Op0129 belimumab After Rituximab Significantly Reduced Igg Anti-Dsdna Antibody Levels and Prolonged Time to Severe Flare in Patients With Systemic Lupus Erythematosus

Abstract

Background:B cell depletion with rituximab, an anti-CD20 mAb, has shown efficacy for systemic lupus erythematosus (SLE) in open-label studies but failed to meet primary endpoints in two randomised, placebo controlled trials. Rituximab increases BAFF levels which has been associated with subsequent lupus flares. We hypothesised that high BAFF levels after rituximab limit its effectiveness in SLE and that the anti-BAFF monoclonal antibody belimumab given immediately after rituximab could be a valuable therapeutic strategy.Objectives:To assess the safety and obtain preliminary evidence for efficacy of belimumab following rituximab therapy in patients with SLE.Methods:BEAT-LUPUS (Belimumab after B cell depletion in SLE) is a 52-week phase IIb, randomised, double-blind, placebo-controlled clinical trial investigating the safety and efficacy of intravenous belimumab after B cell depletion therapy (rituximab). The maximum permissible prednisolone dose throughout the trial was 20mg/day with encouragement to reduce by 50% from baseline by 6 months. The primary outcome measure was log IgG anti-dsDNA antibody serum levels at 52 weeks measured by ELISA. A linear regression ANCOVA model was fitted to evaluate the difference in 52-week anti-dsDNA levels between treatment arms adjusting for anti-dsDNA value at screening (before rituximab) and randomisation (4-8 weeks after the 1st infusion of rituximab), CD19 > or < 0.01x109/l at randomisation, and renal involvement at screen. Secondary outcomes included measures of disease activity and incidence of adverse events. B cell (CD19) counts were measured by flow cytometry. Intention to treat analysis was adopted. Full ethical and regulatory approval was obtained. A comprehensive description of the protocol and statistical analysis plan is available(1,2).Results:52 patients with active SLE received rituximab (2 infusions, 2 weeks apart) and then randomised to receive either belimumab (n=26) or placebo (n=26) 4-8 weeks after their 1st dose of rituximab. 32 patients completed trial treatment protocol (belimumab or placebo) through to 52 weeks, withdrawals were equally split between belimumab and placebo. There was a significant reduction in IgG anti-dsDNA antibody levels in patients treated with belimumab compared to placebo at 52 weeks (p<0.001, Figure 1); 43 patients were included in the intention to treat analysis at 52 weeks.Figure 1.Serum IgG anti-dsDNA antibody levels (geometric means with 95% confidence intervals) in patients treated with rituximab, then randomised to belimumab or placebo at 1st trial infusion. An intention to treat linear regression ANCOVA model was fitted to evaluate the difference in 52-week anti-dsDNA between belimumab or placebo adjusting for baseline values and stratification factors. N= patient numbers who provided serum samples at time indicated.Kaplan-Meier curves demonstrated that belimumab reduced the risk of severe flare (BILAG A flare) compared to placebo (hazard ratio 0.27, 95% confidence interval 0.07-0.97, unadjusted log-rank p=0.03). There were 10 and 3 severe flares in the placebo and belimumab group respectively. There was no difference in cumulative steroid dose over the course of the trial between belimumab and placebo.Belimumab did not increase the incidence of infections, serious or total adverse events, nor withdrawals due to adverse events compared to placebo. Belimumab significantly suppressed B cell repopulation at 52 weeks compared to placebo (p=0.001), but not total serum IgG.Conclusion:This placebo controlled double blind trial met its primary endpoint, a significant reduction in IgG anti-dsDNA antibody levels, and demonstrated that belimumab prolongs the time to severe flare compared to placebo. These results suggest that belimumab after rituximab is a safe and effective treatment for patients with SLE and supports further development of this combination as a novel therapeutic strategy.References:[1]Jones A, et al. BMJ Open. 2019;9:e032569.[3]Muller P, et al. Trials. 2020;21:652.Acknowledgements:We acknowledge the important contribution of the BEAT Lupus Trial Steering Committee, the Data Monitoring Committee, the BEAT-LUPUS trial investigators, and all the patients participating in the trial or involved in its development.Funding:This trial was supported by Versus Arthritis (grant number 20873) and the UCLH Biomedical Research Centre (BRC). GSK provided belimumab free of charge, as well as additional funding.GSK had no role in the design of this study and will not have any role during its execution, analyses, interpretation of the data, or decision to submit results. Versus Arthritis and the UCLH BRC reviewed the relevant grant proposals and monitor progress of relevant aspects of the study but did not play any role in the analyses, interpretation of data, or decision to submit results.Disclosure of Interests:Muhammad Shipa: None declared, Andrew Embleton-Thirsk: None declared, Mariea Parvaz: None declared, Liliana Santos Ribeiro: None declared, Patrick Muller: None declared, Kashfia Chowdhury: None declared, David Isenberg Speakers bureau: Paid by GSK to deliver educational talks, Consultant of: Received consultancy fees from GSK for attending advisory boards, Caroline Doré: None declared, Caroline Gordon Speakers bureau: Paid for educational speaker role by GSK, Consultant of: Received consultancy fees from GSK for attending advisory boards, Michael Ehrenstein Speakers bureau: Paid by GSK as a speaker in educational sessions, Consultant of: Received consultancy fees from GSK for attending advisory boards, Grant/research support from: GSK provided part of the funding for the BEAT-LUPUS trial

A randomized, phase II study of sequential belimumab and rituximab in primary Sjögren’s syndrome

“…The overall safety of belimumab, rituximab, and belimumab + rituximab sequential treatment in this study was consistent with the known individual safety profiles for belimumab and rituximab (21,34,58). Although the safety profile of belimumab + rituximab in pSS has not been explored widely, this combination has previously demonstrated acceptable safety profiles in case studies of patients with pSS (50,57), as well as in previously published phase II studies of patients with SLE or LN, which are consistent with the results shown in this study (59)(60)(61). Overall, there were no imbalances of clinical concern in the incidence of reported AEs or AEs of special interest (AESIs; malignant neoplasms, PASR, infections, depression, suicide/self-injury) across treatment groups.…”

“…The hypothesis that sequential belimumab + rituximab treatment may result in an improved clinical response has been supported by controlled, randomized clinical trials in patients with SLE and several small case studies ( 50 , 55 – 57 , 60 , 72 ). One case study in particular reported long-term efficacy and safety of belimumab + rituximab in pSS ( 50 , 51 ).…”

“…In addition, combination treatment of rituximab and belimumab in the SynBioSe clinical trial led to specific reductions in anti-nuclear antibodies and neutrophil extracellular trap formation; combination treatment also achieved an acceptable safety profile, a reduction in SLE disease activity, positive renal responses, and immunosuppressive medication tapering ( 59 ). In the BEAT-LUPUS study, significant reductions in IgG anti–double-stranded DNA antibody levels and prolonged time to severe flare were also observed with combination treatment versus rituximab monotherapy in patients with SLE ( 60 ). The randomized controlled trial presented here is the first to study the sequential administration of these 2 complementary therapies in patients with pSS.…”

The Role of B Cells in Adult and Paediatric Liver Injury

“…In SLE, pilot trials and observational studies were initially promising but larger scale clinical trials did not show a clear benefit. Recent trials of a combination of Belimumab, which targets the cytokine BLyS with Rituximab, however, show promise in SLE (216). Direct cross-linking of CD20 on B cell tumour cell lines was shown to be sufficient for the induction of apoptosis through MAP kinase activation (212, (190,191,193,199,201,207) A brief summary of the clinical features and immune compartment involvement in adult and paediatric liver diseases.…”