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- Gomez, A., et al.
(författare)
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LOW-DOSE BELIMUMAB AND ANTIMALARIAL AGENTS PREVENT RENAL FLARES IN SYSTEMIC LUPUS ERYTHEMATOSUS : RESULTS FROM FOUR RANDOMISED CLINICAL TRIALS
- 2023
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Ingår i: Annals of the Rheumatic Diseases. - : HighWire Press. - 0003-4967 .- 1468-2060. ; 82:Suppl. 1, s. 1467-1468
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- 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.
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- Parodis, Ioannis, 1981-, et al.
(författare)
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PREDICTORS OF DE NOVO RENAL FLARES IN SYSTEMIC LUPUS ERYTHEMATOSUS - TIME TO REVISIT BELIMUMAB DOSE FOR EXTRA-RENAL DISEASE? : RESULTS FROM FIVE PHASE III CLINICAL TRIALS OF BELIMUMAB
- 2023
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Ingår i: Annals of the Rheumatic Diseases. - : HighWire Press. - 0003-4967 .- 1468-2060. ; 82:Suppl. 1, s. 909-910
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- Background: Each lupus nephritis (LN) flare causes nephron loss that equals a decade or more of reduction in renal function lifespan, making prompt initiation of therapy imperative and prevention of flares even more desirable. Identification of readily available signals of imminent flare is therefore expected to improve prognosis.Objectives: In light of observed cases of de novo LN during belimumab treatment (1), 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 (ST) with or without add-on belimumab in clinical trial settings.Methods: Data from five clinical trials of belimumab in SLE (BLISS-52 NCT00424476; BLISS-76 NCT00410384; BLISS-NEA NCT01345253; BLISS-SC NCT01484496; EMBRACE NCT01632241) were utilised. The study population comprised 1932 patients with a baseline renal British Isles Lupus Assessment Group (BILAG) score E. De novo renal flares were defined as a change from renal BILAG E to A or B within a 52-week follow-up. Comparisons of baseline data were made using the Mann-Whitney U test, Pearson’s chi-squared (χ2) test or Fisher’s exact test as appropriate. Predictors of renal flare occurrence were investigated using univariable and multivariable Cox regression analysis. p values <0.05 were considered statistically significant.Results: De novo renal flares were documented in 146 (7.6%) patients. Among patients who developed at least one renal flare, greater proportions were Asians (30.8% versus 20.2%; p<0.003), had positive baseline anti-dsDNA levels (74.0% versus 61.3%; p=0.003), and had low baseline levels of C3 (51.4% versus 38.2%; p=0.002) and C4 (45.2% versus 35.8%; p=0.030) compared with patients who did not flare. In univariable Cox regression analysis, azathioprine use was protective against renal flares (HR: 0.70; 95% CI: 0.49–0.99; p=0.047), while anti-Sm positivity at baseline showed a trend towards an association with imminent renal flare (HR: 1.68; 95% CI: 0.99–2.85; p=0.057). In multivariable Cox regression analysis adjusting for age, sex, ethnicity, serum creatinine, and variables that differed significantly in univariable analysis, Asian ancestry (HR: 1.60; 95% CI: 1.03–2.49; p=0.036), high mean prednisone dose from baseline until renal flare occurrence or throughout the follow-up (HR: 1.03; 95% CI: 1.02–1.05; p<0.001), and baseline serum creatinine (HR: 1.02; 95% CI: 1.01–1.03; p=0.001) were associated with imminent de novo renal flare, while extra-renal clinical SLE Disease Activity Index 2000 (cSLEDAI) showed a negative association (HR: 0.92; 95% CI: 0.86–0.98; p=0.007). Notably, use of belimumab 1 mg/kg by intravenous (IV) infusion yielded a nearly 3 times decreased hazard of renal flare (HR: 0.37; 95% CI: 0.20–0.68; p=0.001), whereas IV belimumab 10 mg/kg and belimumab 200 mg administered subcutaneously (SC) displayed no clear protection.Conclusion: Asian patients appeared particularly susceptible to new-onset renal involvement, corroborating the substantial vulnerability of Asian SLE populations to renal affliction. Add-on low-dose IV belimumab on top of ST appeared protective against renal flares in SLE patients with no prior history of nephritis, while addition of the approved 10 mg/kg IV belimumab dose and SC belimumab yielded no clear protection. Discrepant results between low and high/approved belimumab doses warrant in-depth mechanistic exploration of underlying reasons e.g., potential effects of belimumab on B cell subsets that acquire regulatory properties.Reference: [1]Parodis I, Vital EM, et al. Rheumatology (Oxford). 2021;60(9):4348-54.
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