Getting to the
The Heart of Rheumatoid Arthritis
For more than 50 years there has been interest in the increased mortality associated with rheumatoid arthritis (RA). One of the major causes for excess deaths is cardiovascular (CV) disease, although it was not clear if this was due to the increase in CV disease in RA or just a general increase in mortality and a consequent increase in CV deaths.
However, in the last decade a series of important studies have shown an overall increase of CV disease in RA, although the degree of increase varies among specific CV problems: myocardial infarction (Ml), congestive heart failure (CHF), stroke (CVA) and peripheral vascular disease (PVD).
The contribution of traditional and RA-specific risk factors to this increased risk of CV morbidity and mortality were also investigated and although traditional CV disease risk factors were found to contribute to the increased risk of mortality in RA patients, they did not fully explain the increased CV mortality observed in RA. Instead, increased inflammation associated with RA appears to contribute substantially to the increased CV mortality.
These data strongly suggest that RA is an independent risk factor for CV disease and, hence, more aggressive management of inflammation in RA may lead to significant improvements in outcomes for patients with RA.
Current evidence suggests that METHOTREXATE (MTX) use is associated with a reduced risk of CV events in patients with RA. It controls several mediators of inflammation and thus may beneficially influence the net outcome of CV disease in RA.
Ann NY Acad Sci. 2007; 1108: 349-58, Am J Med 2008; 121(10): S9-S14. Best Pract Res Clin Rheumol. 2007; 21(5):885-906
To determine the cardiovascular risk in patients with RA on the basis of standard and new risk factors.
- Incidence of standard CV risk factors was studied in 312 RA patients and 57 healthy controls. Overall coronary risk (OCR) and CV death risk (SCORE scale), coronary heart disease risk (Framingem scale) were analysed.
- In addition, risk factors such as severity of systemic inflammation, some hemostatic indices and arterial wall stiffness were assessed.
Arterial hypertension in RA males is detected significantly more often than in population while blood lipid composition is satisfactory because of HDL-cholesterol.The Framingem index in RA patients is lower than in the controls (7.7 +/- 5.4 and 9.4 +/- 9.3%), mean SCORE was 2.16 +/- 2.9% (17.3% patients had high SCORE), a high OCR was registered in 25.7%.
- RA is accompanied with high activity of Willebrand factor, a low level of antithrombin III, and suppression of fibrinolysis in blood plasma (p < 0.05), that reflects high thrombogenic blood potential, high risk of thrombosis and related complications of coronary heart disease.
- Aortic pulse wave velocity over 12 m/s was recorded significantly more frequently in RA than in control patients (p < 0.001), RA females had high arterial rigidity both in the periphery and aorta.
CV risk indices based on standard risk factors cannot assess the risk in RA patients. Additional factors like severity of inflammation, hemostasis and arterial stiffness should be taken into consideration.
Ter Arkh. 2009; 81(6): 29-34
Inflammation and autoimmunity are associated with increased CV risk in patients with RA. This association may also be present in those without rheumatic diseases. The aim was to determine whether rheumatoid factor (RF), antinuclear antibody (ANA), and cyclic citrullinated peptide antibody (CCP) positivity are associated with increased risk of CV events and overall mortality in those with and without rheumatic diseases.
- A population-based cohort study was performed of all subjects who had a RF and/or ANA test performed between January 1,1990, and January 1, 2000, and/or CCP test performed between September 1, 2003, and January 1, 2005, with follow-up until April 1, 2007.
- Outcomes were ascertained using diagnostic indices from complete medical records, including CV events (Ml, CHF, and PVD) and mortality. Cox models were used to analyze the data.
- Adjusting for age, sex, calendar year, comorbidity and rheumatic disease, RF and ANA positivity were significant predictors of CV events and death (HR 1.43 and 1.18).
- Adjusting for age, CCP positivity was associated with CV events, but this association was not statistically significant (HR 3.1; 95% CI o.8,12.3).
RF and ANA positivity are significant predictors of CV events and mortality in both, those with and without rheumatic diseases. These results support the role of immune dysregulation in the etiology of CV disease.
J Rheumatol. 2009; 36(11): 2462-9
An accelerated progression of atherosclerosis may contribute to the increased mortality due to CVD reported in RA.
The aim was to identify variables, related to disease onset as well as to disease progression, of importance for the presence of atherosclerosis, as diagnosed by B- mode ultrasonography, in patients with medium-term RA.
The results are based on the co-analysis of retrospective data as well as cross-sectional data. The impact of RA per se on atherosclerosis was evaluated relative to age- and sex-matched controls.
- 39 RA patients, with a maximum age of 65 years, who had previously been included in a large retrospective cohort study, were assessed by duplex scanning after a disease duration of 19-23 years
- In the present study, factors identified in the two earlier studies were assessed for their potential relationship with intima-media wall thickness (IMT) of the common carotid artery (CCA), and the presence and grade of atherosclerotic plaques of the CCA and the common femoral artery, in regression models.
- Candidate co-variates : variables reflecting inflammatory activity at disease onset and at the time of ultrasound assessment, established CV risk factors, pharmacological treatment (corticosteroids, DMARDs), presence of complications and co-morbidity identified during disease progression, lipid levels, anti-lipid antibodies, haemostatic factors, markers of immune activation measured at ultrasound assessment.
- In patients with RA, analysis of simple linear regression models revealed that -
- Age, tissue plasminogen activator (tPA) antigen, cholesterol, LDL-cholesterol, triglycerides, and atherosclerotic plaques were significantly associated with IMT-CCA.
- Neither inflammatory status at disease onset, traditional CV risk factors, or pharmacological treatment during disease had any significant impact on IMT.
- In an estimated multiple linear regression model, log of cholesterol and of soluble intracellular adhesion molecule 1 were associated with increasing log of IMT-CCA, while MTX treatment tended to have a decreasing effect.
- In simple binary logistic regression, atherosclerotic plaques were associated with age, IMT-CCA, smoking, and the levels of slCAM-1, sE-selectin, interleukin-2 soluble receptor alpha, plasminogen activator inhibitor-1 mass, cholesterol, LDL-cholesterol, and the LDL/HDL ratio.
- A multiple approach indicated that plaques were associated with age, cholesterol, and sE-selectin. Severe plaques were associated with LDL-cholesterol and disease duration. Logistic regression in the age- and sex-matched case-control study revealed that IMT-CCA was, together with the D-dimer, associated with RA per se.
Levels of lipids and adhesion molecules were associated with the presence of atherosclerosis in RA. IMT-CCA was associated with RA per se. Disease duration could predict severe atherosclerotic plaques. Treatment with MTX seemed to decrease the IMT-CCA.
Scand J Rheumatol. 2004; 33(6): 373-9
Early Treatment Reduces the Cardiovascular Risk Factors in Newly Diagnosed Rheumatoid Arthritis Patients
To investigate subclinical atherosclerosis and the effect of treatment in patients with early RA.
- 40 patients with early RA who met the revised ACR criteria and disease duration of <1 year were included in the study.
- Smokers and patients with classical risk factors for atherosclerosis were excluded.
- Serum levels of total cholesterol (TC), triglycerides, HDL- cholesterol, and LDL-cholesterol were determined in all patients before and after 1 year of therapy. Carotid artery IMT and carotid plaque were measured before and after treatment.
- RA disease activity was measured using the 28 joint indices score (DAS-28) and clinical improvement was determined by the ACR response criteria. 45 age- and sex-matched nonsmoking volunteers were used as controls.
- All patients were treated with MTX and prednisone.
- RA patients had a baseline mild dyslipidemia characterized by a decrease in serum HDL-cholesterol levels and a highTC/HDL-cholesterol atherogenic ratio compared with controls.
- Both lipid parameters were significantly improved after treatment (P<0.01). Common carotid artery IMTs at baseline were higher in RA patients compared with controls (P<0.05).
- After 1 year of therapy there was a significant decrease in the IMTs (P<0.001). 35 patients (88%) achieved the ACR 20%, while 30 (75%) reached the ACR 50% response criteria. A significant decrease of DAS-28 was observed aftertreatment (P<0.03).
The atherogenic lipid profile and subclinical atherosclerosis are features of early RA, which improved after therapy. Early intervention and control of the disease activity may reduce the risk of atherosclerosis and CV events in patients with RA.
Semin Arthritis Rheum. 2008; 38(1): 13-9
Disease-Modifying Antirheumatic Drugs are Associated with a Reduced Risk for Cardiovascular Disease in Patient with Rheumatoid Arthritis: a Case Control Study
RA is characterized by inflammation and an increased risk for CVD. This study investigated possible associations between CVD and the use of conventional DMARDs in RA
- Using a case control design, 613 RA patients (5,649 patient-years) were studied, 72 with CVD and 541 without CVD. Data on RA, CVD and drug treatment were evaluated from time of RA diagnosis up to the first CV event or the end of the follow-up period.
- The dataset was categorized according to DMARD use: SSZ, HCQ or MTX. Odds ratios (ORs) for CVD, corrected for age, gender, smoking and RA duration, were calculated per DMARD group. Patients who never used SSZ, HCQ or MTX were used as a reference group
MTX treatment was associated with a significant CVD risk reduction.
- Risk reductions remained significant after additional correction for the presence of RF and erosions.
- After correction for hypertension, diabetes and hypercholesterolemia, 'MTX or SSZ ever' and 'MTX, SSZ and HCQ ever' showed significant CVD risk reduction. RF positivity and erosions both increased CVD risk, with ORs of 2.04 (1.02 to 4.07) and 2.36 (0.92 to 6.08), respectively.
- MTX and, to a lesser extent, SSZ were associated with significantly lower CVD risk compared to RA patients who never used SSZ, HCQ or MTX
It is hypothesized that DMARD use, in particular MTX use, results in powerful suppression of inflammation, thereby reducing the development of atherosclerosis and subsequently clinically overt CVD.
Arthritis Res Ther. 2006; 8(5): R151
The Effect of Methotrexate on Cardiovascular Disease in Patients with Rheumatoid Arthritis: a Systematic Literature Review
Patients with RA have an increased prevalence of CVD. This is due to traditional risk factors and the effects of chronic inflammation. MTX is the first-choice DMARD in RA. A systematic literature review was performed to determine whether MTX affects the risk of CVD in patients with RA.
Medline, Embase, Cochrane database, database of abstracts of reviews of effects, health technology assessment and Science Citation Index were searched from 1980 to 2008. Conference proceedings (British Society of Rheumatology, ACR and EULAR) were searched from 2005 to 2008. Papers were included if they assessed the relationship between MTX use and CVD in patients with RA. Two reviewers independently assessed each title and abstract for relevance and quality.
- A total of 2420 abstracts were identified, of which 18 fulfilled the inclusion criteria.
- Two studies assessed the relationship between MTX use and CVD mortality, one demonstrated a significant reduction in CVD mortality and the second a trend towards reduction.
- Five studies considered all-cause CVD morbidity. Four demonstrated a significant reduction in CVD morbidity and the fifth a trend towards reduction.
- MTX use in the year prior to the development of RA decreased the risk of CVD for 3-4 years. Four studies considered myocardial infarction, one demonstrated a decreased risk and three a trend towards decreased risk with MTX use.
The current evidence suggests that MTX use is associated with a reduced risk of CVD events in patients with RA. This suggests that reducing the inflammation in RA using MTX not only improves disease-specific outcomes but may also reduce collateral damage such as atherosclerosis.
Rheumatology (Oxford). 2009 Nov 27
Methotrexate Therapy Associates with Reduced Prevalence of the Metabolic Syndrome in Rheumatoid Arthritis Patients Over the age of 60 - More than just an Anti-Inflammatory Effect? A Cross Sectional Study
Metabolic syndrome (MetS) may contribute to the excess CV burden observed in RA. The prevalence and associations of the MetS in RA remain uncertain: systemic inflammation and anti-rheumatic therapy may contribute. MTX use has recently been linked to a reduced presence of MetS, via an assumed generic anti-inflammatory mechanism. The aim was to assess the prevalence of the MetS in RA; identify factors that associate with its presence; and assess their interaction with the potential influence of MTX.
MetS prevalence was assessed cross-sectionally in 400 RA patients, using five MetS definitions (National Cholesterol Education Programme 2004 and 2001, International Diabetes Federation, World Health Organisation and European Group for Study of Insulin Resistance). Logistic regression was used to identify independent predictors of the MetS. Further analysis established the nature of the association between MTX and the MetS.
MetS prevalence rates varied from 12.1% to 45.3% in RA according to the definition used. Older age and higher HAQ scores associated with the presence of the MetS. MTX use, but not other DMARDs or glucocorticoids, associated with significantly reduced chance of having the MetS in RA (P = 0.004).
The prevalence of the MetS in RA varies according to the definition used. MTX therapy, unlike other DMARDs or glucocorticoids, independently associates with a reduced propensity to MetS, suggesting a drug-specific mechanism, and makes MTX a good first-line DMARD in RA patients at high risk of developing the MetS, particularly those aged over 60 years.
Arthritis Res Ther. 2009; 11(4); R110
Long-term Safety of Methotrexate Monotherapy in Patient with Rheumatoid Arthritis: A Systematic Literature Research
To perform a systematic literature review of the long-term safety of MTX monotherapy in RA
A search was performed in Medline, Cochrane and EMBASE. Adults with RA who had received MTX monotherapy for more than 2 years were studied.
- 88 published studies were included. Over 12 years of treatment, the termination rate of MTX due to toxicity was less than for sulfasalazine (SSZ), gold, d-penicillamine.
- Long-term use of MTX does not appear to be a risk factor for serious infections, including herpes zoster, and could provide a survival benefit by reducing CV mortality.
- Prevalence of raised liver enzymes (more than twice the upper limit of normal) is close to 13% of patients; 3.7% of patients stopped MTX permanently owing to liver toxicity. Data on the risk for liver fibrosis/cirrhosis are conflicting: a meta-analysis showed an incidence of fibrosis of 2.7% after 4 years of MTX. However, two other studies on sequential liver biopsies did not show evidence for developing severe damage.
- Insufficient data are available to fully assess the risk of lymphoma and malignancies, although there is no strong evidence of increased risk.
This systematic literature search on MTX monotherapy with relatively low-dose use during at least 2 years shows favourable long-term safety.
Ann Rhwum Dis. 2009; 68(7): 1100-4
Atheroprotective Effects of Methotrexate on Reverse Cholesterol Transport Proteins and Foam Cell Transformation in Human THP-1 Monocyte/Macrophages
To determine whether MTX can overcome the atherogenic effects of cyclooxygenase 2 (COX-2) inhibitors and interferon-gamma (IFN γ), both of which suppress cholesterol efflux protein and promote foam cell transformation in human THP-1 monocyte/macrophages.
- Message and protein levels of the reverse cholesterol transport proteins cholesterol 27-hydroxylase and ATP-binding cassette transporter A1 (ABCA1) in THP-1 cells were evaluated by real-time polymerase chain reaction and immunoblot, respectively.
- Expression was evaluated in cells incubated in the presence or absence of the COX-2 inhibitor NS398 or IFN γ, with and without MTX. Foam cell transformation of lipid-ladenTHP-1 macrophages was detected with oil red O staining and light microscopy.
- MTX increased 27-hydroxylase message and completely blocked NS398-induced down-regulation of 27-hydroxylase (mean +/- SEM 112.8 +/- 13.1% for NS398 plus MTX versus 71.1 +/- 4.3% for NS398 alone; P< 0.01).
- It also negated COX-2 inhibitor-mediated down-regulation of ABCA1. The ability of MTX to reverse inhibitory effects on 27-hydroxylase and ABCA1 was blocked by the adenosine A2A receptor-specific antagonist ZM241385. MTX also prevented NS398 and IFN γ from increasing transformation of lipid-laden THP-1 macrophages into foam cells.
This study provides evidence supporting the notion of an atheroprotective effect of MTX. Through adenosine A2A receptor activation, MTX promotes reverse cholesterol transport and limits foam cell formation inTHP-1 macrophages.This is the first reported evidence that any commonly used medication can increase expression of antiatherogenic reverse cholesterol transport proteins and can counteract the effects of COX-2 inhibition. These results suggest that one mechanism by which MTX protects against CVD in RA patients is through facilitation of cholesterol outflow from cells of the artery wall.
Arthritis Rheum. 2008; 58(12): 3675-83
Results of studies have shown the efficacy of such drugs, including MTX, on RA morbidity measures, but their effect on mortality in patients with the disease remains unknown.
The aim was to prospectively assess the effect on mortality of MTX in a cohort of patients with RA.
- Cohort included 1240 patients with RA seen at the Wichita Arthritis Center, an outpatient rheumatology facility. Patients' details were entered into a computerised database at the time of their first clinic visit. Demographic, clinical, laboratory, and self-reported data at each follow-up visit (average interval 3.5 months) were also obtained and recorded.
- Mortality hazard ratio of MTX with a marginal structural Cox proportional hazards model was estimated.
- 191 individuals died during follow-up. Patients who began treatment with MTX (n=588) had worse prognostic factors for mortality
- After adjustment for this confounding by indication, the mortality hazard ratio for MTX use compared with no MTX use was 0.4 (95% CI 0.2-0.8).
- Other conventional DMARDs did not have a significant effect on mortality. The hazard ratio of MTX use for CV death was 0.3 (0.2-0.7), whereas that for non-CV deaths was 0.6 (0.2-1.2).
The data indicate that MTX may provide a substantial survival benefit, largely by reducing CV mortality. This survival benefit of MTX would set a standard against which new DMARDs could be compared.
Lancet. 2002; 359(9313): 1773-7
METHOTREXATE has been used for the treatment of RA for about three decades now.
- It is one of the most effective and commonly used medicines to treat various forms of arthritis and other rheumatic conditions.
- It has shown to improve signs and symptoms of RA, disease activity and function, to a similar degree as the TNF blockers, and it inhibits radiographic progression to a smaller degree than the anti TNF agents
- It is considered as the anchor drug among the DMARDs, and is internationally accepted as the first choice in the management of RA.
- It seems to even prolong the life span of patients who tolerate the drug and have clinical benefit from this therapy; this may partly be explained by beneficial effects on cardiovascular mortality. The reason for this may well be the suppression of inflammation, but direct atheroprotective effects of methotrexate may also play a role.
- It is used as monotherapy and in combination with other DMARDs or biologic agents such as the anti TNF agents. The 'early' use of methotrexate within 5 years after disease onset is clearly associated with improved outcomes.
Curr Opin Rhwumatol. 2009; 21(3): 216-23