title: Blood-based identification of non-responders to anti-TNF therapy in rheumatoid arthritis.
abstract: BACKGROUND
  Faced with an increasing number of choices for biologic therapies, rheumatologists have a critical need for better tools to inform rheumatoid arthritis (RA) disease management. The ability to identify patients who are unlikely to respond to first-line biologic anti-TNF therapies prior to their treatment would allow these patients to seek alternative therapies, providing faster relief and avoiding complications of disease.
  
  
  METHODS
  We identified a gene expression classifier to predict, pre-treatment, which RA patients are unlikely to respond to the anti-TNF infliximab. The classifier was trained and independently evaluated using four published whole blood gene expression data sets, in which RA patients (n = 116 = 44 + 15 + 30 + 27) were treated with infliximab, and their response assessed 14-16 months post treatment according to the European League Against Rheumatism (EULAR) response criteria. For each patient, prior knowledge was used to group gene expression measurements into disease-relevant biological signaling mechanisms that were used as the input features for regularized logistic regression.
  
  
  RESULTS
  The classifier produced a substantial enrichment of non-responders (59 %, given by the cross validated test precision) compared to the full population (27 % non-responders), while identifying nearly a third of non-responders. Given this classifier performance, treatment of predicted non-responders with alternative biologics would decrease their chance of non-response by between a third and a half, substantially improving their odds of effective treatment and stemming further disease progression. The classifier consisted of 18 signaling mechanisms, which together indicated that higher inflammatory signaling mediated by TNF and other cytokines was present pre-treatment in the blood of patients who responded to infliximab treatment. In contrast, non-responders were classified by relatively higher levels of specific metabolic activities in the blood prior to treatment.
  
  
  CONCLUSIONS
  We were able to successfully produce a classifier to identify a population of RA patients significantly enriched in anti-TNF non-responders across four different patient cohorts. Additional prospective studies are needed to validate and refine the classifier for clinical use.
authors.affiliation: Selventa, Inc., Cambridge, MA, USA. tthomson@selventa.com.
authors.forename: Ty M
authors.initials: TM
authors.lastname: Thomson
authors.affiliation: Selventa, Inc., Cambridge, MA, USA. reynald.lescarbeau@gmail.com.
authors.forename: Reynald M
authors.initials: RM
authors.lastname: Lescarbeau
authors.affiliation: Selventa, Inc., Cambridge, MA, USA. ddrubin@selventa.com.
authors.forename: David A
authors.initials: DA
authors.lastname: Drubin
authors.affiliation: Selventa, Inc., Cambridge, MA, USA. dlaifenfeld@gmail.com.
authors.forename: Daphna
authors.initials: D
authors.lastname: Laifenfeld
authors.affiliation: Selventa, Inc., Cambridge, MA, USA. ddegraaf@selventa.com.
authors.forename: David
authors.initials: D
authors.lastname: de Graaf
authors.affiliation: Selventa, Inc., Cambridge, MA, USA. dfryburg@roibiopharma.com.
authors.forename: David A
authors.initials: DA
authors.lastname: Fryburg
authors.affiliation: Translational Medicine Associates, Stonington, CT, USA. bruce.littman@transmedassociates.com.
authors.forename: Bruce
authors.initials: B
authors.lastname: Littman
authors.affiliation: Selventa, Inc., Cambridge, MA, USA. rkenney@selventa.com.
authors.forename: Renée
authors.initials: R
authors.lastname: Deehan
authors.affiliation: Selventa, Inc., Cambridge, MA, USA. avanhooser@selventa.com.
authors.forename: Aaron
authors.initials: A
authors.lastname: Van Hooser
mesh_terms: D000465:Algorithms; D018501:Antirheumatic Agents / Q000627:therapeutic use*; D019540:Area Under Curve; D001172:Arthritis, Rheumatoid / Q000097:blood* / Q000188:drug therapy*; D001688:Biological Products / Q000627:therapeutic use*; D015331:Cohort Studies; D030541:Databases, Genetic; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D006801:Humans; D000069285:Infliximab / Q000627:therapeutic use*; D016015:Logistic Models; D020411:Oligonucleotide Array Sequence Analysis; D015398:Signal Transduction; D012984:Software; D016896:Treatment Outcome; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors*
chemical_list: D018501:Antirheumatic Agents; D001688:Biological Products; D014409:Tumor Necrosis Factor-alpha; D000069285:Infliximab