcomes and ignore the competing risk of death due to other causes. We aimed to predict the potential lifetime benefits with statin therapy, taking into account competing risks.
Methods and Findings
A microsimulation model based on 5-y follow-up data from the Rotterdam Study, a population-based cohort of individuals aged 55 y and older living in the Ommoord district of Rotterdam, the Netherlands, was used to estimate lifetime outcomes with and without statin therapy. The model was validated in-sample using 10-y follow-up data. We used baseline variables and model output to construct (1) a web-based calculator for gains in total and CVD-free life expectancy and (2) color charts for comparing these gains to the Systematic Coronary Risk Evaluation (SCORE) charts. In 2,428 participants (mean age 67.7 y, 35.5% men), statin therapy increased total life expectancy by 0.3 y (SD 0.2) and CVD-free life expectancy by 0.7 y (SD 0.4). Age, sex, smoking, blood pressure, hypertension, lipids, diabetes, glucose, body mass index, waist-to-hip ratio, and creatinine were included in the calculator. Gains in total and CVD-free life expectancy increased with blood pressure, unfavorable lipid levels, and body mass index after multivariable adjustment. Gains decreased considerably with advancing age, while SCORE 10-y CVD mortality risk increased with age. Twenty-five percent of participants with a low SCORE risk achieved equal or larger gains in CVD-free life expectancy than the median gain in participants with a high SCORE risk.
Conclusions
We developed tools to predict personalized increases in total and CVD-free life expectancy with statin therapy. The predicted gains we found are small. If the underlying model is validated in an independent cohort, the tools may be useful in discussing with patients their individual outcomes with statin therapy.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Cardiovascular disease (CVD) affects the heart and/or the blood vessels and is a major cause of illness and death worldwide. In the US, for example, coronary heart disease—a CVD in which narrowing of the heart's blood vessels by fatty deposits slows the blood supply to the heart and may eventually cause a heart attack—is the leading cause of death, and stroke—a CVD in which the brain's blood supply is interrupted—is the fourth leading cause of death. Established risk factors for CVD include smoking, high blood pressure, obesity, and high blood levels of a fat called low-density lipoprotein (“bad cholesterol”). Because many of these risk factors can be modified by lifestyle changes and by drugs, CVD can be prevented. Thus, physicians can assess a healthy individual's risk of developing CVD using a CVD prediction model (equations that take into account the CVD risk factors to which the individual is exposed) and can then recommend lifestyle changes and medications to reduce that individual's CVD risk.
Why Was This Study Done?
Current guidelines recommend that asymptomatic (healthy) individuals whose likely CVD risk is high should be encouraged to take statins—cholesterol-lowering drugs—as a preventative measure. Statins help to prevent CVD in healthy people with a high predicted risk of CVD, but, like all medicines, they have some unwanted side effects, so it is important that physicians can communicate both the benefits and drawbacks of statins to their patients in a way that allows them to make an informed decision about taking these drugs. Telling a patient that statins will reduce his or her short-term risk of CVD is not always helpful—patients really need to know the potential lifetime benefits of statin therapy. That is, they need to know how much longer they might live if they take statins. Here, the researchers use a mathematical model to predict the personalized lifetime benefits (increased total and CVD-free life expectancy) of statin therapy for individuals without a history of CVD.
What Did the Researchers Do and Find?
The researchers used the Rotterdam Ischemic Heart Disease & Stroke Computer Simulation (RISC) model, which simulates the life courses of individuals through six health states, from well through to CVD or non-CVD death, to estimate lifetime outcomes with and without statin therapy in a population of healthy elderly individuals. They then used these outcomes and information on baseline risk factors to develop a web-based calculator suitable for personalized prediction of the lifetime benefits of statins in routine clinical practice. The model estimated that statin therapy increases average life expectancy in the study population by 0.3 years and average CVD-free life expectancy by 0.7 years. The gains in total and CVD-free life expectancy associated with statin therapy increased with blood pressure, unfavorable cholesterol levels, and body mass index (an indicator of body fat) but decreased with age. Notably, the web-based calculator predicted that some individuals with a low ten-year CVD risk might achieve a similar or larger gain in CVD-free life expectancy with statin therapy than some individuals with a high ten-year risk. So, for example, both a 55-year-old non-smoking woman with a ten-year CVD mortality risk of 2% (a two in a hundred chance of dying of CVD within ten years) and a 65-year-old male smoker with a ten-year CVD mortality risk of 15% might both gain one year of CVD-free life expectancy with statin therapy.
What Do These Findings Mean?
These findings suggest that statin therapy can lead on average to small gains in total life expectancy and slightly larger gains in CVD-free life expectancy among healthy individuals, and show that life expectancy benefits can be predicted using an individual's risk factor profile. The accuracy and generalizability of these findings is limited by the assumptions included in the model (in particular, the model did not allow for the known side effects of statin therapy) and by the data fed into it—importantly, the risk prediction model needs to be validated using an independent dataset. If future research confirms the findings of this study, the researchers' web-based calculator could provide complementary information to the currently recommended ten-year CVD mortality risk assessment. Whether communication of personalized outcomes will ultimately result in better clinical outcomes remains to be seen, however, because patients may be less likely to choose statin therapy when provided with more information about its likely benefits.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001361.
The web-based calculator for personalized prediction of lifetime benefits with statin therapy is available (after agreement to software license)
The American Heart Association provides information about many types of cardiovascular disease for patients, carers, and professionals, including information about drug therapy for cholesterol and a heart attack risk calculator
The UK National Health Service Choices website provides information about cardiovascular disease and about statins
Information is available from the British Heart Foundation on heart disease and keeping the heart healthy; information is also available on statins, including personal stories about deciding to take statins
The US National Heart Lung and Blood Institute provides information on a wide range of cardiovascular diseases
The European Society of Cardiology's cardiovascular disease risk assessment model (SCORE) is available
MedlinePlus provides links to many other sources of information on heart diseases, vascular diseases, stroke, and statins (in English and Spanish)
doi:10.1371/journal.pmed.1001361
PMCID: PMC3531501  PMID: 23300388
7.  Mortality in Pharmacologically Treated Older Adults with Diabetes: The Cardiovascular Health Study, 1989–2001 
PLoS Medicine  2006;3(10):e400.
Background
Diabetes mellitus (DM) confers an increased risk of mortality in young and middle-aged individuals and in women. It is uncertain, however, whether excess DM mortality continues beyond age 75 years, is related to type of hypoglycemic therapy, and whether women continue to be disproportionately affected by DM into older age.
Methods and Findings
From the Cardiovascular Health Study, a prospective study of 5,888 adults, we examined 5,372 participants aged 65 y or above without DM (91.2%), 322 with DM treated with oral hypoglycemic agents (OHGAs) (5.5%), and 194 with DM treated with insulin (3.3%). Participants were followed (1989–2001) for total, cardiovascular disease (CVD), coronary heart disease (CHD), and non-CVD/noncancer mortality. Compared with non-DM participants, those treated with OHGAs or insulin had adjusted hazard ratios (HRs) for total mortality of 1.33 (95% confidence interval [CI], 1.10 to 1.62) and 2.04 (95% CI, 1.62 to 2.57); CVD mortality, 1.99 (95% CI, 1.54 to 2.57) and 2.16 (95% CI, 1.54 to 3.03); CHD mortality, 2.47 (95% CI, 1.89 to 3.24) and 2.75 (95% CI, 1.95 to 3.87); and infectious and renal mortality, 1.35 (95% CI, 0.70 to 2.59) and 6.55 (95% CI, 4.18 to 10.26), respectively. The interaction of age (65–74 y versus ≥75 y) with DM was not significant. Women treated with OHGAs had a similar HR for total mortality to men, but a higher HR when treated with insulin.
Conclusions
DM mortality risk remains high among older adults in the current era of medical care. Mortality risk and type of mortality differ between OHGA and insulin treatment. Women treated with insulin therapy have an especially high mortality risk. Given the high absolute CVD mortality in older people, those with DM warrant aggressive CVD risk factor reduction.
The negative impact on mortality of diabetes persists into old age. Elderly people with diabetes might be twice as likely to die from CVD as people without diabetes. More aggressive treatment of CVD risk factors in older patients should be considered.
Editors' Summary
Background.
Diabetes is a growing global health problem. By 2030, 300 million people worldwide may have this chronic, incurable disorder, double the current number. People with diabetes have dangerously high amounts of sugar in their blood. Blood-sugar levels are normally controlled by insulin, a hormone made by the pancreas that tells cells to absorb sugar from the blood. This control fails in people with diabetes, either because they make no insulin (type 1 diabetes) or because their cells are insensitive to insulin (type 2 diabetes). Type 1 diabetes is controlled with insulin injections; type 2 diabetes is controlled with diet, exercise, and pills that reduce blood-sugar levels. Long-term complications of diabetes include kidney failure, blindness, and nerve damage. Individuals with diabetes also have an increased risk of developing cardiovascular disease (CVD)—heart problems, strokes, and poor circulation—because of damage to their blood vessels.
Why Was This Study Done?
Epidemiological studies (investigations of disease patterns, causes, and control in populations) have indicated that diabetes increases the risk of death (mortality) from CVD in young and middle-aged people, but it is not known whether this is also true for old people. It is also not known what effect long-term treatment for diabetes has on mortality or whether the risk of death from CVD is decreasing in diabetic people as it is in the general US population. This information would help physicians provide health care and lifestyle advice to people with diabetes. In this study, the researchers have investigated mortality patterns in elderly diabetic people by looking at data collected between 1989 and 2001 by the US Cardiovascular Health Study, an observational study of nearly 6,000 people aged over 65 years (in this type of study participants are observed without imposing any specific changes to their lifestyle, behavior, medical care, or treatments).
What Did the Researchers Do and Find?
Participants were screened at the start of the Cardiovascular Health Study for CVD and diabetes (defined as drug-treated disease), for established CVD risk factors such as high blood pressure and smoking, for recently recognized CVD risk factors (for example, subclinical CVD), and for psychosocial factors associated with diabetes that might influence mortality, such as frailty and depression. At this time, about 5% of the participants were taking oral hypoglycemic agents for diabetes and about 3% were taking insulin. During the 11-year study, 40% of the participants died. After adjusting for CVD risk factors and psychosocial factors, the researchers calculated that people treated with oral hypoglycemic agents were 1.3 times as likely to die from all causes and people treated with insulin were twice as likely to die as people without diabetes. The risk of death from CVD was about twice as high in both groups of diabetic participants as in non-diabetic participants; the risk of death from coronary heart disease was increased about 2.5-fold. These adjusted relative risks are very similar to those found in previous studies. The researchers also report that participants treated with insulin were six times more likely to die from infectious diseases or renal failure than nondiabetic participants, and women treated with insulin had a particularly high mortality risk.
What Do These Findings Mean?
These findings indicate that the negative impact on mortality of diabetes persists into old age and that death from CVD is currently declining in both older diabetic people and nondiabetic people. In addition, they show that diabetic people treated with insulin are at a greater risk of dying relative to people without diabetes and those taking oral hypoglycemic agents. This might reflect the type of diabetes that these people had, but this was not investigated. How long participants had had diabetes was also not considered, nor how many people developed diabetes during the study. These and other limitations might mean that the reported excess mortality due to diabetes is an underestimate. Nevertheless, the estimate that elderly people with diabetes are twice as likely to die from CVD as people without diabetes is important. Many elderly people die anyway because of CVD, so this increased risk represents many more deaths than the similar increased risk in younger diabetic populations. Yet, elderly people often receive less-intensive management of CVD risk factors than younger people. The results of this study suggest that rectifying this situation could prolong the lives of many elderly people with diabetes.
Additional Information.
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0030400.
MedlinePlus encyclopedia has pages on diabetes, heart disease, stroke and poor circulation
The US National Institute of Diabetes and Digestive and Kidney Diseases provides patient information on diabetes
Information for patients on prevention, diagnosis, and management of diabetes is available from the America Diabetes Association
Patient information is available from the American Heart Association on all aspects of heart disease, including its association with diabetes
Wikipedia pages on diabetes and cardiovascular disease (note that Wikipedia is a free online encyclopedia that anyone can edit)
Further information is available about the Cardiovascular Health Study
doi:10.1371/journal.pmed.0030400
PMCID: PMC1609124  PMID: 17048978
8.  Independent Associations of Fasting Insulin, Glucose, and Glycated Haemoglobin with Stroke and Coronary Heart Disease in Older Women 
PLoS Medicine  2007;4(8):e263.
Background
Evidence suggests that variations in fasting glucose and insulin amongst those without frank type 2 diabetes mellitus are important determinants of cardiovascular disease. However, the relative importance of variations in fasting insulin, glucose, and glycated haemoglobin as risk factors for cardiovascular disease in women without diabetes is unclear. Our aim was to determine the independent associations of fasting insulin, glucose, and glycated haemoglobin with coronary heart disease and stroke in older women.
Methods and Findings
We undertook a prospective cohort study of 3,246 British women aged 60–79 y, all of whom were free of baseline coronary heart disease, stroke, and diabetes, and all of whom had fasting glucose levels below 7 mmol/l. Fasting insulin and homeostasis model assessment for insulin sensitivity (HOMA-S) were linearly associated with a combined outcome of coronary heart disease or stroke (n = 219 events), but there was no association of fasting glucose or glycated haemoglobin with these outcomes. Results were similar for coronary heart disease and stroke as separate outcomes. The age, life-course socioeconomic position, smoking, and physical activity adjusted hazard ratio for a combined outcome of incident coronary heart disease or stroke per one standard deviation of fasting insulin was 1.14 (95% CI 1.02–1.33). Additional adjustment for other components of metabolic syndrome, low-density lipoprotein cholesterol, fasting glucose, and glycated haemoglobin had little effect on this result.
Conclusions
Our findings suggest that in women in the 60–79 y age range, insulin resistance, rather than insulin secretion or chronic hyperglycaemia, is a more important risk factor for coronary heart disease and stroke. Below currently used thresholds of fasting glucose for defining diabetes, neither fasting glucose nor glycated haemoglobin are associated with cardiovascular disease.
From a prospective study of women aged 60-79 years, Debbie Lawlor and colleagues conclude that insulin resistance is an important risk factor for coronary heart disease and stroke.
Editors' Summary
Background.
Narrowing of the vessels that take blood to the heart and brain is a common form of cardiovascular disease—i.e., a disorder of the heart and blood vessels. It is a major cause of illness and death. By starving the heart and brain of oxygen, this condition causes coronary heart disease (CHD; heart problems such as angina and heart attacks) and strokes. A major risk factor for CHD and strokes is diabetes, a common chronic disease characterized by high levels of sugar (glucose) in the blood. In people who don't have diabetes, the hormone insulin controls blood-sugar levels. Insulin, which is released by the pancreas after eating, “instructs” insulin-responsive muscle and fat cells to absorb the glucose (released from food) from the bloodstream. In the very early stages of type 2 diabetes (the commonest type of diabetes, also called “adult onset” or “noninsulin-dependent” diabetes”), muscle and fat cells become unresponsive to insulin, so blood-sugar levels increase. This is called “insulin resistance.” The pancreas responds by making more insulin. As a result, people with insulin resistance have high blood levels of both insulin (hyperinsulinemia) and glucose (hyperglycemia). Eventually, the insulin-producing cells in the pancreas start to malfunction, insulin secretion decreases, and type 2 diabetes is the result.
Why Was This Study Done?
It is not yet clear whether it is insulin resistance or reduced insulin secretion that is responsible for the association between diabetes and cardiovascular disease. Physicians would like to know this information to help them to prevent CHD and strokes in their patients. There is evidence that variations in fasting glucose levels (blood glucose measured more than 8 h after eating), which provide an indication of how well pancreatic cells are producing insulin, and in fasting insulin levels, which provide an indication of insulin resistance, determine cardiovascular disease risk among people without type 2 diabetes, but the relative importance of these risk factors is unclear. In this study, the researchers have investigated whether markers of insulin resistance (fasting hyperinsulinemia) and of altered insulin secretion (fasting hyperglycemia, and increased glycated hemoglobin, which indicates how much sugar has been in the blood over the past few months) are associated with CHD and strokes in elderly women without diabetes. Their aim is to gain new insights into how diabetes affects cardiovascular disease risk.
What Did the Researchers Do and Find?
The researchers measured glucose, insulin, and glycated hemoglobulin in fasting blood samples taken from about 3,000 women aged 60–79 y when they enrolled in the British Women's Heart and Health Study. None of the women had CHD at enrollment, none had had a stroke, none had diagnosed diabetes, and all had a fasting blood glucose below 7 mmol/l (a higher reading indicates diabetes). After monitoring the women for nearly 5 y for CHD and strokes, the researchers looked for statistical associations between the occurrence of cardiovascular disease and markers of insulin resistance and reduced insulin secretion. They found that fasting insulin levels, but not fasting glucose or glycated hemoglobin levels, were associated with CHD and stroke, even after allowing for other factors that affect cardiovascular disease risk such as smoking and physical activity. In other words, raised fasting insulin levels increased the women's risk of developing cardiovascular disease.
What Do These Findings Mean?
These results indicate that in elderly women without diabetes, fasting insulin (a marker of insulin resistance) is a better predictor of future cardiovascular disease risk than fasting glucose or glycated hemoglobin (markers of reduced insulin secretion). This suggests that insulin resistance might be the main mechanism linking type 2 diabetes to CHD and stroke in elderly women. (Elderly women are known to run a high risk of developing these conditions, but they have been relatively neglected in previous studies of the risk factors for cardiovascular disease.) However, because relatively few women developed CHD during the study and even fewer had a stroke, this conclusion needs confirming in larger studies, preferably ones that include more rigorous tests of insulin resistance and secretion and also include women from more ethnic backgrounds than this study did. If the association between fasting insulin levels and cardiovascular disease risk is confirmed, therapeutic interventions or lifestyle interventions (for example, increased physical activity or weight loss) that prevent or reverse insulin resistance might reduce cardiovascular disease risk better than interventions that prevent chronic hyperglycemia.
Additional Information.
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0040263.
MedlinePlus encyclopedia page on coronary heart disease, stroke, and diabetes (in English and Spanish)
Information for patients and caregivers from the US National Diabetes Information Clearinghouse on diabetes, including information on insulin resistance and on diabetes, heart disease, and stroke
Information on the British Women's Heart and Health Study
doi:10.1371/journal.pmed.0040263
PMCID: PMC1952205  PMID: 17760500
9.  Effect of Combination Therapy on Joint Destruction in Rheumatoid Arthritis: A Network Meta-Analysis of Randomized Controlled Trials 
PLoS ONE  2014;9(9):e106408.
Background
Despite significant cost differences, the comparative effect of combination treatments of disease modifying anti-rheumatic drugs (DMARDs) with and without biologic agents has rarely been examined. Thus we performed a network meta-analysis on the effect of combination therapies on progression of radiographic joint erosions in patients with rheumatoid arthritis (RA).
Methods and Findings
The following combination drug therapies compared versus single DMARD were investigated: Double DMARD: 2 DMARDs (methotrexate, sulfasalazine, leflunomide, injectable gold, cyclosporine, chloroquine, azathioprin, penicillamin) or 1 DMARD plus low dose glucocorticoid (LDGC); triple DMARD: 3 DMARDs or 2 DMARDs plus LDGC; biologic combination: 1 DMARD plus biologic agent (tumor necrosis factor α inhibitor (TNFi) or abatacept or tocilizumab or CD20 inhibitor (CD20i)). Randomized controlled trials were identified in a search of electronic archives of biomedical literature and included in a star-shaped network meta-analysis and reported according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement protocol. Effects are reported as standardized mean differences (SMD). The effects of data from 39 trials published in the period 1989–2012 were as follows: Double DMARD: −0.32 SMD (CI: −0.42, −0.22); triple DMARD: −0.46 SMD (CI: −0.60, −0.31); 1 DMARD plus TNFi: −0.30 SMD (CI: −0.36, −0.25); 1 DMARD plus abatacept: −0.20 SMD (CI: −0.33, −0.07); 1 DMARD plus tocilizumab: −0.34 SMD (CI: −0.48, −0.20); 1 DMARD plus CD20i: −0.32 SMD (CI: −0.40, −0.24). The indirect comparisons showed similar effects between combination treatments apart from triple DMARD being significantly better than abatacept plus methotrexate (−0.26 SMD (CI: −0.45, −0.07)) and TNFi plus methotrexate (−0.16 SMD (CI: −0.31, −0.01)).
Conclusion
Combination treatment of a biologic agent with 1 DMARD is not superior to 2–3 DMARDs including or excluding LDGC in preventing structural joint damage. Future randomized studies of biologic agents should be compared versus a combination of DMARDs.
doi:10.1371/journal.pone.0106408
PMCID: PMC4171366  PMID: 25244021
10.  Atherogenic lipid profile is a feature characteristic of patients with early rheumatoid arthritis: effect of early treatment – a prospective, controlled study 
We investigated lipid profiles and lipoprotein modification after immuno-intervention in patients with early rheumatoid arthritis (ERA). Fifty-eight patients with ERA who met the American College of Rheumatology (ACR) criteria were included in the study. These patients had disease durations of less than one year and had not had prior treatment for it. Smokers or patients suffering from diabetes mellitus, hypothyroidism, liver or kidney disease, Cushing's syndrome, obesity, familiar dyslipidemia and those receiving medications affecting lipid metabolism were excluded from the study. Sixty-three healthy volunteers (controls) were also included. Patients were treated with methotrexate and prednisone. Lipid profiles, disease activity for the 28 joint indices score (DAS-28) as well as ACR 50% response criteria were determined for all patients. The mean DAS-28 at disease onset was 5.8 ± 0.9. After a year of therapy, 53 (91.3%) patients achieved the ACR 20% response criteria, while 45 (77.6%) attained the ACR 50% criteria. In addition, a significant decrease in the DAS-28, C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR) were observed. ERA patients exhibited higher serum levels of total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C) and triglycerides, whereas their serum high-density lipoprotein cholesterol (HDL-C) levels were significantly lower compared to controls. As a consequence, the atherogenic ratio of TC/HDL-C as well as that of LDL-C/HDL-C was significantly higher in ERA patients compared to controls. After treatment, a significant reduction of the atherogenic ratio of TC/HDL-C as well as that of LDL-C/HDL-C was observed, a phenomenon primarily due to the increase of serum HDL-C levels. These changes were inversely correlated with laboratory changes, especially CRP and ESR. In conclusion, ERA patients are characterized by an atherogenic lipid profile, which improves after therapy. Thus, early immuno-intervention to control disease activity may reduce the risk of the atherosclerotic process and cardiovascular events in ERA patients.
doi:10.1186/ar1952
PMCID: PMC1526648  PMID: 16646989
11.  Infliximab therapy increases body fat mass in early rheumatoid arthritis independently of changes in disease activity and levels of leptin and adiponectin: a randomised study over 21 months 
Arthritis Research & Therapy  2010;12(5):R197.
Introduction
Rheumatoid arthritis (RA) is associated with changes in body composition and bone mineral density (BMD). The purpose of the present study was to evaluate whether anti-TNF treatment in early RA has an impact on body composition and BMD besides that which could be achieved by intensive disease-modifying anti-rheumatic drug (DMARD) combination therapy.
Methods
Forty patients with early RA who failed treatment with methotrexate up to 20 mg/week for 3 months were randomised to addition of sulphasalazine and hydroxychloroquine (treatment A) or addition of infliximab (treatment B). At 3, 12 and 24 months, body composition and BMD were assessed by total-body dual-energy X-ray absorptiometry. At the same time points, leptin, adiponectin, apolipoproteins, insulin-like growth factor-1 (IGF-1) and markers of bone remodelling were analysed. Compliance to treatment was considered in the analyses. Data were analysed with a mixed, linear model.
Results
Patients treated with anti-TNF had a significant increase in fat mass at 2 years, 3.8 (1.6 to 5.9) kg, in contrast to patients in treatment A, 0.4 (-1.5 to 2.2) kg (P = 0.040), despite similar reduction in disease activity. Both treatment strategies prevented loss of muscle mass and bone. Leptin concentrations increased significantly in both groups at 2 years and adiponectin increased significantly at 2 years in treatment A and at 1 year in treatment B. There were no significant changes in apolipoproteins or IGF-1. The markers of bone resorption decreased at 12 months in both treatment groups with no significant difference between the treatment groups.
Conclusions
Infliximab therapy increased body fat mass, an effect that was not achieved with the combination of DMARDs, despite a similar reduction in disease activity, and thus seemed to be drug specific. The increase of fat mass was not associated with an exacerbated atherogenic lipid profile. Leptin and adiponectin concentrations increased in both treatment groups. The increase of adiponectin may partially explain the reduced frequency of cardiovascular diseases found when disease activity is reduced in RA.
Trial registration
ISRCTN39045408.
doi:10.1186/ar3169
PMCID: PMC2991034  PMID: 20964833
12.  Methotrexate in rheumatoid arthritis is frequently effective, even if re-employed after a previous failure 
Effectiveness of therapy with individual disease-modifying antirheumatic drugs (DMARDs) in rheumatoid arthritis (RA) is limited, and the number of available DMARDs is finite. Therefore, at some stage during the lengthy course of RA, institution of traditional DMARDs that have previously been applied may have to be reconsidered. In the present study we investigated the effectiveness of re-employed methotrexate in patients with a history of previous methotrexate failure (original course). A total of 1,490 RA patients (80% female, 59% rheumatoid factor positive) were followed from their first presentation, yielding a total of 6,470 patient-years of observation. We identified patients in whom methotrexate was re-employed after at least one intermittent course of a different DMARD. We compared reasons for discontinuation, improvement in acute phase reactants, and cumulative retention rates of methotrexate therapy between the original course of methotrexate and its re-employment. Similar analyses were peformed for other DMARDs. Methotrexate was re-employed in 86 patients. Compared with the original courses, re-employment was associated with a reduced risk for treatment termination because of ineffectiveness (P = 0.02, by McNemar test), especially if the maximum methotrexate dose of the original course had been low (<12.5 mg/week; P = 0.02, by logistic regression). In a Cox regression model, re-employed MTX was associated with a significantly reduced hazard of treatment termination compared with the original course of methotrexate, adjusting for dose and year of employment (hazard ratio 0.64, 95% confidence interval 0.42–0.97; P = 0.04). These findings were not recapitulated in analyses of re-employment of other DMARDs. Re-employment of MTX despite prior inefficacy, but not re-employment of other DMARDs, is an effective therapeutic option, especially in those patients in whom the methotrexate dose of the original course was low.
doi:10.1186/ar1902
PMCID: PMC1526609  PMID: 16507172
13.  Association between dietary iron, iron stores, and serum lipid profile in reproductive age women 
Background:
Some studies have shown that increased rate of iron stores even in a normal range may increase cardiovascular diseases (CVDs) in some individuals. Lipid disorders are also the risk factors for CVDs. Therefore, the question is whether or not iron store is correlated with lipid profile, this study evaluates the association between dietary iron, iron stores and serum lipid profiles.
Materials and Methods:
This cross-sectional study was done on 82 healthy university students and university staff females in Isfahan University of Medical Sciences who were in reproductive age and announced their readiness to participate in the study. Serum ferritin concentration, components of lipid profile, blood glucose, and insulin were measured in all the subjects. Dietary intake was assessed by semi-quantitative food frequency questionnaire. Data analysis was done through SPSS software, version 18.
Results:
Pearson correlation test showed a positive and significant correlation between serum ferritin concentration levels with triglyceride (r = 0.278; P = 0.006), total cholesterol (r = 0.267; P = 0.008), and blood glucose (r = 0.275; P = 0.006); however, the correlation between serum ferritin, high-density lipoprotein-cholesterol, low-density lipoprotein-cholesterol, and insulin was not significant. After adjustment of confounding factors, only the significant correlation occurred for blood glucose (P = 0.016). Before and after adjustment of confounding factors, there was no significant correlation between hemoglobin and hematocrit with concentration of lipid profile components, glucose and insulin. Before and after adjustment of confounding factors, there was no significant correlation between total amount of iron, heme iron, and non-heme dietary iron with concentration of lipid profile components, glucose and insulin.
Conclusion:
According to the current study, serum ferritin is directly and significantly correlated with concentration of fasting blood glucose, which emphasized on the amount of iron store with blood glucose even in healthy people. The results of the present study indicate no significant correlation between iron store and dietary iron intake with lipid parameters and insulin. Conducting more extensive epidemiologic studies in men and other age groups is recommended.
doi:10.4103/2277-9531.127586
PMCID: PMC3977407  PMID: 24741655
Iron intake; iron store; lipid profile; reproductive age women
14.  Cardiovascular disease risk factor profiles in children with celiac disease on gluten-free diets 
AIM: To describe the cardiovascular disease (CVD) risk factors in a population of children with celiac disease (CD) on a gluten-free diet (GFD).
METHODS: This cross-sectional multicenter study was performed at Schneider Children’s Medical Center of Israel (Petach Tiqva, Israel), and San Paolo Hospital (Milan, Italy). We enrolled 114 CD children in serologic remission, who were on a GFD for at least one year. At enrollment, anthropometric measurements, blood lipids and glucose were assessed, and compared to values at diagnosis. The homeostasis model assessment-estimated insulin resistance was calculated as a measure of insulin resistance.
RESULTS: Three or more concomitant CVD risk factors [body mass index, waist circumference, low density lipoprotein (LDL) cholesterol, triglycerides, blood pressure and insulin resistance] were identified in 14% of CD subjects on a GFD. The most common CVD risk factors were high fasting triglycerides (34.8%), elevated blood pressure (29.4%), and high concentrations of calculated LDL cholesterol (24.1%). On a GFD, four children (3.5%) had insulin resistance. Fasting insulin and HOMA-IR were significantly higher in the Italian cohort compared to the Israeli cohort (P < 0.001). Children on a GFD had an increased prevalence of borderline LDL cholesterol (24%) when compared to values (10%) at diagnosis (P = 0.090). Trends towards increases in overweight (from 8.8% to 11.5%) and obesity (from 5.3% to 8.8%) were seen on a GFD.
CONCLUSION: This report of insulin resistance and CVD risk factors in celiac children highlights the importance of CVD screening, and the need for dietary counseling targeting CVD prevention.
doi:10.3748/wjg.v19.i34.5658
PMCID: PMC3769902  PMID: 24039358
Celiac disease; Cardiovascular disease risk factors; Gluten-free diet; Insulin resistance; Children; Hyperlipidemia; Cholesterol
15.  Masitinib in the treatment of active rheumatoid arthritis: results of a multicentre, open-label, dose-ranging, phase 2a study 
Introduction
Since current treatment options for patients suffering from active rheumatoid arthritis (RA) remain inadequate, especially for those unresponsive to disease-modifying antirheumatic drugs (DMARDs), new and improved medication is needed. This study evaluates the safety and efficacy of masitinib (AB1010), a potent and selective protein tyrosine kinase inhibitor of c-KIT, in the monotherapy treatment of DMARD-refractory RA.
Methods
This was a multicentre, uncontrolled, open-label, randomised, dose-ranging, phase 2a trial. Masitinib was administered orally to 43 patients who had inadequate response to DMARDs, at initial randomised dosing levels of 3 and 6 mg/kg per day over a 12-week period. Dose adjustment was permitted based upon tolerability and response criteria. Efficacy was assessed via American College of Rheumatology 20%/50%/70% improvement criteria (ACR20/50/70) responses, disease activity score using 28 joint counts (DAS28), index of improvement in RA (ACRn) and C-reactive protein (CRP) improvement, relative to baseline at week 12.
Results
Improvement was observed in all efficacy endpoints, including ACR20/50/70 scores of 54%, 26% and 8%, respectively, and a reduction in CRP level by greater than 50% for approximately half the population. This improvement was sustainable throughout an extension phase (> 84 weeks) and was also independent of initial DMARD resistance (anti-tumour necrosis factor-alpha and/or methotrexate). A relatively high patient withdrawal rate (37%) required the use of last observation carried forward (LOCF) data imputation. Incidence of adverse events was high (95%), although the majority were of mild or moderate severity with a considerable decline in frequency observed after 12 weeks of treatment. Two nonfatal serious adverse events were reported. Dose-response analyses tentatively indicate that an initial dosing level of 6.0 mg/kg per day administered orally in two daily intakes is the most appropriate, based upon potency and tolerability trends.
Conclusions
Treatment with masitinib improved DMARD-refractory active RA. Following an initial high incidence of mostly mild to moderate side effects during the first 12 weeks of treatment, masitinib appears to be generally well tolerated. This, together with evidence of a sustainable efficacy response, suggests that masitinib is suitable for long-term treatment regimens. Since this was the first study of masitinib in a nononcologic pathology, the relatively high patient withdrawal rate observed can be partly attributed to a highly cautious response to adverse events. There is sufficient compelling evidence to warrant further placebo-controlled investigation.
Trial registration
ClinicalTrials.gov NCT00831922.
doi:10.1186/ar2740
PMCID: PMC2714151  PMID: 19549290
16.  Trajectory of intensive treat-to-target disease modifying drug regimen in an observational study of an early rheumatoid arthritis cohort 
BMJ Open  2013;3(7):e003083.
Objectives
Studies of early rheumatoid arthritis (RA) cohorts have analysed treatment response and prognostic factors at fixed time points. However, in treat-to-target protocols, therapeutic decision-making is dynamic and responsive to disease activity over time. To determine when a minimal residual disease response target should be expected, our primary objective was to identify the time-dependent therapeutic response to combination disease modifying antirheumatic drugs (DMARDs) for 12 months. Our secondary objective determined factors affecting this response trajectory.
Design
Observational cohort.
Setting
Treat-to-target early RA clinic in Australian tertiary referral hospital.
Participants
We enrolled consecutive patients attending an early arthritis clinic with symptom duration less than 12 months, who were diagnosed with RA for the first time between 2004 and 2008. 101 met these eligibility criteria and data were available at baseline through 12 months.
Interventions
intensive DMARDs according to a treat-to-target protocol.
Primary and secondary outcome measures
We measured disease activity scores (DAS) at each visit, then analysed therapeutic response and associated factors in a time-dependent fashion over 12 months.
Results
The median DAS4vESR of 4.46 at baseline decreased 12 weeks later by 24%, while the proportion with DAS4v ≤ 2.6 increased (p<0.01). DAS4v continued to decrease over 52 weeks. DAS4v reduction of at least −0.45 at 4 weeks was predictive of DAS4v at 28 and 52 weeks. Female gender, current smoking, primary education and an interaction between baseline weight and C reactive protein (CRP) negatively impacted DAS4v reduction over 4 and 52 weeks. Time-varying effects of blood pressure, neutrophils, erythrocyte sedimentation rate and CRP also significantly influenced DAS4v over 52 weeks.
Conclusions
Time-dependent data suggest that the largest reduction of DAS4v to combination DMARDs occurs in the first month of therapy, and this predicts subsequent response. Variables known to impact long-term treatment response in RA also impacted early DAS4v response to combination DMARDs.
doi:10.1136/bmjopen-2013-003083
PMCID: PMC3731780  PMID: 23903812
RHEUMATOLOGY; EPIDEMIOLOGY; STATISTICS & RESEARCH METHODS
17.  Step‐up combination versus switching of non‐biological disease‐modifying antirheumatic drugs in rheumatoid arthritis: results from a retrospective observational study 
Annals of the Rheumatic Diseases  2007;66(8):1059-1065.
Background
In rheumatoid arthritis (RA), treatment with disease‐modifying antirheumatic drugs (DMARDs) frequently needs to be changed because of insufficient effectiveness.
Aim
To compare the clinical outcomes of two potential strategies for patients experiencing DMARD discontinuations related to ineffectiveness: switching to another DMARD or step‐up combination therapy of the present DMARD with a new one.
Methods
In a large observational database of 4585 DMARD courses in 1214 patients with RA, all patients who had experienced a change in treatment regimen were identified, and retention, effectiveness and safety of these subsequent treatment courses between the two strategies (switching vs step‐up combination). All analyses were stratified according to the type of the new DMARD into methotrexate (MTX), sulphasalazine (SSZ) or leflunomide (LEF); all other DMARDs were excluded.
Results
Kaplan–Meier analysis for MTX courses showed no significant difference in overall retention rates between the strategies of adding MTX and switching to MTX (p = 0.49 by log rank test). Likewise, switching or adding did not result in significantly different retention rates for SSZ and LEF (p = 0.61 and 0.74, respectively). This similarity between strategies remained after adjusting for several confounding variables. The frequencies of treatment terminations related to ineffectiveness or toxicity were likewise similar between the two strategies for the MTX, SSZ and LEF groups. This was also confirmed by the similarity of erythrocyte sedimentation rates that were reached at the end of the two therapeutic strategies for all three drugs, in adjusted analysis.
Conclusion
Given all limitations of observational studies, the present data indicate that in situations of ineffective DMARD treatments, step‐up combination therapy using traditional DMARDs, such as MTX, SSZ or LEF, bears no clear clinical advantage over switching to the new DMARD. Our results do not implicate any predication about step‐up design including biologicals, where the benefit of combination therapy has been suggested convincingly.
doi:10.1136/ard.2006.061820
PMCID: PMC1954688  PMID: 17307765
18.  Effect of Dietary Composition of Weight Loss Diets on High Sensitivity C-Reactive Protein: The Randomized POUNDS LOST Trial 
Obesity (Silver Spring, Md.)  2013;21(4):681-689.
Overweight and obesity are associated with increased high sensitivity C-reactive protein (hsCRP) levels. The purpose of this study was to determine if weight loss diets differing in fat, protein, or carbohydrate composition differentially reduce hsCRP. POUNDS (Preventing Overweight Using Novel Dietary Strategies) LOST was a two-year trial of overweight and obese adults randomly allocated to one of four weight loss diets with targeted percentages of energy derived from fat, protein, and carbohydrates (20,15,65%;20,25,55%;40,15,45%;40,25,35%, respectively). hsCRP was measured at baseline, 6, and 24 months among 710 participants, and adiposity as measured by dual X-ray absorptiometry (N=340) or abdominal computed tomography (N=126) was correlated with hsCRP change. At 6 months, hsCRP was reduced in all trial participants by −24.7% (IQR +7%,−50%), weight by −6.7% (IQR −3%,−11%), and waist circumference by −6.0% (IQR −3%,−10%) (all P<.002), with no significant differences according to dietary composition. The percent change in hsCRP at 6 and 24 months correlated modestly with change in weight, waist circumference, fasting insulin, fasting glucose, HOMA, and most lipid levels. Reductions in hsCRP persisted despite an approximate 50% regain of weight by 24 months. The percent change in hsCRP at 24 months significantly correlated with changes in total body fat (r=0.42), total abdominal adiposity (r=0.52), subcutaneous abdominal adiposity (r=0.52), visceral adiposity (r=0.47), and hepatic tissue density (r=−0.34) (all P<0.0006). In conclusion, weight loss decreased hsCRP by similar magnitude, irrespective of dietary composition. Clinicians concerned about inflammation and cardiovascular risk should recommend weight loss diets most likely to succeed for their patients.
doi:10.1002/oby.20072
PMCID: PMC3671388  PMID: 23712970
19.  Systematic review of disease-modifying antirheumatic drugs for juvenile idiopathic arthritis 
BMC Pediatrics  2012;12:29.
Background
Treatment of juvenile idiopathic arthritis (JIA) with disease-modifying antirheumatic drugs (DMARDs) may improve outcomes compared to conventional therapy (e.g., non-steroidal anti-inflammatory drugs, intra-articular corticosteroids). The purpose of this systematic review was to evaluate the comparative effectiveness and safety of DMARDs versus conventional therapy and versus other DMARDs.
Results
A systematic evidence review of 156 reports identified in MEDLINE®, EMBASE®, and by hand searches. There is some evidence that methotrexate is superior to conventional therapy. Among children who have responded to a biologic DMARD, randomized discontinuation trials suggest that continued treatment decreases the risk of having a flare. However, these studies evaluated DMARDs with different mechanisms of action (abatacept, adalimumab, anakinra, etanercept, intravenous immunoglobulin, tocilizumab) and used varying comparators and follow-up periods. Rates of serious adverse events are similar between DMARDs and placebo in published trials. This review identified 11 incident cases of cancer among several thousand children treated with one or more DMARD.
Conclusions
Few data are available to evaluate the comparative effectiveness of either specific DMARDs or general classes of DMARDs. However, based on the overall number, quality, and consistency of studies, there is moderate strength of evidence to support that DMARDs improve JIA-associated symptoms. Limited data suggest that short-term risk of cancer is low.
doi:10.1186/1471-2431-12-29
PMCID: PMC3340294  PMID: 22420649
Juvenile rheumatoid arthritis; Disease-modifying antirheumatic drugs; Comparative effectiveness research; Systematic review
20.  Enhancement of a modified Mediterranean-style, low glycemic load diet with specific phytochemicals improves cardiometabolic risk factors in subjects with metabolic syndrome and hypercholesterolemia in a randomized trial 
Background
As the worldwide dietary pattern becomes more westernized, the metabolic syndrome is reaching epidemic proportions. Lifestyle modifications including diet and exercise are recommended as first-line intervention for treating metabolic syndrome. Previously, we reported that a modified Mediterranean-style, low glycemic load diet with soy protein and phytosterols had a more favorable impact than the American Heart Association Step 1 diet on cardiovascular disease (CVD) risk factors. Subsequently, we screened for phytochemicals with a history of safe use that were capable of increasing insulin sensitivity through modulation of protein kinases, and identified hops rho iso-alpha acid and acacia proanthocyanidins. The objective of this study was to investigate whether enhancement of a modified Mediterranean-style, low glycemic load diet (MED) with specific phytochemicals (soy protein, phytosterols, rho iso-alpha acids and proanthocyanidins; PED) could improve cardiometabolic risk factors in subjects with metabolic syndrome and hypercholesterolemia.
Methods
Forty-nine subjects with metabolic syndrome and hypercholesterolemia, aged 25–80, entered a randomized, 2-arm, 12-week intervention trial; 23 randomized to the MED arm; 26 to the PED arm. Forty-four subjects completed at least 8 weeks [MED (n = 19); PED (n = 25)]. All subjects were instructed to follow the same aerobic exercise program. Three-day diet diaries and 7-day exercise diaries were assessed at each visit. Fasting blood samples were collected at baseline, 8 and 12 weeks for analysis.
Results
Both arms experienced equal weight loss (MED: -5.7 kg; PED: -5.9 kg). However, at 12 weeks, the PED arm experienced greater reductions (P < 0.05) in cholesterol, non-HDL cholesterol, triglycerides (TG), cholesterol/HDL and TG/HDL compared with the MED arm. Only the PED arm experienced increased HDL (P < 0.05) and decreased TG/HDL (P < 0.01), and continued reduction in apo B/apo A-I from 8 to 12 weeks. Furthermore, 43% of PED subjects vs. only 22% of MED subjects had net resolution of metabolic syndrome. The Framingham 10-year CVD risk score decreased by 5.6% in the PED arm (P < 0.01) and 2.9% in the MED arm (P < 0.05).
Conclusion
These results demonstrate that specific phytochemical supplementation increased the effectiveness of the modified Mediterranean-style low glycemic load dietary program on variables associated with metabolic syndrome and CVD.
doi:10.1186/1743-7075-5-29
PMCID: PMC2588603  PMID: 18983673
21.  Effect of a High Protein Weight Loss Diet on Weight, High-Sensitivity C-Reactive Protein, and Cardiovascular Risk among Overweight and Obese Women: A Parallel Clinical Trial 
Studies regarding the effects of high protein (HP) diets on cardiovascular (CVD) risk factors have reported contradictory results. We aimed to determine the effects of an HP diet on CVD risk factors and high-sensitivity C-reactive protein (hs-CRP) among overweight and obese women. In this randomized controlled trial, we recruited 60 overweight and obese women, aged 20–65, into an HP or energy-restricted control diet for three months (protein, carbohydrate, and fat: 25%, 45%, and 30% versus 15%, 55%, and 30%, resp.). Total protein was divided between animal and plant sources in a 1 : 1 ratio, and animal sources were distributed equally between meats and dairy products. Fasting blood samples, hs-CRP, lipid profile, systolic and diastolic blood pressure, and anthropometric measurements were assessed using standard guidelines. Percent change was significantly different between the two diet groups for weight (standard protein (SP): −3.90 ± 0.26 versus HP: −6.10 ± 0.34%; P < 0.0001, resp.) and waist circumference (SP: −3.03 ± 0.21 versus HP: −5.06 ± 0.28%; P < 0.0001, resp.). Percent change of fasting blood glucose (FBG) substantially decreased in the control group compared to the HP group (−9.13 ± 0.67 versus −4.93 ± 1.4%; P = 0.01, resp.). Total cholesterol, systolic blood pressure (SBP), and diastolic blood pressure (DBP) decreased both in the HP and in the control diet groups (P = 0.06, P = 0.07, and P = 0.09, resp.); however, the results were marginally significant. Serum levels of hs-CRP were reduced both in the control (−0.08 ± 0.11%, P = 0.06) and in the high protein groups (−0.04 ± 0.09%, P = 0.06). The energy-restricted HP diet resulted in more beneficial effects on weight loss and reduction of waist circumference. CVD risk factors may improve with HP diets among overweight and obese women. When using isoenergetic weight loss diets, total cholesterol, hs-CRP, and SBP were marginally significantly reduced, independent of dietary protein content. This trial is registered with ClinicalTrials.gov NCT01763528.
doi:10.1155/2013/971724
PMCID: PMC3748746  PMID: 23986778
22.  Effect of dietary patterns differing in carbohydrate and fat content on blood lipid and glucose profiles based on weight-loss success of breast-cancer survivors 
Introduction
Healthy body weight is an important factor for prevention of breast cancer recurrence. Yet, weight loss and weight gain are not currently included in clinical-practice guidelines for posttreatment of breast cancer. The work reported addresses one of the questions that must be considered in recommending weight loss to patients: does it matter what diet plan is used, a question of particular importance because breast cancer treatment can increase risk for cardiovascular disease.
Methods
Women who completed treatment for breast cancer were enrolled in a nonrandomized, controlled study investigating effects of weight loss achieved by using two dietary patterns at the extremes of macronutrient composition, although both diet arms were equivalent in protein: high fat, low carbohydrate versus low fat, high carbohydrate. A nonintervention group served as the control arm; women were assigned to intervention arms based on dietary preferences. During the 6-month weight-loss program, which was menu and recipe defined, participants had monthly clinical visits at which anthropometric data were collected and fasting blood was obtained for safety monitoring for plasma lipid profiles and fasting glucose. Results from 142 participants are reported.
Results
Adverse effects on fasting blood lipids or glucose were not observed in either dietary arm. A decrease in fasting glucose was observed with progressive weight loss and was greater in participants who lost more weight, but the effect was not statistically significant, even though it was observed across both diet groups (P = 0.21). Beneficial effects of weight loss on cholesterol (4.7%; P = 0.001), triglycerides (21.8%; P = 0.01), and low-density lipoprotein (LDL) cholesterol (5.8%; P = 0.06) were observed in both groups. For cholesterol (P = 0.07) and LDL cholesterol (P = 0.13), greater reduction trends were seen on the low-fat diet pattern; whereas, for triglycerides (P = 0.01) and high-density lipoprotein (HDL) cholesterol (P = 0.08), a decrease or increase, respectively, was greater on the low-carbohydrate diet pattern.
Conclusions
Because an individual's dietary preferences can affect dietary adherence and weight-loss success, the lack of evidence of a negative effect of dietary pattern on biomarkers associated with cardiovascular risk is an important consideration in the development of breast cancer practice guidelines for physicians who recommend that their patients lose weight. Whether dietary pattern affects biomarkers that predict long-term survival is a primary question in this ongoing clinical trial.
doi:10.1186/bcr3082
PMCID: PMC3496116  PMID: 22225711
23.  Combined anti-tumor necrosis factor-α therapy and DMARD therapy in rheumatoid arthritis patients reduces inflammatory gene expression in whole blood compared to DMARD therapy alone 
Periodic assessment of gene expression for diagnosis and monitoring in rheumatoid arthritis (RA) may provide a readily available and useful method to detect subclinical disease progression and follow responses to therapy with disease modifying anti-rheumatic agents (DMARDs) or anti-TNF-α therapy. We used quantitative real-time PCR to compare peripheral blood gene expression profiles in active (“unstable”) RA patients on DMARDs, stable RA patients on DMARDs, and stable RA patients treated with a combination of a disease-modifying anti-rheumatoid drug (DMARD) and an anti-TNF-α agent (infliximab or etanercept) to healthy human controls. The expression of 48 inflammatory genes were compared between healthy controls (N = 122), unstable DMARD patients (N = 18), stable DMARD patients (N = 26), and stable patients on combination therapy (N = 20). Expression of 13 genes was very low or undetectable in all study groups. Compared to healthy controls, patients with unstable RA on DMARDs exhibited increased expression of 25 genes, stable DMARD patients exhibited increased expression of 14 genes and decreased expression of five genes, and combined therapy patients exhibited increased expression of six genes and decreased expression of 10 genes. These findings demonstrate that active RA is associated with increased expression of circulating inflammatory markers whereas increases in inflammatory gene expression are diminished in patients with stable disease on either DMARD or anti-TNF-α therapy. Furthermore, combination DMARD and anti-TNF-α therapy is associated with greater reductions in circulating inflammatory gene expression compared to DMARD therapy alone. These results suggest that assessment of peripheral blood gene expression may prove useful to monitor disease progression and response to therapy.
doi:10.3389/fimmu.2012.00366
PMCID: PMC3525111  PMID: 23264777
gene expression; rheumatoid arthritis; anti-TNF-α; whole blood; biomarker
24.  Baseline factors predicting change from the initial DMARD treatment during the first 2 years of rheumatoid arthritis: experience in the ERAN inception cohort 
Background
Outcomes in early Rheumatoid Arthritis (RA) may be improved by rapidly establishing a stable and effective disease modifying anti-rheumatic drug (DMARD) treatment regimen. We aimed to investigate whether baseline factors and initial treatment strategies are associated with changes to the first DMARD treatment, due to either Lack of Efficacy (LoE) or Adverse Drug Reaction (ADR) within 2 years of presentation.
Methods
Reasons for changes from initial DMARD therapy within 2 years of baseline, and associated factors, were examined using logistic regression in data from the Early RA Network (ERAN) inception cohort.
Results
Data were available for 766 participants. 410 (54%) changed their initial DMARD regime within 2 years, including 230 (56%) due to Lack of Efficacy (LoE) and 139 (34%) due to Adverse Drug Reaction (ADR). The first DMARD was recorded as methotrexate monotherapy in 336 (44%), sulphasalazine monotherapy in 273 (36%), or combined methotrexate/sulphasalazine/hydroxychlorquine in 52 (7%).
Baseline predictors of changing DMARD (for all reasons) were HAQ-disability (aOR 1.44, 95% CI 1.12 – 1.86), poor mental health (aOR 1.44, 95% CI 1.16 – 1.78) and extra-articular disease (aOR 1.78, 95% CI 1.00 – 3.16). In this model, the triple combination therapy also predicted lower likelihood of DMARD change (aOR 0.30, 95% CI 0.12 – 0.79).
Subgroup analyses showed that MTX monotherapy was associated with lower risk of change due to ADR. Combination therapy conferred lower risk of change due to LoE. Poor mental health was associated with change due to ADR, and extra-articular disease, HAQ-disability at baseline, and younger age predicted LoE.
Conclusions
Our findings suggest that non-pharmacological interventions to improve disability and mental health, may reduce initial DMARD treatment failure.
doi:10.1186/1471-2474-14-153
PMCID: PMC3648486  PMID: 23634781
Rheumatoid arthritis; DMARD; Sulfasalazine; Methotrexate; Cohort
25.  Effects of Disease-Modifying Antirheumatic Drugs on Non-Vertebral Fracture Risk in Rheumatoid Arthritis: a Population-based Cohort Study 
Objective
Several prior investigations demonstrate an improvement in bone mineral density associated with use of TNF inhibitors (TNFi). We compared the risk of osteoporotic fractures among patients with rheumatoid arthritis (RA) initiating a disease-modifying antirheumatic drug (DMARD).
Methods
A population-based cohort study was conducted using health care utilization data (1996–2008) from a Canadian province and a US commercial insurance plan. Patients with at least two RA diagnoses were identified and follow-up began with the first prescription for a DMARD. Drug regimens were categorized into three mutually exclusive hierarchical groups: 1) TNFi with or without non-biologic DMARDs (nbDMARD), 2) methotrexate (MTX) without a TNFi, or 3) other nbDMARD without a TNFi or MTX. Main outcomes were hospitalizations for fractures of the hip, wrist, humerus, or pelvis based on diagnoses and procedure codes.
Results
The study cohort consisted of 16,412 RA patients with 25,988 new treatment episodes: 5,856 TNFi, 12,554 MTX, and 7,578 other nbDMARD. The incidence rate per 1,000 person-years for osteoporotic fracture were 5.11 (95% CI 3.50 – 7.45) for TNFi, 5.35 (95% CI 4.08–7.02) for MTX, and 6.38 (95% CI 3.78–10.77) for other nbDMARD. After multivariable adjustment for osteoporosis and fracture-related risk factors, the risk of non-vertebral osteoporotic fracture was not different in either TNFi (hazard ratio (HR) 1.07, 95% CI 0.57–1.98) or MTX (HR 1.18, 95% CI 0.60– 2.34) compared with nbDMARD.
Conclusion
Among subjects diagnosed with RA, the adjusted risk of non-vertebral fracture was similar across persons starting a TNFi, MTX, or other nbDMARD.
doi:10.1002/jbmr.1489
PMCID: PMC3725780  PMID: 22162140
rheumatoid arthritis; fracture; disease modifying antirheumatic drugs

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