To Örebro University

Background: Lupus nephritis (LN) is one of the most severe manifestations in systemic lupus erythematosus (SLE), constituting a substantial cause of end-stage kidney disease, dialysis, and mortality. Prompt and adequate treatment of LN, and prevention of renal flares are key components of disease management towards improved outcomes in patients with SLE.

Objectives: We aimed to determine the effect of the use of antimalarial agents (AMA) and different doses and pharmaceutical forms of belimumab on preventing renal flares in patients with active SLE.

Methods: We pooled data from the BLISS-52, BLISS-76, BLISS-SC and BLISS-Northeast Asia randomised clinical trials of belimumab (N=3225), that included patients with seropositive (antinuclear antibody titres ≥1:80 and/or anti-dsDNA levels ≥30 IU/mL), active SLE yet no severe ongoing renal disease. Participants were allocated to receive intravenous (IV) belimumab 1 mg/kg (N=559), IV belimumab 10 mg/kg (N=1033), subcutaneous (SC) belimumab 200 mg (N=556) or placebo (N=1077) in addition to standard therapy. Additionally, we classified patients as AMA users if they had received hydroxychloroquine, chloroquine, mepacrine, or quinine sulphate in stable doses for at least 30 days prior to the trial commencement. The outcome of the present post-hoc analysis was development of renal flares, defined according to the analysis plan within the BLISS programme. The hazard of renal flare was assessed with Cox proportional hazards regression models, adjusted for age, sex, ethnicity, previous renal involvement, baseline proteinuria and glomerular filtration rate, and use of glucocorticoids and immunosuppressants.

Results: In total, 192 patients developed a renal flare after a median of 197 days. In multivariable Cox regression analysis, use of AMA was associated with a lower risk of renal flares (HR: 0.64; 95% CI: 0.54–0.96; p=0.026). Compared with placebo, the risk of renal flares was lower among patients receiving IV belimumab 1 mg/kg (HR: 0.44; 95% CI: 0.25–0.79; p=0.006) and IV belimumab 10 mg/kg (HR: 0.63; 95% CI: 0.45–0.87; p=0.005), but not SC belimumab 200 mg (HR: 0.90; 95% CI: 0.57–1.42; p=0.648). When analysing all study arms with and without antimalarials separately, patients receiving IV belimumab 1 mg/kg along with AMA experienced the lowest rate of renal flares (18.5 (7.4–38.1) cases per 1000 person-years). Using patients who received placebo but not AMA as the reference comparator, patients receiving IV belimumab 1 mg/kg (OR: 0.30; 95% CI: 0.13–0.70; p=0.005) and patients receiving IV belimumab 10 mg (OR: 0.45; 95% CI: 0.27–0.75; p=0.002) were protected against renal flares only when belimumab use was combined with AMA.

Conclusion: In this RCT setting, belimumab and AMA protected against renal flares in patients with active seropositive SLE yet no ongoing severe renal involvement. The protective effect of IV belimumab against renal flares appeared optimal when belimumab was combined with AMA. The prominent effect of low-dose belimumab motivates investigation of the efficacy of intermediate doses of belimumab.