Home

Current Issue

Archives

Guidelines for Authors & Reviewers

Classified Ads

Links

Search PubMed

Subscriptions

Subscriber Registration

Guidelines for Website Users

JRheum Update Service

Contact Info

To the Editor:

Rheumatoid arthritis (RA) is a chronic inflammatory condition resulting in excessive cardiovascular (CV) mortality, irrespective of classic CV risk factors¹. Population-based studies have highlighted the importance of inflammatory mediators within atherosclerotic plaques, suggesting that chronic inflammation acts independently or synergistically with other factors in the pathogenesis of atherosclerosis^1,2. Vascular endothelial dysfunction (ED) precedes atherosclerosis and represents an early sign of vascular damage².

Prospective and cross-sectional studies have demonstrated higher ED in patients with RA than in healthy subjects^2,3, and that different antiinflammatory therapeutic strategies can dramatically improve endothelial function^4,5. However, a consistent finding is the persistence of ED in a significant subset of patients despite a successful antiarthritic response. Clinical and serological factors underlying this persistence of ED remain poorly understood.

Our pilot exploratory observational study was performed to investigate if different inflammatory markers are associated with persistence of ED. Protocols were approved by our local ethics committee. For inclusion, patients must have fulfilled the 1987 American Rheumatism Association (American College of Rheumatology) classification criteria for RA⁶, therapy with ≥ 2 disease modifying antirheumatic drugs (DMARD) plus a biological agent for at least 1 year, and an improvement ≥ 1.2 on Disease Activity Score-28 after initiation of biologic therapy (to define successful antiarthritic response). Use of prednisone ≤ 10 mg/day, angiotensin-converting enzyme inhibitors, beta-blockers, and calcium-antagonists at the time of study was allowed. Patients were excluded if they had a history of cardiovascular/cerebrovascular disease, smoking within previous year, other rheumatic disease (except Sjögren's syndrome and fibromyalgia), use of insulin, nitrates or thiazolidinediones, or active infectious disease or neoplasm was present.

Sera were tested for high-sensitivity C-reactive protein (hsCRP) and rheumatoid factor (RF) by nephelometry, as well as anti-cyclic citrullinated peptide-2 (anti-CCP2) antibodies, interferon-g (IFN-g), interleukin 6 (IL-6), IL-4, IL-10, and soluble E-selectin and soluble vascular cell adhesion molecule-1 by ELISA. Flow-mediated vasodilation (FMV, a validated surrogate marker for endothelial function) was measured by high resolution ultrasound with a 10 MHz linear-array transducer (Hewlett Packard SonoS5500), in accord with guidelines of the International Brachial Artery Reactivity Task Force⁷. Differences were estimated by Kruskal-Wallis and post-hoc analysis using Mann-Whitney tests. Proportions were assessed by Fisher's exact tests, and Spearman's rank coefficient was used for correlations.

Twenty-three patients (20 women; mean age 50 yrs, range 25–77) were included. According to absolute change in brachial artery diameter, 8 patients were allocated into the first tertile (0.32 mm), 7 in the second (0.74 mm), and 8 in third (1.12 mm). There were no differences in demographics, clinical features, inflammatory status, concurrent diseases, or treatment (including DMARD, biologic agent, and antihypertensive drugs; Table 1). Median IFN-g concentration (Table 2) in patients with lowest FMV (first tertile) was 601 pg/ml [interquartile range (IQR) 374–970]; it was only 16 in those with highest FMV (IQR 0–244; p = 0.03). No differences for other cytokines, adhesion molecules, or autoantibodies were found. Analyses of correlation did not attain statistical significance (data not shown).

Table 1. Selected clinical characteristics of 23 patients with RA, allocated in tertiles according to the magnitude of absolute change in flow-mediated vasodilation (FMV). Except for proportions, results are expressed as median (interquartile range).

Table 2. Serum levels of selected biomarkers, allocated in tertiles according to magnitude of absolute change in flow-mediated vasodilation (FMV).

Our study confirms that a subset of patients with RA persists with ED even when successful antiarthritic therapy has been achieved. Additionally, our findings suggest this persistence is associated with IFN-g (albeit a dose-dependent effect was not seen), but not with other cytokines or prognostic markers of RA (bone erosions, rheumatoid nodules, RF, anti-CCP2).

The rationale to implicate IFN-g in the disturbed FMV emerges from CD4+ T-cells lacking CD28 expression⁸. CD4+CD28^null T-cells represent a pool of prematurely senescent lymphocytes resulting from chronic activation, implicated in autoimmune phenomena because of their proinflammatory activity^8,9. CD4+CD28^null cells produce large amounts of IFN-g, a T_H1-cytokine closely involved in both rheumatoid synovitis and atherosclerosis^9,10. IFN-g is the main trigger for production and release of reactive oxygen species in endothelium; additionally, it inhibits collagen synthesis and facilitates production of matrix metalloproteinases in plaque's fibrous cap¹⁰. These effects seem to play a key role not only in the formation of plaques but most importantly in ED and its consequent instability and rupture. Accordingly, Aubry, et al compared autopsies of patients with RA and non-RA controls matched for sex and CV risk factors¹¹, finding that among subjects with CV disease, 54% of controls had grade 3–4 lesions versus 7% of patients; nevertheless, vulnerable plaques and inflammatory changes in media/adventitia artery layers were significantly more common in patients than in controls. These findings suggest that patients with RA have less chronic atherosclerosis but more inflammation and plaque instability than controls. Recently, Kerekes, et al reported that levels of IFN-g were significantly higher in patients with RA and low FMV (r = 0.51, p = 0.014) than in those with high FMV¹².

Although in the recommended range for a crossover design evaluating FMV (at least 20–30 patients)⁷, our small sample prevented us from adjusting groups for traditional CV risk factors, limiting any other inferences. However, our study supports the implementation of longitudinal studies of larger numbers of patients.

In our study, the subgroup of patients with aggressive RA that persisted with ED despite successful antiarthritic therapy showed high serum concentrations of IFN-g.

LUIS M. AMEZCUA-GUERRA, MD, Department of Immunology, Instituto Nacional de Cardiología Ignacio Chávez, LaSalle University School of Medicine; RICARDO MÁRQUEZ-VELASCO, BSc, Department of Immunology; RICARDO HERNÁNDEZ-ÁVALOS, MD, Department of Echocardiography; ANGÉLICA VARGAS, MD, Department of Rheumatology, Instituto Nacional de Cardiología Ignacio Chávez; RAFAEL BOJALIL, MD, PhD, Department of Immunology, Instituto Nacional de Cardiología Ignacio Chávez, Department of Health Care, Universidad Autónoma Metropolitana-Xochimilco, Mexico City, Mexico. Address reprint requests to Dr. R. Bojalil, Department of Immunology, Instituto Nacional de Cardiología Ignacio Chávez, Juan Badiano 1, Sección XVI, Tlalpan, 14080, Mexico City, Mexico. E-mail: bojraf@yahoo.com

REFERENCES

Search PubMed for: