Integrative Analysis Reveals a Molecular Stratification of Systemic Autoimmune Diseases.
Adult
Aged
Antiphospholipid Syndrome
/ genetics
Arthritis, Rheumatoid
/ genetics
Autoimmune Diseases
/ classification
Case-Control Studies
Cluster Analysis
Cross-Sectional Studies
Epigenome
Epigenomics
Female
Gene Expression Profiling
Humans
Inflammation
/ immunology
Interferons
/ immunology
Lupus Erythematosus, Systemic
/ genetics
Male
Middle Aged
Mixed Connective Tissue Disease
/ genetics
Scleroderma, Systemic
/ genetics
Sjogren's Syndrome
/ genetics
Undifferentiated Connective Tissue Diseases
/ genetics
Journal
Arthritis & rheumatology (Hoboken, N.J.)
ISSN: 2326-5205
Titre abrégé: Arthritis Rheumatol
Pays: United States
ID NLM: 101623795
Informations de publication
Date de publication:
06 2021
06 2021
Historique:
received:
13
07
2020
accepted:
01
12
2020
pubmed:
27
1
2021
medline:
13
8
2021
entrez:
26
1
2021
Statut:
ppublish
Résumé
Clinical heterogeneity, a hallmark of systemic autoimmune diseases, impedes early diagnosis and effective treatment, issues that may be addressed if patients could be classified into groups defined by molecular pattern. This study was undertaken to identify molecular clusters for reclassifying systemic autoimmune diseases independently of clinical diagnosis. Unsupervised clustering of integrated whole blood transcriptome and methylome cross-sectional data on 955 patients with 7 systemic autoimmune diseases and 267 healthy controls was undertaken. In addition, an inception cohort was prospectively followed up for 6 or 14 months to validate the results and analyze whether or not cluster assignment changed over time. Four clusters were identified and validated. Three were pathologic, representing "inflammatory," "lymphoid," and "interferon" patterns. Each included all diagnoses and was defined by genetic, clinical, serologic, and cellular features. A fourth cluster with no specific molecular pattern was associated with low disease activity and included healthy controls. A longitudinal and independent inception cohort showed a relapse-remission pattern, where patients remained in their pathologic cluster, moving only to the healthy one, thus showing that the molecular clusters remained stable over time and that single pathogenic molecular signatures characterized each individual patient. Patients with systemic autoimmune diseases can be jointly stratified into 3 stable disease clusters with specific molecular patterns differentiating different molecular disease mechanisms. These results have important implications for future clinical trials and the study of nonresponse to therapy, marking a paradigm shift in our view of systemic autoimmune diseases.
Substances chimiques
Interferons
9008-11-1
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1073-1085Commentaires et corrections
Type : CommentIn
Informations de copyright
© 2020, American College of Rheumatology.
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