Effects of repeated infliximab therapy on serum lipid profile in patients with refractory rheumatoid arthritis

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Abstract

Background

Patients with rheumatoid arthritis (RA) frequently display an atherogenic lipid profile which has been linked with inflammation. Tumor necrosis factor-α (TNF-α), a pivotal pro-inflammatory cytokine in RA may be involved in the development of the disturbed lipid metabolism. We investigated whether infliximab, an anti-TNF-α therapy, may modify the lipid profile.

Methods

56 consecutive RA patients were treated with infliximab (3 mg/kg at weeks 0, 2, 6, 14, 22, 30). Lipid profile and CRP were assayed at baseline and before infusion at weeks 6 and 30. Baseline values were compared with those in 56 healthy volunteers.

Results

At baseline, the concentrations of HDL-cholesterol were lower in RA patients than in the controls (1.3 ± 0.4 vs. 1.5 ± 0.2 mmol/L; p < 0.01). The triglyceride concentrations (1.6 ± 0.8 vs. 1.3 ± 0.4 mmol/L, p < 0.01), the ratio of total cholesterol / HDL-cholesterol (4.3 ± 1.6 vs. 3.2 ± 0.5, p < 0.001) and LDL-cholesterol / HDL-cholesterol (2.6 ± 1.2 vs. 1.7 ± 0.5, p < 0.001) were significantly higher in RA patients than in controls. After 6 weeks of infliximab therapy, the mean total cholesterol concentration increased by 25% (p < 0.001), LDL-cholesterol by 24% (p < 0.001) and HDL-cholesterol by 30% (p < 0.001). The decrease in CRP levels to 30 week inversely correlated with the increase in HDL-cholesterol (r =  0.47, p = 0.005).

Conclusions

Infliximab administration is associated with important increases in cholesterol levels in all its forms but as no significant beneficial effect on the atherogenic ratio.

Introduction

Premature mortality due to cardiovascular disease has been reported to be more frequent among patients with rheumatoid arthritis (RA) than in the general population [1], [2], [3] and this mortality is largely a consequence of atherosclerotic coronary artery disease [4], [5]. There are several risk factors for this in the general population, including the association between vascular events and various serum lipid markers; the ratio of high density lipoprotein (HDL) cholesterol to total cholesterol is a strong predictor of this risk [6]. Active RA has been found to be associated with dyslipidemia [7]. RA inflammation appears to affect lipid levels, thereby increasing the risk of atherosclerosis [8]. A consistent finding is low HDL-cholesterol concentrations in active or untreated RA patients [9], [10], a profile associated with high cardiovascular risk [11].

Tumor necrosis factor-α (TNF-α), a pivotal pro-inflammatory cytokine in RA may be involved in the development of the disturbed lipid metabolism. TNF-α has been found to produce a 25% increase in serum cholesterol levels and a 2–3 fold increase in hepatic hydro-3-methyl-glutaryl coenzyme A (HMG-CoA) reductase activity in C57B1/6 mice [12]. TNF-α can also induce the maturation of sterol regulatory element binding protein-1 (SREBP-1), a key transcription factor in cholesterol biosynthesis, in a time- and dose-dependent manner [13]. In healthy subjects, TNF-α, as reflected by plasma soluble receptors, was associated with total and LDL-cholesterol [14]. TNF-α has been implicated in the metabolic syndrome by promoting insulin resistance through modifications of the insulin receptor [15]. Moreover, the excess cardiovascular risk in RA patients as compared with OA patients has been suggested to be partly due to lower insulin sensitivity and HDL-cholesterol [16]. Increased LDL-cholesterol might be the result of impaired insulin action on LDL receptor activity. TNF-α also increases serum triglyceride levels in vivo by stimulating low density lipoprotein production [17].

In recent years, TNF-α has been the target of biological therapy. Infliximab is a chimeric monoclonal anti-TNF-α IgG1 antibody which specifically binds to both soluble and membrane-bound TNF-α with high affinity and forms stable non-dissociating immune complexes [18]. Infliximab is effective against active RA refractory to methotrexate (MTX) [19], [20], [21]: it often results in rapid clinical improvement [19], [20], [21], [22], down regulates inflammatory cytokines including IL-6 and decreases in CRP concentrations [23].

Drug treatment may affect lipid profile (lowering total cholesterol and LDL- cholesterol levels, elevation of HDL-cholesterol) and the control of disease activity may reverse some of the abnormalities [13], [24], [25]. Reports describing the influence of anti-TNF-α on the lipid profile are contrasted and only after short-term treatment (2 to 6 weeks). One group found in a very limited number of patients with RA that lipid profile changed to a more atherogenic profile during treatment with infliximab [26], but others shown an improvement of the lipid profile [27], [28]. Therefore, we followed lipid levels during infliximab therapy in patients with active refractory RA after short-term (6 weeks) and long-term (30 weeks) treatment.

Section snippets

Patients and controls

We included 59 consecutive patients with RA fulfilling American College of Rheumatology criteria [29] and refractory to disease-modifying antirheumatic drugs (DMARDs) including methotrexate. We excluded patients if they had clinical condition that affects lipid profiles, such as diabetes mellitus, chronic liver disease, hypothyroidism, alcoholism, Cushing syndrome or obesity (body mass index > 30 kg/m2). None of the patients was taking drugs known to influence lipid levels. All patients gave an

Characteristics of the patients

In the group of RA patients treated by infliximab, fifty-one women and 8 men were enrolled in this study and 56 completed the study with the following characteristics (Table 1): the mean age (± SD) of the patients was 52 ± 14 years and their disease duration was 13 ± 7 years. At baseline, the mean DAS44 was 7.8 ± 2.2, the mean ESR was 30.7 ± 21.5 mm/h and the mean CRP was 29.8 ± 30.4 mg/L. Most (47 / 56) patients were positive for rheumatoid factors (median titer 87 U/L; range 0– 300 U/L).

The group of RA

Discussion

This study shows (i) that RA patients with active disease exhibit an abnormal lipid profile consisting in low HDL-cholesterol, (ii) that treatment with infliximab is associated with increased concentrations of both total cholesterol and HDL-cholesterol correlated with decrease of inflammation but without reducing the number of patients with a high atherogenic index (the total cholesterol / HDL-cholesterol ratio).

Cardiovascular disease is the commonest cause of premature mortality in RA patients

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    The authors declare that they have no competing interests.

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