3.3 Serum albumin
Figure 4 shows 4 studies (2 based on adults,[9,10] and other 2 based on children)[12,13] assessed the difference in serum albumin levels between 2 groups after treatment.[9,10,12,13] After treatment, no difference in serum albumin levels between rituximab and control groups, SMD (95% CI) was 0.06 (−0.32, 0.44), P > 0.05. NO matter in adults or children patients, the difference was also not found, the SMD (95% CI) were −0.12 (−0.65, 0.42) and 0.23 (−0.30, 0.77), respectively.
3.4 Serum creatinine
Two studies based on the adult patients and 2 based on the children reported serum creatinine levels at the end of treatment, respectively.[9,10,12,13] None of them showed a difference between 2 groups. The pooled analysis showed that serum creatinine levels in rituximab group were not different from those in control group, the SMD and 95% CI was −0.01 (−0.47, 0.44), P > 0.05. The results are presented in Fig. 5.
3.5 Urinary protein
Figure 6 indicates 4 studies reported the urinary protein levels after treatment,[9–12] only 1 study that was based on the children showed a lower urinary protein level after treatment with rituximab; however, the combined analysis did not show a significant difference in urinary protein levels between the 2 groups, the SMD and 95% CI were −0.80 (−2.30, 0.71), P > 0.05. Meanwhile, there was a strong evidence of heterogeneity among these studies (P > 0.05, I 2 < 50%).
3.6 Serum cholesterol
As shown in Fig. 7, 2 studies were based on the adult patients and only 1 was based on the children reported serum cholesterol levels at the end of treatment, respectively.[9,10,13] The pooled analysis showed that there was a significant difference between 2 groups among the adults; however, no difference was found among all patients, the SMD and 95% CI were 0.59 (0.04, 1.14), P < 0.05, and 0.43 (−0.03, 0.89), P > 0.05, respectively.
3.7 Relapse-free survival
In total, 4 studies were based on the children reported the relapse-free survival rate.[11–13,15] The pooled analysis suggested that there was a significant difference in relapse-free survival rate between the 2 groups, the pooled OR (95% CI) was 0.42 (0.29, 0.62), P < 0.05. The result is presented in Fig. 8.
3.8 Adverse effect
Almost all included studies reported adverse effects during the treatment in 2 groups. The common adverse effects included nausea, vomiting, sweating, hypotension, bronchospasm, and skin rash. However, after reducing the drug infusion rate or providing temporary treatment interruption, these adverse events were rapidly and completely resolved.
3.9 Publication bias
The funnel plot showed that all the included studies were symmetrically distributed in the triangle area; this means that the results of present study were less affected by publication bias. The funnel plot of the studies is presented in Fig. 9.
In our study, 8 studies, including 154 patients with rituximab treatment and 189 controls with other drug treatment, were identified. In addition, our study showed that patients with rituximab treatment might have a higher relapse-free survival rate; however, we did not observe significant differences in complete and overall remission rate, serum albumin, serum creatinine, urinary protein, and serum cholesterol levels between the 2 groups.
It is known that the patients with NS often suffer from the presence of heavy proteinuria (>3.5 g/24 h), hypoalbuminemia (<30 g/L), hyperlipidemia and peripheral edema, the changes or remission of proteinuria, hypoalbuminemia, hyperlipidemia, and serum creatinine are often used to evaluate the efficacy of clinical treatment. Therefore, we assessed the efficacy of rituximab versus other drugs on patients with refractory NS trough these indicators.
The proteinuria and hypoalbuminemia are the indispensable diadynamic criteria of NS; therefore, decreasing proteinuria levels and increasing serum albumin are the main objectives of treatment. In the included studies, only 1 showed that rituximab treatment could reduce proteinuria levels ; this study was similar to another study which reported that about 90% of patients with refractory NS achieved complete or partial remission of proteinuria after receiving rituximab treatment. However, pooled analysis of our study did not show a good treatment efficacy of rituximab on proteinuria and hypoalbuminemia. Consequently, the difference in complete and overall remission rate was not remarkable.
In the present study, we also assessed the changes of serum creatinine levels after treatment. None of the included studies showed a significant difference in serum creatinine levels after different treatments between the 2 groups; the pooled result was coincident with the single included study.
Although we did not find a significant difference in serum cholesterol levels between the 2 groups, the adults achieved higher levels of serum cholesterol after treatment with rituximab; this result implied that patients, especially the adults, should be monitored for serum cholesterol levels when treated with rituximab, even when lipid regulating drugs were administered.
Although we did not find any significant differences between the 2 groups, these results should be discussed further, because the following reasons: a small number of included study and sample size in each analysis, which unquestionably influence the statistical result; the patients in each included study had different pathological types of NS, different dosages of rituximab, and different treatment responses to rituximab.[17,22]
The present study suggested that rituximab treatment significantly improved relapse-free survival rate. This result was consistent with previous studies.[17,23,24] The mechanism of this treatment efficacy is unclear, but as is well known that, NS is an autoimmune disease, rituximab is a monoclonal anti-CD20 antibody. CD20 expression is localized on B cells from prolymphocytes to lymphoplasmacyte. It is also weakly expressed on about 20% of plasma cells responsible for immunoglobulin (Ig)G and IgA secretion. Rituximab(RTX) binding to the CD20 antigen leads to rapid destruction of the CD20-expressing cell. B-cell depletion after RTX injection is complete and lasts for several weeks to several months. These may be a reasonable explanation of the treatment efficacy of rituximab on improving relapse-free survival rate.
Although a previous meta-analysis had assessed the efficacy of rituximab versus other drugs on patients with refractory NS, it was found that rituximab significantly improved relapse-free survival, complete remission rate, and reduced the occurrence of proteinuria; only 5 studies based on the children were included, the sample size was small; moreover, an increased complete remission rate (P = 0.09) was based on the P < 0.1, the statistical efficiency was lower. In the present study, we included more published studies, a larger sample size, and we conducted subgroup-analysis to assess the efficacy of rituximab versus other drugs on the adults and children patients with refractory NS; it provided more strong evidence.
However, several limitations in the present study should be considered. First, we identified all published studies; however, only 3 RCTs were included; recall bias and selection bias of case–control and cohort studies were not excluded. Second, most of included studies were based on the European populations, whether these findings were supported by other populations was needed to be further assessed. Third, although we included more studies and patients than the previous patients, the sample size was also small. Fourth, we did not find evidence of publication bias, but we were not able to completely rule out such bias because of the limited number of studies. Fifth, although patients with refractory NS would have achieved several benefits after treatment with rituximab, the cost of rituximab treatment was high; few of the included studied reported this issue. Sixth, the included studies were not only based on the children, but also on the adults; however, there were only 2 studies based on the adults,[9,10] and the number of subgroups was fewer; hence, the results of our study should be weighed and considered. These limitations should be taken into consideration in the future studies.
Our study suggested that rituximab might be a new agent in the treatment of refractory NS, it also could be used as an alternative to conventional immunosuppressive drugs-dependent or drugs-resistant. However, more high-quality, large sample, multicenter, double-blind, randomized, and placebo-controlled trials are needed to further confirm the efficacy of rituximab on the patients with refractory NS in the future.
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Keywords:Copyright © 2016 The Authors. Published by Wolters Kluwer Health, Inc. All rights reserved.
meta-analysis; refractory nephrotic syndrome; rituximab