Background/Purpose: Antiphospholipid antibodies (aPL) induce a pro-inflammatory and pro-thrombotic state by upregulating various cytokines, chemokines, and tissue factor (TF). Fluvastatin reduces TF expression and decrease thrombogenic effects of aPL in vitro and in mice. The purpose of this prospective pilot study was to examine the effects of fluvastatin on pro-inflammatory and pro-thrombotic biomarkers (BMR) in persistently aPL-positive patients.
Methods: Persistently aPL-positive patients (IgG/M aCL≥40 GPL/MPL, IgG/M aβ2GPI≥20U, and/or positive lupus anticoagulant (LA) test on 2 occasions at least 12w apart) received fluvastatin 40 mg daily for at least 3 months. At 3 months, patients were instructed to stop fluvastatin and they were followed for another 3 months. Serum samples were collected at baseline and monthly thereafter for 6 months. Selected exclusion criteria were pregnancy, statin use, prednisone >10 mg/day, and immunosuppressive use (except hydroxychloroquine [HCQ]). Interferon (IFN)-α, Interleukin (IL)1b, IL6, IL8, inducible protein (IP)10, tumor necrosis factor (TNF)-α, vascular endothelial growth factor (VEGF), and soluble CD40 ligand (sCD40L) levels were determined by the MILLIPLEXMAP human cytokine/chemokine assay (Millipore, Billerica,MA) in serum of patients and controls. Plasma samples were used to detect sTF using a chromogenic assay. aCL IgG/M/A, aβ2GPI IgG/M /A, soluble intercellular cell adhesion molecule (ICAM)-1, vascular cell adhesion molecule (VCAM)-1, and E-selectin (E-sel) were evaluated by ELISA. We used Spearman test to analyze the significance of monthly changes in BMR levels.
Results: Of 41 patients recruited, 24 completed the study (mean age: 44.6 + 13.6y; female: 70%; Primary APS: 8, SLE/APS: 7, Primary aPL: 5; SLE /aPL: 4; HCQ: 61%; and Anticoagulation: 43%). The early withdrawal reasons for 15/41 patients were: 6 lost to follow-up or refused further treatment without adverse events; 4 stopped treatment due to myalgia (normal muscle/liver enzymes); 3 wanted to continue fluvastatin after 3 months; 1 screen failure after the baseline visit; and i stopped treatment due to insomnia. The table shows the number of patients with elevated BMR (above the assay cut-off) at baseline as well follow-up BMR levels during and after fluvastatin. The levels of 6/12 (50%) BMR (IL-6, IL-1b, VEGF, TNF-α, IP-10, sCD40L, and sTF) significantly decreased with fluvastatin, followed by significant increases after stopping the treatment. Of note, aCL/aΒ2GPI and LA tests remained unchanged throughout the study.
|
Biomarker (BMR) |
# of Patients with Elevated BMR at BL |
# of Patients with Decreased BMR after Fluvastatin |
Mean+SD Maximum BMR reduction with fluvastatin |
# of Patients with Increased BMR After Stopping Fluvastatin |
Mean+SD maximum BMR Increase After Stopping Fluvastatin |
|
IL-6 |
17/24 (71%) |
12/17 (71%) |
80.5 ± 25.3* |
9/12 (75%) |
56.7 ± 34.5 |
|
IL-1b |
11/24 (45%) |
6/11 (54%) |
67.5 ± 24.5* |
5/6 (83%) |
89.0 ± 23.5* |
|
IL-8 |
6/24 (25%) |
5/6 (83%) |
33.9 ± 11.0 |
3/5 (60%) |
45.6 ± 34.1 |
|
VEGF |
13/24 (54%) |
10/13 (77%) |
87.8 ± 13.0* |
5/10 (50%) |
57.8 ± 28.5* |
|
TNF-α |
23/24 (96%) |
9/23 (39%) |
87.3 ± 45.8* |
6/9 (67%) |
90.3 ± 4.5* |
|
IFN-α |
9/24 (37%) |
8/9 (89%) |
71.8 ± 15.4* |
6/8 (75%) |
56.7 ± 21.0 |
|
IP-10 |
19/24 (79%) |
12/19 (63%) |
65.4 ± 13.9* |
8/12 (67%) |
87.5 ± 14.5 * |
|
sCD40L |
22/24 (92%) |
10/22 (45%) |
68.0 ± 21.0* |
9/10 (90%) |
90.6 ± 4.3* |
|
sTF |
24/24 (100) |
20/24 (83) |
57.0 ± 29.9* |
13/20 (65%) |
80.4 ± 10.3* |
|
sICAM-1 |
9/24 (37) |
7/9 (77) |
45.6 ± 35.9 |
1/7 (14%) |
23.4 ± 12.0 |
|
sVCAM-1 |
15/24 (62) |
4/15 (27) |
38.7 ± 34.6 |
3/4 (75%) |
47.6 ± 10.4 |
|
sE-sel |
8/24 (33) |
2/8 (25) |
43.8 ± 36.1 |
0/2 (0) |
N/A |
*p<0.05
Conclusion: Our pilot study demonstrating that fluvastatin can reversibly reduce the pro-inflammatory and prothrombotic biomarkers in persistently aPL-positive patients with or without SLE provide the basis for future larger randomized-control trials to examine the effects of the statins on the aPL-induced biomarkers as well as on the aPL-related clinical manifestations.
Disclosure:
D. Erkan,
None;
R. Willis,
None;
J. Vega,
None;
V. L. Murthy,
None;
A. L. Carrera Marin,
None;
G. Basra,
None;
P. Ruiz Limon,
None;
E. B. Gonzalez,
None;
S. S. Pierangeli,
None.
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