Belimumab in Childhood Onset SLE: Update and Evidence

Abstract

Childhood onset systemic lupus erythema (cSLE) or pediatric onset SLE is a rare autoimmune disease among children and young adolescents, accounting for 10%–20% of all SLE patients. cSLE has a reported incidence rate of 0.3–0.9 per 100,000 children-years and a prevalence ranging from 3.3 to 8.8 per 100,000 children [1]. The average age of presentation of cSLE is 11–12, and it rarely happens in children aged below 5 [2]. Previous studies have concluded that cSLE is more common in females than males with a ratio of 4–5:1, but the sex ratio was lower compared to adult SLE, with a ratio of 9:1 [1]. In contrast to adult SLE, cSLE patients usually have greater accrual of damage, higher disease activity, more frequent organ involvement, and worse outcomes compared to adult onset SLE [3, 4]. Other studies have shown a higher risk of developing major depression in cSLE patients and juvenile SLE patients compared to adult onset SLE [5], posing a great challenge for treatment and maintaining quality of life.

Before the recent breakthrough of biologic in SLE treatment, hydroxychloroquine, glucocorticoids, and immunosuppressants were the main treatment options for SLE [6]. Despite standard regime's efficacy in disease control, it also compromised patient immunity, making infection one of the major causes of morbidity and mortality in the SLE population [7]. Nonetheless, osteoporosis, cataracts, and coronary artery disease are significant side effects that should not be overlooked in long-term steroid users [ref]Above all these complications, children and adolescents before puberty are more likely to be exposed to prolonged high-dosed corticosteroid treatment and are more vulnerable. Long-term use of supraphysiological doses of corticosteroids, undernutrition, altered body composition with lean mass reduction, physical inactivity, delays in pubertal onset, or slow pubertal progression [8]. The need for steroid-sparing agents to achieve better disease control is therefore urgent for this population.

Trial of belimumab in children with lupus was reported in 2020 by Brunner et al. [9] suggesting that intravenous pharmacokinetics and benefit–risk profile in cSLE are consistent with adult belimumab studies.

To assess the efficacy and potential complications of belimumab in children, we aim to review the latest real-world evidence of its use in patients under the age of 18. We conducted a literature search on PubMed using keywords “Belimumab,” “SLE,” “systemic lupus erythematosus,” “lupus nephritis,” “lupus,” “childhood onset,” “childhood,” “pediatric,” “juvenile,” “children,” and filtered literature published in the last 5 years; the search term is as follows:

(Belimumab[Title/Abstract]) AND ((((SLE[Title/Abstract]) OR (systemic lupus erythematosus[Title/Abstract])) OR (lupus nephritis[Title/Abstract])) OR (lupus[Title/Abstract])) AND (((((childhood[Title/Abstract]) OR (childhood onset[Title/Abstract])) OR (pediatric[Title/Abstract])) OR (juvenile[Title/Abstract])) OR (children)) AND (y_5[Filter]).

In total, sixty-six research articles were identified. Upon screening, 29 were review articles or case reports, 24 were unrelated to the efficacy of belimumab in cSLE, and 7 focused on the pharmacokinetics, extrapolation, or safety of belimumab. These articles were excluded. After screening, six articles including clinical trials and a retrospective study met the inclusion criteria and were selected for further discussion (Table 1). The selection process is shown in (Figure 1).

In the recent study of the efficacy and safety of belimumab in cSLE, the PLUTO trial, a phase II double-blinded, randomized controlled study [9] demonstrated that 10 mg/kg intravenous belimumab every 4 weeks combined with standard therapy achieved numerically more SLE Responder Index (SRI 4) responders (52.8% vs. 43.6%;OR 1.49) and Pediatric Rheumatology International Trials Organization/American College of Rheumatology response after 52 weeks of treatment. Furthermore, parent global assessment, physician global assessment (PGA) and proteinuria all showed numeric improvement after 52 weeks of treatment. Although a significant difference in the primary outcome, SRI4, was not achieved due to a lack of a sufficient sample size, the response to belimumab among cSLE was consistent with adult belimumab studies.

A single-center retrospective study by Wang et al. (2022) demonstrated that treatment with intravenous belimumab at a dose of 10 mg/kg every 2 weeks for the first three doses, followed by every 4 weeks thereafter, led to significant reductions in 24-h urine protein levels, SLEDAI-2 K scores, PGA scores, and glucocorticoid use. Additionally, complement 3 and complement 4 levels were significantly elevated. By the end of the 52-week treatment period, 53.8% of patients achieved LLDAS, whereas 15.4% attained clinical remission [10, 11].

One arm prospective study by Wang et al. (2024) demonstrated that after being treated with belimumab combined with standard of care, a statistically significantly greater proportion of the cSLE patients reached lupus low disease activity state (LLDAS) and clinical remission compared to their baseline at the entry of the study. SELENA-SLEDAI score significantly decreased after 3 months of treatment and maintained a lower score at 6 and 12 months follow-up. Improvement in disease severity according to physician global assessment was also noted [12].

A study by Gong et al. (2024) reported significantly higher rates of primary efficacy renal response (PERR), complete renal response (CRR), Definitions of Remission in Systemic Lupus Erythematosus (DORIS), and LLDAS in the Belimumab group compared to the standard immunotherapy group. The Belimumab group also demonstrated a significantly faster and greater reduction in glucocorticoid dose and SLEDAI scores. Additionally, no cases of lupus nephritis relapse or need for rescue therapy were observed in the Belimumab group, whereas 10 patients in the standard immunotherapy group required rescue therapy, and three experienced relapses [13].

Another retrospective cohort study revealed that when used in childhood patients with lupus nephritis, Belimumab combined with a traditional regimen achieved an equivocal remission rate at 6 and 12 months compared with standard treatment [14]. With an equivalent renal remission rate, belimumab combined with the standard traditional regimen might promote the tapering of glucocorticoids, and the incidence of adverse events is low.

Summarizing the selected literatures (Table 1), most of the studies have proven belimumab's efficacy in decreasing disease activity, whether by lowering SLEDAI score, PGA score, or achieving a higher proportion of LLADS after treatment for up to 52 weeks. In some studies, however, patients only improved numerically, which was likely the result of small sample sizes.

In the retrospective cohort study by Li et al. [14] revealed that after treatment with Belimumab combined with a traditional regimen, the glucocorticoid dosage is significantly lower than that of the placebo group by 6-month and 12-month follow-up of the trial, demonstrating Belimumab's corticosteroid sparing effect as a adjuvant treatment. Similar result was found in study by Wang et al. [12], demonstrating adjuvant belimumab combined with standard of care significantly reduced the dosage of corticosteroid from baseline 31.0 to 6.4 mg/day at 12 months. Study by Wang et al. [10] demonstrated a significant reduction in corticosteroid use compared to baseline following intravenous belimumab treatment at 4, 12, 24, and 52 weeks. Additionally, 42% of patients had discontinued corticosteroids by their last follow-up. Study by Roberts et al. [11] also showed significant reduction of corticosteroid dose compared to baseline after receiving intravenous belimumab for 6 and 12 months. Cohort study from Yinv Gong et al. [13] reported significantly faster and greater reduction in glucocorticoid dose in belimumab group compared to standard immunotherapy group. Corticosteroids' strong association with increased risk of major infections, cataract, osteoporosis, cardiovascular disease, retarded growth, and delayed puberty was reported in multiple studies, making corticosteroid-sparing effect critically important considering cSLE patients' high exposure to corticosteroids [15].

From a cohort study of adult SLE treated with belimumab, infection and infusion reaction were the most common among the adverse events [16, 17]. PLUTO studies showed no significant difference in adverse effects in the belimumab group (79.2%) and the placebo group 82.5%. Discontinuation due to treatment or severe adverse effects also showed no difference [9]. In Li et al. [14], non-significant decreased immunoglobulin levels and few infections without severe adverse effects were reported. As for the prospective study from Wang et al. (2024) only reported one case with a severe adverse effect and one with a fungal infection out of 193 patients. Currently available trials and prospective studies have proven that belimumab's use in cSLE has no more safety concerns compared to its use in adult SLE.

The successful phase II trials and cohort studies had shown that Belimumab brings clinical benefits in cSLE when combined with traditional regime. However, the small population in this research often results in a lack of statistical power and population bias. Furthermore, different endpoints and measurements for efficacy also make it difficult to compare directly or statistically between research.

Despite only being approved for 5 years, where belimumab's long-term safety and patient outcomes still need to be confirmed, belimumab had demonstrated its efficacy in disease control and reduction of corticosteroid use in cSLE patients. Further research is needed to determine whether the corticosteroid-sparing effects of belimumab can lead to a reduced infection rate or a decrease in long-term complications, such as growth retardation in children, to provide more definitive conclusions.

T.L.Y. and S.-B.Y.: writing – original draft. C.-Y.Y., C.-Y.W.: writing – review and editing. S.-B.Y., C.-Y.W.: writing – review and editing.

The authors declare no conflicts of interest.