A Retrospective Study of Efficacy and Safety of Rituximab Biosimilar for Treatment of Membranous Nephropathy

A Retrospective Study of Efficacy and Safety of Rituximab Biosimilar for Treatment of Membranous Nephropathy | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article A Retrospective Study of Efficacy and Safety of Rituximab Biosimilar for Treatment of Membranous Nephropathy Yu-zhen Zou, Xiao-li Du, Shao-hong Wang, Rui Dai, Xiao Ran, Biao Wang This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4586149/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 11 You are reading this latest preprint version Abstract Background Rituximab (RTX) is a monoclonal antibody targeting CD20, recommended by KDIGO guideline as fist line treatment for membranous nephropathy (MN). RTX biosimilar is the first biosimilar licensed in China in 2019 as HLX01. However, its efficacy and safety for MN treatment is unclear. This study aimed to evaluate the the performance of RTX biosimilar for MN in the real-world setting. Methods This study retrospectively collected the medical records of 201 inpatients of MN treated with high-dose RTX biosimilar and followed up for one year from January 2020 to December 2022 at PUMCH. The efficacy was evaluated according to KDIGO guideline. Adverse reactions recorded in medical records during or after infusion were collected. Results Within one year of follow-up period, the overall effective rate of high-dose RTX biosimilar treatment for MN was 75.12% (151/201) with 53 patients achieving complete remission and 98 patients reaching partial remission. The median time to remission was 6 months. Among patients who gained remission, relapse rate was 7.95% (12/151) and among whom 7 patients gained remission again after re-administration. The overall effective rate was 78.79% (52/66) for treatment-naïve patients and 73.33% (99/135) for treated patients ( P = 0.401). The adverse reactions included pruritus, flushed face, hypotension, fever, rash, oropharyngeal discomfort, chest distress, eyelid edema, nausea and vomiting, blocked or watery nose, with an overall incidence of 30.85% (62/201). Conclusions Rituximab biosimilar has acceptable efficacy and safety for MN patients, and the outcome is similar with that of innovator RTX product reported in literature, which may be taken as an alternative to innovator RTX as first-line treatment for MN. Rituximab biosimilar Membranous nephropathy Efficacy Safety Introduction Membranous nephropathy (MN) is a glomerular disease with alteration of the glomerular basement membrane mediated by the deposition of subepithelial autoimmune complexes formed of antibodies directed against specific targeting antigens. M-type phospholipase A2 receptor (PLA2R) is the most important one of these antigens, most MN patients have positive anti-PLA2R auto-antibody (PLA2Rab), and IgG-PLA2R is the main deposition of autoimmune complexes [1] . Therefore, hyperactive proliferation of auto-immune B cells and the overgeneration of PLA2Rab is the pathogenesis of MN. Rituximab (RTX) is a B cell depleted monoclonal antibody targeting CD20 [2] , and ranged first-line treatment for moderate-risk or high-risk MN by 2021 Kidney Disease Improving Global Outcomes (KDIGO) guideline [3] . And the recommended dosage is a high-dose regimen. 1g rituximab will be given as a single dose or a second 1g dose will be given 2 weeks later. Associated outcome indexes are measured after 6 months; re-administrate will be given if PLA2R is positive or relapse or non-remission [3] . RTX biosimilar is the first biosimilar in China licensed in 2019 as HLX01 (Shanghai Henlius Biotech, Inc.) [4] . The evaluation system for marketing of biosimilars is based on clinical efficacy and safety. There were already studies of innovator RTX for MN, however, there is few research on high-dose RTX for MN in China, let alone that on RTX biosimilar for MN. The aim of this study was to explore the real-world therapeutic efficacy and safety of rituximab biosimilar in the treatment of membranous nephropathy. Materials and Methods Study Design and Patient Population We retrospectively collected the medical records of 201 inpatients of MN treated with high-dose RTX biosimilar and followed up for one year from January 2020 to December 2022 at Peking Union Medical College Hospital (PUMCH). Patients were diagnozed with MN under the standards of KDIGO guideline, which is whether confirmed by kidney biopsy, or with nephrotic syndrome and a positive anti-PLA2R antibody test. The inclusion criteria were (1) diagnosis with MN; (2) age ≥ 18 years old; (3) first administration of RTX biosimilar during study time and finished at least one infusion of 1g; (4) follow-up for at least one-year after first administration. The exclusion criteria were (1) treated with innovator RTX; (2) the medical records during one-year follow-up were incomplete. Treatment-naïve patients were defined as patients who have not taken immunosuppressants such as corticosteroids, calcineurin inhibitor (CNI), mycophenolate mofetil (MMF), cyclophosphamide (CTX) for more than 6 months. Patients were given high-dose regimen, i.e. , rituximab should be given with 1 infusion of 1 g, and re-administrate of 1 g was conducted if there was non-remission or relapse after respond evaluation, with or without immunosuppressants such as corticosteroids, CNI, MMF, CTX, etc. Patients’ basic information such as age, sex, height, weight, diagnosis, combination medication, medical history, accompanying diseases etc., were collected through hospital information system (HIS). Effectiveness assessments Outcome indexes such as 24-h proteinuria quantitation, serum albumin, serum creatinine, serum anti-PLA2R antibody, and blood B cell (CD19+) quantitation were measured at 1, 3, 6, 12 months. Remissions were defined according to the 2021 KDIGO guidelines. Complete remission was defined by a reduction of proteinuria to 35g/l) and a stable serum creatinine. Partial remission was defined by a reduction of proteinuria to 0.3–3.5 g/24h, and a decrease > 50% from baseline, accompanied by an improvement of the serum albumin concentration and preserved kidney function. A relapse was defined by an increase of proteinuria to > 3.5 g/24h after remission has been achieved. Safety assessments Safety assessments included adverse events (AEs) and infusion-related reactions (IRRs) after each infusion recorded in HIS. However, as a retrospective study the severity of adverse events may be subjective, and the records of adverse reactions during discharge might be incomplete. Statistical methods Data were recorded, processed, and analyzed by Excel office16 and SPSS 27.0. The research data conforming to normal distribution were represented by ( \(\stackrel{-}{x}\) ±ན), and t test was used to compare between groups. The research data that do not conform to the normal distribution were expressed as median (maximum value, minimum value) [M(min, max)], and χ༒test was used to compare between groups. P < 0.05 indicates a significant difference, and a very significant difference is indicated of P < 0.001. Results Patient characteristics Patient characteristics at baseline is presented in Table 1 . In total, 201 patients were included in this study, contains 111 males and 90 females, aged (53 ± 13.6) years, BMI (25.8 ± 4.3) kg/m 2 . There were 66 treatment-naïve patients and 135 treated patients. During the one-year follow-up period, 79 patients received one infusion, 77 patients received two infusions, 39 patients received three infusions, and 6 patients received four infusions, and no patients received more than four infusions. Eighty of 201 patients (39.80%) were treated with RTX biosimilar alone, and 121 patients were treated with RTX biosimilar combined with at least one of immunosuppressants (such as corticosteroid, CNI, MMF, CTX, etc.). Table 1 Baseline characteristics and demographics of patients characteristics data Age (y, x ̅± s) 53 ± 13.6 Sex ratio (F/M) 90 / 111 Body mass index (kg/m 2 , x ̅± s) 25.8 ± 4.3 Number of rituximab infusions [median (interquartile ranges)] 2 (1, 2) IgG (g/L) at first infusion (x ̅± s) 6.43 ± 2.59 CD19 count (/mm 3 ) within 1 week after first infusion [median (max, min) 4.5 (0, 48) Effectiveness The comparison of laboratory indexes at baseline and after treatment were shown in Table 2 , and the efficacy results are presented in Table 3 . There was no significant difference in serum creatinine level between baseline and 1 year after the first infusion (P > 0.05), suggesting that the renal function was generally stable. The serum albumin level after one-year follow-up was (38.6 ± 6.6) g/L, which was significantly higher than baseline (28.4 ± 5.9) g/L, P < 0.001. Proteinuria was 0.96 (0.03,21.30) g/24h after treatment, which was significantly lower than baseline 4.27 (0.32,21.95) g/24h, P < 0.001. Table 2 Comparison of laboratory outcome indexes between baseline and after one-year treatment of RTX biosimilar (Mean ± SD) indexes baseline 1 month 3 months 6 months 12 months P 值* Serum creatinine ( \(\stackrel{-}{x}\) ± s, µmol/L) 84.9 ± 41.3 88.7 ± 37.8 86.6 ± 40.4 83.8 ± 37.7 88.8 ± 58.3 0.44 Serum albumin ( \(\stackrel{-}{x}\) ± s, g/L) 28.4 ± 5.9 32.1 ± 6.6 34.1 ± 6.5 35.8 ± 6.9 38.6 ± 6.6 < 0.001 Proteinuria [M(min, max), g/24h] 4.27 (0.32,21.95) 3.04 (0.11,22.16) 2.53 (0.09,23.53) 1.93 (0.05,24.42) 0.96 (0.03,21.30) < 0.001 *Compared between the same indicators tested before and 12 months after the first infusion During the one-year follow-up, 151 of 201 patients achieved remission, with an overall remission rate of 75.12%, and 53 of them achieved complete remission, while 98 of them achieved partial remission. Among the patients who achieved remission, 34 of them got response at 1 month after the first infusion, 40 got response at 3 months after the first infusion, 42 got response at 6 months after the first infusion, and 35 got response at 12 months after the first infusion. The median time to remission was 6 months. During the one-year follow-up, 12 patients (7.95%) relapsed after remission, and 7 of them achieved remission again after re- administration of rituximab biosimilar. Among the treatment-naïve patients, 52 patients achieved remission, and the remission rate was 78.79%. Among the treated patients, 99 patients achieved remission, the remission rate was 73.33%, while difference was not statistically significant (P = 0.401). Table 3 Outcomes of MN patients after 12 months of RTX biosimilar treatment Index Number (%) Composite remission*, n (%) 151 (75.12%) Complete remission, n (%) 53 (26.37%) Time for achieving composite remission [month, median (interquartile ranges)] 6 (3,6) Relapse, n (%) 12 (7.95%) *Composite remission includes complete remission and partial remission The baseline PLA2Rab test showed that 60 patients were negative, 137 patients were positive, while 4 patients were not detected PLA2Rab at baseline. Only one of baseline PLA2Rab negative patients turned positive during the follow-up period, and returned negative after re-administration. Among the 137 baseline positive patients, 94 turned negative during 12 months of treatment; 12 turned negative and returned positive later, the overall negative transformation rate was 77.37% (106/137); 26 patients stayed positive during follow-up period; 5 patients had not re-tested PLA2Rab after administration. These data suggests that PLA2Rab levels were most likely reduced and turned negative after RTX biosimilar treatment. Grouping the patients according to whether the baseline PLA2Rab was negative nor not, the overall remission rate of 12 months in the negative group was 86.67% (52/60), and that in the positive group was 72.26% (99/137), the difference was statistically significant (P = 0.03). However, there was also a significant difference in the baseline 24-h proteinuria quantitation between the two groups (P = 0.005), which the PLA2Rab negative group was 3.21 (0.40, 21.95) g/24h, and the PLA2Rab positive group was 4,71 (0.32, 19.14) g/24h. Safety RTX biosimilar was well tolerated and no AEs were reported during or after infusions for 139 of 201 patients. One or more AEs occurred in 62 of 201 patients, with an overall rate of 30.85%. AEs occurred during RTX biosimilar treatment are shown in Table 4 , including pruritus, flushed face, hypotension, fever, rash, oropharyngeal discomfort, chest distress, eyelid edema, nausea and vomiting, blocked or watery nose. The most common AE was flushed face with pruritus or rash. Most of these AEs were transient, and relieved after suspended administration and giving diphenhydramine intramuscularly. The infusion can be continued if the drip rate is reduced. Most adverse reactions occurred during the first administration. Two patients had a smooth first administration but adverse reactions happened during the third administration. One of them showed pharyngeal discomfort, and the other one had cheek itching with flushing. Only 2 cases had serious adverse reactions (SAE), with a percentage of 1.00% (2/201). One case presented with severe wheal-like rash accompanied by itching and abdominal discomfort, and one case presented with chest tightness and breathlessness, accompanied by wheezing sound and indifferent face. The RTX treatment was discontinued because of intolerance. Table 4 Adverse events related to RTX biosimilar (cases) Adverse events First administration Repeated administration flushed face with pruritus 37 8 laryngeal edema 1 0 hypotension 2 0 fever 2 0 rash 21 7 oropharyngeal discomfort 8 6 chest distress 3 0 eyelid edema 3 0 nausea and vomiting 1 1 blocked or watery nose 3 1 Other AEs 2* 1** *One case was hyperglycemia lasted for about 24 hours after administration for a diabetic patient, and then the hypoglycemic drug regimen was adjusted; the other case had transient precordial discomfort, which relieved spontaneously. ** The symptoms were numbness and pain in the limbs, which relieved spontaneously. Discussion And Conclusion In recent years, biological agents have become a hot topic in scientific research of pharmaceuticals and been marketed intensively around the world, which significantly changed the clinical practice model and patients’ outcome. However, the prices of innovator biological products are generally extremely high, thus the burden of patients and medical insurance funds are heavy. Under such circumstances, biosimilars are desirable substitutes because they have lower prices. The questions is, although biosimilars are proved to have sufficient similarity to the innovators in terms of quality, safety and efficacy for therapeutic use in the pre-marketing clinical trials [6] , due to the inherent nature of biological agents, the physical, chemical and biological properties of a biosimilar are never identical to its reference product, which aroused the concerns of clinicians and patients. MN remains an off-label indication for rituximab. There are a few publications of high-dose regimens of the innovator RTX for the treatment of MN. In Fervenza’s study [9] the patients achieved a remission rate of 71% at 12 months without serious adverse reactions; in Waldman’s study [10] the remission rate was 85% at 12 and 24 months, and the incidence of serious adverse reactions was 30%; in Fervenza's MENTOR study [11,12] , the 12-month remission rate was 60%, and the incidence of serious adverse reactions was 17%; in Fernandez-Juarez’s STARMEN study [13] the remission rate was 58% at 24 months and a serious adverse reaction rate was 14%; in the NICE protocol of Barbara [1] the remission rate was 64% at 6 months and adverse reaction rate was 0.03%. However, there is no study on RTX biosimilar for MN so far. This study is the first real-world study investigating the efficacy and safety of RTX biosimilar for MN. The analysis demonstrated that the remission rate was 75.12%, and the median remission time was 6 months. Rituximab biosimilar have significant therapeutic effects on MN patients, indicating by the increase of serum albumin level, the decrease of proteinuria, and the negative conversion of PLA2Rab. The overall incidence of adverse events was 30.85%, and only 2 patients had serious adverse reactions (1.00%). The drug-related adverse reactions in this study were all known adverse reactions of rituximab [8] , and no new adverse reactions clearly related to drugs were reported. According to the standard of clinical trial guidelines for rituximab biosimilars [4] , the efficacy and safety results of RTX biosimilars in the treatment of membranous nephropathy are consistent with the innovator product. The remission rate of treatment-naïve patients was 78.79%, close to that of treated patients (73.33%) (P = 0.401), which may confirm the recommendations of the guidelines, i.e. , Rituximab could be used as the first-line treatment for MN [3,5] . Patients with negative baseline PLA2Rab had a significantly higher remission rate and a significantly lower baseline proteinuria quantification level than positive baseline PLA2Rab, suggesting that patients with negative PLA2Rab before treatment have an overall lower disease risk and better prognosis. In KDIGO guidelines, PLA2Rab level > 50 RU/ml is recommended as one of the indicators for assessing disease risk [2,3] . RTX biosimilars potentially reduce the burden of treatment cost. One analysis using the base-case results indicated that adoption of rituximab biosimilar would result in net cost savings, which ranged from €4.05 million to 303.86 million at the year 5. The cost saving could potentially extend treatment to 291–15,671 more patients with rituximab [14] . Another analysis evaluated 5 phase III RCTs, including 2,362 patients, and resulted in an economic advantage of rituximab biosimilars versus innovator of €274 per month for time to treatment failure (TTF), which is about 40% less than the innovator [15] . In our study, 201 patients received altogether 374g RTX biosimilar, which is at 60.9% price of innovator product, and saved about ¥11436.8 per patient per year. Admittedly, this study has several limitations. First, as a single-center retrospective study, there is potential inaccuracy of data especially that for safety. Patients may under-report or over-report adverse effects. Second, the follow-up time is one year, which is common in similar studies [1,10] , but may not be long enough for chronic course of MN to indicate long-term efficacy, it is better to follow up for 24 months or longer. However, the sample of this study is quite large compared with similar studies of innovator RTX [1,16,17] which enrolled dozens of patients, indicating the representativeness of the findings. In conclusion, this study confirmed that the clinical efficacy and safety of rituximab biosimilar in the treatment of membranous nephropathy are consistent with the innovator product, and it can be used as first-line treatment option for membranous nephropathy. PLA2Rab can be tested as one of the indicators for assessing disease risk. However, prospective, multi-center, randomized controlled clinical trials are needed to confirm the results. Declarations Ethics approval and consent to participate This study has been approved by Peking Union Medical College Hospital Ethics Committee [reference number I-22PJ401]. As this study is a retrospective and non-interventive study, and also there is no individual person’s data to reveal, informed consent to participate has been granted an exemption from ethical approval. Availability of data and materials The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request. Competing interests The authors declare that they have no competing interests Funding This work was supported by the Special Research Fund for the Central High-level Hospitals of Peking Union Medical College Hospital [grant number 2022-PUMCH-B-058] and Special Funds of WU JIEPING medical foundation for clinical research project [grant number 320.6750.2022-20-40]. Authorship XL. Du and YZ. Zou conceived the study. Sample determination and data collection were conducted by YZ. Zou, R. Dai, SH. Wang and B. Wang. Data analyses were done by YZ. Zou, R. Xiao, and XL. Du. And YZ. Zou wrote the first draft of the manuscript, and XL. Du revised it. All authors critically reviewed and revised the manuscript and approved the final version. Acknowledgements Not applicable References Seitz-Polski, Barbara, Dahan, et al. High-Dose Rituximab and Early Remission in PLA2R1-Related Membranous Nephropathy[J]. Clin J Am Soc Nephrol, 2019(8): 1-10. DOI:10.2215/cjn.11791018. Gauckler P, Shin J I, Alberici F, et al. Rituximab in Membranous Nephropathy[J]. Kidney International Reports, 2021(6): 881–893. DOI: 10.1016/j.ekir.2020.12.035. Brad H. Rovin, Sharon G. Adler, Jonathan Barratt, et al, KDIGO 2021 Clinical Practice Guideline for the Management of Glomerular Diseases[J], Kidney International, Volume 100, Issue 4, 2021, Pages S1-S276, ISSN 0085-2538, https://doi.org/10.1016/j.kint.2021.05.021. National Medical Products Administration (NMPA) Center for Drug Evaluation. Guidelines for clinical trials of rituximab biosimilars [EB/OL]. https://www.nmpa.gov.cn/xxgk/ggtg/ypggtg/ypqtggtg/20200720171501333.html.2020-7-20/2023-1-14 Nephrology Expert Panel of the Peking University Health Science Center. Expert consensus on the application of Rituximab in the treatment of membranous nephropathy[J]. Chinese Journal of Intern Medical, 2022, 61(3): 282-290. DOI:10.3760/cma.j.cn112138-20210927-00660. NMPA. Technical guidelines for the Development and evaluation of Biosimilars (Trial)[EB/OL]. https://www.nmpa.gov.cn/xxgk/ggtg/ypggtg/ypqtggtg/20150228155701114.html. 2015-2-28/2023-1-14. EMA. Guideline on similar biological medicinal products [EB/OL]. https://www.fdanews.com/ext/resources/files/10-14/10-14-EMA-Biosimilars.pdf?1520782705. 2014-20-23/2023-01-14. ZHANG Chun-yan，XING Li-qiu，ZHONG Lei, et al. Analysis of rituximab-induced serious adverse drug reaction between 2003--2019 in Beijing [J]. Chinese Journal of New Drugs, 2021, 30(8): 765-768. DOI:10.3969/j.issn.1003-3734.2020.18.020. Fervenza FC, Cosio FG, Erickson SB, et al. Rituximab treatment of idiopathic membranous nephropathy. Kidney Int. 2008;73: 117–125. DOI:10.1038/sj.ki.5002628. Waldman M, Beck LH Jr, Braun M, et al. Membranous nephropathy: pilot study of a novel regimen combining cyclosporine and rituximab. Kidney Int Rep. 2016;1: 73–84. DOI: 10.1016/j.ekir.2016.05.002 Fervenza FC, Appel GB, Barbour SJ, et al. Rituximab or cyclosporine in the treatment of membranous nephropathy. N Engl J Med. 2019; 381:36–46. DOI: 10.1056/NEJMoa1814427 F. Fervenza, P. Canetta, et al. A Multicenter Randomized Controlled Trial of Rituximab versus Cyclosporine in the Treatment of Idiopathic Membranous Nephropathy (MENTOR)[J]. Nephron, 2015, 130(3): 159-168. DOI:10.1159/000430849. Fernández-Juárez G, Rojas-Rivera J, Logt A-Evd, et al. The STARMEN trial indicates that alternating treatment with corticosteroids and cyclophosphamide is superior to sequential treatment with tacrolimus and rituximab in primary membranous nephropathy [e-pub ahead of print]. Kidney Int. https://doi.org/10.1016/j.kint.2020.10.014, Accessed March 12, 2021. Jang M, Simoens S, Kwon T. Budget Impact Analysis of the Introduction of Rituximab and Trastuzumab Intravenous Biosimilars to EU-5 Markets [J]. Springer International Publishing, 2021(1). DOI:10.1007/S40259-020-00461-8. JACOPO GIULIANI, ANDREA BONETTI. The Economic Impact of Biosimilars in Oncology and Hematology: The Case of Trastuzumab and Rituximab [J]. ANTICANCER RESEARCH, 2019 (39): 3971-3973. doi:10.21873/anticanres.13552. Gao S, Cui Z, Wang X, et al. Rituximab Therapy for Primary Membranous Nephropathy in a Chinese Cohort[J]. Frontiers in Medicine, 2021, 8. DOI:10.3389/fmed.2021.663680. Ruggenenti P, Cravedi P, Chianca A, et al. Rituximab in idiopathic membranous nephropathy[J]. Journal of the American Society of Nephrology, 2012, 9(4): 1416-1425. DOI:10.1007/BF00197219. Additional Declarations No competing interests reported. Cite Share Download PDF Status: Under Review Version 1 posted Editorial decision: Revision requested 27 Apr, 2025 Reviews received at journal 09 Apr, 2025 Reviewers agreed at journal 01 Apr, 2025 Reviews received at journal 04 Sep, 2024 Reviewers agreed at journal 04 Sep, 2024 Reviewers agreed at journal 02 Sep, 2024 Reviewers invited by journal 02 Sep, 2024 Editor invited by journal 24 Jun, 2024 Editor assigned by journal 19 Jun, 2024 Submission checks completed at journal 19 Jun, 2024 First submitted to journal 15 Jun, 2024 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-4586149","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":321232826,"identity":"c6d19d45-9bd2-4b81-856c-5e3eee2dbcc0","order_by":0,"name":"Yu-zhen Zou","email":"","orcid":"","institution":"Chinese Academy of Medical Science","correspondingAuthor":false,"prefix":"","firstName":"Yu-zhen","middleName":"","lastName":"Zou","suffix":""},{"id":321232829,"identity":"19e62f6c-dd18-4936-b2cb-bdca41659f5a","order_by":1,"name":"Xiao-li Du","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA30lEQVRIiWNgGAWjYDCCA2BkwQNiMzNUSMjJE6lFAqrljIWxYQMRWoBAAkwyM7ZVJEJFcAO+GzmGB35USMiYS2Qnfi6cJ5HA2MD88NENPFokb6QlHOw5I8FjOSN3s/TMbRJ57AxsxsY5eLQY3Eg+cIC3TYLH4EbuNmbebRLFjA08bNL4tSQ2HPwL1zJHIrHhAEEtyQcOI2xpIEKL5JlnCYdlQH7pebtZmueYhLFhMwG/8B3PMf74psLG3pw9d+Nnnpo6OXn25oeP8WlBuBDOYiZGOaqWUTAKRsEoGAVoAACA2kro5Azz0QAAAABJRU5ErkJggg==","orcid":"","institution":"Chinese Academy of Medical Science","correspondingAuthor":true,"prefix":"","firstName":"Xiao-li","middleName":"","lastName":"Du","suffix":""},{"id":321232834,"identity":"0fdff8d4-3486-4f9b-9573-270ac8ce8c3e","order_by":2,"name":"Shao-hong Wang","email":"","orcid":"","institution":"Chinese Academy of Medical Science","correspondingAuthor":false,"prefix":"","firstName":"Shao-hong","middleName":"","lastName":"Wang","suffix":""},{"id":321232836,"identity":"04dbf59e-6d0f-4adf-a1b9-2675a301abdc","order_by":3,"name":"Rui Dai","email":"","orcid":"","institution":"Chinese Academy of Medical Science","correspondingAuthor":false,"prefix":"","firstName":"Rui","middleName":"","lastName":"Dai","suffix":""},{"id":321232839,"identity":"a7975316-eabc-4ed6-96a9-453a433fa52d","order_by":4,"name":"Xiao Ran","email":"","orcid":"","institution":"Chinese Academy of Medical Science","correspondingAuthor":false,"prefix":"","firstName":"Xiao","middleName":"","lastName":"Ran","suffix":""},{"id":321232840,"identity":"9ba51e9f-0726-4792-bf63-5ad97efce2fc","order_by":5,"name":"Biao Wang","email":"","orcid":"","institution":"Chinese Academy of Medical Science","correspondingAuthor":false,"prefix":"","firstName":"Biao","middleName":"","lastName":"Wang","suffix":""}],"badges":[],"createdAt":"2024-06-15 10:42:21","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-4586149/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-4586149/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":59686206,"identity":"e37778ef-aa96-4077-a9e8-d6e7921cefeb","added_by":"auto","created_at":"2024-07-04 20:43:00","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":418004,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4586149/v1/6f423561-38c2-423e-ad5a-a5b80c5f8edf.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"A Retrospective Study of Efficacy and Safety of Rituximab Biosimilar for Treatment of Membranous Nephropathy","fulltext":[{"header":"Introduction","content":"\u003cp\u003eMembranous nephropathy (MN) is a glomerular disease with alteration of the glomerular basement membrane mediated by the deposition of subepithelial autoimmune complexes formed of antibodies directed against specific targeting antigens. M-type phospholipase A2 receptor (PLA2R) is the most important one of these antigens, most MN patients have positive anti-PLA2R auto-antibody (PLA2Rab), and IgG-PLA2R is the main deposition of autoimmune complexes \u003csup\u003e[1]\u003c/sup\u003e. Therefore, hyperactive proliferation of auto-immune B cells and the overgeneration of PLA2Rab is the pathogenesis of MN.\u003c/p\u003e \u003cp\u003eRituximab (RTX) is a B cell depleted monoclonal antibody targeting CD20\u003csup\u003e[2]\u003c/sup\u003e, and ranged first-line treatment for moderate-risk or high-risk MN by 2021 Kidney Disease Improving Global Outcomes (KDIGO) guideline \u003csup\u003e[3]\u003c/sup\u003e. And the recommended dosage is a high-dose regimen. 1g rituximab will be given as a single dose or a second 1g dose will be given 2 weeks later. Associated outcome indexes are measured after 6 months; re-administrate will be given if PLA2R is positive or relapse or non-remission \u003csup\u003e[3]\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eRTX biosimilar is the first biosimilar in China licensed in 2019 as HLX01 (Shanghai Henlius Biotech, Inc.) \u003csup\u003e[4]\u003c/sup\u003e. The evaluation system for marketing of biosimilars is based on clinical efficacy and safety. There were already studies of innovator RTX for MN, however, there is few research on high-dose RTX for MN in China, let alone that on RTX biosimilar for MN. The aim of this study was to explore the real-world therapeutic efficacy and safety of rituximab biosimilar in the treatment of membranous nephropathy.\u003c/p\u003e"},{"header":"Materials and Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eStudy Design and Patient Population\u003c/h2\u003e \u003cp\u003eWe retrospectively collected the medical records of 201 inpatients of MN treated with high-dose RTX biosimilar and followed up for one year from January 2020 to December 2022 at Peking Union Medical College Hospital (PUMCH). Patients were diagnozed with MN under the standards of KDIGO guideline, which is whether confirmed by kidney biopsy, or with nephrotic syndrome and a positive anti-PLA2R antibody test. The inclusion criteria were (1) diagnosis with MN; (2) age\u0026thinsp;\u0026ge;\u0026thinsp;18 years old; (3) first administration of RTX biosimilar during study time and finished at least one infusion of 1g; (4) follow-up for at least one-year after first administration. The exclusion criteria were (1) treated with innovator RTX; (2) the medical records during one-year follow-up were incomplete. Treatment-na\u0026iuml;ve patients were defined as patients who have not taken immunosuppressants such as corticosteroids, calcineurin inhibitor (CNI), mycophenolate mofetil (MMF), cyclophosphamide (CTX) for more than 6 months.\u003c/p\u003e \u003cp\u003ePatients were given high-dose regimen, \u003cem\u003ei.e.\u003c/em\u003e, rituximab should be given with 1 infusion of 1 g, and re-administrate of 1 g was conducted if there was non-remission or relapse after respond evaluation, with or without immunosuppressants such as corticosteroids, CNI, MMF, CTX, etc.\u003c/p\u003e \u003cp\u003ePatients\u0026rsquo; basic information such as age, sex, height, weight, diagnosis, combination medication, medical history, accompanying diseases etc., were collected through hospital information system (HIS).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003eEffectiveness assessments\u003c/h2\u003e \u003cp\u003eOutcome indexes such as 24-h proteinuria quantitation, serum albumin, serum creatinine, serum anti-PLA2R antibody, and blood B cell (CD19+) quantitation were measured at 1, 3, 6, 12 months. Remissions were defined according to the 2021 KDIGO guidelines. Complete remission was defined by a reduction of proteinuria to \u0026lt;\u0026thinsp;0.3 g/24h, accompanied by a normal serum albumin concentration (\u0026gt;\u0026thinsp;35g/l) and a stable serum creatinine. Partial remission was defined by a reduction of proteinuria to 0.3\u0026ndash;3.5 g/24h, and a decrease\u0026thinsp;\u0026gt;\u0026thinsp;50% from baseline, accompanied by an improvement of the serum albumin concentration and preserved kidney function. A relapse was defined by an increase of proteinuria to \u0026gt;\u0026thinsp;3.5 g/24h after remission has been achieved.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003eSafety assessments\u003c/h2\u003e \u003cp\u003eSafety assessments included adverse events (AEs) and infusion-related reactions (IRRs) after each infusion recorded in HIS. However, as a retrospective study the severity of adverse events may be subjective, and the records of adverse reactions during discharge might be incomplete.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec6\" class=\"Section2\"\u003e \u003ch2\u003eStatistical methods\u003c/h2\u003e \u003cp\u003eData were recorded, processed, and analyzed by Excel office16 and SPSS 27.0. The research data conforming to normal distribution were represented by (\u003cspan class=\"InlineEquation\"\u003e\u003cspan class=\"mathinline\"\u003e\\(\\stackrel{-}{x}\\)\u003c/span\u003e\u003c/span\u003e\u0026plusmn;ན), and t test was used to compare between groups. The research data that do not conform to the normal distribution were expressed as median (maximum value, minimum value) [M(min, max)], and χ༒test was used to compare between groups. \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05 indicates a significant difference, and a very significant difference is indicated of \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001.\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003ePatient characteristics\u003c/h2\u003e \u003cp\u003ePatient characteristics at baseline is presented in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e. In total, 201 patients were included in this study, contains 111 males and 90 females, aged (53\u0026thinsp;\u0026plusmn;\u0026thinsp;13.6) years, BMI (25.8\u0026thinsp;\u0026plusmn;\u0026thinsp;4.3) kg/m\u003csup\u003e2\u003c/sup\u003e. There were 66 treatment-na\u0026iuml;ve patients and 135 treated patients. During the one-year follow-up period, 79 patients received one infusion, 77 patients received two infusions, 39 patients received three infusions, and 6 patients received four infusions, and no patients received more than four infusions. Eighty of 201 patients (39.80%) were treated with RTX biosimilar alone, and 121 patients were treated with RTX biosimilar combined with at least one of immunosuppressants (such as corticosteroid, CNI, MMF, CTX, etc.).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eBaseline characteristics and demographics of patients\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"2\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003echaracteristics\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003edata\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge (y, x ̅\u0026plusmn; s)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e53\u0026thinsp;\u0026plusmn;\u0026thinsp;13.6\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSex ratio (F/M)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e90 / 111\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBody mass index (kg/m\u003csup\u003e2\u003c/sup\u003e, x ̅\u0026plusmn; s)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e25.8\u0026thinsp;\u0026plusmn;\u0026thinsp;4.3\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNumber of rituximab infusions [median (interquartile ranges)]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2 (1, 2)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eIgG (g/L) at first infusion (x ̅\u0026plusmn; s)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e6.43\u0026thinsp;\u0026plusmn;\u0026thinsp;2.59\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCD19 count (/mm\u003csup\u003e3\u003c/sup\u003e) within 1 week after first infusion [median (max, min)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4.5 (0, 48)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec9\" class=\"Section2\"\u003e \u003ch2\u003eEffectiveness\u003c/h2\u003e \u003cp\u003eThe comparison of laboratory indexes at baseline and after treatment were shown in Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e, and the efficacy results are presented in Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e. There was no significant difference in serum creatinine level between baseline and 1 year after the first infusion (P\u0026thinsp;\u0026gt;\u0026thinsp;0.05), suggesting that the renal function was generally stable. The serum albumin level after one-year follow-up was (38.6\u0026thinsp;\u0026plusmn;\u0026thinsp;6.6) g/L, which was significantly higher than baseline (28.4\u0026thinsp;\u0026plusmn;\u0026thinsp;5.9) g/L, P\u0026thinsp;\u0026lt;\u0026thinsp;0.001. Proteinuria was 0.96 (0.03,21.30) g/24h after treatment, which was significantly lower than baseline 4.27 (0.32,21.95) g/24h, P\u0026thinsp;\u0026lt;\u0026thinsp;0.001.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eComparison of laboratory outcome indexes between baseline and after one-year treatment of RTX biosimilar (Mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD)\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"7\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eindexes\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003ebaseline\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1 month\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003e3 months\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003e6 months\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003e12 months\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c7\"\u003e \u003cp\u003e\u003cem\u003eP\u003c/em\u003e值*\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSerum creatinine (\u003cspan class=\"InlineEquation\"\u003e\u003cspan class=\"mathinline\"\u003e\\(\\stackrel{-}{x}\\)\u003c/span\u003e\u003c/span\u003e \u0026plusmn; s, \u0026micro;mol/L)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e84.9\u0026thinsp;\u0026plusmn;\u0026thinsp;41.3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e88.7\u0026thinsp;\u0026plusmn;\u0026thinsp;37.8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e86.6\u0026thinsp;\u0026plusmn;\u0026thinsp;40.4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e83.8\u0026thinsp;\u0026plusmn;\u0026thinsp;37.7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e88.8\u0026thinsp;\u0026plusmn;\u0026thinsp;58.3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.44\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSerum albumin (\u003cspan class=\"InlineEquation\"\u003e\u003cspan class=\"mathinline\"\u003e\\(\\stackrel{-}{x}\\)\u003c/span\u003e\u003c/span\u003e \u0026plusmn; s, g/L)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e28.4\u0026thinsp;\u0026plusmn;\u0026thinsp;5.9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e32.1\u0026thinsp;\u0026plusmn;\u0026thinsp;6.6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e34.1\u0026thinsp;\u0026plusmn;\u0026thinsp;6.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e35.8\u0026thinsp;\u0026plusmn;\u0026thinsp;6.9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e38.6\u0026thinsp;\u0026plusmn;\u0026thinsp;6.6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eProteinuria [M(min, max), g/24h]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4.27\u003c/p\u003e \u003cp\u003e(0.32,21.95)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3.04\u003c/p\u003e \u003cp\u003e(0.11,22.16)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2.53\u003c/p\u003e \u003cp\u003e(0.09,23.53)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1.93\u003c/p\u003e \u003cp\u003e(0.05,24.42)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.96\u003c/p\u003e \u003cp\u003e(0.03,21.30)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"7\"\u003e*Compared between the same indicators tested before and 12 months after the first infusion\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eDuring the one-year follow-up, 151 of 201 patients achieved remission, with an overall remission rate of 75.12%, and 53 of them achieved complete remission, while 98 of them achieved partial remission. Among the patients who achieved remission, 34 of them got response at 1 month after the first infusion, 40 got response at 3 months after the first infusion, 42 got response at 6 months after the first infusion, and 35 got response at 12 months after the first infusion. The median time to remission was 6 months. During the one-year follow-up, 12 patients (7.95%) relapsed after remission, and 7 of them achieved remission again after re- administration of rituximab biosimilar. Among the treatment-na\u0026iuml;ve patients, 52 patients achieved remission, and the remission rate was 78.79%. Among the treated patients, 99 patients achieved remission, the remission rate was 73.33%, while difference was not statistically significant (P\u0026thinsp;=\u0026thinsp;0.401).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab3\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eOutcomes of MN patients after 12 months of RTX biosimilar treatment\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"2\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eIndex\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eNumber (%)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eComposite remission*, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e151 (75.12%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eComplete remission, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e53 (26.37%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTime for achieving composite remission [month, median (interquartile ranges)]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e6 (3,6)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRelapse, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e12 (7.95%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"2\"\u003e*Composite remission includes complete remission and partial remission\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eThe baseline PLA2Rab test showed that 60 patients were negative, 137 patients were positive, while 4 patients were not detected PLA2Rab at baseline. Only one of baseline PLA2Rab negative patients turned positive during the follow-up period, and returned negative after re-administration. Among the 137 baseline positive patients, 94 turned negative during 12 months of treatment; 12 turned negative and returned positive later, the overall negative transformation rate was 77.37% (106/137); 26 patients stayed positive during follow-up period; 5 patients had not re-tested PLA2Rab after administration. These data suggests that PLA2Rab levels were most likely reduced and turned negative after RTX biosimilar treatment. Grouping the patients according to whether the baseline PLA2Rab was negative nor not, the overall remission rate of 12 months in the negative group was 86.67% (52/60), and that in the positive group was 72.26% (99/137), the difference was statistically significant (P\u0026thinsp;=\u0026thinsp;0.03). However, there was also a significant difference in the baseline 24-h proteinuria quantitation between the two groups (P\u0026thinsp;=\u0026thinsp;0.005), which the PLA2Rab negative group was 3.21 (0.40, 21.95) g/24h, and the PLA2Rab positive group was 4,71 (0.32, 19.14) g/24h.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec10\" class=\"Section2\"\u003e \u003ch2\u003eSafety\u003c/h2\u003e \u003cp\u003eRTX biosimilar was well tolerated and no AEs were reported during or after infusions for 139 of 201 patients. One or more AEs occurred in 62 of 201 patients, with an overall rate of 30.85%. AEs occurred during RTX biosimilar treatment are shown in Table\u0026nbsp;\u003cspan refid=\"Tab4\" class=\"InternalRef\"\u003e4\u003c/span\u003e, including pruritus, flushed face, hypotension, fever, rash, oropharyngeal discomfort, chest distress, eyelid edema, nausea and vomiting, blocked or watery nose. The most common AE was flushed face with pruritus or rash. Most of these AEs were transient, and relieved after suspended administration and giving diphenhydramine intramuscularly. The infusion can be continued if the drip rate is reduced. Most adverse reactions occurred during the first administration. Two patients had a smooth first administration but adverse reactions happened during the third administration. One of them showed pharyngeal discomfort, and the other one had cheek itching with flushing. Only 2 cases had serious adverse reactions (SAE), with a percentage of 1.00% (2/201). One case presented with severe wheal-like rash accompanied by itching and abdominal discomfort, and one case presented with chest tightness and breathlessness, accompanied by wheezing sound and indifferent face. The RTX treatment was discontinued because of intolerance.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab4\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 4\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eAdverse events related to RTX biosimilar (cases)\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"3\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAdverse events\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eFirst administration\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eRepeated administration\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eflushed face with pruritus\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e37\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e8\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003elaryngeal edema\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ehypotension\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003efever\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003erash\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e21\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e7\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eoropharyngeal discomfort\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e6\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003echest distress\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eeyelid edema\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003enausea and vomiting\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eblocked or watery nose\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eOther AEs\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2*\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1**\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e*One case was hyperglycemia lasted for about 24 hours after administration for a diabetic patient, and then the hypoglycemic drug regimen was adjusted; the other case had transient precordial discomfort, which relieved spontaneously.\u003c/p\u003e \u003cp\u003e** The symptoms were numbness and pain in the limbs, which relieved spontaneously.\u003c/p\u003e \u003c/div\u003e "},{"header":"Discussion And Conclusion","content":"\u003cdiv id=\"Sec11\" class=\"Section2\"\u003e \u003cp\u003eIn recent years, biological agents have become a hot topic in scientific research of pharmaceuticals and been marketed intensively around the world, which significantly changed the clinical practice model and patients\u0026rsquo; outcome. However, the prices of innovator biological products are generally extremely high, thus the burden of patients and medical insurance funds are heavy. Under such circumstances, biosimilars are desirable substitutes because they have lower prices. The questions is, although biosimilars are proved to have sufficient similarity to the innovators in terms of quality, safety and efficacy for therapeutic use in the pre-marketing clinical trials \u003csup\u003e[6]\u003c/sup\u003e, due to the inherent nature of biological agents, the physical, chemical and biological properties of a biosimilar are never identical to its reference product, which aroused the concerns of clinicians and patients.\u003c/p\u003e \u003cp\u003eMN remains an off-label indication for rituximab. There are a few publications of high-dose regimens of the innovator RTX for the treatment of MN. In Fervenza\u0026rsquo;s study \u003csup\u003e[9]\u003c/sup\u003e the patients achieved a remission rate of 71% at 12 months without serious adverse reactions; in Waldman\u0026rsquo;s study \u003csup\u003e[10]\u003c/sup\u003e the remission rate was 85% at 12 and 24 months, and the incidence of serious adverse reactions was 30%; in Fervenza's MENTOR study \u003csup\u003e[11,12]\u003c/sup\u003e, the 12-month remission rate was 60%, and the incidence of serious adverse reactions was 17%; in Fernandez-Juarez\u0026rsquo;s STARMEN study\u003csup\u003e[13]\u003c/sup\u003e the remission rate was 58% at 24 months and a serious adverse reaction rate was 14%; in the NICE protocol of Barbara \u003csup\u003e[1]\u003c/sup\u003e the remission rate was 64% at 6 months and adverse reaction rate was 0.03%. However, there is no study on RTX biosimilar for MN so far.\u003c/p\u003e \u003cp\u003eThis study is the first real-world study investigating the efficacy and safety of RTX biosimilar for MN. The analysis demonstrated that the remission rate was 75.12%, and the median remission time was 6 months. Rituximab biosimilar have significant therapeutic effects on MN patients, indicating by the increase of serum albumin level, the decrease of proteinuria, and the negative conversion of PLA2Rab. The overall incidence of adverse events was 30.85%, and only 2 patients had serious adverse reactions (1.00%). The drug-related adverse reactions in this study were all known adverse reactions of rituximab \u003csup\u003e[8]\u003c/sup\u003e, and no new adverse reactions clearly related to drugs were reported. According to the standard of clinical trial guidelines for rituximab biosimilars \u003csup\u003e[4]\u003c/sup\u003e, the efficacy and safety results of RTX biosimilars in the treatment of membranous nephropathy are consistent with the innovator product.\u003c/p\u003e \u003cp\u003eThe remission rate of treatment-na\u0026iuml;ve patients was 78.79%, close to that of treated patients (73.33%) (P\u0026thinsp;=\u0026thinsp;0.401), which may confirm the recommendations of the guidelines, \u003cem\u003ei.e.\u003c/em\u003e, Rituximab could be used as the first-line treatment for MN \u003csup\u003e[3,5]\u003c/sup\u003e. Patients with negative baseline PLA2Rab had a significantly higher remission rate and a significantly lower baseline proteinuria quantification level than positive baseline PLA2Rab, suggesting that patients with negative PLA2Rab before treatment have an overall lower disease risk and better prognosis. In KDIGO guidelines, PLA2Rab level\u0026thinsp;\u0026gt;\u0026thinsp;50 RU/ml is recommended as one of the indicators for assessing disease risk \u003csup\u003e[2,3]\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eRTX biosimilars potentially reduce the burden of treatment cost. One analysis using the base-case results indicated that adoption of rituximab biosimilar would result in net cost savings, which ranged from \u0026euro;4.05\u0026nbsp;million to 303.86\u0026nbsp;million at the year 5. The cost saving could potentially extend treatment to 291\u0026ndash;15,671 more patients with rituximab\u003csup\u003e[14]\u003c/sup\u003e. Another analysis evaluated 5 phase III RCTs, including 2,362 patients, and resulted in an economic advantage of rituximab biosimilars versus innovator of \u0026euro;274 per month for time to treatment failure (TTF), which is about 40% less than the innovator \u003csup\u003e[15]\u003c/sup\u003e. In our study, 201 patients received altogether 374g RTX biosimilar, which is at 60.9% price of innovator product, and saved about \u0026yen;11436.8 per patient per year.\u003c/p\u003e \u003cp\u003eAdmittedly, this study has several limitations. First, as a single-center retrospective study, there is potential inaccuracy of data especially that for safety. Patients may under-report or over-report adverse effects. Second, the follow-up time is one year, which is common in similar studies \u003csup\u003e[1,10]\u003c/sup\u003e, but may not be long enough for chronic course of MN to indicate long-term efficacy, it is better to follow up for 24 months or longer. However, the sample of this study is quite large compared with similar studies of innovator RTX \u003csup\u003e[1,16,17]\u003c/sup\u003e which enrolled dozens of patients, indicating the representativeness of the findings.\u003c/p\u003e \u003cp\u003eIn conclusion, this study confirmed that the clinical efficacy and safety of rituximab biosimilar in the treatment of membranous nephropathy are consistent with the innovator product, and it can be used as first-line treatment option for membranous nephropathy. PLA2Rab can be tested as one of the indicators for assessing disease risk. However, prospective, multi-center, randomized controlled clinical trials are needed to confirm the results.\u003c/p\u003e \u003c/div\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study has been approved by Peking Union Medical College Hospital Ethics Committee [reference number I-22PJ401].\u003c/p\u003e\n\u003cp\u003eAs this study is a retrospective and non-interventive study, and also there is no individual person\u0026rsquo;s data to reveal, informed consent to participate has been granted an exemption from ethical approval.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe datasets used and/or analysed during the current study are available from the corresponding author on reasonable request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare that they have no competing interests\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis work was supported by the Special Research Fund for the Central High-level Hospitals of Peking Union Medical College Hospital [grant number 2022-PUMCH-B-058] and Special Funds of WU JIEPING medical foundation for clinical research project [grant number 320.6750.2022-20-40].\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthorship\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eXL. Du and YZ. Zou conceived the study. Sample determination and data collection were conducted by YZ. Zou, R. Dai, SH. Wang and B. Wang. Data analyses were done by YZ. Zou, R. Xiao, and XL. Du. And YZ. Zou wrote the first draft of the manuscript, and XL. Du revised it. All authors critically reviewed and revised the manuscript and approved the final version.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eSeitz-Polski, Barbara, Dahan, et al. High-Dose Rituximab and Early Remission in PLA2R1-Related Membranous Nephropathy[J]. Clin J Am Soc Nephrol, 2019(8): 1-10. DOI:10.2215/cjn.11791018.\u003c/li\u003e\n\u003cli\u003eGauckler P, Shin J I, Alberici F, et al. Rituximab in Membranous Nephropathy[J]. Kidney International Reports, 2021(6): 881\u0026ndash;893. DOI: 10.1016/j.ekir.2020.12.035.\u003c/li\u003e\n\u003cli\u003eBrad H. Rovin, Sharon G. Adler, Jonathan Barratt, et al, KDIGO 2021 Clinical Practice Guideline for the Management of Glomerular Diseases[J], Kidney International, Volume 100, Issue 4, 2021, Pages S1-S276, ISSN 0085-2538, https://doi.org/10.1016/j.kint.2021.05.021.\u003c/li\u003e\n\u003cli\u003eNational Medical Products Administration (NMPA) Center for Drug Evaluation. Guidelines for clinical trials of rituximab biosimilars [EB/OL]. https://www.nmpa.gov.cn/xxgk/ggtg/ypggtg/ypqtggtg/20200720171501333.html.2020-7-20/2023-1-14\u003c/li\u003e\n\u003cli\u003eNephrology Expert Panel of the Peking University Health Science Center. Expert consensus on the application of Rituximab in the treatment of membranous nephropathy[J]. Chinese Journal of Intern Medical, 2022, 61(3): 282-290. DOI:10.3760/cma.j.cn112138-20210927-00660.\u003c/li\u003e\n\u003cli\u003eNMPA. Technical guidelines for the Development and evaluation of Biosimilars (Trial)[EB/OL]. https://www.nmpa.gov.cn/xxgk/ggtg/ypggtg/ypqtggtg/20150228155701114.html. 2015-2-28/2023-1-14.\u003c/li\u003e\n\u003cli\u003eEMA. Guideline on similar biological medicinal products [EB/OL]. https://www.fdanews.com/ext/resources/files/10-14/10-14-EMA-Biosimilars.pdf?1520782705. 2014-20-23/2023-01-14.\u003c/li\u003e\n\u003cli\u003eZHANG Chun-yan，XING Li-qiu，ZHONG Lei, et al. Analysis of rituximab-induced serious adverse drug reaction between 2003--2019 in Beijing [J]. Chinese Journal of New Drugs, 2021, 30(8): 765-768. DOI:10.3969/j.issn.1003-3734.2020.18.020.\u003c/li\u003e\n\u003cli\u003eFervenza FC, Cosio FG, Erickson SB, et al. Rituximab treatment of idiopathic membranous nephropathy. Kidney Int. 2008;73: 117\u0026ndash;125. DOI:10.1038/sj.ki.5002628.\u003c/li\u003e\n\u003cli\u003eWaldman M, Beck LH Jr, Braun M, et al. Membranous nephropathy: pilot study of a novel regimen combining cyclosporine and rituximab. Kidney Int Rep. 2016;1: 73\u0026ndash;84. DOI: 10.1016/j.ekir.2016.05.002\u003c/li\u003e\n\u003cli\u003eFervenza FC, Appel GB, Barbour SJ, et al. Rituximab or cyclosporine in the treatment of membranous nephropathy. N Engl J Med. 2019; 381:36\u0026ndash;46. DOI: 10.1056/NEJMoa1814427\u003c/li\u003e\n\u003cli\u003eF. Fervenza, P. Canetta, et al. A Multicenter Randomized Controlled Trial of Rituximab versus Cyclosporine in the Treatment of Idiopathic Membranous Nephropathy (MENTOR)[J]. Nephron, 2015, 130(3): 159-168. DOI:10.1159/000430849.\u003c/li\u003e\n\u003cli\u003eFern\u0026aacute;ndez-Ju\u0026aacute;rez G, Rojas-Rivera J, Logt A-Evd, et al. The STARMEN trial indicates that alternating treatment with corticosteroids and cyclophosphamide is superior to sequential treatment with tacrolimus and rituximab in primary membranous nephropathy [e-pub ahead of print]. Kidney Int. https://doi.org/10.1016/j.kint.2020.10.014, Accessed March 12, 2021.\u003c/li\u003e\n\u003cli\u003eJang M, Simoens S, Kwon T. Budget Impact Analysis of the Introduction of Rituximab and Trastuzumab Intravenous Biosimilars to EU-5 Markets [J]. Springer International Publishing, 2021(1). DOI:10.1007/S40259-020-00461-8.\u003c/li\u003e\n\u003cli\u003eJACOPO GIULIANI, ANDREA BONETTI. The Economic Impact of Biosimilars in Oncology and Hematology: The Case of Trastuzumab and Rituximab [J]. ANTICANCER RESEARCH, 2019 (39): 3971-3973. doi:10.21873/anticanres.13552.\u003c/li\u003e\n\u003cli\u003eGao S, Cui Z, Wang X, et al. Rituximab Therapy for Primary Membranous Nephropathy in a Chinese Cohort[J]. Frontiers in Medicine, 2021, 8. DOI:10.3389/fmed.2021.663680.\u003c/li\u003e\n\u003cli\u003eRuggenenti P, Cravedi P, Chianca A, et al. Rituximab in idiopathic membranous nephropathy[J]. Journal of the American Society of Nephrology, 2012, 9(4): 1416-1425. DOI:10.1007/BF00197219.\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"bmc-pharmacology-and-toxicology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"phat","sideBox":"Learn more about [BMC Pharmacology and Toxicology](http://bmcpharmacoltoxicol.biomedcentral.com)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/phat/Default.aspx","title":"BMC Pharmacology and Toxicology","twitterHandle":"@BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Rituximab biosimilar, Membranous nephropathy, Efficacy, Safety","lastPublishedDoi":"10.21203/rs.3.rs-4586149/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4586149/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e \u003cp\u003e Rituximab (RTX) is a monoclonal antibody targeting CD20, recommended by KDIGO guideline as fist line treatment for membranous nephropathy (MN). RTX biosimilar is the first biosimilar licensed in China in 2019 as HLX01. However, its efficacy and safety for MN treatment is unclear. This study aimed to evaluate the the performance of RTX biosimilar for MN in the real-world setting.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eThis study retrospectively collected the medical records of 201 inpatients of MN treated with high-dose RTX biosimilar and followed up for one year from January 2020 to December 2022 at PUMCH. The efficacy was evaluated according to KDIGO guideline. Adverse reactions recorded in medical records during or after infusion were collected.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eWithin one year of follow-up period, the overall effective rate of high-dose RTX biosimilar treatment for MN was 75.12% (151/201) with 53 patients achieving complete remission and 98 patients reaching partial remission. The median time to remission was 6 months. Among patients who gained remission, relapse rate was 7.95% (12/151) and among whom 7 patients gained remission again after re-administration. The overall effective rate was 78.79% (52/66) for treatment-na\u0026iuml;ve patients and 73.33% (99/135) for treated patients (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.401). The adverse reactions included pruritus, flushed face, hypotension, fever, rash, oropharyngeal discomfort, chest distress, eyelid edema, nausea and vomiting, blocked or watery nose, with an overall incidence of 30.85% (62/201).\u003c/p\u003e\u003ch2\u003eConclusions\u003c/h2\u003e \u003cp\u003eRituximab biosimilar has acceptable efficacy and safety for MN patients, and the outcome is similar with that of innovator RTX product reported in literature, which may be taken as an alternative to innovator RTX as first-line treatment for MN.\u003c/p\u003e","manuscriptTitle":"A Retrospective Study of Efficacy and Safety of Rituximab Biosimilar for Treatment of Membranous Nephropathy","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-07-04 20:34:53","doi":"10.21203/rs.3.rs-4586149/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2025-04-27T09:15:57+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-04-09T06:56:25+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"46227188754477869004047999208778039381","date":"2025-04-01T06:40:25+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2024-09-04T15:52:00+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"202156202624579867393901566152304702185","date":"2024-09-04T15:07:30+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"244480648644601296711676816334473441622","date":"2024-09-02T16:25:31+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2024-09-02T15:00:59+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2024-06-24T15:09:54+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2024-06-19T09:24:18+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2024-06-19T09:23:20+00:00","index":"","fulltext":""},{"type":"submitted","content":"BMC Pharmacology and Toxicology","date":"2024-06-15T10:41:05+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"bmc-pharmacology-and-toxicology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"phat","sideBox":"Learn more about [BMC Pharmacology and Toxicology](http://bmcpharmacoltoxicol.biomedcentral.com)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/phat/Default.aspx","title":"BMC Pharmacology and Toxicology","twitterHandle":"@BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"2b0c97cd-af67-4f90-8d61-a981ed47bf27","owner":[],"postedDate":"July 4th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[],"tags":[],"updatedAt":"2026-05-14T19:54:12+00:00","versionOfRecord":[],"versionCreatedAt":"2024-07-04 20:34:53","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-4586149","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4586149","identity":"rs-4586149","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}