title: Brief Report: Clinical Trials Aiming to Prevent Rheumatoid Arthritis Cannot Detect Prevention Without Adequate Risk Stratification: A Trial of Methotrexate Versus Placebo in Undifferentiated Arthritis as an Example.
abstract: Prevention of rheumatoid arthritis (RA) was the aim of several trials in undifferentiated arthritis (UA), with overall negative results. As preparatory work has revealed that only ∼30% of UA patients progress to having RA, we hypothesized that inclusion of patients without imminent RA could lead to false-negative results. We undertook this study to evaluate this hypothesis by reinvestigating the Probable Rheumatoid Arthritis: Methotrexate versus Placebo Treatment (PROMPT) trial (a 1-year course of methotrexate [MTX] versus placebo in UA) after excluding patients without a high risk of developing RA.
  
  
  
  A validated prediction model was used to determine the risk of RA in all patients included in the PROMPT trial. Patients with a prediction score of ≥8 (positive predictive value of ≥84% for developing RA) were considered to have a high risk of developing RA. The effect of a 1-year course of MTX during 5 years of follow-up was reinvestigated in these patients.
  
  
  
  Twenty-two of the 110 patients in the PROMPT trial had a high risk of RA at baseline. In the MTX arm, 6 of 11 patients (55%) developed RA, compared to 11 of 11 patients (100%) in the placebo arm (P = 0.011). Time to RA development was longer in the MTX arm than in the placebo arm (median 22.5 months versus 3 months; P < 0.001). Drug-free remission was achieved by 4 of 11 patients (36%) in the MTX arm compared to 0 of 11 patients (0%) in the placebo arm (P = 0.031). These beneficial effects of MTX were observed both in anti-citrullinated protein antibody (ACPA)-positive and in ACPA-negative UA patients with a high risk of RA, but not in UA patients without a high risk of RA. In retrospect, 43 of 110 patients fulfilled the American College of Rheumatology/European League Against Rheumatism 2010 classification criteria for RA at baseline. In addition, beneficial effects were observed only in patients with a high prediction score.
  
  
  
  A 1-year course of MTX delayed and prevented RA development in high-risk UA patients. This emphasizes the importance of adequate risk prediction in trials that aim to prevent RA.
authors.affiliation: Leiden University Medical Centre, Leiden, The Netherlands.
authors.forename: Leonie E
authors.initials: LE
authors.lastname: Burgers
authors.affiliation: Leiden University Medical Centre, Leiden, The Netherlands.
authors.forename: Cornelia F
authors.initials: CF
authors.lastname: Allaart
authors.affiliation: Leiden University Medical Centre, Leiden, The Netherlands.
authors.forename: Tom W J
authors.initials: TWJ
authors.lastname: Huizinga
authors.affiliation: Leiden University Medical Centre, Leiden, The Netherlands.
authors.forename: Annette H M
authors.initials: AHM
authors.lastname: van der Helm-van Mil
mesh_terms: D018501:Antirheumatic Agents / Q000627:therapeutic use*; D001168:Arthritis / Q000188:drug therapy*; D001172:Arthritis, Rheumatoid / Q000517:prevention & control*; D003661:Decision Support Techniques; D006801:Humans; D053208:Kaplan-Meier Estimate; D008727:Methotrexate / Q000627:therapeutic use*; D016032:Randomized Controlled Trials as Topic; D018570:Risk Assessment; D016896:Treatment Outcome
chemical_list: D018501:Antirheumatic Agents; D008727:Methotrexate