Background/Purpose: Systemic lupus erythematosus (SLE) is associated with an increased risk of placental insufficiency and adverse pregnancy outcomes, even when the disease is clinically quiescent. This suggests the existence of underlying molecular pathologies not reflected by standard clinical disease activity measures or serological markers. This study aimed to determine whether steroid and hydroxychloroquine (HCQ) exposure during pregnancy has the potential to restore placental transcriptomic abnormalities compared to healthy controls.

Methods: We analyzed publicly available RNA-seq data from the NCBI GEO dataset (GSE177029), which included placental samples obtained from 8 SLE patients matched to healthy donors (HD) following delivery. Differential gene expression analysis was performed using the DESeq2 R package. Benjamin & Hochberg correction (false discovery rate) was applied, with significance set at p < 0.05. Out of 19,151 genes, the analysis identified 1,051 differentially expressed genes between the SLE and HD groups.The interferon signature was calculated using a standard set of genes (IFI27, IFI44L, ISG15, RSAD2, IFIT1, MX1, OAS1). For other statistical comparisons between groups, a t-test was used.

Results: Characteristics of the SLE patients are shown in Table 1. On average, disease duration was 57 months prior to delivery (IQR: 10–157). The median SLEDAI score was 3. All SLE patients were on daily prednisone (< 15 mg) and HCQ (200–400 mg). Aspirin was used by 3 patients. There were no differences in maternal age, gestational age, or BMI between the SLE and HD groups (30 ± 2 years; 28 ± 1 weeks; 27 ± 2; p > 0.05). There was no history of preeclampsia in either group. Newborn weight was significantly lower in the SLE group (2,950 ± 491 g vs. 3,378 ± 261 g; p < 0.05). Despite low SLEDAI scores and steroid or HCQ use, placentas obtained from SLE patients showed almost a threefold increase in the type I interferon gene signature (IFN score 1.566, log₂ fold change; padj = 0.0034), indicating unresolved immunological activation. Additionally, genes encoding epithelial cytoskeletal proteins, such as keratin 14 and keratin 24, were significantly upregulated—by more than 5- and 7-fold, respectively—in SLE placentas compared to HD, suggesting impaired maturation and dedifferentiation in response to inflammation. Importantly, angiopoietin-2 (ANG-2), a critical regulator of angiogenesis, was significantly downregulated in SLE placentas (log₂ fold change = –1.59; padj = 0.0296), corresponding to a 67% reduction in expression compared to healthy controls. This suggests persistent defects in placental vascular remodeling and endothelial homeostasis. In SLE patients with SLEDAI scores of 4–6, there was a 19% reduction in ANG-2 expression compared to those with SLEDAI scores of 0–4.

Conclusion: Low disease activity and the use of steroids or HCQ were insufficient to normalize placental gene expression in SLE pregnancies. Persistent interferon signaling, angiogenic dysregulation, and impaired cytoskeletal remodeling highlight a disconnect between clinical disease control and molecular placental health, underscoring the need for biomarkers and interventions targeting subclinical placental inflammation.

Table 1. Clinical and serological characteristics

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/failure-of-steroid-and-antimalarial-therapy-to-normalize-placental-interferon-and-angiogenic-gene-expression-in-sle/