title: Identification of CXCL13 as a marker for rheumatoid arthritis outcome using an in silico model of the rheumatic joint.
abstract: OBJECTIVE
  Rheumatoid arthritis (RA) is characterized by inflammation and joint destruction, with the degree of damage varying greatly among patients. Prediction of disease severity using known clinical and serologic risk factors is inaccurate. This study was undertaken to identify new serologic markers for RA severity using an in silico model of the rheumatic joint.
  
  
  METHODS
  An in silico model of a prototypical rheumatic joint was used to predict candidate markers associated with erosiveness. The following 4 markers were chosen for validation: tartrate-resistant acid phosphatase 5b (TRAP-5b), N-telopeptide of type I collagen (NTX), angiopoietin 2 (Ang-2), and CXCL13. Serum from 74 RA patients was used to study whether radiologic joint destruction (total erosion score and total Sharp/van der Heijde score [SHS]) after 4 years of disease was associated with serum levels at the time of diagnosis. Serum marker levels were determined using enzyme-linked immunosorbent assays. For confirmation, baseline serum levels were analyzed for an association with progression of joint damage over 7 years of followup in a cohort of 155 patients with early RA.
  
  
  RESULTS
  Comparison of high and low quartiles of erosion score and SHS at 4 years showed a difference in baseline serum CXCL13 level (P = 0.011 and P = 0.018, respectively). In the confirmation cohort, elevated baseline CXCL13 levels were associated with increased rates of joint destruction during 7 years of followup (P < 0.001 unadjusted and P ≤ 0.004 with adjustment for C-reactive protein level). Analyzing anti-CCP-2-positive and anti-CCP-2–negative RA separately yielded a significant result only in the anti-CCP-2-negative group (P ≤ 0.001).
  
  
  CONCLUSIONS
  Our findings indicate that CXCL13 is a novel serologic marker predictive of RA severity.This marker was identified with the help of an in silicomodel of the RA joint.
authors.affiliation: Merck, Sharp, & Dohme, Oss, The Netherlands.
authors.forename: Cees M
authors.initials: CM
authors.lastname: Meeuwisse
authors.forename: Michael P
authors.initials: MP
authors.lastname: van der Linden
authors.forename: Ton A
authors.initials: TA
authors.lastname: Rullmann
authors.forename: Cornelia F
authors.initials: CF
authors.lastname: Allaart
authors.forename: Rob
authors.initials: R
authors.lastname: Nelissen
authors.forename: Tom W
authors.initials: TW
authors.lastname: Huizinga
authors.forename: Anja
authors.initials: A
authors.lastname: Garritsen
authors.forename: René E
authors.initials: RE
authors.lastname: Toes
authors.forename: René
authors.initials: R
authors.lastname: van Schaik
authors.forename: Annette H
authors.initials: AH
authors.lastname: van der Helm-van Mil
mesh_terms: D000328:Adult; D000368:Aged; D018501:Antirheumatic Agents / Q000627:therapeutic use; D001172:Arthritis, Rheumatoid / Q000097:blood* / Q000000981:diagnostic imaging / Q000188:drug therapy; D001175:Arthrography; D015415:Biomarkers / Q000097:blood; D054382:Chemokine CXCL13 / Q000097:blood*; D018450:Disease Progression; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D033023:Foot Joints / Q000000981:diagnostic imaging*; D050823:Hand Joints / Q000000981:diagnostic imaging*; D006801:Humans; D008297:Male; D008875:Middle Aged; D008953:Models, Anatomic; D012074:Remission Induction; D012720:Severity of Illness Index; D018709:Statistics, Nonparametric; D016896:Treatment Outcome
chemical_list: D018501:Antirheumatic Agents; D015415:Biomarkers; D054382:Chemokine CXCL13