| 1. |
- 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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| 2. |
- 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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| 3. |
- Walhelm, T., et al.
(författare)
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FACTORS ASSOCIATED WITH SURVIVAL AND DISCONTINUATION OF ANTIMALARIAL AGENTS IN SYSTEMIC LUPUS ERYTHEMATOSUS : RESULTS FROM A SWEDISH LONGITUDINAL REGISTRY
- 2023
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Ingår i: Annals of the Rheumatic Diseases. - : HighWire Press. - 0003-4967 .- 1468-2060. ; 82:Suppl. 1, s. 902-903
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- Background: Hydroxychloroquine (HCQ) and chloroquine, referred to as antimalarial agents (AMA), are cornerstone drugs in systemic lupus erythematosus (SLE), which inhibit type I interferon release via toll-like receptor binding and increasing the pH in plasmacytoid dendritic cell lysosomes [1]. AMA use has established benefits in SLE, such as improved prognosis and decelerated accrual of organ damage. Use of HCQ is safe for most patients and serious side-effects are uncommon, even during pregnancy. Medical therapy to prevent repeated disease flares is of essential weight in the treatment of SLE. However, it is well-known that non-adherence to prescription of AMA is a considerable problem [2].Objectives: The aim of this cross-sectional study was to investigate the frequency of AMA prescription, and evaluate factors associated with ongoing use and discontinuation of AMA in a Swedish SLE population.Methods: We retrieved data from the Clinical Lupus Register in North-Eastern Gothia (Swedish acronym: KLURING), a longitudinal research and quality registry, including all prevalent and incident cases of SLE in the Östergötland County from 2008 onwards. All included subjects fulfilled the validated 1982 American College of Rheumatology (ACR) and/or the 2012 Systemic Lupus International Collaborating Clinics (SLICC) classification criteria and had been diagnosed from 1963 onwards. Factors associated with ongoing use and discontinuation of AMA were investigated using logistic regression analysis, Mann-Whitney U test and chi-square test.Results: A total of 328 subjects were included in the analysis. The mean age at diagnosis was 40.0 years (range: 3–85; standard deviation [SD]: 17.7) and 85.7% were females. The mean SLICC/ACR damage index (SDI) score at last visit was 2.0 (range: 0—11; SD: 2.5). In total, 92.4% had used AMA at some point during their disease course (“ever” users; Table 1). Data from the last available visit indicated that 73.2% were currently prescribed AMA, exclusively HCQ, yielding a daily mean HCQ dose of 228.0 mg (range: 100—400; SD: 71.0). Among individuals who had discontinued AMA, 25.9% had developed a contraindication, mostly on ophthalmological basis (33.3%). Less common reasons were cardiac conditions (19.0%) and renal failure (9.5%). Subjective side-effects were also common; the most frequently reported were gastrointestinal symptoms (n=20/37). Most common patient-related factor associated with discontinuation was intentional non-adherence (e.g., low motivation; 8/11). Patients who had discontinued AMA showed a higher SDI score at the last visit (mean: 2.9; SD: 2.8; mean follow-up: 20.0 years) compared with patients on AMA (mean: 1.4; SD: 1.8; p=0.001; mean follow-up: 15.3 years). Those who fulfilled the immunological disorder ACR criterion (ACR-10) were more likely to continue on AMA (p=0.003). No significant differences were found regarding gender or smoking status. Conclusion: The vast majority of patients in KLURING had been exposed to AMA, and approximately 25% discontinued AMA therapy during follow-up. The main reason for discontinuation were therapy-related factors, such as contraindications and experience of side-effects. Above 50% of the reported side-effects that led to discontinuation were gastrointestinal symptoms. The group of discontinued AMA users accrued more damage over time.References:[1]Crow MK, Rönnblom L. Type I interferons in host defence and inflammatory diseases. Lupus Sci Med 2019;6:e000336[2]Costedoat-Chalumeau N, Houssiau F, Izmirly P, et al. A Prospective International Study on Adherence to Treatment in 305 Patients With Flaring SLE: Assessment by Drug Levels and Self-Administered Questionnaires. Clin Pharmacol Ther 2018;103:1074-1082
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