Advanced glycation end-products inhibition improves endothelial dysfunction in rheumatoid arthritis

Aim: Chronic inflammation in rheumatoid arthritis is associated with vascular endothelial dysfunction. The objective was to study the efficacy and safety of advanced glycation end products (AGEs) inhibitor (benfotiamine 50 mg + pyridoxamine 50 mg + methylcobalamin 500 μg, Vonder^® (ACME Lifescience, Baddi, Himachal Pradesh, India)) on endothelial function in rheumatoid arthritis (RA). Methods: Twenty‐four patients with established active RA with high disease activity (Disease Activity Score of 28 joints [DAS28 score] > 5.1) despite treatment with stable doses of conventional disease‐modifying antirheumatic drugs were investigated. Inflammatory disease activity (DAS28 and Health Assessment Questionnaire‐Disability Index [HAQ‐DI] scores, erythrocyte sedimentation rate [ESR] and C‐reactive protein [CRP]), markers of endothelial dysfunction, serum nitrite concentration and endothelium‐dependent and ‐independent vasodilation of the brachial artery were measured before and after 12 weeks therapy with twice a day oral AGEs inhibitor. Results: After treatment, flow‐mediated vasodilation improved from 9.64 ± 0.65% to 15.82 ± 1.02% (P < 0.01), whereas there was no significant change in endothelium‐independent vasodilation with nitroglycerin and baseline diameter; serum nitrite concentration significantly reduced from 5.6 ± 0.13 to 5.1 ± 0.14 μmol/L (P = 0.004), ESR from 63.00 ± 3.5 to 28.08 ± 1.5 mm in the first h (P < 0.01) and CRP levels from 16.7 ± 4.1 to 10.74 ± 2.9 mg/dL (P < 0.01). DAS28 and HAQ‐DI scores were significantly reduced, from 5.9 ± 0.17 to 3.9 ± 0.17 (P < 0.01) and 4.6 ± 0.17 to 1.7 ± 0.22 (P < 0.01), respectively. Conclusions: Advanced glycation end products inhibitor improves endothelial dysfunction and inflammatory disease activity in RA. In RA, endothelial dysfunction is part of the disease process and is mediated by AGEs‐induced inflammation.     

Anti-tumor necrosis factor therapy increases serum adiponectin levels with the improvement of endothelial dysfunction in patients with rheumatoid arthritis

Lower adiponectin levels in circulation are shown to be associated with endothelial dysfunction, which is a crucial feature in the evolution of atherosclerosis. The aim of our study is to evaluate the effect of anti-tumor necrosis factor (TNF) therapy on adiponectin levels with endothelial function and arterial stiffness. Fifteen Japanese patients with rheumatoid arthritis (RA) received infusions with infliximab (3 mg/kg) at weeks 0, 2, and 6. Serum concentrations of adiponectin, endothelial function, and pulse wave velocity (PWV) were measured before each infusion. Endothelium-dependent vasodilatation and endothelium-independent vasodilatation were evaluated as forearm blood flow response to reactive and nitroglycerin-induced hyperemia using strain-gauge plethysmography. Endothelium-dependent vasodilatation was significantly improved at 2 weeks and 6 weeks by treatment with infliximab. PWV remained unchanged. Anti-TNF therapy significantly increased serum adiponectin levels at 2 weeks and 6 weeks. The adiponectin levels were positively correlated with the endothelium-dependent vasodilatation, and negatively with the disease activity score of 28 joints. Our study shows a short-term efficacy of infliximab on adiponectin levels and endothelial dysfunction of patients with RA, and provides additional evidence to support the regulatory role of TNF-α on the expression of adiponectin in vivo.     

Anti-tumor necrosis factor therapy increases serum adiponectin levels with the improvement of endothelial dysfunction in patients with rheumatoid arthritis

Abstract

Lower adiponectin levels in circulation are shown to be associated with endothelial dysfunction, which is a crucial feature in the evolution of atherosclerosis. The aim of our study is to evaluate the effect of anti-tumor necrosis factor (TNF) therapy on adiponectin levels with endothelial function and arterial stiffness. Fifteen Japanese patients with rheumatoid arthritis (RA) received infusions with infliximab (3?mg/kg) at weeks 0, 2, and 6. Serum concentrations of adiponectin, endothelial function, and pulse wave velocity (PWV) were measured before each infusion. Endothelium-dependent vasodilatation and endothelium-independent vasodilatation were evaluated as forearm blood flow response to reactive and nitroglycerin-induced hyperemia using strain-gauge plethysmography. Endothelium-dependent vasodilatation was significantly improved at 2 weeks and 6 weeks by treatment with infliximab. PWV remained unchanged. Anti-TNF therapy significantly increased serum adiponectin levels at 2 weeks and 6 weeks. The adiponectin levels were positively correlated with the endothelium-dependent vasodilatation, and negatively with the disease activity score of 28 joints. Our study shows a short-term efficacy of infliximab on adiponectin levels and endothelial dysfunction of patients with RA, and provides additional evidence to support the regulatory role of TNF-α on the expression of adiponectin in vivo.     

Association of asymptomatic hyperuricemia and endothelial dysfunction in psoriatic arthritis

IntroductionCardiovascular disease is an increasingly recognized contributor to excess morbidity and mortality in psoriatic arthritis (PsA). Traditional cardiovascular risk factors do not adequately account for the extent of cardiovascular disease in PsA.Aim of the workTo examine the prevalence of subclinical atherosclerosis in patients with PsA to emphasize the potential role of serum uric acid on endothelial dysfunction, as an early predictor for atherosclerosis in PsA patients.Patients and methodsThis study included 60 PsA patients as well as 60 age and sex matched healthy controls. Assay of serum uric acid, interleukin-6 (IL-6) and soluble intercellular adhesion molecule-1 (sICAM-1) was done for all patients and controls. Patients were subjected to psoriasis area severity index (PASI) and assessment of disease activity. Patients and controls underwent brachial flow-mediated dilatation (FMD) assessment by color duplex sonography to determine endothelial dysfunction as well as extracranial carotid arteries assessment by high-resolution B-mode ultrasound to measure the common carotid intima-media thickness (CIMT) and the detection of atheromatous plaques.ResultsPsA patients have a high significant difference in CIMT, FMD of the brachial artery and mean levels of serum uric acid compared to healthy controls (p < 0.001). PsA patients with hyperuricemia have a high significant difference in CIMT and FMD of the brachial artery than those with normal serum uric acid. Serum uric acid levels showed a high significant positive correlation with each of CIMT, disease duration, markers of inflammation (ESR, CRP, IL-6, sICAM-1), disease activity score in 28 joints (DAS 28) and PASI (r = 0.71, 0.893, 0.956, 0.858, 0.853, 0.877, 0.907, 0.847, respectively, as p < 0.001). A high significant negative correlation was found between serum uric acid levels and FMD of the brachial artery as r = ?0.634, p < 0.001.ConclusionPatients with PsA have a high prevalence of subclinical atherosclerosis dependent on serum uric acid, suggesting that chronic systemic inflammation and endothelial dysfunction appear to be the link between asymptomatic hyperuricemia and atherosclerosis. Therefore, proper control of serum uric acid may play a preventive role in the development of atherosclerosis in PsA patients.     

Static orthoses in the prevention of hand dysfunction in rheumatoid arthritis: a review of the literature

Static orthoses are recommended for individuals who have early rheumatoid arthritis (Scottish Intercollegiate Guidelines Network, 2002; College of Occupational Therapists, 2003). These orthoses aim to rest and immobilize weakened joint structures and decrease local inflammation (Janssen et al., 1990; Nicholas et al., 1982); correctly position joints (Nordenski?ld, 1990; Ouellette, 1991); minimize joint contractures (McClure et al., 1994); increase joint stability (Kjeken et al., 1995); relieve pain (Feinberg, 1992; Callinan and Mathiowetz, 1996; Kjeken et al., 1995) and improve function (Janssen et al., 1990; Pagnotta et al., 1998; Nordenski?ld, 1990). Wrist and hand orthoses have been routinely prescribed for individuals with rheumatoid arthritis (RA) for the last 30 years with limited evidence that they are effective in achieving their purported aims. This article reviews the possible deterioration in hand structure that can occur in RA and discusses the theoretical basis for the application of static orthoses in RA. The evidence for the effectiveness of four commonly used static orthoses is then examined.     

Managing comorbidity in patients with rheumatoid arthritis

Rheumatoid arthritis (RA) is a chronic inflammatory disease that decreases physical function and imposes substantial medical costs. Comorbid conditions are common in patients with RA and they adversely affect quality of life and RA‐related outcomes such as work disability and mortality. Rheumatologists have the important responsibility to consider comorbidities and their risks when treating patients and to adapt therapies to the specific situation of individual patients. This paper discusses the common comorbidities in patients with RA and management approaches.     

Effects of rituximab treatment on endothelial dysfunction, carotid atherosclerosis, and lipid profile in rheumatoid arthritis

Increased cardiovascular mortality has been associated with rheumatoid arthritis (RA). There have been reports indicating that tumor necrosis factor blockers may exert favorable but transient effects on lipid profile, flow-mediated vasodilation (FMD) of the brachial artery, and common carotid intima–media thickness (ccIMT) in RA. In this study, we assessed the effects of rituximab on FMD, ccIMT, and lipid profile. Five female RA patients received two infusions of 1000 mg rituximab i.v. High-resolution B-mode ultrasound was used to assess brachial FMD and ccIMT. We also determined plasma total cholesterol (TC), HDL-C, LDL-C, and triglyceride (Tg) levels. Assessments were performed at baseline, as well as at weeks 2, 6, and 16 after the first infusion. Rituximab (RTX) treatment resulted in a rapid and sustained improvement in FMD. The mean improvement was 30%, 22%, and 81% at weeks 2, 6, and 16, respectively. RTX had little effect on atherosclerosis within this short period of time; however, we observed 10%, 9%, and 2% decreases in ccIMT at weeks 2, 6, and 16, respectively. RTX therapy resulted in 3–11% decrease in TC, as well as 14–35% increase in HDL-C levels. Two infusions of RTX exerted early and sustained favorable effects on endothelial dysfunction, as well as plasma TC and HDL-C levels. RTX may also decrease ccIMT; however, longer follow-up is needed to assess the prolonged effects of RTX on vascular function and lipid profile in RA patients.     

A cross-sectional study of diastolic dysfunction in rheumatoid arthritis and its association with disease activity

Aims: The aim of this study was to evaluate the left ventricular (LV) diastolic dysfunction in rheumatoid arthritis (RA) patients without clinically evident cardiovascular manifestations and to estimate whether there is any correlation between RA disease severity and disability and LV diastolic dysfunction. Methods: The study was a cross‐sectional study involving 53 patients (47 female and 6 male) with RA without clinically evident heart disease and 53 healthy subjects (47 female and 6 male) who served as a control group. Both groups were matched for age and sex. Echocardiographic and Doppler studies were conducted in all patients with RA and control subjects. Results: Of 17 cardiac parameters assessed, only two were abnormal. None of the specific cardiac diastolic dysfunction parameters were significantly different in RA patients compared to the control group. There was no significant correlation between diastolic function values in RA patients and value of Disease Activity Score 28 (DAS‐28) and value of Health Assessment Questionnaires Disability Index (HAQDI). Atrial (A) wave velocity was greater in RA patients compared to the control group (0.71 [0.58–0.83] vs. 0.61 [0.51–0.71]; P < 0.04). However, interventricular relaxation time (IVRT) ([73.08 ± 9.92 vs. 70.74 ± 9.02], P = 0.207), lower E/A ratio (1.27 [1.02–1.56] vs. 1.42 [1.20–1.68], P = 0.102), diastolic dysfunction parameters according to Redfield Classification (25 [47.2%] vs. 27 [50.9%] P = 0.56), diastolic dysfunction using E/A (P = 0.321) and tissue doppler imaging (E/E′) (P = 0.148) were not different. Conclusion: Prevalence of diastolic dysfunction in the rheumatoid arthritis group (47.2%) was not different from controls (50.9%). LV diastolic function had no significant correlation with RA disease severity and duration of disease.     

来氟米特及甲氨蝶呤对早期严重类风湿关节炎的治疗作用

目的研究来氟米特及甲氨蝶呤联合运用对早期严重类风湿关节炎临床症状，特别是对关节损害的作用。方法108例早期严重类风湿关节炎患者随机分为来氟米特组、来氟米特＋甲氨蝶呤组及来氟米特＋羟氯喹组，治疗前作相应的临床、实验室及影像学检查，以来氟米特30mg／d，连续2天后改为20mg／d，甲氨蝶呤10mg／w，羟氯喹400mg／d治疗12个月后，再评价患者临床、实验室及影像学的改变。结果来氟米特组、来氟米特＋甲氨蝶呤组及来氟米特＋羟氯喹组治疗12个月后，关节疼痛数明显减少，关节肿胀亦得到明显改善，晨僵时间显著缩短，其中尤以来氟米特＋甲氨蝶呤效果明显。关节侵蚀及Larsen-Dale积分在来氟米特＋甲氨蝶呤组改善亦较其他两组显著。但血沉及C反应蛋白改变不显著。结论来氟米特及甲氨蝶呤联合运用对早期类风湿关节炎的临床症状及关节损害的改善具有明显的效果。     

Cardiac involvement in patients with rheumatoid arthritis

Background and aim: In rheumatoid arthritis (RA), although the target organ is the synovium, extra‐articular involvement is also seen. All layers of the heart can be inflamed and pericarditis is the most common type of involvement. The frequency of cardiac involvement in patients with RA and its relation with other patient characteristics were analysed in this study. Methods: One hundred patients with RA were included in the study. Patients were evaluated in terms of their sex, age, disease duration, activity of the disease and history of previous heart disease. Electrocardiography (ECG) and echocardiography were performed. The cardiac abnormalities, laboratory parameters, disease duration and the age of the patient were separately compared. Student t‐test was used for these comparisons and P < 0.05 was accepted to be statistically significant. Results: Ages of the patients, 15 of whom were male and 85 were female, varied between 19 and 78 years (mean 50.5 ± 12.7 years). 23% of the patients were RF‐negative and 77% were RF‐positive. The distribution of the patients according to the Steinbrocker's functional classification was as follows: 16 patients (16%) Class I, 55 patients (55%) Class II, 23 patients (23%) Class III and 5 patients (5%) Class IV. ECG abnormalities were found in 7 patients (7%). Echocardiographic abnormality was detected in 67 of the 100 patients (67%) with minimal pericardial effusion in 15 patients (15%), mitral valvular involvement in 26 patients (26%), aortic valve involvement in 24 patients (24%), ascendant aorta dilatation in 7 patients (7%) and diastolic dysfunction in 57 patients (57%). Conclusions: Cardiovascular system involvement which is an extra‐articular involvement of RA is asymptomatic in most of the patients. Thus, we believe that by a periodical thorough evaluation of patients and aggressive treatment for identified problems can significantly reduce cardiovascular morbidity and mortality in patients with RA.     

Effects of disease modifying anti-rheumatic drugs on subclinical atherosclerosis and endothelial dysfunction which has been detected in early rheumatoid arthritis: 1-year follow-up study

Objective

The study was designed to explore the effect of disease modifying anti-rheumatic drugs (DMARDs) on synovial inflammation as well as on atherosclerotic indices in patients with early rheumatoid arthritis (RA).

Methods

The study included 35 early RA patients (disease duration <12 months). Inflammatory variables, like erythrocyte sedimentation rate (ESR) and high sensitivity C-reactive protein (hsCRP) were measured. Carotid intima-media thickness (cIMT) and endothelial dependent flow-mediated vasodilatation (ED-FMD) were measured by high-resolution ultrasonography. Disease activity of RA was assessed by disease activity score (DAS28) and quality of life was determined by Health Assessment Questionnaire-Disability Index (HAQ-DI) Score. All the above parameters were assessed both at baseline and follow-up after 1 year. Patients were treated with methotrexate (MTX), hydroxycholoroquine (HCQ) and sulfasalazine (SSZ) depending on their disease activity.

Results

After a year of treatment, variables like ESR, hsCRP, DAS28 and HAQ-DI showed significant improvement (p < 0.0001 for each variable). However, there was no such significant change observed in the lipid profile after 1 year from the baseline. Average body mass index (BMI) of patients remained same at the one year follow-up. The cIMT values after 1 year decreased significantly [0.43 ± 0.08 mm] from the baseline [0.50 ± 0.16 mm] [p = 0.002]. Similarly, in case of FMD%, the post-1-year treatment values [7.57 (4.04–13.03)] improved significantly from the baseline [5.26 (2.9–10.6)] [p = 0.041].

Conclusion

Subclinical atherosclerosis and endothelial dysfunction are demonstrable features even in early RA which improved after therapy. Early intervention of RA with DMARDs not only controls the disease but also retards the atherosclerotic progression.     

Assessment of endothelial function as a marker of cardiovascular risk in patients with rheumatoid arthritis

The endothelium is a major regulator of cardiovascular function and maintains an atheroprotective role through several mechanisms, including vasodilatation, inhibition of platelet aggregation, having anticoagulant and profibrinolytic effects, and having an anti‐inflammatory effect. Early changes in the normal functioning of the endothelium are key initiating factors in the development and progression of atherosclerosis. These changes are present well before the presentation of clinical symptoms. Thus, researchers have focused much attention on developing methods for reliable non‐invasive testing of endothelial function to allow early detection and monitoring and progression of subclinical atherosclerosis. To date, there is a wide range of methods in use to assess endothelial function, each with its own advantages and limitations. Ideally, the tests should be non‐invasive to allow repeated measurements and be applicable in normal healthy subjects and also in children. Given the wide range of regulatory functions of the endothelium, it is not surprising that there is no single measure of endothelial function that provides all the necessary information regarding vascular integrity in different vascular beds. Therefore, a combination of tests examining different components of the vascular system is more appropriate. Since patients with rheumatoid arthritis have increased mortality due to cardiovascular disease, assessment of endothelial function could prove to be useful tools in the identification and monitoring of cardiovascular risk. The purpose of this review is to give a brief overview of some of the commonly used techniques for assessment of endothelial function, and in particular on those that have been used in studies of patients with rheumatoid arthritis.     

TNF-alpha induces endothelial dysfunction in diabetic adults, an effect reversible by the PPAR-gamma agonist pioglitazone.

AIMS: Inflammation contributes to the pathogenesis of cardiovascular disease. Tumour necrosis factor (TNF)-alpha, in particular, is a key mediator of inflammation and vascular dysfunction and progression of atherosclerotic disease. Pioglitazone, a peroxisome proliferator-activated receptor-gamma agonist, not only improves insulin sensitivity, but may also have anti-inflammatory effects. The aims of this study were to investigate the acute effects of local intra-arterial infusion with low-dose TNF-alpha on resistance vessel endothelial function in type 2 diabetes and to determine whether short-term pioglitazone treatment protects against vascular dysfunction induced by this inflammatory stimulus. METHODS AND RESULTS: A randomized, parallel, placebo-controlled, double blind trial with 30 mg pioglitazone once daily for 4 weeks was performed in 16 male patients with recently diagnosed type 2 diabetes. Forearm plethysmography (FBF) was used to evaluate the effect on resistance vessel responses of intra-arterial administration of serotonin (NO-dependent vasodilation) and nitroprusside (endothelium-independent vasodilation) followed by another FBF-measurement during the second hour of intra-arterial infusion with TNF-alpha (10 ng/100 mL forearm volume/min for 2 h). Endothelial-dependent FBF of type 2 diabetic patients was significantly impaired (25.4%) by intra-arterial TNF-alpha infusion (P = 0.01), whereas nitroprusside-induced vasodilation did not change. Treatment with pioglitazone for 4 weeks completely blocked TNF-alpha-induced impairment of endothelial-dependent FBF compared with placebo. No significant changes in plasma concentrations of TNF-alpha, interleukin-6, soluble TNF-alpha-receptors, or CD40L were observed. CONCLUSION: Pioglitazone treatment can convey direct protection against cytokine (TNF-alpha)-induced endothelial dysfunction in humans with an increased cardiovascular risk due to type 2 diabetes.     

妊娠对类风湿关节炎患者内皮祖细胞的影响及机制研究

目的:探讨妊娠对RA患者内皮祖细胞(EPC)的影响及机制。方法:将2016年1月至2018年6月来本院就诊的RA初治患者纳入本项研究,按照有无妊娠,将患者分为单纯RA组和RA合并妊娠组,均为女性患者,每组各30例;免疫组织化学染色检测滑膜组织内淋巴细胞共同抗原(LCA)+淋巴细胞和CD68+巨噬细胞的数目;流式细胞术检测EPC和内皮细胞的比例;ELISA检测EPC上清中血管内皮生长因子(VEGF)、基质细胞衍生因子(SDF)-1、IL-6和IL-10的浓度。2组之间比较采用t检验,多组间比较用单因素方差分析。结果:免疫组织化学结果显示RA合并妊娠组关节滑膜内CD68+巨噬细胞和LCA+淋巴细胞的数目低于单纯RA组;ELISA的结果显示单纯RA组外周血可溶性人HLA-G的浓度为(8.9±1.7)pg/ml,RA合并妊娠组的浓度为(396.7±89.6)pg/ml,2组差异有统计学意义(t=4.329,P<0.01);流式细胞学检测结果显示单纯RA组患者淋巴细胞中EPC的比例为(0.13±0.03)%,RA合并妊娠组的比例为(0.76±0.09)%,2组差异有统计学意义(t=6.671,P<0.01);相关性分析结果显示2组患者外周血中EPC比例与可溶性HLA-G浓度呈正相关(r=0.8861,P<0.01);体外的实验结果显示HLA-G能够促进单纯RA患者EPC旁分泌和分化功能的恢复。结论:妊娠能够提高RA患者体内EPC的数量和生物学功能,HLA-G在这个过程中可能发挥着重要作用。     

Interleukin-17 gene expression in patients with rheumatoid arthritis

Interleukin-17 is a proinflammatory cytokine. Recent animal studies have shown that IL-17 plays a role in the initiation and progression of arthritis. However, whether IL-17 has a prominent role in human rheumatoid arthritis (RA) or not remains unclear. Here we investigated the role of IL-17 in patients with RA. cDNA was prepared from knee joint synovial tissues of RA (n = 11) and osteoarthritic (OA, n = 10) patients and PBMC of RA (n = 52) and healthy subjects (n = 34). IL-17 gene expression level was measured by real-time PCR, and was compared with various clinical parameters. IL-17 gene expression in synovial tissues of RA was similar to that in OA. IL-17 gene expression level in PBMC of RA patients was significantly higher than in the control. The response (changes in DAS) to two-week treatment with anti-TNF-α blockers (infliximab or etanercept) did not correlate with changes in IL-17 gene expression levels. The IL-17/TNF-α gene expression ratio at baseline (before treatment) tended to be lower in responders to the treatment. Expression of IL-17 gene in PBMC may be associated with the inflammatory process of RA. IL-17/TNF-α expression ratio is a potentially suitable marker of response to anti-TNF-α therapy.