We evaluated the efficacy and safety of belimumab combined with the standard regimen in treating children with active lupus nephritis and found that belimumab plus standard therapy promoted rapid reduction of proteinuria, and the complement C3 and C4 levels recovered faster, although there was no difference in renal remission rate at 6 months and 1 year compared to traditional treatment alone. Our findings also demonstrate that belimumab as an adjuvant treatment can promote the tapering of glucocorticoid.

Standard treatment with corticosteroids combined with immunosuppressive agents (including CTX or MMF) improves renal prognosis, but it is not an ideal therapy. According to adult data, approximately 45% of patients with proliferative LN did not improve within 6 months of standard treatment [7], and 25–30% of patients develop end-stage kidney disease (ESKD) within 20 years [8]. A cohort study of adults with LN in the UK [9] showed that 33% of patients with histologically confirmed grade III or IV LN experienced renal recurrence at an average of 3.5 years after induction, and 44% of patients with PR experienced renal recurrence. The recurrence rate was only 5% among patients who achieved initial CR. Subsequent studies [10, 11] also suggest that an inadequate renal response to induction therapy primarily causes recurrence and poor prognosis.

Compared with adults, there are few reports on pediatric LN. In recent long-term prognostic data on pediatric LN, survival rates without advanced CKD, ESKD, or death were 92.7% and 83.2% at 10 and 20 years, respectively [12]. Proliferative LN is the most common and severe type of LN in children [13, 14] and is a risk factor for progression to CKD [15]. Recurrence is common in children, especially those aged < 13 years [16]. In this study, proliferative LN accounted for 97.6% of the cases. We evaluated the renal response rates at 6 and 12 months of induction therapy, with CR rates of 78.7% and 90.9% and PR rates of 19.1% and 9.1%, respectively. Notably, both were higher than previous literature reports, which indicated that only 40–60% of children achieved a CR at 6 months of induction therapy [6]; however, our data showed that 43.3% of children in the traditional treatment group experienced recurrence within 5 years after remission, which is close to the recent data from children with LN in Hong Kong, China (recurrence rate of 41%) [12] and the United States (recurrence rate of 46%) [17]. In this study, 61.9% of relapses occurred after infection, fatigue, or irregular medication use. The 2017 European Children’s LN Evidence-Based Recommendation [18] also indicated that the noncompliance rate in children’s treatment was as high as 50%. Notably, some children with long-term glucocorticoid use experienced different degrees of adverse effects on their psychology, growth, and development due to Cushing syndrome, infection, diabetes, hypertension, and ocular hypertension [19], which led to a decline in compliance with the standard treatment. Therefore, to achieve and maintain sustained renal remission, reduce long-term exposure to glucocorticoids, and improve treatment compliance, it is equally crucial to prevent recurrence and improve prognosis.

Previous studies showed elevated serum BAFF levels are associated with SLE pathogenesis, supporting the basic principle of targeted molecular therapy for SLE. The 2-year BLISS-LN trial [20] showed that belimumab plus standard therapy had a primary efficacy renal response. Yu et al. [21] analyzed the data of the BLISS-LN East Asian subgroup, in which more patients achieved PR (53% vs. 37%; OR, 1.76 [95% CI, 0.88–3.51]) and CR (35% vs. 25%; OR, 1.73 [95% CI, 0.80–3.74]) at week 104 with belimumab treatment, which confirmed that safety and efficacy profiles were consistent with BLISS-LN overall population. Research on BAFF blockade therapy for childhood LN remains limited; however, multiple randomized trials of nonrenal SLE have shown that the efficacy and safety of belimumab are comparable in pediatric and adult patients [22, 23]. This study analyzed the efficacy and safety of the early use of belimumab combined with standard traditional regimens for treating active LN. Forty-seven patients were included in this study. After a median follow-up of 13 months, it was observed that the belimumab group had a higher SLEDAI score (23.59 ± 7.78 vs. 19.13 ± 6.10) at enrollment and a higher median 24-h proteinuria level (75.9 mg/kg. d vs. 63.3 mg/kg. d) and renal pathological activity index (10.47 ± 2.72 vs. 9.59 ± 2.78). Although the statistical results showed no difference in renal remission rate and 1-year recurrence rate between the two groups, the renal remission rate of the belimumab group was slightly higher than that of the traditional treatment group (88.2% vs. 73.3% at months 6 and 92.9% vs. 90.0% at month 12). There was no renal recurrence at 1 year, which was significantly lower than that in the traditional treatment group (13.3%), which indicated that belimumab may effectively reduce disease activity and maintain LN remission without recurrence. However, in this study, the median recurrence time for children in the traditional treatment group was 2 years. In contrast, the follow-up time for the belimumab group was still short, and the number of enrolled cases was not large.

Consequently, whether belimumab can maintain long-term nonrecurrence in patients still requires a larger sample size and extended follow-up time to further observe the long-term efficacy of belimumab. Similarly, our data showed that, under similar conditions of renal remission, glucocorticoid dosage in the belimumab group was significantly lower than that in the traditional treatment group at 6 and 12 months of treatment. This is also consistent with a recent observational study of 17 real-world studies on the application of belimumab to SLE patients, for whom the reduction in SLEDAI score, glucocorticoid equivalent dose, and recurrence rates were significant within 6–12 months of belimumab treatment [24].

Belimumab is a recombinant whole human monoclonal antibody that inhibits the survival of autoreactive B cells and promotes their apoptosis. It has a relatively small impact on advanced B cells, as it can retain a certain level of immunity. In this study, we also compared the serum levels of immunoglobulins, such as IgM, IgG, and IgA, during belimumab therapy. There was a downward trend compared with the baseline; however, no serious adverse reactions were observed clinically. In this multicenter, open-label study on the safety and efficacy of belimumab combined with standard therapy in treating patients with SLE for 13 years [25], the total exposure time of belimumab was 2294 patient-years, with an average median infusion frequency of 115.5 times which showed that with the extension of the observation years, the serum IgG levels of most patients (65.9%) were normal, with only 4.1% of patients experiencing a grade 3 decrease in IgG (250–399 mg/dL) and 2.4% reaching grade 4 (< 250 mg/dL), and there was an average decrease of 16.2% in the IgG levels; however, the risk of infection, including severe infections, did not increase. Therefore, the long-term safety of belimumab was acceptable.

At present, the timing and duration of belimumab treatment in children with LN remain unclear. However, it is unanimously believed that BAFF inhibition is a favorable adjunctive treatment based on the existing traditional treatments for proliferative LN.

This study has the following limitations: single-center design, small sample size, retrospective design, risk of data collection and recording bias, the short application time of belimumab, belimumab not used alone in these patients, and lack of long-term follow-up data.