To Örebro University

Background including aims: Each lupus nephritis (LN) flare causes substantial nephron loss. Identification of reliable signals of impending flare is imperative. In light of observed cases of de novo LN during belimumab treatment, we evaluated predictors of de novo renal flare occurrence in patients with systemic lupus erythematosus (SLE) and no prior history of renal disease undergoing standard therapy with or without add-on belimumab within the frame of five phase III clinical trials.

Methods: Data from five phase III clinical trials of belimumab in SLE i.e., BLISS-52 (NCT00424476; N=865); BLISS-76 (NCT00410384; N=819); BLISS-NEA (NCT01345253; N=677); BLISS-SC (NCT01484496; N=836); EMBRACE (NCT0163224; N=448) were utilised. De novo renal flares were defined as a change from renal British Isles Lupus Assessment Group (BILAG) E to A or B within a 52-week follow-up. Predictors of renal flare occurrence were investigated using Cox regression analysis.

Results: Of 1844 eligible patients, 136 (7.4%) developed a de novo renal flare during a 52-week long follow-up. In multivariable analysis adjusting for potential confounders, Asian origin (HR: 1.97; 95% CI: 1.33–2.94; p=0.001), high mean prednisone dose from baseline until renal flare occurrence or throughout follow-up (HR: 1.03; 95% CI: 1.02–1.04; p<0.001), and positive levels of anti-dsDNA (HR: 1.32; 95% CI: 1.08–1.63; p=0.008) were associated with de novo renal flares. Low-dose intravenous (IV) belimumab (1 mg/kg) yielded a nearly 3-fold lower hazard of de novo renal flare occurrence (HR: 0.38; 95% CI: 0.20–0.73; p=0.004) and subcutaneous (SC) belimumab (200 mg weekly) yielded a lower, but less decreased, hazard (HR: 0.69; 95% CI: 0.54–0.88; p=0.003). However, the labelled dose of IV belimumab (10 mg/kg) did not provide protection (HR: 0.74; 95% CI: 0.50–1.09; p=0.127).

Conclusions: Our findings corroborate the substantial vulnerability of Asian SLE populations to renal affliction. Add-on low-dose IV belimumab 1 mg/kg appeared most protective against renal flares in nephritis-naïve SLE patients, while the approved IV dose (10 mg/kg) yielded no clear protection.