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Preclinical Carotid Atherosclerosis in Patients with Rheumatoid Arthritis

Mary J. Roman, MD; Elfi Moeller, AB; Adrienne Davis, AB; Stephen A. Paget, MD; Mary K. Crow, MD; Michael D. Lockshin, MD; Lisa Sammaritano, MD; Richard B. Devereux, MD; Joseph E. Schwartz, PhD; Daniel M. Levine, PhD; and Jane E. Salmon, MD
[+] Article and Author Information

From Weill Medical College of Cornell University, Hospital for Special Surgery, and The Rogosin Institute, New York, New York, and SUNY-Stony Brook, Stony Brook, New York.


Grant Support: By the National Institutes of Health (grants AR 45591 and M10RR0047).

Potential Financial Conflicts of Interest: Stock ownership or options (other than mutual funds): M.K. Crow (Johnson & Johnson, Pfizer Inc.).

Requests for Single Reprints: Mary J. Roman, MD, Division of Cardiology, Weill Medical College of Cornell University, 525 East 68th Street, New York, NY 10021; e-mail, mroman@med.cornell.edu.

Current Author Addresses: Drs. Roman and Devereux and Ms. Davis: Weill Medical College of Cornell University, 525 East 68th Street, New York, NY 10021.

Ms. Moeller: P.O. Box 415, Ridgefield, CT 06877.

Drs. Paget, Crow, Lockshin, Sammaritano, and Salmon: Hospital for Special Surgery, 535 East 70th Street, New York, NY 10021.

Dr. Schwartz: Department of Psychiatry, SUNY-Stony Brook, 129 Putnam Hall, Stony Brook, NY 11794-8790.

Dr. Levine: The Rogosin Institute, The Rockefeller University, 1230 York Avenue, New York, NY 10021.

Author Contributions: Conception and design: M.J. Roman, S.A. Paget, M.K. Crow, M.D. Lockshin, L. Sammaritano, J.E. Salmon.

Analysis and interpretation of the data: M.J. Roman, S.A. Paget, J.E. Schwartz, D.M. Levine, J.E. Salmon.

Drafting of the article: M.J. Roman.

Critical revision of the article for important intellectual content: M.J. Roman, S.A. Paget, M.K. Crow, M.D. Lockshin, L. Sammaritano, R.B. Devereux, D.M. Levine, J.E. Salmon.

Final approval of the article: M.J. Roman, E. Moeller, A. Davis, S.A. Paget, M.K. Crow, M.D. Lockshin, L. Sammaritano, R.B. Devereux, J.E. Schwartz, D.M. Levine, J.E. Salmon.

Provision of study materials or patients: S.A. Paget, M.D. Lockshin, L. Sammaritano, J.E. Schwartz, J.E. Salmon.

Statistical expertise: J.E. Schwartz.

Obtaining of funding: M.J. Roman, M.K. Crow, J.E. Salmon.

Administrative, technical, or logistic support: A. Davis, J.E. Salmon.

Collection and assembly of data: M.J. Roman, E. Moeller, A. Davis, L. Sammaritano, J.E. Schwartz, J.E. Salmon.


Ann Intern Med. 2006;144(4):249-256. doi:10.7326/0003-4819-144-4-200602210-00006
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The 98 patients with rheumatoid arthritis ranged in age from 20 to 83 years; mean age at diagnosis was 35 years, and mean duration of disease was 12 years. Rheumatoid factor was present in 56 patients (57%), and anticyclic citrullinated peptide antibodies were present in 49 patients (50%). The mean number of irreversibly damaged joints was 8 per patient, and 26 (27%) patients had undergone joint replacement. The Sjögren syndrome was present in 23 patients, 5 of whom also had vasculitis and 1 of whom had leg ulcers. A total of 71% of patients were receiving prednisone therapy or had received it in the past; 63% and 46% of patients were receiving therapy (or had received therapy in the past) with methotrexate or tumor necrosis factor-α (TNF-α) inhibitors, respectively. Additional demographic and cardiovascular risk factor variables are described in Table 1.

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Figure.
Prevalence of atherosclerotic plaque in controls and in patients with rheumatoid arthritis, subdivided according to age.

Error bars indicate 95th percentiles.

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Atherosclerosis in Rheumatoid Arthritis
Posted on February 27, 2006
Francisco R. Lafita
Gabinet Mèdic. 43850 Cambrils.Baix Camp. Spain
Conflict of Interest: None Declared

Rheumatoid arthritis (RA) as other inflammatory diseases is associated with an increase in cardiovascular morbidity and mortality. The increased cardiovascular risk is supposed to be mediated by the inflammatory process (1). Roman et al.(2) showed interesting data on the presence of preclinical atherosclerosis in RA patients, suggesting again that chronic inflammation and disease severity could play a role as atherogenic factors. Curiously, patients needing TNF-á inhibitor therapy were found to have higher plaque prevalence. Dysregulation of TNF has been implicated in a wide variety of inflammatory diseases including rheumatoid arthritis TNF-á as other mediators (IL-1, oxygen radicals) stimulates Nuclear Factor kappa-B (NF-kappa B) to regulate genes that play an important role in inflammation (3). NF-kappa B has been found in RA in synovial lining and in endothelium (4). However, the paper by Roman et al brings up some questions. Rheumatoid Arthritis as a systemic disease may have different extrarticular manifestations. It should be interesting to investigate if RA patients with plaques presented more extraarticular manifestations that those without plaques mostly in younger patients where plaque prevalence was particularly higher. This aspect should have been reported on. Beside its interest this elegant cross-sectional study should be complemented with prospective studies. Are RA patients with an increased population of CD4+ CD28null T cells more prone to develop atherosclerotic events? Should biological therapies decrease RA associated risk for atherosclerotic events as suggested by previous data? (5)

1. Soubrier M, Dougados M. Atherosclerosis and rheumatoid arthritis. Rev Med Interne. 2006 Feb;27(2):125-136 2. Roman MJ, Moeller E, Davis A, Paget SA, Crow MK et al. Preclinical Carotid Atherosclerosis in Patients with Rheumatoid Arthritis. Ann Intern Med. 2006; 144:249-256 3. Aupperle KR, Bennett B, Boyle DL et al. Regulation of NF-kB by IkB kinase in fibroblast-like synoviocytes. J Immunol 1999; 163: 427-433. 4. Handel ML, McMorrow LB, Gravallese EM. Nuclear factor-kappa B in rheumatoid synovium. Localization of p50 and p65. Arthritis Rheum 1995; 38: 1762-1770. 5. Jacobsson LT, Turesson C, Gulfe A, Kapetanovic MC, Petersson IF, et al. Treatment with tumor necrosis factor blockers is associated with a lower incidence of first cardiovascular events in patients with rheumatoid arthritis. J Rheumatol. 2005 Jul;32(7):1213-1218

Conflict of Interest:

None declared

Carotid atherosclerosis and rheumatoid arthritis.
Posted on March 1, 2006
Giovanni Targher
Division of Internal Medicine, Sacro Cuore Hospital, Negrar (VR), Italy
Conflict of Interest: None Declared

Dear Editor,

I read with interest the recent article by Roman and colleagues [1] assessing the presence of carotid atherosclerosis in patients with rheumatoid arthritis (RA). The authors conclude that compared with matched control subjects, patients with RA have a much higher prevalence of ultrasonographically determined carotid atherosclerotic plaques independent of a broad spectrum of potential confounders. Uxpectedly, they did not find a significant association between the levels of plasma inflammatory markers (i.e., C-reactive protein and some endothelial adhesion molecules) and carotid artery intima-media thickness and plaque among RA patients. Nevertheless, the authors have postulated that the biological mechanisms by which premature atherosclerosis develops in RA could be largely mediated by underlying chronic inflammation. Given the cross-sectional design and the relatively small sample size of this study, however, it is clear that chronic inflammation (a typical feature of RA patients irrespective of their atherosclerotic status) could likely be a key mechanism in the development of atherosclerosis. However, it would be interesting to known whether among these RA patients there were significant associations between the prevalence of carotid atherosclerotic plaques and the circulating levels of auto-antibodies, which have been measured in this study, such as rheumatoid factor titres, anti-cyclic citrullinated peptide antibodies (anti-CCP), and antinuclear antibodies (ANA). This additional information could be potentially useful because it might further confirms the evidence of a possible biological link between autoimmune mechanisms and accelerated atherosclerosis in RA as well as in other autoimmune diseases. Future interventional studies with disease-modifying agents that effectively suppress the production of autoantibodies, are obviously necessary to determine whether these autoimmune mechanisms can really play a pathogenetic role in RA atherogenesis, and whether these pharmacological interventions may be effective in reducing the increased cardiovascular risk of RA patients.

REFERENCES

1. Roman MJ, Moeller E, Davis A, Paget SA, Crow MK, Lockshin MD, Sammaritano L, Devereux RB, Schwartz JE, Levine DM, Salmon JE. Preclinical carotid atherosclerosis in patients with rheumatoid arthritis. Ann Intern Med 2006; 144: 249-256.

Conflict of Interest:

None declared

Preclinical Carotid Atherosclerosis in Rheumatoid Arthritis
Posted on March 6, 2006
Hidekatsu Yanai
The Jikei University School of Medicine
Conflict of Interest: None Declared

Roman and colleagues (1) reported that patients with rheumatoid arthritis have a high prevalence of preclinical atherosclerosis independent of traditional atherosclerotic risk factors, suggesting the association between chronic inflammation and atherosclerosis. Regrettably, they failed to prove that inflammatory mediators predict atherosclerosis, but, we agree with their suggestion.

To date, a great number of prospective epidemiologic studies have demonstrated that high-sensitivity C-reactive protein (hs-CRP) independently predicts vascular risk, and several cohort studies confirmed that hs-CRP evaluation adds prognostic information beyond that available from the Framingham Risk Score (2). Therefore, the American Heart Association and Centers for Disease Control and Prevention stated that measurement of hs-CRP is an independent marker of risks and, in those judged at intermediate risk by global risk assessment (10 to 20% risk of cardiovascular heart disease (CHD) per 10 years), may help direct further evaluation and therapy in the primary prevention of CHD in their recommendations (Class IIa, Level of Evidence B) (3).

Tumor necrosis factor-alpha (TNF-alpha) and interleukin-6 are major and important cytokines accelerating atherosclerosis (4). It may be due to the use of TNF-alpha inhibitor therapy which is a possible marker of disease severity (1) that the authors could not obtain the significant association between inflammatory markers and atherosclerotic plaque presence. They determined inflammatory markers only once in their study. We believe that serial measurements of inflammatory markers may prove that inflammatory mediators predict atherosclerosis among patients with rheumatoid arthritis.

1. Roman MJ, Moeller E, Davis A, Paget SA, Crow MK, Lockshin MD, et al. Preclinical carotid atherosclerosis in patients with rheumatoid arthritis. Ann Intern Med. 2006;144:249-256.

2. Ridker PM, Wilson PWF, Grundy SM. Should C-reactive protein be added to metabolic syndrome and to assessment of global cardiovascular risk? Circulation. 2004;109:2818-2825.

3. Pearson TA, Mensah GA, Alexander RW, Anderson JL, Cannon III RO, Criqui M, et al. Markers of inflammation and cardiovascular disease. Application to clinical and public health practice: A statement for healthcare professionals for the Centers for Disease Control and Prevention and the American Heart Association. Circulation. 2003;107:499-511.

4. Fernandez-Real JM, Ricart W. Insulin resistance and chronic cardiovascular inflammatory syndrome. Endocrine Reviews. 2003;24:278-301.

Conflict of Interest:

None declared

Authors Respond
Posted on March 31, 2006
Mary J. Roman
Weill Medical College of Cornell University
Conflict of Interest: None Declared

We appreciate Dr. Targher's comments. We, too, expected to find a relationship between markers of systemic inflammation and evidence of carotid atherosclerosis in rheumatoid arthritis patients. Although our study did not define the mediators of accelerated atherosclerosis or the markers that predict it, we believe our findings support an important role for chronic inflammation. The analyses suggested by Dr. Targher revealed no association between autoantibodies (rheumatoid factor [RF] or anti- cyclic citrullinated protein [anti-CCP] antibodies) and the presence of carotid atherosclerosis in our patients. Carotid plaque was detected in 49% of patients positive for RF and 46% of patients negative for RF (p=0.78), and in 42% of patients with anti-CCP antibodies compared to 44% without anti-CCP antibodies (p=0.84). Furthermore, although titers of anti-CCP antibodies may predict radiographic outcome and disease severity in rheumatoid arthritis1, they did not predict carotid atherosclerosis (plaque vs. no plaque: 388±783 vs. 480±842 units/mL, p=0.85). However, the cross-sectional design of our study and single determinations of autoantibodies and inflammatory mediators do not allow us to determine cumulative exposure and therefore limit the interpretation of our results. These findings contrast with those of our study in lupus patients in whom the prevalence of atherosclerosis was comparable to that in rheumatoid arthritis, but the presence of certain autoantibodies was inversely associated with carotid plaque2. We agree that more focused and effective immunomodulatory therapy may prevent or attenuate morbidity and mortality due to atherosclerosis in rheumatoid arthritis. However, the specific targets for intervention are not yet clear. Indeed, it will be important to determine whether disease-modifying therapies that ameliorate symptoms and prevent joint damage in rheumatoid arthritis will also decrease the prevalence and severity of atherosclerosis in patients with rheumatoid arthritis.

Jane E. Salmon, MD Hospital for Special Surgery

Stephen A. Paget, MD Hospital for Special Surgery

Mary J. Roman, MD Weill Medical College of Cornell University

1. Berglin E, Johansson T, Sundin U, Jidell E, Wadell G, Hallmans G, Rantapaa-Dahlqvist S. Radiological outcome in rheumatoid arthritis is predicted by presence of antibodies against cyclic citrullinated peptide before and at disease onset, and by IgA-RF at disease onset. Ann Rheum Dis 2006;65:453-458.

2. Roman MJ, Moeller E, Davis A, Paget SA, Crow MK, Lockshin MD, Sammaritano L, Devereux RB, Schwartz JE, Levine DM, Salmon JE. Preclinical carotid atherosclerosis in patients with rheumatoid arthritis: prevalence and associated factors. Ann Intern Med 2006; 144:249-256.

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Summary for Patients

Asymptomatic Changes in the Carotid Arteries of Patients with Rheumatoid Arthritis

The summary below is from the full report titled “Preclinical Carotid Atherosclerosis in Patients with Rheumatoid Arthritis.” It is in the 21 February 2006 issue of Annals of Internal Medicine (volume 144, pages 249-256). The authors are M.J. Roman, E. Moeller, A. Davis, S.A. Paget, M.K. Crow, M.D. Lockshin, L. Sammaritano, R.B. Devereux, J.E. Schwartz, D.M. Levine, and J.E. Salmon.

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