Effects of disease modifying anti-rheumatic drugs on subclinical atherosclerosis and endothelial dysfunction which has been detected in early rheumatoid arthritis: 1-year follow-up study

Abstract

Objective

The study was designed to explore the effect of disease modifying anti-rheumatic drugs (DMARDs) on synovial inflammation as well as on atherosclerotic indices in patients with early rheumatoid arthritis (RA).

Methods

The study included 35 early RA patients (disease duration <12 months). Inflammatory variables, like erythrocyte sedimentation rate (ESR) and high sensitivity C-reactive protein (hsCRP) were measured. Carotid intima-media thickness (cIMT) and endothelial dependent flow-mediated vasodilatation (ED-FMD) were measured by high-resolution ultrasonography. Disease activity of RA was assessed by disease activity score (DAS28) and quality of life was determined by Health Assessment Questionnaire-Disability Index (HAQ-DI) Score. All the above parameters were assessed both at baseline and follow-up after 1 year. Patients were treated with methotrexate (MTX), hydroxycholoroquine (HCQ) and sulfasalazine (SSZ) depending on their disease activity.

Results

After a year of treatment, variables like ESR, hsCRP, DAS28 and HAQ-DI showed significant improvement (p < 0.0001 for each variable). However, there was no such significant change observed in the lipid profile after 1 year from the baseline. Average body mass index (BMI) of patients remained same at the one year follow-up. The cIMT values after 1 year decreased significantly [0.43 ± 0.08 mm] from the baseline [0.50 ± 0.16 mm] [p = 0.002]. Similarly, in case of FMD%, the post-1-year treatment values [7.57 (4.04–13.03)] improved significantly from the baseline [5.26 (2.9–10.6)] [p = 0.041].

Conclusion

Subclinical atherosclerosis and endothelial dysfunction are demonstrable features even in early RA which improved after therapy. Early intervention of RA with DMARDs not only controls the disease but also retards the atherosclerotic progression.

Introduction

In the last two decades there have been several studies showing premature coronary heart disease and cardiovascular disease (CVD) as major causes of morbidity and mortality in patients with rheumatoid arthritis (RA) [1], [2], [3], [4], [5]. In general, CVD in RA leads to an excess 35–50% of the mortality rate in comparison to general population and reduces life expectancy by 5–10 years [3], [5]. Prevalence of CVD was observed in 13% of the RA patients in general compared to 5% of the normal population [6]. In a recent study [7], the overall incidence rate ratio (IRR) of myocardial infarction in RA was 1.7 (95% CI 1.5–1.9), which was similar to the risk in type 2 diabetes mellitus [1.7 (95% CI 1.6–1.8)].

The etiopathogenesis of the excess risk of CVD in RA is postulated to be multifactorial. The traditional cardiovascular (CV) risk factors like hypertension, diabetes and hyperlipidemia are identified, in part, as common confounders. However, of recent interest is the fact that RA itself is a major cause for higher CV mortality and morbidity due to underlying inflammatory process [8]. Few therapeutic drugs like corticosteroids and nonsteroidal anti-inflammatory drugs may accelerate the risk of atherosclerosis in RA [9], [10]. Contrary to what may be expected there are reports claiming improvement of atherosclerosis due to decrease in inflammation with the use of corticosteroids [11], [12].

The initiation and progression of atherosclerosis occurs in very early stages of RA and it can be easily detected by high-resolution ultrasonography as already shown by few recent studies [13], [14], [15], [16]. In this respect, carotid artery intima-media thickness (cIMT) and endothelial dependent flow-mediated vasodilatation (ED-FMD) are two simple, noninvasive tools used for detecting subclinical atherosclerosis and endothelial dysfunction [17], [18], [19].

As already known, disease modifying anti-rheumatic drugs (DMARDs) are quite effective in lowering the disease activity and halting the progression of joint damage [20]. Recent therapeutic strategy suggests that early diagnosis and early use of DMARDs are more effective in controlling inflammatory activity in RA [21], [22], [23]. According to the “2008 American College of Rheumatology (ACR) Recommendations for Rheumatoid Arthritis Treatments”, the combination of DMARDs [Methotrexate (MTX), Hydroxychloroquine (HCQ) and Sulfasalazine (SSZ)] was recommended for patients with moderate to high levels of disease activity [24].

Earlier studies have shown that DMARDs can improve cardiovascular risk in RA by influencing the traditional risk factors of atherosclerosis directly or through controlling inflammation [25], [26]. However, studies showing the effect of DMARDs on CVD are limited, most of which predominantly focus on the role of MTX only [27]. In view of the recommendations suggesting treatment with combination of DMARDs for such patients as stated earlier, we chose to conduct our study involving three combination DMARDs.

Very little is known as to how these DMARDs affect subclinical atherosclerosis and endothelial dysfunction while controlling joint inflammation in RA. Few sporadic studies have shown the effect of DMARDs on cIMT and FMD separately. Georgiadis et al. have shown the positive effect of MTX and Prednisolone on cIMT in early RA patients (n = 40) at the 1-year follow-up [13]. Similarly, Hannawi et al. have shown improvement in FMD of early RA patients (n = 20) with combination of MTX, HCQ and SSZ [15]. However, no such study, till date, has reported the effect of these three DMARDs on both cIMT and FMD in early RA patients.

In this background, the present study was undertaken to investigate as to how the control of disease activity and inflammatory burden in RA with combination of DMARDs (MTX, HCQ and SSZ) could affect the atherosclerotic progression in early RA patients.