Immunopathogenesis of Rheumatoid Arthritis

The excess risk of cardiovascular disease (CVD) associated with inflammatory rheumatic diseases has long been recognized. Patients with established rheumatoid arthritis (RA) or systemic lupus erythematosus (SLE) have higher mortality compared with the general population. Over 50% of premature deaths in RA are attributable to CVD. Excess mortality in SLE follows a bimodal pattern, with the early peak predominantly a consequence of active lupus or its complications, and the later peak largely attributable to atherosclerosis. Patients with RA or SLE are also at increased risk of nonfatal ischemic heart disease. The management and outcome of myocardial infarction and congestive heart failure in patients with RA or SLE differs from that in the general population. Traditional CVD risk factors (TRF) include increasing age, male gender, smoking, hypertension, hypercholesterolemia and diabetes. Whereas some TRFs are elevated in patients with RA or SLE, several are not, and others exhibit paradoxical relationships. Risk scores developed for the general population based on TRFs are likely, therefore, to underestimate CVD risk in RA and SLE. Until additional research and disease-specific risk prediction tools are available, current evidence supports aggressive treatment of disease activity, and careful screening for and management of TRFs.

Epidemiology of CVD in rheumatic disease, with a focus on RA and SLE.

Rheumatoid arthritis is associated with an increased risk for cardiovascular events, such as myocardial infarction and stroke. Epidemiological evidence suggests that classic cardiovascular risk factors, such as hypertension, dyslipidaemia, insulin resistance and body composition alterations are important but not sufficient to explain all of the excess risk. High-grade systemic inflammation and its interplay with classic risk factors may also contribute. Some associations between classic risk factors and cardiovascular risk in people with rheumatoid arthritis appear counterintuitive but may be explained on the basis of biological alterations. More research is necessary to uncover the exact mechanisms responsible for this phenomenon, develop accurate systems used to identify patients at high risk, design and assess prevention strategies specific to this population of patients.

https://ard.bmj.com/content/annrheumdis/early/2010/11/24/ard.2010.142133.full.pdf

Cardiovascular disease in rheumatoid arthritis: state of the art and future perspectives.

Rheumatoid arthritis is a systemic autoimmune disease characterized by excess morbidity and mortality from cardiovascular disease. Mechanisms linking rheumatoid arthritis and cardiovascular disease include shared inflammatory mediators, post-translational modifications of peptides/proteins and subsequent immune responses, alterations in the composition and function of lipoproteins, increased oxidative stress, and endothelial dysfunction. Despite a growing understanding of these mechanisms and their complex interplay with conventional cardiovascular risk factors, optimal approaches of risk stratification, prevention, and treatment in the context of rheumatoid arthritis remain unknown. A multifaceted approach to reduce the burden posed by cardiovascular disease requires optimal management of traditional risk factors in addition to those intrinsic to rheumatoid arthritis such as increased disease activity. Treatments for rheumatoid arthritis seem to exert differential effects on cardiovascular risk as well as the mechanisms linking these conditions. More research is needed to establish whether preferential rheumatoid arthritis therapies exist in terms of prevention of cardiovascular disease. Ultimately, understanding the unique mechanisms for cardiovascular disease in rheumatoid arthritis will aid in risk stratification and the identification of novel targets for meaningful reduction of cardiovascular risk in this patient population.

https://www.bmj.com/content/bmj/361/bmj.k1036.full.pdf

Increased cardiovascular risk in rheumatoid arthritis: mechanisms and implications.

Chapter 69 – Etiology and Pathogenesis of Rheumatoid Arthritis

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.

Association between anti–cyclic citrullinated peptide antibodies and ischemic heart disease in patients with rheumatoid arthritis

cells, in vitro fertilization, intravenousimmunoglobulin, NK cells, recurrentmiscarriageCorrespondenceSilvia Sa´nchez-Ramo´n, Division of ClinicalImmunology, Department of Immunology,Hospital General Universitario GregorioMaran˜o´n, Calle Doctor Esquerdo 46, 28007Madrid, Spain.E-mail: ssanchez.hgugm@salud.madrid.orgSubmission November 20, 2011;accepted March 13, 2012.CitationMoraru M, Carbone J, Alecsandru D, Castillo-Rama M, Garci´a-Segovia A, Gil J, Alonso B,Aguaro´n A, Ramos-Medina R, Marti´nez deMari´a J, Oliver-Min˜arro D, Rodri´guez-MahouM, Ortega V, Caballero P, Meliā E, Vidal J,Cianchetta-Sivori M, Esteban C, Vargas-HennyL, Dale J, Ortiz-Quintana L, Ferna´ndez-Cruz E,Sa´nchez-Ramo´n S. Intravenousimmunoglobulin treatment increased live birthrate in a Spanish cohort of women withrecurrent reproductive failure and expandedCD56

Intravenous immunoglobulin treatment increased live birth rate in a Spanish cohort of women with recurrent reproductive failure and expanded CD56(+) cells.

NK cell expansion in obstetrical antiphospholipid syndrome: guilty by association?

https://www.fertstert.org/article/S0015-0282(06)04415-3/pdf

Desamparados Oliver-Miñarro

Papers

Association between anti–cyclic citrullinated peptide antibodies and ischemic heart disease in patients with rheumatoid arthritis

Intravenous immunoglobulin treatment increased live birth rate in a Spanish cohort of women with recurrent reproductive failure and expanded CD56(+) cells.

NK cell expansion in obstetrical antiphospholipid syndrome: guilty by association?

Isolated type 5 antimitochondrial autoantibodies are associated with a history of thrombocytopenia and fetal loss