ACR 2020 lupus nephritis updates: Urinary IL-16 as biomarker, belimumab outdoes standard therapy
Lupus nephritis (LN) is a common severe complication of systemic lupus erythematosus (SLE) and a major cause of kidney failure and death in SLE patients. A study reported at the American College of Rheumatology Convergence 2020 (ACR 2020) virtual annual meeting demonstrated the potential value of urinary interleukin-16 (IL-16) as a noninvasive biomarker for predicting renal histological activity and monitoring response to immunosuppressive therapy in SLE patients with active LN. Results of the BLISS-LN trial, also reported at ACR 2020, demonstrated improvements in renal outcomes and SLE disease activity as well as reduction in steroid use in patients with active LN treated with belimumab plus standard therapy vs standard therapy alone.
LN in SLE: High risks of kidney failure and mortality
LN is reported in 25–60 percent of patients with SLE. [Rheumatology (Oxford) 2016;55:252-262] “SLE patients with LN have a 10–20 percent chance of developing kidney failure requiring dialysis, and an 8-fold increased risk of mortality,” said Dr Andrea Fava of the John Hopkins University, Baltimore, Maryland, US.
A study in 694 SLE patients in Hong Kong found that 53 percent had renal disease, with renal damage and end-stage renal disease (ESRD) found in 11 percent and 3 percent of the patients, respectively. Patients with renal involvement had a 2- to 9-fold increase in mortality risk. Mortality risk was also significantly increased in those with proliferative LN (adjusted hazard ratio [HR], 2.28; 95 percent confidence interval [CI], 1.22 to 4.24), but not in those with pure membranous LN (adjusted HR, 1.05; 95 percent CI, 0.38 to 3.14). [Arthritis Rheum 2013;65:2154-2160]
Urinary IL-16 as biomarker of LN activity and treatment response
“As LN is mostly asymptomatic, patients with SLE are screened for proteinuria at every clinic visit, with a threshold of >500 mg/24 hours prompting a renal biopsy,” said Fava. [Ann Rheum Dis 2020, doi: 10.1136/annrheumdis-2020-218272]
“A majority [87 percent] of repeat biopsies leads to a change in LN treatment. While this highlights the importance of repeat biopsy in LN patients on maintenance immunosuppression, renal biopsy does not capture patient-specific active biological pathways, and biomarkers that better reflect tissue biology are needed to guide personalized treatment,” he continued. [Fava A, et al, ACR 2020, abstract 1512; Lupus Sci Med 2014, doi: 10.1136/lupus-2013-000004; Kidney Int 2018;94:788-794]
In a urine proteomics and single-cell transcriptomics study, Fava and colleagues quantified 1,000 proteins from 112 longitudinal urine samples collected from 30 SLE patients with active LN and seven healthy controls. Results showed that chemotaxis pathways were enriched in proliferative LN. [Fava A, et al, ACR 2020, abstract 0936]
“Urinary IL-16 was highly correlated with LN histological activity [r=0.73; p=1.2 x 10-5] and most significantly increased in proliferative vs membranous LN [6-fold change; p=0.002],” Fava reported. “Of note, urinary IL-16 concentration was independent of proteinuria [r=0.25; p=0.18], potentially providing actionable clinical information not captured by currently used biomarkers.”
“In addition, urinary IL-16 concentration progressively diminished over time in patients responding to immunosuppression, supporting its value as a biomarker for treatment response monitoring in patients with LN,” he highlighted. (Figure 1)
BLISS-LN: Belimumab improves renal response
In patients with LN, rates of renal response to aggressive immunosuppressive therapy are low, at only 10–30 percent. [Rev Recent Clin Trials 2018;13:105-113; Rheumatology (Oxford) 2016;55:252-262; Nephrol Dial Transplant 2012;27:3248-3254]
“In the BLISS-LN trial, the largest LN study to date, belimumab in combination with standard therapy demonstrated significant improvements in all primary and key secondary endpoints vs standard therapy alone,” said investigator Dr Richard Furie of Northwell Health, Great Neck, New York, US. [N Engl J Med 2020;383:1117-1128; Furie R, et al, ACR 2020, abstract 1441]
The phase III, randomized, double-blind, placebo-controlled trial included 448 adult patients (mean age, 33.4 years; Asian, 50 percent) with SLE and active LN. The patients were randomized (1:1) to receive 104 weeks of double-blind treatment with belimumab (10 mg/kg) or placebo in addition to standard therapy (high-dose corticosteroids plus cyclophosphamide [CYC] induction followed by azathioprine [AZA] maintenance, or high-dose corticosteroids plus mycophenolate mofetil [MMF] induction followed by MMF maintenance), followed by 28 weeks of open-label treatment with belimumab plus standard therapy for all patients.
At baseline, 56.5 percent vs 59.2 percent of patients in the belimumab vs placebo group had class III/IV (ie, focal or diffuse proliferative) LN, 16.1 percent in each group had class V (ie, membranous) LN, while 27.4 percent vs 24.7 percent had class III and V or class IV and V (ie, mixed) LN. The mean SLE Disease Activity Index-2000 (SLEDAI-S2K) score was 12.5 vs 12.2. [Furie R, et al, ACR 2020, abstract 1441]
Primary and key secondary endpoints
Primary efficacy renal response (PERR; defined as urine protein-creatinine ratio [uPCR] ≤0.7, estimated glomerular filtration rate [eGFR] ≥20 percent below pre-flare value or ≥60 mL/min/1.73 m2, and no use of rescue therapy) at week 104, the trial’s primary endpoint, was achieved by significantly more patients in the belimumab vs placebo group (43 percent vs 32.3 percent; odds ratio [OR], 1.6; 95 percent CI, 1.0 to 2.3; p=0.0311). At week 52, PERR was achieved by 46.6 percent vs 35.4 percent of the patients (OR, 1.6; 95 percent CI, 1.1 to 2.4; p=0.0245).
Complete renal response (CRR; defined as uPCR <0.5, eGFR ≥10 percent below pre-flare value or ≥90 mL/min/1.73 m2, and no use of rescue therapy) at week 104 was achieved by 30 percent vs 19.7 percent of patients in the belimumab vs placebo group (OR, 1.7; 95 percent CI, 1.1 to 2.7; p=0.0167).
“There were significantly more PERRs and CRRs in the belimumab vs placebo group from week 24 and week 12, respectively. The between-group differences remained significant through week 104,” said Furie. (Figure 2)
Belimumab also demonstrated significant improvements vs placebo in time to a renal-related event (ie, ESRD, serum creatinine doubling, renal worsening, renal disease–related treatment failure) or death (15.7 percent vs 28.3 percent; HR, 0.5; 95 percent CI, 0.3 to 0.8; p=0.0014), as well as ordinal renal response (ORR) at week 104 (p=0.0096). “The ORR improvement was mainly driven by improvement in complete renal response with belimumab vs placebo [30 percent vs 19.7 percent],” noted Furie.
Subgroup analyses and other efficacy endpoints
Subgroup analyses showed consistent benefit of belimumab vs placebo in terms of PERR and CRR at week 104 regardless of standard therapy regimen, race, and LN class except pure class V. (Table) [Furie R, et al, ACR 2020, abstract 1441]
Patients in the belimumab group also had significant reductions in SLE flare, SLE disease activity and prednisone dose vs placebo recipients (first severe SLE Flare Index [SFI] flare: HR, 0.6; 95 percent CI, 0.4 to 0.8; p=0.0042) (SLEDAI-S2K score <4 at week 104: OR, 1.8; 95 percent CI, 1.1 to 2.8; p=0.0164) (prednisolone ≤7.5 mg/day at week 104: OR, 1.6; 95 percent CI, 1.1 to 2.4; p=0.0139) (prednisolone ≤5 mg/day at week 104: OR, 1.5; 95 percent CI, 1.0 to 2.3; p=0.0444).
“The safety profile of belimumab in combination with standard therapy was acceptable,” Furie noted. Treatment-related adverse events (AEs) occurred in 54.9 percent vs 53.1 percent of patients in the belimumab vs placebo group, with treatment-related serious AEs (SAEs) reported in 10.3 percent vs 11.2 percent of the patients. AEs leading to study drug discontinuation occurred in 12.9 percent of patients in both groups, while fatal SAEs were reported in 2.7 percent vs 2.2 percent of the patients.