A prospective open-label pilot study of fluvastatin on proinflammatory and prothrombotic biomarkers in antiphospholipid antibody positive patients

Abstract

Objective: To determine if pro-inflammatory and pro-thrombotic biomarkers are differentially upregulated in persistently antiphospholipid antibody (aPL)-positive patients, and to examine the effects of fluvastatin on these biomarkers. Methods: Four groups of patients (age 18-65) were recruited: a) Primary Antiphospholipid Syndrome (PAPS); b) Systemic Lupus Erythematosus (SLE) with APS (SLE/APS); c) Persistent aPL positivity without SLE or APS (Primary aPL); and d) Persistent aPL positivity with SLE but no APS (SLE/aPL). The frequency-matched control group, used for baseline data comparison, was identified from a databank of healthy persons. Patients received fluvastatin 40 mg daily for three months. At three months, patients stopped the study medication and they were followed for another three months. Blood samples for 12 pro-inflammatory and pro-thrombotic biomarkers were collected monthly for six months. Results: Based on the comparison of the baseline samples of 41 aPL-positive patients with 30 healthy controls, 9/12 (75%) biomarkers (interleukin [IL]-6, IL1β, vascular endothelial growth factor [VEGF], tumor necrosis factor [TNF]-□α, interferon [IFN]-α, inducible protein-10 [IP10], soluble CD40 ligand [sCD40L], soluble tissue factor [sTF], and intracellular cellular adhesion molecule [ICAM]-1) were significantly elevated. Twenty-four patients completed the study; fluvastatin significantly and reversibly reduced the levels of 6/12 (50%) biomarkers (IL1β, VEGF, TNFα, IP10, sCD40L, and sTF). Conclusion: Our prospective mechanistic study demonstrates that pro-inflammatory and pro-thrombotic biomarkers, which are differentially upregulated in persistently aPL-positive patients, can be reversibly reduced by fluvastatin. Thus, statin-induced modulation of the aPL effects on target cells can be a valuable future approach in the management of aPL-positive patients.

Pravastatin improves pregnancy outcomes in obstetric antiphospholipid syndrome refractory to antithrombotic therapy

“…It is tempting to speculate that pravastatin might increase placental blood flow by its antiatherogenic effects and by stimulating the release of vasoactive substances from the endothelium, such as nitric oxide or carbon monoxide (42,43). Statins have also been shown to downregulate tissue factor, a crucial molecule in the crosstalk between inflammation and thrombosis in mice and humans with APS (29,44). These protective effects of pravastatin on the endothelium together with its effect restoring angiogenic balance (24) might also explain the amelioration of placental and maternal preeclamptic signs.…”

Obstetrical APS: Is there a place for hydroxychloroquine to improve the pregnancy outcome?

“…Although the vitamin D levels were low 324 in obstetrical APS, no correlation was found with adverse pregnancy 325 outcomes in one report[58]. The physiopathological data support the 326 potential benefit of vitamin D supplementation, but further clinical 327 studies are necessary to confirm its use in obstetrical APS[47,58].328Statins have shown interesting results in vitro studies, but their ter-329 atogenicity prohibits their use during pregnancy[59].330 Other drugs which have not been tested yet in obstetrical APS could 331 have potential interest according to their pharmacological effects [47]. 332 Among them, fondaparinux can bind β2GP-I, interface with the comple-333 ment cascades, and inhibit thrombin generation via TF expression.…”

Antiphospholipid syndrome: an update for clinicians and scientists

“…In mouse models of APS, statins mitigate aPL-mediated thrombotic events and fetal death [11,16]. Furthermore, when administered to APS patients, statins decrease both prothrombotic and proinflammatory biomarkers [68]. …”