Skip to main content
SpringerLink
Log in

Unfavorable impact of anti-rituximab antibodies on clinical outcomes in children with complicated steroid-dependent nephrotic syndrome

  • Brief Report
  • Published:
Pediatric Nephrology Aims and scope Submit manuscript

Abstract

Background

Anti-rituximab antibodies (ARA) are associated not only with adverse events, such as infusion reactions (IR) and serum sickness, but also with rituximab efficacy. However, the clinical relevance of ARA in children with steroid-dependent nephrotic syndrome (SDNS) remains unknown.

Methods

We retrospectively reviewed clinical outcomes of 13 children with complicated SDNS receiving repeated single-dose rituximab treatments at 375 mg/m2 to assess whether ARA formation could impact toxicity and efficacy of additional rituximab. Pre-rituximab 22 samples collected from patients who developed IR during the second or subsequent rituximab doses were measured by electrochemiluminescence analysis.

Results

ARA were identified in 5 of 13 patients (9 of 22 samples). Median time to recovery of CD19+ B cells to > 1% of total lymphocytes and median relapse-free time after rituximab treatment were significantly shorter in the 9 ARA-positive samples than the 13 ARA-negative samples (41 vs. 100 days, p < 0.01 and 119 vs. 308 days, p < 0.05, respectively). Kaplan–Meier analysis showed that time to CD19+ B cell recovery after rituximab was significantly shorter in ARA-positive samples than in ARA-negative samples (p < 0.005). Severe IR developed in two ARA-positive patients and serum sickness in one ARA-positive patient.

Conclusions

The incidence of ARA formation was high in the pre-rituximab samples of patients with complicated SDNS who developed IR during the second or subsequent rituximab doses, suggesting that ARA formation might have an unfavorable impact on the toxicity and efficacy of additional rituximab doses in these patients.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

References

  1. Fujinaga S, Hirano D, Nishizaki N, Kamei K, Ito S, Ohtomo Y, Shimizu T, Kaneko K (2010) Single infusion of rituximab for persistent steroid-dependent minimal-change nephrotic syndrome after long-term cyclosporine. Pediatr Nephrol 25:539–544

    Article  Google Scholar 

  2. Iijima K, Sako M, Nozu K, Mori R, Tuchida N, Kamei K, Miura K, Aya K, Nakanishi K, Ohtomo Y, Takahashi S, Tanaka R, Kaito H, Nakamura H, Ishikura K, Ito S, Ohashi Y, Rituximab for Childhood-onset Refractory Nephrotic Syndrome Study Group (2014) Rituximab for childhood-onset, complicated, frequently relapsing nephrotic syndrome or steroid-dependent nephrotic syndrome: a multicentre, double-blind, randomised, placebo-controlled trial. Lancet 384:1273–1281

    Article  CAS  Google Scholar 

  3. Albert D, Dunham J, Khan S, Stansberry J, Kolasinski S, Tsai D, Pullman-Mooar S, Barnack F, Striebich C, Looney RJ, Prak ET, Kimberly R, Zhang Y, Eisenberg R (2008) Variability in the biological response to anti-CD20 B cell depletion in systemic lupus erythaematosus. Ann Rheum Dis 67:1724–1731

    Article  CAS  Google Scholar 

  4. Einarsson JT, Evert M, Geborek P, Saxne T, Lundgren M, Kapetanovic MC (2017) Rituximab in clinical practice: dosage, drug adherence, Ig levels, infections, and drug antibodies. Clin Rheumatol 36:2743–2750

    Article  Google Scholar 

  5. Maloney DG, Grillo-López AJ, White CA, Bodkin D, Schilder RJ, Neidhart JA, Janakiraman N, Foon KA, Liles TM, Dallaire BK, Wey K, Royston I, Davis T, Levy R (1997) IDEC-C2B8 (Rituximab) anti-CD20 monoclonal antibody therapy in patients with relapsed low-grade non-Hodgkin's lymphoma. Blood 90:2188–2195

    Article  CAS  Google Scholar 

  6. Levin AS, Otani IM, Lax T, Hochberg E, Banerji A (2017) Reactions to rituximab in an outpatient infusion center: a 5-year review. J Allergy Clin Immunol Pract 5:107–113

    Article  Google Scholar 

  7. Fujinaga S, Nishino T (2018) Is cytokine-release syndrome the cause of rituximab treatment-related infusion reactions in children with nephrotic syndrome? Impact of anti-rituximab antibodies. Pediatr Nephrol 33:1097–1098

    Article  Google Scholar 

  8. Vogel WH (2010) Infusion reactions: diagnosis, assessment, and management. Clin J Oncol Nurs 14:E10–E21

    Article  Google Scholar 

  9. Ishikura K, Matsumoto S, Sako M, Tsuruga K, Nakanishi K, Kamei K, Saito H, Fujinaga S, Hamasaki Y, Chikamoto H, Ohtsuka Y, Komatsu Y, Ohta T, Nagai T, Kaito H, Kondo S, Ikezumi Y, Tanaka S, Kaku Y, Iijima K, Japanese Society for Pediatric Nephrology; Japanese Society for Pediatric Nephrology (2015) Clinical practice guideline for pediatric idiopathic nephrotic syndrome 2013: medical therapy. Clin Exp Nephrol 19:6–33

    Article  Google Scholar 

  10. Fujinaga S, Hirano D, Mizutani A, Sakuraya K, Yamada A, Sakurai S, Shimizu T (2017) Predictors of relapse and long-term outcome in children with steroid-dependent nephrotic syndrome after rituximab treatment. Clin Exp Nephrol 21:671–676

    Article  CAS  Google Scholar 

  11. Fujinaga S, Sakuraya K, Yamada A, Urushihara Y, Ohtomo Y, Shimizu T (2015) Positive role of rituximab in switching from cyclosporine to mycophenolate mofetil for children with high-dose steroid-dependent nephrotic syndrome. Pediatr Nephrol 30:687–691

    Article  Google Scholar 

  12. Fujinaga S, Someya T, Watanabe T, Ito A, Ohtomo Y, Shimizu T, Kaneko K (2013) Cyclosporine versus mycophenolate mofetil for maintenance of remission of steroid-dependent nephrotic syndrome after a single infusion of rituximab. Eur J Pediatr 172:513–518

    Article  CAS  Google Scholar 

  13. Dunn N, Juto A, Ryner M, Manouchehrinia A, Piccoli L, Fink K, Piehl F, Fogdell-Hahn A (2018) Rituximab in multiple sclerosis: frequency and clinical relevance of anti-drug antibodies. Mult Scler 24:1224–1233

    Article  CAS  Google Scholar 

  14. van Schouwenburg PA, Rispens T, Wolbink GJ (2013) Immunogenicity of anti-TNF biologic therapies for rheumatoid arthritis. Nat Rev Rheumatol 9:164–172

    Article  Google Scholar 

  15. Ahn YH, Kang HG, Lee JM, Choi HJ, Ha IS, Cheong HI (2014) Development of antirituximab antibodies in children with nephrotic syndrome. Pediatr Nephrol 29:1461–1464

    Article  Google Scholar 

  16. Wincup C, Menon M, Smith E, Schwartz A, Isenberg D, Jury EC, Mauri C, ABIRISK Consortium (2019) Presence of anti-rituximab antibodies predicts infusion-related reactions in patients with systemic lupus erythematosus. Ann Rheum Dis 78:1140–1142

    Article  Google Scholar 

  17. Fujinaga S, Sakuraya K (2018) Single infusion of low-dose ofatumumab in a child with complicated nephrotic syndrome with anti-rituximab antibodies. Pediatr Nephrol 33:527–528

    Article  Google Scholar 

Download references

Funding

SF has received clinical research funding B at Saitama Children’s Medical Center.

Author information

Authors and Affiliations

  1. Division of Nephrology, Saitama Children’s Medical Center, 1-2 Shintoshin, Chuo-ku, Saitama, 330-8777, Japan

    Shuichiro Fujinaga, Tomohiko Nishino, Shota Endo, Chisato Umeda, Yoshitaka Watanabe & Mayu Nakagawa

Authors
  1. Shuichiro Fujinaga
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Tomohiko Nishino
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Shota Endo
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Chisato Umeda
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Yoshitaka Watanabe
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Mayu Nakagawa
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Shuichiro Fujinaga.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional research committee and/or national research committee at which the study was conducted with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

Additional information

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Fujinaga, S., Nishino, T., Endo, S. et al. Unfavorable impact of anti-rituximab antibodies on clinical outcomes in children with complicated steroid-dependent nephrotic syndrome. Pediatr Nephrol 35, 2003–2008 (2020). https://doi.org/10.1007/s00467-020-04629-w

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00467-020-04629-w

Keywords

Search

Navigation