Subsets of Patients With Lupus Identified by Gene Expression Profiles Exhibit Differential Clinical Responsiveness to Baricitinib

IF 9.9 1区医学 Q1 RHEUMATOLOGY

Arthritis & Rheumatology Pub Date : 2026-09-28 Epub Date: 2026-04-07 DOI:10.1002/art.70130

Prathyusha Bachali MS, Amrie Grammer PhD, Peter E. Lipsky MD

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引用次数: 0

Abstract

Objective

Baricitinib is a JAK1 inhibitor that showed efficacy in patients with systemic lupus erythematosus (SLE) in a phase 2 study but failed to meet the primary endpoint in phase 3 trials. To understand this discrepancy and identify patients with SLE who are responsive to baricitinib, we conducted baseline and longitudinal transcriptomic analysis in patients enrolled in the phase 2 trial.

Methods

Whole-blood samples from 272 patients with SLE were analyzed. Clinical response was assessed using SLE Responder Index-4 after 24 weeks of placebo or baricitinib (2 or 4 mg daily). Gene expression profiling was conducted using Gene Set Variation Analysis (GSVA) of 32 immune-related gene modules.

Results

Eight distinct molecular endotypes (A–H) were identified from baseline GSVA scores, with progressively increasing immune disturbances. Baseline demographics were similar across endotypes, with modest but significant differences in anti–double-stranded DNA and complement levels but no SLE Disease Activity Index differences. Significant clinical responses to baricitinib were confined to endotypes D and G (P = 0.004 and 0.048 vs placebo, with effect sizes of 41.54% and 31.89%, respectively). Importantly, patient clustering based on clinical features failed to identify treatment-responsive subsets. Endotype G demonstrated the most pronounced treatment-related transcriptional modulation, with dose-dependent suppression of interferon, JAK1/JAK2/TYK2 signaling, immunoproteasome, and inflammatory pathways evident as early as week 2 and sustained through week 24. Transcriptional changes in response to baricitinib were largely confined to clinical responders in endotype G. Feature importance analysis identified the interferon and Treg cell signatures as major predictors of response.

Conclusion

Transcriptomic analysis identified subsets of patients with SLE responsive to baricitinib.

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由基因表达谱鉴定的狼疮患者亚群对Baricitinib表现出不同的临床反应性。

baricitinib是一种JAK1抑制剂，在2期研究中显示对系统性红斑狼疮（SLE）患者有效，但在3期试验中未能达到主要终点。为了了解这种差异并确定对巴西替尼有反应的SLE患者，我们对参加2期试验的患者进行了基线和纵向转录组分析。方法对272例SLE患者全血标本进行分析。在服用安慰剂或巴西替尼（每日2或4毫克）24周后，使用SLE Responder Index-4 （SRI-4）评估临床反应。采用基因集变异分析（GSVA）对32个免疫相关基因模块进行基因表达谱分析。结果从基线GSVA评分中鉴定出8种不同的分子内型（A-H），免疫干扰逐渐增加。不同内型的基线人口统计数据相似，抗dsdna和补体水平存在适度但显著的差异，但SLEDAI没有差异。baricitinib的显著临床反应局限于D和G内型（与安慰剂相比，p=0.004和0.048，效应量分别为41.54%和31.89%）。重要的是，基于临床特征的患者聚类无法识别治疗反应亚群。Endotype G表现出最明显的治疗相关转录调节，干扰素、JAK1/JAK2/TYK2信号、免疫蛋白酶体和炎症途径的剂量依赖性抑制早在第2周就出现，并持续到第24周。对巴西替尼应答的转录变化主要局限于内啡肽g型临床应答者，特征重要性分析确定干扰素和Treg特征是应答的主要预测因子。结论：转录组学分析证实SLE患者亚群对巴西替尼有反应。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Arthritis & Rheumatology RHEUMATOLOGY-

CiteScore

20.90

自引率

3.00%

发文量

371

期刊介绍： Arthritis & Rheumatology is the official journal of the American College of Rheumatology and focuses on the natural history, pathophysiology, treatment, and outcome of rheumatic diseases. It is a peer-reviewed publication that aims to provide the highest quality basic and clinical research in this field. The journal covers a wide range of investigative areas and also includes review articles, editorials, and educational material for researchers and clinicians. Being recognized as a leading research journal in rheumatology, Arthritis & Rheumatology serves the global community of rheumatology investigators and clinicians.