title: Integration of known DNA, RNA and protein biomarkers provides prediction of anti-TNF response in rheumatoid arthritis: results from the COMBINE study.
abstract: OBJECTIVE
  In rheumatoid arthritis (RA) several recent efforts have sought to discover means of predicting which patients would benefit from treatment. However, results have been discrepant with few successful replications. Our objective was to build a biobank with DNA, RNA and protein measurements to test the claim that the current state-of-the-art precision medicine will benefit RA patients.
  
  
  METHODS
  We collected 451 blood samples from 61 healthy individuals and 185 RA patients initiating treatment, before treatment initiation and at a 3 month follow-up time. All samples were subjected to high-throughput RNA sequencing, DNA genotyping, extensive proteomics and flow cytometry measurements, as well as comprehensive clinical phenotyping. Literature review identified 2 proteins, 52 single-nucleotide polymorphisms (SNPs) and 72 gene-expression biomarkers that had previously been proposed as predictors of TNF inhibitor response (∆DAS28-CRP).
  
  
  RESULTS
  From these published TNFi biomarkers we found that 2 protein, 2 SNP and 8 mRNA biomarkers could be replicated in the 59 TNF initiating patients. Combining these replicated biomarkers into a single signature we found that we could explain 51% of the variation in ∆DAS28-CRP. This corresponds to a sensitivity of 0.73 and specificity of 0.78 for the prediction of three month ∆DAS28-CRP better than -1.2.
  
  
  CONCLUSIONS
  The COMBINE biobank is currently the largest collection of multi-omics data from RA patients with high potential for discovery and replication. Taking advantage of this we surveyed the current state-of-the-art of drug-response stratification in RA, and identified a small set of previously published biomarkers available in peripheral blood which predicts clinical response to TNF blockade in this independent cohort.
authors.affiliation: Department of Systems Biology, Technical University of Denmark, Lyngby, Denmark.|Unit of Rheumatology, Department of Medicine Solna, Karolinska Institutet and Karolinska University Hospital, Stockholm, Sweden.
authors.forename: Lasse
authors.initials: L
authors.lastname: Folkersen
authors.affiliation: Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Boel
authors.initials: B
authors.lastname: Brynedal
authors.affiliation: Unit of Rheumatology, Department of Medicine Solna, Karolinska Institutet and Karolinska University Hospital, Stockholm, Sweden.
authors.forename: Lina Marcela
authors.initials: LM
authors.lastname: Diaz-Gallo
authors.affiliation: Unit of Rheumatology, Department of Medicine Solna, Karolinska Institutet and Karolinska University Hospital, Stockholm, Sweden.
authors.forename: Daniel
authors.initials: D
authors.lastname: Ramsköld
authors.affiliation: Unit of Rheumatology, Department of Medicine Solna, Karolinska Institutet and Karolinska University Hospital, Stockholm, Sweden.
authors.forename: Klementy
authors.initials: K
authors.lastname: Shchetynsky
authors.affiliation: Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Helga
authors.initials: H
authors.lastname: Westerlind
authors.affiliation: Unit of Rheumatology, Department of Medicine Solna, Karolinska Institutet and Karolinska University Hospital, Stockholm, Sweden.
authors.forename: Yvonne
authors.initials: Y
authors.lastname: Sundström
authors.affiliation: Unit of Rheumatology, Department of Medicine Solna, Karolinska Institutet and Karolinska University Hospital, Stockholm, Sweden.
authors.forename: Danika
authors.initials: D
authors.lastname: Schepis
authors.affiliation: Unit of Rheumatology, Department of Medicine Solna, Karolinska Institutet and Karolinska University Hospital, Stockholm, Sweden.
authors.forename: Aase
authors.initials: A
authors.lastname: Hensvold
authors.affiliation: Unit of Rheumatology, Department of Medicine Solna, Karolinska Institutet and Karolinska University Hospital, Stockholm, Sweden.
authors.forename: Nancy
authors.initials: N
authors.lastname: Vivar
authors.affiliation: Department of Medical Sciences, Uppsala Universitet, Uppsala, Sweden.
authors.forename: Maija-Leena
authors.initials: ML
authors.lastname: Eloranta
authors.affiliation: Department of Medical Sciences, Uppsala Universitet, Uppsala, Sweden.
authors.forename: Lars
authors.initials: L
authors.lastname: Rönnblom
authors.affiliation: Department of Systems Biology, Technical University of Denmark, Lyngby, Denmark.
authors.forename: Søren
authors.initials: S
authors.lastname: Brunak
authors.affiliation: Unit of Rheumatology, Department of Medicine Solna, Karolinska Institutet and Karolinska University Hospital, Stockholm, Sweden.
authors.forename: Vivianne
authors.initials: V
authors.lastname: Malmström
authors.affiliation: Unit of Rheumatology, Department of Medicine Solna, Karolinska Institutet and Karolinska University Hospital, Stockholm, Sweden.
authors.forename: Anca
authors.initials: A
authors.lastname: Catrina
authors.affiliation: Current affiliation: AbbVie, Copenhagen, Denmark.
authors.forename: Ulrik Gw
authors.initials: UG
authors.lastname: Moerch
authors.affiliation: Unit of Rheumatology, Department of Medicine Solna, Karolinska Institutet and Karolinska University Hospital, Stockholm, Sweden.
authors.forename: Lars
authors.initials: L
authors.lastname: Klareskog
authors.affiliation: Unit of Rheumatology, Department of Medicine Solna, Karolinska Institutet and Karolinska University Hospital, Stockholm, Sweden.
authors.forename: Leonid
authors.initials: L
authors.lastname: Padyukov
authors.affiliation: Unit of Rheumatology, Department of Medicine Solna, Karolinska Institutet and Karolinska University Hospital, Stockholm, Sweden.
authors.forename: Louise
authors.initials: L
authors.lastname: Berg
keywords: TNF-alpha; biobank; drug response; pharmacogenetics; rheumatoid arthritis