Predictors and prevention of renal flares: Pooled analysis of four phase III trials of belimumab

Renal involvement occurs in 30–60% of the patients with systemic lupus erythematosus (SLE) and remains a substantial contributor to end-stage kidney disease, dialysis, and mortality.^1,2 However, there is uncertainty in the identification of circumstances leading to renal flares and belimumab’s efficacy in preventing them.^1,2

Below, we summarize a pooled analysis of four phase III trials of belimumab assessing predictors of renal flares in patients with SLE, published by Jägerback et al.¹ in Rheumatology; and on their prevention using belimumab alongside antimalarials, published by Gomez et al.² in Rheumatology.

Methods^1,2

• A post-hoc analyses of four phase III trials of belimumab in patients with active extrarenal SLE:

• • BLISS-52, NCT00424476
  • BLISS-76, NCT00410384
  • BLISS-Northeast Asia, NCT01345253
  • BLISS-SC, NCT01484496

• Patients were administered different doses of belimumab (intravenous [IV] 1 mg/kg, IV 10 mg/kg, and subcutaneous 200 mg) or placebo on top of standard therapy.
• Patients received follow-ups from Weeks 52–76. Predictors of renal flares were assessed using proportional hazards regression analysis,¹ and the effect of antimalarials and different doses of belimumab on renal flares was assessed using Cox regression analysis.²

Key findings^1,2

• Of 3,225 patients with SLE, 192 developed ≥1 renal flare, with the first occurring after a median follow-up of 197 days.
  • The patients had a mean age of 36.7 years, with 94% being women, and 54.6% had current/former renal involvement at baseline.
• The most robust determinants of impending renal flares were current/former renal involvement (hazards ratio [HR]: 15.4; 95% confidence interval [CI], 8.3–28.2; p < 0.001], low serum albumin levels, proteinuria, and low C3 levels at baseline (Figure 1)
  • Anti-dsDNA and anti-Smith positivity were also associated with renal flares (Figure 1); however, the association reduced after adjustments

BAFF, B-cell activating factor; CI, confidence interval; dsDNA, double-stranded DNA; HR, hazard ratio.
*Adapted from Jägerback, et al.¹

• Treatment with belimumab IV 10 mg/kg and 1 mg/kg resulted in a significantly reduced risk of renal flares (HR, 0.62; 95% CI, 0.41–0.92; p = 0.018 and HR, 0.42; 95% CI, 0.22–0.79; p = 0.007, respectively), while no significant association was found for subcutaneous 200 mg, compared with placebo.
• While antimalarials led to a lower hazard of renal flares (HR, 0.66; 95% CI, 0.55–0.78; p < 0.001), the prevention was conferred when antimalarials were coadministered with belimumab, particularly with the IV 1 mg/kg dose (Figure 2).

AMA, antimalarial; IV, intravenous; SC, subcutaneous.
*Data from Gomez, et al.²

Key learnings

A history of renal involvement, high baseline proteinuria, hypoalbuminaemia, and C3 consumption were robust determinants of renal flares. Meanwhile, anti-dsDNA, anti-Smith,and anti-ribosomal P protein antibody positivity may prove useful markers of renal SLE. The effectiveness of belimumab in preventing renal flares was improved when used alongside antimalarials, advocating for combination regimens to achieve favorable renal outcomes. The findings supported the previously reported beneficial effects of antimalarials in preventing renal flares, and support their use in all patients with SLE, unless contraindicated. The prominent effect of low dose belimumab in the reduction of renal flare warrants study on intermediate doses.