Background/Purpose: Pro-inflammatory/thrombotic biomarkers (BMR), which are associated with aPL-mediated pathogenic effects in vitro/vivo, are also increased in aPL-positive patients. Here we examined whether those BMR are differentially upregulated in persistently aPL-positive patients with or without systemic lupus erythematosus (SLE),

Methods: In this cross-sectional study, persistently aPL-positive patients (aCL IgG/M≥40 GPL/MPL,  aβ₂GPI≥20U IgG/M, and/or positive lupus anticoagulant [LA] test on 2 occasions at least 12w apart) were identified from our open-label prospective mechanistic pilot study of fluvastatin (selected exclusion criteria for this trial were pregnancy, prior statin use, prednisone >10 mg/day, and immunosuppressive use [except hydroxychloroquine]).  Control samples (age/sex matched) were identified from our databank of healthy people. 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 the serum of patients and controls. Plasma samples were used to detect sTF using a chromogenic assay. aCL (IgG, IgM and IgA), aβ₂GPI (IgG, IgM and IgA), soluble intercellular cell adhesion molecule (ICAM)-1, vascular cell adhesion molecule (VCAM)-1, and E-selectin (E-sel) were evaluated by ELISA.  Mann-Whitney Rank Sum test was used to analyze the data for differences between patient subgroups and controls; Kruskal-Walllis One Way Analysis of Variance was used to compare medians of BMR among groups.   

Results: 41 persistently aPL-positive patients (mean age: 44.6±13.6 y; female: 70%; primary APS; 18, SLE/APS: 7; Primary aPL [no history of thrombosis or pregnancy morbidity]: 9; and SLE /aPL: 7) and 30 healthy controls were included in this analysis. All APS patients had history of thrombosis except two SLE/APS patients who had only obstetric APS. Median levels of: a) all BMR except IL-8, sVCAM-1, and sE-sel was significantly higher in all groups combined when compared to the controls; b) IL-8 , TNF-α, and IP-10, were significantly higher in Primary APS, SLE/APS and SLE/aPL when compared to primary aPL; c) VEGF, sICAM-1, and sVCAM-1 were significantly higher in Primary APS when compared to the other groups; and d) sTF was elevated in all subgroups (Table). There was no difference in aCL/aβ₂GPI titers among the groups.

Biomarkers (median)	Controls n: 30	Combined n:41	Primary APS n:18	SLE/APS n:7	Primary aPL n:9	SLE/aPL n:7
IL-6 (pg/ml)	0.7	38.0*	31.2*	12.2*	0.4	2.7*
IL-1b (pg/ml)	0.3	4.7*	3.0*	11.4*	0.3	0.5
IL-8 (pg/ml)	27.4	42.6	24.5	27.4	7.2	21.6
VEGF (pg/ml)	88.3	225.1*	242.2	109.1	74.6	67.2
TNF-α (pg/ml)	0.5	29.9*	21.5*	11.6*	8.9*	53.9
IFN-α  (pg/ml)	0.1	12.9*	10.1	0.3	0.3	13.2
IP-10 (pg/ml)	96.2	584.4*	427.2*	656.2*	249.7	472.5*
sCD40L (pg/ml)	16.4	230.1*	276.5*	145.6*	149.7*	76.9*
sTF   pM	13.0	134*	153.6*	329.2*	190.4*	102.1*
sICAM-1  (pg/ml)	9.5	151.3*	281.6*	55.1*	163.5	2.8
sVCAM-1 (pg/ml)	33.7	41.9	1128.4*	156.4	321.3	41.1
sE-sel (pg/ml)	10.1	14.1	27.7*	14.7	10.9	4.1
# of BMR elevated		9/12	9/12	7/12	3/12	4/12

*  significantly different from the median of controls (p<0.05)

Conclusion: Our study suggests that the pro-inflammatory and prothrombotic markers are differentially upregulated in persistently aPL-positive patients with or without vascular events and/or SLE. These findings have implications in the pathophysiology of APS and the risk-stratification of aPL-positive patients.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/pro-inflammatory-and-pro-thrombotic-markers-in-persistently-antiphospholipid-antibody-positive-patients-withwithout-systemic-lupus-erythematosus/