Long-Term Efficacy and Safety of Repeated Rituximab to Maintain Remission in Idiopathic Childhood Nephrotic Syndrome: An International Study

Abstract

Background: Long-term outcomes following multiple rituximab courses among children with frequently-relapsing, steroid-dependent nephrotic syndrome (FRSDNS) are unknown. Methods: A retrospective cohort study at 16 pediatric nephrology centers from 10 countries in Asia, Europe, and North America included children with FRSDNS who received ≥2 rituximab courses. Primary outcomes were relapse-free survival and adverse events. Results: 346 children (age 9.8 years, IQR 6.6-13.5; 73% boys) received 1149 rituximab courses. 145, 83, 50, 28, 22, and 18 children received 2, 3, 4, 5, 6 and ≥7 courses, respectively. Median follow-up was 5.9 years (IQR, 4.3-7.7). Relapse-free survival differed by treatment courses (clustered log-rank test p<0.001). Compared to the first course (10.0 months, 95% CI, 9.0-10.7), relapse-free period and relapse risk progressively improved following subsequent courses (12.0-16.0 months; HRadj, 0.03-0.13; 95% CI, 0.01-0.18; ps<0.001). B-cell depletion duration remained similar with repeated treatments (6.1 months, 95% CI, 6.0-6.3). Adverse events were mostly mild, most commonly hypogammaglobulinemia (50.9%), infection (4.5%), and neutropenia (3.7%). Side effects did not increase with more treatment courses nor higher cumulative dose. Only 78 of the 353 episodes of hypogammaglobulinemia were clinically significant. Younger age at presentation (2.8 vs 3.3 years; p=0.05) and at first rituximab (8.0 y vs 10.0 years; p=0.01) and history of steroid resistance (28% vs 18%; p=0.01) were associated with significant hypogammaglobulinemia. All 53 infective episodes resolved, except one patient with hepatitis B infection and another with EBV infection. There were 42 episodes of neutropenia, associated with history of steroid resistance (30% vs 20%, p=0.04). Upon last follow-up, 332 children (96%) had normal kidney function. Conclusion: Children receiving repeated rituximab for FRSDNS experience an improving clinical response. Side effects appear acceptable but significant complications can occur. These findings support repeated rituximab use in FRSDNS.

IPNA clinical practice recommendations for the diagnosis and management of children with steroid-sensitive nephrotic syndrome

“…Evidence for the most correct approach is lacking [ 164 ]. Based on a recent retrospective survey, 30 of 346 included children tolerated up to 7 courses of RTX infusions (mainly dosed with 375 mg/m 2 /course) with an acceptable side effect profile (most common hypogammaglobulinema, followed by infections and neutropenia) and good efficacy [ 182 ].…”

Humoral and Cellular Immunogenicity and Safety of 3 Doses of CoronaVac and BNT162b2 in Young Children and Adolescents with Kidney Diseases

“…Rituximab has emerged as an important therapeutic option in several pediatric immunemediated glomerular diseases, such as idiopathic nephrotic syndrome and ANCA-associated vasculitis glomerulonephritis. 2,22,23 Our data showed that rituximab exposure up to 1 year prior to vaccination resulted in poor immunogenicity. Furthermore, patients with glomerular disease are at risk of relapse and often require multiple courses of rituximab to maintain disease remission.…”

“…Furthermore, patients with glomerular disease are at risk of relapse and often require multiple courses of rituximab to maintain disease remission. 22 Therefore, the timing of vaccination and rituximab should be individualized, balancing the risk of infection and disease relapse. Fortunately, our current findings did not suggest an overtly increased risk of graft rejection and disease relapse following vaccination, indicating the safety of COVID-19 vaccination in children and adolescents with kidney diseases.…”

“…Furthermore, patients with glomerular disease are at risk of relapse and often require multiple courses of rituximab to maintain disease remission. 22 Therefore, the timing of vaccination and rituximab should be The SARS-CoV-2 Omicron variant has caused repeated surges in COVID-19 cases and hospitalizations across the globe, with more than 30 mutations in S protein which cause extensive neutralization escape and reduce the effectiveness of COVID-19 vaccines. [24][25][26] According to our data, when compared with WT sVNT, we found that a significantly lower sVNT% level against Omicron BA.1 following doses 2 and 3, signifying partial neutralization escape.…”

Clinical practice guidelines for nephrotic syndrome: consensus is emerging

“…Chief concerns associated with therapy have been the risks of infusion reactions (4 studies, 252 children; RR 5.8, 95% CI 1.3-25.3) [25], severe infections [32], vaccine hyporesponsiveness [33], and reactivation of viral infections, such as hepatitis B and JC virus [34]. Recent studies suggest that therapy may lead to variable hypogammaglobulinemia in 35-58% of children, particularly in patients < 8-10 years old, those with preexisting hypogammaglobulinemia, and those receiving multiple rituximab doses or additional immunosuppression [35].…”