An update on belimumab for the treatment of lupus.
Ontology highlight
ABSTRACT:
SUBMITTER: Thanou-Stavraki A
PROVIDER: S-EPMC3044792 | biostudies-literature | 2011
REPOSITORIES: biostudies-literature
Publications
An update on belimumab for the treatment of lupus.
Thanou-Stavraki Aikaterini A Sawalha Amr H AH
Biologics : targets & therapy 20110214
B-lymphocyte stimulator (BLyS), a homeostatic factor for B-cell differentiation and survival, has a major role in B-cell expansion and autoreactivity that characterize systemic lupus erythematosus (SLE). Belimumab, a BLyS-specific inhibitor, has shown promising evidence of efficacy in several preclinical and clinical studies in SLE. Two recent large randomized controlled trials yielded a significant positive effect of the drug compared to placebo in patients with active disease. In this review, ...[more]
Similar Datasets
Project description:Systemic lupus erythematosus (SLE) is a chronic inflammatory disorder that is driven by autoantibodies that target multiple organ systems. B-lymphocyte stimulator (BLyS) and its receptors on B-cell subsets play an important role in autoimmune B-cell development and SLE pathogenesis. Targeted therapy with belimumab, the monoclonal antibody against BLyS, has shown clinical benefit in two large-scale, multicenter phase III trials leading to US Food and Drug Administration approval for patients with serologically positive SLE who have active disease despite standard therapy. This review will discuss the challenges in lupus drug development and clinical trials, the basics of B-cell pathogenesis in SLE, the recent lupus clinical trials of B-cell targeted treatments, and other potential targeted therapies under investigation for patients with lupus.
| S-EPMC3513897 | biostudies-literature
Project description:ObjectiveIn light of reports of de novo LN during belimumab (BLM) treatment, we sought to determine its frequency and contributing or protective factors in a real-life setting.MethodsPatients with SLE who received BLM between 2011 and 2017 at five European academic practices were enrolled (n = 95) and followed longitudinally for a median time of 13.1 months [interquartile range (IQR): 6.0-34.7]; 52.6% were anti-dsDNA positive, 60.0% had low complement levels, and 69.5% had no renal involvement prior to/at BLM initiation [mean disease duration at baseline: 11.4 (9.3) years]. Age- and sex-matched patients with non-renal SLE who had similar serological profiles, but were not exposed to BLM, served as controls (median follow-up: 132.0 months; IQR: 98.3-151.2).ResultsWe observed 6/66 cases (9.1%) of biopsy-proven de novo LN (4/6 proliferative) among the non-renal BLM-treated SLE cases after a follow-up of 7.4 months (IQR: 2.7-22.2). Among controls, 2/66 cases (3.0%) of de novo LN (both proliferative) were observed after 21 and 50 months. BLM treatment was associated with an increased frequency and/or shorter time to de novo LN [hazard ratio (HR): 10.7; 95% CI: 1.7, 67.9; P = 0.012], while concomitant use of antimalarial agents along with BLM showed an opposing association (HR: 0.2; 95% CI: 0.03, 0.97; P = 0.046).ConclusionAddition of BLM to standard-of-care did not prevent LN in patients with active non-renal SLE, but a favourable effect of concomitant use of antimalarials was implicated. Studies of whether effects of B-cell activating factor inhibition on lymphocyte subsets contribute to LN susceptibility are warranted.
| S-EPMC8409994 | biostudies-literature
Project description:Belimumab is the first biologic approved for patients with systemic lupus erythematosus (SLE). Belimumab is the first of a new class of drug targeting B cell-stimulating factors or their receptors to reach the market. Its target, BLyS, also known as BAFF (B cell-activating factor from the tumor necrosis factor family), is a type II transmembrane protein that exists in both membrane-bound and soluble forms. Additionally to a robust rational from murine experiments conducted in lupus prone mice, BLyS circulating levels are increased in SLE patients. After the negative results of a Phase II trial, two Phase III trials met their primary endpoints. Some SLE patients are still refractory to the standard options of care or necessitate prolonged high-dose corticotherapy and/or long-term immunosuppressive regimens. However, some experts still feel that the effect of this biologic might not be clinically relevant and blame the use of the new systemic lupus response index as well as the discrepancies between both trials and the noninclusion of the severe form of the disease as nephritis. In this review, we aim to discuss the characteristics of belimumab, critically evaluate the different steps of its development, and consider its future place in the arsenal against SLE, taking into account the patients' perspectives.
| S-EPMC3277870 | biostudies-literature
Project description:Systemic lupus erythematosus (SLE) is one of the most challenging autoimmune disorders with a complex pathophysiology and diverse clinical presentation. Many drugs have been used to treat SLE with suboptimal results, especially in patients with moderate-to-severe disease. Belimumab is the first biological drug to be approved for the treatment of SLE in more than 50?years. This monoclonal antibody blocks B-cell activating factor, a cytokine important for B-cell differentiation and survival. In this review we focus on the activity of belimumab in patients with SLE and discuss the controversies of its use.
| S-EPMC4612697 | biostudies-literature
Project description:We investigated whether belimumab treatment impacts on levels of autoantibodies and cytokines of interest in systemic lupus erythematosus (SLE). Longitudinally collected serum samples from 78 belimumab-treated Swedish SLE patients were analysed. Serum cytokine levels were determined using Luminex xMAP technology, and nuclear antigen autoantibody specificities using addressable laser bead immunoassay. In patients with detectable levels at baseline, interferon (IFN)-α2 levels were lower at month 6 (median; interquartile range (IQR): 8.9; 1.5-54.9 pg/mL) versus baseline (28.4; 20.9-100.3 pg/mL; p = 0.043). Interleukin (IL)-6 (baseline: 7.1; 2.9-16.1 pg/mL) decreased from month 6 (0.5; 0.5-6.3 pg/mL; p = 0.018) and throughout a 24 month follow-up. IL-10 (baseline: 12.6; 2.8-29.7 pg/mL) showed more rapid decreases from month 3 (1.8; 0.6-9.1 pg/mL; p = 0.003). Levels of anti-dsDNA (p < 0.001), anti-Smith antigen (Sm) (p = 0.002), anti-U1 small nuclear ribonucleoprotein (U1RNP) (p < 0.001), anti-Sm-U1RNP complex (p = 0.028), and anti-ribosomal P (p = 0.012) antibodies decreased from month 3 and remained decreased. Anti-Sm positivity at baseline was associated with higher probability and/or shorter time to achieve sustained SLE responder index-4 response (hazard ratio (HR): 2.52; 95% CI: 1.20-5.29; p = 0.015), independently of other factors. Decline of IL-6 levels through month 3 was greater in responders. In summary, belimumab treatment lowered IFN-α2, IL-6, and IL-10 levels, as well as levels of multiple autoantibodies, however after different time spans. Notably, anti-Sm positivity and early decline in IL-6 levels were associated with favorable treatment outcome.
| S-EPMC7278961 | biostudies-literature
Project description:ObjectivesTo identify factors that predict response to belimumab treatment in the phase 3 BLISS trials of autoantibody-positive systemic lupus erythematosus (SLE) and further analyse clinical efficacy in various patient subsets.MethodsThe BLISS trials compared belimumab 1 and 10 mg/kg versus placebo, all plus standard SLE therapy, over 52 or 76 weeks. Pooled subgroup analyses of week 52 SLE responder index rates (the primary endpoint in both trials) were performed based on demographic characteristics and baseline disease activity indicators. Pooled multivariate analysis was performed to determine predictors of response and treatment effect.ResultsPooled univariate and multivariate analyses (N=1684) identified baseline factors associated with an increased benefit of belimumab versus placebo. These factors included the Safety Of Estrogens In Lupus Erythematosus National Assessment-Systemic Lupus Erythematosus Disease Activity Index (SELENA-SLEDAI) ≥10, low complement, anti-dsDNA positivity and corticosteroid use. Efficacy outcomes were assessed in the low complement/anti-dsDNA-positive and SELENA-SLEDAI ≥10 subgroups. Week 52 SLE Responder Index rates in the low complement/anti-dsDNA-positive subgroup were 31.7%, 41.5% (p=0.002) and 51.5% (p<0.001) with placebo and belimumab 1 mg/kg and 10 mg/kg, respectively; corresponding rates in the SELENA-SLEDAI ≥10 subgroup were 44.3%, 58.0% (p<0.001) and 63.2% (p<0.001). Further analysis of secondary endpoints in the low complement/anti-dsDNA-positive subgroup showed that compared with placebo, belimumab produced greater benefits regarding severe flares, corticosteroid use and health-related quality of life.ConclusionsThese findings suggest that belimumab has greater therapeutic benefit than standard therapy alone in patients with higher disease activity, anti-dsDNA positivity, low complement or corticosteroid treatment at baseline. CLINICALTRIALS.GOV: identifiers NCT00424476 and NCT00410384.
| S-EPMC3396451 | biostudies-literature
Project description:ObjectivesTo identify predictors of low disease activity and clinical remission following belimumab treatment in SLE.MethodsSLE patients who received belimumab 10 mg/kg (N = 563) in the BLISS-52 and BLISS-76 clinical trials were surveyed. The performance of baseline factors in predicting attainment of low disease activity (defined as Lupus Low Disease Activity State) or clinical remission [defined as clinical (c)SLEDAI-2K = 0] at week 52 from treatment initiation was evaluated using logistic regression. Organ damage was assessed using the SLICC/ACR Damage Index (SDI).ResultsWe demonstrated a negative impact of established organ damage on attainment of Lupus Low Disease Activity State [SDI > 0; odds ratio (OR): 0.44; 95% CI 0.22, 0.90; P = 0.024] and the primary Lupus Low Disease Activity State condition, i.e. SLEDAI-2K ⩽ 4 with no renal activity, pleurisy, pericarditis or fever (SDI > 1; OR: 0.46; 95% CI 0.27, 0.77; P = 0.004); cognitive impairment/psychosis was found to mainly account for the latter association. Baseline SDI scores > 1 predicted failure to attain cSLEDAI-2K = 0 (OR: 0.53; 95% CI 0.30, 0.94; P = 0.030), with cutaneous damage mainly driving this association. Anti-dsDNA positivity increased (OR: 1.82; 95% CI 1.08, 3.06; P = 0.025) and cardiovascular damage reduced (OR: 0.13; 95% CI 0.02, 0.97; P = 0.047) the probability of attaining cSLEDAI-2K = 0 along with a daily prednisone equivalent intake restricted to ⩽7.5 mg.ConclusionBelimumab might be expected to be more efficacious in inducing low disease activity and clinical remission in SLE patients with limited or no organ damage accrued prior to treatment initiation. Patients with positive anti-dsDNA titres might be more likely to achieve clinical remission along with limited or no CS use.
| S-EPMC6880848 | biostudies-literature
Project description:The phase 2 placebo-controlled, double-blind PLUTO trial characterized the pharmacokinetics of belimumab plus standard systemic lupus erythematosus (SLE) therapy in patients with childhood-onset SLE (cSLE) and demonstrated similar efficacy and safety to that in adult SLE. Patients with active cSLE aged 5-17 years were randomized to intravenous belimumab 10 mg/kg every 4 weeks (n = 53). A linear 2-compartment population pharmacokinetics (popPK) model with first-order elimination was developed, and an exploratory exposure-response analysis assessed the impact of between-patient exposure variability on clinical response (SLE Responder Index 4 [SRI4]) in week 52, and occurrence of serious adverse events during the study. The popPK model estimated clearance of 158 mL/day, steady-state volume of distribution of 3.5 L, terminal half-life of 16.3 days, and distribution half-life of 0.8 days in the overall population. Fat-free mass (FFM) better characterized the pharmacokinetics than total body weight and was more consistent with allometric scaling theory; belimumab pharmacokinetics were largely determined by FFM. Age, sex, disease activity, and concomitant medication had no impact on pediatric belimumab exposure after accounting for body size. Individual and median steady-state pediatric pharmacokinetic profiles were similar to known adult profiles and pediatric exposure estimates for belimumab 10 mg/kg intravenously were consistent with adult exposures. Exposures were similar between SRI4 responders and nonresponders, and patients who did or did not experience a serious adverse event. There was no clinically relevant correlation between exposure and efficacy or safety, confirming belimumab 10 mg/kg intravenous dose every 4 weeks as appropriate for pediatric patients with cSLE.
| S-EPMC8246766 | biostudies-literature
Project description:BACKGROUND:Lupus nephritis (LN) is a frequent severe complication of Systemic Lupus Erythematosus (SLE), especially in patients of non-Caucasian ethnicity. Induction treatment for LN consists in the combination of steroids plus a second agent (cyclophosphamide or mycophenolate mofetil) or, as a second-line, calcineurin inhibitors or Rituximab. Induction treatment for LN can be complicated by a series of side effects, the most severe being serious infections. Belimumab is a fully humanized monoclonal antibody that targets soluble B lymphocyte stimulator (BLyS), approved for treatment of serologically active SLE in addition to standard of care. CASE PRESENTATION:A young Hispanic woman was diagnosed with SLE at the age of 15. After several immunosuppressive treatments for arthritic symptoms (high-dose steroids, mycophenolate mofetil, Rituximab, cyclophosphamide) leading to serious complications and scarce clinical improvement, she developed severe LN. Induction treatment with a combination of intravenous high-dose methylprednisolone and cyclophosphamide was started but, after few days, the patient developed cryptococcal meningitis. After institution of appropriate antifungal therapy, treatment with Tacrolimus was attempted but poorly tolerated by the patient and withdrawn. Eventually, Belimumab was initiated off-label as a last resource to treat LN. Belimumab was well tolerated by the patient and resulted in a rapid and marked improvement in clinical symptoms and reduction in proteinuria, serum complement levels and anti-dsDNA titer; of note, the patient developed no infectious complications. CONCLUSIONS:We report the case of a severe LN in a young Hispanic woman who did not respond to conventional and second-line induction therapies, due both to intolerance and to the development of serious infectious complications. Eventually, Belimumab was successfully added to steroids and was well tolerated by the patient, resulting in a marked improvement in clinical and biochemical parameters. We suggest that Belimumab should be considered as a potentially efficacious treatment in patients with LN who cannot tolerate conventional therapies.
| S-EPMC6196012 | biostudies-other
Project description:ObjectiveTo assess the safety, mechanism of action, and preliminary efficacy of rituximab followed by belimumab in the treatment of refractory lupus nephritis (LN).MethodsIn a multicenter, randomized, open-label clinical trial, 43 patients with recurrent or refractory LN were treated with rituximab, cyclophosphamide (CYC), and glucocorticoids followed by weekly belimumab infusions until week 48 (RCB group), or treated with rituximab and CYC but no belimumab infusions (RC group). Patients were followed up until week 96. Percentages of total and autoreactive B cell subsets in the patients' peripheral blood were analyzed by flow cytometry.ResultsTreatment with belimumab did not increase the incidence of adverse events in patients with refractory LN. At week 48, a complete or partial renal response occurred in 11 (52%) of 21 patients receiving belimumab, compared to 9 (41%) of 22 patients in the RC group who did not receive belimumab (P = 0.452). Lack of improvement in or worsening of LN was the major reason for treatment failure. B cell depletion occurred in both groups, but the percentage of B cells remained lower in those receiving belimumab (geometric mean number of B cells at week 60, 53 cells/μl in the RCB group versus 11 cells/μl in the RC group; P = 0.0012). Percentages of total and autoreactive transitional B cells increased from baseline to week 48 in both groups. However, percentages of total and autoreactive naive B cells decreased from baseline to week 48 in the belimumab group compared to the no belimumab RC group (P = 0.0349), a finding that is consistent with the observed impaired maturation of naive B cells and enhanced censoring of autoreactive B cells.ConclusionThe addition of belimumab to a treatment regimen with rituximab and CYC was safe in patients with refractory LN. This regimen diminished maturation of transitional to naive B cells during B cell reconstitution, and enhanced the negative selection of autoreactive B cells. Clinical efficacy was not improved with rituximab and CYC in combination with belimumab when compared to a therapeutic strategy of B cell depletion alone in patients with LN.
| S-EPMC7839443 | biostudies-literature