Review“Non-criteria” antiphospholipid syndrome: A nomenclature proposal
Introduction
The classification criteria for antiphospholipid syndrome (APS) are a source of heated discussion, with a growing impression among clinicians, researchers and even certain patients that they are inadequately excluded from the classification. The report of the 14th International Congress on Antiphospholipid Antibodies Technical Task Force on APS clinical features emphasized the role of certain “non-criteria” manifestations on the clinical course of the disease, setting the path for an eventual inclusion as part of the criteria [1]. Moreover, the EULAR 2019 recommendations for the management of antiphospholipid syndrome in adults included some considerations on the management of clinical “non-criteria” obstetric APS [2]. In addition, rising evidence suggests that several seronegative patients for the laboratory criteria result from the limited array of antibodies considered, and that testing for “non-criteria” antiphospholipid antibodies (aPL) could increase the diagnostic yield in APS [[3], [4], [5], [6], [7], [8], [9]].
Nevertheless, caution should be exercised when deriving conclusions regarding these matters, as most data currently accessible originate from low-grade evidence (e.g., case reports, small sample studies, narrative reviews, and expert consensus) [1,10,11]. Additionally, another factor makes it difficult to accurately assess the available evidence: there is a marked divergence between studies regarding the definitions used to describe different potential subsets of “non-criteria” APS patients.
We reviewed the various “non-criteria” APS subgroups depicted in the literature while attempting to organize these subsets in a nomenclature proposal that could be used for future research purposes.
Section snippets
Methods
A literature search was conducted on PubMed, Web of Science and Scopus using the following keywords: “antiphospholipid syndrome”, “non-criteria”, “seronegative”, “probable”, “possible”, “incomplete”, “non-conventional”, “gap”, “low titer”, “transient” and “obstetric morbidity”. No temporal restriction was imposed, and the references of retrieved articles were also screened for potentially relevant publications. Studies specifying a definition of “non-criteria” APS subsets or featuring a
“Non-criteria” APS subsets
Table 1 summarizes the studies describing potential types/subsets of “non-criteria APS”, allowing for a historical contextualization and a perception of the evolution of these concepts across recent decades. The analysis of these studies resulted in the following four potential patient profiles: (A) patients with clinical APS criteria, plus the presence of “non-criteria” manifestations, but persistently negative criteria aPL; (B) patients with “non-criteria” manifestations, plus aPL positivity
Conclusion
We hypothesize the following patient profiles for future research purposes, grouped under the broad term “non-criteria APS” (Fig. 1):
- -
“Seronegative APS”: patients with clinical manifestations fulfilling APS classification criteria, plus the presence of “non-criteria” manifestations (at least one obstetric or one major non-obstetric or two minor non-obstetric), with persistently negative aPL (at least 2 determinations 12 weeks apart), and exclusion of other thrombophilias that justify the whole
Funding
This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
Declaration of Competing Interest
None.
References (59)
- et al.
The relevance of “non-criteria” clinical manifestations of antiphospholipid syndrome: 14th international congress on antiphospholipid antibodies technical task force report on antiphospholipid syndrome clinical features
Autoimmun Rev
(2015) - et al.
Does seronegative antiphospholipid syndrome really exist?
Autoimmun Rev
(2012) - et al.
Does seronegative obstetric APS exist? “pro” and “cons”
Autoimmun Rev
(2019) - et al.
Increased risk of thrombosis in antiphospholipid syndrome patients treated with direct oral anticoagulants. Results from an international patient-level data meta-analysis
Autoimmun Rev
(2018) - et al.
The antiphospholipid syndrome in patients with systemic lupus erythematosus
J Autoimmun
(2017) - et al.
Are pregnancies with lupus but without APS of good prognosis?
Autoimmun Rev
(2020) - et al.
Antiphospholipid antibodies and the risk of thrombocytopenia in patients with systemic lupus erythematosus: a systematic review and meta-analysis
Autoimmun Rev
(2019) - et al.
International consensus statement on an update of the classification criteria for definite antiphospholipid syndrome (APS)
J Thromb Haemost
(2006) New subsets of the antiphospholipid syndrome in 2006: “PRE-APS” (probable APS) and microangiopathic antiphospholipid syndromes (“MAPS”)
Autoimmun Rev
(2006)- et al.
Comparative study between obstetric antiphospholipid syndrome and obstetric morbidity related with antiphospholipid antibodies
Med Clin (Barc)
(2018)