Anti–TNFα = anti–tumor necrosis factor α; IMT = intima-media thickness.
Contribution from the Field
Effect of anti–tumor necrosis factor α therapy on the progression of subclinical atherosclerosis in severe rheumatoid arthritis
Article first published online: 6 FEB 2006
Copyright © 2006 by the American College of Rheumatology
Arthritis Care & Research
Volume 55, Issue 1, pages 150–153, 15 February 2006
How to Cite
Gonzalez-Juanatey, C., Llorca, J., Garcia-Porrua, C., Martin, J. and Gonzalez-Gay, M. A. (2006), Effect of anti–tumor necrosis factor α therapy on the progression of subclinical atherosclerosis in severe rheumatoid arthritis. Arthritis & Rheumatism, 55: 150–153. doi: 10.1002/art.21707
- Issue published online: 6 FEB 2006
- Article first published online: 6 FEB 2006
- Manuscript Accepted: 13 SEP 2005
- Manuscript Received: 22 JUN 2005
Epidemiologic observations suggest that mechanisms other than the classic atherosclerotic risk factors may play a role in the increased prevalence of cardiovascular (CV) events found in patients with rheumatoid arthritis (RA) (1, 2). In these patients, the development of accelerated atherosclerosis is closely linked to the presence of a chronic inflammatory response (3). Tumor necrosis factor α (TNFα) is a pivotal proinflammatory cytokine implicated in the mechanisms associated with proatherogenic changes in RA (3). Endothelial dysfunction, an early step in the development of atherosclerosis, is present in patients with RA with both early (4) and long-standing disease actively treated with methotrexate (MTX) (5).
Subclinical atherosclerosis, confirmed by increased carotid intima-media wall thickness (IMT) on carotid ultrasonography, was found in patients with long-term RA actively treated with MTX without clinical history of atherosclerosis or CV risk factors (6). In these patients, the magnitude and chronicity of the inflammatory response, measured by longitudinal evaluation of C-reactive protein (CRP) levels, showed a strong correlation with the presence of subclinical atherosclerosis (7).
Short-term TNFα blockade using the chimeric monoclonal antibody infliximab reduced disease activity and CRP levels and significantly improved endothelial function in patients with RA with refractory disease (8). Also, infliximab therapy yielded a rapid positive effect on endothelial function in patients with RA treated with this drug for at least 1 year. In these patients, percentages of endothelium-dependent vasodilatation (EDV) at day 2 after infusion were greater than those observed 2 days before infusion. However, EDV values returned to baseline levels by 4 weeks after infusion of the drug (9).
In the present study, we sought to assess whether the use of anti–TNFα infliximab might be associated with reduction in the progression of subclinical atherosclerosis in patients with RA with long-standing disease refractory to at least 2 disease-modifying antirheumatic drugs, including MTX, who had been periodically treated with infliximab for at least 2 years.
Patients and Methods
A series of consecutive patients with RA attending hospital outpatient clinics from Hospital Xeral-Calde (Lugo, Spain) who were switched from standard therapy to anti–TNFα infliximab treatment because of severe and active disease (Disease Activity Score in 28 joints >5.1) (10) between March and December 2002 were assessed for carotid IMT within 1 month before the onset of infliximab therapy and again in March 2005. For the purpose of this study, patients with RA seen during the recruitment period who had traditional CV risk factors of atherosclerosis, renal insufficiency, and history of CV or cerebrovascular disease were excluded.
The study group comprised 8 white patients with RA (7 women and 1 man, 6 of them rheumatoid factor positive). The median age at disease onset was 38 years, and the median disease duration prior to the onset of infliximab therapy was 14 years (range 8–25 years). The median age at the start of the study was 52 years (range 25–68 years). Infliximab therapy (in all cases, the initial dosage was 3 mg/kg) was administered intravenously at 0, 2, and 6 weeks and then every 8 weeks until the time of the second carotid IMT assessment. At the end of this study, all patients were receiving infliximab therapy and had received periodic infliximab therapy for at least 2 years following the 8-week administration intervals; 5 of them had been treated for 3 years (median for the whole group: 3 years). At the end of this study, 3 of the 8 patients were still receiving treatment with infliximab at a dosage of 3 mg/kg every 8 weeks. The other 5 had required an increase of the dosage to 5 mg/kg every 8 weeks because of severity of the disease. During the period of study, all patients receiving intravenous infliximab therapy took oral prednisone (median dosage 7.5 mg/day). In addition, 6 of them received MTX (median dosage 15 mg/week) and 2 received leflunomide (median dosage 20 mg/day). Other clinical data are shown in Table 1.
|Variable||Anti–TNFα therapy (n = 8)||Conventional therapy (n = 15)||P|
|Age at study onset, years||0.560|
|Mean ± SD||50.4 ± 14.3||53.5 ± 12.0|
|Median (range)||52 (25–68)||52 (27–68)|
|Rheumatoid factor positive, no. (%)||6 (75)||13 (87)||0.589|
|Disease duration at study onset||0.821|
|Mean ± SD||15.4 ± 6.1||16.0 ± 9.0|
|Median (range)||14 (8–25)||13 (7–40)|
|At study onset||0.300|
|Mean ± SD||0.69 ± 0.12||0.74 ± 0.12|
|Median (range)||0.67 (0.54–0.87)||0.70 (0.56–0.99)|
|At the end of the study||0.771|
|Mean ± SD||0.80 ± 0.15||0.83 ± 0.16|
|Median (range)||0.84 (0.54–1.02)||0.80 (0.56–1.13)|
|Carotid IMT progression at the end of the study, no. (%)||7 (87.5)||13 (86.7)||1.00|
For each patient with RA who required infliximab therapy, 3 age- (±3 years), sex-, and ethnicity-matched patients with RA receiving conventional treatment with prednisone plus MTX or leflunomide from the Lugo region were also assessed for carotid IMT between March 2002 and December 2002. None had a history of hypertension, diabetes mellitus, renal insufficiency, CV events, or cerebrovascular events or had smoked within the 5 years prior to the study. However, over the course of this study, 8 of the 24 patients with RA who were initially receiving conventional therapy had to be switched to anti–TNFα therapy because of disease severity, and 1 woman experienced sudden cardiac death. Information about the 15 patients who continued receiving conventional therapy with prednisone (n = 15; median dosage 7.5 mg/day) and MTX (n = 14; median dosage 12.5 mg/week) or leflunomide (n = 1; median dosage 20 mg/day) at the end of this study is shown in Table 1.
Carotid IMT was measured in the right common carotid artery as previously reported (6). The study was performed using high-resolution B-mode ultrasound (Hewlett Packard SONOS 5500; Hewlett Packard, Palo Alto, CA) with a 10-MHz linear transducer. In all cases, a single cardiologist (CGJ) who was blinded to clinical information performed all the tests. Because the baseline measurement was performed 2–3 years between the first and second study in each patient and because the ultrasound images were recorded, new blind measurements were performed by the same cardiologist. The correlation coefficient for carotid IMT was 0.97.
Quantitative variables were compared using the Mann-Whitney U test; Fisher's exact test was used to test equality of proportions. The relationship between yearly progression of carotid IMT and presumed associated variables (age, disease duration, rheumatoid factor, and anti–TNFα therapy) was tested by linear regression.
The local institutional committee approved anti–TNFα therapy and ultrasonography studies in patients with RA. Also, patients gave informed consent to participate in this study. Neither this study nor the former study (9) was supported by any pharmaceutical drug company.
The main clinical and ultrasonographic differences between patients with RA receiving anti–TNFα infliximab therapy and those receiving conventional therapy are shown in Table 1. No significant differences in the carotid IMT were found between patients with RA receiving anti–TNFα or those receiving conventional therapy (Table 1). Also, carotid IMT progression was observed in both groups (Table 1). In the group treated with anti–TNFα infliximab, the mean ± SD change was 0.04 ± 0.038 mm/year compared with 0.034 ± 0.038 mm/year in those treated with conventional therapy, a difference that was not statistically significant by Mann-Whitney U test (P = 0.633). Furthermore, comparison of the median values (0.036 mm/year in the group treated with anti–TNFα infliximab versus 0.017 mm/year in the group receiving conventional therapy) did not show statistically significant differences (P = 0.539 by Mann-Whitney U test).
The influence of independent factors that might be associated with the annual increase in the carotid IMT is shown in Table 2. As expected, the annual increase of carotid IMT was associated with age (Table 2).
|Factor||Coefficient (95% confidence interval)||P|
|Age||0.001 (0.000, 0.002)||0.046|
|Disease duration||0.001 (−0.001, 0.003)||0.323|
|Rheumatoid factor status||−0.004 (−0.047, 0.040)||0.855|
|Anti–TNFα therapy||0.008 (−0.026, 0.042)||0.633|
The results from the present study support the evidence of progression of subclinical atherosclerosis in patients with RA with severe disease despite periodic treatment with anti–TNFα monoclonal antibody infliximab. These observations are in concordance with our former study that disclosed a positive but transient effect on endothelial function in patients with RA who were periodically treated with this drug (9).
Other studies have found that some carotid IMT readers have evidenced systematic changes in their reading patterns over time (11). Although a second blind measurement performed by the same cardiologist yielded a high correlation coefficient for carotid IMT, this may be an important point of concern in the present study because all patients with RA either receiving infliximab treatment or not receiving treatment were assessed for carotid IMT at least 2 years after the basal determination.
Another point of concern was that patients with RA receiving anti–TNFα therapy and controls receiving conventional therapy were exposed to significant median doses of corticosteroids and MTX/leflunomide during the study period. Therefore, we cannot exclude the fact that the effect on carotid IMT progression can be attributed to anti–TNFα therapy or to the other simultaneous therapies, or even to interactions between therapies. This is particularly worrisome because corticosteroid level may be a risk factor for atherosclerosis, although no relationship between corticotherapy and atherosclerosis in RA as measured by carotid IMT has been found (6, 12, 13) and the association between cortisol and the carotid IMT progression in the general population is not clear (14, 15).
Atherosclerosis is a chronic process that is strongly associated with age. In fact, studies that modeled the effect of risk factors on the progression of carotid IMT found that the independent effect of age is greater than or similar to other CV risk factors, such as hypertension or dyslipidemia (16, 17). Considering the patient's age at RA onset and disease duration in our series, it is apparent that the age of the patients was even more relevant if one considers that the effect of age on atherosclerosis is Gompertzian rather than linear (17). Furthermore, studies that addressed the effect of CV risk factors' control on the progression of atherosclerosis, as measured by carotid IMT, used the concept of “change in the progression of IMT” because a progression in the measurements of carotid IMT is expected with time/age (18) and because a reduction in this progression should be of great clinical significance.
Additional therapies should be considered to delay the progression of atherosclerosis in patients with RA. Statins improve endothelium-dependent coronary vasodilatation in patients with atherosclerosis (19). This vascular improvement, which is independent of statins' cholesterol-lowering actions, has been associated with their antiinflammatory and immunomodulatory properties. Interestingly, Hermann et al demonstrated a dramatic improvement of endothelial function in patients with RA following simvastatin therapy (19). Therefore, drugs not specifically aimed at treating rheumatic manifestations might be considered in the management of RA to reduce the increased incidence of CV events in patients with this condition. However, other than some studies with intensive doses of statins, some regarding a special population such as patients with familial hypercholesterolemia (20), most studies of patients treated with hypolipidemic therapy, antihypertensive therapy, and antidiabetic therapy demonstrate that the progression of carotid IMT is slowed down, but not inhibited or reversed.