Coronary artery disease and rheumatoid arthritis

Patients with rheumatoid arthritis (RA) have a reduced life expectancy when compared with the general population. Cardiovascular death is considered the leading cause of mortality in patients with RA; it is responsible for approximately half the deaths observed in RA cohorts. The prevalence of cardiovascular comorbidity is difficult to assess accurately, because cardiovascular disease (CVD) has a tendency to remain silent in the rheumatoid patient. It is not clear why rheumatoid patients have higher rates of coronary disease. Traditional cardiovascular risk factors do not seem to be wholly responsible for the increased cardiovascular risk. Novel cardiovascular risk factors, including inflammatory markers, have been identified over the past few years. It may be that these new cardiovascular risk factors are responsible for accelerating coronary heart disease in patients with RA. This article reviews recent literature relating to the epidemiology of cardiovascular disease in the context of RA.     

The best cardiovascular risk calculator to predict carotid plaques in rheumatoid arthritis patients

Clinical Rheumatology - Atherosclerotic cardiovascular disease (ASCVD) is the leading cause of death in patients with rheumatoid arthritis (RA). Chronic inflammation and traditional risk factors...     

A型滑膜细胞与类风湿关节炎血管新生

类风湿关节炎(RA)是一种常见的多系统性炎症性自身免疫性疾病.RA最主要病理特征是关节滑膜血管新生和对关节破坏力极强的血管翳形成.血管的新生是个复杂的过程,多种细胞及其所分泌的细胞因子参与了此过程.近来大量的研究表明,A型滑膜细胞即滑膜巨噬细胞在RA病理过程中起着非常重要的作用,其参与了炎症和血管新生的整个过程.A型滑膜细胞表达黏附分子、趋化因子受体和多种表面抗原物质,还能分泌产生大量的细胞因子、生长因子和其它化学活性物质.它们在RA滑膜病理过程中起着关键性作用.因此,A型滑膜细胞可能将成为RA治疗很好的靶点.     

Targeting Inflammation as a Therapeutic Strategy in Accelerated Atherosclerosis in Rheumatoid Arthritis

Rheumatoid arthritis (RA) is an autoimmune disease affecting approximately 1% of the population. Patients have reduced life expectancy and the leading cause of death is cardiovascular disease (CVD), with patients experiencing at least a 2‐fold increased risk of myocardial infarction. RA is recognized as an independent risk factor for CVD. Inflammation is a key contributor to the pathogenesis of atherosclerosis and cardiovascular events. As a common catalyst of both diseases, inflammation is the likely cause of increased prevalence of CVD in the RA population. Abating disease‐related inflammation in RA may be an effective strategy in reducing CVD risk. Several other therapies used to modify cardiovascular risk factors in the general population such as statins and angiotensin‐converting enzyme inhibitors are under investigation in patients with RA. This review discusses the parallels in the pathology of RA and atherosclerosis and discusses current therapies for RA and how they affect cardiovascular risk.     

Multiple coronary aneurysms and acute myocardial infarction in a female patient with rhupus: case report and literature review

Clinical Rheumatology - Coronary artery aneurysms (CAA) are an infrequent cause of coronary artery disease in both systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA), most occurring...     

Pulmonary pathology of the rheumatic diseases

Thoracic manifestations of the rheumatic diseases (RDs) are a significant cause of morbidity and mortality worldwide. The five RDs most frequently associated with pleuropulmonary disease are (1) rheumatoid arthritis (RA), (2) systemic lupus erythematosus (SLE), (3) progressive systemic sclerosis (PSS), (4) polymyositis/dermatomyositis (PM/DM), and (5) Sj?gren syndrome (SS). The clinical presentation is highly variable, ranging from pleuritic pain alone to slowly progressive breathlessness accompanied by cough. On occasion RD may present acutely with overwhelming respiratory failure as the first pulmonary manifestation. In all of the RDs, the pathology is dominated by either or both inflammation and fibrosis, but the anatomical distribution in each varies somewhat. For example, airway-associated lymphoid hyperplasia is a common manifestation of SS, PM/DM preferentially involves the alveolar parenchyma, and pleural inflammation is most commonly seen in RA. Such changes may be detected radiologically as peribronchovascular disease in SS, ground-glass infiltrates in PM/DM, and pleural disease with effusion in RA. Some RDs are more commonly associated with distinctive histopathology, such as rheumatoid nodules in RA, or lymphoid hyperplasia in both RA and SS. Patients with PSS are at particular risk for pulmonary hypertension when the lung is involved. Also, statistically, acute lung injury occurs more commonly in some, such as SLE and PM/DM. The very common use of immunosuppressive agents in the treatment of RD creates additional diagnostic problems related to drug toxicity and infection. Finally, a major confounding factor occurs when preclinical RD presents first as pulmonary disease (particularly PM/DM), an occurrence that may invoke one of the so-called idiopathic interstitial pneumonias. The most common pleuropulmonary pathological manifestations of the five major RDs are presented and discussed with brief radiological correlations.     

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.     

Amino-terminal fragment of the prohormone brain-type natriuretic peptide in rheumatoid arthritis

OBJECTIVE: Increased concentrations of N-terminal pro-brain natriuretic peptide (NT-proBNP) are associated with cardiovascular morbidity and mortality, but little is known about their relationship to chronic inflammation. Patients with rheumatoid arthritis (RA) have chronic inflammation, increased arterial stiffness, and accelerated coronary atherosclerosis. This study was undertaken to test the hypothesis that NT-proBNP concentrations are elevated in patients with RA and are associated with coronary artery calcification and markers of inflammation. METHODS: In 159 patients with RA (90 with early RA and 69 with longstanding RA) without heart failure and 88 control subjects, serum concentrations of NT-proBNP, interleukin-6 (IL-6), and tumor necrosis factor alpha (TNFalpha) were measured and coronary calcification was assessed. Associations between NT-proBNP levels and the other parameters were investigated. RESULTS: NT-proBNP concentrations were elevated in patients with longstanding RA (median 142.8 pg/ml [interquartile range 54.8-270.5]) and those with early RA (median 58.1 pg/ml [interquartile range 19.4-157.6]) compared with controls (18.1 [3.2-46.0]) (P < 0.001). In patients with RA, NT-proBNP concentrations were associated with age (rho = 0.35, P < 0.001), levels of IL-6 (rho = 0.33, P < 0.001), TNFalpha (rho = 0.23, P = 0.003), and C-reactive protein (CRP) (rho = 0.21, P = 0.01), coronary calcium score (rho = 0.30, P < 0.001), systolic blood pressure (rho = 0.30, P < 0.001), and disease activity (rho = 0.29, P < 0.001). After adjustment for age, race, and sex, the associations between NT-proBNP concentrations and disease activity, TNFalpha, IL-6, and CRP remained significant, but those with systolic blood pressure and coronary calcium score were attenuated. CONCLUSION: NT-proBNP concentrations are increased in patients with RA without clinical heart failure and may indicate subclinical cardiovascular disease and a chronic inflammatory state.     

Cellular immunohistopathology of acute, subacute, and chronic synovitis in rheumatoid arthritis.

Cellular inflammation in rheumatoid arthritis (RA) synovial membrane was studied in biopsy specimens taken at different stages of synovitis and disease. Patients were classified into three subgroups: acute RA, subacute RA, and chronic RA. Inflammatory cells were characterised by a histochemical esterase method and immunohistochemical peroxidase-antiperoxidase (PAP) and avidin-biotin-peroxidase (ABC) staining. The amounts and distribution of inflammatory cells were different in various stages of the synovitis. In acute onset RA monocytes and granulocytes predominated, suggesting that the beginning of rheumatoid inflammation is similar to inflammatory reaction in general. The presence of T cells and also of plasma cells in subacute RA suggests underlying subclinical changes also in apparently healthy joints in RA. The most typical feature of prolonged synovitis in chronic RA was its intensity, characterised by the presence of large T cell and plasma cell infiltrates. Our findings suggest that the immunological mechanisms are secondary to the tissue damage caused by the initial inflammatory events of unknown cause. However, the immunological mechanisms may still play a central role in the aetiopathogenesis, because findings in chronic RA suggest a defective down-regulation of the immune response.     

Explaining how "high-grade" systemic inflammation accelerates vascular risk in rheumatoid arthritis

There is intense interest in mechanisms whereby low-grade inflammation could interact with conventional and novel vascular risk factors to promote the atheromatous lesion. Patients with rheumatoid arthritis (RA), who by definition manifest persistent high levels of inflammation, are at greater risk of developing cardiovascular disease. Mechanisms mediating this enhanced risk are ill defined. On the basis of available evidence, we argue here that the systemic inflammatory response in RA is critical to accelerated atherogenesis operating via accentuation of established and novel risk factor pathways. By implication, long-term suppression of the systemic inflammatory response in RA should be effective in reducing risk of coronary heart disease. Early epidemiological observational and clinical studies are commensurate with this hypothesis. By contrast, risk factor modulation with conventional agents, such as statins, may provide unpredictable clinical benefit in the context of uncontrolled systemic inflammatory parameters. Unraveling such complex relationships in which exaggerated inflammation-risk factor interactions are prevalent may elicit novel insights to effector mechanisms in vascular disease generally.     

Cardiovascular death in rheumatoid arthritis: a population-based study

OBJECTIVE: To determine whether systemic inflammation confers any additional risk for cardiovascular death among patients with rheumatoid arthritis (RA), after adjusting for traditional cardiovascular risk factors and comorbidities. METHODS: Using the population-based data resources of the Rochester Epidemiology Project, we assembled an incidence cohort of all Rochester, Minnesota residents ages >or=18 years who first fulfilled the American College of Rheumatology 1987 criteria for RA between January 1, 1955 and January 1, 1995. All subjects were followed up longitudinally through their complete (inpatient, outpatient) medical records, beginning at age 18 years and continuing until death, migration, or January 1, 2001. Detailed information on the occurrence of various cardiovascular risk factors (personal history of coronary heart disease [CHD], congestive heart failure, smoking, hypertension, dyslipidemia, body mass index [BMI], diabetes mellitus, menopausal status) as well as indicators of systemic inflammation and RA disease severity (rheumatoid factor [RF] seropositivity, erythrocyte sedimentation rate [ESR], joint swelling, radiographic changes, RA nodules, RA complications, RA treatments, disease duration) and comorbidities were collected on all subjects. Causes of death were ascertained from death certificates and medical records. Cox regression models were used to estimate the independent predictors of cardiovascular death. RESULTS: This inception cohort comprised a total of 603 RA patients whose mean age was 58 years, of whom 73% were women. During a mean followup of 15 years, 354 patients died and cardiovascular disease was the primary cause of death in 176 patients. Personal history of CHD, smoking, hypertension, low BMI, and diabetes mellitus, as well as comorbidities, including peripheral vascular disease, cerebrovascular disease, chronic pulmonary disease, dementia, ulcers, malignancies, renal disease, liver disease, and history of alcoholism, were all significant risk factors for cardiovascular death (P < 0.01 for each). Multivariable Cox regression analyses, controlled for cardiovascular risk factors and comorbidities, revealed that the risk of cardiovascular death was significantly higher among RA patients with at least 3 ESR values of >or=60 mm/hour (hazard ratio [HR] 2.03, 95% confidence interval [95% CI] 1.45-2.83), RA vasculitis (HR 2.41, 95% CI 1.00-5.81), and RA lung disease (HR 2.32, 95% CI 1.11-4.84). CONCLUSION: These results indicate that markers of systemic inflammation confer a statistically significant additional risk for cardiovascular death among patients with RA, even after controlling for traditional cardiovascular risk factors and comorbidities.     

Vascular comorbidity in rheumatoid arthritis: potential mechanisms and solutions

PURPOSE OF REVIEW: To summarise recent evidence for elevated risk of coronary heart disease (CHD) in rheumatoid arthritis (RA) and explore explanatory mechanisms and modalities that may lessen such risk. RECENT FINDINGS: Evidence for elevated CHD risk in RA is convincing. On current estimates, individuals who have had RA for several years have around a twofold higher risk for CHD compared with non-RA persons after taking account of most traditional risk factors. Such excess risk appears to be driven by systemic inflammation both directly via its deleterious effects on blood vessels (endothelial dysfunction inclusive of myocardial microvascular abnormalities) and indirectly by its accentuation of multiple risk pathways including lipid abnormalities. Established therapies that lessen RA disease activity and systemic inflammation will likely lessen CHD risk, although there remains considerable scope for more robust studies employing better measures of vascular disease (e.g., carotid intima-media thickening). Other emerging evidence indicates statins may have dual effects in RA, with a modest disease-modifying effect (requiring confirmation) and significant lipid-lowering action. The latter finding is particularly important because extrapolation of data from all statin endpoint trials suggests that the extent of low-density lipoprotein cholesterol reduction may account for most statin clinical benefit. SUMMARY: Systemic inflammation is the major driver for excess vascular comorbidity in RA. Controlling systemic inflammation should lessen vascular risk but complete, long-term suppression of articular inflammation is rarely achieved. Thus, the use of conventional CHD risk reduction strategies, in particular statins, should be considered in patients with RA with prevalent CHD or at elevated risk.     

The role of collagen antibodies in mediating arthritis

This review examines evidence that rheumatoid arthritis (RA) depends on autoimmunity to articular collagen, and mechanisms whereby autoantibodies to type II collagen contribute to disease development. Three major autoantigenic reactants have been identified in RA; the corresponding autoantibodies are rheumatoid factor (RF), antibodies to citrullinated peptide antigens (ACPA), citrullinated peptides (anti-CCP), and anti-type II collagen (anti-CII). Both RF and ACPA are well-validated and predictive markers of severe erosive RA, but cannot be linked to pathogenesis. By contrast, in various animal species immunized with CII there occurs an erosive inflammatory arthritis resembling that seen in human RA, together with antibodies to CII with an epitope specificity similar to that in RA. We discuss the well-known role of immune complexes in the induction of inflammation within the joint, and present recent data showing, additionally, that antibodies to CII cause direct damage to cartilage in vitro. The close resemblances between human RA and collagen-induced arthritis in animals suggest that autoimmunity, and particularly autoantibodies to CII, are important for both the initiation and perpetuation of RA in a dual manner: as contributors to the inflammation associated with immune complex deposition, and as agents with direct degradative effects on cartilage integrity and its repair.     

Coexistence of rheumatoid arthritis and sarcoidosis: difficulties encountered in the differential diagnosis of common manifestations

Two patients with rheumatoid arthritis (RA) and sarcoidosis illustrate the dilemmas posed by their coexistence in the same patient. The first patient with classical RA developed iridocyclitis, interstitial lung disease and cranial neuropathies, initially attributed to extraarticular rheumatoid disease. Subsequent lung and skin biopsy revealed many granulomas consistent with sarcoidosis whereas synovium revealed changes typical for RA. In the second patient with cutaneous and pulmonary sarcoidosis development of persistent erosive polyarthritis and a subcutaneous nodule with typical pathology permitted the diagnosis of coexistent RA. These cases emphasize that uveitis alone or multiple cranial neuropathies are not features of RA and symptomatic interstitial lung disease in patients with RA warrants further investigation.     

Myocardial infarction caused by rheumatoid vasculitis: histological evidence of the involvement of T lymphocytes

Rheumatoid arthritis (RA) is a chronic joint disease that can be complicated with extra-articular manifestations due to vasculitis. We describe a patient with RA who developed systemic vasculitis and died of myocardial infarction. Autopsy demonstrated vasculitis of the left anterior descendent and circumflex coronary arteries, which were narrowed or occluded with organizing thrombosis. Formation of granuloma with multinucleated giant cells was also observed in media of the circumflex artery. There was no microscopic evidence of atheroma formation in the coronary arteries. Of note, there was a follicle-like infiltration of CD45RO-positive T lymphocytes in interna of the left coronary arteries and the right renal artery. Although not frequently reported, coronary vasculitis as a cause of myocardial infarction should be considered in patients with RA. Moreover, our results suggest that infiltration of T lymphocytes might be involved in the development of rheumatoid vasculitis.     

Depression in patients with rheumatoid arthritis: description, causes and mechanisms

Two sets of contributory factors to depression among patients with rheumatoid arthritis (RA) are generally examined - the social context of the individual and the biologic disease state of that person's RA. This article will review the evidence for both. RA affects patients both physically and psychologically. Comorbid depression is common with RA and leads to worse health outcomes. Low socioeconomic status, gender, age, race/ethnicity, functional limitation, pain and poor clinical status have all been linked to depression among persons with RA. Systemic inflammation may also be associated with, cause, or contribute to depression in RA. Understanding the socioeconomic factors, individual patient characteristics and biologic causes of depression in RA can lead to a more comprehensive paradigm for targeting interventions to eliminate depression in RA.     

C-reactive protein and implications in rheumatoid arthritis and associated comorbidities

C-reactive protein (CRP) is routinely assessed as a marker of systemic inflammation in rheumatoid arthritis (RA). However, it is also an immune regulator that plays an important role in inflammatory pathways associated with RA and promotes atherogenic effects. Comorbidities linked to systemic inflammation are common in RA, and CRP has been associated with the risk for cardiovascular disease, diabetes, metabolic syndrome, pulmonary diseases, and depression. The relationship between systemic inflammation, CRP, and comorbidities in RA is complex, and it is challenging to determine how changing CRP levels may affect the risk or progression of these comorbidities. We review the biological role of CRP in RA and its implications for disease activity and treatment response. We also discuss the impact of treatment on CRP levels and whether reducing systemic inflammation and inhibiting CRP-mediated inflammatory pathways may have an impact on conditions commonly comorbid with RA.     

Renal disorders in rheumatoid arthritis

Renal disorders are a frequent cause of death in patients with rheumatoid arthritis (RA), but are less apparent in living RA patients. In part, this may be because of insensitive screening methods. In this review, some of the relations among renal pathology, renal function, and antirheumatic therapy are clarified. A classification of renal disorders according to etiology is proposed. Two categories of disorders are distinguished: those related to RA and its complications, and those related to drug therapy. The disorders belonging to these categories are reviewed. Finally, a case is made for the existence of a third category, "RA nephropathy." It is hypothesized that this mild and nonspecific nephropathy is the result of cumulative minor insults caused by the disease and its therapy. The presence of such a "subclinical" nephropathy would explain the greater sensitivity of RA patients to other renal insults, and the high prevalence of renal failure at death.     

类风湿关节炎合并冠心病临床特点分析

目的:探讨类风湿关节炎(RA)合并冠心病患者的临床特点。方法:入选接受冠状动脉造影检查的RA患者47例,根据冠状动脉造影情况分为单纯RA组(31例)和RA合并冠心病组(16例);收集入选患者临床资料及冠状动脉造影结果进行回顾性病例-对照分析,并通过Logistic回归分析确定RA患者发生冠心病的危险因素。结果:RA合并冠心病组患者血清同型半胱氨酸(Hcy)水平、免疫球蛋白E(IgE)水平及甲氨蝶呤服用率较单纯RA组明显升高,空腹血糖水平较单纯RA组低,差异均有统计学意义(P0.05);Hcy是RA发生冠心病的独立危险因素(OR=1.583,95%CI:1.070~2.342,P0.05)。结论:RA合并冠心病患者体内存在高Hcy血症较单纯RA更加普遍,且Hcy是RA发生冠心病的独立危险因素;IgE水平升高是RA合并冠心病的另一个血清学特点。     

Methotrexate can prevent cardiovascular events in patients with rheumatoid arthritis: An updated meta-analysis

Aims:The incidence of cardiovascular events (CVEs) in patients with rheumatoid arthritis (RA) is higher than that in people without RA. This may be because inflammation promotes the progression of atherosclerosis. Anti-inflammatory drugs might reduce the occurrence of CVEs in patients with RA. Methotrexate (MTX) is a conventional synthetic anti-rheumatic drug that is widely used in the treatment of RA. We performed a meta-analysis to determine whether MTX can prevent CVEs in RA patients. Then, we discussed the possibility of using MTX to prevent recurred CVEs in patients with coronary heart disease (CHD).Methods:We searched PubMed, Embase, Web of Science, and the Cochrane Library using the key words “methotrexate,” “cardiovascular,” “acute coronary syndrome,” “coronary heart disease,” “myocardial infarction,” “angina pectoris,” and “rheumatoid arthritis.” The efficacy outcome was defined as a composite of CVEs, including stable angina, acute coronary syndrome, stroke, heart failure, and cardiac death.Results:A total of 10 studies and 195,416 RA patients were included in our meta-analysis, and the effect size of relative risk (RR) was pooled using a fixed effect model. The results showed that MTX prevented CVEs in RA patients (RR: 0.798, 95% CI 0.726–0.876, P = .001, I² = 27. 9%).Conclusion:MTX can prevent CVEs in RA patients, but there is not sufficient evidence for using MTX to treat patients with CHD.