Rethinking antiphospholipid syndrome to guide future management and research

Antiphospholipid syndrome (APS) consists of thrombotic, non-thrombotic and obstetric clinical manifestations developing in individuals with persistent antiphospholipid antibodies (aPL). Although researchers have made progress in characterizing different clinical phenotypes of aPL-positive people, the current approach to clinical management is still mostly based on a ‘one size fits all’ strategy, which is derived from the results of a limited number of prospective, controlled studies. With the 2023 publication of the ACR–EULAR APS classification criteria, it is now possible to rethink APS, to lay the groundwork for subphenotyping through novel pathophysiology-informed approaches, and to set a future APS research agenda guided by unmet needs in clinical management. In this Review, Knight and Erkan consider how the 2023 ACR–EULAR classification criteria for antiphospholipid syndrome (APS) can guide future research to subphenotype APS by understanding its pathophysiology, paving the way for the personalized and proactive management of individuals with APS. Key points People with antiphospholipid syndrome (APS) can develop thrombotic, non-thrombotic and obstetric clinical problems in the persistent presence of antiphospholipid antibodies (aPL). Definitions of APS vary in sophistication and have different purposes, such as describing APS to patients and learners, diagnosing and risk-stratifying patients in the clinic, or classifying patients for research purposes. Future aims include better definition and subphenotyping of APS based on greater understanding of its underlying pathophysiology, using precisely defined autoantibodies, pathway-informed biomarkers, and modern genomic, transcriptomic and proteomic approaches. Despite different clinical phenotypes among aPL-positive individuals, current management is mostly based on a ‘one size fits all’ strategy, derived from a limited number of prospective controlled studies. The 2023 ACR–EULAR APS classification criteria should support a future research agenda aiming for better definition and subphenotyping of APS, and for more personalized and proactive management of all aPL-positive individuals.