Rituximab vs Low-Dose Mycophenolate Mofetil in Recurrence of Steroid-Dependent Nephrotic Syndrome in Children and Young Adults: A Randomized Clinical Trial | Adolescent Medicine | JAMA Pediatrics | JAMA Network
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Figure 1.  Schematic View of Trial Design
Schematic View of Trial Design

MMF indicates mycophenolate mofetil; PDN, prednisone.

Figure 2.  One-Year Relapse-Free Survival in the Rituximab and Mycophenolate Mofetil (MMF) Arms
One-Year Relapse-Free Survival in the Rituximab and Mycophenolate Mofetil (MMF) Arms

The risk of relapse was 0.8 (12/15) in the MMF and 0.13 (2/15; P = .008 in the rituximab arm, with higher odds in the MMF arm (odds ratio, 26; 95% CI, 2.9-311.0).

1.
Ravani  P, Rossi  R, Bonanni  A,  et al.  Rituximab in children with steroid-dependent nephrotic syndrome: a multicenter, open-label, noninferiority, randomized controlled trial.   J Am Soc Nephrol. 2015;26(9):2259-2266. doi:10.1681/ASN.2014080799PubMedGoogle ScholarCrossref
2.
Ravani  P, Lugani  F, Pisani  I,  et al.  Rituximab for very low dose steroid-dependent nephrotic syndrome in children: a randomized controlled study.   Pediatr Nephrol. 2020;35(8):1437-1444. doi:10.1007/s00467-020-04540-4PubMedGoogle ScholarCrossref
3.
Gellermann  J, Weber  L, Pape  L, Tönshoff  B, Hoyer  P, Querfeld  U; Gesellschaft für Pädiatrische Nephrologie (GPN).  Mycophenolate mofetil versus cyclosporin A in children with frequently relapsing nephrotic syndrome.   J Am Soc Nephrol. 2013;24(10):1689-1697. doi:10.1681/ASN.2012121200PubMedGoogle ScholarCrossref
4.
Novak  I, Frank  R, Vento  S, Vergara  M, Gauthier  B, Trachtman  H.  Efficacy of mycophenolate mofetil in pediatric patients with steroid-dependent nephrotic syndrome.   Pediatr Nephrol. 2005;20(9):1265-1268. doi:10.1007/s00467-005-1957-yPubMedGoogle ScholarCrossref
5.
Moudgil  A, Bagga  A, Jordan  SC.  Mycophenolate mofetil therapy in frequently relapsing steroid-dependent and steroid-resistant nephrotic syndrome of childhood: current status and future directions.   Pediatr Nephrol. 2005;20(10):1376-1381. doi:10.1007/s00467-005-1964-zPubMedGoogle ScholarCrossref
6.
Sinha  A, Puraswani  M, Kalaivani  M, Goyal  P, Hari  P, Bagga  A.  Efficacy and safety of mycophenolate mofetil versus levamisole in frequently relapsing nephrotic syndrome: an open-label randomized controlled trial.   Kidney Int. 2019;95(1):210-218. doi:10.1016/j.kint.2018.08.039PubMedGoogle ScholarCrossref
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    Research Letter
    February 22, 2021

    Rituximab vs Low-Dose Mycophenolate Mofetil in Recurrence of Steroid-Dependent Nephrotic Syndrome in Children and Young Adults: A Randomized Clinical Trial

    Author Affiliations
    • 1Division of Nephrology, University of Calgary, Calgary, Alberta, Canada
    • 2Division of Nephrology, Dialysis and Transplantation, Istituto Giannina Gaslini IRCCS, Genoa, Italy
    • 3Laboratory on Molecular Nephrology, Istituto Giannina Gaslini IRCCS, Genoa, Italy
    JAMA Pediatr. 2021;175(6):631-632. doi:10.1001/jamapediatrics.2020.6150

    Children and young adults with steroid-dependent nephrotic syndrome (SDNS) are exposed to the toxic effects of both steroids and common steroid-sparing agents, such as calcineurin inhibitors, reporting an increased risk of kidney failure.1 Alternative low-toxicity, long-acting therapies are needed to treat SDNS.1

    Methods

    This randomized clinical trial was designed to test the superiority of a single dose of rituximab (375 mg/m2) vs low-dose mycophenolate mofetil (MMF) (350 mg/m2 twice daily) in preventing the recurrence of SDNS. Eligibility criteria were age 3 to 24 years and SDNS requiring prednisone 0.3 mg/kg/d to 1 mg/kg/d during at least 6 months before enrollment.

    Eligible White patients were randomly assigned in a 1:1 ratio to receive either rituximab (intervention) or oral MMF (active comparator) (Figure 1). Sex and age were equally distributed. The trial protocol (Supplement 1) and study were approved by the regional review board (Liguria, IT) and Italian Drugs Agency (AIFA) and the trial protocol was registered at ClinicalTrials.gov (NCT04402580). Written consent was obtained by patients or by their parents.

    The primary outcome was the occurrence of a relapse of SDNS within 12 months of randomization; the secondary outcome was the probability of remaining relapse-free up to 24 months from randomization. Relapse was defined by a urine protein/creatinine ratio (uPCR) of 2000 mg/g or more. Logistic regression was used to compare the risk of relapse at 1 year with a 2-sided P value of <.05 as statistical significance.

    Results

    The monitoring board recommended stopping the trial after the randomization of only 30 study participants owing to unexpectedly high rates of relapse in the MMF arm (Figure 1). Of note, no relapses occurred in the intervention arm in the first 6 months. After rituximab, CD19+ B cells immediately decreased to 0%, maintaining low values until 6 to 9 months after infusion, with no differences between relapse or not.

    The risk of relapse was 0.8 (12/15) in the comparator arm and 0.13 (2/15; P = .008) in the intervention arm, with a significantly higher odds among children in the MMF arm (odds ratio [OR], 26; 95% CI, 2.9-311.0). The median time to the relapse in the active comparator arm was 3.15 months (95% CI, 2.5-9.9 months; Figure 2). No adverse effects were observed in either group and none related to rituximab infusion.

    Discussion

    Approximately 90% of children with idiopathic nephrotic syndrome develop steroid dependence.1 Considering the toxic effects of calcineurin inhibitors, alternative interventions or low-dose approaches are needed for long-term treatments.

    The anti-CD20 monoclonal antibody rituximab emerged as a promising steroid-sparing drug in patients with SDNS.1,2 In the present study, single-dose rituximab, withdrawing steroids, resulted in effective control of SDNS. Given the limited adverse effects, rituximab should be considered as the main steroid-sparing drug in patients with SDNS.

    Previous reports indicate that MMF can maintain steroid-free remission in children with SDNS.2 However, existing small and uncontrolled studies on MMF generated conflicting data2,3: the minimum dose of MMF sufficient to maintain remission of SDNS is unknown, and variable doses (ranging from 700 mg/m2-1200 mg/m2 daily) are reported.4

    This study aimed to address the efficacy of low-dose MMF, and the inefficacy provides useful evidence for designing future trials. The adherence to MMF, monitored with monthly reports, was complete in all patients. The strategy of monitoring may represent a weakness and better strategies to estimate MMF exposure are to be defined.

    Conclusions

    Rituximab was effective in maintaining long-term remission of SDNS; MMF given at low dose (350 mg/m2 twice daily) was, instead, inadequate. The effect of higher doses (1200 mg/m2) deserve testing in randomized clinical trials. Lack of efficacy of low-dose MMF may have implications in clinical practice or research of other immune-mediated conditions.5,6

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    Article Information

    Accepted for Publication: October 20, 2020.

    Published Online: February 22, 2021. doi:10.1001/jamapediatrics.2020.6150

    Trial Registration: clinicaltrials.gov Identifier: NCT04402580

    Corresponding Author: Gian Marco Ghiggeri, MD, Division of Nephrology, Dialysis, Transplantation, Istituto Giannina Gaslini IRCCS, Via Gerolamo Gaslini 5, 16148 Genoa, Italy (gmarcoghiggeri@gaslini.org).

    Author Contributions: Drs Ghiggeri and Ravani had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

    Concept and design: Ravani, Ghiggeri.

    Acquisition, analysis, or interpretation of data: All authors.

    Drafting of the manuscript: Ravani, Lugani, Angeletti, Ghiggeri.

    Critical revision of the manuscript for important intellectual content: Ravani, Drovandi, Caridi, Angeletti, Ghiggeri.

    Statistical analysis: Ravani, Ghiggeri.

    Obtained funding: Ghiggeri.

    Administrative, technical, or material support: Lugani, Drovandi, Caridi, Angeletti, Ghiggeri.

    Supervision: Lugani, Ghiggeri.

    Conflict of Interest Disclosures: Dr Ghiggeri reported grants from Italian Ministry of Health No Profit grant (Ricerca Finalizzata PE-2016-02361576) during the conduct of the study. No other disclosures were reported

    Funding/Support: Drs Ravani, Lugani, Caridi, and Ghiggeri were supported by Italian Ministry of Health, RicercaFinalizzatagrant: WFR:PE-2016-02361576.

    Role of the Funder/Sponsor: The Italian Ministry of Health had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

    Data Sharing Statement: See Supplement 2.

    Additional Contributions: The following individuals were involved in clinical settings and data collection: Enrico Verrina, MD, Division of Nephrology, Dialysis and Transplantation, Istituto Giannina Gaslini IRCCS, Genoa, Italy (enricoverrina@gaslini.org); Giorgio Piaggio, MD, Division of Nephrology, Dialysis and Transplantation, Istituto Giannina Gaslini IRCCS, Genoa, Italy (giorgiopiaggio@gaslini.org); Maria LudovicaDegl’innocenti, MD, Division of Nephrology, Dialysis and Transplantation, Istituto Giannina Gaslini IRCCS, Genoa, Italy, (marialudovicadeglinnocenti@gaslini.org); and Michela Cioni, PhD, Laboratory on Molecular Nephrology, Istituto Giannina Gaslini IRCCS, Genoa, Italy (michelacioni@gaslini.org).

    References
    1.
    Ravani  P, Rossi  R, Bonanni  A,  et al.  Rituximab in children with steroid-dependent nephrotic syndrome: a multicenter, open-label, noninferiority, randomized controlled trial.   J Am Soc Nephrol. 2015;26(9):2259-2266. doi:10.1681/ASN.2014080799PubMedGoogle ScholarCrossref
    2.
    Ravani  P, Lugani  F, Pisani  I,  et al.  Rituximab for very low dose steroid-dependent nephrotic syndrome in children: a randomized controlled study.   Pediatr Nephrol. 2020;35(8):1437-1444. doi:10.1007/s00467-020-04540-4PubMedGoogle ScholarCrossref
    3.
    Gellermann  J, Weber  L, Pape  L, Tönshoff  B, Hoyer  P, Querfeld  U; Gesellschaft für Pädiatrische Nephrologie (GPN).  Mycophenolate mofetil versus cyclosporin A in children with frequently relapsing nephrotic syndrome.   J Am Soc Nephrol. 2013;24(10):1689-1697. doi:10.1681/ASN.2012121200PubMedGoogle ScholarCrossref
    4.
    Novak  I, Frank  R, Vento  S, Vergara  M, Gauthier  B, Trachtman  H.  Efficacy of mycophenolate mofetil in pediatric patients with steroid-dependent nephrotic syndrome.   Pediatr Nephrol. 2005;20(9):1265-1268. doi:10.1007/s00467-005-1957-yPubMedGoogle ScholarCrossref
    5.
    Moudgil  A, Bagga  A, Jordan  SC.  Mycophenolate mofetil therapy in frequently relapsing steroid-dependent and steroid-resistant nephrotic syndrome of childhood: current status and future directions.   Pediatr Nephrol. 2005;20(10):1376-1381. doi:10.1007/s00467-005-1964-zPubMedGoogle ScholarCrossref
    6.
    Sinha  A, Puraswani  M, Kalaivani  M, Goyal  P, Hari  P, Bagga  A.  Efficacy and safety of mycophenolate mofetil versus levamisole in frequently relapsing nephrotic syndrome: an open-label randomized controlled trial.   Kidney Int. 2019;95(1):210-218. doi:10.1016/j.kint.2018.08.039PubMedGoogle ScholarCrossref
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