Performance of the 2023 ACR/EULAR antiphospholipid syndrome classification criteria: long-term outcomes in primary and secondary APS

Background: The 2023 ACR/EULAR antiphospholipid syndrome (APS) classification criteria distinguish between anticardiolipin (aCL) or anti-β2-glycoprotein I (aβ2GPI) IgG vs. IgM isotypes and define aCL and aβ2GPI thresholds based on fixed cut-off values established only through ELISA solid-phase essay. Low weight is attributed to Isolate IgM positivity, insufficient for APS classification. In addition, the new criteria differentiate venous and arterial thrombosis depending on patient’s venous thromboembolism and cardiovascular profile risk, assigning lower significance to thrombosis occurred within the context of high-risk VTE or CVD profile. We assessed the performance of the 2023 ACR/EULAR APS classification criteria in a cohort of primary vascular APS patients (PAPS) and in a cohort of secondary vascular APS (SAPS), previously classified according to the Sydney criteria. Methods: PAPS and SAPS patients meeting the Sydney classification criteria with previous arterial, venous, or small-vessel manifestations followed between 1980 and 2023 were re-evaluated to identify cases that would not be classified as PAPS based on the 2023 ACR/EULAR criteria. Sensitivity and specificity were estimated exclusively in SAPS cohort using clinical judgment as gold standard. Results: Our cohort included 205 PAPS patients and 57 SAPS patients. 170 out of 205 were confirmed as PAPS by the new ACR/EULAR criteria, while 35 (17.1%) were not, 32 due to insufficient score in laboratory domain, 1 due to insufficient score in clinical domain, 2 due to insufficient score in both domains. On the other hand, 50 out of 57 patients were confirmed as SAPS, while 7 (12.2%) were not, 1 due to insufficient score in laboratory domain, 6 due to insufficient score in clinical domain. Notably, 9 out of 35 (25.7%) patients not confirmed as PAPS and 1 out of 7 (14.3%) patients not confirmed as SAPS had a thrombotic relapse during the follow-up, confirming a pro-thrombotic profile. ACR/EULAR APS classification criteria sensitivity and specificity in a cohort of aPL positive patients (57 SAPS and 49 aPL carriers) with SLE were 82% and 100%, respectively. Conclusion: In this report, 17.1% of PAPS patients and 12.2% of SAPS patients classified as APS by the Sydney criteria would not meet the 2023 ACR/EULAR criteria. In clinical practice, inappropriately using these criteria as diagnostic, could result in the lack of adequate antithrombotic therapy, exposing these patients to the risk of a new thrombotic event.