Efficacy, safety, and biomarker changes of B-cell activating factor- and A proliferation-inducing ligand-targeted therapies in IgA nephropathy: A systematic review and meta-analysis of randomized controlled trials

Efficacy, safety, and biomarker changes of B-cell activating factor- and A proliferation-inducing ligand-targeted therapies in IgA nephropathy: A systematic review and meta-analysis of randomized controlled trials | 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 Efficacy, safety, and biomarker changes of B-cell activating factor- and A proliferation-inducing ligand-targeted therapies in IgA nephropathy: A systematic review and meta-analysis of randomized controlled trials Rafael dos Santos Borges, Rodrigo Lara Santos, Luiza Haikal de Paula, and 4 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-5743662/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background: IgA nephropathy (IgAN) is the most common primary glomerular disease worldwide. BAFF (B-cell activating factor) and APRIL (A proliferation-inducing ligand) are cytokines involved in B-cell activation and survival, contributing to the pathogenesis of IgAN. This meta-analysis aimed to evaluate the efficacy, safety, and biomarkers of BAFF and APRIL-targeted therapies in patients with IgAN. Methods: This review followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) and was registered with PROSPERO (CRD42024598157). We searched PubMed, Scopus, and the Cochrane Library for randomized controlled trials (RCTs) comparing BAFF or APRIL-targeted drugs with placebo in adults with biopsy-confirmed IgAN. The efficacy outcomes were the mean percent change in the urine protein to creatinine ratio (UPCR) at 24 hours and the mean change in the estimated glomerular filtration rate (eGFR) from baseline. Safety included the incidence of adverse events. The biomarkers were changes in serum Gd-IgA1, IgG, IgA, and IgM from baseline. We used the R software version 4.2.1 for statistics. Results: Four phase II RCTs including 331 patients were included. Compared to placebo, treatment significantly reduced 24-hour UPCR (mean difference [MD] –38.94%; 95% confidence interval [CI] –58.98 to –18.90; p = 0.0001; I² = 0%) and significantly improved eGFR (MD 7.05 mL/min/1.73 m²; 95% CI 3.83 to 10.27; p<0.0001; I²=0%). The incidence of adverse events did not differ significantly in the treatment and placebo groups. The drug significantly decreased serum Gd-IgA1, IgG, IgA, and IgM compared to placebo. Conclusions BAFF and APRIL-targeted therapies effectively and safely reduce proteinuria in patients with IgAN. Urology & Nephrology Clinical Pharmacology Internal Medicine IgA Nephropathy A Proliferation Inducing Ligand Protein B-Cell Activating Factor Glomerulonephritis IGA Proteinuria Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 INTRODUCTION IgA nephropathy (IgAN) is the most common primary glomerular disease in the world. IgAN is characterized by the deposition of abnormally glycosylated IgA1 (Gd-IgA1) immune complexes in the glomerular mesangial matrix, which promotes inflammation and progressive renal dysfunction [ 1 ]. Despite the great variability in clinical presentation, many patients develop a persistent decline in renal function, progressing to end-stage renal disease (ESRD) in 10%-60% of cases within 10 years and up to 40% within 20 years [ 2 ]. The currently available therapy for IgAN focuses on the management of symptoms by reducing proteinuria and controlling blood pressure with angiotensin converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs), as recommended by international guidelines [ 3 ]. However, these strategies are often insufficient to slow the progression of the disease, especially in patients with persistent proteinuria [ 2 ]. Advances in understanding IgAN pathophysiology have led to the exploration of new therapeutic strategies targeting disease mechanisms. BAFF (B-cell activating factor) and APRIL ((A proliferation-inducing ligand) are cytokines that play central roles in the activation and survival of specific B-cell populations responsible for IgA production [ 4 ]. These cytokines are directly involved in the production of Gd-IgA1 and the formation of immune complexes, and their circulation levels have been directly correlated with both the clinical and histological severity of IgAN [ 5 ]. Unlike conventional therapies that aim primarily to reduce proteinuria and control blood pressure, BAFF and APRIL-targeted therapies act on the immunological root of the disease by modulating B-cell responses and reducing Gd-IgA1 production [ 6 ]. In this context, BAFF/APRIL inhibitors, including atacicept, sibeprenlimab, and telitacicept, have been investigated in clinical studies as adjunctive agents for patients with IgAN, showing the ability to reduce proteinuria, reduce disease severity, stabilize kidney function, improve serum biomarkers, and slow disease progression in patients who failed conventional therapy [ 5 – 9 ]. However, the restricted number of clinical trials, which are all Phase II with relatively small sample sizes [ 5 – 8 ], requires a thorough data synthesis to fully evaluate the efficacy, safety and biomarker changes of BAFF and APRIL therapy in patients with IgAN. Therefore, we performed a systematic review and meta-analysis in order to refine the understanding of individual results in terms of efficacy, safety, and biomarker changes. MATERIALS AND METHODS The present systematic review and meta-analysis is registered in the International Prospective Register of Systematic Reviews (PROSPERO) [ 10 ] under the registration number CRD42024598157. This systematic review with meta-analysis was carried out following the methodological principles delineated in the Cochrane Handbook for Systematic Reviews of Interventions [ 11 ], and the findings are reported following the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines [ 12 ]. Eligibility criteria The inclusion criteria for this systematic review with meta-analysis were: (1) randomized controlled trials; (2) that directly compared BAFF or APRIL-targeted drugs versus placebo; (3) in adult patients aged ≥ 18 years old; (4) with biopsy-confirmed IgA nephropathy; (5) published in the English language. On the contrary, we excluded studies that were nonrandomized controlled trials, case reports or series, in vitro studies, animal studies, reviews, book chapters, opinions, conference abstracts, overlapping populations, or those that lacked a comparative analysis of clinically relevant outcomes of BAFF or APRIL-targeted drugs. Search strategy and data extraction The databases PubMed, Scopus, and the Cochrane Library were searched without time limits until December 2024. Our search strategy used a combination of keywords, including: "IgA Nephropathy", "Berger disease", "Berger’s disease”, “Berger”, "synpharyngitic glomerulonephritis", "synpharyngitic hematuria", “BAFF”, "B-cell activation factor", "B-cell activating factors", “Povetacicept”, “ALPN-303”, “Telitacicept”, “Atacicept”, “Blisibimod”, “APRIL”, "A proliferation inducing ligand", "TNFSF13", “tumor necrosis factor ligand superfamily member 13", "TNF superfamily member 13", “Zigakibart”, "BION-1301", “Sibeprenlimab”, “VIS639”, and “VIS649”. The complete search strategy is presented in the supplementary information. Furthermore, we meticulously examined the reference lists of the included manuscripts to identify any additional relevant studies. Two authors (RDSB and LHDP) independently extracted the data following predefined search criteria. Any discrepancy was resolved by discussion in a consensus meeting between the authors. Outcomes The efficacy outcomes considered were the mean percent change in the urine protein to creatinine ratio (UPCR) at 24 hours from baseline and the mean change in the estimated glomerular filtration rate (eGFR) from baseline. Safety outcomes comprised the rate of adverse effects, drug- or placebo-related adverse effects, serious adverse effects, adverse events leading to discontinuation of the drug or placebo, and upper respiratory tract infections. The biomarker results were the mean percent change in galactose-deficient IgA1 (Gd-IgA1) from baseline; the mean percent change in IgG, IgA, and IgM from baseline; and the final levels of serum IgG, IgA, and IgM. Risk of bias assessment Two authors (RLS and RDSB) separately performed the risk of bias and quality assessment of the studies using the Cochrane Collaboration tool to assess the risk of bias in randomised studies (RoB v2.0) [ 13 ]. For each trial, the authors designated a score indicating 'high risk', 'low risk' or 'some concerns' in five domains: selection, performance, detection, attrition, and reporting bias. Publication bias was not evaluated using funnel plot asymmetry and Egger’s test due to the low number of included studies, as recommended in the Cochrane Handbook for Systematic Reviews of Interventions [ 11 ]. The quality of evidence was evaluated using the Grading of Recommendations, Assessment, Development, and Evaluations (GRADE) approach, considering aspects that may increase or decrease the quality of evidence. The factors analyzed were study limitations, inconsistency, indirectness, imprecision, and publication bias. Ultimately, the final level of evidence was classified into high, moderate, low, and very low [ 14 ]. Statistical analysis Risk ratios (RR) alongside 95% confidence intervals (CI) were calculated to compare the occurrence of binary endpoints between the two groups, while continuous results were evaluated as mean differences (MD) with the corresponding 95% CI. For the conversion of continuous data initially reported in the median (interquartile range), we used the estimated mean and standard deviation provided by Luo et al. (2018) [ 15 ] and Wan et al. (2014) [ 16 ], respectively. The inverse variance (IV) method was used for continuous outcomes and the Mantel-Haenszel (MH) method for binary outcomes [ 11 ]. Cochran’s Q Test and I² statistics were employed to assess heterogeneity. The endpoints were classified as having low heterogeneity if p > 0.10 and I²<30%, moderate heterogeneity if I² fell between 30 and 75%, and high heterogeneity if I² exceeded 75%. Significance was attributed to p values < 0.05. We used the random effects model to account for potential variability among studies, which often yields a more realistic approach in real-world scenarios, in which study populations, interventions, and conditions differ, making it more suitable for generalizing results to different settings and populations. Furthermore, this approach covers unobserved sources of variability and can better handle heterogeneity if it arises in future updates of the meta-analysis as more studies are included [ 11 ]. Statistical analyzes were performed using the packages 'meta' and 'metafor' on the R version 4.2.1 statistical software (R Foundation for Statistical Computing) [ 17 ]. Sensitivity analysis The DerSimonian-Laird (DL) was used as the default method to estimate tau2 [ 11 ]. However, we conducted a prespecified sensitivity analysis to evaluate the stability, robustness, and consistency of our findings, and to address any uncertainty or potential imprecision in the effect estimates. The data were re-assessed using the Sidik-Jonkman-Hartung-Knapp (SJHK) method, as recommended in the Cochrane Handbook (Section 10.10.4.4) for meta-analyzes with a small number of studies or in cases where there is low apparent heterogeneity but potential uncertainty due to study sizes [ 11 ]. Additionally, a leave-one-out analysis was conducted by systematically eliminating one study at a time to ensure that the results were not disproportionately influenced by a single study [ 18 ]. RESULTS Study selection and baseline characteristics As shown in Fig. 1, the search strategy initially yielded 3,215 articles. After removing 1,175 duplicates, an additional 2,019 manuscripts were excluded based on title and abstract screening due to the lack of compliance with the research question. Subsequently, the remaining 21 studies were fully reviewed. Of these, 15 were excluded as abstracts from unpublished trials, 1 because it was a nonrandomized trial, and 17 for reporting preliminary results of a published trial. Therefore, four published RCTs met all the inclusion criteria. The non-overlapping population consisted of 331 patients with IgAN. The overall cohort was predominantly Asian (51.06%) and male (56.80%), with a mean age of 40.72 ± 26.74 years. Baseline urinary protein excretion was 3.46 ± 6.13 g/day, and baseline eGFR, estimated using the CKD-EPI equation, was 73.52 ± 60.79 mL/min/1.73 m². Table 1 provides an overview of the study characteristics and baseline demographics for the BAFF or APRIL-targeted drug and placebo groups. Quality assessment The four included RCTs followed a similar design, with ORIGIN, ENVISION, and Janus considered at low risk of bias in all RoB2 domains. The Jicheng study was flagged with some concerns due to deviations from the intended interventions (Fig. 2). Since we only included four RCTs in this meta-analysis, no formal assessment of publication bias using funnel plot asymmetry and Egger’s test is recommended. Regarding the GRADE quality of the evidence (Table S1), the mean percentage change in 24-hour UPCR from baseline, the mean change in eGFR from baseline, the rate of drug- or placebo-related adverse events, the rate of serious adverse effects and the final level of serum IgG were considered with moderate certainty downgraded due to potential publication bias. The rate of any adverse effect and the mean percent change in Gd-IgA1 from baseline were also considered moderate certainty due to the heterogeneity of the pooled data and potential publication bias. The rate of adverse events leading to discontinuation of the study was rated as low certainty, downgraded due to the limited sample size and wide CI that may reduce confidence in the estimate of effect, and potential publication bias. Of particular interest, the rate of upper respiratory tract infection was considered with very low certainty due to (1) some concerns about the risk of bias assessment of the Jicheng Lv trial, which accounts for 74.24% of the weight of this outcome; (2) heterogeneity of the pooled data; (3) the limited sample size, which could result in unreliable statistical power to detect statistical significance; and (4) potential publication bias (Table S1). Efficacy The mean percent change in 24-hour UPCR from baseline showed a significant decrease with the use of BAFF or APRIL-targeted drugs compared to placebo (MD -38.80%; 95% CI -59.17 to -18.44; p = 0.0002; I²=0%; Fig. 3A). In the sensitivity analysis using the SJHK method, the superior effect of BAFF or APRIL-targeted drugs over placebo was maintained (MD -38.81%; 95% CI -59.21 to -18.40; p = 0.0002; I²=0%; Figure S1A). In the leave-one-out sensitivity analysis, the removal of each study from the pooled analysis did not affect this endpoint (Figure S1B). The trial conducted by Jicheng Lv et al. (2023), which evaluated the drug Telitacicept, did not report UPCR. However, their data showed that Telitacicept 240 mg reduced the mean proteinuria 24 hours (g/day) by 49% from baseline (change in proteinuria vs. placebo 0.88; 95% CI -1.57 to -0.20; p = 0.013), whereas Telitacicept 160 mg reduced it by 25% (change in proteinuria vs. placebo − 0.29; 95% CI -0.95 to 0.37; p = 0.389) [ 8 ]. The mean change in eGFR from baseline showed a significant improvement with BAFF or APRIL-targeted drugs compared to placebo (MD 7.05 mL/min/1.73 m²; 95% CI 3.83 to 10.27; p < 0.0001; I²=0%; Fig. 3B). In the sensitivity analysis using the SJHK method, the superior effect of BAFF or APRIL-targeted drugs over placebo was maintained (MD 7.08 mL/min/1.73 m²; 95% CI 3.68 to 10.48; p < 0.0001; I²=0%; Figure S2A). In the leave-one-out sensitivity analysis, the removal of each study from the pooled analysis did not affect this endpoint (Figure S2B). Safety The rate of any adverse effect was comparable between the BAFF or APRIL-targeted drug and the placebo groups (BAFF or APRIL-targeted drug: 189/240 = 78.75%; placebo: 71/91 = 78.02%; RR 0.99; 95% CI 0.86 to 1.13; p = 0.8381; I²=25.9%; Fig. 4A). In the sensitivity analysis using the SJHK method, the outcome was consistently maintained (RR 0.98; 95% CI 0.85 to 1.15; p = 0.8423; I²=21.1%; Figure S3A). In the leave-one-out sensitivity analysis, the removal of each study from the pooled analysis did not affect this outcome, and the removal of the JANUS 2022 trial yielded homogeneity (I²=0%; Figure S3B). Of particular interest, the rate of upper respiratory tract infection was similar in the BAFF or APRIL-targeted drug and placebo groups (RR 2.02; 95% CI 0.37 to 11.15; p = 0.4208; I²=51.7%; Fig. 4B). In the sensitivity analysis using the SJHK method, the outcome was consistently maintained (RR 1.69; 95% CI 0.43 to 6.63; p = 0.4538; I²=33.3%; Figure S4A). In the leave-one-out sensitivity analysis, the removal of each study from the pooled analysis did not affect this outcome, and the removal of the Jicheng Lv 2023 trial removed heterogeneity (I²=0%; Figure S4B). Specifically evaluating the presence of drug or placebo-related adverse events, there was no significant difference between the groups (RR 1.30; 95% CI 0.87 to 1.93; p = 0.2001; I²=0%; Figure S5A). In the sensitivity analysis, the outcome was maintained consistently using the SJHK method (RR 1.37; 95% CI 0.73 to 2.60; p = 0.3286; I²=0%; Figure S5B) and in the leave-one-out analysis (Figure S5C). Regarding the presence of serious adverse effects, there was no significant difference between the BAFF or APRIL-targeted drug and placebo groups (RR 0.74; 95% CI 0.30 to 1.86; p = 0.5215; I²=0%; Figure S6A). In the sensitivity analysis, the outcome remained significant using the SJHK method (RR 0.75; 95% CI 0.27 to 2.07; p = 0.5793; I²=0%; Figure S6B) and in the leave-one-out analysis (Figure S6C). Regarding the rate of adverse events that led to discontinuation of the study, no significant differences were found between the BAFF or APRIL-targeted drug and placebo groups (RR 0.79; 95% CI 0.14 to 4.93; p = 0.7893; I²=0%; Figure S7A). In the sensitivity analysis, the outcome was consistently maintained using the SJHK method (RR 0.79; 95% CI 0.14 to 4.48; p = 0.7924; I²=0%; Figure S7B) and in the leave-one-out analysis (Figure S7C). Biomarkers The mean percent change in serum Gd-IgA1 from baseline showed a significant decrease with the use of BAFF or APRIL-targeted drugs compared to placebo (MD -46.48%; 95% CI -63.46 to -29.49; p < 0.0001; I²=61.2%; Fig. 5). In the sensitivity analysis using the SJHK method, the superior effect of BAFF or APRIL-targeted drugs over placebo was maintained (MD -46.43%; 95% CI -60.77 to -32.08; p < 0.0001; I²=61.2%; Figure S8A). In the leave-one-out sensitivity analysis, the removal of each study from the pooled analysis did not affect this endpoint, and homogeneity was achieved by omitting ORIGIN 2024 or ENVISION 2023 (Figure S8B). About the serum IgG level, the mean percent change from baseline showed a significant decrease with the use of BAFF or APRIL-targeted drugs compared to placebo (MD -29.76%; 95% CI -34.48 to -25.03; p < 0.0001; I²=0%; Figure S9A). In the sensitivity analysis using the SJHK method, the superior effect of BAFF or APRIL-targeted drugs over placebo was maintained (MD -29.65%; 95% CI -35.89 to -23.42; p < 0.0001; I²=0%; Figure S9B). Specifically, the serum IgG level (g/L) at the end of the study was significantly lower in the BAFF or APRIL-targeted drug group compared to placebo (MD -3.11 g/L; 95% CI -4.00 to -2.22; p < 0.0001; I²=0%; Figure S9C). In the sensitivity analysis, the outcome remained consistent using the SJHK method (MD -3.00 g/L; 95% CI -4.13 to -1.86; p < 0.0001; I²=0%; Figure S9D) and in the leave-one-out analysis (Figure S9E). Concerning the serum IgA level, the mean percent change from baseline showed a significant decrease with the use of BAFF or APRIL-targeted drugs compared to placebo (MD -49.04%; 95% CI -57.53 to -40.54; p < 0.0001; I²=0%; Figure S10A). In the sensitivity analysis using the SJHK method, the superior effect of BAFF or APRIL-targeted drugs over placebo was maintained (MD -49.04%; 95% CI -57.53 to -40.54; p < 0.0001; I²=0%; Figure S10B). Specifically, the serum IgA level (g/L) at the end of the study was significantly lower in the BAFF or APRIL-targeted drug group (MD -1.20 g/L; 95% CI -2.07 to -0.32; p = 0.0072; I²=0%; Figure S10C). In the sensitivity analysis, the outcome did not change (MD -1.20 g/L; 95% CI -2.07 to -0.32; p = 0.0072; I²=0%; Figure S10D). In terms of serum IgM level, the mean percent change from baseline showed a significant decrease with the use of BAFF or APRIL-targeted drugs compared to placebo (MD -65.56%; 95% CI -75.62 to -55.49; p < 0.0001; I²=0%; Figure S11A). In the sensitivity analysis using the SJHK method, the superior effect of BAFF or APRIL-targeted drugs over placebo was maintained (MD -65.55%; 95% CI -75.64 to -55.47; p < 0.0001; I²=0%; Figure S11B). Specifically, the serum IgM (g/L) level at the end of the study was significantly lower in the BAFF or APRIL-targeted drug group compared to placebo (MD -0.59 g/L; 95% CI -0.77 to -0.40; p < 0.0001; I²=0%; Figure S11C). It did not change with the sensitivity analysis, (MD -0.59 g/L; 95% CI -0.85 to -0.34; p < 0.0001; I²=0%; Figure S11D). DISCUSSION This systematic review and meta-analysis analyzed the efficacy of BAFF and APRIL inhibitors in adult patients with biopsy-confirmed IgAN. We found four similarly designed RCTs that compared these therapies with placebo. We consistently showed that BAFF or APRIL inhibitors significantly decreased 24-hour UPCR and increased eGFR compared to placebo; the drugs were safe and tolerable for patients 18 years or older. In addition, BAFF or APRIL inhibitors significantly decreased serum levels of Gd-IgA1, IgG, IgA, and IgM compared to placebo. Regarding the mean change in 24-hour UPCR from baseline, our study found a significant reduction in proteinuria that favors BAFF and APRIL inhibitors over placebo. Although the pathophysiology of IgAN is complex, robust evidence suggests that sustained stabilization of eGFR and proteinuria may halt the progression to ESRD [ 19 – 21 ]. To date, therapies targeting Gd-IgA1 and its autoantibody stand out as some of the most promising treatments for IgAN. While sibeprenlimab exclusively inhibits APRIL signaling; atacicept and telitacicept are dual APRIL/BAFF antagonists. Although these two cytokines share considerable homology, their specific interactions with receptors are of particular interest in IgAN studies [ 22 ]. BAFF uniquely binds to the BAFF receptor (BAFF-R), mainly expressed on immature and mature naïve B cells. However, both BAFF and APRIL interact with B-cell maturation antigen (BCMA), transmembrane activator, calcium modulator, and cyclophilin ligand interactor (TACI) [ 23 ]. These findings align with other immunological therapies for IgAN. Zigakibart, a humanized IgG4 monoclonal antibody targeting APRIL, has shown promising interim results in a phase 2 trial for IgAN, with substantial reductions in proteinuria and a significant decrease in serum IgA and Gd-IgA1 levels [ 23 – 25 ]. For this reason, a phase 3 trial (ClinicalTrials.gov number NCT05852938) [ 26 ] is underway to further assess its efficacy and safety in slowing the progression of renal dysfunction in IgAN patients. In parallel, a targeted release formulation of budesonide (TRF-budesonide) also led to a reduction in proteinuria in patients with IgAN by downregulating aberrant IgA production [ 27 ]. In addition, several other therapies, including complement pathway inhibitors, protein degradation inhibitors, and endothelin receptor antagonists, are under investigation in clinical trials. The findings will help us better understand the pathophysiology of IgAN and allow comparisons between these novel immune therapies [ 28 ]. Safety was evaluated based on the rates of any adverse events, drug- or placebo-related adverse events, serious adverse events, adverse events leading to discontinuation and upper respiratory tract infection. The incidence was similar in the treated groups compared to placebo. As expected, all studies showed reductions in Gd-IgA1, IgA, IgG, and IgM levels in patients treated with atacicept, telitacicept, or sibeprenlimab, which was not observed in the placebo group [ 5 – 8 ]. However, no increase in infection-related adverse events was observed. Importantly, the trials analyzed were conducted during the COVID-19 pandemic [ 5 – 8 ]. Although the authors cited the limited number of participants as a study limitation, the absence of infection-related adverse events may be attributed to selective inhibition of APRIL and BAFF, thus avoiding significant lymphocyte depletion [ 29 ]. However, long-term safety studies are necessary to assess the risk of immunosuppression, as patients will likely require repeated dosing to obtain sustained responses. Our meta-analysis supports the idea that targeting the APRIL/BAFF signaling pathway in IgAN may be promising in terms of efficacy and safety. However, certain limitations in our data deserve careful consideration. The few available phase II studies, along with slight variations in design and small sample sizes, prevent the possibility of conducting in-depth subgroup analyses and yield a moderate quality of evidence. The ENVISION (2023) trial [ 7 ] showed some baseline differences in the percentage of crescents and the time since the biopsy, which could affect the efficacy results to some extent. In the study by Jicheng Lv et al. (2023) [ 8 ], the short follow-up period limited the evaluation of the long-term efficacy of telitacicept on kidney function. Furthermore, there was an imbalance of confounders between the three analyzed groups (placebo, telitacicept 160 mg and telitacicept 240 mg), with a higher proportion of women, patients with lower body mass index, and more people with a history of immunosuppressive therapy in the high-dose groups, resulting in a higher dose of telitacicept per kilogram. Additionally, the slightly accelerated decrease in eGFR in the placebo group may be attributed to the small sample size. In the ORIGIN (2024) trial [ 5 ], limitations included a disproportionate number of white participants assigned to the placebo group compared to those receiving atacicept, which may affect the generalizability of the findings to other populations. Additional studies are also needed to assess the effect of different types and doses of BAFF/APRIL inhibitors. It should be mentioned that the efficacy and safety of sibeprenlimab in a larger population of patients with IgAN are being investigated in an ongoing phase 3 trial (ClinicalTrials.gov number NCT05248646) [ 30 ]. To our knowledge, this is the first systematic review and meta-analysis that evaluates the efficacy and safety of drugs targeting BAFF or APRIL in adults with IgAN. Taken together, our results indicate that BAFF and APRIL-targeted drugs appear to be clinically effective and safe for the improvement of proteinuria, eGFR, and serum biomarkers in patients with IgAN. Larger, phase III RCTs with comprehensive subgroup analyses and extended long-term data are required to support our findings and thoroughly assess the clinical feasibility of BAFF- or APRIL-targeted drugs in IgAN. Declarations Conflict of interest: All authors declare that they have no affiliations or involvement with any organization or entity with a financial or nonfinancial interest in the subject matter or materials addressed in this manuscript. Ethical approval : This is not applicable as the manuscript is a review paper. Human and animal rights: This article does not include any studies involving human participants or animals conducted by the authors. Informed consent: This is not applicable as the manuscript is a review paper. Data availability: The primary data that support the findings of this study are derived from published literature, and the relevant citations are provided in the references section. The raw data sets analyzed and the collection forms are available from the corresponding author upon reasonable request. CRediT Author Contributions: Conceptualization: R.d.S.B., A.C.S.e.S.; Data curation: L.H.d.P., R.d.S.B.; Formal analysis: R.d.S.B., P.A.M.G.d.S.; Investigation: L.H.d.P., R.d.S.B.; Methodology: R.d.S.B., J.M.B.M.; Project administration: R.d.S.B., A.C.S.e.S.; Supervision: R.d.S.B., A.C.S.e.S.; Validation: G.G.B., J.M.B.M.; Visualization: R.d.S.B., L.H.d.P., R.L.S., P.A.M.G.d.S.; Writing – original draft: R.d.S.B., J.M.B.M., G.G.B., R.L.S., L.H.d.P., P.A.M.G.d.S.; Writing – review & editing: A.C.S.e.S., R.d.S.B., G.G.B. Funding: The authors did not receive support from any organization for the submitted work. Acknowledgments: None. References Suzuki H, Kiryluk K, Novak J, Moldoveanu Z, Herr AB, Renfrow MB, Wyatt RJ, Scolari F, Mestecky J, Gharavi AG, Julian BA (2011) The pathophysiology of IgA nephropathy. J Am Soc Nephrol 22(10):1795–1803. https://doi.org/10.1681/ASN.2011050464 Coppo R (2018) Treatment of IgA nephropathy: Recent advances and prospects. 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Kidney Int 105(6):1306–1315. https://doi.org/10.1016/j.kint.2024.03.012 Barratt J, Tumlin J, Suzuki Y, Kao A, Aydemir A, Pudota K, Jin H, Gühring H, Appel G, JANUS study investigators (2022) Randomized Phase II JANUS Study of Atacicept in Patients With IgA Nephropathy and Persistent Proteinuria. Kidney Int Rep 7(8):1831–1841. https://doi.org/10.1016/j.ekir.2022.05.017 Mathur M, Barratt J, Chacko B, Chan TM, Kooienga L, Oh KH, Sahay M, Suzuki Y, Wong MG, Yarbrough J, Xia J, Pereira BJG, ENVISION Trial Investigators Group (2024) A Phase 2 Trial of Sibeprenlimab in Patients with IgA Nephropathy. N Engl J Med 390(1):20–31. https://doi.org/10.1056/NEJMoa2305635 Lv J, Liu L, Hao C, Li G, Fu P, Xing G, Zheng H, Chen N, Wang C, Luo P, Xie D, Zuo L, Li R, Mao Y, Dong S, Zhang P, Zheng H, Wang Y, Qin W, Wang W, Li L, Jiao W, Fang J, Zhang H (2023) Randomized Phase 2 Trial of Telitacicept in Patients With IgA Nephropathy With Persistent Proteinuria. Kidney Int Rep 8(3):499–506. https://doi.org/10.1016/j.ekir.2022.12.014 Mathur M, Chan TM, Oh KH, Kooienga L, Zhuo M, Pinto CS, Chacko B (2023) A PRoliferation-Inducing Ligand (APRIL) in the Pathogenesis of Immunoglobulin A Nephropathy: A Review of the Evidence. J Clin Med 12(21):6927. https://doi.org/10.3390/jcm12216927 Schiavo JH (2019) PROSPERO: An International Register of Systematic Review Protocols. Med Ref Serv Q 38(2):171–180. https://doi.org/10.1080/02763869.2019.1588072 Higgins JPT, Thomas J, Chandler J, Cumpston M, Li T, Page MJ, Welch VA (2024) Cochrane Handbook for Systematic Reviews of Interventions version 6.5. Cochrane. https://www.training.cochrane.org/handbook . Accessed 14 Nov 2024 Page MJ, McKenzie JE, Bossuyt PM, Boutron I, Hoffmann TC, Mulrow CD, Shamseer L, Tetzlaff JM, Akl EA, Brennan SE, Chou R, Glanville J, Grimshaw JM, Hróbjartsson A, Lalu MM, Li T, Loder EW, Mayo-Wilson E, McDonald S, McGuinness LA, Stewart LA, Thomas J, Tricco AC, Welch VA, Whiting P, Moher D (2021) The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. BMJ 372:n71. https://doi.org/10.1136/bmj.n71 Sterne JAC, Savović J, Page MJ, Elbers RG, Blencowe NS, Boutron I, Cates CJ, Cheng HY, Corbett MS, Eldridge SM, Emberson JR, Hernán MA, Hopewell S, Hróbjartsson A, Junqueira DR, Jüni P, Kirkham JJ, Lasserson T, Li T, McAleenan A, Reeves BC, Shepperd S, Shrier I, Stewart LA, Tilling K, White IR, Whiting PF, Higgins JPT (2019) RoB 2: a revised tool for assessing risk of bias in randomized trials. BMJ 366:l4898. https://doi.org/10.1136/bmj.l4898 Guyatt GH, Oxman AD, Vist GE, Kunz R, Falck-Ytter Y, Alonso-Coello P, Schünemann HJ, GRADE Working Group (2008) GRADE: an emerging consensus on rating quality of evidence and strength of recommendations. BMJ 336(7650):924–926. https://doi.org/10.1136/bmj.39489.470347.AD Luo D, Wan X, Liu J, Tong T (2018) Optimally estimating the sample mean from the sample size, median, mid-range, and/or mid-quartile range. Stat Methods Med Res 27(6):1785–1805. https://doi.org/10.1177/0962280216669183 Wan X, Wang W, Liu J, Tong T (2014) Estimating the sample mean and standard deviation from the sample size, median, range and/or interquartile range. BMC Med Res Methodol 14:135. https://doi.org/10.1186/1471-2288-14-135 RStudio Team (2020) RStudio: Integrated Development for R. http://www.rstudio.com/ . Accessed 14 Nov 2024 Viechtbauer W (2010) Conducting Meta-Analyses in R with the metafor Package. J Stat Soft 36:1–48. https://doi.org/10.18637/jss.v036.i03 Pitcher D, Braddon F, Hendry B, Mercer A, Osmaston K, Saleem MA, Steenkamp R, Wong K, Turner AN, Wang K, Gale DP, Barratt J (2023) Long-Term Outcomes in IgA Nephropathy. Clin J Am Soc Nephrol 18(6):727–738. https://doi.org/10.2215/CJN.0000000000000135 Canney M, Barbour SJ, Zheng Y, Coppo R, Zhang H, Liu ZH, Matsuzaki K, Suzuki Y, Katafuchi R, Reich HN, Cattran D, International IgA Nephropathy Network; International IgA Nephropathy Network Investigators (2021) Quantifying Duration of Proteinuria Remission and Association with Clinical Outcome in IgA Nephropathy. J Am Soc Nephrol 32(2):436–447. https://doi.org/10.1681/ASN.2020030349 Le W, Liang S, Hu Y, Deng K, Bao H, Zeng C, Liu Z (2012) Long-term renal survival and related risk factors in patients with IgA nephropathy: results from a cohort of 1155 cases in a Chinese adult population. Nephrol Dial Transpl 27(4):1479–1485. https://doi.org/10.1093/ndt/gfr527 Kalled SL, Ambrose C, Hsu YM (2005) The biochemistry and biology of BAFF, APRIL and their receptors. Curr Dir Autoimmun 8:206–242. https://doi.org/10.1159/000082105 Muto M, Suzuki H, Suzuki Y (2024) New Insights and Future Perspectives of APRIL in IgA Nephropathy. Int J Mol Sci 25(19):10340. https://doi.org/10.3390/ijms251910340 Barratt J, Kooienga L, Hour B, Agha I, Schwartz B, Sorensen B, Lo J, King A, Sathaliya T, Iyer S, Endsley A, Glicklich A (2022) MO212: Updated Interim Results of A Phase 1/2 Study to Investigate the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics and Clinical Activity of BION-1301 in Patients With IGA Nephropathy. Nephrol Dial Transpl 37(Supplement3). gfac067.011 Barratt SG, Kim I, Agha L, Kooienga A, Madan P, Ruiz-Ramon H, Thomas B, Workeneh R, Narayanan B, Sorensen BM, Schwartz AJ, King C, Jones-Burton EY, Lee (2023) WCN23-1175 Updated interim results of a phase 1/2 study of BION-1301 in patients with IgA nephropathy. Kidney Int Rep 8(3):S280–S281. https://doi.org/10.1016/j.ekir.2023.02.632 Chinook T (2024) A Phase 3, Randomized, Double-blind, Placebo-controlled Study of BION-1301 in Adults With IgA Nephropathy (The BEYOND Study). clinicaltrials.gov. Report No.: NCT05852938. https://clinicaltrials.gov/study/NCT05852938 . Accessed 14 Nov 2024 Fellström BC, Barratt J, Cook H, Coppo R, Feehally J, de Fijter JW, Floege J, Hetzel G, Jardine AG, Locatelli F, Maes BD, Mercer A, Ortiz F, Praga M, Sørensen SS, Tesar V, Del Vecchio L, NEFIGAN Trial Investigators (2017) Targeted-release budesonide versus placebo in patients with IgA nephropathy (NEFIGAN): a double-blind, randomized, placebo-controlled phase 2b trial. Lancet 389(10084):2117–2127. https://doi.org/10.1016/S0140-6736(17)30550-0 Noor SM, Abuazzam F, Mathew R, Zhang Z, Abdipour A, Norouzi S (2023) IgA nephropathy: a review of existing and emerging therapies. Front Nephrol 3:1175088. https://doi.org/10.3389/fneph.2023 Kaegi C, Steiner UC, Wuest B, Crowley C, Boyman O (2020) Systematic Review of Safety and Efficacy of Atacicept in Treating Immune-Mediated Disorders. Front Immunol 11:433. https://doi.org/10.3389/fimmu.2020.00433 Otsuka Pharmaceutical Development (2024) A Phase 3, Multicenter, Randomized, Double-blind, Placebo-controlled Trial to Evaluate the Efficacy and Safety of Sibeprenlimab Administered Subcutaneously in Subjects With Immunoglobulin A Nephropathy. clinicaltrials.gov. Report No.: NCT05248646. https://clinicaltrials.gov/study/NCT052486 . Accessed 14 Nov 2024 Table 1 Table 1 is available in the supplemental file section. Additional Declarations The authors declare no competing interests. Supplementary Files Table1.docx Supplementaryinformation.docx SUPPLEMENTARY INFORMATION The supporting material contains the following information: complete search strategy; Figure S1 (sensitivity analysis for the mean percent change in 24-hour UPCR from baseline); Figure S2 (Sensitivity analysis for the mean change in eGFR from baseline); Figure S3 (Sensitivity analysis for the rate of any adverse effect); Figure S4 (Sensitivity analysis for the rate of upper respiratory tract infection); Figure S5 (The rate of drug- or placebo-related adverse events); Figure S6 (The rate of serious adverse effects); Figure S7 (The rate of adverse events leading to discontinuation of the study); Figure S8 (Sensitivity analysis for the mean percent change in serum Gd-IgA1 from baseline); Figure S9 (The serum IgG level); Figure S10 (The serum IgA level); Figure S11 (The serum IgM level). Table S1. 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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-5743662","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":396276864,"identity":"d15974bf-4b73-4477-a71a-99c897dd150c","order_by":0,"name":"Rafael dos Santos Borges","email":"","orcid":"https://orcid.org/0000-0003-1530-6523","institution":"Faculty of Medicine - Federal University of Minas Gerais (UFMG). 190 Prof. Alfredo Balena Avenue - Santa Efigênia, Belo Horizonte - MG, Brazil, 30130-100.","correspondingAuthor":false,"prefix":"","firstName":"Rafael","middleName":"dos Santos","lastName":"Borges","suffix":""},{"id":396276865,"identity":"b44f1f7c-84f2-4a5c-b328-967c7a52a20e","order_by":1,"name":"Rodrigo Lara Santos","email":"","orcid":"https://orcid.org/0009-0007-5594-0664","institution":"Faculty of Medicine - Federal University of Minas Gerais (UFMG). 190 Prof. Alfredo Balena Avenue - Santa Efigênia, Belo Horizonte - MG, Brazil, 30130-100.","correspondingAuthor":false,"prefix":"","firstName":"Rodrigo","middleName":"Lara","lastName":"Santos","suffix":""},{"id":396276866,"identity":"2d18d7fb-ddd5-4fb0-9162-c6ce189ab662","order_by":2,"name":"Luiza Haikal de Paula","email":"","orcid":"https://orcid.org/0009-0000-8530-211X","institution":"Faculty of Medicine - Federal University of Minas Gerais (UFMG). 190 Prof. Alfredo Balena Avenue - Santa Efigênia, Belo Horizonte - MG, Brazil, 30130-100.","correspondingAuthor":false,"prefix":"","firstName":"Luiza","middleName":"Haikal","lastName":"de Paula","suffix":""},{"id":396276867,"identity":"f2e6b3ba-4db9-4184-8fc2-dc3fec57fdb8","order_by":3,"name":"Jefferson Manoel Borges Martins","email":"","orcid":"https://orcid.org/0009-0004-1516-3109","institution":"Faculty of Medicine - Federal University of Pará (UFPA). 1 Augusto Corrêa Street - Guamá, Belém - PA, Brazil, 66075-110.","correspondingAuthor":false,"prefix":"","firstName":"Jefferson","middleName":"Manoel Borges","lastName":"Martins","suffix":""},{"id":396276868,"identity":"faeb5570-f884-455a-9708-9725f5e4271c","order_by":4,"name":"Pedro Antônio Machado Gomes de Sousa","email":"","orcid":"https://orcid.org/0009-0004-6842-2397","institution":"Faculty of Medicine - Federal University of Uberlândia (UFU). 1720 Pará Avenue - Umuarama, Uberlândia - MG, Brazil, 38400-902.","correspondingAuthor":false,"prefix":"","firstName":"Pedro","middleName":"Antônio Machado Gomes","lastName":"de Sousa","suffix":""},{"id":396276869,"identity":"638ee44c-56dd-4f7e-b859-45d5b7bce605","order_by":5,"name":"Giovanni Gosch Berton","email":"data:image/png;base64,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","orcid":"https://orcid.org/0000-0001-6152-2564","institution":"School of Medicine - University of Passo Fundo (UPF). Teixeira Soares Street, 817 - Centro, Passo Fundo - RS, Brazil, 99010-080; Department of Medicine and Department of Molecular Medicine - Università degli Studi di Padova. Via Giustiniani, 2 - Padova, Italy, 35128.","correspondingAuthor":true,"prefix":"","firstName":"Giovanni","middleName":"Gosch","lastName":"Berton","suffix":""},{"id":396276870,"identity":"28207eca-6ead-46f7-9978-7c9f78dd6e34","order_by":6,"name":"Ana Cristina Simões e Silva","email":"","orcid":"https://orcid.org/0000-0001-9222-3882","institution":"Faculty of Medicine - Federal University of Minas Gerais (UFMG). 190 Prof. Alfredo Balena Avenue - Santa Efigênia, Belo Horizonte - MG, Brazil, 30130-100; Interdisciplinary Laboratory of Medical Investigation, Unit of Pediatric Nephrology, Faculty of Medicine, UFMG. 190 Prof. Alfredo Balena Avenue - Santa Efigênia, Belo Horizonte - MG, Brazil, 30130-100.","correspondingAuthor":false,"prefix":"","firstName":"Ana","middleName":"Cristina Simões e","lastName":"Silva","suffix":""}],"badges":[],"createdAt":"2024-12-31 19:53:09","currentVersionCode":1,"declarations":{"humanSubjects":false,"vertebrateSubjects":false,"conflictsOfInterestStatement":false,"humanSubjectEthicalGuidelines":false,"humanSubjectConsent":false,"humanSubjectClinicalTrial":false,"humanSubjectCaseReport":false,"vertebrateSubjectEthicalGuidelines":false},"doi":"10.21203/rs.3.rs-5743662/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-5743662/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":73297303,"identity":"2af61e6d-1b24-4eaa-a889-a60b85ed099e","added_by":"auto","created_at":"2025-01-08 15:28:52","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":811123,"visible":true,"origin":"","legend":"\u003cp\u003ePRISMA flow diagram of study screening and selection\u003c/p\u003e","description":"","filename":"Fig1.png","url":"https://assets-eu.researchsquare.com/files/rs-5743662/v1/69442d1b2b23b81a15d16e3f.png"},{"id":73297301,"identity":"92da6ce1-9464-465d-b8c1-cf76aea5cd6c","added_by":"auto","created_at":"2025-01-08 15:28:52","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":1204526,"visible":true,"origin":"","legend":"\u003cp\u003eRoB2 Risk of bias assessment\u003c/p\u003e","description":"","filename":"Fig2.png","url":"https://assets-eu.researchsquare.com/files/rs-5743662/v1/b30d8325a344509a795cd1a1.png"},{"id":73297305,"identity":"39761d39-783f-4092-a05f-69a5eadacdc3","added_by":"auto","created_at":"2025-01-08 15:28:52","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":1597249,"visible":true,"origin":"","legend":"\u003cp\u003eEfficacy of the BAFF- or APRIL-targeted drug. (\u003cstrong\u003eA)\u003c/strong\u003e Meta-analysis of the mean percent change in UPCR for 24 hours from baseline, (\u003cstrong\u003eB)\u003c/strong\u003e Meta-analysis of the mean change in eGFR from baseline\u003c/p\u003e","description":"","filename":"Fig3.png","url":"https://assets-eu.researchsquare.com/files/rs-5743662/v1/072224e62880797f1cadcf48.png"},{"id":73297947,"identity":"1896edd1-a458-46ee-9de8-51463bf0fdb3","added_by":"auto","created_at":"2025-01-08 15:36:52","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":1471724,"visible":true,"origin":"","legend":"\u003cp\u003eSafety of the BAFF or APRIL-targeted drug. \u003cstrong\u003e(A)\u003c/strong\u003e Meta-analysis of the rate of any adverse effect; \u003cstrong\u003e(B)\u003c/strong\u003e Meta-analysis of the rate of upper respiratory tract infection\u003c/p\u003e","description":"","filename":"Fig4.png","url":"https://assets-eu.researchsquare.com/files/rs-5743662/v1/efca7213ca7c58bd885d0337.png"},{"id":73297948,"identity":"7477d7d6-b071-4f25-90d7-7b9ced714f9b","added_by":"auto","created_at":"2025-01-08 15:36:52","extension":"png","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":810695,"visible":true,"origin":"","legend":"\u003cp\u003eMeta-analysis of the mean percentage change in serum Gd-IgA1 from baseline\u003c/p\u003e","description":"","filename":"Fig5.png","url":"https://assets-eu.researchsquare.com/files/rs-5743662/v1/1f983b1d18df2cdac2da401d.png"},{"id":73298868,"identity":"8d7cd2fc-b788-4a60-87fb-7211c972fb90","added_by":"auto","created_at":"2025-01-08 15:44:55","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":6017800,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-5743662/v1/23c26473-f0b0-474a-839f-03dd21ddd0fe.pdf"},{"id":73297300,"identity":"35ee2c5b-c6a6-4690-a9ef-33bc0b673bb0","added_by":"auto","created_at":"2025-01-08 15:28:52","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":30173,"visible":true,"origin":"","legend":"","description":"","filename":"Table1.docx","url":"https://assets-eu.researchsquare.com/files/rs-5743662/v1/8b46c409783d1b783077741e.docx"},{"id":73297308,"identity":"408b2294-90df-4855-a14a-439930afcdd1","added_by":"auto","created_at":"2025-01-08 15:28:52","extension":"docx","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":1754172,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eSUPPLEMENTARY INFORMATION\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe supporting material contains the following information: complete search strategy; Figure S1 (sensitivity analysis for the mean percent change in 24-hour UPCR from baseline); Figure S2 (Sensitivity analysis for the mean change in eGFR from baseline); Figure S3 (Sensitivity analysis for the rate of any adverse effect); Figure S4 (Sensitivity analysis for the rate of upper respiratory tract infection); Figure S5 (The rate of drug- or placebo-related adverse events); Figure S6 (The rate of serious adverse effects); Figure S7 (The rate of adverse events leading to discontinuation of the study); Figure S8 (Sensitivity analysis for the mean percent change in serum Gd-IgA1 from baseline); Figure S9 (The serum IgG level); Figure S10 (The serum IgA level); Figure S11 (The serum IgM level). Table S1.\u0026nbsp;\u003c/p\u003e","description":"","filename":"Supplementaryinformation.docx","url":"https://assets-eu.researchsquare.com/files/rs-5743662/v1/66b3893c068cd2ce413bc340.docx"}],"financialInterests":"The authors declare no competing interests.","formattedTitle":"\u003cp\u003eEfficacy, safety, and biomarker changes of B-cell activating factor- and A proliferation-inducing ligand-targeted therapies in IgA nephropathy: A systematic review and meta-analysis of randomized controlled trials\u003c/p\u003e","fulltext":[{"header":"INTRODUCTION","content":"\u003cp\u003eIgA nephropathy (IgAN) is the most common primary glomerular disease in the world. IgAN is characterized by the deposition of abnormally glycosylated IgA1 (Gd-IgA1) immune complexes in the glomerular mesangial matrix, which promotes inflammation and progressive renal dysfunction [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. Despite the great variability in clinical presentation, many patients develop a persistent decline in renal function, progressing to end-stage renal disease (ESRD) in 10%-60% of cases within 10 years and up to 40% within 20 years [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThe currently available therapy for IgAN focuses on the management of symptoms by reducing proteinuria and controlling blood pressure with angiotensin converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs), as recommended by international guidelines [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. However, these strategies are often insufficient to slow the progression of the disease, especially in patients with persistent proteinuria [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eAdvances in understanding IgAN pathophysiology have led to the exploration of new therapeutic strategies targeting disease mechanisms. BAFF (B-cell activating factor) and APRIL ((A proliferation-inducing ligand) are cytokines that play central roles in the activation and survival of specific B-cell populations responsible for IgA production [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. These cytokines are directly involved in the production of Gd-IgA1 and the formation of immune complexes, and their circulation levels have been directly correlated with both the clinical and histological severity of IgAN [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. Unlike conventional therapies that aim primarily to reduce proteinuria and control blood pressure, BAFF and APRIL-targeted therapies act on the immunological root of the disease by modulating B-cell responses and reducing Gd-IgA1 production [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. In this context, BAFF/APRIL inhibitors, including atacicept, sibeprenlimab, and telitacicept, have been investigated in clinical studies as adjunctive agents for patients with IgAN, showing the ability to reduce proteinuria, reduce disease severity, stabilize kidney function, improve serum biomarkers, and slow disease progression in patients who failed conventional therapy [\u003cspan additionalcitationids=\"CR6 CR7 CR8\" citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eHowever, the restricted number of clinical trials, which are all Phase II with relatively small sample sizes [\u003cspan additionalcitationids=\"CR6 CR7\" citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e], requires a thorough data synthesis to fully evaluate the efficacy, safety and biomarker changes of BAFF and APRIL therapy in patients with IgAN. Therefore, we performed a systematic review and meta-analysis in order to refine the understanding of individual results in terms of efficacy, safety, and biomarker changes.\u003c/p\u003e"},{"header":"MATERIALS AND METHODS","content":"\u003cp\u003eThe present systematic review and meta-analysis is registered in the International Prospective Register of Systematic Reviews (PROSPERO) [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e] under the registration number CRD42024598157. This systematic review with meta-analysis was carried out following the methodological principles delineated in the Cochrane Handbook for Systematic Reviews of Interventions [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e], and the findings are reported following the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e].\u003c/p\u003e \u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eEligibility criteria\u003c/h2\u003e \u003cp\u003eThe inclusion criteria for this systematic review with meta-analysis were: (1) randomized controlled trials; (2) that directly compared BAFF or APRIL-targeted drugs versus placebo; (3) in adult patients aged\u0026thinsp;\u0026ge;\u0026thinsp;18 years old; (4) with biopsy-confirmed IgA nephropathy; (5) published in the English language. On the contrary, we excluded studies that were nonrandomized controlled trials, case reports or series, in vitro studies, animal studies, reviews, book chapters, opinions, conference abstracts, overlapping populations, or those that lacked a comparative analysis of clinically relevant outcomes of BAFF or APRIL-targeted drugs.\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eSearch strategy and data extraction\u003c/h3\u003e\n\u003cp\u003eThe databases PubMed, Scopus, and the Cochrane Library were searched without time limits until December 2024. Our search strategy used a combination of keywords, including: \"IgA Nephropathy\", \"Berger disease\", \"Berger\u0026rsquo;s disease\u0026rdquo;, \u0026ldquo;Berger\u0026rdquo;, \"synpharyngitic glomerulonephritis\", \"synpharyngitic hematuria\", \u0026ldquo;BAFF\u0026rdquo;, \"B-cell activation factor\", \"B-cell activating factors\", \u0026ldquo;Povetacicept\u0026rdquo;, \u0026ldquo;ALPN-303\u0026rdquo;, \u0026ldquo;Telitacicept\u0026rdquo;, \u0026ldquo;Atacicept\u0026rdquo;, \u0026ldquo;Blisibimod\u0026rdquo;, \u0026ldquo;APRIL\u0026rdquo;, \"A proliferation inducing ligand\", \"TNFSF13\", \u0026ldquo;tumor necrosis factor ligand superfamily member 13\", \"TNF superfamily member 13\", \u0026ldquo;Zigakibart\u0026rdquo;, \"BION-1301\", \u0026ldquo;Sibeprenlimab\u0026rdquo;, \u0026ldquo;VIS639\u0026rdquo;, and \u0026ldquo;VIS649\u0026rdquo;. The complete search strategy is presented in the supplementary information. Furthermore, we meticulously examined the reference lists of the included manuscripts to identify any additional relevant studies. Two authors (RDSB and LHDP) independently extracted the data following predefined search criteria. Any discrepancy was resolved by discussion in a consensus meeting between the authors.\u003c/p\u003e\n\u003ch3\u003eOutcomes\u003c/h3\u003e\n\u003cp\u003eThe efficacy outcomes considered were the mean percent change in the urine protein to creatinine ratio (UPCR) at 24 hours from baseline and the mean change in the estimated glomerular filtration rate (eGFR) from baseline. Safety outcomes comprised the rate of adverse effects, drug- or placebo-related adverse effects, serious adverse effects, adverse events leading to discontinuation of the drug or placebo, and upper respiratory tract infections. The biomarker results were the mean percent change in galactose-deficient IgA1 (Gd-IgA1) from baseline; the mean percent change in IgG, IgA, and IgM from baseline; and the final levels of serum IgG, IgA, and IgM.\u003c/p\u003e\n\u003ch3\u003eRisk of bias assessment\u003c/h3\u003e\n\u003cp\u003eTwo authors (RLS and RDSB) separately performed the risk of bias and quality assessment of the studies using the Cochrane Collaboration tool to assess the risk of bias in randomised studies (RoB v2.0) [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. For each trial, the authors designated a score indicating 'high risk', 'low risk' or 'some concerns' in five domains: selection, performance, detection, attrition, and reporting bias. Publication bias was not evaluated using funnel plot asymmetry and Egger\u0026rsquo;s test due to the low number of included studies, as recommended in the Cochrane Handbook for Systematic Reviews of Interventions [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. The quality of evidence was evaluated using the Grading of Recommendations, Assessment, Development, and Evaluations (GRADE) approach, considering aspects that may increase or decrease the quality of evidence. The factors analyzed were study limitations, inconsistency, indirectness, imprecision, and publication bias. Ultimately, the final level of evidence was classified into high, moderate, low, and very low [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e].\u003c/p\u003e \u003cdiv id=\"Sec7\" class=\"Section2\"\u003e \u003ch2\u003eStatistical analysis\u003c/h2\u003e \u003cp\u003eRisk ratios (RR) alongside 95% confidence intervals (CI) were calculated to compare the occurrence of binary endpoints between the two groups, while continuous results were evaluated as mean differences (MD) with the corresponding 95% CI. For the conversion of continuous data initially reported in the median (interquartile range), we used the estimated mean and standard deviation provided by Luo et al. (2018) [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e] and Wan et al. (2014) [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e], respectively. The inverse variance (IV) method was used for continuous outcomes and the Mantel-Haenszel (MH) method for binary outcomes [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. Cochran\u0026rsquo;s Q Test and I\u0026sup2; statistics were employed to assess heterogeneity. The endpoints were classified as having low heterogeneity if p\u0026thinsp;\u0026gt;\u0026thinsp;0.10 and I\u0026sup2;\u0026lt;30%, moderate heterogeneity if I\u0026sup2; fell between 30 and 75%, and high heterogeneity if I\u0026sup2; exceeded 75%. Significance was attributed to p values\u0026thinsp;\u0026lt;\u0026thinsp;0.05. We used the random effects model to account for potential variability among studies, which often yields a more realistic approach in real-world scenarios, in which study populations, interventions, and conditions differ, making it more suitable for generalizing results to different settings and populations. Furthermore, this approach covers unobserved sources of variability and can better handle heterogeneity if it arises in future updates of the meta-analysis as more studies are included [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. Statistical analyzes were performed using the packages 'meta' and 'metafor' on the R version 4.2.1 statistical software (R Foundation for Statistical Computing) [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e].\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003eSensitivity analysis\u003c/h2\u003e \u003cp\u003eThe DerSimonian-Laird (DL) was used as the default method to estimate tau2 [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. However, we conducted a prespecified sensitivity analysis to evaluate the stability, robustness, and consistency of our findings, and to address any uncertainty or potential imprecision in the effect estimates. The data were re-assessed using the Sidik-Jonkman-Hartung-Knapp (SJHK) method, as recommended in the Cochrane Handbook (Section 10.10.4.4) for meta-analyzes with a small number of studies or in cases where there is low apparent heterogeneity but potential uncertainty due to study sizes [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. Additionally, a leave-one-out analysis was conducted by systematically eliminating one study at a time to ensure that the results were not disproportionately influenced by a single study [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e].\u003c/p\u003e \u003c/div\u003e"},{"header":"RESULTS","content":"\u003cdiv id=\"Sec10\" class=\"Section2\"\u003e\n\u003ch2\u003eStudy selection and baseline characteristics\u003c/h2\u003e\n\u003cp\u003eAs shown in Fig.\u0026nbsp;1, the search strategy initially yielded 3,215 articles. After removing 1,175 duplicates, an additional 2,019 manuscripts were excluded based on title and abstract screening due to the lack of compliance with the research question. Subsequently, the remaining 21 studies were fully reviewed. Of these, 15 were excluded as abstracts from unpublished trials, 1 because it was a nonrandomized trial, and 17 for reporting preliminary results of a published trial. Therefore, four published RCTs met all the inclusion criteria. The non-overlapping population consisted of 331 patients with IgAN. The overall cohort was predominantly Asian (51.06%) and male (56.80%), with a mean age of 40.72\u0026thinsp;\u0026plusmn;\u0026thinsp;26.74 years. Baseline urinary protein excretion was 3.46\u0026thinsp;\u0026plusmn;\u0026thinsp;6.13 g/day, and baseline eGFR, estimated using the CKD-EPI equation, was 73.52\u0026thinsp;\u0026plusmn;\u0026thinsp;60.79 mL/min/1.73 m\u0026sup2;. Table\u0026nbsp;1 provides an overview of the study characteristics and baseline demographics for the BAFF or APRIL-targeted drug and placebo groups.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec11\" class=\"Section2\"\u003e\n\u003ch2\u003eQuality assessment\u003c/h2\u003e\n\u003cp\u003eThe four included RCTs followed a similar design, with ORIGIN, ENVISION, and Janus considered at low risk of bias in all RoB2 domains. The Jicheng study was flagged with some concerns due to deviations from the intended interventions (Fig.\u0026nbsp;2). Since we only included four RCTs in this meta-analysis, no formal assessment of publication bias using funnel plot asymmetry and Egger\u0026rsquo;s test is recommended. Regarding the GRADE quality of the evidence (Table S1), the mean percentage change in 24-hour UPCR from baseline, the mean change in eGFR from baseline, the rate of drug- or placebo-related adverse events, the rate of serious adverse effects and the final level of serum IgG were considered with moderate certainty downgraded due to potential publication bias. The rate of any adverse effect and the mean percent change in Gd-IgA1 from baseline were also considered moderate certainty due to the heterogeneity of the pooled data and potential publication bias. The rate of adverse events leading to discontinuation of the study was rated as low certainty, downgraded due to the limited sample size and wide CI that may reduce confidence in the estimate of effect, and potential publication bias. Of particular interest, the rate of upper respiratory tract infection was considered with very low certainty due to (1) some concerns about the risk of bias assessment of the Jicheng Lv trial, which accounts for 74.24% of the weight of this outcome; (2) heterogeneity of the pooled data; (3) the limited sample size, which could result in unreliable statistical power to detect statistical significance; and (4) potential publication bias (Table S1).\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec12\" class=\"Section2\"\u003e\n\u003ch2\u003eEfficacy\u003c/h2\u003e\n\u003cp\u003eThe mean percent change in 24-hour UPCR from baseline showed a significant decrease with the use of BAFF or APRIL-targeted drugs compared to placebo (MD -38.80%; 95% CI -59.17 to -18.44; p\u0026thinsp;=\u0026thinsp;0.0002; I\u0026sup2;=0%; Fig.\u0026nbsp;3A). In the sensitivity analysis using the SJHK method, the superior effect of BAFF or APRIL-targeted drugs over placebo was maintained (MD -38.81%; 95% CI -59.21 to -18.40; p\u0026thinsp;=\u0026thinsp;0.0002; I\u0026sup2;=0%; Figure S1A). In the leave-one-out sensitivity analysis, the removal of each study from the pooled analysis did not affect this endpoint (Figure S1B).\u003c/p\u003e\n\u003cp\u003eThe trial conducted by Jicheng Lv et al. (2023), which evaluated the drug Telitacicept, did not report UPCR. However, their data showed that Telitacicept 240 mg reduced the mean proteinuria 24 hours (g/day) by 49% from baseline (change in proteinuria vs. placebo 0.88; 95% CI -1.57 to -0.20; p\u0026thinsp;=\u0026thinsp;0.013), whereas Telitacicept 160 mg reduced it by 25% (change in proteinuria vs. placebo \u0026minus;\u0026thinsp;0.29; 95% CI -0.95 to 0.37; p\u0026thinsp;=\u0026thinsp;0.389) [\u003cspan class=\"CitationRef\"\u003e8\u003c/span\u003e].\u003c/p\u003e\n\u003cp\u003eThe mean change in eGFR from baseline showed a significant improvement with BAFF or APRIL-targeted drugs compared to placebo (MD 7.05 mL/min/1.73 m\u0026sup2;; 95% CI 3.83 to 10.27; p\u0026thinsp;\u0026lt;\u0026thinsp;0.0001; I\u0026sup2;=0%; Fig.\u0026nbsp;3B). In the sensitivity analysis using the SJHK method, the superior effect of BAFF or APRIL-targeted drugs over placebo was maintained (MD 7.08 mL/min/1.73 m\u0026sup2;; 95% CI 3.68 to 10.48; p\u0026thinsp;\u0026lt;\u0026thinsp;0.0001; I\u0026sup2;=0%; Figure S2A). In the leave-one-out sensitivity analysis, the removal of each study from the pooled analysis did not affect this endpoint (Figure S2B).\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec13\" class=\"Section2\"\u003e\n\u003ch2\u003eSafety\u003c/h2\u003e\n\u003cp\u003eThe rate of any adverse effect was comparable between the BAFF or APRIL-targeted drug and the placebo groups (BAFF or APRIL-targeted drug: 189/240\u0026thinsp;=\u0026thinsp;78.75%; placebo: 71/91\u0026thinsp;=\u0026thinsp;78.02%; RR 0.99; 95% CI 0.86 to 1.13; p\u0026thinsp;=\u0026thinsp;0.8381; I\u0026sup2;=25.9%; Fig.\u0026nbsp;4A). In the sensitivity analysis using the SJHK method, the outcome was consistently maintained (RR 0.98; 95% CI 0.85 to 1.15; p\u0026thinsp;=\u0026thinsp;0.8423; I\u0026sup2;=21.1%; Figure S3A). In the leave-one-out sensitivity analysis, the removal of each study from the pooled analysis did not affect this outcome, and the removal of the JANUS 2022 trial yielded homogeneity (I\u0026sup2;=0%; Figure S3B).\u003c/p\u003e\n\u003cp\u003eOf particular interest, the rate of upper respiratory tract infection was similar in the BAFF or APRIL-targeted drug and placebo groups (RR 2.02; 95% CI 0.37 to 11.15; p\u0026thinsp;=\u0026thinsp;0.4208; I\u0026sup2;=51.7%; Fig.\u0026nbsp;4B). In the sensitivity analysis using the SJHK method, the outcome was consistently maintained (RR 1.69; 95% CI 0.43 to 6.63; p\u0026thinsp;=\u0026thinsp;0.4538; I\u0026sup2;=33.3%; Figure S4A). In the leave-one-out sensitivity analysis, the removal of each study from the pooled analysis did not affect this outcome, and the removal of the Jicheng Lv 2023 trial removed heterogeneity (I\u0026sup2;=0%; Figure S4B).\u003c/p\u003e\n\u003cp\u003eSpecifically evaluating the presence of drug or placebo-related adverse events, there was no significant difference between the groups (RR 1.30; 95% CI 0.87 to 1.93; p\u0026thinsp;=\u0026thinsp;0.2001; I\u0026sup2;=0%; Figure S5A). In the sensitivity analysis, the outcome was maintained consistently using the SJHK method (RR 1.37; 95% CI 0.73 to 2.60; p\u0026thinsp;=\u0026thinsp;0.3286; I\u0026sup2;=0%; Figure S5B) and in the leave-one-out analysis (Figure S5C).\u003c/p\u003e\n\u003cp\u003eRegarding the presence of serious adverse effects, there was no significant difference between the BAFF or APRIL-targeted drug and placebo groups (RR 0.74; 95% CI 0.30 to 1.86; p\u0026thinsp;=\u0026thinsp;0.5215; I\u0026sup2;=0%; Figure S6A). In the sensitivity analysis, the outcome remained significant using the SJHK method (RR 0.75; 95% CI 0.27 to 2.07; p\u0026thinsp;=\u0026thinsp;0.5793; I\u0026sup2;=0%; Figure S6B) and in the leave-one-out analysis (Figure S6C).\u003c/p\u003e\n\u003cp\u003eRegarding the rate of adverse events that led to discontinuation of the study, no significant differences were found between the BAFF or APRIL-targeted drug and placebo groups (RR 0.79; 95% CI 0.14 to 4.93; p\u0026thinsp;=\u0026thinsp;0.7893; I\u0026sup2;=0%; Figure S7A). In the sensitivity analysis, the outcome was consistently maintained using the SJHK method (RR 0.79; 95% CI 0.14 to 4.48; p\u0026thinsp;=\u0026thinsp;0.7924; I\u0026sup2;=0%; Figure S7B) and in the leave-one-out analysis (Figure S7C).\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec14\" class=\"Section2\"\u003e\n\u003ch2\u003eBiomarkers\u003c/h2\u003e\n\u003cp\u003eThe mean percent change in serum Gd-IgA1 from baseline showed a significant decrease with the use of BAFF or APRIL-targeted drugs compared to placebo (MD -46.48%; 95% CI -63.46 to -29.49; p\u0026thinsp;\u0026lt;\u0026thinsp;0.0001; I\u0026sup2;=61.2%; Fig.\u0026nbsp;5). In the sensitivity analysis using the SJHK method, the superior effect of BAFF or APRIL-targeted drugs over placebo was maintained (MD -46.43%; 95% CI -60.77 to -32.08; p\u0026thinsp;\u0026lt;\u0026thinsp;0.0001; I\u0026sup2;=61.2%; Figure S8A). In the leave-one-out sensitivity analysis, the removal of each study from the pooled analysis did not affect this endpoint, and homogeneity was achieved by omitting ORIGIN 2024 or ENVISION 2023 (Figure S8B).\u003c/p\u003e\n\u003cp\u003eAbout the serum IgG level, the mean percent change from baseline showed a significant decrease with the use of BAFF or APRIL-targeted drugs compared to placebo (MD -29.76%; 95% CI -34.48 to -25.03; p\u0026thinsp;\u0026lt;\u0026thinsp;0.0001; I\u0026sup2;=0%; Figure S9A). In the sensitivity analysis using the SJHK method, the superior effect of BAFF or APRIL-targeted drugs over placebo was maintained (MD -29.65%; 95% CI -35.89 to -23.42; p\u0026thinsp;\u0026lt;\u0026thinsp;0.0001; I\u0026sup2;=0%; Figure S9B). Specifically, the serum IgG level (g/L) at the end of the study was significantly lower in the BAFF or APRIL-targeted drug group compared to placebo (MD -3.11 g/L; 95% CI -4.00 to -2.22; p\u0026thinsp;\u0026lt;\u0026thinsp;0.0001; I\u0026sup2;=0%; Figure S9C). In the sensitivity analysis, the outcome remained consistent using the SJHK method (MD -3.00 g/L; 95% CI -4.13 to -1.86; p\u0026thinsp;\u0026lt;\u0026thinsp;0.0001; I\u0026sup2;=0%; Figure S9D) and in the leave-one-out analysis (Figure S9E).\u003c/p\u003e\n\u003cp\u003eConcerning the serum IgA level, the mean percent change from baseline showed a significant decrease with the use of BAFF or APRIL-targeted drugs compared to placebo (MD -49.04%; 95% CI -57.53 to -40.54; p\u0026thinsp;\u0026lt;\u0026thinsp;0.0001; I\u0026sup2;=0%; Figure S10A). In the sensitivity analysis using the SJHK method, the superior effect of BAFF or APRIL-targeted drugs over placebo was maintained (MD -49.04%; 95% CI -57.53 to -40.54; p\u0026thinsp;\u0026lt;\u0026thinsp;0.0001; I\u0026sup2;=0%; Figure S10B). Specifically, the serum IgA level (g/L) at the end of the study was significantly lower in the BAFF or APRIL-targeted drug group (MD -1.20 g/L; 95% CI -2.07 to -0.32; p\u0026thinsp;=\u0026thinsp;0.0072; I\u0026sup2;=0%; Figure S10C). In the sensitivity analysis, the outcome did not change (MD -1.20 g/L; 95% CI -2.07 to -0.32; p\u0026thinsp;=\u0026thinsp;0.0072; I\u0026sup2;=0%; Figure S10D).\u003c/p\u003e\n\u003cp\u003eIn terms of serum IgM level, the mean percent change from baseline showed a significant decrease with the use of BAFF or APRIL-targeted drugs compared to placebo (MD -65.56%; 95% CI -75.62 to -55.49; p\u0026thinsp;\u0026lt;\u0026thinsp;0.0001; I\u0026sup2;=0%; Figure S11A). In the sensitivity analysis using the SJHK method, the superior effect of BAFF or APRIL-targeted drugs over placebo was maintained (MD -65.55%; 95% CI -75.64 to -55.47; p\u0026thinsp;\u0026lt;\u0026thinsp;0.0001; I\u0026sup2;=0%; Figure S11B). Specifically, the serum IgM (g/L) level at the end of the study was significantly lower in the BAFF or APRIL-targeted drug group compared to placebo (MD -0.59 g/L; 95% CI -0.77 to -0.40; p\u0026thinsp;\u0026lt;\u0026thinsp;0.0001; I\u0026sup2;=0%; Figure S11C). It did not change with the sensitivity analysis, (MD -0.59 g/L; 95% CI -0.85 to -0.34; p\u0026thinsp;\u0026lt;\u0026thinsp;0.0001; I\u0026sup2;=0%; Figure S11D).\u003c/p\u003e\n\u003c/div\u003e"},{"header":"DISCUSSION","content":"\u003cp\u003eThis systematic review and meta-analysis analyzed the efficacy of BAFF and APRIL inhibitors in adult patients with biopsy-confirmed IgAN. We found four similarly designed RCTs that compared these therapies with placebo. We consistently showed that BAFF or APRIL inhibitors significantly decreased 24-hour UPCR and increased eGFR compared to placebo; the drugs were safe and tolerable for patients 18 years or older. In addition, BAFF or APRIL inhibitors significantly decreased serum levels of Gd-IgA1, IgG, IgA, and IgM compared to placebo.\u003c/p\u003e \u003cp\u003eRegarding the mean change in 24-hour UPCR from baseline, our study found a significant reduction in proteinuria that favors BAFF and APRIL inhibitors over placebo. Although the pathophysiology of IgAN is complex, robust evidence suggests that sustained stabilization of eGFR and proteinuria may halt the progression to ESRD [\u003cspan additionalcitationids=\"CR20\" citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]. To date, therapies targeting Gd-IgA1 and its autoantibody stand out as some of the most promising treatments for IgAN. While sibeprenlimab exclusively inhibits APRIL signaling; atacicept and telitacicept are dual APRIL/BAFF antagonists. Although these two cytokines share considerable homology, their specific interactions with receptors are of particular interest in IgAN studies [\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]. BAFF uniquely binds to the BAFF receptor (BAFF-R), mainly expressed on immature and mature na\u0026iuml;ve B cells. However, both BAFF and APRIL interact with B-cell maturation antigen (BCMA), transmembrane activator, calcium modulator, and cyclophilin ligand interactor (TACI) [\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThese findings align with other immunological therapies for IgAN. Zigakibart, a humanized IgG4 monoclonal antibody targeting APRIL, has shown promising interim results in a phase 2 trial for IgAN, with substantial reductions in proteinuria and a significant decrease in serum IgA and Gd-IgA1 levels [\u003cspan additionalcitationids=\"CR24\" citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e]. For this reason, a phase 3 trial (ClinicalTrials.gov number NCT05852938) [\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e] is underway to further assess its efficacy and safety in slowing the progression of renal dysfunction in IgAN patients. In parallel, a targeted release formulation of budesonide (TRF-budesonide) also led to a reduction in proteinuria in patients with IgAN by downregulating aberrant IgA production [\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e]. In addition, several other therapies, including complement pathway inhibitors, protein degradation inhibitors, and endothelin receptor antagonists, are under investigation in clinical trials. The findings will help us better understand the pathophysiology of IgAN and allow comparisons between these novel immune therapies [\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eSafety was evaluated based on the rates of any adverse events, drug- or placebo-related adverse events, serious adverse events, adverse events leading to discontinuation and upper respiratory tract infection. The incidence was similar in the treated groups compared to placebo. As expected, all studies showed reductions in Gd-IgA1, IgA, IgG, and IgM levels in patients treated with atacicept, telitacicept, or sibeprenlimab, which was not observed in the placebo group [\u003cspan additionalcitationids=\"CR6 CR7\" citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. However, no increase in infection-related adverse events was observed. Importantly, the trials analyzed were conducted during the COVID-19 pandemic [\u003cspan additionalcitationids=\"CR6 CR7\" citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. Although the authors cited the limited number of participants as a study limitation, the absence of infection-related adverse events may be attributed to selective inhibition of APRIL and BAFF, thus avoiding significant lymphocyte depletion [\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e]. However, long-term safety studies are necessary to assess the risk of immunosuppression, as patients will likely require repeated dosing to obtain sustained responses.\u003c/p\u003e \u003cp\u003eOur meta-analysis supports the idea that targeting the APRIL/BAFF signaling pathway in IgAN may be promising in terms of efficacy and safety. However, certain limitations in our data deserve careful consideration. The few available phase II studies, along with slight variations in design and small sample sizes, prevent the possibility of conducting in-depth subgroup analyses and yield a moderate quality of evidence. The ENVISION (2023) trial [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e] showed some baseline differences in the percentage of crescents and the time since the biopsy, which could affect the efficacy results to some extent. In the study by Jicheng Lv et al. (2023) [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e], the short follow-up period limited the evaluation of the long-term efficacy of telitacicept on kidney function. Furthermore, there was an imbalance of confounders between the three analyzed groups (placebo, telitacicept 160 mg and telitacicept 240 mg), with a higher proportion of women, patients with lower body mass index, and more people with a history of immunosuppressive therapy in the high-dose groups, resulting in a higher dose of telitacicept per kilogram. Additionally, the slightly accelerated decrease in eGFR in the placebo group may be attributed to the small sample size. In the ORIGIN (2024) trial [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e], limitations included a disproportionate number of white participants assigned to the placebo group compared to those receiving atacicept, which may affect the generalizability of the findings to other populations. Additional studies are also needed to assess the effect of different types and doses of BAFF/APRIL inhibitors. It should be mentioned that the efficacy and safety of sibeprenlimab in a larger population of patients with IgAN are being investigated in an ongoing phase 3 trial (ClinicalTrials.gov number NCT05248646) [\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eTo our knowledge, this is the first systematic review and meta-analysis that evaluates the efficacy and safety of drugs targeting BAFF or APRIL in adults with IgAN. Taken together, our results indicate that BAFF and APRIL-targeted drugs appear to be clinically effective and safe for the improvement of proteinuria, eGFR, and serum biomarkers in patients with IgAN. Larger, phase III RCTs with comprehensive subgroup analyses and extended long-term data are required to support our findings and thoroughly assess the clinical feasibility of BAFF- or APRIL-targeted drugs in IgAN.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eConflict of interest:\u003c/strong\u003e All authors declare that they have no affiliations or involvement with any organization or entity with a financial or nonfinancial interest in the subject matter or materials addressed in this manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthical approval\u003c/strong\u003e: This is not applicable as the manuscript is a review paper.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eHuman and animal rights:\u003c/strong\u003e This article does not include any studies involving human participants or animals conducted by the authors.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eInformed consent:\u0026nbsp;\u003c/strong\u003eThis is not applicable as the manuscript is a review paper.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData availability:\u003c/strong\u003e The primary data that support the findings of this study are derived from published literature, and the relevant citations are provided in the references section. The raw data sets analyzed and the collection forms are available from the corresponding author upon reasonable request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCRediT Author Contributions: Conceptualization:\u0026nbsp;\u003c/strong\u003eR.d.S.B., A.C.S.e.S.;\u003cstrong\u003e\u0026nbsp;Data curation:\u0026nbsp;\u003c/strong\u003eL.H.d.P., R.d.S.B.;\u003cstrong\u003e\u0026nbsp;Formal analysis:\u0026nbsp;\u003c/strong\u003eR.d.S.B., P.A.M.G.d.S.;\u003cstrong\u003e\u0026nbsp;Investigation:\u0026nbsp;\u003c/strong\u003eL.H.d.P., R.d.S.B.;\u003cstrong\u003e\u0026nbsp;Methodology:\u0026nbsp;\u003c/strong\u003eR.d.S.B., J.M.B.M.;\u003cstrong\u003e\u0026nbsp;Project administration:\u0026nbsp;\u003c/strong\u003eR.d.S.B., A.C.S.e.S.;\u003cstrong\u003e\u0026nbsp;Supervision:\u0026nbsp;\u003c/strong\u003eR.d.S.B., A.C.S.e.S.;\u003cstrong\u003e\u0026nbsp;Validation:\u0026nbsp;\u003c/strong\u003eG.G.B., J.M.B.M.;\u003cstrong\u003e\u0026nbsp;Visualization:\u0026nbsp;\u003c/strong\u003eR.d.S.B., L.H.d.P., R.L.S., P.A.M.G.d.S.;\u003cstrong\u003e\u0026nbsp;Writing \u0026ndash; original draft:\u0026nbsp;\u003c/strong\u003eR.d.S.B., J.M.B.M., G.G.B., R.L.S., L.H.d.P., P.A.M.G.d.S.; \u003cstrong\u003eWriting \u0026ndash; review \u0026amp; editing:\u0026nbsp;\u003c/strong\u003eA.C.S.e.S., R.d.S.B., G.G.B.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding:\u0026nbsp;\u003c/strong\u003eThe authors did not receive support from any organization for the submitted work.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgments:\u0026nbsp;\u003c/strong\u003eNone.\u0026nbsp;\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eSuzuki H, Kiryluk K, Novak J, Moldoveanu Z, Herr AB, Renfrow MB, Wyatt RJ, Scolari F, Mestecky J, Gharavi AG, Julian BA (2011) The pathophysiology of IgA nephropathy. 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Front Immunol 11:433. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.3389/fimmu.2020.00433\u003c/span\u003e\u003cspan address=\"10.3389/fimmu.2020.00433\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eOtsuka Pharmaceutical Development (2024) A Phase 3, Multicenter, Randomized, Double-blind, Placebo-controlled Trial to Evaluate the Efficacy and Safety of Sibeprenlimab Administered Subcutaneously in Subjects With Immunoglobulin A Nephropathy. clinicaltrials.gov. Report No.: NCT05248646. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://clinicaltrials.gov/study/NCT052486\u003c/span\u003e\u003cspan address=\"https://clinicaltrials.gov/study/NCT052486\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e. Accessed 14 Nov 2024\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"},{"header":"Table 1","content":"Table 1 is available in the supplemental file section. "}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"IgA Nephropathy, A Proliferation Inducing Ligand Protein, B-Cell Activating Factor, Glomerulonephritis, IGA, Proteinuria","lastPublishedDoi":"10.21203/rs.3.rs-5743662/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-5743662/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground:\u003c/strong\u003e IgA nephropathy (IgAN) is the most common primary glomerular disease worldwide. BAFF (B-cell activating factor) and APRIL (A proliferation-inducing ligand) are cytokines involved in B-cell activation and survival, contributing to the pathogenesis of IgAN. This meta-analysis aimed to evaluate the efficacy, safety, and biomarkers of BAFF and APRIL-targeted therapies in patients with IgAN.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods:\u003c/strong\u003e This review followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) and was registered with PROSPERO (CRD42024598157). We searched PubMed, Scopus, and the Cochrane Library for randomized controlled trials (RCTs) comparing BAFF or APRIL-targeted drugs with placebo in adults with biopsy-confirmed IgAN. The efficacy outcomes were the mean percent change in the urine protein to creatinine ratio (UPCR) at 24 hours and the mean change in the estimated glomerular filtration rate (eGFR) from baseline. Safety included the incidence of adverse events. The biomarkers were changes in serum Gd-IgA1, IgG, IgA, and IgM from baseline. We used the R software version 4.2.1 for statistics.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults:\u003c/strong\u003e Four phase II RCTs including 331 patients were included. Compared to placebo, treatment significantly reduced 24-hour UPCR (mean difference [MD] –38.94%; 95% confidence interval [CI] –58.98 to –18.90; p = 0.0001; I² = 0%) and significantly improved eGFR (MD 7.05 mL/min/1.73 m²; 95% CI 3.83 to 10.27; p\u0026lt;0.0001; I²=0%). The incidence of adverse events did not differ significantly in the treatment and placebo groups. The drug significantly decreased serum Gd-IgA1, IgG, IgA, and IgM compared to placebo.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusions\u003c/strong\u003e BAFF and APRIL-targeted therapies effectively and safely reduce proteinuria in patients with IgAN.\u003c/p\u003e","manuscriptTitle":"Efficacy, safety, and biomarker changes of B-cell activating factor- and A proliferation-inducing ligand-targeted therapies in IgA nephropathy: A systematic review and meta-analysis of randomized controlled trials","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-01-08 15:28:47","doi":"10.21203/rs.3.rs-5743662/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"48241092-9539-4927-8056-d0e19b404d29","owner":[],"postedDate":"January 8th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[{"id":42219481,"name":"Urology \u0026 Nephrology"},{"id":42219482,"name":"Clinical Pharmacology"},{"id":42219483,"name":"Internal Medicine"}],"tags":[],"updatedAt":"2025-01-08T15:28:47+00:00","versionOfRecord":[],"versionCreatedAt":"2025-01-08 15:28:47","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-5743662","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-5743662","identity":"rs-5743662","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}