In patients with systemic sclerosis (SSc), endothelial cell activation or damage in small vessels is followed by intimal hyperplasia and peripheral ischaemia.1 Raised levels of plasma von Willebrand factor (vWF), thrombomodulin (TM), and other endothelial/thrombotic markers have been found in patients with SSc2,3,4,5; vWF is increased in plasma from patients with SSc with diffuse skin involvement and with severe disease, presumably correlating with disease activity.3 Besides a cholesterol lowering effect, statins exert non‐lipid related mechanisms, so‐called “pleiotropic effects”, which may contribute to reducing risks of cardiovascular events. In this study the effect of a low dose pravastatin on markers of endothelial cell activation/injury and coagulation was investigated in patients with SSc.
This clinical trial was approved by the ethical committee of Hokkaido University Graduate School of Medicine, and all the patients gave their informed consent. The study comprised 18 patients with SSc without hyperlipidaemia (16 women, two men) attending the connective tissue disease clinic of Hokkaido University Hospital (mean (SD) age 52.3 (12.5)). Diagnosis of SSc was based on the American College of Rheumatology criteria.6 Patients with morphoea were not included in the study.
Nine patients were treated with low dose (10 mg/day) pravastatin for 8 weeks and the other nine patients were not treated. No differences in age, sex, treatment or severity were found between the groups. Three patients from the pravastatin group and four from the non‐treatment group were receiving low dose steroids. Ten disease‐free subjects matched for age and sex served as healthy controls. Lipid profiles (total cholesterol, low density lipoprotein cholesterol, and high density lipoprotein cholesterol), vWF activity, TM, thrombin‐antithrombin complex (TAT), soluble intercellular adhesion molecule‐1 (sICAM‐1), soluble vascular cell adhesion molecule‐1 (sVCAM‐1), and P‐selectin were measured on days 0 and 56. Fisher's exact test was used for statistical analysis. Values of p<0.05 were regarded as significant.
Data before pravastatin treatment were compared between the patient groups and the healthy control group. vWF, TM, TAT, sICAM‐1, and sVCAM‐1 were significantly increased in the patient groups compared with the healthy controls (fig 1). Before pravastatin administration, no significant difference was found in any measures between the pravastatin group and non‐pravastatin group. In the pravastatin group, plasma activity of vWF and TAT on day 56 were significantly reduced compared with those before treatment (table 1). vWF activity in the pravastatin group was significantly lower than in the non‐treatment group (p = 0.024) on day 56. During the follow up period, low dose pravastatin did not have significant effect on the other measures, including lipid profiles.
Figure 1 Laboratory data in healthy controls (grey bars), the pravastatin treated group (black bars), and the non‐treated group (white bars) before pravastatin treatment. Asterisks indicate that the variable is significantly higher in the treatment group than in the healthy control group. TC, total cholesterol (mg/dl); LDL, low density lipoprotein cholesterol (mg/dl); HDL, high density lipoprotein cholesterol (mg/dl); vWF, von Willebrand factor activity (%); TM, thrombomodulin (fU/ml); TAT, thrombin‐antithrombin complex (μg/l); ICAM‐1, soluble intercellular adhesion molecule‐1 (ng/ml); VCAM‐1, soluble vascular cell adhesion molecule‐1 (ng/ml); and P‐selectin (ng/ml). Error bars indicate standard deviations.
Table 1 Laboratory data in patients with SSc at days 0 and 56.
| Data | Pravastatin | Day 0 | Day 56 | p Value |
|---|---|---|---|---|
| TC (mmol/l) | (+) | 5.00 (0.65) | 4.50 (1.10) | NS |
| (−) | 4.85 (1.35) | 4.75 (1.20) | NS | |
| LDL (mmol/l) | (+) | 2.80 (0.55) | 2.35 (1.00) | NS |
| (−) | 2.40 (0.60) | 2.55 (1.10) | NS | |
| HDL (mmol/l) | (+) | 1.60 (0.50) | 1.45 (0.35) | NS |
| (−) | 1.40 (0.35) | 1.35 (0.25) | NS | |
| vWF (%) | (+) | 201.4 (30.9 | 163.8 (32.9) | 0.0053 |
| (−) | 226.9 (33.5 | 250.8 (66.1) | NS | |
| TM (fU/ml) | (+) | 2.6 (0.6) | 2.5 (0.9) | NS |
| (−) | 3.1 (0.9) | 3.2 (0.9) | NS | |
| TAT (mg/l) | (+) | 1.7 (0.7) | 0.9 (0.3) | 0.0052 |
| (−) | 1.7 (1.0) | 1.6 (1.3) | NS | |
| ICAM‐1 (ng/ml) | (+) | 304.6 (90.2) | 294.1 (72.0) | NS |
| (−) | 245.0 (51.1) | 253.6 (48.2) | NS | |
| VCAM‐1 (ng/ml) | (+) | 641.4 (191.4) | 691.3 (244.8) | NS |
| (−) | 702.6 (228.2) | 641.4 (191.4) | NS | |
| P‐selectin (ng/ml) | (+) | 74.1 (37) | 75.1 (32) | NS |
| (−) | 55.6 (35) | 56.2 (36) | NS |
NS, not significantly different when the values were compared between days 0 and 56.
There were no significant differences in the measures between the pravastatin group and the non‐treatment group.
Cholesterol (mmol/l ÷ 0.025084 = mg/dl).
vWF is synthesised by endothelial cells and its secretion is triggered by inflammatory/thrombotic mediators, thus establishing it as a marker of endothelial activation/injury. Although TAT is not a generally accepted marker of endothelial injury, it reflects thrombin generation induced by endothelial perturbation. Statins induce an increment in plasminogen activator synthesis and release, a decrease in plasminogen activator inhibitor‐1 activity and endothelin‐1 expression, and an up regulation of nitric oxide synthase, thus diminishing procoagulant activity and vasoconstriction.7,8
In this pilot study, we have shown that low dose pravastatin reduces plasma vWF activity and TAT without affecting lipid profiles and has a protective effect against perturbation of endothelial cells, leading to some beneficial effects in the affected patients.
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