title: Genomic stratification by expression of HLA-DRB4 alleles identifies differential innate and adaptive immune transcriptional patterns - A strategy to detect predictors of methotrexate response in early rheumatoid arthritis.
abstract: Effective drug selection is the current challenge in rheumatoid arthritis (RA). Treatment failure may follow different pathomechanisms and therefore require investigation of molecularly defined subgroups. In this exploratory study, whole blood transcriptomes of 68 treatment-naïve early RA patients were analyzed before initiating MTX. Subgroups were defined by serologic and genetic markers. Response related signatures were interpreted using reference transcriptomes of various cell types, cytokine stimulated conditions and bone marrow precursors. HLA-DRB4-negative patients exhibited most distinctive transcriptional differences. Preponderance of transcripts associated with phagocytes and bone marrow activation indicated response and transcripts of T- and B-lymphocytes non-response. HLA-DRB4-positive patients were more heterogeneous, but also linked failure to increased adaptive immune response. RT-qPCR confirmed reliable candidate selection and independent samples of responders and non-responders the functional patterning. In summary, genomic stratification identified different molecular pathomechanisms in early RA and preponderance of innate but not adaptive immune activation suggested response to MTX therapy.
authors: Department of Rheumatology and Clinical Immunology, Charité University Medicine, Berlin, Germany. Electronic address: bruno.stuhlmueller@charite.de.
authors: Bruno
authors: B
authors: Stuhlmüller
authors: Department of Rheumatology and Clinical Immunology, Charité University Medicine, Berlin, Germany.
authors: Karsten
authors: K
authors: Mans
authors: Department of Rheumatology and Clinical Immunology, Charité University Medicine, Berlin, Germany.
authors: Neeraj
authors: N
authors: Tandon
authors: Department of Rheumatology and Clinical Immunology, Charité University Medicine, Berlin, Germany.
authors: Marc O
authors: MO
authors: Bonin
authors: Department of Rheumatology and Clinical Immunology, Charité University Medicine, Berlin, Germany.
authors: Biljana
authors: B
authors: Smiljanovic
authors: Department of Rheumatology and Clinical Immunology, Charité University Medicine, Berlin, Germany.
authors: Till A
authors: TA
authors: Sörensen
authors: Department of Rheumatology and Clinical Immunology, Charité University Medicine, Berlin, Germany.
authors: Pascal
authors: P
authors: Schendel
authors: Institute of Clinical Epidemiology and Applied Biostatistics, University of Tübingen, Germany.
authors: Peter
authors: P
authors: Martus
authors: German Rheumatism Research Center, Berlin, Germany.
authors: Joachim
authors: J
authors: Listing
authors: Department of Rheumatology and Clinical Immunology, Charité University Medicine, Berlin, Germany.
authors: Jacqueline
authors: J
authors: Detert
authors: Department of Rheumatology and Clinical Immunology, Charité University Medicine, Berlin, Germany.
authors: Marina
authors: M
authors: Backhaus
authors: Department of Rheumatology, University Medicine Jena, Germany.
authors: Thomas
authors: T
authors: Neumann
authors: Department of Medicine, Columbia University, NY, New York, United States.
authors: Robert J
authors: RJ
authors: Winchester
authors: Department of Rheumatology and Clinical Immunology, Charité University Medicine, Berlin, Germany.
authors: Gerd-R
authors: GR
authors: Burmester
authors: Department of Rheumatology and Clinical Immunology, Charité University Medicine, Berlin, Germany.
authors: Thomas
authors: T
authors: Häupl
mesh_terms: D056704:Adaptive Immunity / Q000235:genetics*; D000328:Adult; D000368:Aged; D000483:Alleles; D018501:Antirheumatic Agents / Q000627:therapeutic use*; D001172:Arthritis, Rheumatoid / Q000188:drug therapy* / Q000235:genetics* / Q000276:immunology; D005260:Female; D023281:Genomics; D059845:HLA-DRB4 Chains / Q000235:genetics*; D006801:Humans; D007113:Immunity, Innate / Q000235:genetics*; D008297:Male; D008727:Methotrexate / Q000627:therapeutic use*; D008875:Middle Aged; D055815:Young Adult
chemical_list: D018501:Antirheumatic Agents; D059845:HLA-DRB4 Chains; D008727:Methotrexate
keywords: Genetics; Innate and adaptive immunity; Methotrexate; Response prediction; Rheumatoid arthritis