Acknowledgment

This continuing medical education activity is supported by an educational grant from Amgen, Thousand Oaks, California.

Disclosure

Dr. Friedewald has received speaker’s honoraria from Novartis, Bridgewater, New Jersey. Dr. Friedewald is a consultant for AstraZeneca, Wilmington, Delaware; and NiCox, Warren Township, New Jersey. Dr. Ganz has received speaker’s honoraria from Pfizer, New York, New York. Dr. Kremer has received speaker’s honoraria from Amgen; Bristol-Myers Squibb, New York, New York; and Wyeth, Madison, Wisconsin. Dr. Mease has received research grants (investigator), consulting fees, and speaker’s honoraria from Abbott Laboratories, Abbott Park, Illinois; Amgen; Biogen Idec, Cambridge, Massachusetts; Bristol-Myers Squibb; Centocor, Horsham, Pennsylvania; Genentech, South San Francisco, California; Roche, Basel, Switzerland; Wyeth; and Pfizer. Dr. Mease has received consulting fees from UCB, Brussels, Belgium. Dr. O’Dell is a consultant for and has received advisory board honoraria from Amgen. Dr. Ridker has received research support from AstraZeneca; Novartis; Pfizer; Roche, Nutley, New Jersey; Sanofi-Aventis, Bridgewater, New Jersey; and Abbott Laboratories. Dr. Ridker has received nonfinancial research support from Amgen. Dr. Ridker is a coinventor on patents held by Brigham and Women’s Hospital that relate to the use of inflammatory biomarkers in cardiovascular disease. Dr. Ridker is a research consultant for Schering-Plough, Kenilworth, New Jersey; Sanofi-Aventis; AstraZeneca; ISIS, Carlsbad, California; Novartis; and Vascular Biogenics, Tel Aviv, Israel. Dr. Salmon is a consultant for Roche; Wyeth; Alexion, Cheshire, Connecticut; Novo Nordisk, Princeton, New Jersey; and Genentech. Dr. Roberts has received speaker’s honoraria from AstraZeneca; Merck/Schering-Plough, Whitehouse Station, New Jersey; and Novartis. All other individuals in a position to control content disclosed no relevant financial relationships.

Disclosure

Dr. Friedewald has received speaker’s honoraria from Novartis, Bridgewater, New Jersey. Dr. Friedewald is a consultant for AstraZeneca, Wilmington, Delaware; and NiCox, Warren Township, New Jersey. Dr. Ganz has received speaker’s honoraria from Pfizer, New York, New York. Dr. Kremer has received speaker’s honoraria from Amgen; Bristol-Myers Squibb, New York, New York; and Wyeth, Madison, Wisconsin. Dr. Mease has received research grants (investigator), consulting fees, and speaker’s honoraria from Abbott Laboratories, Abbott Park, Illinois; Amgen; Biogen Idec, Cambridge, Massachusetts; Bristol-Myers Squibb; Centocor, Horsham, Pennsylvania; Genentech, South San Francisco, California; Roche, Basel, Switzerland; Wyeth; and Pfizer. Dr. Mease has received consulting fees from UCB, Brussels, Belgium. Dr. O’Dell is a consultant for and has received advisory board honoraria from Amgen. Dr. Ridker has received research support from AstraZeneca; Novartis; Pfizer; Roche, Nutley, New Jersey; Sanofi-Aventis, Bridgewater, New Jersey; and Abbott Laboratories. Dr. Ridker has received nonfinancial research support from Amgen. Dr. Ridker is a coinventor on patents held by Brigham and Women’s Hospital that relate to the use of inflammatory biomarkers in cardiovascular disease. Dr. Ridker is a research consultant for Schering-Plough, Kenilworth, New Jersey; Sanofi-Aventis; AstraZeneca; ISIS, Carlsbad, California; Novartis; and Vascular Biogenics, Tel Aviv, Israel. Dr. Salmon is a consultant for Roche; Wyeth; Alexion, Cheshire, Connecticut; Novo Nordisk, Princeton, New Jersey; and Genentech. Dr. Roberts has received speaker’s honoraria from AstraZeneca; Merck/Schering-Plough, Whitehouse Station, New Jersey; and Novartis. All other individuals in a position to control content disclosed no relevant financial relationships.

Objectives

Upon completion of this activity, the physician should be able to:

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  Diagnose increased risk for cardiovascular disease (CVD) in patients with rheumatoid arthritis (RA).

  
  
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  Advise patients and physicians caring for patients with RA in cardiovascular risk reduction.

  
  
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  Appropriately modify RA treatment regimens in patients with acute myocardial infarctions.

  
  
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  Participate in clinical research using clinical information retrieval technology for better understanding of the link between RA and CVD.

Introduction

The consumption of animal fat, composed mainly of low-density lipoprotein (LDL) cholesterol, is the primary cause of CAD and an important contributory factor to many other forms of atherosclerotic CVD. Other factors— traditional risk factors—such as hypertension, tobacco use, and physical inactivity also are major contributors to atherogenesis. In addition, in recent years, insights into the possible role of inflammation as a significant contributing factor to atherogenesis have led to a more complete understanding of atherosclerosis in all its stages, from initial plaque formation through its thrombotic complications. The significance of inflammation in atherosclerotic CVD is further evidenced by the increased prevalence of CVD in many other conditions linked to systemic inflammation, such as psoriasis, periodontitis, hypertension, diabetes mellitus, and the focus of this Editor’s Consensus: RA.

The role of inflammation in atherosclerotic CVD gained added attention with the Justification for the Use of Statins in Prevention: An Intervention Trial Evaluating Rosuvastatin (JUPITER) results. JUPITER was a randomized, double-blind, placebo-controlled primary prevention trial involving rosuvastatin. Almost 18,000 subjects with LDL cholesterol levels <130 mg/dl and high-sensitivity C-reactive protein (hs-CRP) levels >2 mg/L were studied. The mean hs-CRP level was about 4 mg/L in the study and control groups, and the mean LDL cholesterol level was 108 mg/dl. The study was terminated early because there were statistically significant reductions in the incidence of acute myocardial infarction, stroke, coronary artery revascularization, unstable angina pectoris, and cardiovascular death in subjects receiving rosuvastatin 20 mg/day compared to those receiving the placebo. All subgroups taking rosuvastatin benefited, including women, minorities, subjects with low Framingham risk scores, and subjects with no traditional major CVD risk factors. The all-cause reduction in mortality was 20% in subjects with elevated hs-CRP.

Overview of Rheumatoid Arthritis

RA is a systemic autoimmune disease of unknown cause with its primary clinical manifestations affecting synovial tissues, including resultant joint swelling, pain, and tenderness, and subsequent structural cartilage and bone damage and progressive physical disability. RA has a prevalence of about 1% in the United States and has a comparable prevalence worldwide. There is a relatively consistent prevalence among different ethnic populations, with some variation such as a slightly lower prevalence in African Americans and higher prevalence in Native Americans. RA is 3 times more common in women, in whom it also occurs at a younger age, than in men. Thus, like some other autoimmune diseases, women with RA develop CAD and cerebrovascular disease at an earlier age than women in general.

In its initial stages, RA usually involves small joints such as the proximal interphalangeal joints in the hands in a symmetric distribution and, later, the large joints. When untreated at an early stage, the joint swelling stretches the surrounding tendons and ligaments, leading to characteristic articular deformities often seen in older patients with RA. Advanced RA, with attendant deformity and disability, has become much less common in Western countries and in other areas of the world where new advances in RA treatment are more widely used.

Although treatment of the synovial pathology of RA has progressed in recent years, patients with RA in the past had a 3- to 12-year decrease in lifetime longevity compared to the general population. Increased RA mortality is due mainly to increased prevalence of atherosclerotic CVD and cerebrovascular disease. Predictors of mortality in RA are

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  the presence of rheumatoid factor and titer,

  
  
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  the number of involved joints,

  
  
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  the level of systemic inflammation (as measured by inflammatory markers such as erythrocyte sedimentation rate [ESR] and CRP),

  
  
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  extra-articular disease (e.g., subcutaneous nodules, pleural and pericardial disease, Sjögren syndrome, Felty syndrome, vasculitis),

  
  
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  HLA-DR4 (“shared epitope”), and

  
  
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  poor functional status.

Current disease-modifying antirheumatic drugs (DMARDs), which may be used alone or in combination (“dual- or triple-DMARD combinations”), are as follows:

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  Nonbiologic DMARDs

  
  
  
  
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    Methotrexate (MTX)

    
    
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    Leflunomide

    
    
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    Hydroxychloroquine

    
    
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    Sulfasalazine

    
    
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    Corticosteroids

    
    
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    Gold

    
    
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    Azathioprine

    
    
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    Cyclosporine A

  
  
  
  
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  Biologic DMARDs (currently not recommended for use in combination with other biologic DMARDs)

  
  
  
  
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    Anti–tumor necrosis factor–α agents

    
    
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    Abatacept

    
    
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    Rituximab

  
  

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  Nonselective nonsteroidal anti-inflammatory drugs (NSAIDs)

  
  
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  Selective cyclooxygenase-2 inhibitors

  
  
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  Analgesics

Rheumatoid Arthritis and Cardiovascular Disease

RA is associated with

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  increased risk for CVD death, which is the most important factor in reduced longevity in patients with RA (although overall mortality rates in patients with RA are diminishing, the rate of reduction has not kept pace with improvements in lifespan in the general population) ;

  
  
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  CAD, including myocardial infarction, which is often silent, and sudden cardiac death secondary to CAD ;

  
  
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  increased prevalence of carotid arterial plaque and accelerated plaque development ;

  
  
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  heart failure (HF), which often has an atypical presentation and is a major contributor to excess mortality in patients with RA ;

  
  
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  pericardial effusion and constrictive pericarditis (uncommon); and

  
  
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  involvement of the cardiac conduction system with secondary heart block (rare).

One study of risk prediction of heart disease in patients with RA found that

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  absolute risk for patients with RA for CVD is similar to that for patients without RA who are 5 to 10 years older;

  
  
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  absolute risk greatly increases in the presence of increases in traditional CVD risk factors (i.e., absolute risk for CVD in RA patients aged 60 to 69 years with no added risk factors is 17%, increasing to 69% in the presence of multiple CVD risk factors); and

  
  
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  paradoxically, patients with low body mass indexes (BMIs) had an even greater risk for CVD, up to 86% in the presence of other risk factors.