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

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