Mycophenolate Mofetil after Rituximab for Childhood-Onset Complicated Frequently-Relapsing or Steroid-Dependent Nephrotic Syndrome
Authors: Iijima Kazumoto , Sako Mayumi , Oba Mari , Tanaka Seiji , Hamada Riku , Sakai Tomoyuki , Ohwada Yoko , Ninchoji Takeshi , Yamamura Tomohiko , Machida Hiroyuki , Shima Yuko , Tanaka Ryojiro , Kaito Hiroshi , Araki Yoshinori , Morohashi Tamaki , Kumagai Naonori , Gotoh Yoshimitsu , Ikezumi Yohei , Kubota Takuo , Kamei Koichi , Fujita Naoya , Ohtsuka Yasufumi , Okamoto Takayuki , Yamada Takeshi , Tanaka Eriko , Shimizu Masaki , Horinochi Tomoko , Konishi Akihide , Omori Takashi , Nakanishi Koichi , Ishikura Kenji , Ito Shuichi , Nakamura Hidefumi , Nozu Kandai ,   on behalf of Japanese Study Group of Kidney Disease in Children
Published: December 2021

Significance Statement
Rituximab is the standard therapy for childhood-onset complicated frequently relapsing or steroid-dependent nephrotic syndrome (FRNS/SDNS). However, most patients redevelop FRNS/SDNS after peripheral B cell recovery. This multicenter, randomized, double-blind, placebo-controlled trial was conducted to examine whether mycophenolate mofetil (MMF) administration after rituximab can prevent treatment failure (FRNS, SDNS, steroid resistance, or use of immunosuppressive agents or rituximab) in these patients. MMF after rituximab decreased the risk of treatment failure during the MMF administration period by 80% and was well tolerated. However, after MMF discontinuation, the relapse-preventing effect disappeared, and most patients in the MMF group presented with treatment failure. In conclusion, MMF maintenance therapy after rituximab may be an option for sustaining remission in children with complicated FRNS/SDNS.

Background
Rituximab is the standard therapy for childhood-onset complicated frequently relapsing or steroid-dependent nephrotic syndrome (FRNS/SDNS). However, most patients redevelop FRNS/SDNS after peripheral B cell recovery.

Methods
We conducted a multicenter, randomized, double-blind, placebo-controlled trial to examine whether mycophenolate mofetil (MMF) administration after rituximab can prevent treatment failure (FRNS, SDNS, steroid resistance, or use of immunosuppressive agents or rituximab). In total, 39 patients (per group) were treated with rituximab, followed by either MMF or placebo until day 505 (treatment period). The primary outcome was time to treatment failure (TTF) throughout the treatment and follow-up periods (until day 505 for the last enrolled patient).

Results
TTFs were clinically but not statistically significantly longer among patients given MMF after rituximab than among patients receiving rituximab monotherapy (median, 784.0 versus 472.5 days, hazard ratio [HR], 0.59; 95% confidence interval [95% CI], 0.34 to 1.05, log-rank test: P=0.07). Because most patients in the MMF group presented with treatment failure after MMF discontinuation, we performed a post-hoc analysis limited to the treatment period and found that MMF after rituximab prolonged the TTF and decreased the risk of treatment failure by 80% (HR, 0.20; 95% CI, 0.08 to 0.50). Moreover, MMF after rituximab reduced the relapse rate and daily steroid dose during the treatment period by 74% and 57%, respectively. The frequency and severity of adverse events were similar in both groups.

Conclusions
Administration of MMF after rituximab may sufficiently prevent the development of treatment failure and is well tolerated, although the relapse-preventing effect disappears after MMF discontinuation.