title: Is it possible to change phenotype progression in Crohn's disease in the era of immunomodulators? Predictive factors of phenotype progression.
abstract: OBJECTIVE
  Crohn's disease (CD) induces cumulative structural damage, initially characterized by a non-stenosing non-penetrating behavior (B1) with progression over time to a fibro-stenosing (B2) and/or penetrating phenotype (B3). Our aim was to assess the long-term evolution of disease behavior of CD and determine what factors predict phenotype progression.
  
  
  METHODS
  This was a study based on prospectively collected data from a CD database in an inflammatory bowel disease outpatient clinic. B1 corresponds to a non-stenosing non-penetrating disease, B2 to a stenosing behavior, and B3 to a penetrating one.
  
  
  RESULTS
  Seven hundred and thirty-six patients with CD (368 female) were followed up for 12.3 years (± 8.4), with 87.0% of them exhibiting B1 phenotype at diagnosis. Of these patients, 28.5% progressed to B2 phenotype and 23.5% to B3. Fifty percent of the patients started azathioprine treatment before phenotype change and 13.9% started anti-tumor necrosis factor-α (anti-TNFα) treatment before phenotype change. Monotherapy with azathioprine before phenotype change as well as combination therapy with azathioprine/anti-TNFα before phenotype change delayed disease progression (B1-B2 or B3) in comparison with patients who did not receive treatment (P<0.001). The hazard ratio (HR) for disease progression was lower for both monotherapy with azathioprine (HR: 0.15, P<0.001) or combination therapy with anti-TNFα (HR: 0.33, P<0.001). Upper gastrointestinal tract involvement, male gender, and steroid use were associated with an early progression of phenotype from B1 to B2 or B3 (P<0.001). The HR for disease progression was higher in patients who used steroids without criteria of dependence or resistance (HR: 2.67, P<0.001) and was even higher in patients with criteria of dependence or resistance (HR: 6.44, P<0.001). Longer delays between CD diagnosis and beginning of therapy with azathioprine and/or anti-TNFα were associated with disease progression. The longer the duration of treatment, the less likely the disease progression.
  
  
  CONCLUSIONS
  Monotherapy with azathioprine before behavior change as well as combination therapy with azathioprine and anti-TNFα before behavior change delays phenotype progression of CD, whereas upper gastrointestinal tract involvement, male gender, and steroid use with or without criteria of steroid dependence are associated with a higher risk for disease progression.
authors.affiliation: 1] Department of Gastroenterology, Centro Hospitalar São João, Porto, Portugal [2] IBMC-Institute for Molecular and Cell Biology, University of Porto, Porto, Portugal [3] The first two authors contributed equally to this work.
authors.forename: Fernando
authors.initials: F
authors.lastname: Magro
authors.affiliation: 1] Department of Gastroenterology, Centro Hospitalar São João, Porto, Portugal [2] The first two authors contributed equally to this work.
authors.forename: Eduardo
authors.initials: E
authors.lastname: Rodrigues-Pinto
authors.affiliation: Department of Gastroenterology, Centro Hospitalar São João, Porto, Portugal.
authors.forename: Rosa
authors.initials: R
authors.lastname: Coelho
authors.affiliation: Department of Gastroenterology, Centro Hospitalar São João, Porto, Portugal.
authors.forename: Patrícia
authors.initials: P
authors.lastname: Andrade
authors.affiliation: 1] Department of Gastroenterology, Centro Hospitalar São João, Porto, Portugal [2] Department of Biochemistry, Faculty of Medicine, University of Porto, Porto, Portugal.
authors.forename: João
authors.initials: J
authors.lastname: Santos-Antunes
authors.affiliation: Department of Gastroenterology, Centro Hospitalar São João, Porto, Portugal.
authors.forename: Susana
authors.initials: S
authors.lastname: Lopes
authors.affiliation: CIDES-Department of Health Information and Decision Sciences, Faculty of Medicine, University of Porto, Porto, Portugal.
authors.forename: Claudia
authors.initials: C
authors.lastname: Camila-Dias
authors.affiliation: Department of Gastroenterology, Centro Hospitalar São João, Porto, Portugal.
authors.forename: Guilherme
authors.initials: G
authors.lastname: Macedo
mesh_terms: D000328:Adult; D001379:Azathioprine / Q000627:therapeutic use; D003424:Crohn Disease / Q000188:drug therapy* / Q000503:physiopathology* / Q000601:surgery; D003952:Diagnostic Imaging; D018450:Disease Progression; D005260:Female; D006801:Humans; D007166:Immunosuppressive Agents / Q000627:therapeutic use; D053208:Kaplan-Meier Estimate; D008297:Male; D010641:Phenotype; D011237:Predictive Value of Tests; D011446:Prospective Studies; D055502:Secondary Prevention; D012720:Severity of Illness Index; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors
chemical_list: D007166:Immunosuppressive Agents; D014409:Tumor Necrosis Factor-alpha; D001379:Azathioprine