Efficacy of Rituximab vs Tacrolimus in Pediatric Corticosteroid-Dependent Nephrotic Syndrome

Abstract

IMPORTANCE Calcineurin inhibitors are an established first-line corticosteroid-sparing therapy for patients with corticosteroid-dependent nephrotic syndrome (CDNS), whereas B-lymphocyte-depleting therapy is mostly used as a rescue for calcineurin inhibitor-resistant cases. The positive efficacy and safety profile of rituximab raises the question of whether it could be used as a first-line alternative to calcineurin inhibitor therapy. OBJECTIVE To compare the efficacy of rituximab and tacrolimus in maintaining relapse-free survival among children with CDNS. DESIGN, SETTING, AND PARTICIPANTS A parallel-arm, open-label, randomized clinical trial was performed from May 8, 2015, to September 20, 2016, with 1-year follow-up in a single-center, tertiary care unit. A total of 176 consecutive children aged 3 to 16 years with CDNS not previously treated with corticosteroid-sparing agents were screened for eligibility. INTERVENTIONS The children received either tacrolimus (along with tapering alternate-day prednisolone) for 12 months or a single course of rituximab (2 infusions of 375 mg/m 2). MAIN OUTCOMES AND MEASURES Twelve-month relapse-free survival in the intention-to-treat population. RESULTS Of the 176 children screened for eligibility, 120 were randomized and all but 3 patients completed 1 year of follow-up. The groups were comparable, with mean (SD) age of 7.2 (2.8) years, 32 boys (53.3%) in each group, mean (SD) disease duration of 2.5 (1.5) years and 2.3 (1.7) in the tacrolimus and rituximab groups, respectively, disease duration less than 1 year among 15 children (25.0%) in each group, median (interquartile range) of 4 (3-5) relapses in each group, and mean (SD) cumulative prednisolone dose of 246 (48) mg/kg and 239 (52) mg/kg in the prestudy year in the tacrolimus and rituximab groups, respectively. Rituximab therapy was associated with a higher 12-month relapse-free survival rate than tacrolimus (54 [90.0%] vs 38 [63.3%] children; P < .001; odds ratio, 5.21; 95% CI, 1.93-14.07). Among the patients who experienced relapse, median time to first relapse was 40 weeks in the rituximab group and 29 weeks in the tacrolimus group. Only 2 patients in the rituximab group had more than 1 relapse during the study period compared with 10 patients in the tacrolimus group. The cumulative corticosteroid dose during the 12-month study period was lower with rituximab compared with tacrolimus (mean [SD], 25.8 [27.8] vs 86.3 [58.0] mg/kg). Although both treatments were well tolerated, mild to moderate infections were twice as common in the tacrolimus group (26 [43.3%] vs 13 [21.7%] events). CONCLUSIONS AND RELEVANCE In children with CDNS, rituximab appears to be more effective than tacrolimus in maintaining disease remission and minimizing corticosteroid exposure and, given its good tolerability and lack of nephrotoxic effects, may be considered as first-line corticosteroid-sparing therapy.

Study protocol: multicenter double-blind, randomized, placebo-controlled trial of rituximab for the treatment of childhood-onset early-stage uncomplicated frequently relapsing or steroid-dependent nephrotic syndrome (JSKDC10 trial)

“…To date, only two major reports have assessed the use of rituximab in early-stage uncomplicated SDNS. Ravani et al conducted a multicenter, open-label, randomized, control trial [10] and Basu et al conducted a single-center, parallel-arm, open-label, randomized, clinical trial [11]. Compared with these previous reports, our trial is of high quality as clinical research.…”

“…The results from this trial indicated that rituximab allows the complete withdrawal of steroids in patients with childhood SDNS without adversely affecting clinical outcomes and that the drug has an acceptable short-term adverse event profile [10]. One clinical trial indicated that rituximab is more effective than tacrolimus over a 12-month period in maintaining disease remission and minimizing corticosteroid exposure [11]. Despite these results, additional data are needed to inform clinical practice.…”

Rituximab Use in the Management of Childhood Nephrotic Syndrome

“…Basu et al conducted an open label randomized clinical trial in India where 120 children with non-complicated courses of SDNS were randomized to receive either tacrolimus for 12 months combined with tapering alternate-day prednisolone or 2–4 weekly infusions of rituximab (375 mg/m2) (43). Frequency of infusions was guided by depletion of B cell count and since all children achieved adequate B cell depletion after the second dose of rituximab, all children received only 2 doses.…”

A Case of Frequently Relapsing Minimal-Change Nephrotic Syndrome with Steroid-Induced Psychiatric Syndrome Treated by Low-Dose, Short-Term Steroid Therapy in Combination with Cyclosporine

“…In recent years, rituximab (RTX) has generally been used in the treatment of patients with PSL-and/or CsA-dependent FRNS, particularly for children [12]. RTX may therefore be considered as the first-line immunosuppressive drug for children.…”