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Background: Antiphospholipid Syndrome (APS) can occur as a primary condition or in association with Systemic Lupus Erythematosus (SLE). Proinflammatory pathways are involved in antiphospholipid antibody (aPL)-related events, which explains why antithrombotic treatment alone might not be sufficient for the management of selected aPL-positive patients. Type I Interferon (IFN-I) is implicated in the initiation, progression, and treatment response of many systemic autoimmune disorders including SLE. There is growing evidence that the interferon pathway also plays a role in the pathogenesis of APS. Gene expression profiling studies have suggested a potential role of IFN-I in differentiating the subsets of APS patients with autoimmune manifestations [1, 2].
Objectives: Our primary objective was to compare the IFN-I activity between three groups of persistently aPL-positive patients with: a) no concomitant systemic autoimmune rheumatic diseases (SARDs); b) SLE classification; and c) SLE-like disease without SLE classification.
Methods: APS ACTION is an international multicenter registry of patients with persistently positive aPL, with or without additional SARDs. Baseline demographic information, aPL-related clinical events, medications, and aPL test results as well as blood samples are collected at registry entry and updated every 12 months. We compared IFN-I activity, in the first available serum or plasma sample, between three groups of persistently aPL-positive patients (with/without APS classification) with: a) no SARDs; b) SLE based on four or more 1997 ACR SLE classification criteria; and c) SLE- like disease defined as 3/11 1997 ACR SLE criteria including aPL. A sensitive and reproducible reporter cell (WISH cells) assay was used to measure the ability of sera to cause IFN-induced gene transcription to generate an IFN-I score. Three IFN-I inducible genes were selected (MX-1, IFIT-1, EIF2AK2). A cut off point of 2 standard deviations (SD) above the mean of 105 healthy controls was used to categorize IFN-I score into high vs. low. The clinical, laboratory characteristics and the IFN-I activity score of the three groups (with no SARDs, with SLE, with SLE-like disease) were compared using Kruskal-Wallis H, Chi-squared and Fisher Exact tests, followed by post hoc tests with Holm–Bonferroni correction. All statistical analyses were performed in R and RStudio (version 2024.04.1). The significance level was set at 0.05.
Results: Of 1,206 patients who were part of the registry as of 2/2/24, 425 from North American Centers were identified. We excluded 36 participants: 18 with SARDs other than SLE, 12 recent recruitments with no available samples, and 6 with an indeterminate IFN-I activity score. We included 389 patients in the final analysis: 163 (42%) with no SARDs, 181 (46%) with SLE, and 45 (12%) with SLE-like disease as described above. The baseline demographic, clinical and aPL characteristics are shown in Table 1; the mean age at registry entry was 45 with female (74%) and white (78%) predominance. There were significantly more triple aPL-positive patients in the SLE-like disease group (62%) compared to patients with SLE (33%) (p-value=0.002). There were significantly more LA only patients in the SLE group (28%) compared to patients in the no SARDs group (17%) (p-value=0.037) or patients in the with SLE-like disease group (7%) (p-value=0.016). Around 30% of patients in each group had a high IFN-I activity score (defined as IFN-I activity score of ≥2); the distribution of patients with high IFN-I activity was similar between the three groups (p-value=0.801) (Table 2).
Conclusion: To our knowledge, this is the largest study to date looking at the association between IFN-I and aPL using a functional assay reflective of the extent to which the IFN-I pathway is activated. We found that one-third of persistently aPL-positive patients had high IFN-I activity score, irrespective of SLE classification or “SLE-like disease”. The percentage of high IFN-I activity score among aPL-positive patients without SLE is striking considering conflicting literature on the association of aPL and IFN-I activation. Multivariable analyses are underway to examine the association of IFN-I and APS clinical phenotype as well as the detailed aPL profile in this well-characterized group of patients.
REFERENCES: [1] Palli et al. Type I Interferon Signature in Primary Antiphospholipid Syndrome: Clinical and Laboratory Associations. Front Immunol. 2019;10:487.
[2] Verrou et al. Whole blood transcriptome identifies interferon-regulated genes as key drivers in thrombotic primary antiphospholipid syndrome. J Autoimmun. 2023;134:102978.
Acknowledgements: NIL.
Disclosure of Interests: None declared.
© The Authors 2025. This abstract is an open access article published in Annals of Rheumatic Diseases under the CC BY-NC-ND license (