Background/Purpose: Criteria antiphospholipid (aPL) antibodies that identify antiphospholipid syndrome (APS) patients, anticardiolipin (aCL) and anti-β2glycoprotein-I (anti-β2GPI), have demonstrated inconsistent specificity and sensitivity in this regard respectively. The purpose of this study was to evaluate the performance characteristics of non-criteria anti-phosphatidic acid (anti-PA), anti-phosphatidylglycerol (anti-PG) and anti-phosphatidylethanolamine (anti-PE) assays (IgG/IgM) in identifying APS related clinical manifestations in a large group of patients with aPL-related diseases.

Methods: Serum samples from 520 patients from the Hopkins (n=344) and Jamaican SLE cohorts (n=42), the PROMISSE cohort (n=77), as well as APS patients (n=29) and healthy controls (n=28) from the Antiphospholipid Standardization Laboratory were examined for IgG/IgM positivity in aCL (in-house), anti-β2GPI (INOVA Diagnostics), anti-PA, anti-PG and anti-PE (Louisville APL) ELISA assays. Assay cut-offs were aCL IgG/IgM (10GPL/10MPL), anti-β2GPI (20SGU/20SMU), anti-PA, anti-PG, anti-PE (15GPL/15MPL). Correlation of assay positivity with clinical manifestations expressed as odds ratio (OR) with 95%CI, the effect of increasing antibody titers, logistic regression multivariate analysis, quantitative and qualitative inter-assay agreement, and various analytical measures of assay performance including sensitivity, specificity, positive (PPV) and negative (NPV) predictive values were evaluated.

Results: The prevalence of IgG/IgM anti-PA positivity was 30.4%, anti-PG was 27.7%, anti-PE was 30.8%, aCL was 24.2% and anti-β2GPI was 18.3%. The IgG isotypes of all assays were associated with at least one or more thrombotic and/or obstetric manifestation, while IgM isotypes of non-criteria assays were associated with obstetric manifestations. All criteria and non-criteria assays (IgG/IgM) were associated with APS diagnosis (Table 1). There was a 3 to 10-fold increased risk for thrombotic manifestations, particularly venous thrombosis, associated with high vs low positive titers in IgG assays. There was moderate to excellent quantitative and qualitative agreement among most assays of corresponding isotypes. Overall, sensitivity (26.3-39.5%), specificity (85.3-94.1%), PPV (39.3-68.0%) and NPV (70.4-76.1%) for APS diagnosis were relatively similar among IgG assays, which performed better than their IgM counterparts. IgG aCL was the only independent predictor for venous thrombosis OR 3.6(2.1-6.1) and arterial thrombosis OR 1.9(1.1-3.4) while IgG anti-PA was the only independent predictor for placental insufficiency due to pre-eclampsia/eclampsia OR 2.4(1.3-4.6) and recurrent miscarriage OR 1.9(1.2-3.0).

Conclusion: IgG anti-PA, anti-PG and anti-PE antibodies were associated with thrombotic and obstetric APS-related manifestations, while their IgM counterparts were associated with mainly obstetric manifestations. Increasing titers of IgG assays imparted an increased risk, particularly for venous thrombosis. These non-criteria PL assays are promising biomarkers for particular APS manifestations and their independent value in APS classification requires further investigation.

Table 1. Association of antiphospholipid assay positivity with APS-related clinical manifestations – Odds Ratios with 95% Confidence Intervals

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/thrombotic-and-obstetric-associations-of-non-criteria-antiphospholipid-immunoassays-that-detect-antibodies-to-neutral-and-negatively-charged-phospholipid/