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Abstract

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. AUTHOR CONTRIBUTIONS
  8. ROLE OF THE STUDY SPONSOR
  9. Acknowledgements
  10. REFERENCES

Objective

Patients with rheumatoid arthritis (RA) have an increased risk of cardiovascular disease that may not always be related to the presence of traditional cardiovascular risk factors. The aim of this study was to determine if anti–cyclic citrullinated peptide (anti-CCP) antibodies are associated with cardiovascular disease in patients with RA.

Methods

Anti-CCP antibodies were determined by enzyme-linked immunosorbent assay in the earliest serum sample available from 937 patients with a diagnosis of RA. We studied the relationship between anti-CCP antibodies with traditional cardiovascular risk factors and cardiovascular events.

Results

We found positive anti-CCP antibodies (>25 units/ml) in 672 patients (71.7%). There was no association between the anti-CCP antibodies and cardiovascular risk factors such as smoking, hypertension, dyslipidemia, being overweight, or diabetes mellitus. However, patients who had positive anti-CCP antibodies experienced more frequent ischemic heart disease (6.5% versus 2.6%; odds ratio [OR] 2.58, 95% confidence interval [95% CI] 1.17–5.65) and had higher mortality rates (11.2% versus 6.8%; OR 1.72, 95% CI 1.01–2.91). Similar results were obtained when we considered anti-CCP titers 20-fold higher (>500 units/ml). Multivariable analysis showed that ischemic heart disease is independently associated with positive anti-CCP antibodies (OR 2.8, 95% CI 1.19–6.56; P = 0.009).

Conclusion

Anti-CCP antibodies in patients with RA are independently associated with the development of ischemic heart disease.


INTRODUCTION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. AUTHOR CONTRIBUTIONS
  8. ROLE OF THE STUDY SPONSOR
  9. Acknowledgements
  10. REFERENCES

The natural course of rheumatoid arthritis (RA), a chronic inflammatory and progressive disease, leads to articular destruction, functional incapacity, deterioration in quality of life, and increased morbidity and mortality (1, 2). RA is also a novel independent risk factor for cardiovascular events such as ischemic heart disease (IHD) or congestive heart failure (3–5), which cause up to 40% of deaths in these patients (6). In patients with RA, severe extraarticular manifestations are associated with a higher risk of the development of cardiovascular events (7). However, in patients with RA, the traditional and nontraditional cardiovascular risk factors have been recently reported to not contribute to the development of their cardiovascular disease (8).

Highly specific RA markers include antibodies against citrullinated proteins and cyclic citrullinated peptides (anti-CCPs) (9, 10). These autoantibodies predict poor clinical outcome and radiologic severity (11, 12), and may be implicated in the pathogenesis of RA (13–15). However, the relationship between anti-CCP antibodies and cardiovascular comorbidity in patients with RA has not been well defined. This study was performed to determine the associations between anti-CCP antibodies in patients with RA and their cardiovascular events.

PATIENTS AND METHODS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. AUTHOR CONTRIBUTIONS
  8. ROLE OF THE STUDY SPONSOR
  9. Acknowledgements
  10. REFERENCES

Patients.

In 1988, the Rheumatology Department at the Hospital General Universitario Gregorio Marañón in Madrid, Spain, launched a still-ongoing prospective cohort to study the incidence of systemic inflammatory rheumatic diseases. In the present study, we only included patients who fulfilled the American College of Rheumatology (formerly the American Rheumatism Association) criteria for RA (16) between 1988 and 2003. Informed consent was obtained from all patients for the use of their blood samples and clinical data. These patients were periodically evaluated until death or loss to followup. Annual followup visits included taking their personal histories and physical examinations. The patient's first-available blood sample was obtained after enrollment and frozen at −40°C until the sample was assayed in this study.

Variables.

All clinical information was collected directly from each patient and included demographic data, family history, and disease onset. The last consultation date for each patient was recorded. In case of death, we registered the date and cause of death (obtained from the medical chart or death certificate).

Cardiovascular risk factors for these patients were rigorously evaluated, and included smoking history (yes or no), being overweight (body mass index ≥25 kg/m2), diabetes mellitus (glycemia on fasting ≥126 mg/dl, diabetes symptoms and random glycemia ≥200 mg/dl, or oral glucose tolerance test glycemia ≥200 mg/dl), hyperlipidemia (cholesterol ≥240 mg/dl, triglycerides ≥200 mg/dl in 3 different determinations, or hypolipemiant therapy), and hypertension (persistent systolic blood pressure ≥140 mm Hg and persistent diastolic blood pressure ≥90 mm Hg). Erythrocyte sedimentation rate (ESR) and rheumatoid factor (RF) were measured by Westergren technique and rate nephelometry (IMMAGE; Beckman Coulter, Fullerton, CA), respectively.

Cardiovascular events for these patients were classified as follows: heart failure, attributed to any underlying cause (defined clinically and, when possible, by more objective evidence such as chest radiographs or echocardiography); IHD, defined as the presence of angina pectoris and/or a myocardial infarction (angina pectoris was diagnosed from a typical history of chest pain with a positive noninvasive test and/or coronary arteriography in the majority of cases, and myocardial infarction was diagnosed by a history of typical chest pain and a significant electrocardiographic and acute enzymatic pattern); acute stroke, including development of ischemic and hemorrhagic stroke as defined by clinical documentation of the diagnosis with confirmatory findings on computed tomography, magnetic resonance imaging, or autopsy (ischemic stroke was defined as the acute onset of a focal neurologic deficit persisting for more than 24 hours, compatible with altered circulation to a limited region of the cerebral hemispheres, brainstem, or cerebellum; hemorrhagic stroke was defined as the acute onset of a focal neurologic deficit associated with some or all of the following: headache, vomiting, altered level of consciousness, signs of meningeal irritation, and/or blood-stained cerebrospinal fluid); and arterial or venous thrombosis occurring in any vascular territories, confirmed by an angiogram or autopsy after excluding cardiac or cerebral thrombosis. All of the events that occurred during the disease evolution were registered.

Detection of anti-CCP antibodies.

We studied the earliest serum sample available from each patient. Serum levels of anti-CCP antibodies were measured with a second-generation commercial enzyme-linked immunosorbent assay (Immunoscan RA; Euro-Diagnostica, Malmö, Sweden), according to the manufacturer's instructions (9, 10). The assays included positive and negative controls. The optimal assay cutoff level in our population (≥25 units/ml) was determined using receiver operating characteristic curves, and was similar to the cutoff level recommended by the manufacturer.

Statistical analysis.

Correlations between numerical variables (i.e., age, disease onset, and disease evolution) were determined using Spearman's correlation coefficient. Data were compared between patients with and without anti-CCP antibodies using chi-square test or, in some cases, Fisher's exact test. Bivariate and multivariate logistic regression including age, sex, comorbid conditions, cardiovascular risk factors, and cardiovascular events as covariables were used to determine the relationship between anti-CCP antibodies and the risk of cardiovascular events. Odds ratios (ORs) were obtained from the best model. P values less than 0.05 were considered significant.

RESULTS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. AUTHOR CONTRIBUTIONS
  8. ROLE OF THE STUDY SPONSOR
  9. Acknowledgements
  10. REFERENCES

We included 937 patients with RA between 1988 and 2003. The mean ± SD disease duration was 10.5 ± 8.3 years (range 0.5–47). The mean ± SD age at disease onset was 51.8 ± 13.2 years, and the mean ± SD age at the end of the study was 62.4 ± 18.3 years. Most patients were women (690 [73.6%] of 937). Clinical features are shown in Table 1.

Table 1. Main clinical features and therapies in 937 patients with rheumatoid arthritis
 No. (%)
  • *

    Including amyloidosis, drug toxicity, glomerulonephritis, and isolated hematuria without infection or urologic problems.

  • Including pleuritis, interstitial fibrosis, nodular lung disease, and pneumonitis.

Polyarthritis937 (100)
Morning stiffness858 (91.5)
Rheumatoid nodules189 (20.2)
Symptomatic Sjögren's syndrome179 (19.1)
Renal disease*134 (14.3)
Pulmonary disease92 (9.8)
Anemia372 (39.7)
Joint space narrowing663 (70.7)
Bony erosions619 (66.1)
Articular deformities249 (26.6)
Rheumatoid factor (>20 IU/ml; n = 929)738 (79.4)
Antinuclear antibodies (HEp-2 cells; n = 864)532 (61.6)
Erythrocyte sedimentation rate (>20 mm/hour; n = 923)783 (84.8)
Nonsteroidal antiinflammatory drugs937 (100)
Low-dose glucocorticoids758 (80.9)
Methotrexate605 (64.6)
Other classic disease-modifying drugs521 (55.6)
Anti–tumor necrosis factor α therapies91 (9.7)
Deaths93 (9.9)

In these patients, cardiovascular risk factors were present as smoking history (299 [31.9%] of 937), being overweight (337 [35.9%] of 937), diabetes mellitus (92 [9.8%] of 937), hyperlipidemia (290 [30.9%] of 937), and hypertension (157 [16.7%] of 937). Sixty-six patients experienced cardiac failure (7%), 51 experienced IHD (5.4%), 39 experienced acute stroke (4.1%), and 44 experienced thrombosis (4.6%). IHD prevalence among female and male RA patients was 3.2% (22 of 690) and 11.7% (29 of 247), respectively. Other cardiovascular events were also more frequent in male than in female RA patients. Cardiac failure was present in 9.7% (24 of 247) and 6.1% (42 of 690), acute stroke was present in 7.3% (18 of 247) and 3% (21 of 690), and thrombosis was present in 6.1% (15 of 247) and 4.2% (29 of 690) of men and women with RA, respectively. Ninety-three patients died (9.9%). The main causes of death included infections (30 [32.2%] of 93), tumors (23 [24.7%] of 93), cardiovascular disease (17 [18.2%] of 93), and amyloidosis (10 [10.7%] of 93).

Approximately 72% of patients (672 of 937) tested positive for anti-CCP antibodies. Anti-CCP positive and negative groups showed no differences for sex, age, time of disease evolution, and traditional cardiovascular risk factors (Table 2). The bivariate analysis showed that patients who tested positive for anti-CCP antibodies (>25 units/ml) experienced both an increased frequency of IHD (6.5% versus 2.6%; OR 2.58, 95% confidence interval [95% CI] 1.17–5.65) and a higher global death rate (11.2% versus 6.8%; OR 1.72, 95% CI 1.01–2.91) (Table 3). However, no association was found between anti-CCP antibodies and causes of death in patients with RA (Table 4).

Table 2. Traditional cardiovascular risk factors in patients with RA with anti-CCP antibodies (>25 units/ml) versus patients with RA without anti-CCP antibodies (<25 units/ml)*
 Anti-CCP positive (n = 672)Anti-CCP negative (n = 265)OR (95% CI)
  • *

    Values are the number (percentage) unless otherwise indicated. RA = rheumatoid arthritis; anti-CCP = anti–cyclic citrullinated peptide; OR = odds ratio; 95% CI = 95% confidence interval; NS = not significant.

Smoking217 (32.2)82 (30.9)NS
Overweight252 (37.5)85 (32.0)NS
Diabetes mellitus58 (8.6)34 (12.8)NS
Hyperlipidemia199 (29.6)91 (34.3)NS
Table 3. Cardiovascular events in patients with RA with anti-CCP antibodies (>25 units/ml) versus patients with RA without anti-CCP antibodies (<25 units/ml) in a bivariate logistic regression analysis*
 Anti-CCP positive (n = 672)Anti-CCP negative (n = 265)OR (95% CI)P
  • *

    Values are the number (percentage) unless otherwise indicated. RA = rheumatoid arthritis; anti-CCP = anti–cyclic citrullinated peptide; OR = odds ratio; 95% CI = 95% confidence interval; NS = not significant.

Heart failure49 (7.2)17 (6.4)NS 
Ischemic heart disease44 (6.5)7 (2.6)2.58 (1.17–5.65)< 0.025
Acute stroke30 (4.4)9 (3.3)NS 
Thrombosis35 (5.2)9 (3.3)NS 
Death75 (11.2)18 (6.8)1.72 (1.01–2.91)< 0.05
Table 4. Main causes of death in patients with RA with anti-CCP antibodies (>25 units/ml) versus patients with RA without anti-CCP antibodies (<25 units/ml)*
 Anti-CCP positive (n = 75)Anti-CCP negative (n = 18)P
  • *

    Values are the number (percentage). RA = rheumatoid arthritis; anti-CCP = anti–cyclic citrullinated peptide; NS = not significant.

Infections22 (29.3)8 (44.4)0.220
Tumors19 (25.3)4 (22.2)NS
Cardiovascular disease15 (20)2 (11.1)NS
Amyloidosis9 (12)1 (5.5)NS
Others10 (13.3)3 (16.6)NS

Anti-CCP antibodies were also associated with an ESR >20 mm/hour and a positive RF. Patients who tested positive for anti-CCP antibodies more frequently received glucocorticoids, methotrexate, and anti–tumor necrosis factor α (anti-TNFα) therapies, but not more nonsteroidal antiinflammatory drugs (NSAIDs). No differences were found when doses were analyzed (Table 5).

Table 5. Laboratory findings and pharmacologic therapies in patients with RA with anti-CCP antibodies (>25 units/ml) versus patients with RA without anti-CCP antibodies (<25 units/ml) in a bivariate logistic regression analysis*
 Anti-CCP positive (n = 672)Anti-CCP negative (n = 265)OR (95% CI)P
  • *

    Values are the number (percentage) unless otherwise indicated. RA = rheumatoid arthritis; anti-CCP = anti–cyclic citrullinated peptide; OR = odds ratio; 95% CI = 95% confidence interval; ESR = erythrocyte sedimentation rate; RF = rheumatoid factor; anti-TNFα = anti–tumor necrosis factor α.

ESR >20 mm/hour392/663 (59.1)190/260 (73.0)3.12 (2.18–4.46)< 0.001
Positive RF617/668 (92.4)121/261 (46.4)13.99 (10.03–19.49)< 0.001
Glucocorticoids558 (83.0)200 (75.5)1.59 (1.12–2.24)< 0.005
Methotrexate463 (68.9)142 (53.6)1.91 (1.43–2.54)< 0.001
Anti-TNFα76 (11.3)15 (5.7)2.12 (1.21–3.71)< 0.01

Variables for multivariate logistic regression models consisted of IHD, global death rate, ESR >20 mm/hour, positive RF, and glucocorticoid, methotrexate, and anti-TNFα therapies. An association between anti-CCP antibodies and the independent risk of developing IHD was found (OR 2.8, 95% CI 1.19–6.56; P = 0.009). There was no relationship between IHD and the quantity of anti-CCP antibodies. Similar results were obtained when we considered titers to be positive at >500 units/ml (Table 6).

Table 6. Cardiovascular events in patients with RA with anti-CCP antibodies (>500 units/ml) versus patients with RA without anti-CCP antibodies (<500 units/ml) in a bivariate logistic regression analysis*
 Anti-CCP positive (n = 299)Anti-CCP negative (n = 638)OR (95% CI)P
  • *

    Values are the number (percentage) unless otherwise indicated. RA = rheumatoid arthritis; anti-CCP = anti–cyclic citrullinated peptide; OR = odds ratio; 95% CI = 95% confidence interval.

Heart failure22 (7.3)44 (6.9) 0.801
Ischemic heart disease28 (9.4)23 (3.6)2.76 (1.59–4.78)< 0.001
Acute stroke16 (5.3)23 (3.6) 0.325
Thrombosis18 (6.0)26 (4.1) 0.182
Death27 (9.0)66 (10.3) 0.522

DISCUSSION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. AUTHOR CONTRIBUTIONS
  8. ROLE OF THE STUDY SPONSOR
  9. Acknowledgements
  10. REFERENCES

Anti-CCP antibodies are highly specific markers of RA and are detected in 58–82% of patients (9, 10, 17, 18). In patients with RA, these autoantibodies are associated with greater inflammatory activity, poorer radiologic outcome, higher frequency of extraarticular manifestations, and poorer outcomes in early arthritis. The anti-CCP response may also be involved in the pathogenesis of RA because of both the presence of antibodies directed against citrullinated proteins in the target tissue and the association between anti-CCP antibodies and severe RA (7, 11, 17–21).

IHD prevalence among the 50-year-old age group in Spain is ∼5%, whereas the prevalence among women is <1% (22). In our study, we found IHD in 5.4% of RA patients in the cohort; however, the prevalence among men and women with RA was 11.7% and 3.2%, respectively. Patients with RA have unusually severe cardiovascular morbidity and higher cardiovascular mortality (1–3, 5); for example, an increased prevalence of IHD, more frequent coronary revascularizations, and lower survival rate after an acute myocardial infarction (3, 23, 24). These patients' cardiovascular disease has not been associated with traditional cardiovascular risk factors such as smoking, hypertension, diabetes mellitus, being overweight, and dyslipidemia (3, 7, 8, 25), although they do frequently show an atherogenic lipid profile associated with corticosteroid treatment and inflammatory activity (26, 27). We found no association between smoking and anti-CCP antibodies in our cohort. In patients with RA, this lack of association among the traditional cardiovascular risk factors and cardiovascular disease suggests the presence of alternate mechanisms or, more likely, additive mechanisms (8) such as chronic inflammation, RF status, or therapies such as glucocorticoids or NSAIDs. In our patients, anti-CCP antibodies were associated with high ESRs, positive RF, and glucocorticoid, methotrexate, and anti-TNFα therapies.

These alternate or additive mechanisms involved in the development of vascular damage include both endothelial dysfunction and impaired vascular repair caused by the chronic exposure to inflammation mediators (3, 25, 28–30). In addition, coronary arteries of patients with RA show less histologic evidence of atherosclerosis than the general population, but do show larger inflammatory lesions (30). This subclinical vascular disease may be linked to the presence of anti-CCP antibodies (31), and the presence of circulating anti-CCP antibodies has recently been associated with stronger evidence of subclinical atherosclerosis in patients with RA (32).

In our RA cohort, anti-CCP antibodies are independently associated with the development of IHD, and the risk of IHD is irrespective of the titers of anti-CCP antibodies. This association revealed an underlying autoimmune inflammatory disorder affecting not only the development of articular RA manifestations, but also the cardiovascular comorbidity of RA. This association may be attributed to chronic inflammation that stimulates the production of anti-CCP antibodies. Patients with RA treated with disease-modifying antirheumatic drugs have a lower annual incidence of acute myocardial infarction because controlling inflammation reduces vascular damage (33, 34).

In conclusion, to our knowledge, our study is the largest RA cohort yet to evaluate the relationship between anti-CCP antibodies and clinically manifest cardiovascular disease. We demonstrated an association between anti-CCP antibodies of patients with RA and the presence of coronary heart disease independent of traditional cardiovascular risk factors. Whether or not citrullinated proteins, peptidyl arginine deiminase activity, or antibodies against citrullinated proteins play a role in the development of the atherosclerosis process in patients with RA remains to be substantiated. Unfortunately, the detection of this antibody is useless as a marker of IHD because of both the low frequency of IHD and the high frequency of patients testing positive for anti-CCP antibodies.

AUTHOR CONTRIBUTIONS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. AUTHOR CONTRIBUTIONS
  8. ROLE OF THE STUDY SPONSOR
  9. Acknowledgements
  10. REFERENCES

Dr. Carreño had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Study design. López-Longo, Monteagudo, González, Carreño.

Acquisition of data. De la Torre, González-Diaz de Rábago, Sánchez-Ramón, Rodríguez-Mahou, García-Castro, Casas.

Analysis and interpretation of data. López-Longo, Paravisini, Monteagudo, González, Carreño.

Manuscript preparation. López-Longo, Oliver-Miñarro, Paravisini.

Statistical analysis. Oliver-Miñarro, González.

ROLE OF THE STUDY SPONSOR

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. AUTHOR CONTRIBUTIONS
  8. ROLE OF THE STUDY SPONSOR
  9. Acknowledgements
  10. REFERENCES

Abbott Laboratories had no role in the study design, data collection, data analysis, writing on the manuscript, or decision to submit the manuscript for publication.

Acknowledgements

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. AUTHOR CONTRIBUTIONS
  8. ROLE OF THE STUDY SPONSOR
  9. Acknowledgements
  10. REFERENCES

We are especially grateful to Dr. María José Cuadrado for her careful revision on this manuscript. David R. Peck and Andrew Boot structurally revised this manuscript using the reader expectations approach; also, we extend special thanks to George Gopen.

REFERENCES

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. AUTHOR CONTRIBUTIONS
  8. ROLE OF THE STUDY SPONSOR
  9. Acknowledgements
  10. REFERENCES
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