Neonatal lupus erythematosus (NLE) is an acquired autoimmune condition caused by the transplacental transfer of maternal immunoglobulin G (primarily anti-SS-A and anti-SS-B antibodies) into the fetal circulation. This transfer targets fetal autoantigens, resulting in transient multiorgan involvement in the fetus (1, 2). Clinical symptoms of NLE typically appear at birth or within 4–6 weeks of life and may affect multiple organs, with skin manifestations being the most common, followed by hematological, hepatobiliary, and cardiac involvement (3, 4). These symptoms usually resolve within 6–12 months as maternal antibodies wane (4).

Atopic dermatitis (AD), or atopic eczema, is a chronic, recurrent inflammatory skin disease with a genetic predisposition, affecting 15–30% of children worldwide (5). Characterized by persistent itching and polymorphic skin lesions, AD is often the first stage in the “allergy march” and significantly impacts a child’s physical and mental development. The recurrent nature of AD leads to sleep disturbances and reduced quality of life, making it a particularly challenging condition to manage in childhood (6, 7).

During clinical studies and follow-up of patients with NLE, we observed a significantly higher rate of late-onset AD compared to its normal prevalence. While the pathogenesis of NLE and AD differs, autoimmune diseases are primarily mediated by Th1 cells, and allergic diseases are mediated by Th2 (8, 9). However, both are now understood to result from complex interactions between genetic, environmental, and other unknown factors (10). Recent evidence suggests a bidirectional relationship, with patients who have allergic diseases being at increased risk for autoimmune conditions (11, 12). Based on this, we hypothesized that certain clinical variables in patients with NLE may contribute to an elevated risk of developing AD. This study aimed to identify early-life risk factors for the development of AD in children with NLE within their first two years of life.

The microecology of the human gastrointestinal tract plays an important role in the onset and progression of allergic conditions by influencing anti-allergic mechanisms such as Th1 immunity, TGF signaling, and IgA production (15). Early colonization and development of the gut microbiota are thought to be closely linked to the risk of allergies in infancy, childhood, and adulthood (16). A large number of studies have confirmed that prenatal and postnatal probiotic supplementation may be an effective means of preventing AD in children, but there is heterogeneity in the results of the existing studies, and further confirmation is still needed (17–19). In this study, the percentage of patients in the AD group who used oral probiotics was significantly lower than that in the non-AD group, while the use of intravenous antibiotics was significantly higher. In addition, among the children with NLE in this study, the number of days of oral administration of probiotics was higher in non-AD children than in children in the AD group, although there was no statistical difference between the two groups, which may be related to the smaller sample size. Although the study population was limited to patients with NLE, our findings suggest that early probiotic supplementation may help maintain a balanced gut microbiota, potentially serving as a therapeutic strategy to prevent the development of allergic diseases.

Relevant studies have shown that anti-SSA/SSB/U1RNP antibodies are associated with rashes in children with NLE, with double positivity for anti-SSA and anti-SSB, as well as triple positivity (Anti-SSA/SSB/U1RNP antibody), greatly increasing the incidence of rashes in patients with NLE (20). Histological examinations have revealed granular IgG deposits at the dermal-epidermal junction and vesicular changes at the skin’s interface and adnexal structures (21). Additionally, many studies have confirmed that immune complex deposition plays an important role in the development of NLE rash. However, to our knowledge, no studies have directly linked autoimmune antibodies to the development of AD. In our study, we found that children with NLE who developed AD had significantly higher rates of anti-SSA, anti-SSB, and anti-SSA/SSB double antibody positivity compared to the non-AD group, identifying double antibody positivity as a risk factor for AD. This may be due to NLE-associated antibodies on processes such as apoptosis, inflammatory responses, T-cell activation and proliferation, and pro-inflammatory interleukin production—mechanisms that are also central to the pathogenesis of AD (22–24).

The use of GC in patients with NLE is common, with intravenous GC administered to 40 patients in our study. The rate of IV GC use was significantly higher in the AD group compared to the non-AD group, identifying it as a risk factor for the development of AD in patients with NLE by age 2. While GCs are typically used to regulate skin homeostasis and are the first-line topical treatment for AD (25, 26), studies on the impact of early-life intravenous GC administration on AD risk are limited. Fetuses and newborns are particularly sensitive to GC, and therapeutic doses have lasting effects on growth, organ function, and immune function (27, 28). Early exposure to GC may increase immune reactivity to foreign antigens and compromise the skin’s natural barrier, both of which increase the risk of allergic diseases.

Epidemiological studies have consistently shown that children exposed to antibiotics in the first months or years of life have a significantly increased risk of developing AD and asthma (16, 29–31). The use of antibiotics early in life disrupts the normal evolution and colonization of gut microorganisms, which, in turn, alters the host’s immune status, thus increasing the susceptibility to AD (16). This was corroborated by the significantly higher percentage of patients in the non-AD group who were taking oral probiotics. In this study, the percentage of antibiotic use in patients in the AD group was significantly higher than that in the non-AD group; however, after multifactorial regression analysis, it was not found to be an independent risk factor for AD development in patients with NLE. Most of these studies, including ours, were observational, and patients on antibiotics often have bacterial infections and varying underlying immune statuses; therefore, more confounding factors may be involved.

This study is the first to establish a correlation between perinatal factors and the occurrence of AD within the first two years of life in patients with NLE. Although the study included patients from four clinical centers, the rarity of NLE resulted in a relatively small final sample size. To reduce bias, we utilized electronic case retrieval, along with outpatient and telephone follow-ups, ensuring all relevant information was collected and cross-checked by specialized physicians in pairs to. In addition, it is important to note that, based on the retrospective of this study, whether relevant factors, including oral probiotics in NLE patients, are associated with the development of AD needs to be further verified. Previous studies have shown that dupilumab or oral JAK inhibitors have good therapeutic effects and a high safety profile in patients with moderate-to-severe AD. Among them, dupilumab can significantly reduce related comorbidities in pediatric AD patients (32, 33). In the future, we need to conduct large-scale, multicenter prospective studies to further explore and confirm the long-term risk factors for developing AD in NLE patients, as well as the corresponding treatment strategies.

Our results indicate that early exogenous probiotic supplementation may be a protective factor against the development of AD in patients with NLE by age 2, while anti-SSA/SSB double positivity and intravenous GC use are risk factors. However, further research and prospective clinical trials are required to elucidate the causal relationships of these associations.