Biologic therapies for lupus nephritis: a systematic review of efficacy, safety, and cost-effectiveness

Biologic therapies for lupus nephritis: a systematic review of efficacy, safety, and cost-effectiveness | 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 Biologic therapies for lupus nephritis: a systematic review of efficacy, safety, and cost-effectiveness Debargha Basuli, Sasmit Roy, Abhisekh Sinha Ray, Akil Serdar Kavcar, and 2 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7608456/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 Lupus nephritis is a major cause of kidney failure worldwide, disproportionately affecting Black, Hispanic, and Asian populations. Standard regimens with mycophenolate mofetil or cyclophosphamide and glucocorticoids remain suboptimal, with many patients experiencing incomplete responses, relapses, or drug-related toxicity. Recently approved biologic and targeted therapies like belimumab, voclosporin, obinutuzumab, rituximab, have expanded treatment options, but direct comparisons of efficacy, safety, and cost are limited. Methods We conducted a systematic review of phase 2–4 randomized controlled trials enrolling adolescents or adults with biopsy-proven lupus nephritis (ISN/RPS class III–V). Eligible trials compared voclosporin, belimumab, obinutuzumab, or rituximab with placebo or standard-of-care and reported renal and/or safety outcomes with ≥ 6 months follow-up. Data were extracted on complete renal response, adverse events, infections, and mortality. Odds ratios and risk differences were calculated, and pooled estimates generated for agents with more than one trial. Cost-per-responder was estimated using U.S. drug acquisition costs. Results Six trials met inclusion criteria. Voclosporin and belimumab demonstrated consistent efficacy, with complete renal response of 30–41% at ~ 1 year, and were associated with acceptable safety. Obinutuzumab showed favorable efficacy trends in NOBILITY and REGENCY but with variable safety signals. Rituximab did not significantly improve complete renal response in the pivotal LUNAR trial. Pooled analyses indicated modest differences in safety, with belimumab having the most favorable profile. Estimated complete renal response varied widely, from ~$118,500 (rituximab) to >$214,000 (voclosporin), underscoring differences in short-term cost-efficiency. Underrepresentation of high-risk racial groups limited external validity. Conclusions Voclosporin and belimumab are supported by robust evidence and guideline endorsement. Obinutuzumab shows emerging promise but is not yet integrated in guidelines. Rituximab remains widely used off-label but lacks RCT support. This systematic review highlights efficacy, safety, and economic considerations across agents, emphasizing the need for harmonized trial design, inclusive enrollment, and cost-effectiveness analyses to ensure equitable access in LN management. Clinical trial number: not applicable lupus nephritis voclosporin belimumab obinutuzumab rituximab complete renal response Figures Figure 1 Figure 2 Figure 3 Introduction Lupus nephritis (LN) remains a major global health challenge, with the highest burden in African, Asian, and Hispanic populations, who often experience more severe disease and faster progression to end-stage kidney disease (ESKD) despite therapeutic advances( 1 )( 2 ). Standard regimens consisting of cyclophosphamide (CYC) or mycophenolate mofetil (MMF) with glucocorticoids still leave many patients with incomplete responses, relapses, or drug-related toxicity, and 10–20% progress to ESKD within 10 years( 3 )( 4 ). The therapeutic landscape has recently expanded with targeted agents, including belimumab (anti-BAFF monoclonal antibody) and voclosporin (novel calcineurin inhibitor), the first FDA-approved LN therapies in over a decade, and obinutuzumab (type II anti-CD20 antibody) showing promising results in recent trials( 5 )( 6 )( 7 ). Yet, treatment selection remains difficult without direct comparative data, as randomized controlled trials (RCTs) differ in complete renal response (CRR) definitions, populations, and glucocorticoid (GC) regimens. To address this gap, we conducted a systematic comparison of voclosporin, belimumab, obinutuzumab, and rituximab across RCTs, integrating efficacy, safety, and cost-effectiveness. By situating results within evolving guideline recommendations, this review provides a practical framework to guide evidence-based and value-conscious LN management, advancing beyond prior narrative summaries. Methods Protocol and registration This systematic review was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. The review protocol was prospectively registered with PROSPERO (CRD420251051391). Eligibility criteria Eligible studies were phase 2–4 RCTs that: (i) enrolled adolescents or adults (≥ 15 years) with biopsy-proven LN (ISN/RPS class III–V); (ii) evaluated voclosporin, belimumab, obinutuzumab, or rituximab; (iii) included a comparator arm with placebo or standard therapy; (iv) reported renal and/or safety outcomes such as complete renal response (CRR), proteinuria, eGFR, serious infections, or mortality; and (v) had ≥ 6 months of follow-up. Phase 1 studies, non-randomized or observational studies, and subgroup/post hoc analyses were excluded. Information sources and search strategy A systematic search of PubMed and Cochrane CENTRAL was performed from database inception through May 2025. Search terms combined Medical Subject Headings (MeSH) and free-text keywords for “lupus nephritis,” “randomized controlled trial,” “voclosporin,” “belimumab,” “obinutuzumab,” and “rituximab.” Reference lists of included studies and relevant reviews were also screened to identify additional trials. Study selection Two reviewers independently screened titles and abstracts for eligibility. Full-text articles were retrieved for potentially relevant studies, and final inclusion was determined by consensus. Study selection was summarized in a PRISMA-style flowchart (Fig. 1 ). Data extraction and quality assessment Data on study design, eligibility criteria, interventions, background therapy, CRR definitions, follow-up duration, and patient demographics were extracted into a standardized template. Efficacy outcomes included CRR as defined in each trial, evaluated at ~ 48–52 weeks where possible. Safety outcomes included serious adverse events (SAEs), serious infections, and all-cause mortality. Risk of bias was assessed independently by two reviewers using the Cochrane Risk of Bias 2 (RoB 2) tool across five domains (Fig S1 ). Data synthesis and statistical analysis When not reported, odds ratios (ORs) for CRR were calculated using Fisher’s exact test, with 95% confidence intervals (CIs) estimated on the log scale via Woolf’s method. Risk differences (RDs) were calculated for safety outcomes based on trial definitions. For agents with two RCTs (voclosporin, obinutuzumab), pooled estimates were generated using random-effects meta-analysis (DerSimonian–Laird method) with inverse-variance weighting. Heterogeneity was assessed with τ² and I² statistics. All statistical analyses were conducted in R (version 4.3.1) using the meta and metafor packages. Results Six RCTs met inclusion criteria, enrolling patients with biopsy-confirmed class III–V lupus nephritis and evaluating biologic or targeted therapies alongside standard immunosuppression (Table 1 ). Although corticosteroid tapering, follow-up duration (24 to 104 weeks), and CRR definitions varied, all trials assessed CRR as a composite of proteinuria remission, preserved kidney function, and absence of treatment failure. Study populations were generally young (mean age ~ 30s) and predominantly female, consistent with lupus epidemiology. Racial representation varied: BLISS-LN and LUNAR enrolled higher proportions of Black patients (~ 43% and 38%), while AURORA 1 and REGENCY included more racially diverse global cohorts. In contrast, trials like AURA-LV had limited diversity. Underrepresentation of Black and Hispanic patients in some studies limits generalizability, given the higher burden of lupus nephritis in these populations. Efficacy To enable standardized cross-trial comparison, CRR outcomes were evaluated at approximately 1 year. ORs for CRR were extracted from six RCTs assessing voclosporin, belimumab, obinutuzumab, and rituximab (Fig. 2 ). When multiple follow-up durations were available, the closest timepoint to 48–52 weeks was selected to align across studies. The REGENCY trial was the only exception, reporting its primary CRR endpoint at 76 weeks; this distinction is denoted in the figure by a diamond symbol. This approach allowed consistent benchmarking of short-term efficacy across different treatments. Recognizing that treatment response in LN often extends beyond the first year, Table 2 summarizes CRR percentages across all reported timepoints at 24, 48, 52, 76, and 104 weeks capturing both early efficacy and the trajectory of sustained renal response. At approximately 1 year, CRR ranged from 26% in the rituximab arm (LUNAR) to 41% in the voclosporin arm (AURORA-1). Earlier evaluations at 24 weeks reported CRRs between 24% and 35%, while longer-term follow-up showed sustained efficacy, with CRRs reaching 43% in BLISS-LN and 41% in NOBILITY at 104 weeks. The REGENCY trial demonstrated a CRR of 46.4% at 76 weeks. While some trials such as AURA-LV and AURORA-1 reported efficacy at a single timepoint, others—particularly BLISS-LN and NOBILITY—included extended follow-up, enabling assessment of response durability beyond the first year. Safety Figure 3 is a heatmap of RDs for SAEs, serious infections, and all-cause mortality across the four agents. Belimumab had the most favorable profile, with reduced risks of both SAEs (–4.0%) and infections (–1.8%), and only a minimal increase in mortality (+ 0.5%), consistent with its targeted mechanism that avoids profound immunosuppression. Voclosporin showed small increases in SAE (+ 5.1%) and mortality (+ 3.5%) risk in pooled analyses, though not statistically significant. Serious infection risk was minimal (+ 0.8%, I² = 0%). Importantly, in AURA-LV both low- and high-dose voclosporin groups had markedly higher SAE rates (25–28% vs. 16% in placebo), highlighting trial-specific safety concerns not captured in pooled data. Obinutuzumab was associated with a pooled RD of + 5.8% for SAEs and negligible infection risk (+ 0.1%). Mortality appeared lower (–1.0%), but results diverged between NOBILITY and REGENCY. Notably, REGENCY reported more infections and COVID-19 events in the obinutuzumab arm, limiting certainty about its safety profile. Rituximab (LUNAR) showed lower SAE (–8.0%) and infection (–0.5%) rates, but mortality was modestly higher (+ 2.7%). Hematologic toxicities, including neutropenia, leukopenia, and hypotension, were more common compared to placebo. Cost per responder Analysis Comprehensive cost-effectiveness modeling is beyond the scope of this review and varies widely across health systems. Instead, we estimated annual cost per responder (CPR) using U.S. drug acquisition costs and the proportion of patients achieving complete renal response (CRR) at 52 weeks in each trial (Table 4 ). Rituximab and belimumab showed CPRs of ~ $ 118,500 and ~ $ 143,300, respectively, based on annual drug costs of $ 30,000 and $ 43,000. For comparison, MMF and hydroxychloroquine (HCQ) cost only ~ $ 1,000– $ 2,000 and $ 100– $ 400 annually. In contrast, voclosporin and obinutuzumab exceeded $ 214,000 per responder, driven by both higher acquisition costs (e.g., ~ $ 92,000/year for voclosporin) and variable CRR rates across trials. Pricing estimates were derived from the Institute for Clinical and Economic Review (ICER) Lupus Nephritis Report (2021), CMS Medicare Part B Average Sales Price (2024), and U.S. retail pharmacy data (GoodRx, 2025). Discussion Biologic and targeted therapies are reshaping LN management by moving beyond uniform immunosuppression toward tailored, mechanism-based strategies. This review synthesizes efficacy, safety, and cost data from six pivotal RCTs, while highlighting how trial design, patient diversity, and economic context shape real-world applicability. Advances in LN therapy are tangible but uneven. Voclosporin showed rapid efficacy in AURA-LV and AURORA-1 and is now recommended by ACR and KDIGO as a first-line option for proliferative disease ( 3 )( 6 )( 8 )( 9 ). Belimumab improved CRR with extended follow-up (104 weeks) ( 5 ) and is the first biologic specifically approved for LN, endorsed by ACR, KDIGO, and EULAR. Its modest benefit suggests greater utility in less aggressive disease, in combination regimens, or for maintenance. Obinutuzumab, a glycoengineered anti-CD20 antibody, showed delayed but sustained efficacy in NOBILITY and REGENCY, supporting its potential for long-term disease control( 7 )( 10 ). Its FDA breakthrough designation and inclusion in EULAR 2025 congress recommendations reflect growing recognition, though guidelines have yet to adopt it. Rituximab, despite encouraging observational data from RITUXIRESCUE( 11 ) and RITUXILUP( 12 ), failed to improve outcomes in the pivotal LUNAR trial and is reserved by KDIGO for refractory disease( 13 ). These examples illustrate that biologic class effects cannot be assumed and that guideline adoption often lags emerging evidence. Considerations of Trial Demographics and External Validity High-risk groups, particularly Black and Hispanic patients, remain underrepresented in pivotal LN RCTs( 4 ). Small subgroup samples often lack power, so nonsignificant findings cannot be interpreted as absence of effect. In BLISS-LN, only ~ 14% were Black, limiting interpretation of race–treatment interactions( 5 ). EMBRACE suggested possible benefit of belimumab in Black patients despite not meeting its primary endpoint( 14 ), while East Asian subgroup analyses from BLISS-LN indicated improved outcomes( 15 ). The key message is that lack of statistical difference should not be misread as therapeutic equivalence across populations. LN trial outcomes reflect both drug biology and protocol design. NOBILITY suggested benefit in Hispanic and Asian patients, but findings in Black patients were underpowered( 16 ). REGENCY broadened enrollment yet has not reported detailed subgroup data( 7 ). Voclosporin trials enrolled diverse cohorts with generally consistent efficacy, though without formal race interaction testing. LUNAR included ~ 22% Black patients but showed no overall or subgroup benefit, contributing to rituximab’s lack of approval. These examples show that background therapy, steroid taper, and follow-up can shape drug signals, and cross-trial contrasts should be viewed in protocol context rather than attributed solely to race. Pooled CRR should be interpreted as context-dependent rather than universal. Averages obscure heterogeneity that matters in practice, especially for under-represented groups or resource limited settings. In such cases, therapy choice should balance mechanistic plausibility, feasibility of delivery and monitoring, and supportive, if imperfect, evidence from subgroups or real-world cohorts. This acknowledges both the strengths and blind spots of current evidence while still guiding rational therapy selection. Future trials should go beyond KDIGO 2024’s call for inclusivity by explicitly powering subgroup analyses, reporting stratified effect sizes, and harmonizing background therapy and GC-taper protocols to separate drug from protocol effects. Individual-patient-data meta-analyses are essential to move from ‘one-size-fits-most’ toward evidence tailored to highest-risk patients. Without this shift, guideline adoption will lag behind science, leaving clinical decisions vulnerable to gaps in external validity. Comparative Analysis of Adverse Events Safety signals in LN trials vary by background therapy, steroid taper, and follow-up, making direct comparisons difficult. Four themes stand out. (i) Potency often trades off with toxicity: voclosporin and obinutuzumab deliver stronger efficacy but higher adverse event rates, while belimumab offers a safer, modestly effective profile. (ii) Each agent has specific risks—voclosporin with renal and hypertensive toxicity, obinutuzumab with infusion reactions, and both obinutuzumab and rituximab with B-cell–related infections; belimumab remains the safest, though rare psychiatric events have been reported( 17 ). (iii) These patterns guide patient selection: aggressive disease may justify voclosporin, whereas infection-prone or comorbid patients may be better suited to belimumab. (iv) Safety outcomes were reported at varying timepoints and are cumulative rather than time-adjusted, so our synthesis reflects relative burdens rather than standardized incidence rates. Integration of New Therapies into LN Management in Clinical Practice and Recent Guidelines increasingly agree that LN should be treated earlier and more aggressively with mechanism-based combinations to sustain remission and minimize steroid toxicity, though strategies differ (Table 3 ). Table 3 Comparison of Recent Clinical Guidelines on the Use of Targeted Therapies in Proliferative Lupus Nephritis Class III/IV (± V) Treatment Domain ACR 2024 KDIGO 2024 EULAR 2023 Overall Approach Continuous, ongoing “triple therapy” upfront. Triple therapy (GC + MMF + belimumab or CNI) for class III/IV (± V). Class V: MMF or CYC, add belimumab/CNI if suboptimal. HCQ for all. Combined ongoing therapy. Flexible dual/triple therapy for class III/IV (± V). Class V: MMF or CYC, add belimumab/voclosporin if proteinuria persists. HCQ for all. Shifting to combining biologics upfront. Dual therapy (GC + MMF or CYC) with belimumab/CNI for high-risk class III/IV (± V), including class V. HCQ mandatory. Induction Therapy Steroid + MMF + one of the following: • Belimumab • CNI • Euro-Lupus Nephritis Trial (ELNT) low-dose CYC + belimumab Steroid plus any one of the following: • CNI + MMF • MPA • CYC • Belimumab + MMF or reduced dose CYC Steroid plus: • MMF or low-dose CYC • MMF/CNI combo for high risk/nephrotic • Rituximab for nonresponder Maintenance Therapy ≥ 3–5 year; MMF > AZA;; continue belimumab if started ≥ 36 mo; MMF > AZA; belimumab optional. ≥ 3–5 year; MMF or AZA; continue belimumab/CNI. Class V LN Recommendations MMF + CNI if proteinuria ≥ 1 g/day. Consider steroid taper ≤ 5 mg/day by 6 months. Duration 3–5 years. MMF or CYC; belimumab or voclosporin add-on if persistent nephrotic proteinuria. MMF or CYC; CNI or belimumab for nephrotic-range proteinuria. Use of New Agents • Belimumab/voclosporin upfront • Rituximab for refractory. • Class V: Belimumab/CNI add-on. • Belimumab/voclosporin optional • Rituximab for relapse • Obinutuzumab expected • Class V: Belimumab/voclosporin add-on. • Belimumab/CNI for high-risk/nephrotic • Rituximab for refractory • Class V: CNI/belimumab prioritized. Obinutuzumab Inclusion Not included yet Not included Not included Steroid Minimization Strategy Taper to ≤ 5–7.5 mg/day. Taper to ≤ 5 mg/day by 6 mo. Taper to ≤ 5 mg/day by 3–6 mo. Nephroprotection SGLT2i, RAAS blockade for CKD. SGLT2i for proteinuria, CKD. SGLT2i, RAAS for proteinuria (> 0.5–0.7 g/24h), CKD. Table 3 compares ACR 2024, KDIGO 2024, and EULAR 2023 guidelines for LN class III/IV (± V), covering induction, new agents, steroid minimization, maintenance, and nephroprotection. ACR emphasizes triple therapy, KDIGO offers flexible regimens, and EULAR prioritizes dual therapy with HCQ. All recommend HCQ, steroid tapering (≤ 5–7.5 mg/day), and SGLT2 inhibitors. Class V LN uses MMF or CYC with belimumab/CNI add-ons. EULAR 2025 Congress proposed quadruple therapy and obinutuzumab pending publication, guiding evidence-based LN management. The 2024 ACR guidelines recommend upfront triple therapy (GC + MMF + belimumab or a CNI) for class III/IV LN, rejecting the induction-maintenance paradigm( 9 ). KDIGO 2024 favors a modular approach, starting with GC + MMF or CYC and adding belimumab or voclosporin based on response( 3 ). Both endorse adjunctive nephroprotection with SGLT2 inhibitors and RAAS blockade. EULAR/ERA-EDTA 2023 emphasizes patient-centered care, dual induction with early escalation in high-risk cases, and universal HCQ( 18 ). Preliminary EULAR 2025 congress recommendations push the envelope further, proposing quadruple upfront therapy (GC, HCQ, MPA/CYC, plus belimumab or a CNI) and introducing obinutuzumab as an option for refractory LN. The absence of obinutuzumab from current guidelines reflects their pre-REGENCY timeline and illustrates how rapidly evolving trial data can outpace the traditional cadence of policy updates. The conditional status of rituximab, despite widespread use, highlights the limits of assuming class effects within anti-CD20 therapies, as differences in antibody engineering yield divergent clinical outcomes. In sum, guidelines increasingly endorse earlier, multi-agent, biologically informed therapy, but differ in pacing and thresholds, reflecting varying risk tolerance and evidence weighting. For clinicians, the challenge is less about choosing one guideline than reconciling these frameworks with local resources and patient risk profiles. Economic Considerations : Global Relevance and Equity Implications Short-term CPR estimates reveal a stark reality. Targeted LN therapies differ in cost-efficiency by more than 100,000 US dollars per responder (Table 4 ), yet those numbers alone say little about real-world value. A therapy can appear unaffordable in one health system and indispensable in another because procurement rules, pricing negotiations, and reimbursement thresholds shape the way value is judged( 19 ). For example, the UK NHS uses explicit QALY cutoffs, while many low- and middle-income countries depend on centralized procurement or tiered pricing. The same drug may therefore be adopted in one country and rejected in another( 20 ). Formal economic evaluations extend beyond our short-term CPR estimates to capture long-term value. The 2021 Institute for Clinical and Economic Review (ICER) report estimated incremental cost-effectiveness ratios of about 90,000 US dollars per quality-adjusted life year (QALY) and 78,000 US dollars per equal value of life years gained (evLYG) for belimumab( 21 ). For voclosporin the corresponding estimates were 149,000 US dollars per QALY and 132,000 US dollars per evLYG. On average voclosporin appeared less cost-effective than belimumab. However, among Black, Hispanic and Latino patients who bear disproportionate disease burden, voclosporin’s cost-effectiveness improved markedly to about 77,000 US dollars per QALY and 68,000 US dollars per evLYG, well within conventional US willingness-to-pay thresholds. This reframes cost-effectiveness as not only an economic measure but also an equity issue. Therapies may deliver their greatest value in the very populations at highest risk, and coverage decisions based only on pooled averages risk hiding subgroup benefits and widening disparities. Delivery and monitoring requirements further influence value. Oral voclosporin avoids infusion centers but requires close renal and blood pressure monitoring. Subcutaneous belimumab reduces hospital resource use compared with intravenous biologics. For aggressive LN, a therapy with higher upfront cost but rapid and durable remission may offset downstream dialysis or ESKD costs, whereas in milder disease or resource-limited settings, older immunosuppressants or biosimilars may yield acceptable outcomes at lower expense( 22 ). The greatest paradox is that regions with the highest burden of LN, including Asia, Africa and Latin America, face the steepest barriers to accessing these therapies( 23 ). Addressing this will require coordinated global action, including international price negotiations, local biosimilar production, and inclusion of LN therapies in essential medicines lists( 24 ). Without such measures, advances will remain celebrated in guidelines but out of reach for many patients who need them most. Expert Opinion on Patient Selection and Treatment Strategies The key challenge is not whether new agents work, but how best to use them. Each therapy has an optimal clinical context rarely reflected in broad guideline recommendations. Voclosporin is best suited for rapidly progressive, high-burden LN where rapid proteinuria reduction is critical, though it requires close renal and blood pressure monitoring( 25 ). Belimumab offers modest CRR gains with a safer profile, making it useful for maintenance, steroid-sparing, or patients with serologic activity and comorbidities. Obinutuzumab provides deeper, more durable B-cell depletion, suggesting a role in refractory or relapsing disease, in contrast to rituximab, which failed in LUNAR despite class similarity. A unifying message is that accelerated steroid tapering is now achievable, potentially reducing long-term morbidity. Ultimately, therapy choice should match disease trajectory, immunologic profile, and patient risk while accounting for feasibility and cost. Advances will matter only if they can be delivered safely, monitored effectively, and accessed equitably. The next phase of progress will depend on pairing scientific precision with equitable access so that advances translate into real-world benefit. Limitations This review has several limitations. First, it relies on indirect comparisons because no head-to-head RCTs exist, and some drugs have only one pivotal trial, which reduces robustness. In LUNAR, effect estimates had to be manually calculated due to incomplete reporting, which introduced imprecision. Pooled data also suggested a possible mortality benefit with obinutuzumab, but results from NOBILITY and REGENCY were conflicting. Second, the synthesis was constrained by heterogeneity across RCTs. CRR definitions varied, background regimens differed, and safety outcomes were reported cumulatively over 48–104 weeks without adjustment for time at risk, which limited comparability. Finally, a network meta-analysis was not feasible. Future harmonized trials with standardized endpoints, diverse patient populations, and aligned treatment protocols are needed to allow more rigorous comparisons. Conclusion LN therapy is shifting from “one-size-fits-all” immunosuppression toward personalized, combination strategies with agents such as belimumab, voclosporin, and obinutuzumab. Their use will depend on patient risk, immunologic profile, and healthcare access, balancing short-term remission with long-term kidney preservation and quality of life. Key gaps remain, including inconsistent CRR definitions, lack of trial harmonization, underrepresentation of high-risk groups, and limited long-term follow-up. These require head-to-head trials, inclusive enrollment, and durability data. Addressing these through head-to-head trials, inclusive enrollment, and integration of economic evidence will be critical to ensure equitable global access and reduce disparities. Declarations Ethics approval and consent to participate Not applicable. Consent for publication Not applicable. Availability of data and materials Not applicable. No new datasets were generated or analyzed. All information used is from published articles cited in the References. Competing interests The authors declare that they have no competing interests. Funding The authors received no financial support for the research, authorship, or publication of this article. Authors’ contributions DB, SR, and ASR conceptualized the study. ASK, FPG, and CL contributed to data acquisition. DB performed statistical analysis. All authors contributed to data interpretation, drafting, and critical revision of the manuscript. All authors read and approved the final manuscript and agree to be accountable for all aspects of the work. Acknowledgements Not applicable. References Almaani S, Meara A, Rovin BH. Update on Lupus Nephritis. CJASN. 2017;12(5):825–35. Uchida K, Nitta K. Recent advances in the treatment of lupus nephritis. Clin Exp Nephrol. 2012;16(2):202–13. Rovin BH, Ayoub IM, Chan TM, Liu ZH, Mejía-Vilet JM, Floege J. KDIGO 2024 Clinical Practice Guideline for the management of LUPUS NEPHRITIS. Kidney Int. 2024;105(1):S1–69. Tektonidou MG, Dasgupta A, Ward MM. Risk of End-Stage Renal Disease in Patients With Lupus Nephritis, 1971–2015: A Systematic Review and Bayesian Meta‐Analysis. Arthritis Rheumatol. 2016 June;68(6):1432–41. Furie R, Rovin BH, Houssiau F, Malvar A, Teng YKO, Contreras G, et al. Two-Year, Randomized, Controlled Trial of Belimumab in Lupus Nephritis. N Engl J Med. 2020 Sept;17(12):1117–28. Rovin BH, Teng YKO, Ginzler EM, Arriens C, Caster DJ, Romero-Diaz J, et al. Efficacy and safety of voclosporin versus placebo for lupus nephritis (AURORA 1): a double-blind, randomised, multicentre, placebo-controlled, phase 3 trial. Lancet. 2021;397(10289):2070–80. Furie RA, Rovin BH, Garg JP, Santiago MB, Aroca-Martínez G, Zuta Santillán AE, et al. Efficacy and Safety of Obinutuzumab in Active Lupus Nephritis. N Engl J Med. 2025;392(15):1471–83. Rovin BH, Solomons N, Pendergraft WF, Dooley MA, Tumlin J, Romero-Diaz J, et al. A randomized, controlled double-blind study comparing the efficacy and safety of dose-ranging voclosporin with placebo in achieving remission in patients with active lupus nephritis. Kidney Int. 2019;95(1):219–31. Sammaritano LR, Askanase A, Bermas BL, Dall’Era M, Duarte-García A, Hiraki LT et al. 2024 American College of Rheumatology (ACR) Guideline for the Screening, Treatment, and Management of Lupus Nephritis. Arthritis & Rheumatology. 2025;art.43212. Furie RA, Aroca G, Cascino MD, Garg JP, Rovin BH, Alvarez A, et al. B-cell depletion with obinutuzumab for the treatment of proliferative lupus nephritis: a randomised, double-blind, placebo-controlled trial. Ann Rheum Dis. 2022;81(1):100–7. Pepper R, Griffith M, Kirwan C, Levy J, Taube D, Pusey C, et al. Rituximab is an effective treatment for lupus nephritis and allows a reduction in maintenance steroids. Nephrol Dialysis Transplantation. 2009;24(12):3717–23. Condon MB, Ashby D, Pepper RJ, Cook HT, Levy JB, Griffith M, et al. Prospective observational single-centre cohort study to evaluate the effectiveness of treating lupus nephritis with rituximab and mycophenolate mofetil but no oral steroids. Ann Rheum Dis. 2013;72(8):1280–6. Rovin BH, Furie R, Latinis K, Looney RJ, Fervenza FC, Sanchez-Guerrero J, et al. Efficacy and safety of rituximab in patients with active proliferative lupus nephritis: The lupus nephritis assessment with rituximab study. Arthr Rhuem. 2012;64(4):1215–26. Ginzler E, Guedes Barbosa LS, D’Cruz D, Furie R, Maksimowicz-McKinnon K, Oates J, et al. Phase III / IV, Randomized, Fifty‐Two –Week Study of the Efficacy and Safety of Belimumab in Patients of Black African Ancestry With Systemic Lupus Erythematosus. Arthritis Rheumatol. 2022;74(1):112–23. Yu X, Chen N, Xue J, Mok CC, Bae SC, Peng X, et al. Efficacy and Safety of Belimumab in Patients With Lupus Nephritis: Subgroup Analyses of a Phase 3 Randomized Trial in the East Asian Population. Am J Kidney Dis. 2023;81(3):294–e3061. Rovin BH, Furie RA, Ross Terres JA, Giang S, Schindler T, Turchetta A, et al. Kidney Outcomes and Preservation of Kidney Function With Obinutuzumab in Patients With Lupus Nephritis: A Post Hoc Analysis of the NOBILITY Trial. Arthritis Rheumatol. 2024;76(2):247–54. Li H, Xie W, Wang C, Guo C. Postmarketing safety evaluation of belimumab: a pharmacovigilance analysis. Lupus Sci Med. 2025;12(1):e001400. Fanouriakis A, Kostopoulou M, Andersen J, Aringer M, Arnaud L, Bae SC, et al. EULAR recommendations for the management of systemic lupus erythematosus: 2023 update. Ann Rheum Dis. 2024;83(1):15–29. WHO Guideline on Country Pharmaceutical Pricing Policies. 2nd ed. Geneva: World Health Organization; 2020. 1 p. Morgan S, Grootendorst P, Lexchin J, Cunningham C, Greyson D. The cost of drug development: A systematic review. Health Policy. 2011;100(1):4–17. Mandrik O, Thokala P, Fotheringham JICER, Report. Lupus Nephritis 2021. 2021. Thompson JC, Mahajan A, Scott DA, Gairy K. The Economic Burden of Lupus Nephritis: A Systematic Literature Review. Rheumatol Ther. 2022;9(1):25–47. Pons-Estel GJ, Ramírez-Flores MF, Quintana R, Bae SC, Dey D, Pons-Estel BA et al. Addressing the challenge of global delays in diagnosis and treatment of systemic lupus erythematosus. Nat Rev Rheumatol [Internet]. 2025 July 21 [cited 2025 July 25]; Available from: https://www.nature.com/articles/s41584-025-01277-y Mendoza-Pinto C, Etchegaray-Morales I, Ugarte-Gil MF. Improving access to SLE therapies in low and middle-income countries. Rheumatology (Oxford). 2023;62(Suppl 1):i30–5. Menn-Josephy H, Hodge LS, Birardi V, Leher H. Efficacy of Voclosporin in Proliferative Lupus Nephritis with High Levels of Proteinuria. Clin J Am Soc Nephrol. 2024;19(3):309–18. Tables Tables 1 to 4 are available in the Supplementary Files section. Additional Declarations No competing interests reported. Supplementary Files Supplemental.docx Tables.docx Cite Share Download PDF Status: Posted Version 1 posted 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. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. 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-7608456","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":521741861,"identity":"daa27edd-fe06-4edd-9196-c5d3ac3b1893","order_by":0,"name":"Debargha Basuli","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAAx0lEQVRIiWNgGAWjYBACAxDxwICZx/54A1iAsYEoLQkGzDIMZw6QpIWB2YbhRgKRWszZjz+TSCiw5mGc+fjgZx4GG9kNBwhosezJMZNIMEjnYZZOS5bmYUgzJqjF4EAOG1DLYR426RwzZh6Gw4mEtZx//gyshUfy/Deglv9EaLmRYAbWIiHBwwbUcoCwFssZb4wtQH4x4EkzlpxjkGw8k5AWc/70hzc+/LG2N2A//PDDmwo72T5CWtDdSZryUTAKRsEoGAU4AABz1T1u/3kFBQAAAABJRU5ErkJggg==","orcid":"","institution":"East Carolina University Brody School of Medicine, North Carolina","correspondingAuthor":true,"prefix":"","firstName":"Debargha","middleName":"","lastName":"Basuli","suffix":""},{"id":521741862,"identity":"557658bc-e55c-42a6-93dc-c51b334ca0e8","order_by":1,"name":"Sasmit Roy","email":"","orcid":"","institution":"University of Virginia","correspondingAuthor":false,"prefix":"","firstName":"Sasmit","middleName":"","lastName":"Roy","suffix":""},{"id":521741863,"identity":"a095f3a4-b1e6-46a3-aac0-4ef65ddfa864","order_by":2,"name":"Abhisekh Sinha Ray","email":"","orcid":"","institution":"Creighton University School of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Abhisekh","middleName":"Sinha","lastName":"Ray","suffix":""},{"id":521741869,"identity":"04f9d5ea-dcc2-400a-9047-e91c0c87d9f1","order_by":3,"name":"Akil Serdar Kavcar","email":"","orcid":"","institution":"Beth Israel Deaconess Medical Center","correspondingAuthor":false,"prefix":"","firstName":"Akil","middleName":"Serdar","lastName":"Kavcar","suffix":""},{"id":521741870,"identity":"066ae496-f92d-4bf6-bbfc-5d475b525379","order_by":4,"name":"Francesco Philip Giorgino","email":"","orcid":"","institution":"East Carolina University Brody School of Medicine, North Carolina","correspondingAuthor":false,"prefix":"","firstName":"Francesco","middleName":"Philip","lastName":"Giorgino","suffix":""},{"id":521741873,"identity":"a7110c13-fbd0-4e53-a8a2-aaf5512e1909","order_by":5,"name":"Cameron Lawson","email":"","orcid":"","institution":"Duke University","correspondingAuthor":false,"prefix":"","firstName":"Cameron","middleName":"","lastName":"Lawson","suffix":""}],"badges":[],"createdAt":"2025-09-13 16:08:22","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-7608456/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-7608456/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":92478331,"identity":"dbbfc533-c675-4c9a-a325-e311ce9766e0","added_by":"auto","created_at":"2025-09-30 07:30:17","extension":"docx","order_by":0,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":186072,"visible":true,"origin":"","legend":"","description":"","filename":"Figures.docx","url":"https://assets-eu.researchsquare.com/files/rs-7608456/v1/fdbe707023f612f03c7cd68a.docx"},{"id":92476526,"identity":"9e740b73-1f95-47bf-88ca-660a07ad62ee","added_by":"auto","created_at":"2025-09-30 07:22:17","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":84656,"visible":true,"origin":"","legend":"","description":"","filename":"MainText.docx","url":"https://assets-eu.researchsquare.com/files/rs-7608456/v1/bea09f9f4b95f1b10ffaa330.docx"},{"id":92476525,"identity":"c6af2713-59f8-4a47-86ba-b839d074fdd3","added_by":"auto","created_at":"2025-09-30 07:22:17","extension":"json","order_by":2,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":8598,"visible":true,"origin":"","legend":"","description":"","filename":"c9b805d5cbfe4d6da58c647b11721ee1.json","url":"https://assets-eu.researchsquare.com/files/rs-7608456/v1/5d760602eab1494e5e7c3970.json"},{"id":92476536,"identity":"501af9ec-6e69-4dfc-abf6-2a9433b72c55","added_by":"auto","created_at":"2025-09-30 07:22:18","extension":"docx","order_by":3,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":277953,"visible":true,"origin":"","legend":"","description":"","filename":"Supplemental.docx","url":"https://assets-eu.researchsquare.com/files/rs-7608456/v1/20a4cde8b963046605fafbd5.docx"},{"id":92478332,"identity":"81c23178-10c4-41ac-b438-29ca611ec0fd","added_by":"auto","created_at":"2025-09-30 07:30:17","extension":"xml","order_by":4,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":116166,"visible":true,"origin":"","legend":"","description":"","filename":"c9b805d5cbfe4d6da58c647b11721ee11enriched.xml","url":"https://assets-eu.researchsquare.com/files/rs-7608456/v1/682eb682fd00c8120fa77f7d.xml"},{"id":92476533,"identity":"d6972e8c-2f00-4b81-bcdc-e752e1fe0019","added_by":"auto","created_at":"2025-09-30 07:22:18","extension":"jpeg","order_by":7,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":587257,"visible":true,"origin":"","legend":"","description":"","filename":"floatimage1.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-7608456/v1/86a4e6e7c29346eb327960c5.jpeg"},{"id":92476534,"identity":"01d8e0c6-9923-495a-89c6-b0d37f657a12","added_by":"auto","created_at":"2025-09-30 07:22:18","extension":"jpeg","order_by":8,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":1074,"visible":true,"origin":"","legend":"","description":"","filename":"floatimage10.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-7608456/v1/ae7160ad3322222fa4d396ec.jpeg"},{"id":92476530,"identity":"7732ef2e-e788-4386-9d70-40c8eeae4860","added_by":"auto","created_at":"2025-09-30 07:22:18","extension":"jpeg","order_by":9,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":215515,"visible":true,"origin":"","legend":"","description":"","filename":"floatimage11.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-7608456/v1/2df40088cde8fe2d4c71f5f4.jpeg"},{"id":92478346,"identity":"66907c10-56a9-419a-b9a3-0406dbb586dd","added_by":"auto","created_at":"2025-09-30 07:30:18","extension":"jpeg","order_by":10,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":1074,"visible":true,"origin":"","legend":"","description":"","filename":"floatimage10.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-7608456/v1/8cd8c1d406bc0d4ca36090f6.jpeg"},{"id":92478333,"identity":"aea1cd54-71dd-47ee-93f3-cce63faf2d06","added_by":"auto","created_at":"2025-09-30 07:30:18","extension":"jpeg","order_by":11,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":231811,"visible":true,"origin":"","legend":"","description":"","filename":"floatimage13.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-7608456/v1/5f68d6253f06d3fc2c2e97ad.jpeg"},{"id":92478335,"identity":"c342d4da-7964-415a-b251-ca154bc42ca6","added_by":"auto","created_at":"2025-09-30 07:30:18","extension":"jpeg","order_by":12,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":1074,"visible":true,"origin":"","legend":"","description":"","filename":"floatimage10.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-7608456/v1/f6324b3aba1fe92b8dc52b82.jpeg"},{"id":92479361,"identity":"4c8b4223-7602-4d4e-a955-166a20b8d8aa","added_by":"auto","created_at":"2025-09-30 07:38:18","extension":"jpeg","order_by":13,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":1074,"visible":true,"origin":"","legend":"","description":"","filename":"floatimage10.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-7608456/v1/41278d97dffd7729bf91fa89.jpeg"},{"id":92479363,"identity":"342fb062-1af2-47db-b92c-1969ef40f76b","added_by":"auto","created_at":"2025-09-30 07:38:18","extension":"jpeg","order_by":14,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":131630,"visible":true,"origin":"","legend":"","description":"","filename":"floatimage3.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-7608456/v1/c45174dea28199401b72b6c2.jpeg"},{"id":92476541,"identity":"3ac21ea8-0564-4c6a-ac9d-1effdc4b9093","added_by":"auto","created_at":"2025-09-30 07:22:18","extension":"jpeg","order_by":15,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":73526,"visible":true,"origin":"","legend":"","description":"","filename":"floatimage4.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-7608456/v1/dc0dc2bba748e3d191ae083b.jpeg"},{"id":92476546,"identity":"5c9bb412-d0ff-4241-8a7c-a34918c9315f","added_by":"auto","created_at":"2025-09-30 07:22:18","extension":"jpeg","order_by":16,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":22149,"visible":true,"origin":"","legend":"","description":"","filename":"floatimage5.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-7608456/v1/26e9250f0183a206f77e94a4.jpeg"},{"id":92478342,"identity":"604787f5-4cf3-4e08-94c9-e562f01d4335","added_by":"auto","created_at":"2025-09-30 07:30:18","extension":"jpeg","order_by":17,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":22842,"visible":true,"origin":"","legend":"","description":"","filename":"floatimage6.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-7608456/v1/a20b7f1912a759c61d9f4f39.jpeg"},{"id":92478341,"identity":"3a462b22-4a07-4f9f-8f53-463b26bde8b9","added_by":"auto","created_at":"2025-09-30 07:30:18","extension":"jpeg","order_by":18,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":62722,"visible":true,"origin":"","legend":"","description":"","filename":"floatimage7.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-7608456/v1/149c0246a603ac735e09c4fc.jpeg"},{"id":92476553,"identity":"26a3ab21-0026-4daf-96aa-9672614dfd33","added_by":"auto","created_at":"2025-09-30 07:22:18","extension":"jpeg","order_by":19,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":94327,"visible":true,"origin":"","legend":"","description":"","filename":"floatimage8.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-7608456/v1/19c14ac4360b9163ef284bcb.jpeg"},{"id":92476543,"identity":"56ee6db2-1b99-478f-83cb-30852a76283e","added_by":"auto","created_at":"2025-09-30 07:22:18","extension":"jpeg","order_by":20,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":48824,"visible":true,"origin":"","legend":"","description":"","filename":"floatimage9.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-7608456/v1/26b740a800794a315878b97b.jpeg"},{"id":92478343,"identity":"f84683a0-2b0e-4588-89c7-4f3e67af4165","added_by":"auto","created_at":"2025-09-30 07:30:18","extension":"png","order_by":21,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":98878,"visible":true,"origin":"","legend":"","description":"","filename":"Onlinefloatimage1.png","url":"https://assets-eu.researchsquare.com/files/rs-7608456/v1/5f38c04d2ba8a61f867975d0.png"},{"id":92476545,"identity":"236112b8-67bf-4869-a9f8-9b359e3ffe28","added_by":"auto","created_at":"2025-09-30 07:22:18","extension":"png","order_by":22,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":935,"visible":true,"origin":"","legend":"","description":"","filename":"Onlinefloatimage10.png","url":"https://assets-eu.researchsquare.com/files/rs-7608456/v1/94cc85126a6cbdd5fa81e1d1.png"},{"id":92478347,"identity":"d5e0b0b4-ca84-48f9-8d86-aba0ace0e330","added_by":"auto","created_at":"2025-09-30 07:30:19","extension":"png","order_by":23,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":50175,"visible":true,"origin":"","legend":"","description":"","filename":"Onlinefloatimage11.png","url":"https://assets-eu.researchsquare.com/files/rs-7608456/v1/8b007f65a9abd3bf04621796.png"},{"id":92476550,"identity":"77bb502c-25cd-4e81-889f-77728ab7a5a5","added_by":"auto","created_at":"2025-09-30 07:22:18","extension":"png","order_by":24,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":935,"visible":true,"origin":"","legend":"","description":"","filename":"Onlinefloatimage10.png","url":"https://assets-eu.researchsquare.com/files/rs-7608456/v1/a2ac12bbb10e4410aa548245.png"},{"id":92478340,"identity":"de7a229e-03eb-46a7-a522-e57746bf39e2","added_by":"auto","created_at":"2025-09-30 07:30:18","extension":"png","order_by":25,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":44311,"visible":true,"origin":"","legend":"","description":"","filename":"Onlinefloatimage13.png","url":"https://assets-eu.researchsquare.com/files/rs-7608456/v1/a95d13fe2e01c49098caa966.png"},{"id":92476555,"identity":"499b8f9d-6f88-48b3-b447-aa869a16cc37","added_by":"auto","created_at":"2025-09-30 07:22:18","extension":"png","order_by":26,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":935,"visible":true,"origin":"","legend":"","description":"","filename":"Onlinefloatimage10.png","url":"https://assets-eu.researchsquare.com/files/rs-7608456/v1/ebe664c420f7fe1aacc64f86.png"},{"id":92478338,"identity":"b65e5351-e5f1-4bab-9246-49e1c9056bf8","added_by":"auto","created_at":"2025-09-30 07:30:18","extension":"png","order_by":27,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":935,"visible":true,"origin":"","legend":"","description":"","filename":"Onlinefloatimage10.png","url":"https://assets-eu.researchsquare.com/files/rs-7608456/v1/2e083e684510eeb02f2a9d90.png"},{"id":92478337,"identity":"21f6cc5d-5504-4314-8599-5ab39c6d7447","added_by":"auto","created_at":"2025-09-30 07:30:18","extension":"png","order_by":28,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":21439,"visible":true,"origin":"","legend":"","description":"","filename":"Onlinefloatimage3.png","url":"https://assets-eu.researchsquare.com/files/rs-7608456/v1/6826b093816a3139b7e700e3.png"},{"id":92476557,"identity":"4f21ccae-ca9e-40d1-8c8e-2943f77c0390","added_by":"auto","created_at":"2025-09-30 07:22:19","extension":"png","order_by":29,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":12687,"visible":true,"origin":"","legend":"","description":"","filename":"Onlinefloatimage4.png","url":"https://assets-eu.researchsquare.com/files/rs-7608456/v1/d4b4c5e76be42681692f56e9.png"},{"id":92478345,"identity":"9b7a0e04-4132-4766-a391-f28400a43ade","added_by":"auto","created_at":"2025-09-30 07:30:18","extension":"png","order_by":30,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":5151,"visible":true,"origin":"","legend":"","description":"","filename":"Onlinefloatimage5.png","url":"https://assets-eu.researchsquare.com/files/rs-7608456/v1/71368b8147d9fc70999cd06f.png"},{"id":92478344,"identity":"a9f4eea6-6ce7-4f17-9076-f1e2a751b8b8","added_by":"auto","created_at":"2025-09-30 07:30:18","extension":"png","order_by":31,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":4941,"visible":true,"origin":"","legend":"","description":"","filename":"Onlinefloatimage6.png","url":"https://assets-eu.researchsquare.com/files/rs-7608456/v1/62b638dc3b937b0daf4ccb37.png"},{"id":92476539,"identity":"340062d5-fd62-4471-a98e-fd89f4a01676","added_by":"auto","created_at":"2025-09-30 07:22:18","extension":"png","order_by":32,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":13652,"visible":true,"origin":"","legend":"","description":"","filename":"Onlinefloatimage7.png","url":"https://assets-eu.researchsquare.com/files/rs-7608456/v1/7bcfb785b20d568ec46dc008.png"},{"id":92476551,"identity":"de980b36-d283-4828-8030-cfb7bcd4a778","added_by":"auto","created_at":"2025-09-30 07:22:18","extension":"png","order_by":33,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":19551,"visible":true,"origin":"","legend":"","description":"","filename":"Onlinefloatimage8.png","url":"https://assets-eu.researchsquare.com/files/rs-7608456/v1/b62c7dfcdd12346ad583f135.png"},{"id":92476548,"identity":"314b0b98-8426-474d-971b-debe9d7c91c1","added_by":"auto","created_at":"2025-09-30 07:22:18","extension":"png","order_by":34,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":7706,"visible":true,"origin":"","legend":"","description":"","filename":"Onlinefloatimage9.png","url":"https://assets-eu.researchsquare.com/files/rs-7608456/v1/44a3b957c23e49827e7a000a.png"},{"id":92476547,"identity":"b69c5929-f1b6-4d31-8230-de4da6a86d3e","added_by":"auto","created_at":"2025-09-30 07:22:18","extension":"xml","order_by":35,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":109519,"visible":true,"origin":"","legend":"","description":"","filename":"c9b805d5cbfe4d6da58c647b11721ee11structuring.xml","url":"https://assets-eu.researchsquare.com/files/rs-7608456/v1/5fba4f6efa4e5e88f47bd23b.xml"},{"id":92476559,"identity":"5e6a6606-fda7-48a2-8432-2e6dc57c05c3","added_by":"auto","created_at":"2025-09-30 07:22:19","extension":"html","order_by":36,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":125477,"visible":true,"origin":"","legend":"","description":"","filename":"earlyproof.html","url":"https://assets-eu.researchsquare.com/files/rs-7608456/v1/f9cc77b3d25dd656e77d1f86.html"},{"id":92476520,"identity":"533638d4-fc51-4bf1-a3be-301b59a2a05f","added_by":"auto","created_at":"2025-09-30 07:22:17","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":18784,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003ePRISMA Flow diagram of study selections.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eFlowchart depicting the study identification and selection process for the systematic review. Six randomized controlled trials met the inclusion criteria and were included in the final synthesis\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-7608456/v1/bfcdad4bfc6c6238dae429b4.png"},{"id":92476523,"identity":"149fc055-da64-4173-a4b6-99ed07ef9a84","added_by":"auto","created_at":"2025-09-30 07:22:17","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":25705,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eOdds Ratios for Complete Renal Response at approximately 1 year in Randomized Trials of Lupus Nephritis Therapies.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis bubble plot shows ORs and 95% confidence intervals (CIs) for CRR from major randomized controlled trials evaluating voclosporin, belimumab, obinutuzumab, and rituximab. The x-axis is on a logarithmic scale centered at OR = 1.0. Each bubble represents a study, with vertical lines denoting 95% CIs. Bubble size reflects the treatment arm sample size, and colors indicate the intervention: voclosporin (green), belimumab (orange), obinutuzumab (blue), and rituximab (pink). All studies reported CRR at ~1 year (48–52 weeks), except REGENCY, which reported at 76 weeks and is marked with a diamond-shaped bubble.\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-7608456/v1/29d25bd5df7051770cc07d36.png"},{"id":92476524,"identity":"4e282cd3-6c67-4a07-a633-29aa95c2b6e1","added_by":"auto","created_at":"2025-09-30 07:22:17","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":33624,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eRisk differences for safety outcomes by treatment agent.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis heatmap shows absolute risk differences (%) for serious adverse events (SAEs), serious infections, and all-cause mortality across four targeted therapies studied in randomized controlled trials of lupus nephritis. Red indicates increased risk with treatment; green indicates decreased risk, with color intensity reflecting magnitude.\u003cbr\u003e\nFor voclosporin (AURA-LV and AURORA 1) and obinutuzumab (NOBILITY and REGENCY), pooled estimates were derived using a random-effects meta-analysis (DerSimonian-Laird method). Risk differences for belimumab (BLISS-LN) and rituximab (LUNAR) were extracted directly or calculated from single-trial data. Values reflect cumulative events at each study’s final timepoint (48–104 weeks); no time adjustment was applied.\u003cbr\u003e\nNote: SAEs were defined by each trial and typically included life-threatening events or hospitalization. Infections include all reported infectious events. Mortality reflects all-cause deaths reported at final follow-up.\u003c/p\u003e","description":"","filename":"3.png","url":"https://assets-eu.researchsquare.com/files/rs-7608456/v1/7d44892ab1f1d1b25b30d8a3.png"},{"id":102907326,"identity":"745198c7-939d-4521-a94d-f588b9137179","added_by":"auto","created_at":"2026-02-18 09:28:18","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":865018,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7608456/v1/051479d0-ae90-4194-867a-4cb98d2f4df7.pdf"},{"id":92476528,"identity":"a208b75d-cef7-4ede-8b94-417d43d37c03","added_by":"auto","created_at":"2025-09-30 07:22:17","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":277953,"visible":true,"origin":"","legend":"","description":"","filename":"Supplemental.docx","url":"https://assets-eu.researchsquare.com/files/rs-7608456/v1/9b808fa6a23df16f06466fb3.docx"},{"id":92478329,"identity":"fa8846d9-70f4-4b34-b9d4-5c8ff4ad4295","added_by":"auto","created_at":"2025-09-30 07:30:17","extension":"docx","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":33393,"visible":true,"origin":"","legend":"","description":"","filename":"Tables.docx","url":"https://assets-eu.researchsquare.com/files/rs-7608456/v1/59fdf33bcf433a42407ca836.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"\u003cp\u003eBiologic therapies for lupus nephritis: a systematic review of efficacy, safety, and cost-effectiveness\u003c/p\u003e","fulltext":[{"header":"Introduction","content":"\u003cp\u003eLupus nephritis (LN) remains a major global health challenge, with the highest burden in African, Asian, and Hispanic populations, who often experience more severe disease and faster progression to end-stage kidney disease (ESKD) despite therapeutic advances(\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e)(\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e). Standard regimens consisting of cyclophosphamide (CYC) or mycophenolate mofetil (MMF) with glucocorticoids still leave many patients with incomplete responses, relapses, or drug-related toxicity, and 10\u0026ndash;20% progress to ESKD within 10 years(\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e)(\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e).\u003c/p\u003e\u003cp\u003eThe therapeutic landscape has recently expanded with targeted agents, including belimumab (anti-BAFF monoclonal antibody) and voclosporin (novel calcineurin inhibitor), the first FDA-approved LN therapies in over a decade, and obinutuzumab (type II anti-CD20 antibody) showing promising results in recent trials(\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e)(\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e)(\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e). Yet, treatment selection remains difficult without direct comparative data, as randomized controlled trials (RCTs) differ in complete renal response (CRR) definitions, populations, and glucocorticoid (GC) regimens.\u003c/p\u003e\u003cp\u003eTo address this gap, we conducted a systematic comparison of voclosporin, belimumab, obinutuzumab, and rituximab across RCTs, integrating efficacy, safety, and cost-effectiveness. By situating results within evolving guideline recommendations, this review provides a practical framework to guide evidence-based and value-conscious LN management, advancing beyond prior narrative summaries.\u003c/p\u003e"},{"header":"Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e\u003ch2\u003eProtocol and registration\u003c/h2\u003e\u003cp\u003e This systematic review was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. The review protocol was prospectively registered with PROSPERO (CRD420251051391).\u003c/p\u003e\u003c/div\u003e\n\u003ch3\u003eEligibility criteria\u003c/h3\u003e\n\u003cp\u003eEligible studies were phase 2\u0026ndash;4 RCTs that: (i) enrolled adolescents or adults (\u0026ge;\u0026thinsp;15 years) with biopsy-proven LN (ISN/RPS class III\u0026ndash;V); (ii) evaluated voclosporin, belimumab, obinutuzumab, or rituximab; (iii) included a comparator arm with placebo or standard therapy; (iv) reported renal and/or safety outcomes such as complete renal response (CRR), proteinuria, eGFR, serious infections, or mortality; and (v) had\u0026thinsp;\u0026ge;\u0026thinsp;6 months of follow-up. Phase 1 studies, non-randomized or observational studies, and subgroup/post hoc analyses were excluded.\u003c/p\u003e\n\u003ch3\u003eInformation sources and search strategy\u003c/h3\u003e\n\u003cp\u003eA systematic search of PubMed and Cochrane CENTRAL was performed from database inception through May 2025. Search terms combined Medical Subject Headings (MeSH) and free-text keywords for \u0026ldquo;lupus nephritis,\u0026rdquo; \u0026ldquo;randomized controlled trial,\u0026rdquo; \u0026ldquo;voclosporin,\u0026rdquo; \u0026ldquo;belimumab,\u0026rdquo; \u0026ldquo;obinutuzumab,\u0026rdquo; and \u0026ldquo;rituximab.\u0026rdquo; Reference lists of included studies and relevant reviews were also screened to identify additional trials.\u003c/p\u003e\n\u003ch3\u003eStudy selection\u003c/h3\u003e\n\u003cp\u003eTwo reviewers independently screened titles and abstracts for eligibility. Full-text articles were retrieved for potentially relevant studies, and final inclusion was determined by consensus. Study selection was summarized in a PRISMA-style flowchart (Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e\n\u003ch3\u003eData extraction and quality assessment\u003c/h3\u003e\n\u003cp\u003eData on study design, eligibility criteria, interventions, background therapy, CRR definitions, follow-up duration, and patient demographics were extracted into a standardized template. Efficacy outcomes included CRR as defined in each trial, evaluated at ~\u0026thinsp;48\u0026ndash;52 weeks where possible. Safety outcomes included serious adverse events (SAEs), serious infections, and all-cause mortality.\u003c/p\u003e\u003cp\u003eRisk of bias was assessed independently by two reviewers using the Cochrane Risk of Bias 2 (RoB 2) tool across five domains (Fig \u003cspan refid=\"MOESM1\" class=\"InternalRef\"\u003eS1\u003c/span\u003e).\u003c/p\u003e\u003cdiv id=\"Sec8\" class=\"Section2\"\u003e\u003ch2\u003eData synthesis and statistical analysis\u003c/h2\u003e\u003cp\u003eWhen not reported, odds ratios (ORs) for CRR were calculated using Fisher\u0026rsquo;s exact test, with 95% confidence intervals (CIs) estimated on the log scale via Woolf\u0026rsquo;s method. Risk differences (RDs) were calculated for safety outcomes based on trial definitions. For agents with two RCTs (voclosporin, obinutuzumab), pooled estimates were generated using random-effects meta-analysis (DerSimonian\u0026ndash;Laird method) with inverse-variance weighting. Heterogeneity was assessed with τ\u0026sup2; and I\u0026sup2; statistics. All statistical analyses were conducted in R (version 4.3.1) using the meta and metafor packages.\u003c/p\u003e\u003c/div\u003e"},{"header":"Results","content":"\u003cp\u003eSix RCTs met inclusion criteria, enrolling patients with biopsy-confirmed class III\u0026ndash;V lupus nephritis and evaluating biologic or targeted therapies alongside standard immunosuppression (Table \u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e). Although corticosteroid tapering, follow-up duration (24 to 104 weeks), and CRR definitions varied, all trials assessed CRR as a composite of proteinuria remission, preserved kidney function, and absence of treatment failure. Study populations were generally young (mean age\u0026thinsp;~\u0026thinsp;30s) and predominantly female, consistent with lupus epidemiology. Racial representation varied: BLISS-LN and LUNAR enrolled higher proportions of Black patients (~\u0026thinsp;43% and 38%), while AURORA 1 and REGENCY included more racially diverse global cohorts. In contrast, trials like AURA-LV had limited diversity. Underrepresentation of Black and Hispanic patients in some studies limits generalizability, given the higher burden of lupus nephritis in these populations.\u003c/p\u003e\n\u003ch3\u003eEfficacy\u003c/h3\u003e\n\u003cp\u003eTo enable standardized cross-trial comparison, CRR outcomes were evaluated at approximately 1 year. ORs for CRR were extracted from six RCTs assessing voclosporin, belimumab, obinutuzumab, and rituximab (Fig. \u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e). When multiple follow-up durations were available, the closest timepoint to 48\u0026ndash;52 weeks was selected to align across studies. The REGENCY trial was the only exception, reporting its primary CRR endpoint at 76 weeks; this distinction is denoted in the figure by a diamond symbol. This approach allowed consistent benchmarking of short-term efficacy across different treatments.\u003c/p\u003e\n\u003cp\u003eRecognizing that treatment response in LN often extends beyond the first year, Table \u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e summarizes CRR percentages across all reported timepoints at 24, 48, 52, 76, and 104 weeks capturing both early efficacy and the trajectory of sustained renal response. At approximately 1 year, CRR ranged from 26% in the rituximab arm (LUNAR) to 41% in the voclosporin arm (AURORA-1). Earlier evaluations at 24 weeks reported CRRs between 24% and 35%, while longer-term follow-up showed sustained efficacy, with CRRs reaching 43% in BLISS-LN and 41% in NOBILITY at 104 weeks. The REGENCY trial demonstrated a CRR of 46.4% at 76 weeks. While some trials such as AURA-LV and AURORA-1 reported efficacy at a single timepoint, others\u0026mdash;particularly BLISS-LN and NOBILITY\u0026mdash;included extended follow-up, enabling assessment of response durability beyond the first year.\u003c/p\u003e\n\u003cdiv id=\"Sec11\" class=\"Section2\"\u003e\n \u003ch2\u003eSafety\u003c/h2\u003e\n \u003cp\u003eFigure \u003cspan class=\"InternalRef\"\u003e3\u003c/span\u003e is a heatmap of RDs for SAEs, serious infections, and all-cause mortality across the four agents.\u003c/p\u003e\n \u003cp\u003eBelimumab had the most favorable profile, with reduced risks of both SAEs (\u0026ndash;4.0%) and infections (\u0026ndash;1.8%), and only a minimal increase in mortality (+\u0026thinsp;0.5%), consistent with its targeted mechanism that avoids profound immunosuppression.\u003c/p\u003e\n \u003cp\u003eVoclosporin showed small increases in SAE (+\u0026thinsp;5.1%) and mortality (+\u0026thinsp;3.5%) risk in pooled analyses, though not statistically significant. Serious infection risk was minimal (+\u0026thinsp;0.8%, I\u0026sup2; = 0%). Importantly, in AURA-LV both low- and high-dose voclosporin groups had markedly higher SAE rates (25\u0026ndash;28% vs. 16% in placebo), highlighting trial-specific safety concerns not captured in pooled data.\u003c/p\u003e\n \u003cp\u003eObinutuzumab was associated with a pooled RD of +\u0026thinsp;5.8% for SAEs and negligible infection risk (+\u0026thinsp;0.1%). Mortality appeared lower (\u0026ndash;1.0%), but results diverged between NOBILITY and REGENCY. Notably, REGENCY reported more infections and COVID-19 events in the obinutuzumab arm, limiting certainty about its safety profile.\u003c/p\u003e\n \u003cp\u003eRituximab (LUNAR) showed lower SAE (\u0026ndash;8.0%) and infection (\u0026ndash;0.5%) rates, but mortality was modestly higher (+\u0026thinsp;2.7%). Hematologic toxicities, including neutropenia, leukopenia, and hypotension, were more common compared to placebo.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec12\" class=\"Section2\"\u003e\n \u003ch2\u003eCost per responder Analysis\u003c/h2\u003e\n \u003cp\u003eComprehensive cost-effectiveness modeling is beyond the scope of this review and varies widely across health systems. Instead, we estimated annual cost per responder (CPR) using U.S. drug acquisition costs and the proportion of patients achieving complete renal response (CRR) at 52 weeks in each trial (Table \u003cspan class=\"InternalRef\"\u003e4\u003c/span\u003e).\u003c/p\u003e\n \u003cp\u003eRituximab and belimumab showed CPRs of ~\u003cspan\u003e$\u003c/span\u003e118,500 and ~\u003cspan\u003e$\u003c/span\u003e143,300, respectively, based on annual drug costs of \u003cspan\u003e$\u003c/span\u003e30,000 and \u003cspan\u003e$\u003c/span\u003e43,000. For comparison, MMF and hydroxychloroquine (HCQ) cost only ~\u003cspan\u003e$\u003c/span\u003e1,000\u0026ndash;\u003cspan\u003e$\u003c/span\u003e2,000 and \u003cspan\u003e$\u003c/span\u003e100\u0026ndash;\u003cspan\u003e$\u003c/span\u003e400 annually. In contrast, voclosporin and obinutuzumab exceeded \u003cspan\u003e$\u003c/span\u003e214,000 per responder, driven by both higher acquisition costs (e.g., ~\u003cspan\u003e$\u003c/span\u003e92,000/year for voclosporin) and variable CRR rates across trials.\u003c/p\u003e\n \u003cp\u003ePricing estimates were derived from the Institute for Clinical and Economic Review (ICER) Lupus Nephritis Report (2021), CMS Medicare Part B Average Sales Price (2024), and U.S. retail pharmacy data (GoodRx, 2025).\u003c/p\u003e\n\u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eBiologic and targeted therapies are reshaping LN management by moving beyond uniform immunosuppression toward tailored, mechanism-based strategies. This review synthesizes efficacy, safety, and cost data from six pivotal RCTs, while highlighting how trial design, patient diversity, and economic context shape real-world applicability.\u003c/p\u003e\u003cp\u003eAdvances in LN therapy are tangible but uneven. Voclosporin showed rapid efficacy in AURA-LV and AURORA-1 and is now recommended by ACR and KDIGO as a first-line option for proliferative disease (\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e)(\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e)(\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e)(\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e). Belimumab improved CRR with extended follow-up (104 weeks) (\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e) and is the first biologic specifically approved for LN, endorsed by ACR, KDIGO, and EULAR. Its modest benefit suggests greater utility in less aggressive disease, in combination regimens, or for maintenance.\u003c/p\u003e\u003cp\u003eObinutuzumab, a glycoengineered anti-CD20 antibody, showed delayed but sustained efficacy in NOBILITY and REGENCY, supporting its potential for long-term disease control(\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e)(\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e). Its FDA breakthrough designation and inclusion in EULAR 2025 congress recommendations reflect growing recognition, though guidelines have yet to adopt it. Rituximab, despite encouraging observational data from RITUXIRESCUE(\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e) and RITUXILUP(\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e), failed to improve outcomes in the pivotal LUNAR trial and is reserved by KDIGO for refractory disease(\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e). These examples illustrate that biologic class effects cannot be assumed and that guideline adoption often lags emerging evidence.\u003c/p\u003e\u003cdiv id=\"Sec14\" class=\"Section2\"\u003e\u003ch2\u003eConsiderations of Trial Demographics and External Validity\u003c/h2\u003e\u003cp\u003eHigh-risk groups, particularly Black and Hispanic patients, remain underrepresented in pivotal LN RCTs(\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e). Small subgroup samples often lack power, so nonsignificant findings cannot be interpreted as absence of effect. In BLISS-LN, only\u0026thinsp;~\u0026thinsp;14% were Black, limiting interpretation of race\u0026ndash;treatment interactions(\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e). EMBRACE suggested possible benefit of belimumab in Black patients despite not meeting its primary endpoint(\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e), while East Asian subgroup analyses from BLISS-LN indicated improved outcomes(\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e). The key message is that lack of statistical difference should not be misread as therapeutic equivalence across populations.\u003c/p\u003e\u003cp\u003eLN trial outcomes reflect both drug biology and protocol design. NOBILITY suggested benefit in Hispanic and Asian patients, but findings in Black patients were underpowered(\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e). REGENCY broadened enrollment yet has not reported detailed subgroup data(\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e). Voclosporin trials enrolled diverse cohorts with generally consistent efficacy, though without formal race interaction testing. LUNAR included\u0026thinsp;~\u0026thinsp;22% Black patients but showed no overall or subgroup benefit, contributing to rituximab\u0026rsquo;s lack of approval. These examples show that background therapy, steroid taper, and follow-up can shape drug signals, and cross-trial contrasts should be viewed in protocol context rather than attributed solely to race.\u003c/p\u003e\u003cp\u003ePooled CRR should be interpreted as context-dependent rather than universal. Averages obscure heterogeneity that matters in practice, especially for under-represented groups or resource limited settings. In such cases, therapy choice should balance mechanistic plausibility, feasibility of delivery and monitoring, and supportive, if imperfect, evidence from subgroups or real-world cohorts. This acknowledges both the strengths and blind spots of current evidence while still guiding rational therapy selection.\u003c/p\u003e\u003cp\u003eFuture trials should go beyond KDIGO 2024\u0026rsquo;s call for inclusivity by explicitly powering subgroup analyses, reporting stratified effect sizes, and harmonizing background therapy and GC-taper protocols to separate drug from protocol effects. Individual-patient-data meta-analyses are essential to move from \u0026lsquo;one-size-fits-most\u0026rsquo; toward evidence tailored to highest-risk patients. Without this shift, guideline adoption will lag behind science, leaving clinical decisions vulnerable to gaps in external validity.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec15\" class=\"Section2\"\u003e\u003ch2\u003eComparative Analysis of Adverse Events\u003c/h2\u003e\u003cp\u003eSafety signals in LN trials vary by background therapy, steroid taper, and follow-up, making direct comparisons difficult. Four themes stand out. (i) Potency often trades off with toxicity: voclosporin and obinutuzumab deliver stronger efficacy but higher adverse event rates, while belimumab offers a safer, modestly effective profile. (ii) Each agent has specific risks\u0026mdash;voclosporin with renal and hypertensive toxicity, obinutuzumab with infusion reactions, and both obinutuzumab and rituximab with B-cell\u0026ndash;related infections; belimumab remains the safest, though rare psychiatric events have been reported(\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e). (iii) These patterns guide patient selection: aggressive disease may justify voclosporin, whereas infection-prone or comorbid patients may be better suited to belimumab. (iv) Safety outcomes were reported at varying timepoints and are cumulative rather than time-adjusted, so our synthesis reflects relative burdens rather than standardized incidence rates.\u003c/p\u003e\u003cp\u003e\u003cb\u003eIntegration of New Therapies into LN Management in Clinical Practice and Recent\u003c/b\u003e Guidelines increasingly agree that LN should be treated earlier and more aggressively with mechanism-based combinations to sustain remission and minimize steroid toxicity, though strategies differ (Table\u0026nbsp;\u003cspan refid=\"Tab5\" class=\"InternalRef\"\u003e3\u003c/span\u003e).\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 3\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eComparison of Recent Clinical Guidelines on the Use of Targeted Therapies in Proliferative Lupus Nephritis Class III/IV (\u0026plusmn;\u0026thinsp;V)\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"4\"\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\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003eTreatment Domain\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eACR 2024\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003eKDIGO 2024\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003eEULAR 2023\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eOverall Approach\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eContinuous, ongoing \u0026ldquo;triple therapy\u0026rdquo; upfront.\u003c/p\u003e\u003cp\u003eTriple therapy (GC\u0026thinsp;+\u0026thinsp;MMF\u0026thinsp;+\u0026thinsp;belimumab or CNI) for class III/IV (\u0026plusmn;\u0026thinsp;V). Class V: MMF or CYC, add belimumab/CNI if suboptimal. HCQ for all.\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eCombined ongoing therapy.\u003c/p\u003e\u003cp\u003eFlexible dual/triple therapy for class III/IV (\u0026plusmn;\u0026thinsp;V). Class V: MMF or CYC, add belimumab/voclosporin if proteinuria persists. HCQ for all.\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eShifting to combining biologics upfront.\u003c/p\u003e\u003cp\u003eDual therapy (GC\u0026thinsp;+\u0026thinsp;MMF or CYC) with belimumab/CNI for high-risk class III/IV (\u0026plusmn;\u0026thinsp;V), including class V. HCQ mandatory.\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eInduction Therapy\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eSteroid\u0026thinsp;+\u0026thinsp;MMF\u0026thinsp;+\u0026thinsp;one of the following:\u003c/p\u003e\u003cp\u003e\u0026bull; Belimumab\u003c/p\u003e\u003cp\u003e\u0026bull; CNI\u003c/p\u003e\u003cp\u003e\u0026bull; Euro-Lupus Nephritis Trial (ELNT) low-dose CYC\u0026thinsp;+\u0026thinsp;belimumab\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eSteroid plus any one of the following:\u003c/p\u003e\u003cp\u003e\u0026bull; CNI\u0026thinsp;+\u0026thinsp;MMF\u003c/p\u003e\u003cp\u003e\u0026bull; MPA\u003c/p\u003e\u003cp\u003e\u0026bull; CYC\u003c/p\u003e\u003cp\u003e\u0026bull; Belimumab\u0026thinsp;+\u0026thinsp;MMF or reduced dose CYC\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eSteroid plus:\u003c/p\u003e\u003cp\u003e\u0026bull; MMF or low-dose CYC\u003c/p\u003e\u003cp\u003e\u0026bull; MMF/CNI combo for high risk/nephrotic\u003c/p\u003e\u003cp\u003e\u0026bull; Rituximab for nonresponder\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eMaintenance Therapy\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e\u0026ge;\u0026thinsp;3\u0026ndash;5\u0026nbsp;year; MMF\u0026thinsp;\u0026gt;\u0026thinsp;AZA;; continue belimumab if started\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e\u0026ge;\u0026thinsp;36 mo; MMF\u0026thinsp;\u0026gt;\u0026thinsp;AZA; belimumab optional.\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e\u0026ge;\u0026thinsp;3\u0026ndash;5\u0026nbsp;year; MMF or AZA; continue belimumab/CNI.\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eClass V LN Recommendations\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eMMF\u0026thinsp;+\u0026thinsp;CNI if proteinuria\u0026thinsp;\u0026ge;\u0026thinsp;1 g/day. Consider steroid taper\u0026thinsp;\u0026le;\u0026thinsp;5 mg/day by 6 months. Duration 3\u0026ndash;5 years.\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eMMF or CYC; belimumab or voclosporin add-on if persistent nephrotic proteinuria.\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eMMF or CYC; CNI or belimumab for nephrotic-range proteinuria.\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eUse of New Agents\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e\u0026bull; Belimumab/voclosporin upfront\u003c/p\u003e\u003cp\u003e\u0026bull; Rituximab for refractory.\u003c/p\u003e\u003cp\u003e\u0026bull; Class V: Belimumab/CNI add-on.\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e\u0026bull; Belimumab/voclosporin optional\u003c/p\u003e\u003cp\u003e\u0026bull; Rituximab for relapse\u003c/p\u003e\u003cp\u003e\u0026bull; Obinutuzumab expected\u003c/p\u003e\u003cp\u003e\u0026bull; Class V: Belimumab/voclosporin add-on.\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e\u0026bull; Belimumab/CNI for high-risk/nephrotic\u003c/p\u003e\u003cp\u003e\u0026bull; Rituximab for refractory\u003c/p\u003e\u003cp\u003e\u0026bull; Class V: CNI/belimumab prioritized.\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eObinutuzumab Inclusion\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eNot included yet\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eNot included\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eNot included\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eSteroid Minimization Strategy\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eTaper to \u0026le;\u0026thinsp;5\u0026ndash;7.5 mg/day.\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eTaper to \u0026le;\u0026thinsp;5 mg/day by 6 mo.\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eTaper to \u0026le;\u0026thinsp;5 mg/day by 3\u0026ndash;6 mo.\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eNephroprotection\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eSGLT2i, RAAS blockade for CKD.\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eSGLT2i for proteinuria, CKD.\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eSGLT2i, RAAS for proteinuria (\u0026gt;\u0026thinsp;0.5\u0026ndash;0.7 g/24h), CKD.\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\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab5\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003ecompares ACR 2024, KDIGO 2024, and EULAR 2023 guidelines for LN class III/IV (\u0026plusmn;\u0026thinsp;V), covering induction, new agents, steroid minimization, maintenance, and nephroprotection. ACR emphasizes triple therapy, KDIGO offers flexible regimens, and EULAR prioritizes dual therapy with HCQ. All recommend HCQ, steroid tapering (\u0026le;\u0026thinsp;5\u0026ndash;7.5 mg/day), and SGLT2 inhibitors. Class V LN uses MMF or CYC with belimumab/CNI add-ons. EULAR 2025 Congress proposed quadruple therapy and obinutuzumab pending publication, guiding evidence-based LN management.\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003eThe 2024 ACR guidelines recommend upfront triple therapy (GC\u0026thinsp;+\u0026thinsp;MMF\u0026thinsp;+\u0026thinsp;belimumab or a CNI) for class III/IV LN, rejecting the induction-maintenance paradigm(\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e). KDIGO 2024 favors a modular approach, starting with GC\u0026thinsp;+\u0026thinsp;MMF or CYC and adding belimumab or voclosporin based on response(\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e). Both endorse adjunctive nephroprotection with SGLT2 inhibitors and RAAS blockade. EULAR/ERA-EDTA 2023 emphasizes patient-centered care, dual induction with early escalation in high-risk cases, and universal HCQ(\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e). Preliminary EULAR 2025 congress recommendations push the envelope further, proposing quadruple upfront therapy (GC, HCQ, MPA/CYC, plus belimumab or a CNI) and introducing obinutuzumab as an option for refractory LN.\u003c/p\u003e\u003cp\u003e The absence of obinutuzumab from current guidelines reflects their pre-REGENCY timeline and illustrates how rapidly evolving trial data can outpace the traditional cadence of policy updates. The conditional status of rituximab, despite widespread use, highlights the limits of assuming class effects within anti-CD20 therapies, as differences in antibody engineering yield divergent clinical outcomes. In sum, guidelines increasingly endorse earlier, multi-agent, biologically informed therapy, but differ in pacing and thresholds, reflecting varying risk tolerance and evidence weighting. For clinicians, the challenge is less about choosing one guideline than reconciling these frameworks with local resources and patient risk profiles.\u003c/p\u003e\u003cp\u003e\u003cb\u003eEconomic Considerations\u003c/b\u003e: \u003cb\u003eGlobal Relevance and Equity Implications\u003c/b\u003e\u003c/p\u003e\u003cp\u003eShort-term CPR estimates reveal a stark reality. Targeted LN therapies differ in cost-efficiency by more than 100,000 US dollars per responder (Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e4\u003c/span\u003e), yet those numbers alone say little about real-world value. A therapy can appear unaffordable in one health system and indispensable in another because procurement rules, pricing negotiations, and reimbursement thresholds shape the way value is judged(\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e). For example, the UK NHS uses explicit QALY cutoffs, while many low- and middle-income countries depend on centralized procurement or tiered pricing. The same drug may therefore be adopted in one country and rejected in another(\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e).\u003c/p\u003e\u003cp\u003eFormal economic evaluations extend beyond our short-term CPR estimates to capture long-term value. The 2021 Institute for Clinical and Economic Review (ICER) report estimated incremental cost-effectiveness ratios of about 90,000 US dollars per quality-adjusted life year (QALY) and 78,000 US dollars per equal value of life years gained (evLYG) for belimumab(\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e). For voclosporin the corresponding estimates were 149,000 US dollars per QALY and 132,000 US dollars per evLYG. On average voclosporin appeared less cost-effective than belimumab. However, among Black, Hispanic and Latino patients who bear disproportionate disease burden, voclosporin\u0026rsquo;s cost-effectiveness improved markedly to about 77,000 US dollars per QALY and 68,000 US dollars per evLYG, well within conventional US willingness-to-pay thresholds. This reframes cost-effectiveness as not only an economic measure but also an equity issue. Therapies may deliver their greatest value in the very populations at highest risk, and coverage decisions based only on pooled averages risk hiding subgroup benefits and widening disparities.\u003c/p\u003e\u003cp\u003eDelivery and monitoring requirements further influence value. Oral voclosporin avoids infusion centers but requires close renal and blood pressure monitoring. Subcutaneous belimumab reduces hospital resource use compared with intravenous biologics. For aggressive LN, a therapy with higher upfront cost but rapid and durable remission may offset downstream dialysis or ESKD costs, whereas in milder disease or resource-limited settings, older immunosuppressants or biosimilars may yield acceptable outcomes at lower expense(\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e).\u003c/p\u003e\u003cp\u003eThe greatest paradox is that regions with the highest burden of LN, including Asia, Africa and Latin America, face the steepest barriers to accessing these therapies(\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e). Addressing this will require coordinated global action, including international price negotiations, local biosimilar production, and inclusion of LN therapies in essential medicines lists(\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e). Without such measures, advances will remain celebrated in guidelines but out of reach for many patients who need them most.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec16\" class=\"Section2\"\u003e\u003ch2\u003eExpert Opinion on Patient Selection and Treatment Strategies\u003c/h2\u003e\u003cp\u003eThe key challenge is not whether new agents work, but how best to use them. Each therapy has an optimal clinical context rarely reflected in broad guideline recommendations. Voclosporin is best suited for rapidly progressive, high-burden LN where rapid proteinuria reduction is critical, though it requires close renal and blood pressure monitoring(\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e). Belimumab offers modest CRR gains with a safer profile, making it useful for maintenance, steroid-sparing, or patients with serologic activity and comorbidities. Obinutuzumab provides deeper, more durable B-cell depletion, suggesting a role in refractory or relapsing disease, in contrast to rituximab, which failed in LUNAR despite class similarity. A unifying message is that accelerated steroid tapering is now achievable, potentially reducing long-term morbidity. Ultimately, therapy choice should match disease trajectory, immunologic profile, and patient risk while accounting for feasibility and cost. Advances will matter only if they can be delivered safely, monitored effectively, and accessed equitably. The next phase of progress will depend on pairing scientific precision with equitable access so that advances translate into real-world benefit.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec17\" class=\"Section2\"\u003e\u003ch2\u003eLimitations\u003c/h2\u003e\u003cp\u003eThis review has several limitations. First, it relies on indirect comparisons because no head-to-head RCTs exist, and some drugs have only one pivotal trial, which reduces robustness. In LUNAR, effect estimates had to be manually calculated due to incomplete reporting, which introduced imprecision. Pooled data also suggested a possible mortality benefit with obinutuzumab, but results from NOBILITY and REGENCY were conflicting. Second, the synthesis was constrained by heterogeneity across RCTs. CRR definitions varied, background regimens differed, and safety outcomes were reported cumulatively over 48\u0026ndash;104 weeks without adjustment for time at risk, which limited comparability. Finally, a network meta-analysis was not feasible. Future harmonized trials with standardized endpoints, diverse patient populations, and aligned treatment protocols are needed to allow more rigorous comparisons.\u003c/p\u003e\u003c/div\u003e"},{"header":"Conclusion","content":"\u003cp\u003eLN therapy is shifting from \u0026ldquo;one-size-fits-all\u0026rdquo; immunosuppression toward personalized, combination strategies with agents such as belimumab, voclosporin, and obinutuzumab. Their use will depend on patient risk, immunologic profile, and healthcare access, balancing short-term remission with long-term kidney preservation and quality of life. Key gaps remain, including inconsistent CRR definitions, lack of trial harmonization, underrepresentation of high-risk groups, and limited long-term follow-up. These require head-to-head trials, inclusive enrollment, and durability data. Addressing these through head-to-head trials, inclusive enrollment, and integration of economic evidence will be critical to ensure equitable global access and reduce disparities.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003eEthics approval and consent to participate\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003eConsent for publication\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003eAvailability of data and materials\u003c/p\u003e\n\u003cp\u003eNot applicable. No new datasets were generated or analyzed. All information used is from published articles cited in the References.\u003c/p\u003e\n\u003cp\u003eCompeting interests\u003c/p\u003e\n\u003cp\u003eThe authors declare that they have no competing interests.\u003c/p\u003e\n\u003cp\u003eFunding\u003c/p\u003e\n\u003cp\u003eThe authors received no financial support for the research, authorship, or publication of this article.\u003c/p\u003e\n\u003cp\u003eAuthors\u0026rsquo; contributions\u003c/p\u003e\n\u003cp\u003eDB, SR, and ASR conceptualized the study. ASK, FPG, and CL contributed to data acquisition. DB performed statistical analysis. All authors contributed to data interpretation, drafting, and critical revision of the manuscript. All authors read and approved the final manuscript and agree to be accountable for all aspects of the work.\u003c/p\u003e\n\u003cp\u003eAcknowledgements\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eAlmaani S, Meara A, Rovin BH. Update on Lupus Nephritis. CJASN. 2017;12(5):825\u0026ndash;35.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eUchida K, Nitta K. Recent advances in the treatment of lupus nephritis. Clin Exp Nephrol. 2012;16(2):202\u0026ndash;13.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eRovin BH, Ayoub IM, Chan TM, Liu ZH, Mej\u0026iacute;a-Vilet JM, Floege J. KDIGO 2024 Clinical Practice Guideline for the management of LUPUS NEPHRITIS. Kidney Int. 2024;105(1):S1\u0026ndash;69.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eTektonidou MG, Dasgupta A, Ward MM. Risk of End-Stage Renal Disease in Patients With Lupus Nephritis, 1971\u0026ndash;2015: A Systematic Review and Bayesian Meta‐Analysis. Arthritis Rheumatol. 2016 June;68(6):1432\u0026ndash;41.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eFurie R, Rovin BH, Houssiau F, Malvar A, Teng YKO, Contreras G, et al. Two-Year, Randomized, Controlled Trial of Belimumab in Lupus Nephritis. N Engl J Med. 2020 Sept;17(12):1117\u0026ndash;28.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eRovin BH, Teng YKO, Ginzler EM, Arriens C, Caster DJ, Romero-Diaz J, et al. Efficacy and safety of voclosporin versus placebo for lupus nephritis (AURORA 1): a double-blind, randomised, multicentre, placebo-controlled, phase 3 trial. Lancet. 2021;397(10289):2070\u0026ndash;80.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eFurie RA, Rovin BH, Garg JP, Santiago MB, Aroca-Mart\u0026iacute;nez G, Zuta Santill\u0026aacute;n AE, et al. Efficacy and Safety of Obinutuzumab in Active Lupus Nephritis. N Engl J Med. 2025;392(15):1471\u0026ndash;83.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eRovin BH, Solomons N, Pendergraft WF, Dooley MA, Tumlin J, Romero-Diaz J, et al. A randomized, controlled double-blind study comparing the efficacy and safety of dose-ranging voclosporin with placebo in achieving remission in patients with active lupus nephritis. Kidney Int. 2019;95(1):219\u0026ndash;31.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eSammaritano LR, Askanase A, Bermas BL, Dall\u0026rsquo;Era M, Duarte-Garc\u0026iacute;a A, Hiraki LT et al. 2024 American College of Rheumatology (ACR) Guideline for the Screening, Treatment, and Management of Lupus Nephritis. Arthritis \u0026amp; Rheumatology. 2025;art.43212.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eFurie RA, Aroca G, Cascino MD, Garg JP, Rovin BH, Alvarez A, et al. B-cell depletion with obinutuzumab for the treatment of proliferative lupus nephritis: a randomised, double-blind, placebo-controlled trial. Ann Rheum Dis. 2022;81(1):100\u0026ndash;7.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003ePepper R, Griffith M, Kirwan C, Levy J, Taube D, Pusey C, et al. Rituximab is an effective treatment for lupus nephritis and allows a reduction in maintenance steroids. Nephrol Dialysis Transplantation. 2009;24(12):3717\u0026ndash;23.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eCondon MB, Ashby D, Pepper RJ, Cook HT, Levy JB, Griffith M, et al. Prospective observational single-centre cohort study to evaluate the effectiveness of treating lupus nephritis with rituximab and mycophenolate mofetil but no oral steroids. Ann Rheum Dis. 2013;72(8):1280\u0026ndash;6.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eRovin BH, Furie R, Latinis K, Looney RJ, Fervenza FC, Sanchez-Guerrero J, et al. Efficacy and safety of rituximab in patients with active proliferative lupus nephritis: The lupus nephritis assessment with rituximab study. Arthr Rhuem. 2012;64(4):1215\u0026ndash;26.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eGinzler E, Guedes Barbosa LS, D\u0026rsquo;Cruz D, Furie R, Maksimowicz-McKinnon K, Oates J, et al. Phase III / IV, Randomized, Fifty‐Two \u0026ndash;Week Study of the Efficacy and Safety of Belimumab in Patients of Black African Ancestry With Systemic Lupus Erythematosus. Arthritis Rheumatol. 2022;74(1):112\u0026ndash;23.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eYu X, Chen N, Xue J, Mok CC, Bae SC, Peng X, et al. Efficacy and Safety of Belimumab in Patients With Lupus Nephritis: Subgroup Analyses of a Phase 3 Randomized Trial in the East Asian Population. Am J Kidney Dis. 2023;81(3):294\u0026ndash;e3061.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eRovin BH, Furie RA, Ross Terres JA, Giang S, Schindler T, Turchetta A, et al. Kidney Outcomes and Preservation of Kidney Function With Obinutuzumab in Patients With Lupus Nephritis: A Post Hoc Analysis of the NOBILITY Trial. Arthritis Rheumatol. 2024;76(2):247\u0026ndash;54.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eLi H, Xie W, Wang C, Guo C. Postmarketing safety evaluation of belimumab: a pharmacovigilance analysis. Lupus Sci Med. 2025;12(1):e001400.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eFanouriakis A, Kostopoulou M, Andersen J, Aringer M, Arnaud L, Bae SC, et al. EULAR recommendations for the management of systemic lupus erythematosus: 2023 update. Ann Rheum Dis. 2024;83(1):15\u0026ndash;29.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eWHO Guideline on Country Pharmaceutical Pricing Policies. 2nd ed. Geneva: World Health Organization; 2020. 1 p.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eMorgan S, Grootendorst P, Lexchin J, Cunningham C, Greyson D. The cost of drug development: A systematic review. Health Policy. 2011;100(1):4\u0026ndash;17.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eMandrik O, Thokala P, Fotheringham JICER, Report. Lupus Nephritis 2021. 2021.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eThompson JC, Mahajan A, Scott DA, Gairy K. The Economic Burden of Lupus Nephritis: A Systematic Literature Review. Rheumatol Ther. 2022;9(1):25\u0026ndash;47.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003ePons-Estel GJ, Ram\u0026iacute;rez-Flores MF, Quintana R, Bae SC, Dey D, Pons-Estel BA et al. Addressing the challenge of global delays in diagnosis and treatment of systemic lupus erythematosus. Nat Rev Rheumatol [Internet]. 2025 July 21 [cited 2025 July 25]; Available from: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://www.nature.com/articles/s41584-025-01277-y\u003c/span\u003e\u003cspan address=\"https://www.nature.com/articles/s41584-025-01277-y\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eMendoza-Pinto C, Etchegaray-Morales I, Ugarte-Gil MF. Improving access to SLE therapies in low and middle-income countries. Rheumatology (Oxford). 2023;62(Suppl 1):i30\u0026ndash;5.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eMenn-Josephy H, Hodge LS, Birardi V, Leher H. Efficacy of Voclosporin in Proliferative Lupus Nephritis with High Levels of Proteinuria. Clin J Am Soc Nephrol. 2024;19(3):309\u0026ndash;18.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003eTables 1 to 4 are available in the Supplementary Files section.\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"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":"lupus nephritis, voclosporin, belimumab, obinutuzumab, rituximab, complete renal response","lastPublishedDoi":"10.21203/rs.3.rs-7608456/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7608456/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eLupus nephritis is a major cause of kidney failure worldwide, disproportionately affecting Black, Hispanic, and Asian populations. Standard regimens with mycophenolate mofetil or cyclophosphamide and glucocorticoids remain suboptimal, with many patients experiencing incomplete responses, relapses, or drug-related toxicity. Recently approved biologic and targeted therapies like belimumab, voclosporin, obinutuzumab, rituximab, have expanded treatment options, but direct comparisons of efficacy, safety, and cost are limited.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe conducted a systematic review of phase 2–4 randomized controlled trials enrolling adolescents or adults with biopsy-proven lupus nephritis (ISN/RPS class III–V). Eligible trials compared voclosporin, belimumab, obinutuzumab, or rituximab with placebo or standard-of-care and reported renal and/or safety outcomes with ≥ 6 months follow-up. Data were extracted on complete renal response, adverse events, infections, and mortality. Odds ratios and risk differences were calculated, and pooled estimates generated for agents with more than one trial. Cost-per-responder was estimated using U.S. drug acquisition costs.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eSix trials met inclusion criteria. Voclosporin and belimumab demonstrated consistent efficacy, with complete renal response of 30–41% at ~ 1 year, and were associated with acceptable safety. Obinutuzumab showed favorable efficacy trends in NOBILITY and REGENCY but with variable safety signals. Rituximab did not significantly improve complete renal response in the pivotal LUNAR trial. Pooled analyses indicated modest differences in safety, with belimumab having the most favorable profile. Estimated complete renal response varied widely, from ~$118,500 (rituximab) to \u0026gt;$214,000 (voclosporin), underscoring differences in short-term cost-efficiency. Underrepresentation of high-risk racial groups limited external validity.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eVoclosporin and belimumab are supported by robust evidence and guideline endorsement. Obinutuzumab shows emerging promise but is not yet integrated in guidelines. Rituximab remains widely used off-label but lacks RCT support. This systematic review highlights efficacy, safety, and economic considerations across agents, emphasizing the need for harmonized trial design, inclusive enrollment, and cost-effectiveness analyses to ensure equitable access in LN management.\u003c/p\u003e\n\u003cp\u003eClinical trial number: not applicable\u003c/p\u003e","manuscriptTitle":"Biologic therapies for lupus nephritis: a systematic review of efficacy, safety, and cost-effectiveness","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-09-30 07:22:13","doi":"10.21203/rs.3.rs-7608456/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":"6104f331-c55d-490a-971a-c44861b90dae","owner":[],"postedDate":"September 30th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2026-02-18T09:27:43+00:00","versionOfRecord":[],"versionCreatedAt":"2025-09-30 07:22:13","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-7608456","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7608456","identity":"rs-7608456","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}