RT Journal Article
SR Electronic
T1 Molecular characterisation of lupus low disease activity state (LLDAS) and DORIS remission by whole-blood transcriptome-based pathways in a pan-European systemic lupus erythematosus cohort
JF Annals of the Rheumatic Diseases
JO Ann Rheum Dis
FD BMJ Publishing Group Ltd and European League Against Rheumatism
SP 889
OP 900
DO 10.1136/ard-2023-224795
VO 83
IS 7
A1 Parodis, Ioannis
A1 Lindblom, Julius
A1 Barturen, Guillermo
A1 Ortega-Castro, Rafaela
A1 Cervera, Ricard
A1 Pers, Jacques-Olivier
A1 Genre, Fernanda
A1 Hiepe, Falk
A1 Gerosa, Maria
A1 Kovács, László
A1 De Langhe, Ellen
A1 Piantoni, Silvia
A1 Stummvoll, Georg
A1 Vasconcelos, Carlos
A1 Vigone, Barbara
A1 Witte, Torsten
A1 ,
A1 Alarcón-Riquelme, Marta E
A1 Beretta, Lorenzo
YR 2024
UL http://ard.bmj.com/content/83/7/889.abstract
AB Objectives To unveil biological milieus underlying low disease activity (LDA) and remission versus active systemic lupus erythematosus (SLE).Methods We determined differentially expressed pathways (DEPs) in SLE patients from the PRECISESADS project (NTC02890121) stratified into patients fulfilling and not fulfilling the criteria of (1) Lupus LDA State (LLDAS), (2) Definitions of Remission in SLE remission, and (3) LLDAS exclusive of remission.Results We analysed data from 321 patients; 40.8% were in LLDAS, and 17.4% in DORIS remission. After exclusion of patients in remission, 28.3% were in LLDAS. Overall, 604 pathways differed significantly in LLDAS versus non-LLDAS patients with an false-discovery rate-corrected p (q)<0.05 and a robust effect size (dr)≥0.36. Accordingly, 288 pathways differed significantly between DORIS remitters and non-remitters (q<0.05 and dr≥0.36). DEPs yielded distinct molecular clusters characterised by differential serological, musculoskeletal, and renal activity. Analysis of partially overlapping samples showed no DEPs between LLDAS and DORIS remission. Drug repurposing potentiality for treating SLE was unveiled, as were important pathways underlying active SLE whose modulation could aid attainment of LLDAS/remission, including toll-like receptor (TLR) cascades, Bruton tyrosine kinase (BTK) activity, the cytotoxic T lymphocyte antigen 4 (CTLA-4)-related inhibitory signalling, and the nucleotide-binding oligomerization domain leucine-rich repeat-containing protein 3 (NLRP3) inflammasome pathway.Conclusions We demonstrated for the first time molecular signalling pathways distinguishing LLDAS/remission from active SLE. LLDAS/remission was associated with reversal of biological processes related to SLE pathogenesis and specific clinical manifestations. DEP clustering by remission better grouped patients compared with LLDAS, substantiating remission as the ultimate treatment goal in SLE; however, the lack of substantial pathway differentiation between the two states justifies LLDAS as an acceptable goal from a biological perspective.Data are available upon reasonable request. Data are available on reasonable request. Raw data are property of the PRECISESADS consortium and protected under the European General Data Protection Regulation (GDPR). Metadata and aggregated processed data are available upon reasonable request from the corresponding author and from the EGA (European Genome-phenome Archive).