Efficacy and safety of belimumab therapy in lupus nephritis: a systematic review and meta-analysis

Figures & data

Figure 1. PRISMA flow diagram of the study-selection process.

Table 1. Characteristics of studies included in the meta-analysis.

Author (years)	Patients (R)	Protocol	Inclusion criteria	Exclusion criteria	Age (years)		Women (%)		Definition of renal response	Outcomes	Follow-up
					Belimumab	Control	Belimumab	Control
MA Dooley et al. (2013) (BLISS-52 and BLISS-76) [14]	1125 (American/White/Asian/Hispanic or Latino)	Belimumab 1 mg/kg or 10 mg/kg, or placebo by intravenous infusion in 1 h on days 0, 14, and 28, and then every 28 d until 48 weeks.	Aged ≥ 18 years; SELENA-SLEDAI score ≥ 6; ANA (titer ≥ 1:80) or anti-dsDNA antibody (≥30 IU/mL); treatment regimen with fixed doses of prednisone (0–40 mg/d), or nonsteroidal anti-inflammatory, antimalarial, or immunosuppressive drugs for at least 30 d before the first study dose.	Severe active LN or CNS lupus; pregnancy; previous treatment with any B-lymphocyte-targeted drug within 3 months.	38.0 ± 11.0	38.1 ± 11.9	(n = 563) 539 (95.7)	(n = 562) 522 (92.9)	≥4-point reduction in SELENA–SLEDAI score, no new BILAG A organ domain score and no more than 1 new BILAG B score, and no worsening in physician’s global assessment score versus baseline	In patients with baseline proteinuria ≥ 1 g/24-h equivalent (n = 220), renal remission rates were numerically higher and time to first renal remission was numerically shorter in the belimumab-treated groups; had numerically lower renal flare rates.	52 Weeks
William Stohl et al. (2017) (BLISS-SC) [21]	836 (Americas/Western Europe/Australia/Israel/Eastern Europe/Asia)	Belimumab 200 mg or placebo by prefilled syringe in addition to standard SLE therapy for 52 weeks.	Aged ≥ 18 years; diagnosis of SLE; positive ANA and/or anti-dsDNA antibodies; SELENA–SLEDAI score ≥ 8	Severe lupus kidney disease (proteinuria > 6 g/24 h or equivalent according to a spot UPCR or a serum creatinine level > 2.5 mg/dL) or severe CNS lupus	38.1 ± 12.10	39.6 ± 12.61	(n = 563) 521 (93.7)	(n = 280) 268 (95.7)	NA	Fewer patients in the belimumab group had a renal flare as compared with placebo, although this difference was not statistically significant (4.7% versus 7.5%; HR 0.57 [95% CI 0.32–1.01]; p = 0.0532).	52 Weeks
Yoshiya Tanaka et al. (2020) (BLISS-NEA) [22]	60 (Japanese)	Belimumab 10 mg/kg or placebo by intravenous infusion plus standard of care, on Days 0, 14, and 28, then 4-weekly until Week 48.	Aged ≥ 18 years; diagnosis of SLE; SELENA–SLEDAI score ≥ 8	Severe lupus kidney disease or active nephritis; CNS lupus; any new SLE medications other than corticosteroids within 60 d prior to baseline, and B cell targeted therapy at any time.	38.1 ± 10.23	33.7 ± 10.61	(n = 39) 35 (89.7)	(n = 21) 20 (95.2)	SELENA–SLEDAI renal domain improvement	The proportion of patients experiencing renal organ system improvement was 60.0% in the belimumab group and 20.0% in the placebo group.	52weeks
Richard Furie et al. (2020) (BLISS-LN) [15]	448 (Asia/Europe/United States or Canada and other)	Belimumab 10 mg/kg or matching by intravenous infusion days 1, 15, and 29 and every 28 d thereafter to week 100.	Aged ≥ 18 years; autoantibody-positive SLE; UPCR ≥ 1; biopsy-proven LN class III or IV with or without coexisting class V, or pure class V LN within 6 months before, or during, screening. Only patients with biopsy specimens showing active lesions or active and chronic lesions.	Dialysis within 1 year; eGFR < 30 mL/min/1.73; previous failures of both CTX and MMF induction; receipt of CTX induction therapy within 3 months; receipt of B-cell–targeted therapy within 1 year.	33.7 ± 10.7	33.1 ± 10.6	(n = 223) 197 (88.3)	(n = 223) 196 (87.9)	PR: UPCR ≤ 0.7; < 20% of eGFR below pre-flare value; eGFR ≥ 60 mL/min/1.73 m^2; No use of rescue therapy CR: UPCR< 0.5, an eGFR that was no worse than 10% below the pre-flare value or ≥ 90 mL/min/1.73 m^2, and no rescue therapy.	Significantly more patients who received belimumab than those who received placebo had a CRR at week 104; The group of patients who received belimumab had a significantly lower risk of a renal-related event or death during the trial than the group of patients who received placebo.	104 Weeks
Yemil Atisha- Fregoso et al. (2021) [23]	43 (White/Black/Asian/Hispanic or Latino)	Rituximab at a dose of 1000 mg, and CYC at a dose of 750 mg intravenously at weeks 0 and 2; Patients in the RCB group received belimumab at a dose of 10 mg/kg at weeks 4, 6, and 8 and every 4 weeks thereafter through week 48.	Aged ≥ 18 years; diagnosis of SLE; positive ANA and/or an-dsDNA antibodies; SELENA–SLEDAI score ≥ 8; recurrent or refractory LN; had been treated previously with either CYC or MMF.	Prior treatment with rituximab at any time or treatment with another B cell biologic therapy within the prior 12 months.	34.5 ± 9.14	32.3 ± 11.43	(n = 21) 19 (90.5)	(n = 22) 18 (81.8)	PR: the same criteria as used for the CR, except that the UPCR component of the partial response definition required only > 50% improvement from baseline. CR: UPCR < 0.5; eGFR ≥ 120 mL/min/1.73 m^2, or if the value was <120 mL/min/1.73 m^2, then >80% of the eGFR recorded at the time of study entry; and adherence to the prednisone dosing provisions.	Overall, renal response was similar between the RC group and the RCB group at all time points.	96 Weeks
Ellen Ginzler et al. (2022) (EMBRACE) [24]	448(in Brazil/ Colombia/France/South Africa/the UK, and the US)	Belimumab 10 mg/kg intravenously or placebo, on days 0, 14, and 28 and every 28 d thereafter up to week 48.	Age ≥ 18 years; self-identified Black race; SELENA–SLEDAI score ≥ 8; positivity for ANA (titer ≥ 1:80) and/or anti-dsDNA (≥30 IU/mL).	Previous treatment with belimumab; severe lupus kidney disease or active nephritis, or CNS lupus.	38.6 ± 11.1	39.3 ± 12.2	(n = 299) 290 (97.0)	(n = 149) 144 (96.6)	SELENA–SLEDAI–SLEDAI-2K renal domain improvement at week 52	SELENA–SLEDAI–SLEDAI-2K renal involvement, more patients in the belimumab group (41.8% [23 of 55]) experienced improvement in this domain compared with those in the placebo group (20.6% [7 of 34]); baseline proteinuria > 0.5 g/24 h was numerically greater with belimumab treatment compared with placebo (65.27% versus 32.89%); 16 patients (42.1%) in the belimumab group and 6 (26.1%) in the placebo group with baseline proteinuria > 0.5 g/24 h experienced a downward shift in proteinuria to ≤ 0.5 g/24 h.	52 Weeks and 6-month open- label extension phase.

SELENA-SLEDAI: Safety of Estrogen in Lupus Erythematosus National Assessment Systemic Lupus Erythematosus Disease Activity Index; ANA: antinuclear antibody; LN: Lupus Nephritis; CNS: central nervous system; SRI: SLE Responder Ind-ex; BILAG: British Isles lupus assessment group; SLE: Systemic lupus erythematosus; anti-dsDNA: anti-double-stranded DNA; UPCR: Urinary protein-to-creatinine ratio from 24-h urine sample collection; NA: denotes not applicable; eGFR: estimated glomerular filtration rate; CYC /CTX: cyclophosphamide; MMF: mycophenolate mofetil; CR: Complete response; PR: Partial response; RC group: participants treated with rituximab and cyclophosphamide but no belimumab infusions; RCB group: participants treated with rituximab, cyclophosphamide, and glucocorticoids followed by weekly belimumab infusions until week 48; SRI–SLEDAI-2K: SLE Disease Activity Index 2000

Figure 2. Risk-of-bias summary of randomized controlled trials.

Figure 3. Comparison of renal response between the belimumab and control groups.

Figure 4. Comparison of renal flare rate between the belimumab and control groups.

Figure 5. Comparison of treatment-related adverse events between the belimumab and control groups.

Figure 6. Comparison of infection between the belimumab and control groups.

Figure 7. Funnel plots for publication bias detection.

Dooley MA, Houssiau F, Aranow C, et al. Effect of belimumab treatment on renal outcomes: results from the phase 3 belimumab clinical trials in patients with SLE. Lupus. 2013;22(1):63–72.

 PubMed Web of Science ®Google Scholar

Stohl W, Schwarting A, Okada M, et al. Efficacy and safety of subcutaneous belimumab in systemic lupus erythematosus: a fifty-two–week randomized, double-blind, placebo-controlled study. Arthritis Rheumatol. 2017;69(5):1016–1027.

 PubMed Web of Science ®Google Scholar

Tanaka Y, Bass D, Chu M, et al. Organ system improvements in Japanese patients with systemic lupus erythematosus treated with belimumab: a subgroup analysis from a phase 3 randomized placebo-controlled trial. Mod Rheumatol. 2020;30(2):313–320.

 PubMed Web of Science ®Google Scholar

Furie R, Rovin BH, Houssiau F, et al. Two-Year, randomized, controlled trial of belimumab in lupus nephritis. N Engl J Med. 2020;383(12):1117–1128.

 PubMed Web of Science ®Google Scholar

Atisha-Fregoso Y, Malkiel S, Harris KM, et al. Phase II randomized trial of rituximab plus cyclophosphamide followed by belimumab for the treatment of lupus nephritis. Arthritis Rheumatol. 2021;73(1):121–131.

 PubMed Web of Science ®Google Scholar

Ginzler E, Guedes Barbosa LS, D’Cruz D, et al. Phase III/IV, randomized, Fifty-Two-Week study of the efficacy and safety of belimumab in patients of black African ancestry with systemic lupus erythematosus. Arthritis Rheumatol. 2022;74(1):112–123.

 PubMed Web of Science ®Google Scholar

Data availability statement

All data generated or analyzed during this study are included in this published article/as Supplementary information files.