Belimumab is a human monoclonal antibody that selectively binds to B-lymphocyte stimulator (BLyS) that has recently been approved for the treatment of lupus nephritis (LN) following the success of the BLISS-LN study.¹ While the trial showed that LN patients treated with belimumab plus standard therapy had significant improvements in kidney responses and lower levels of serum disease markers, predictors of patient response towards belimumab treatment are not yet identified.¹ As such, post-hoc analyses of the BLISS-LN study was performed to identify the characteristics of LN patients who would benefit the most from the addition of belimumab to standard therapy.¹ On behalf of his research team, Dr. Brad Rovin from the Ohio State University Wexner Medical Center, the United States (US), presented the results of the analyses at the ASN Kidney Week 2023.¹

BLISS-LN was a phase 3, multicenter, double-blind, placebo-controlled study that randomized adult patients with active LN to receive monthly belimumab 10mg/kg intravenously or placebo, in addition to standard therapy of high-dose corticosteroids plus either mycophenolate mofetil (MMF) or cyclophosphamide (CYC) followed by azathioprine (AZA).¹ A total of 446 patients were included in the analyses.¹ Biomarkers that were evaluated for their ability to predict renal response included immunoglobulins (Ig) G, IgA, and IgM levels, anti-double stranded DNA (anti-dsDNA) and anti-C1q autoantibodies, C3 and C4, total B cells and subsets of naïve B cells, plasmablasts, and memory B cells.¹

Logistic regression models were developed to assess the ability of each biomarker’s baseline value as well as its percentage change from baseline over time to predict the attainment of Primary Efficacy Renal Response (PERR) and Complete renal response (CRR) at week 104.¹ PERR was defined as urine protein/creatinine ratio (uPCR) ≤0.7g/g and estimated glomerular filtration rate (eGFR) ≤20% below pre-flare value or ≥60ml/min/1.73m², while CRR was defined as uPCR <0.5g/g and eGFR ≤10% below pre-flare value or ≥90ml/min/1.73m².¹ Covariates in the models included induction regimen (CYC vs. MMF), race, baseline uPCR and baseline eGFR.¹

Patient baseline characteristics, including age, sex, LN disease duration, renal biopsy class, and Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K) scores, were balanced across the treatment groups within the induction regimen.¹ The results showed that high baseline levels of IgA were predictive of PERR [odds ratio (OR)=1.40; p<0.05] in the belimumab group, while high baseline levels of naïve B cells were predictive of both PERR (OR=1.0017; p<0.05) and CRR (OR=1.0017; p<0.05) in the belimumab group.¹ Early decrease in IgA at week 8 in the belimumab group was also predictive of PERR (OR=0.98; p<0.05) in the belimumab group.¹

At week 24, a decrease in IgA levels was shown to be predictive of PERR in both the belimumab (OR=0.97; p<0.01) and placebo (OR=0.98; p<0.05) groups.¹ Nevertheless, for CRR, the decrease of IgA levels at week 24 was exclusively predictive for the belimumab group (OR=0.98; p<0.05).¹ In addition, PERR and CRR in both groups can also be predicted with a reduction in anti-C1q at week 52 (p<0.01 for PERR in both groups, p<0.05 for CRR in both groups) and uPCR at week 12 (p<0.01 for PERR and CRR in the belimumab group, p<0.001 for PERR and CRR in the placebo group).¹

In conclusion, high levels of IgA and naïve B cells at belimumab initiation, as well as early reductions in IgA during the course of treatment were correlated to the achievement of PERR and/or CRR for belimumab but not placebo.¹ The biomarkers identified may not only serve as predictors for treatment response, but also aid in our understanding of the disease pathogenesis and mechanism of the drug.¹ It should be noted that uPCR and eGFR results should be interpreted with caution as these were components of the PERR and CRR endpoints.¹ In addition, the results of the analyses may have been confounded as all patients received background induction therapy, which may have affected baseline biomarker levels prior to receiving belimumab or placebo.¹