Autoantibodies Targeting Domain 1 Of Beta 2 Glycoprotein I As Promising Marker In The Diagnosis and Risk Stratification Of The Antiphospholipid Syndrome

Navid Zohoury¹, Munther A. Khamashta², Tatsuya Atsumi³, Jacek Musial⁴, Toshiyuki Watanabe⁵, Maria Papp⁶, Concepción González-Rodríguez⁷, Roger Albesa¹, Gary L. Norman¹, Pier-Luigi Meroni⁸ and Michael Mahler¹, ¹Research, INOVA Diagnostics, San Diego, CA, ²Lupus Research Unit, The Rayne Institute, St Thomas Hospital, Kings College London School of Medicine, London, United Kingdom, ³Division of Rheumatology, Endocrinology and Nephrology, Hokkaido University Graduate School of Medicine, Sapporo, Japan, ⁴Depment of Medicine, Jagiellonian University Medical College, Krakow, Poland, ⁵Division of Rheumatology, Endocrinology and Nephrology, Hokkaido University Graduate School of Medicine, Hokkaido, Japan, ⁶MHSCInstitute of Medicine, Department of Gastroenterology, University of Debrecen, Debrecen, Hungary, ⁷University Hospital Virgen Macarena, Sevilla, Spain, ⁸Int Medicine, University of Milan, Milano, Italy

Meeting: 2013 ACR/ARHP Annual Meeting

Keywords: Antiphospholipid antibodies, antiphospholipid syndrome, autoantibodies, autoimmune diseases and thrombosis

Session Information

Title: Antiphospholipid Syndrome: Clinical Manifestations and New Biomarkers in Antiphospholipid Syndrome

Session Type: Abstract Submissions (ACR)

Background/Purpose:

Antiphospholipid Syndrome (APS) is characterized by the presence of antibodies to phospholipids (aPL) and to β₂glycoprotein I (β₂GPI) in patients with thrombosis or pregnancy morbidity. Several studies provided evidence that antibodies to Domain 1 of β₂GPI (β₂GPI-D1) represent a promising biomarker for the diagnosis and risk assessment of APS patients. Here we aimed to analyze the diagnostic potential of β₂GPI-D1 antibodies and the value in risk stratification of APS patients using a large multi-centric cohort of patients.

Methods:

A total of 273 APS patients and 1096 controls (including healthy individuals, patients with infectious or autoimmune diseases) were tested for anti-β₂GPI-D1 by QUANTA Flash CIA (INOVA). A reduced number of samples (n=622) were also tested on anti-β₂GPI by QUANTA Flash CIA (INOVA). Clinical data including the history of thrombosis was known in 89 APS patients (58 had a history of thrombosis).

Results:

In the entire cohort, anti-β₂GPI-D1 antibodies differentiated APS and controls with a sensitivity and specificity of 49.8% and 99.6%, respectively. The likelihood ratios were LR+ 136.5 and LR- 0.5. The prevalence of anti-β₂GPI antibodies was higher in primary than in secondary APS and reach significance for anti-β₂GPI-D1 (p=0.0029), but not for anti-β₂GPI antibodies (p=0.06). When compared with the anti-β₂GPI assay, both assays showed good qualitative (79.8%, 95% CI 69.1-86.5; kappa=0.60, 95% CI 0.44-0.76) and quantitative agreements (spearman`s rho=0.81, 95% CI 0.73-0.87) as well as similar discrimination between APS patients and controls as shown by ROC analysis. In the smaller sub-cohort (n=622), sensitivity/specificity were 50.2%/99.2% (β₂GPI-D1) and 72.8%/87.3% (β₂GPI), respectively.

Assay	Cut-off	Sensitivity (95% Confidence interval)	Specificity (95% Confidence interval)	LR+/LR- at cut-off
β₂GPI	20 CU	72.8 (66.6-78.4)	83.7 (79.7-87.3)	4.5/0.33
β₂GPI-D1	20 CU	50.2 (43.6-56.8)	99.2 (97.8-99.8)	64.8/0.50
β₂GPI	50.9 CU	62.1 (55.6-68.4)	96.9 (94.6-98.4)	20.0/0.39
β₂GPI-D1	7.3 CU	60.0 (53.4-66.3)	96.9 (94.6-98.4)	19.4/0.41
β₂GPI	91.1 CU	57.4 (50.9-63.9)	99.0 (97.4-99.7)	55.6/0.43
β₂GPI-D1	11.1 CU	56.2 (49.6-62.6)	99.0 (97.4-99.7)	54.3/0.44

When APS patients were stratified according to the history of thrombosis, anti-β₂GPI-D1 and anti-β₂GPI antibodies showed sensitivities/specificities of 37.9%/93.5% and 60.3%/67.7% respectively. At high specificity (96.8%), the sensitivity for thrombosis was significantly higher for β₂GPI-D1 than for β₂GPI (22.4% vs. 12.1%; p<0.05).

Assay	Cut-off	Sensitivity (95% Confidence interval)	Specificity (95% Confidence interval)	LR+/LR- at cut-off
β₂GPI	20 CU	60.3 (46.6-73.0)	67.7 (48.6-83.3)	1.87/0.59
β₂GPI-D1	20 CU	37.9 (25.5-51.6)	93.5 (78.6-99.2)	5.88/0.66
β₂GPI	4868 CU	12.1 (5.0-23.3)	96.8 (83.3-99.9)	3.74/0.91
β₂GPI-D1	286.9 CU	22.4 (12.5-35.3)	96.8 (83.3-99.9)	6.95/0.80

Conclusion:

Anti-β₂GPI-D1 and anti-β₂GPI antibodies show similar performance characteristics in differentiation of APS patients and controls. The correlation with history of thrombosis appears to be stronger for anti-β₂GPI-D1 compared to anti-β₂GPI-antibodies. Therefore, anti-β₂GPI-D1 antibodies are a promising biomarker to aid in the diagnosis and risk assessment of APS patients, but further studies are needed to verify those preliminary findings.

Disclosure:

N. Zohoury,

Inova Diagnostics, Inc.,

M. A. Khamashta,

Inova Diagnostics, Inc.,

T. Atsumi,
None;

J. Musial,
None;

T. Watanabe,
None;

M. Papp,
None;

C. González-Rodríguez,
None;

R. Albesa,

Inova Diagnostics, Inc.,

G. L. Norman,

Inova Diagnostics, Inc.,

P. L. Meroni,

Inova Diagnostics, Inc.,

M. Mahler,

Inova Diagnostics, Inc.,

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