title: Serum survivin predicts responses to treatment in active rheumatoid arthritis: a post hoc analysis from the SWEFOT trial.
abstract: BACKGROUND
  The identification of biomarkers that predict optimal and individual choices of treatment for patients with rheumatoid arthritis gains increasing attention. The purpose of this study was to investigate if the proto-oncogene survivin might aid in treatment decisions in early rheumatoid arthritis.
  
  
  METHODS
  Serum survivin levels were measured in 302 patients who completed the Swedish pharmacotherapy (SWEFOT) trial at baseline, 3, 12, and 24 months. Survivin levels > 0.45 ng/mL were considered positive. Based on the survivin status, core set outcomes measuring disease activity, functional disability, as well as global health and pain were evaluated after methotrexate (MTX) monotherapy at 3 months, and at 12 and 24 months of follow-up. Treatment of non-responders was randomly intensified with either a combination of disease-modifying antirheumatic drugs (triple therapy: MTX, sulfasalazine, and hydroxychloroquine) or by adding antibodies against tumor necrosis factor (anti-TNF).
  
  
  RESULTS
  Antirheumatic treatment resulted in an overall decrease of serum survivin levels. Survivin-positive patients at baseline who initially responded to MTX had a higher risk of disease re-activation (OR 3.21 (95% CI 1.12-9.24), P = 0.032) and failed to improve in their functional disability (P = 0.018) if having continued on MTX monotherapy compared to survivin-negative patients. Ever-smokers who were survivin-positive were less likely to respond to MTX than those who were survivin-negative (OR 1.91 (1.01-3.62), P = 0.045). In survivin-positive patients, triple therapy led to better improvements in disease activity than did MTX + anti-TNF. At 24 months, survivin-positive patients randomized to anti-TNF had a higher risk of active disease than those randomized to triple therapy (OR 3.15 (1.09-9.10), P = 0.037).
  
  
  CONCLUSIONS
  We demonstrate for the first time that survivin is a valuable serologic marker that can distinguish drug-specific clinical responses in early rheumatoid arthritis through the pragmatic clinical setting of the care-based SWEFOT trial. Although treatment response cannot solely be attributable to survivin status, per protocol sensitivity analyses confirmed the superior effect of triple therapy on survivin-positive patients.
  
  
  CONCLUSIONS
  Survivin-positive patients have poor outcomes if treated with MTX monotherapy. A decrease of survivin levels during treatment is associated with better clinical responses. For survivin-positive patients who fail MTX, triple therapy is associated with better outcomes than anti-TNF therapy.
  
  
  BACKGROUND
  WHO database at the Karolinska University Hospital: CT20080004 ; ClinicalTrials.gov: NCT00764725, registered 1 October 2008.
authors.affiliation: Unit for Clinical Therapy Research, Inflammatory Diseases (ClinTRID), Karolinska Institutet, D1:00, Karolinska University Hospital, 17176, Stockholm, Sweden. adrian.levitsky@ki.se.
authors.forename: Adrian
authors.initials: A
authors.lastname: Levitsky
authors.affiliation: Department of Rheumatology and Inflammation Research, Sahlgrenska University Hospital, University of Gothenburg, Gothenburg, Sweden. malin.erlandsson@gu.se.
authors.forename: Malin C
authors.initials: MC
authors.lastname: Erlandsson
authors.affiliation: Unit for Clinical Therapy Research, Inflammatory Diseases (ClinTRID), Karolinska Institutet, D1:00, Karolinska University Hospital, 17176, Stockholm, Sweden. ronald.van.vollenhoven@ki.se.
authors.forename: Ronald F
authors.initials: RF
authors.lastname: van Vollenhoven
authors.affiliation: Department of Rheumatology and Inflammation Research, Sahlgrenska University Hospital, University of Gothenburg, Gothenburg, Sweden. maria.bokarewa@rheuma.gu.se.
authors.forename: Maria I
authors.initials: MI
authors.lastname: Bokarewa
mesh_terms: D000328:Adult; D018501:Antirheumatic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D001172:Arthritis, Rheumatoid / Q000097:blood* / Q000188:drug therapy; D015415:Biomarkers / Q000097:blood; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D006886:Hydroxychloroquine / Q000494:pharmacology / Q000627:therapeutic use; D051034:Inhibitor of Apoptosis Proteins / Q000097:blood*; D008297:Male; D008727:Methotrexate / Q000494:pharmacology / Q000627:therapeutic use; D008875:Middle Aged; D000090063:Proto-Oncogene Mas; D016032:Randomized Controlled Trials as Topic; D012460:Sulfasalazine / Q000494:pharmacology / Q000627:therapeutic use; D000077022:Survivin; D016896:Treatment Outcome; D014409:Tumor Necrosis Factor-alpha / Q000097:blood
chemical_list: D018501:Antirheumatic Agents; C107489:BIRC5 protein, human; D015415:Biomarkers; D051034:Inhibitor of Apoptosis Proteins; C000715470:MAS1 protein, human; D000090063:Proto-Oncogene Mas; D000077022:Survivin; C439524:TNF protein, human; D014409:Tumor Necrosis Factor-alpha; D012460:Sulfasalazine; D006886:Hydroxychloroquine; D008727:Methotrexate