Efficacy and safety of BAFF/APRIL-pathway inhibitors versus placebo in adults with IgA nephropathy: a systematic review with pairwise and network meta-analysis

Abstract

B-cell activating factor (BAFF) and a proliferation-inducing ligand (APRIL) drive the galactose-deficient IgA1 (Gd-IgA1) production that underlies IgA nephropathy (IgAN). Several BAFF/APRIL-pathway inhibitors have entered randomized testing, but none has been compared head-to-head. We systematically searched MEDLINE, Scopus, the Cochrane Central Register, Web of Science, and Embase to July 2026 for randomized, placebo-controlled trials of BAFF/APRIL-pathway inhibitors in adults with biopsy-proven IgAN. Random-effects pairwise meta-analysis used the standardized mean change for proteinuria and estimated glomerular filtration rate (eGFR), change-score standardization for biomarkers, and risk ratios (RR) for safety, and a frequentist star network meta-analysis with placebo as reference ranked agents by P-score. Seven trials (1,590 adults) evaluating telitacicept, atacicept, and sibeprenlimab were included. Versus placebo, BAFF/APRIL-pathway inhibition reduced proteinuria (SMCR −0.73, 95% CI −0.88 to −0.58, p < 0.001, I 2 = 0%) and a small difference in eGFR favouring active treatment (+0.21, 95% CI 0.04 to 0.38, p = 0.016, I 2 = 0%). Serum Gd-IgA1 and total IgA fell substantially but with high heterogeneity (I 2 > 95%). Serious adverse events (RR 0.52, 95% CI 0.30 to 0.90) and treatment discontinuations (RR 0.31, 95% CI 0.11 to 0.88) were fewer with active treatment, overall adverse events did not differ (RR 1.03, 95% CI 0.92 to 1.16), and injection-site reactions were more frequent (RR 5.98, 95% CI 2.39 to 14.96). In the network, the exploratory P-score for proteinuria reduction was highest for sibeprenlimab (0.94), with no significant between-agent difference, and atacicept showed the only significant reduction in serious adverse events (RR 0.24, 95% CI 0.08 to 0.70). In adults with IgAN, BAFF/APRIL-pathway inhibitors consistently and substantially reduced proteinuria versus placebo, with a small short-term eGFR difference and no evident short-term safety signal, although longer follow-up is required to define uncommon, infectious, and immunological risks. Whether this antiproteinuric effect, seen over approximately 6 to 12 months, translates into durable preservation of kidney function remains uncertain. The between-agent and biomarker estimates are exploratory, and longer trials reporting kidney-failure endpoints are needed to confirm a disease-modifying effect. Not applicable.