Attainment of remission and low disease activity after treatment with belimumab in patients with systemic lupus erythematosus: a post-hoc analysis of pooled data from five randomised clinical trials

IF 15 1区 医学 Q1 RHEUMATOLOGY Lancet Rheumatology Pub Date : 2024-08-26 DOI:10.1016/S2665-9913(24)00162-0
Ioannis Parodis MD , Julius Lindblom MD , Prof Roger A Levy MD , Margherita Zen MD , Nursen Cetrez MD , Alvaro Gomez MD , Shereen Oon MBBS , Christine Henning PharmD , Prof Munther Khamashta MD , Holly A Quasny PharmD , Deven Chauhan MSc , Prof Anca Askanase MD , Prof Ronald van Vollenhoven MD , Prof Mandana Nikpour MBBS
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In this study, we aimed to pool data across trials to assess attainment of remission and low disease activity in a large, racially and culturally diverse patient population with SLE.</div></div><div><h3>Methods</h3><div>In this integrated post-hoc analysis, we pooled data from five phase 3 trials of belimumab (BLISS-76 [<span><span>NCT00410384</span><svg><path></path></svg></span>], BLISS-52 [<span><span>NCT00424476</span><svg><path></path></svg></span>], BLISS-NEA [<span><span>NCT01345253</span><svg><path></path></svg></span>], BLISS-SC [<span><span>NCT01484496</span><svg><path></path></svg></span>], and EMBRACE [<span><span>NCT01632241</span><svg><path></path></svg></span>]), in patients with active, autoantibody-positive SLE. Patients were randomly assigned to receive belimumab (10 mg/kg per month intravenously or 200 mg per week subcutaneously) or placebo, plus standard therapy. The proportion of patients with Definitions of Remission in SLE (DORIS) remission and lupus low disease activity state (LLDAS) were analysed every 4 weeks from week 4 to week 52 for belimumab versus placebo, using modified Poisson regression adjusted for trial variance, in all patients and in subgroups per baseline SLE Disease Activity Index-2000 score (&lt;10 or ≥10); anti-double stranded DNA positivity (yes or no); low complement 3 (C3) or C4 levels (yes or no); anti-dsDNA positivity or low C3 or C4 levels (yes and no); prednisone-equivalent dose (≤7·5 mg per day or &gt;7·5 mg per day); antimalarial use (yes or no); and by race (Black African ancestry or African American, Asian, Indigenous American, or White).</div></div><div><h3>Findings</h3><div>Data for 3086 patients (1869 in the belimumab group and 1217 in the placebo group) were analysed. 2913 (94%) of 3086 patients were women and 173 (6%) were men, and the median age was 36 years (IQR 28–45). The proportion of patients with DORIS remission was significantly higher in the belimumab group than the placebo group at weeks 28, 48, and 52 (week 52: 148 [8%] of 1869 participants <em>vs</em> 68 [6%] of 1217 participants; risk ratio 1·51 [95% CI 1·15–1·99]; p=0·0055). The proportion of patients who attained LLDAS was higher in the belimumab group than the placebo group at weeks 8, 24, 32–52 (week 52: 322 [17%] of 1869 participants <em>vs</em> 125 [10%] of 1217 participants; 1·74 [1·44–2·12]; p&lt;0·0001). A higher proportion of patients had DORIS remission at week 52 in the belimumab group than the placebo group among all baseline subgroups denoting high disease activity, with the exception of those on a prednisone-equivalent dose higher than 7·5 mg per day in whom there was no difference for DORIS remission with belimumab versus placebo. The proportion of patients with LLDAS was significantly higher among patients in the belimuab group than those who received placebo from week 44 in all baseline subgroups denoting high disease activity or earlier in some subgroups, and the differences were maintained at week 52.</div></div><div><h3>Interpretation</h3><div>In adults with active SLE, belimumab plus standard therapy yielded greater benefit than placebo plus standard therapy in attaining DORIS remission (for which low rates were attained in both groups) and LLDAS, with differences observed as early as week 28 for DORIS remission and week 8 for LLDAS.</div></div><div><h3>Funding</h3><div>Swedish Rheumatism Association, King Gustaf V's 80-year Foundation, Swedish Society of Medicine, Nyckelfonden, Professor Nanna Svartz Foundation, Ulla and Roland Gustafsson Foundation, Region Stockholm, and the Karolinska Institutet.</div></div>","PeriodicalId":48540,"journal":{"name":"Lancet Rheumatology","volume":"6 11","pages":"Pages e751-e761"},"PeriodicalIF":15.0000,"publicationDate":"2024-08-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Lancet Rheumatology","FirstCategoryId":"3","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S2665991324001620","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"RHEUMATOLOGY","Score":null,"Total":0}
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Abstract

Background

Disease remission or low disease activity are key treatment targets for patients with systemic lupus erythematosus (SLE). Pivotal trials of belimumab were conducted before the introduction of these targets. In this study, we aimed to pool data across trials to assess attainment of remission and low disease activity in a large, racially and culturally diverse patient population with SLE.

Methods

In this integrated post-hoc analysis, we pooled data from five phase 3 trials of belimumab (BLISS-76 [NCT00410384], BLISS-52 [NCT00424476], BLISS-NEA [NCT01345253], BLISS-SC [NCT01484496], and EMBRACE [NCT01632241]), in patients with active, autoantibody-positive SLE. Patients were randomly assigned to receive belimumab (10 mg/kg per month intravenously or 200 mg per week subcutaneously) or placebo, plus standard therapy. The proportion of patients with Definitions of Remission in SLE (DORIS) remission and lupus low disease activity state (LLDAS) were analysed every 4 weeks from week 4 to week 52 for belimumab versus placebo, using modified Poisson regression adjusted for trial variance, in all patients and in subgroups per baseline SLE Disease Activity Index-2000 score (<10 or ≥10); anti-double stranded DNA positivity (yes or no); low complement 3 (C3) or C4 levels (yes or no); anti-dsDNA positivity or low C3 or C4 levels (yes and no); prednisone-equivalent dose (≤7·5 mg per day or >7·5 mg per day); antimalarial use (yes or no); and by race (Black African ancestry or African American, Asian, Indigenous American, or White).

Findings

Data for 3086 patients (1869 in the belimumab group and 1217 in the placebo group) were analysed. 2913 (94%) of 3086 patients were women and 173 (6%) were men, and the median age was 36 years (IQR 28–45). The proportion of patients with DORIS remission was significantly higher in the belimumab group than the placebo group at weeks 28, 48, and 52 (week 52: 148 [8%] of 1869 participants vs 68 [6%] of 1217 participants; risk ratio 1·51 [95% CI 1·15–1·99]; p=0·0055). The proportion of patients who attained LLDAS was higher in the belimumab group than the placebo group at weeks 8, 24, 32–52 (week 52: 322 [17%] of 1869 participants vs 125 [10%] of 1217 participants; 1·74 [1·44–2·12]; p<0·0001). A higher proportion of patients had DORIS remission at week 52 in the belimumab group than the placebo group among all baseline subgroups denoting high disease activity, with the exception of those on a prednisone-equivalent dose higher than 7·5 mg per day in whom there was no difference for DORIS remission with belimumab versus placebo. The proportion of patients with LLDAS was significantly higher among patients in the belimuab group than those who received placebo from week 44 in all baseline subgroups denoting high disease activity or earlier in some subgroups, and the differences were maintained at week 52.

Interpretation

In adults with active SLE, belimumab plus standard therapy yielded greater benefit than placebo plus standard therapy in attaining DORIS remission (for which low rates were attained in both groups) and LLDAS, with differences observed as early as week 28 for DORIS remission and week 8 for LLDAS.

Funding

Swedish Rheumatism Association, King Gustaf V's 80-year Foundation, Swedish Society of Medicine, Nyckelfonden, Professor Nanna Svartz Foundation, Ulla and Roland Gustafsson Foundation, Region Stockholm, and the Karolinska Institutet.
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系统性红斑狼疮患者接受贝利木单抗治疗后病情缓解和疾病活动度降低:对五项随机临床试验汇总数据的事后分析。
背景:疾病缓解或疾病活动度低是系统性红斑狼疮(SLE)患者的主要治疗目标。贝利木单抗的关键性试验是在引入这些目标之前进行的。在这项研究中,我们旨在汇集各项试验的数据,以评估大量具有种族和文化多样性的系统性红斑狼疮患者达到缓解和低疾病活动度的情况:在这项综合事后分析中,我们汇总了贝利木单抗五项三期试验(BLISS-76 [NCT00410384]、BLISS-52 [NCT00424476]、BLISS-NEA [NCT01345253]、BLISS-SC [NCT01484496]和EMBRACE [NCT01632241])的数据,这些试验均针对活动性自身抗体阳性系统性红斑狼疮患者。患者被随机分配接受贝利木单抗(每月静脉注射10毫克/千克或每周皮下注射200毫克)或安慰剂以及标准疗法。从第4周到第52周,每隔4周分析一次贝利木单抗与安慰剂的对比情况,采用经试验方差调整的改良泊松回归法,对所有患者以及按系统性红斑狼疮疾病活动指数-2000基线评分(每天7-5毫克)、抗疟药物使用情况(是或否)和种族(黑非洲血统或非裔美国人、亚洲人、土著美国人或白人)划分的亚组进行分析。研究结果:分析了3086名患者(贝利木单抗组1869人,安慰剂组1217人)的数据。3086名患者中有2913名(94%)为女性,173名(6%)为男性,年龄中位数为36岁(IQR为28-45岁)。在第28、48和52周,贝利木单抗组患者的DORIS缓解比例明显高于安慰剂组(第52周:1869名参与者中的148人[8%] vs 1217名参与者中的68人[6%];风险比1-51 [95% CI 1-15-1-99];P=0-0055)。在第8、24、32-52周,贝利木单抗组达到LLDAS的患者比例高于安慰剂组(第52周:1869名参与者中的322[17%]对1217名参与者中的125[10%];1-74 [1-44-2-12];p解释:在活动性系统性红斑狼疮成人患者中,贝利木单抗联合标准疗法比安慰剂联合标准疗法在获得DORIS缓解(两组均达到较低比例)和LLDAS方面的获益更大,最早在DORIS缓解的第28周和LLDAS的第8周就观察到了差异:瑞典风湿病协会、古斯塔夫五世国王 80 年基金会、瑞典医学会、Nyckelfonden、Nanna Svartz 教授基金会、Ulla 和 Roland Gustafsson 基金会、斯德哥尔摩地区以及卡罗林斯卡医学院。
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来源期刊
Lancet Rheumatology
Lancet Rheumatology RHEUMATOLOGY-
CiteScore
34.70
自引率
3.10%
发文量
279
期刊介绍: The Lancet Rheumatology, an independent journal, is dedicated to publishing content relevant to rheumatology specialists worldwide. It focuses on studies that advance clinical practice, challenge existing norms, and advocate for changes in health policy. The journal covers clinical research, particularly clinical trials, expert reviews, and thought-provoking commentary on the diagnosis, classification, management, and prevention of rheumatic diseases, including arthritis, musculoskeletal disorders, connective tissue diseases, and immune system disorders. Additionally, it publishes high-quality translational studies supported by robust clinical data, prioritizing those that identify potential new therapeutic targets, advance precision medicine efforts, or directly contribute to future clinical trials. With its strong clinical orientation, The Lancet Rheumatology serves as an independent voice for the rheumatology community, advocating strongly for the enhancement of patients' lives affected by rheumatic diseases worldwide.
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