Transcriptomic stratification predicts response to rituximab, abatacept, or the association of hydroxychloroquine and leflunomide in 3 randomised controlled clinical trials of Sjögren's disease.

We previously identified 4 transcriptomic endotypes in SjD patients using whole-blood RNA sequencing.

我们之前通过全血RNA测序在SjD患者中识别出4种转录组表型。

We hypothesised that these endotypes may predict differential therapeutic responses.

我们假设这些内型可能预测不同的治疗反应。

Methods

We analysed clinical, biological, and transcriptomic data from 3 randomised controlled trials evaluating hydroxychloroquine-leflunomide (HCQ-LEF; n = 18; RepurpSS-I trial), rituximab (RTX; n = 56; TRACTISS trial), and abatacept (n = 117).

我们分析了来自三项随机对照试验的临床、生物学和转录组数据，这些试验评估了羟氯喹-来氟米特（HCQ-LEF; n = 18; RepurpSS-I试验）、利妥昔单抗（RTX; n = 56; TRACTISS试验）和阿巴西普（n = 117）。

Patients were assigned to the 4 endotypes using semisupervised uniform manifold approximation and projection combined with a support vector machine model.

患者根据半监督的统一流形近似和投影结合支持向量机模型被分配到4种内型。

Demographics, disease activity, and therapeutic response, as defined by the Sjögren Tool for Assessing Response index, were compared across clusters in both pooled and individual trial analyses.

在合并和个别试验分析中，根据Sjögren评估反应指数定义的患者人口统计学特征、疾病活动度和治疗反应在各个群集中进行了比较。

Results

Of 170 patients, 81, 24, 80, and 6 were classified into clusters 1 to 4, respectively.

在170名患者中，分别有81名、24名、80名和6名被归类为第1至第4群。

European Alliance of Associations for Rheumatology (EULAR) Sjögren's Syndrome Patient Reported Index scores were comparable across clusters, while the EULAR Sjögren's Syndrome Disease Activity Index was significantly higher in clusters 3 and 4 vs clusters 1 and 2 (P = .003).

欧洲风湿病协会联盟（EULAR）干燥综合征患者报告指数在各群之间是可比的，而EULAR干燥综合征疾病活动指数在第3群和第4群中显著高于第1群和第2群（P = .003）。

In pooled analyses, patients in cluster 1 had significantly greater response rates with active treatment vs placebo (61.5% vs 32.6%: P = .016), with a similar trend in the RTX trial. In contrast, patients in cluster 3 benefitted from HCQ-LEF, whereas cluster 2 (healthy-like patients) showed no significant response to any therapy.

在汇总分析中，1类患者在接受活性治疗与安慰剂治疗时，反应率显著更高（61.5%对比32.6%: P = .016），RTX试验中也显示出类似趋势。相比之下，3类患者从HCQ-LEF治疗中获益，而2类（类似健康患者）对任何治疗均无显著反应。

Conclusions

Transcriptomic stratification of SjD patients revealed differential responses to HCQ-LEF and RTX.

对SjD患者的转录组分层揭示了对HCQ-LEF和RTX的不同反应。

Notably, healthy-like patients exhibited minimal treatment response, suggesting they may be unsuitable candidates for future therapeutic trials.

值得注意的是，健康状况良好的患者表现出最小的治疗反应，这表明他们可能不适合未来治疗试验的候选人。