Therapy of Rituximab in Idiopathic Membranous Nephropathy with Nephrotic Syndrome: A Systematic Review and Meta-analysis

Peimei Zou, Hang Li, Jianfang Cai, Zhenjie Chen,Chao Li, Xuewang Li＊

Department of Nephrology, Peking Union Medical College Hospital,Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100730, China

IDIOPATHIC membranous nephropathy (IMN)is one of the most common cause of adult nephrotic syndrome (NS), accounting for about 75% of membranous nephropathy (MN) cases.About 20%-30% IMN patients (often with non-nephrotic proteinuria) entered spontaneous remission,1and 30%-40% of patients progress to end-stage renal disease (ESRD) within 5 to 15 years.2M-type phospholipase A2 receptor (PLA2R) , which can be detected on glomerular podocytes and in subepithelial immune deposits, presented in 70%-80% IMN patients.3

Immunosuppressive treatment including corticosteroid, alkylating agents, calcineurin inhibitors (CNIs),mycophenolate mofetil (MMF) and azathioprine, is advised to high-risk patients (proteinuria ＞ 8 g/d with or without renal insufficiency) and medium-risk patients(normal renal function, proteinuria ＞ 4 to ＜ 8 g/d)when nephrotic proteinuria persisted more than 6 months.4-5However, these immunosuppressive agents bring along with adverse events such as infection,myelosuppression and nephrotoxicity. Novel drugs are needed to improve the situation.

Rituximab (RTX), a monoclonal antibody targeting CD20, applied in chronic lymphocytic leukaemia,non-Hodgkin lym phoma, vasculitis and rheumatoid arthritis, recently emerged to be an option for the treatment of NS.6Animal experiments suggested that B cells were involved in the pathological process of MN.B cells mediate typical subepithelial immune deposits in glomeruli, accelerate injury of the glomerular filtering barrier and result in proteinuria. Although IMN autoantigens remain elusive and the role of B cells has not been fully understood in humans, agents that specifically interfere with B cells would ideally represent the first step toward selective therapy in humans.7Lots of studies reported successful use of RTX in the treatment of both IMN and secondary MN, as first-line and second-line therapy. However, these studies were small sample prospective observation studies or case reports, further investigation is required. Thus, combing the current evidences of RTX therapy in IMN from eligible studies, we carried out this systematic review and meta-analysis, to systematically evaluate the efficacy and safety of RTX in IMN.

MATERIALS AND METHODS

This meta-analysis was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) Statement protocol.8

Eligibility and exclusion criteria

Prospective cohort studies that reported the use of RTX in biopsy-proven IMN adult patients with NS were included for review. Publications on secondary MN,other pathological types of glomerular diseases, and recurrence of disease after renal transplantation were excluded. Studies with follow-up period less than 12 months were excluded. Pediatric patients were excluded. We also excluded retrospective studies and two ongoing multicenter randomized controlled trials (RCTs).9-10

Literature search

A systematic literature search of the PubMed (2002 to December 2016), Embase (2002 to December 2016),Cochrane Library (2007 to December 2016) and Clinical Trials (2007 to December 2016) was conducted, using the key words “Rituximab”, “anti-CD20 monoclonal antibodies”, “membranous nephropathy”, “membranous glomerulonephritis”, “primary”, “idiopathic”, “nephrotic syndrome”, and “adults”. We also manually identified additional relevant studies. The search was limited to articles published in English language.

Study selection and data extraction

The eligible references obtained by literature search were assessed by two independent reviewers (Zou PM and Chen ZJ) according to a predetermined protocol.Data extracted by two independent reviewers (Zou PM and Chen ZJ) included: study characteristics (design,country, publication year), follow-up period, baseline data of patients (age, gender, course of disease, histopathologic features, baseline proteinuria, baseline renal function, previous treatment), RTX administration regime, and treatment response (remission situation and the definition, renal function, relapse, adverse events).Differences over inclusion of studies and interpretation of data were resolved by consensus discussion.

Quality assessment

The Newcastle-Ottawa Scale (http://www.ohri.ca/programs/clinical_epidemiology/oxford.asp), which graded studies according to the quality of selection,comparability and outcome of cohort, was performed to make quality assessments of the eligible references. Discrepancies were addressed by consensus discussion.

Statistical and bias analysis

Complete remission (CR) or partial remission (PR) was regarded as effective therapy, and the cumulate rate(CR + PR) was calculated. We evaluated the 12-month and the 24-month pooled remission rates. Pooled relapse rate in 24-month was also assessed. Cochrane Q test and the inconsistency index (I2) statistic were applied to analyze the heterogeneity of the included studies. We used a random effects model for the data analysis when a significant heterogeneity was observed(P＜0.1 or I2＞50%), otherwise we used a fixed effect model. Sensitivity analysis was used by sequential omission of individual studies. Funnel plots were used to estimate the publication bias of the meta-analysis.All analyses were performed using R software and the meta/metaphor package (www.r-project.org). P value less than 0.05 was considered statistically significant.

RESULTS

Literature search

Totally, 639 articles were identified via database search.And 255 duplicate studies were removed by Endnote Software. After exclusion based on title and abstract,37 full-text articles were reviewed. Five studies were excluded for the following reasons: three studies used the same series of patients7,11-12and two studies did not reach our inclusion criteria.13-14Finally, 7 studies were included.15-21A flowchart of article screening for the meta-analysis has been illustrated in Fig. 1.

Study characteristics

Basic characteristics of 7 included studies are summarized in Table 1. All patients were renal biopsy-proven IMN with creatinine clearance ＞ 20 ml/(min·1.73 m2), and persistent proteinuria ＞ 3.5 g/d for at least 6 months with previous treatment ［44 (36.7%) had immunosuppressive treatment］. Quality assessment by the Newcastle-Ottawa Scale is shown in Table 2. Among the 7 included studies, Ruggenenti et al21organized their research in two steps—first came the retrospective analysis of 14 IMN patients treated with RTX in their Nephrology Unit (the outcome of 8 of these patients was reported previously20) and finally concluded that tubulointerstitial (TI) scores ＜ 1.7 predicted better response to RTX. Then they did a prospective study including 9 IMN patients of TI scores ＜ 1.7. We only assessed the prospective part. Cravedi et al15carried out a matched cohort study that compared the B cell-driven and the four-dose protocol of RTX, data of the 24 IMN patients of the four-dose protocol group came from their previous studies. To avoid inclusion of repeated data,we only evaluated the experimental group-12 patients accepted the B cell-driven protocol. All included studies defined CR as proteinuria≤0.3 g/24 h or≤0.5 g/24 h,and PR as proteinuria≤3.5 g/24 h or≤3.0 g/24 h. One study did not mention the definitions of CR and PR,21so we regarded the authors used the generally accepted definitions (CR as proteinuria≤0.3 g/24 h with normal serum creatinine, PR as proteinuria ＜ 3.5 g/24 h and a≥ 50% reduction from peak values with improvement of serum albumin22).

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Table 2. Quality assessment of the included studies by the Newcastle-Ottawa Scale (score)

Efficiency of RTX therapy in severe IMN patients

The pooled CR rate and cumulate remission (CR + PR)rate at 12-month were 15% (95%CI, 0.09-0.23) and 56% (95%CI, 0.47-0.65) (Fig. 2). Only 3 studies16-17,19had a follow-up period of 24 months, the pooled CR rate and cumulate remission rate at 24-month were 20% (95%CI, 0.12-0.32) and 68% (95%CI, 0.41-0.87). Heterogeneity was revealed at 24-month remission rate with I2of 73% (Fig. 3). Sensitivity analysis suggested that the 24-month pooled remission rate was stable and omitting a single study did not change the significance of the pooled survival rates (95%CI,0.49-0.74) (Fig. 4).

Renal function was stable and did not change significantly in most studies. But, Fervenza et al17reported creatinine clearance increased from 72.4±33 ml/(min·1.73 m2) at baseline to 88.4 ± 31.5 ml/(min/1.73 m2) at 24 months (P = 0.02) in their study published in 2010. Quite the opposite, in Moroni et al’s study,19the mean serum creatinine of the 24 patients who were followed for at least 18 months after RTX therapy was significantly higher than that at 12 months (141.4 ± 70.7 versus 114.9 ± 44.2 μmol/L;P = 0.02), however we cannot rule out the confounding factors brought by 6 non-responders. In Fervenza et al’s study,182 patients who had the lowest creatinine clearance at entry ［40 and 59 ml/(min·1.73 m2)］ and proteinuria remained unchanged in the whole study,progressed to ESRD at 18-month and 19-month after RTX treatment.

Four studies16-17,19,21reported relapse cases,mostly happened in the second year. Pooled data of the relapse rate in 24-month after RTX treatment was 8% (95%CI, 0.03-0.16) (Fig. 5).

Other parameters

The reduction in proteinuria was paralleled to a significant increase in serum albumin and decrease in total serum cholesterol.

After the first administration of RTX infusion,most included studies15-17,19-21recorded that circulating CD19+, CD20+ B cells depletion were achieved and remained below normal ranges by study end. Only one study found that the majority of patients had CD19+B cells recovered to the normal range (mean 110 ± 97 cells/ml, range: 28-317) at 6-month.18No significant changes in total white blood cell, hemoglobin, platelet,and lymphocyte counts and in lymphocyte subpopulations including CD3+, CD4+, CD8+, natural killer cells,and CD4+/CD8+ ratios.

Figure 2. Pooled CR rate and remission (CR + PR) rate at 12 months. A. pooled 12-month CR rate; B. pooled 12-month CR+PR rate. CR: complete remission; PR: partial remission; W: weight. *In the 15 enrolled patients, 14 patients completed 12 months of follow-up; ?In the 20 enrolled patients, 1 patient who was immunosuppression naive before entry was removed from the study at 6 months because of worsening proteinuria and rapidly declining kidney function.

Figure 3. Pooled CR rate and remission (CR + PR) rate at 24 months. A. pooled 24-month CR rate; B. pooled 24-month CR+PR rate.

Figure 4. Sensitivity analysis of pooled 24-month CR+PR rate.

Figure 5. Pooled relapse rate at 24 months.

Two studies reported that serum concentrations of IgG, IgA, and IgM did not change significantly throughout its whole study period;20-21but Fervenza et al in their two studies recorded significantly increase of baseline IgG level and decrease of IgM level, while serum IgA remained relatively stable at 12 months and later. Subsequent quantification of IgG subclasses proved total IgG increase was due to an increase in IgG1, IgG2, and IgG3 isotypes, whereas IgG4 levels remained unchanged.17-18

Safety

Adverse events observed in RTX treatment were mainly infusion-related reactions, including itchy throat,skin rash, chills, flu-like symptoms, et al. Symptoms were varied but generally not serious. Infections were uncommon, three studies17-19reported infectious complications: 3 patients experienced community-acquired pneumonia and 2 patients experienced herpes zoster,relieved with oral-medications. Myocardial infarction,happened in 2 patients from two studies,17,19respectively occurred 3 months and 5 months after RTX infusion. Another patient was diagnosed with adenocarcinoma in the lung 3 months after the first infusion.18

Publication bias

As shown in Fig. 6, the shape of funnel plots did not reveal any obvious asymmetry. Begger’s and Egger’s test confirmed that there was no publication bias(P＞0.05).

DISCUSSION

Seven studies involving 120 patients (73% were men) were included in our systematic review and meta-analysis. RTX was used as first-line therapy or second-line therapy. Our results demonstrated that RTX was efficient in the treatment of IMN. The reduction in proteinuria was gradual and obvious, paralleled with serum albumin increasing and serum cholesterol decreasing. Renal functions were stable. Relapse was rare. Adverse events about RTX therapy were mostly infusion-related reactions and generally were not serious.

Spontaneous remission is a special characteristic of MN, occurred in about 30% patients, and generally happens in the first 2 years. Although spontaneous remission was more often seen in patients with lower baseline proteinuria levels, it also frequently occurred in patients with massive proteinuria: 26% among those with baseline proteinuria 8-12 g/24 h and 22%among those with proteinuria ＞ 12 g/24 h.23Important independent predictors for spontaneous remission include: baseline serum creatinine and proteinuria,treatment with angiotensin-converting enzyme inhibitors or angiotensin receptor blockers (ACEi/ARBs), and a ＞ 50% decline of proteinuria from baseline during the first year of follow-up.23Patients in all included studies had massive proteinuria, supportive treatment consisted of ACEi, and/or ARB at maximal tolerated dose was conducted with RTX administration. However,most patients selected had a prolonged disease course,proteinuria maintained unchanged despite conservative treatment and even immunosuppressive therapy added for enough time previously. Hence spontaneous remission was unlikely to occur.

Figure 6. Funnel plots of the meta-analysis. A: 12-month CR rate; B: 12-month CR+PR rate; C: 24-month CR rate; D:24-month CR+PR rate; E: relapse rate at 24 months.

Traditional RTX protocol is 375 mg/m2RTX once weekly for 4 weeks, or 1 g RTX on day 1 and day 15.Some nephrologists give a second course routinely or according to the B cell counts (when B cells≥5/mm3)after 6 months. It’s confusing whether clinical efficacy is different in different protocols. Limited to the very few study and detail data unavailable, we failed to make a relative meta-analysis. Remuzzi et al7firstly demonstrated RTX was efficient in the treatment of IMN, used the four-dose protocol. Segarra et al13successfully used the four-dose protocol in 13 IMN patients with long-term calcineurin inhibitors (CNIs)dependence to overcome dependence of CNIs. Studies of Fervenza et al17-18suggested that four doses of RTX resulted in more effective B cell depletion, but proteinuria reduction was similar to RTX at 1 g every 2 weeks. In addition, there was no difference in proteinuria response between patients who were immunosuppression naive versus those who had been previously treated.17-18In 2007, Cravedi et al15conducted a matched-cohort study, concluded that B cell titrated RTX protocol was as effective as standard fourdose RTX treatment in achieving B cell depletion and IMN remission, but cost only a quarter of the standard regimen. Based on their previous finding, these investigators further demonstrated that second-line RTX therapy was equally efficient to first-line RTX therapy in IMN as well.16Contrary to Cravedi’s opinion, recently in 2016, results from a multi-centric study involving 34 IMN patients (15 patients had been treated with glucocorticoids and immunosuppressive agents) suggested that low-dose RTX was poorly effective, obtained remission in ＜50% of IMN patients.19

There was no significant difference between RTX applied as the first-line therapy and the second-line therapy. No conclusion was drawn on which RTX protocol is preferred. Lack of rigorous RCTs, we cannot assert RTX is superior to other treatments commonly applied in clinic. Whether to use RTX combined or continued with other medications include supportive regimes and immunosuppressive agents can induce more remission remain uncertain and needs further study. Luckily there are 2 ongoing multicenter RCTs:the MENTOR study (rituximab versus cyclosporine) and the STARMEN study (sequential treatment with tacrolimus-tituximab versus steroids plus cyclophosphamide), and we are looking forward to the publication of their results.

The mechanism of RTX to MN is unknown. It was supposed that RTX develops its role of reducing urinary proteins and protects renal function by specifically interferes with B lymphocytes and disturbs B cell differentiation. The treatment response may be related to the remaining B cells counts. Unfortunately, different outcomes in patients could not be explained, since all studies recorded circulating B lymphocytes in all patients depleted and maintained below normal range during whole studies after RTX first administration,CD19+ B cells followed an identical trend as well. Most studies reported serum hemoglobin levels, total white blood cells, platelet counts and levels of IgG, IgA, and IgM had no significant difference. However, data from studies of Fervenza et al17-18showed the not very consistent results of CD19+ B cells recovery and the IgG level, making these conclusions controversial.

Pharmacokinetics and pharmacodynamics analyses showed serum RTX levels in IMN patients were lower than patients with rheumatoid arthritis, and half-life of RTX was also shorter. However, there were no differences in serum RTX levels at any point between responders and non-responders.18

Human antichimeric antibodies (HACAs) can be induced by repeated or prolonged exposure to RTX.24The production of HACAs may limit the effect of treatment and increase the risk for hypersensitivity reactions of the immediate type upon drug re-exposure.Six and two patients in two studies of Fervenza17-18were detected to have HACAs, but the titers were low and the presence of HACAs was not associated with treatment respond.24

Nephrologists never stop looking for factors that can efficiently predict response to RTX in IMN patients.In 2006, a pilot study of Ruggenenti suggested that TI score was the only significant predictor, patients with a TI score of ＜ 1.7 showed better response to RTX.21However, it was not consolidated demonstrated by Cravedi,15since average proteinuria reduction on follow-up versus baseline tended to correlate with TI score, but the correlation did not reach statistical significance (P=0.10). It was reported the CD4+/CD8+T cell ratio predict response to RTX therapy by Zucchelli et al,25but Fervenza’s study18failed to certify it.In addition they found there was no relation between the total number of CD20+ or CD3+ cells, the ratio of CD20+/CD3+ cells, or the number of CD20+ cells/mm2present in the diagnostic renal biopsies and the response to rituximab treatment.17-18Irazabal et al12suggested low- and high-molecular-weight urinary proteins predict response to RTX in IMN patients. Anti-PLA2R lever measuring were commonly developed in clinical works nowadays, levels of anti-PLA2R correlate with the immunological activity of MN and can well predict response to treatment with RTX.26One study reported that patients with lower serum creatinine,higher estimated glomerular filtration rate, lower proteinuria, lower titer of anti-PLA2R antibodies at baseline showed better outcome to RTX therapy.19However,relationship between response and initial proteinuria remains controversial.

RTX is well tolerated and safe in IMN patients.Adverse events were mainly infusion-related reaction and mostly were not serious. Infections were uncommon since RTX targeted on B cells, and caused no significant changes in total white blood cell, lymphocyte counts and in lymphocyte subpopulations, even some studies recorded serum IgG levels increased. Two researches reported one patient happen myocardial infarction 5 and 3 months after RTX administration respectively;17,19one study reported a patient diagnosed with adenocarcinoma of the lung 3 months after the first RTX infusion.18Previous research verified that patients with NS and IMN were at high risk of cardiovascular events.27-28Approximately 10% MN patients had a malignancy (predominantly solid organ cancers,mainly in the lung, colon, or breast) at the time of renal biopsy or within a year thereafter, and the incidence increased up to 20%-25% after age 60.29-30Thus, we should be cautious to conclude that these severe events were due to the RTX administration. Compared to immunosuppressive agents, side effects of RTX are fewer and milder. Most obvious disadvantage of RTX may be its experience cost. Perhaps it’s better accepted by wealthy patients who care more about adverse events of glucocorticoid and immunosuppressive drugs. However, the safety of RTX still needs more observation.

There are several limitations in our study. All included researches were small sample prospective observation cohort studies or matched-cohort studies,mainly came from two common centers, one study was multi-centric (4 nephrology units in northern Italy). Only three studies followed up for 24 months,which may weaken the role of meta-analysis of pooled 24-month remission rate. Limited to the very few study and detail data unavailable, we failed to make a relative meta-analysis of clinical efficacy in different RTX protocols. Prognostic factors specifically to RTX treatment are controversial since each publication came to different conclusions, making a meta-analysis on the prognostic factors unrealistic. More investigations are needed in the future.

In conclusion, RTX provides a new approach for the treatment of IMN, and it can be seemed as a narrow, disease-specific treatment to IMN. Rigorous and large multicenter RCTs still need to be well performed.It is also necessary to further evaluate the long-term outcome, safety, and factors predict treatment efficacy.

Acknowledgements

The authors appreciate Dandan Hu, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College for her kind support in language editing.

Conflicts of interest statement

The authors have no conflicts of interest to disclose.

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