CRA Forum: Review by Dr. PETER LEE

Increase in circulating endothelial precursors by atorvastatin in patients with systemic sclerosis.
Kuwana M, et al. Arthritis Rheum 2006; 54: 1946-1951

Dr. PETER LEE
M.D., FRCPC

Editorial by Dr. PETER LEE

A characteristic vasculopathy occurs in systemic sclerosis (SSc) mainly affecting small arterioles but larger vessels can be involved giving rise to severe Raynaud's phenomenon and pulmonary arterial hypertension.

Increased stiffness of the radial artery correlates with elevated plasma levels of soluble endothelial adhesion molecules, consistent with endothelial damage. The mechanisms of vascular damage in SSc include alterations in mediators of vascular tone (such as increased plasma endothelin levels), the presence of vascular cytotoxicity factors and defective vasculogenesis.

Circulating endothelial precursors (CEPs) are a newly described population of circulating non-hematopoietic cells defined by specific surface molecules. CEPs participate in vascular homeostasis, being recruited from the bone marrow by angiogenesis factors to replace the aging endothelium. Dysfunction of such physiological repair mechanisms may predispose to endothelial injury. Longitudinal studies indicate a higher incidence of death from cardiovascular causes in those with low baseline levels of CEPs. Likewise, increased atherosclerotic risk is positively correlated with the number of CEPs.

Levels of CEPs can be favorably altered by medication with statin drugs. Treatment of normal mice with atorvastatin increase the number of CEPs with improvement and recovery from reperfusion ischemic injury and in patients with stable coronary artery disease treatment with statins augmented CEP levels. Low levels of CEPs in SSc may be a biomarker of severe vascular manifestations. Patients with pitting scars or finger-tip ulcers had significantly lower numbers of CEPs compared to normal controls.

In the currently reviewed study, levels of CEPs were found to be extremely low in patients with SSc and associated with increased levels of angiogenic factors and endothelial activation/injury markers. Treatment with atorvastatin transiently increased the CEP count (with a corresponding decreased in the up-regulated levels of angiogenic factors) but was not restored to normal. Raynaud’s phenomenon was subjectively improved. There was an inability of CEPs in patients with SSc to maturate and this defect is not restored with statin therapy. It is likely that CEPs in SSc are reduced in numbers and also functionally altered and intrinsically hypo-responsive to angiogenic factors and statins.

Although the study was uncontrolled and only involving small numbers of patients, it nevertheless provides further insights into the underlying pathogenesis of the vasculopathy in SSc and offers the possibility of alternative therapies. However the precise vascular abnormality in this disease still needs to be defined.

LEARNING OBJECTIVES

To understand the underlying pathogenesis of the vasculopathy seen in
systemic sclerosis.

Be informed of recent observations that may have important implications
in the management of the vascular manifestations in this disease.

ABSTRACT

Increase in circulating endothelial precursors by atorvastatin in patients with systemic sclerosis.
Kuwana M, Kaburaki J, Okazaki Y, Yasuoka H, Kawakami Y, Ikeda Y
Keio University School of Medicine, Tokyo

Objective:
To investigate whether atorvastatin can increase bone marrow-derived CEPs and improve vascular symptoms in patients with SSc.

Patients and Methods:
Single-centre, open label, prospective study with enrollment of 14 patients (all females) with SSc according to the ACR classification criteria irrespective of disease type and cholesterol level. All patients received atorvastatin 10 mg daily for 12 weeks. Blood samples were taken at four-week intervals to week 16. Outcome measures: Severity of Raynaud's phenomenon using a daily diary and VAS; absolute numbers of CEPs; circulating levels of angiogenic factors; and potential of CEPs to maturate into mature endothelial cells.

Results:
CEPs were scarcely detectable at baseline and at 16 weeks. Atorvastatin resulted in a 1.8 to 8.0 fold (mean 3.8 ± 1.9) increase in CEP numbers from baseline (P < 0.0001). However CEP numbers at 4 (300), 8 (295) and 12 (308) weeks did not reach levels reported in healthy individuals (1074). CEP numbers returned to baseline levels after cessation of atorvastatin treatment. There was a significant reduction (33%) in the Raynaud's condition and patient VAS (40%) scores at week 12. Worsening tended to occur after discontinuation of atorvastatin. Levels of angiogenic factors were significantly reduced during atorvastatin treatment but returned to baseline after treatment discontinuation. The maturation potential of CEPs (evaluated in 5 patients) was found impaired at baseline in all patients and did not improve at week 12.

Conclusions:
Short-term treatment with atorvastatin in patients with SSc resulted in an increase in numbers of CEPs, reduction in up-regulated levels of angiogenic factors and improvement in the Raynaud's phenomenon. However the beneficial effects were lost once treatment was discontinued. The maturation potential of CEPs in systemic sclerosis was impaired and did not improve with atorvastatin treatment.

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