Is It Time to Change Our Approach to Childhood Lupus Nephritis?

The management of lupus nephritis is challenging, with kidney involvement maintaining a leading role in driving organ damage accrual and mortality risks in patients affected by SLE worldwide. In a rapidly advancing therapy landscape that includes next-generation B-cell therapies and novel calcineurin inhibitors for the treatment of SLE nephritis, why do we still need studies focused on cyclophosphamide and mycophenolate mofetil (MMF)?

In adults, the early National Institutes of Health cyclophosphamide and industry-sponsored MMF trials fueled early clinical practice guidelines that promoted a distinction between a period of remission induction and maintenance for patients with lupus nephritis.¹ The Aspreva Lupus Management Study failed to meet the primary objective of showing that MMF was superior to intravenous cyclophosphamide in the number and percentage of patients who showed a response to treatment.² This study was not powered as a noninferiority study, but the investigators highlighted comparable remission rates between MMF and cyclophosphamide and a more favorable side effect profile when considering concerns for ovarian failure in young women treated with intravenous (i.v.) cyclophosphamide. Although these treatments have been broadly accepted as standard-of-care therapies for lupus nephritis, they have never met regulatory approval. The approval of belimumab and voclosporin in Europe, Canada, and the United States has prompted a conceptual shift from induction and maintenance therapy to one of combination regimens targeting different parts of the immune system. This framework centers a goal of preserving kidney function, reducing morbidity and mortality of CKD, and minimizing medication-related toxicities.³

In children, high-quality evidence is lacking, and the management of lupus nephritis is largely established based on data derived from adults or from cohort studies. Consistent with this paucity of pediatric data, the recent Kidney Disease Improving Global Outcomes⁴ and American College of Rheumatology guidelines³ advise to follow a similar strategy in adults and children. However, childhood-onset SLE appears to carry a particularly severe prognosis and to present more frequently than adult-onset SLE kidney involvement, organ damage accrual, and mortality.⁵ Moreover, the burden of treatment-related toxicity is much higher in children due to the need for longer treatment with a higher risk of infection and malignancy and due to the greater impact of glucocorticoids and immunosuppression on a developing individual, for both skeletal growth and pubertal development and for the establishment of immune competence.

Guidelines addressing pediatric management of lupus nephritis are lacking. A recent large study conducted on medical records from children treated in North America⁶ showed that induction medications in 575 children with lupus nephritis included corticosteroids (i.v. and oral), cytotoxic agents (i.v. cyclophosphamide), antimetabolites (MMF, mycophenolic acid), and biologics (rituximab, belimumab). The most common first noncorticosteroid agents were antimetabolites (61.6%), followed by cytotoxic agents (21%).

Supporting this real-world practice, in this issue of JASN, a study performed in children with lupus nephritis compared the efficacy of MMF versus i.v. cyclophosphamide as induction therapy for childhood-onset proliferative lupus nephritis in a prospective, multicenter, randomized controlled trial.⁷ The study assessed 107 children from 17 hospitals in China aged 5–17 years with proliferative lupus nephritis (class 3/4±5), an eGFR ≥60 ml/min per 1.73 m² and severely increased proteinuria, randomly assigned to receive either MMF or i.v. cyclophosphamide at induction, alongside glucocorticoids. All patients in the cyclophosphamide group received monthly i.v. cyclophosphamide (750 mg/m², not exceeding 1 g, administered over 1–2 days) for 6 months combined with glucocorticoids. All patients in the MMF group received MMF therapy (30–40 mg/kg per day, divided into two doses, not exceeding 1 g/dose), in conjunction with glucocorticoids. The glucocorticoid treatment was identical, and all patients were given supportive therapy including hydroxychloroquine and angiotensin-converting enzyme inhibitors. The primary end point of the study was total renal response at 24 weeks, with the aim of demonstrating the noninferiority of MMF compared with i.v. cyclophosphamide, using a noninferiority margin of 12%. Total renal response was a composite end point comprising complete renal response, primary efficacy renal response, and partial renal response as defined in the Kidney Disease Improving Global Outcomes 2024 guidelines.⁴ After 24 weeks of therapy, total renal response was achieved by 96% of patients in the MMF group versus 94% of patients in the cyclophosphamide group (test for noninferiority, P = 0.009) in the per-protocol population. Therefore, oral MMF was noninferior to i.v. cyclophosphamide. It also exhibited a similar safety profile, with no significant differences in the incidence of adverse drug reactions between the treatment groups.

This study is significant, representing the first high-quality prospective study conducted in children demonstrating the noninferiority of an induction regime based on MMF in proliferative lupus nephritis. It confirms previous smaller studies, reinforces the need to move away whenever possible from the use of cytotoxic drugs, and provides 24-month evidence of the validity of this approach also in pediatric lupus nephritis. Although a longer follow-up will be important, it is a first step in the right direction. Not addressed in this study is one caveat to real-world implementation, particularly in adolescent patients, which is poor adherence to prescribed MMF exacerbated by gastrointestinal intolerance in some.

As the authors acknowledge, an important potential limitation of this study is its geographic origin, comprising only patients of Asian descent. Lupus has well-known major differences based on ancestry. A consistent finding across epidemiologic studies is that SLE is significantly more common in Black individuals, followed by other non-White groups, compared with White individuals.⁸ Black, East Asian, South Asian, and Hispanic individuals with SLE tend to develop more severe disease with a greater number of manifestations and accumulate damage from lupus more rapidly.⁸ Therefore, the extremely high rates of response reported in this study may not be reproduced in a more diverse population, especially including children of African descent.

The difficulty of performing high-quality, sufficiently powered clinical trials in rare diseases in children is well known.⁹ Sadly, even in clinical trials conducted in adults with SLE, a recent important study evaluating all randomized controlled trials conducted between 2000 and 2024 found that Asian participants were the most represented race in the clinical trials, comprising 55.2%, followed by White participants, representing 28.4%. Black participants and those of other races composed only 7.2% and 9.2%, respectively, in randomized controlled trials.¹⁰ Therefore, under-representation of pediatric Black participants will certainly represent a major hurdle moving forward. This racial disparity has therapeutic implications, as studies assessing the effect of geographic ancestry on the genetic architecture of SLE show differences in the representation of risk haplotypes between ethnic groups, which may contribute to different disease phenotypes and explain, at least in part, varying severity and response to treatment.¹¹ Given that race is a social construct, it is also important to consider the social and structural factors linked to race that influence treatment outcomes in SLE nephritis.

Moreover, when choosing the best treatment strategy for SLE nephritis, the most recent American College of Rheumatology guidelines³ advocate initiating treatment with triple therapy. This approach entails adding to glucocorticoids and MMF a third agent, that is, a calcineurin inhibitor in patients with nephrotic-range proteinuria or belimumab, which is the only approved lupus treatment also in children, in other cases. The objective of this approach is to achieve remission more rapidly and more frequently, minimizing glucocorticoid cumulative dose. Current trials investigating new-generation B-cell therapies such as the phase 2 POSTERITY Trial, a randomized, double-blind, placebo-controlled study evaluating the safety, efficacy, and pharmacokinetics of obinutuzumab on a background of MMF in adolescents with proliferative lupus nephritis, underscore the need for confidence that MMF performs comparably with cyclophosphamide (NCT05039619). High-quality, inclusive trials assessing the validity of this approach also in children with SLE nephritis are therefore urgently needed.

Until then, this noninferiority trial supports avoiding cyclophosphamide when feasible and strengthens evidence to use MMF as a component of first-line therapy for most children with proliferative lupus nephritis.

Supplementary Material

jasn-37-442-s001.pdf ^{(1.4MB, pdf)}

Disclosures

Disclosure forms, as provided by each author, are available with the online version of the article at http://links.lww.com/JSN/F651.

Author Contributions

Conceptualization: Keisha L. Gibson, Marina Vivarelli.

Writing – original draft: Keisha L. Gibson, Marina Vivarelli.

Writing – review & editing: Keisha L. Gibson, Marina Vivarelli.

Funding

None.