Effect of statin therapy in animal models of SLE

The first preclinical study investigating the role of statin therapy in an animal model of lupus was performed by Lawman et al12 (see table 1). Treatment of New Zealand Black/NewZealand White (NZB/NZW) mice with atorvastatin (30 mg/kg/day) resulted in a reduction in serum IgG anti-dsDNA antibodies and diminished the progression of lupus nephritis. Thus, atorvastatin reduced glomerular hypercellularity, interstitial infiltrates and was associated with a smaller increase in glomerular matrix. These beneficial effects could not be reproduced, however, by Graham et al13 in a study where NZB/NZW mice were treated with atorvastatin at a lower dose (10 mg/kg/day) for a longer period of time. Atorvastatin neither had significant impact on the production of anti-dsDNA antibodies nor on the age of onset or the severity of proteinuria. One explanation for this apparent discrepancy relates to the atorvastatin dose. It should be noted that a dose of 30 mg/kg/day exceeds the clinical dose. Statins typically do not affect serum lipid levels in mice and although Graham et al did not observe any differences in serum cholesterol levels, Lawman et al reported a significant 34% decrease in atorvastatin-treated NZB/NZW mice, indicative of high dosing in the latter study. Consistent with the findings of Graham et al, the effects of pravastatin on lupus activity were limited in a recent study in MRL-Fas^lpr mice.14 Although pravastatin lowered serum titres of IgG anti-DNA antibodies, it had no effect on glomerular and tubular damage, leucocyte infiltration in the kidney or proteinuria. Interestingly, the combination of pravastatin and imidapril, an angiotensin-converting enzyme inhibitor, had a synergistic effect with (more pronounced) beneficial effects on renal pathology then either of the monotherapies.

Although various animal models have recently been generated that display lupus-enhanced atherogenesis, the effect of statin therapy on the atherosclerotic process has thus far only been evaluated in apoE^–/– mice with either an inactivating mutation in Fas ligand (gld/gld)15 or Fas (lpr/lpr).16 In gld mice on a C57BL/6 background daily treatment with simvastatin (0.125 mg/kg/day) had no effect on antinuclear antibody titres, splenomegaly, lymphadenopathy or the apoptotic cell accumulation in lymph nodes.15 Interestingly, crossing of gld with apoE^–/– mice results in increased lymphadenopathy, splenomegaly and autoimmune antibodies. In addition, gld.apoE^–/– mice also display immune-mediated glomerular injury which does not occur in gld mice. In gld.apoE^–/– mice, contrary to gld mice, simvastatin treatment was shown to significantly reduce antinuclear antibody titres, splenomegaly, submandibular lymph node size as well as renal disease. Also, in gld.apoE^–/– mice, simvastatin treatment induced a 25% decrease in atherosclerotic lesion size without affecting serum cholesterol levels. These findings are in conflict with a recent study evaluating pravastatin and L4-F (an apoAI mimetic peptide) in apoE^–/–Fas^–/– mice.16 Pravastatin treatment appeared to reduce cellular infiltration of the glomeruli but had no effect on serum IgG anti-dsDNA, spleen size, lymph nodes size or parameters of renal disease. Surprisingly, pravastatin appeared to increase the lesion burden in apoE^–/–Fas^–/– mice. No differences could be detected in plaque phenotype between untreated and pravastatin-treated mice.

In summary, the currently available animal studies evaluating the effect of statins on lupus activity and lupus-mediated atherogenesis use different animal models, statins, dosages, diets, study duration, study parameters and demonstrate opposite effects. Therefore, there is still much to be learnt from these animal models and additional studies using various treatments in combination with statins are warranted.

Effect of statin therapy on lupus activity in patients with SLE

Only a limited number of studies have evaluated the effect of statin therapy in patients with SLE. In the first pilot study, three patients with SLE (mean erythrocyte sedimentation rate 24 mm/h) with severe renal disease refractory to treatment (prednisone plus cyclophosphamide and azathioprine or methotrexate) were treated with 80 mg of simvastatin daily for a period of 8 days without modification of previous treatments.17 Surprisingly, simvastatin induced a significant reduction in proteinuria, urine casts, erythrocyturia and leucocyturia, and also diminished expression of CD69 by lymphocytes. Consistent with this, treatment of eight female lupus patients (mean SLE disease activity index (SLEDAI) 14.6) with 20 mg of simvastatin/day for a period of 4 weeks resulted in a significant reduction of serum tumour necrosis factor α levels.18 As a result of these hopeful cases, Costenbader et al20 set out to determine the dose effectiveness and tolerability of statin therapy in patients with SLE. In a dose-escalating study, 41 patients with SLE (mean SLEDAI 7.4) were treated for 1 month with pravastatin 10 mg, followed by a daily dose of 40 mg. Although pravastatin had beneficial effects on lipid levels to the same degree observed in non-SLE patients, an unexpectedly high number of dropouts (17/41 patients) was reported. In only three cases, however, was this directly related to statin side effects. Pravastatin did not affect SLEDAI or C-reactive protein levels in this study. Similarly, no beneficial effects of statin therapy on lupus pathophysiology were observed in a recent study evaluating the effects of a 3-month course of 10 mg/day of rosuvastatin. In 19 patients with SLE with stable, chronic disease (mean C-reactive protein 5.2 mg/l) rosuvastatin treatment induced a potent lipid-lowering effect but did not reduce SLEDAI, proteinuria or a variety of circulating activation markers of inflammation and complement.21

Effect of statin therapy on atherogenesis in patients with SLE

Ferreira et al22 were the first to assess the effect of statin therapy on a parameter of cardiovascular risk in SLE in addition to lipid levels. They evaluated the effect of statins on a surrogate marker for atherosclerotic vascular disease, endothelial function. Endothelial dysfunction precedes the onset of atherosclerotic lesion formation and various groups have demonstrated endothelial dysfunction in patients with SLE.24 In the study by Ferreira et al, 20 mg/day of atorvastatin for 8 weeks in a group of 64 patients with SLE (mean SLEDAI 4.4) significantly improved endothelial function. Of note, endothelial function improved similarly in patients with and without dyslipidaemia present at baseline.23 This is in line with a similar study demonstrating a beneficial effect on endothelial function of 12-months' treatment with 40 mg pravastatin combined with 10 mg ezetimibe in a group of 22 patients with SLE.25

Unfortunately, an attempt to carry out a randomised controlled trial (RCT) evaluating the antiatherosclerotic effect of pravastatin in SLE (Prevention of Accelerated Atherosclerosis in SLE Study)26 was discontinued. The study had six treatment arms aiming to assess the atheroprotective potential of pravastatin, aspirin, ramipril and vitamin supplementation. In total, 45% of identified patients were ineligible owing to a medical contraindication to one of the study drugs and another 22% dropped out owing to a potential side effect of one of the study drugs.

Two other RCTs analysing the effect of statin therapy on surrogate markers for atherosclerotic vascular disease in SLE have been completed. Finished in 2006, the Lupus Atherosclerosis Prevention Study (LAPS)27 compared the antiatherosclerotic efficacy of a 2-year treatment period with atorvastatin 40 mg to placebo in 200 patients with SLE. Progression of atherosclerosis was assessed by helical CT (coronary calcification) and carotid duplex (carotid intima-media thickness (cIMT)). Preliminary analyses indicated that atorvastatin significantly attenuated progression of atherosclerosis as assessed by cIMT. As expected, no reversal of coronary calcification was seen. In fact, recent studies have shown that the increase in coronary calcification following statin therapy may represent lesion stabilisation, thereby limiting the use of coronary calcification as a suitable surrogate target in prospective cardiovascular prevention trials.28

The APPLE (Atherosclerosis Prevention in Pediatric Lupus Erythematosus) trial is a 3-year, multicentre RCT using cIMT to determine the efficacy and safety of atorvastatin (10 or 20 mg) in preventing the progression of atherosclerosis, in children and adolescents (10–21 years of age) with SLE. In total, 221 participants were enrolled during the inclusion period which was finalised in 2006; study results are expected in 2010.29

Finally, the ability of fluvastatin to reduce major cardiac events was evaluated in kidney transplant recipients with SLE. The ALERT (Assessment of Lescol in Renal Transplantation trial) is a RCT of the effect of fluvastatin on cardiovascular outcomes in renal transplant recipients. In a post hoc analysis, 33 patients with SLE were identified, of whom 23 were randomised to fluvastatin.30 In these 23 fluvastatin-treated patients there was a robust 73.4% reduction in the frequency of major cardiac events compared with 10 patients receiving placebo. It should be noted, however, that the numbers of patients and major cardiac events in this analysis are low and that (end stage) renal disease itself constitutes a major risk factor for CVD.