Background/Purpose: Antiphospholipid syndrome (APS) is a systemic autoimmune disorder characterized by the persistent presence of antiphospholipid antibodies (aPL) along with clinical manifestations such as venous or arterial thrombosis and obstetric morbidity, including recurrent pregnancy loss and preeclampsia. Among aPL isotypes, IgG antibodies (particularly those targeting cardiolipin and β2-glycoprotein I) are well established as the primary pathogenic drivers and are central to current classification criteria. In contrast, the clinical relevance of IgM antibodies (especially when coexisting with IgG) is less well understood and often underrecognized in clinical settings. Determining whether concurrent IgM positivity confers additional clinical risk is key to enhancing diagnostic precision, prognostic evaluation, and clinical management in APS.To determine whether the added aPL IgM positivity is associated with a more severe clinical phenotype in patients with aPL IgG positive APS.

Methods: A cross-sectional, multicenter study was conducted at two European tertiary care centers: Reina Sofía University Hospital (Cordoba, Spain) and Ospedale San Giovanni Bosco (Turin, Italy). Patients with confirmed APS, according to the revised Sydney classification criteria, were included and stratified based on the presence or absence of concurrent IgM positivity. Clinical, immunological, and therapeutic data were collected from electronic medical records. Valvular involvement (valvulopathy) was assessed by transthoracic echocardiography in accordance with institutional protocols. Univariate analyses were followed by multivariate logistic regression to identify independent associations, adjusting for the Global Antiphospholipid Syndrome Score (GAPSS), a validated tool for APS risk stratification.

Results: Among the 100 patients included, 65 were classified as IgG+ only and 35 as IgG+IgM+. No statistically significant differences were found between groups in age, sex, systemic lupus erythematosus (SLE) prevalence, or thrombotic burden. However, the IgG+IgM+ group had a significantly higher median GAPSS (13 vs. 10; p=0.04) and a markedly increased prevalence of echocardiographically confirmed valvulopathy (17% vs. 2%; p< 0.01). Detailed clinical and serological comparisons are shown in Table 1. In multivariable analysis, IgM positivity remained independently associated with valvulopathy (OR: 12.5; 95% CI: 1.73–274.5; p=0.03), after adjusting for potential confounders including GAPSS and the presence of SLE. The wide confidence interval highlights statistical uncertainty, limiting the precision and interpretability of this association.

Conclusion: The presence of IgM aPL in patients with IgG-positive APS defines a clinically distinct subgroup, characterized by greater valvular involvement despite similar thrombotic profiles. These findings suggest that IgM antibodies may contribute to a more complex, organ-specific disease phenotype and support their inclusion in APS risk stratification and therapeutic decision-making. Future research should explore the role of other isotypes, such as IgA, to comprehensively characterize their contribution to APS manifestations.

Table 1. Clinical, immunological, and treatment characteristics of IgG+ versus IgG+IgM+ APS patients. ANA: antinuclear antibody; ASA: acetylsalicylic acid; VKA: vitamin K antagonist; HTN: hypertension; HCQ: hydroxychloroquine. Valvulopathy was assessed by transthoracic echocardiography according to institutional protocols.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/when-one-isnt-enough-does-adding-igm-worsen-the-antiphospholipid-syndrome-phenotype/