Review
“Non-criteria” antiphospholipid syndrome: A nomenclature proposal

https://doi.org/10.1016/j.autrev.2020.102689Get rights and content

Highlights

  • “Non-criteria” antiphospholipid syndrome (APS) is heterogeneously described across the literature.

  • We describe four subsets: “Seronegative APS”, “Clinical non-criteria APS”, “Incomplete laboratory APS”, and “Laboratory non-criteria APS”.

  • This nomenclature aims to allow for a more uniform research approach to APS.

Abstract

The classification criteria for antiphospholipid syndrome (APS) generate discussion, with a growing impression that certain patients not fulfilling these criteria might be inadequately excluded from the classification. Nonetheless, these “non-criteria” patients are heterogeneously defined across different publications. We reviewed the “non-criteria” APS subgroups depicted in the literature and attempted to organize these subsets in a nomenclature proposal that could be used for research purposes.

We established four potential patient profiles, grouped under the broad term “non-criteria APS”: (A) “Seronegative APS”: patients fulfilling clinical criteria, plus “non-criteria” manifestations, with persistently negative antiphospholipid antibodies (aPL); (B) “Clinical non-criteria APS”: patients with “non-criteria” manifestations, plus aPL positivity fulfilling the classification criteria; (C) “Incomplete laboratory APS”: patients fulfilling clinical criteria, plus positive aPL, but not fulfilling the classification criteria (low titer aPL); and (D) “Laboratory non-criteria APS”: patients fulfilling clinical criteria, with negative or low titer criteria aPL, plus positive “non-criteria” aPL. This categorization could allow for a more homogeneous research approach to APS, enabling more sustained and universal conclusions.

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.

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