Seronegative antiphospholipid syndrome: Diagnostic challenges, novel biomarkers, therapeutic ambiguities, and future perspectives

This review synthesizes recent advancements in understanding seronegative antiphospholipid syndrome (SN-APS), a condition characterized by clinical manifestations of antiphospholipid syndrome (APS) despite persistently negative conventional antiphospholipid antibody (aPL) tests. The absence of these traditional markers necessitates a deeper exploration into novel biomarkers and advanced diagnostic methodologies to bridge the existing serological gap. This includes scrutinizing “non-criteria” antiphospholipid antibodies and exploring their clinical utility in improving diagnostic precision for patients with high clinical suspicion yet negative conventional markers. The review also addresses the significant diagnostic overlap with other systemic autoimmune diseases, complicating accurate diagnosis and often leading to therapeutic ambiguities. Furthermore, an emphasis is placed on emerging omics technologies and immunophenotyping as promising avenues for unraveling the intricate pathological mechanisms underlying SN-APS, thereby potentially identifying novel diagnostic targets and therapeutic strategies. Such advancements are crucial given that SN-APS patients, despite fulfilling clinical criteria, often remain undiagnosed and untreated until severe clinical events occur, necessitating improved diagnostic frameworks beyond the 2006 Sydney classification criteria. The advent of the 2023 American College of Rheumatology/European Alliance of Associations for Rheumatology classification criteria for APS, while incorporating additive weight for clinical and laboratory domains, still necessitates at least one positive conventional aPL, thereby leaving a subset of patients with clinical signs but negative criteria aPL in a diagnostic void.