TY - JOUR
T1 - Transcriptomic stratification predicts response to rituximab, abatacept, or the association of hydroxychloroquine and leflunomide in 3 randomised controlled clinical trials of Sjögren's disease
AU - Chevet, Baptiste
AU - Devauchelle-Pensec, Valérie
AU - Pontarini, Elena
AU - Baloche, Valentin
AU - Bombardieri, Michele
AU - Bowman, Simon J
AU - Barnes, Michael
AU - Sreih, Antoine G
AU - Liu, Jinqi
AU - Kelly, Sheila
AU - Christodoulou, Antonia
AU - Moingeon, Philippe
AU - Laigle, Laurence
AU - Soret, Perrine
AU - Le Dantec, Christelle
AU - Pers, Jacques-Olivier
AU - Alarcon-Riquelme, Marta E
AU - Barturen, Guillermo
AU - Mariette, Xavier
AU - van Roon, Joel
AU - Seror, Raphaèle
AU - Nocturne, Gaetane
AU - Cornec, Divi
AU - Foulquier, Nathan
N1 - Publisher Copyright:
© 2025 European Alliance of Associations for Rheumatology (EULAR). Published by Elsevier B.V. All rights are reserved, including those for text and data mining, AI training, and similar technologies.
PY - 2026/5
Y1 - 2026/5
N2 - OBJECTIVES: Sjögren's disease (SjD) is clinically and biologically heterogeneous, and no immunomodulatory drug has yet demonstrated efficacy in phase 3 trials. We previously identified 4 transcriptomic endotypes in SjD patients using whole-blood RNA sequencing. We hypothesised that these endotypes may predict differential therapeutic responses.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). Patients were assigned to the 4 endotypes using semisupervised uniform manifold approximation and projection combined with a support vector machine model. 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.RESULTS: Of 170 patients, 81, 24, 80, and 6 were classified into clusters 1 to 4, respectively. 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). 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.CONCLUSIONS: Transcriptomic stratification of SjD patients revealed differential responses to HCQ-LEF and RTX. Notably, healthy-like patients exhibited minimal treatment response, suggesting they may be unsuitable candidates for future therapeutic trials.
AB - OBJECTIVES: Sjögren's disease (SjD) is clinically and biologically heterogeneous, and no immunomodulatory drug has yet demonstrated efficacy in phase 3 trials. We previously identified 4 transcriptomic endotypes in SjD patients using whole-blood RNA sequencing. We hypothesised that these endotypes may predict differential therapeutic responses.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). Patients were assigned to the 4 endotypes using semisupervised uniform manifold approximation and projection combined with a support vector machine model. 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.RESULTS: Of 170 patients, 81, 24, 80, and 6 were classified into clusters 1 to 4, respectively. 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). 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.CONCLUSIONS: Transcriptomic stratification of SjD patients revealed differential responses to HCQ-LEF and RTX. Notably, healthy-like patients exhibited minimal treatment response, suggesting they may be unsuitable candidates for future therapeutic trials.
UR - https://www.scopus.com/pages/publications/105030237474
U2 - 10.1016/j.ard.2025.11.017
DO - 10.1016/j.ard.2025.11.017
M3 - Article
C2 - 41448992
SN - 0003-4967
VL - 85
SP - 873
EP - 879
JO - Annals of the rheumatic diseases
JF - Annals of the rheumatic diseases
ER -