Accelerated atherosclerosis in pre-menopausal female patients with rheumatoid arthritis

Increased mortality due to cardiovascular disease in rheumatoid arthritis (RA) patients was reported. Using B-mode ultrasonography we compared intima-media thickness (IMT) and plaque occurrence (indicators of asymptomatic atherosclerosis) in the carotid arteries in 70 pre-menopausal, female RA patients and 40 controls. Correlations with different risk factors were evaluated. The IMT values were higher in RA patients (0.59 mm vs. 0.47 mm, P < 0.0001) and they had more plaques (P = 0.023). In RA patients higher levels of sensitive CRP (P < 0.0001), ICAM (P < 0.0001), VCAM (P < 0.0001), IL-2 (P < 0.001), IL-6 (P = 0.009) and TNF-alfa (P < 0.01) were found. A correlation between IMT and triglycerides (P = 0.018) and a negative correlation between IMT and HDL cholesterol (P = 0.037) were found. With multiple regression analysis the association between IMT and sensitive CRP (P = 0.027) and presence of plaques and apolipoprotein B (P = 0.028) was established. The results indicate that even pre-menopausal, female RA patients had accelerated atherosclerosis. Chronic systemic inflammation may play an important role in atherogenesis.     

Atherosclerosis and inflammation: insights from rheumatoid arthritis

Cardiovascular disease is a major health care problem and the most common cause of death among individuals from developed nations. Our understanding of atherosclerosis has evolved from a passive process resulting in narrowing of the lumen and consequent myocardial ischemia to a dynamic process that involves inflammation. The study of atherosclerosis in patients with chronic inflammation, such as rheumatoid arthritis (RA), will provide insights into the relationship between inflammation and atherosclerosis. We review the relationship between atherosclerosis and inflammation within the context of RA, providing evidence that patients with RA have increased cardiovascular morbidity and mortality and accelerated coronary and extra-coronary atherosclerosis. In addition, traditional and novel cardiovascular risk factors are discussed. Finally, actions that a rheumatologist can take to better control this cardiovascular morbidity are suggested. These can be summarized as follows: (1) careful assessment and treatment of cardiovascular risk, (2) better control of inflammation, and (3) individual risk–benefit evaluation of need for cyclo-oxygenase-2 inhibitors, nonsteroidal anti-inflammatory drugs, and high doses of corticosteroids. Presented as Medicine Grand Rounds at the University of Alberta. This review was supported by grants (HL04012 and HL67964) from the National Institutes of Health.     

Lp(a) lipoprotein and lipids in patients with rheumatoid arthritis: serum levels and relationship to inflammation

Objectives Changes in lipid profiles, Lp(a) lipoprotein, and acute phase reactants are associated with early atherosclerosis in rheumatoid arthritis (RA). The associations of Lp(a) levels with atherosclerotic disorders, diabetes, RA, and renal diseases suggest that Lp(a) might be involved in autoimmune reactions.Methods Eighty-seven women with RA diagnosed according to American Rheumatism Association criteria (mean age 45.4±9.4 years) were recruited and 50 healthy women (mean age 44±10.7 years) included as a control group. Serum Lp(a), total cholesterol (TC), triglyceride (TG), LDL cholesterol (LDL-C), HDL cholesterol (HDL-C), and C-reactive protein levels were analyzed.Results In the RA and C groups, serum Lp(a) levels were 39.2±20.6 mg/dl and 14.8±9.7 mg/dl, respectively (P<0.001). The TC levels were 188.4±41.8 mg/dl and 185.3±19.3 mg/dl (P>0.05), TG levels were 124.5±50.1 mg/dl and 94.6±24.9 mg/dl (P<0.01), HDL-C levels were 40.0±7.4 mg/dl and 52.8±4.8 mg/dl (P<0.01), and LDL-C levels were 123.4±24.6 mg/dl and 113.3±21.1 mg/dl (P>0.05). While serum CRP levels showed a positive correlation with Lp(a), they correlated negatively with HDL-C levels (r=0.83 and P<0.0001, r=–0.49 and P<0.0001, respectively). It was meaningful that Lp(a) correlated negatively with serum HDL-C level (r=–0.36, P<0.001).Conclusions It is suggested that higher serum Lp(a), lower HDL-C, higher TG level, and a high ratio of TC/HDL-C might show high risk of atherosclerosis. Inflammation in RA may cause changes in HDL-C and Lp(a) metabolisms.     

男性类风湿关节炎患者的血清性激素水平测定及其临床意义

采用放射免疫法检测34例男性类风湿关节炎（RA）患者（RA组）的血清雌二醇（E2）,睾酮（T）,硫酸脱氢表雄酮（DHEAS）水平,并与30例健康男性（对照组）作对照。结果发现患者血清T,DHEAS水平明显低于正常对照组（P＜0．05,P＜0．001）,而E2水平虽低于对照组,但无显著差异（P＞0．05）,提示雄激素减低在男性RA的发病中起一定的作用。     

炎症及免疫指标对类风湿关节炎患者血脂的影响分析

目的 探讨类风湿关节炎(RA)患者血脂情况以及炎症和免疫状态对血脂的影响.方法 选取2008年至2009年在我院住院的225例RA患者,检测入院第1天的血脂、血沉(ESR)、C反应蛋白(CRP)、类风湿因子(RF)、抗环瓜氨酸肽抗体(抗CCP)、抗角蛋白抗体(AKA)、抗核周因子抗体(APF)、补体(C),分析上述指标对血脂及致动脉粥样硬化指数(AIP)的影响.结果 (1)225例患者中,12.9％的患者总胆固醇(TC)升高,43.6％的患者高密度脂蛋白胆固醇(HDL-C)降低,10.2％的患者低密度脂蛋白胆固醇(LDL-C)升高,14.2％的患者TG升高.(2) TC升高组中C3高于TC正常组(P＜0.05),HDL-C降低组的ESR及CRP高于HDL-C正常组(P＜0.05),LDL-C升高组CRP、C3及C4高于LDL-C正常组(P＜0.05).(3)多因素逐步回归分析显示:C3与TC水平正相关(R2=0.067,P＜0.05),ESR、CRP与HDL-C水平负相关(R2=0.202,P＜0.05),CRP、抗CCP抗体与LDLC正相关(R2=0.129,P＜0.05),ESR、C4与AIP正相关(R2=0.046,P＜0.05).结论 类风湿关节炎患者的系统性炎症及异常免疫反应影响其血脂水平及血脂的致动脉粥样硬化作用.     

Serum osteoprotegerin concentration is associated with carotid atherosclerotic plaque in patients with rheumatoid arthritis

Objective

Osteoprotegerin (OPG), a regulator of bone resorption, is involved in the pathogenesis of rheumatoid arthritis (RA) and atherosclerosis. OPG is elevated in patients with coronary artery disease, and high OPG levels are associated with cardiac disease severity and mortality in the general population. The purpose of this study was to investigate the relationship of serum OPG levels, traditional coronary risk factors, and RA-related factors to carotid atherosclerosis in RA patients.

Methods

Ninety-one RA patients were studied (85 % women, age 60 ± 10 years). Serum OPG levels were measured by an enzyme-linked immunosorbent assay. The prevalence of carotid plaque was assessed by ultrasonographic imaging in all patients. The relationship between various clinical characteristics, OPG, and carotid plaque was examined.

Results

Serum OPG levels were significantly higher in patients with carotid plaque than in those without plaque (median level 1,397 vs. 887 pg/mL, respectively; P = 0.006). There were no significant differences between RA patients with and without carotid plaque with respect to sex, duration of RA, blood pressure, body mass index, smoking, low-density lipoprotein cholesterol, Disease Activity Score-28, van der Heijde-modified Sharp score, and prednisolone dose. After adjusting for age, sex, and C-reactive protein, elevated levels of OPG were still associated with a higher prevalence of carotid plaque in patients with RA (P = 0.038).

Conclusion

RA patients suffer from accelerated atherosclerosis and also have increased levels of OPG. The serum OPG level is independently associated with carotid plaque.     

类风湿关节炎动脉粥样硬化的研究进展

类风湿关节炎是一种慢性自身免疫性疾病,主要损害外周关节滑膜,类风湿关节炎的致残率较高.近年来,心血管疾病作为其主要的死亡原因之一,引起人们越来越多的关注.绝大部分患者在心血管方面的改变以动脉粥样硬化为主,本文就与类风湿关节炎有关的动脉粥样硬化发病机制的研究进展作一综述.     

Cardiovascular disease in patients with rheumatoid arthritis

The risk of cardiovascular disease (CVD) in patients with rheumatoid arthritis (RA) is 1.5–2-fold higher than age- and sex-matched individuals from the general population. This excess risk is attributed to the systemic chronic inflammation which is a hallmark of RA. Challenges to optimizing CV risk management in RA include the need for improved methods to predict CV risk, and defining the target risk factor(s) to reduce CV risk. Lessons learned from RA studies can also inform CV risk prevention in the general population, where inflammation also has an important role in the pathogenesis of atherosclerosis.     

Treatment of rheumatoid arthritis: a global perspective on the use of antirheumatic drugs

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.     

sRANKL and OPG in serum and synovial fluid of patients with rheumatoid arthritis in comparison to non-destructive chronic arthritis

The aim of this study was to investigate sRANKL and OPG levels in serum and synovial fluid (SF) and to evaluate their relations in patients with RA in comparison to those with non-erosive arthritis (NEA). The study included 45 unselected RA patients with knee joint effusions and 27 patients with knee joint effusions because of NEA. Serum and SF samples were investigated isochronously. OPG and sRANKL were measured by ELISA assays. In RA, sRANKL levels were higher in serum than in SF (P = 0.007). In contrast, the NEA revealed higher sRANKL in SF compared to the serum (P = 0.001). Though in RA the average levels of sRANKL_ser were 5.6 times and of sRANKL_syn 1.5 times higher than in NEA, the differences were not significant. The free (unbound) OPG in SF was not significantly different in RA compared to NEA. Also in serum, the measured free OPG was only slightly higher in RA. There were no significant differences between RA and NEA concerning ESR and CRP. Significant correlations could be found between sRANKL_syn and CRP (r = 0.453; P = 0.005) as well as ESR (r = 0.362; P = 0.033) in RA. Nearly a positive correlation was evident also between sRANKL_syn and CRP in NEA (r = 0.520; P = 0.08). RA and NEA differ in particular concerning their power and intensity to destruct the juxtaarticular bone. This is the most remarkable finding of this study, that in RA a high part of sRANKL seems to be OPG bound and cleared by the blood stream, but the sRANKL neutralizing capacity of produced OPG in opposite to NEA is not sufficient to prevent osteoclast activation and bone destruction in the RA joint.     

Influence of serum folic acid levels on plasma homocysteine concentrations in patients with rheumatoid arthritis

The purpose of this study was to investigate whether negative effects of methotrexate (mtx) on blood homocysteine (hmc) levels can be prevented with the replacement of folic acid. 42 female patients with rheumatoid arthritis (RA) were studied. Patients were separated into two groups according to their treatment status with mtx (group I: 27 patients taking mtx and folic acid; group II: 15 patients not using mtx). The level of hmc was found to be 6.3±2.4 µmol/l in group I and 7.87±3.2 µmol/l in group II (p>0.05). Folic acid levels of group I and II were found to be 21.3±15.9 ng/ml and 8.41±2.86 ng/ml respectively (p<0.001). There was a statistically-significant correlation between age and hmc levels (r=0.386, p=0.012). Negative statistically-significant correlations were observed between folic acid and hmc levels. The effects of mtx on hmc can be prevented with the replacement of folic acid.This revised version was published in February 2005 with corrections to the authors affiliations and the abstract.     

Hemorheological parameters are related to subclinical atherosclerosis in systemic lupus erythematosus and rheumatoid arthritis patients

Objectives

Rheological characteristics of blood are strongly linked to atherothrombosis in the general population, but its contribution to atherosclerosis in systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA) is currently unclear. This work examines the relationship between blood rheology, traditional cardiovascular (CV) risk factors, inflammation and subclinical atherosclerosis in SLE and RA.

Methods

Whole blood viscosity (WBV), plasma viscosity (PV), erythrocyte deformability (ED), aggregation (EA) and erythrocyte NO production were measured in 197 patients (96 SLE and 101 RA) and compared to 97 controls, all females without previous CV events. Clinical information was obtained and fasting lipids and acute phase reactants were measured. The relationship between hemorheological parameters, CV risk factors and inflammation was assessed in patients and the impact of these variables on carotid intima-media thickness (cIMT) was evaluated in univariate followed by multivariate regression analyses.

Results

WBV and ED are significantly lower in patients, while EA is elevated as compared with controls. Hemorheological disturbances correlate with CV risk factors and markers of inflammation and are more profound in patients with metabolic syndrome. Multivariable analysis showed that menopause (OR 34.72, 95%CI 4.44–271.77), obesity (OR 4.09, 95%CI 1.00–16.68) and WBV (OR 3.98; 95%CI 1.23–12.83) are positively associated whereas current corticosteroid dose (OR 0.87; 95%CI 0.78–0.98), and erythrocyte NO production (OR 0.16; 95%CI 0.05–0.52) are negatively associated with cIMT.

Conclusion

Disturbed hemorheological parameters in SLE and RA women are related to the presence of CV risk factors and inflammation. WBV and erythrocyte NO are independently associated with the early stages of atherosclerosis.     

Increased prevalence of subclinical atherosclerosis in rheumatoid arthritis patients of Indian descent

BACKGROUND:

Studies have shown that rheumatoid arthritis (RA) patients are two to five times more likely to develop premature cardiovascular disease, thus shortening their life expectancy by five to 10 years. This risk has risen to approximately 12.6% in the urban population and 7.4% in the rural population of India. The Framingham risk score (FRS) identifies patients at increased cardiovascular risk and helps determine the need for preventive interventions. An investigation of the patients’ coronary arteries and coronary artery calcification (CAC) – a measure of atherosclerotic plaque – has been found to be a strong predictor of cardiovascular disease.

OBJECTIVE:

To identify important biological markers for easy and non-invasive identification of cardiovascular disease in RA patients, and to investigate whether there is a relationship between the FRS and coronary artery atherosclerosis in RA patients.

METHODS:

The present study included 43 established RA patients and 50 healthy individuals (controls). Traditional and nontraditional risk factors were studied and compared with the control group. Insulin resistance was assessed using the homeostasis model of assessment of insulin resistance (HOMA-IR) and the homeostasis model of assessment of beta cell function. The FRS and the 10-year cardiovascular risk were compared between RA patients and controls. The presence of CAC was determined using electron-beam computed tomography, and the association between the FRS and CAC was examined.

RESULTS:

Significant differences in body mass index, waist circumference, rheumatoid factors (immunoglobulin [Ig]G, IgM and IgA) and inflammatory markers – C-reactive protein and erythrocyte sedimentation rate – were noted. There was significant correlation between HOMA-IR and body mass index, hypertension and C-reactive protein, but no correlation was seen with the homeostasis model of assessment of beta cell function. Significant differences were observed in the nontraditional biomarkers in RA patients, thus supporting their importance. Calcium deposition was observed in only seven RA patients.

CONCLUSIONS:

RA patients with increased C-reactive protein levels and erythrocyte sedimentation rates showed an increase in serum insulin levels and significant differences in HOMA-IR, thus indicating insulin resistance, which could lead to underlying progression of artherosclerosis. Significant differences were observed in the nontraditional risk factors, which could be chosen as biomarkers for endothelial dysfunction. There was a significant correlation between calcium score and the FRS in seven patients, suggestive of an underlying risk of atherosclerosis.     

The importance of the disease process and disease‐modifying antirheumatic drug treatment in the development of septic arthritis in patients with rheumatoid arthritis

Objective

To evaluate the effect of disease‐modifying antirheumatic drugs (DMARDs) on the likelihood of patients with rheumatoid arthritis (RA) developing septic arthritis (SA).

Methods

The United Kingdom General Practice Research Database (GPRD) was used to identify adults with RA, and age‐, sex‐, and practice‐matched control subjects. Subjects were studied between 1987 and 2002. The risk of developing SA (excluding infected joint replacements) for individuals with RA was calculated and the effect of DMARD use determined.

Results

A total of 136,977 subjects (34,250 patients with RA, 102,747 controls) were identified. SA was identified in 345 subjects, of which 321 (236 in patients with RA, 85 in controls) cases occurred during the study period. The incidence rate of SA was 12.9 times higher in subjects with RA than in those without (95% confidence interval [95% CI] 10.1–16.5, P < 0.001). The incident rate ratios (IRRs) for developing SA while receiving DMARDs compared with receiving no DMARDs were different for different medications. Penicillamine (adjusted IRR 2.51, 95% CI 1.29–4.89, P = 0.004), sulfasalazine (adjusted IRR 1.74, 95% CI 1.04–2.91, P = 0.03), and prednisolone (adjusted IRR 2.94, 95% CI 1.93–4.46, P < 0.001) were associated with an increased incidence of SA when compared with not receiving any DMARD. The use of other DMARDs including methotrexate showed no such effect.

Conclusion

Individuals with RA have an increased risk of developing SA. This increased risk can be attributed to both the disease process and the use of DMARDs.     

Effects of rheumatoid factor isotypes on disease activity and severity in patients with rheumatoid arthritis: a comparative study

The value of rheumatoid factor (RF) isotypes for assessing rheumatoid arthritis (RA) remains debatable. In this study, we have examined the relationships between RF isotypes and disease activity and severity in RA patients. Sixty-two patients with RA, 48 women and 14 men, were studied. RF was measured by nephelometry (RF–N) and IgG–, IgA–, and IgM–RF isotypes were measured using enzyme-linked immunosorbent assay. Serum C-reactive protein and erythrocyte sedimentation rate were also determined. The patients were classified according to disease activity, joint damage, functional status, and presence of pulmonary involvement, rheumatoid nodule, and secondary Sjögren’s syndrome. Although the patients with active disease had significantly higher IgA–RF and IgM–RF levels compared to inactive patients, IgA–RF and IgM–RF were not found to be independently associated with disease activity in multivariate analysis. In patients with severe joint damage, IgA–RF and RF–N were significantly higher than those of the other patients. Multiple regression analysis showed that IgA–RF was the unique variable independently associated to severe joint damage. The patients with class III and IV functional index had significantly higher IgM–RF, IgA–RF, and RF–N levels compared to the patients with class I and II functional index; however, RFs were not significantly associated with functional status in multivariate analysis. IgA–RF and IgM–RF were significantly associated with pulmonary involvement and rheumatoid nodule, respectively. No significant associations were found between RF isotypes and secondary Sjögren’s syndrome. Our results suggest that the clinical usefulness of IgA and IgM isotypes is better than RF–N. Elevated IgA–RF may be a marker of erosive disease. The usefulness of RF isotypes for monitoring disease activity or functional status appears to be limited.     

Effects of glucosamine administration on patients with rheumatoid arthritis

The purpose of this study was to examine whether glucosamine has an antirheumatic effect in a randomized placebo-controlled study.The subjects were 51 rheumatoid arthritis (RA) patients: 25 patients in the glucosamine group and 26 patients in the placebo group. Glucosamine hydrochloride at a daily dose of 1,500 mg and placebo, respectively, were administered for 12 weeks along with conventional medication.While significant improvement was not found in joint counts and in the rate of ACR20 responders, the face scale and a visual analogue scale pain were significantly in favor of the glucosamine group. ESR and CRP levels did not change, but serum MMP-3 levels decreased in the glucosamine group. Results of the patients’ self-evaluations and the physicians’ global evaluations indicated that the glucosamine treatment produced noticeable improvements in symptoms.Although glucosamine administration had no antirheumatic effect evaluated by conventional measures, it seemed to have some symptomatic effects on RA.     

Associations with subregional BMD-measurements in patients with rheumatoid arthritis

Patients with rheumatoid arthritis (RA) have bone loss to various degrees at different skeletal sites. The subregional bone mineral density (BMD) of the hand and the correlation of BMD to other regional bone losses, parameters of inflammation or bone resorption was evaluated in 421 patients with RA and controls. RA patients had significantly (P < 0.01) lower BMD values in the carpus (0.405 ± 0.004 g/cm²), metacarpal joint II (0.318 ± 0.036 g/cm²) and metacarpal joint III (0.326 ± 0.022 g/cm²) compared to controls. There was no difference in bone density at the lumbar spine or hip. Significant (P < 0.001) correlations were found between BMD total of the hand, its subregions, the forearm and hip. Parameters of inflammation correlated significantly (P < 0.001) with pyridinolines (r = 0.378), desoxypyridinolines (r = 0.183), forearm (r = −10, P < 0.05), MCP II (r = −0.190, P < 0.001), MCP III (r = 0.204, P < 0.001) and carpus (r = 0.191, P < 0.001).     

Elevation of serum KL-6 levels in 3 patients with rheumatoid arthritis treated with adalimumab

Abstract

We describe 3 cases of rheumatoid arthritis presenting with elevated serum KL-6 levels during treatment with adalimumab, which was discontinued because of suspected onset of complications. However, no complications were observed following discontinuation despite comprehensive assessments, and KL-6 levels subsequently returned to baseline levels. In our institutes, 3 out of 29 cases treated with adalimumab showed elevated KL-6 levels. The baseline levels were 445, 347, and 547 U/ml, while the peak levels were 1010, 546, and 2007 U/ml, respectively. The elevated KL-6 levels seem to have been innocuous; nevertheless, further careful observation is deemed necessary.     

Infliximab treatment reduces the serum levels of interleukin-23 in patients with rheumatoid arthritis

Abstract

In this study, we investigated the effect of the antitumor necrosis factor alpha (anti-TNF-α) antibody, infliximab, combined with methotrexate (MTX) and MTX alone on the serum levels of interleukin (IL)-23 and IL-17 in rheumatoid arthritis (RA) patients. Infliximab combined with MTX was administered to 26 patients with RA (infliximab group), and MTX alone was given to 20 patients with RA (MTX group). We evaluated clinical and laboratory parameters, including the Disease Activity Scores of 28 joints (DAS28) and serum levels of IL-23 and IL-17 at baseline and at 14 and 30 weeks after the initial treatment with these drugs. Single regression analysis was performed between the levels of serum IL-23 and other clinical and laboratory parameters at baseline before the initial treatment with infliximab or MTX. A significant reduction of DAS28 scores was observed in both the infliximab and the MTX group at 14 and 30 weeks after the initial treatment. A significant decrease in serum levels of IL-23 was observed in the infliximab group but not in the MTX group at 14 and 30 weeks after the initial treatment. Serum IL-17 levels did not show a significant change during the follow-up period. At baseline, before the initial treatment with infliximab or MTX, serum IL-23 levels showed a significant correlation with DAS28 and the number of swollen joints. This study indicated that the reduction of serum IL-23 levels in RA patients was a novel action of infliximab.