The Efficacy and Safety of Rituximab in the Treatment of Steroid-dependent or Frequently Relapsing Nephrotic Syndrome in Children
Purpose: To analyse the efficacy and safety of rituximab (RTX) in the treatment of children with steroid-dependent or frequently relapsing nephrotic syndrome (NS). Methods: A total of 44 children were eligible for inclusion in this study, and they were randomly divided into the control group and the RTX group in a 1:1 ratio. The children in the control group received traditional treatment, that is, steroid and/or calcineurin inhibitors. As well as the traditional treatment, the RTX group was given RTX (375 mg/m2/time, maximum 500 mg/time, once a week) after the urine protein turned negative. Findings: After one year of follow-up, there were 17 cases (77.27%) in the RTX group who maintained continuous remission for six months, and 7 cases (31.81%) in the control group. The difference was statistically significant (p<0.1). The annual recurrence rate was 54.54% (12/22) in the RTX group and 95.45% (21/22) in the control group, and the difference was statistically significant (p<0.01). Compared with the control group, the recurrence-free survival time of the RTX group was significantly longer (p=0), the cumulative amount of steroid was reduced (p<0.05), and the period of being steroid-free was significantly longer (p=0). One case of pneumocystis pneumonia occurred in the RTX group, and there were no serious adverse events. There was no significant difference in the incidence of adverse events between the two groups. Conclusions: Rituximab is safe and effective in treating children with frequently relapsing or steroid-dependent NS.
Keyword : CD19; Children with nephrotic syndrome; Rituximab; Steroid-dependent or frequently relapsing nephrotic syndrome
Nephrotic syndrome (NS) is a common glomerular disease in childhood. It is a group of clinical syndromes in which the permeability of the glomerular filtration membrane is increased due to various reasons, leading to the loss of a large amount of plasma protein in the urine. It can be divided into primary and secondary NS, according to its aetiology. Primary NS (PNS) accounts for about 90% of nephropathy in childhood, and its basic clinical features are massive proteinuria, hypoalbuminaemia, hyperlipidaemia and varying degrees of oedema.1 At present, the recognsed first-line treatment for PNS is adequate oral glucocorticosteroids (GC) to induce remission. Depending on the child's response to the GC, the NS can be classified as steroid-sensitive NS (SSNS), steroid-dependent NS (SDNS), frequent relapse NS (FRNS) and steroid-resistant NS (SRNS). Among them, SDNS accounts for about 45% to 55% of PNS. These children are sensitive to steroids, and those who have relapses within two weeks of two consecutive dose reductions or withdrawals, more than twice in six months or more than four times in one year are called FRNS. For the treatment of children with FRNS/SDNS, large doses of steroid or combined immunosuppressive agents (ISA) are required. Due to repeated illness, the treatment with steroids or immunosuppressants will be prolonged, which will inevitably increase the toxic and side effects on children, and the combined use of multiple drugs will reduce their compliance. In addition, about 35% of children with FRNS/SDNS treated with immunosuppressive therapy still have no remission,2 causing a bottleneck in clinical treatment. Therefore, it is necessary to explore new therapeutic drugs. Rituximab (RTX) is an anti-CD20 monoclonal antibody commonly used clinically to treat children with refractory nephrotic syndrome. A review of relevant research at home and abroad has found that the vast majority of studies have explored the dosage and use of RTX, its efficacy, its adverse reactions, the correlation between B cell exhaustion and disease recurrence and related factors affecting the efficacy, and relatively positive results have been achieved,3-7 but there are few reports of randomised controlled studies. In view of this, this single-centre randomised controlled study was conducted in 44 children, aged between 1 and 18 years old, who were treated in the Paediatric Nephrology and Rheumatology Professional Group of the Second Hospital of Hebei Medical University and were clinically diagnosed as having SDNS or FRNS, with steroid dependence or frequent relapses lasting more than two years. The aim of the study was to explore the efficacy and safety of RTX in the treatment of children with FRNS/SDNS in order to guide clinical treatment.
Materials and Methods
Group A only received traditional treatment, namely glucocorticoids and/or calcineurin inhibitors (CNIs). A total of 22 children were included in this group, including 16 males and 6 females, with an average enrolment age of 10.18±2.36 years old. As well as glucocorticoid and/or CNI treatment, group B received RTX treatment. A single dose of RTX treatment was given after the urine protein turned negative. A total of 22 children were included in this group, including 17 males and 5 females, with an average enrolment age of 10.5±2.94 years old.
Follow-up and Observation Indicators
Safety: Any adverse events were recorded.
Main Experimental Equipment
Statistical Analysis Methods
General Baseline Data
The Comparison of the Continuous Remission Rate in 6 Months, the Recurrence Frequency in 6 and 12 Months and the Annual Recurrence Rate
The Comparison of the Cumulative Quantity of Steroids and Steroid-free Duration
Children with FRNS/SDNS account for about 50% of children with PNS, which is a common refractory NS in clinical practice. At present, immunosuppressant agents are commonly used in clinic to alleviate the disease, mainly by affecting the immune pathway of T lymphocytes. However, the immune dysfunction of B lymphocytes also plays an important role in the pathogenesis of the disease. Therefore, taking B cells as a therapeutic target is a feasible approach.
CD20 is a surface antigen expressed during the differentiation of B lymphocytes as they mature. RTX is a human mouse chimeric anti-CD20 monoclonal antibody. The main mechanism of RTX is as follows:
At present, the research and application of RTX treatment for children with FRNS/SDNS by scholars at home and abroad is becoming more extensive. Ito et al14 conducted a multicentre retrospective study and included 55 children with FRNS/SDNS who were treated with RTX. During follow-up, 51% (28 cases) of children relapsed. A multi-centre randomised controlled study in South Korea15 studied the efficacy of RTX in the treatment of children with FRNS/SDNS. The results showed that the 6-month sustained remission rate of the RTX group was significantly higher than that of the control group, and the recurrence rate of the RTX group was significantly lower than that of the control group. Fujinaga et al16 used a single dose of RTX as a rescue treatment for 10 children with SDNS to study its efficacy. The results showed that the number of relapses at 12 months was significantly reduced. In this paper, a single-centre randomised controlled study method was used to randomly divide 44 children with FRNS/SDNS with a course of more than 2 years into a control group and an RTX group in a 1:1 ratio. The control group used traditional treatment programs (steroids and/or CNIs), and the RTX group was given RTX as well as traditional treatment. The maximum dose was no more than 500 mg/time, and the second dose could be given after B cell reconstitution or recurrence. The results showed that there were 17 children (77.27%) in the RTX group who maintained continuous remission for six months without recurrence, while there were only 7 children (31.81%) in the control group (p=0.002); the annual recurrence rate in the RTX group was 54.54% (12/22), and in the control group it was 95.45% (21/22), which was similar to the results of the multicentre randomised controlled study in South Korea carried out by Fujinaga et al. In their study, the number of patients with steroid resistance in group A was 20 (partial remission + no remission), and the number in group B was 13. Moreover, the combined use of RTX was found to reduce steroid resistance.16 reported a study of 10 children with SDNS who were given a single dose of RTX treatment and also showed that RTX treatment could reduce the cumulative quantity of steroids. During the follow-up period of more than one year, the average quantity of steroids was reduced from 0.39 mg/ (kg•d) to 0.15 mg/ (kg•d). This is similar to the results of this paper. Iijima et al17 reported the results of a randomised placebo-controlled study that found the median time to recurrence in the RTX treatment group was longer than that of the placebo group. The survival time of the two groups in this paper showed that the RTX group was significantly longer than the control group, but because the cumulative recurrence-free survival rate of the RTX group was greater than 50% after one year of follow-up, the median recurrence-free survival time of group B could not be obtained. At present, most studies have concluded that RTX is safe in the treatment of SDNS in children, and its adverse reactions are relatively mild, most of them being infusion reactions.18 There are still some shortcomings in this study. First, the sample size is relatively small, so there may be some errors in the research results, and second, because of the short follow-up time of some children, the long-term prognosis could not be studied.
RTX is effective in the treatment of children with FRNS or SDNS. It can increase the remission rate, reduce the annual recurrence rate, reduce the quantity of steroids taken and prolong the recurrence-free survival time. In addition, the incidence of adverse events is small, and they tend to be mild. Most of the manifestations are allergic-like reactions during the infusion process, and only a few children have serious adverse reactions such as pneumocystis pneumonia. However, it is necessary to expand the sample size and extend the follow-up time in the future to understand the long-term prognosis after RTX treatment.
Statement of Ethics
This study was conducted in accordance with the declaration of Helsinki.This study was conducted with approval from the Ethics Committee of The Second Hospital of HeBei Medical University.Written informed consent was obtained from all parents/local guardians.
Su QX have made substantial contributions to conception and design, Qi XJ, Shen YN and Dou ZY acquisition of data, analysis and interpretation of data; Rong ZH and Zhao X have been involved in drafting the manuscript and revising it critically for important intellectual content; Yu B, Wang YX and Wang XL have given final approval of the version to be published.
Conflict of Interest
The authors have no conflicts of interest to declare.
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