Secondary Antiphospholipid Syndrome in Patients with Systemic Lupus Erythematosus: A Clinical and Laboratory Analysis of a Monocentric Cohort in Light of the 2023 ACR/EULAR Classification Criteria

Background: Secondary Antiphospholipid syndrome (SAPS) associated with systemic lupus erythematosus (SLE), is an acquired thrombophilia driven by diverse antiphospholipid antibodies (aPL) and complex pathogenic mechanisms involving hemostatic dysregulation and immunothrombosis. The recently published 2023 ACR/EULAR classification criteria for APS aim to standardize patient classification for research, but their applicability in diverse clinical settings, especially for SAPS, requires further evaluation. This study aimed to characterize SAPS patients with SLE, evaluate the diagnostic performance of the 2023 ACR/EULAR classification criteria compared to clinical judgment and the 2006 revised Sapporo criteria, identify predictors of thrombotic recurrence, and analyze the significance of extra-criteria manifestations. Methods: We conducted a retrospective cohort study on a cohort of 589 SLE patients followed up from 1980 to 2025, identifying 70 with SAPS based on clinical judgment, which were re-evaluated using the 2006 revised Sapporo and 2023 ACR/EULAR criteria. Clinical, demographic, laboratory, and therapeutic data were collected. Statistical analyses included t-tests, Mann-Whitney tests, χ² tests with Fisher's correction, and Receiver Operating Characteristic curves. Results: Among 589 SLE patients, we identified 70 SAPS patients (45 female (64.3%), mean age at APS diagnosis 31.8±12.4 years). Venous thromboembolism (VTE) was the most common manifestation (55 patients, 78.6%), followed by arterial thrombosis (21 patients, 30%). Persistent lupus anticoagulant (LA) positivity was observed in 58 patients, with IgG isotypes of anticardiolipin (aCL) and anti-β2 glycoprotein I (aβ2GPI) being more prevalent and having higher titers than IgM. 44 patients (62,9%) exhibited triple aPL positivity. 47 patients (67.1%) fulfilled the 2023 ACR/EULAR criteria, while 23 did not, primarily due to insufficient clinical domain scores. VTE with a high-risk profile was significantly more frequent in unclassified patients (p=0.0001). Thrombotic relapse occurred in 33 patients (47,1%), with male sex (p=0.0469) and arterial thrombosis as the first event (p=0.0098) being significantly associated with recurrence. Hypocomplementemia (p=0.0148) and triple aPL positivity (p=0.0308) were more prevalent in non-relapsing patients. Hematuria was significantly more common in relapsing patients (p=0.0188). Compared to physician judgment, the 2006 Sydney criteria showed 95.7% sensitivity and 100% specificity, while the 2023 ACR/EULAR criteria showed 67.1% sensitivity and 100% specificity. SAPS patients also demonstrated increased neurological involvement (p=0.027) and greater damage accrual (SLICC score, p=0.005) compared to SLE patients without SAPS. Extra-criteria manifestations, such as epilepsy and chorea, were predominantly observed in non-classified patients. Discussion: Most unclassified SAPS patients failed to meet the 2023 ACR/EULAR criteria due to insufficient clinical domain scores, suggesting a potential under-recognition of clinically significant APS phenotypes in SLE patients, despite moderate to high aPL titers. The similar thrombotic relapse rates between classified and unclassified groups imply that exclusion from classification does not equate to lower risk. Aggressive anticoagulation in triple-positive patients likely contributes to lower relapse rates in this subgroup. The high prevalence of extra-criteria manifestations in non-classified individuals highlights the limitations of the new criteria in capturing the full clinical spectrum of APS. Conclusion: the 2023 ACR/EULAR classification criteria represent a valuable tool for standardizing research in APS, however, they should not supersede clinical judgment for diagnosis and management. The criteria may not fully capture high-risk patients or the clinical diversity of APS, underscoring the need for continued vigilance and individualized therapeutic approaches.