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Tumor Necrosis Factor-a as a Potential Target in the Treatment of Systemic Lupus Erythematosus: A Role for the HMG-CoA Reductase Inhibitor Simvastatin

To the Editor:

In their excellent editorial, Shovman, et al have reviewed possible autoimmune mechanisms involved in the beginning and progression of atherosclerosis among patients with systemic lupus erythematosus (SLE)¹. The phenomenon of premature atherosclerosis is a well known clinical entity from the mid-1970s, when Urowitz, et al described the so-called bimodal pattern of mortality and attributed the second peak of mortality to the premature atherosclerosis and its fatal cardiovascular complications². Premature atherosclerosis in connective tissue disorders in general and in systemic lupus in particular was not explained well before Ross, who pointed out that the atherosclerotic process is inflammatory in its nature³.

We reviewed the role of interleukin 6 (IL-6), IL-8, and monocyte chemoattractant protein-1 and pinpointed some promising therapeutic targets including tumor necrosis factor-a (TNF-a) blockade. The role of TNF-a in SLE is controversial. Some studies show a positive correlation between disease activity and TNF-a⁴ and others do not⁵. Although TNF-a belongs to the group of TH1-dependent cytokines, and is recognized as a key cytokine in rheumatoid arthritis, several articles suggest that the level of TNF-a may reflect the level of inflammation in patients with SLE, and that these patients are characterized by a higher level of this cytokine compared to a healthy population⁶. On the other hand atherosclerosis itself is characterized by a high level of TNF-a and C-reactive protein that is produced in the liver in the response to cytokine stimulation. Therefore the idea of TNF-a blockade as the possible therapeutic target in lupus is very promising. In the same issue of The Journal, Yokota and colleagues⁷ showed that simvastatin, a HMG-CoA reductase inhibitor, inhibits synthesis of IL-6 and IL-8 after TNF-a stimulation. To support results presented by the authors of both articles we present results of our preliminary study, where we focused on TNF-a as the potential therapeutic target in patients with SLE. Eight women aged 26–57 years (42 ± 10.3) fulfilling the American College of Rheumatology lupus criteria were enrolled. A group of 8 healthy women age matched to the patients served as controls. Lipid profile parameters including total, high density lipoprotein-cholesterol (HDL), and low density lipoprotein-cholesterol (LDL), triglyceride, and TNF-a concentration were measured. In the patients we also measured disease activity with the SLE Disease Activity Index (SLEDAI) scale. Additionally in the patients and controls the intima-media complex (IMC) measurements of both carotid arteries were done to detect the patients with subclinical atherosclerosis and exclude them. Then the patients were treated with simvastatin (20 mg/day) for 4 weeks. Before the study, patients with SLE showed very high levels of TNF-a compared to the controls. As expected, we showed lipid profile abnormalities with triglyceride, total and LDL cholesterol levels being higher and HDL cholesterol lower compared to the controls.

Twenty-eight days of treatment with simvastatin reduced LDL and total cholesterol and increased HDL cholesterol, but more importantly also prominently decreased TNF-a level in the sera of patients with lupus as compared to the period before study. We also observed decreased lupus activity in the SLEDAI scale. All results are summarized in Table 1.

Table 1. Characteristics of patients with SLE and healthy subjects.

The patients in our study were characterized by very high TNF-a levels that support the role of this cytokine in SLE and may indicate the blockade of TNF-a as a possible therapeutic target in the disease. The role of statins in lupus was suggested for the first time by Abud-Mendoza, et al, who showed beneficial effect of the drug in patients with drug-resistant lupus⁸. Due to their pleiotropic properties, statins interfere with inflammatory processes. These pleiotropic effects are realized via inhibition of geranylation of small G proteins, resulting in the restoration of the endothelium function and immunosuppressive and immunomodulatory activities⁹.

Treatment with statins in lupus may be a unique opportunity to correct many risk factors with a single drug: to correct the lipid profile abnormalities often seen among patients with SLE, and at the same time to decrease inflammation as in atherosclerosis not evoked by autoimmune disorders. Statins seem to be good candidates for lupus-modifying drugs. They have been shown to limit progression of lupus nephropathy⁸ and decrease the TNF-a concentration and disease activity in our pilot study. The more we know about the immune mechanism involved in progression of lupus and lupus-dependent atherosclerosis, the more therapeutic options we could apply. But before we decide to use cytokine-targeting therapy for lupus patients we should verify the usefulness of old drugs that are being successfully used in the treatment of atherosclerosis.

PRZEMYSLAW J. KOTYLA, MD, PhD, Lecturer; BOGNA SLIWINSKA-KOTYLA, MD; EUGENE J. KUCHARZ, MD, PhD, Professor of Medicine, Chairman, Department of Internal Medicine and Rheumatology, Medical University of Silesia, ul. Ziolowa 45/47 40-635, Katowice, Poland. E-mail: pkotyla@slam.katowice.pl

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