title: Immunohistochemical and T-cell receptor gene rearrangement analyses as predictors of morbidity and mortality in refractory celiac disease.
abstract: BACKGROUND
  Classification of refractory celiac disease (RCD) is based on the presence or absence of monoclonal expansions of intraepithelial lymphocytes (IELs) with an aberrant immunophenotype.
  
  
  OBJECTIVE
  To investigate the contribution of IEL parameters toward mortality and morbidity in RCD.
  
  
  METHODS
  IEL phenotype by immunohistochemistry and T-cell receptor (TCR) gene rearrangement by polymerase chain reaction were assessed in 73 RCD patients (type I=67, type II=6). Detection of a monoclonal TCR gene rearrangement and presence of <50% CD3 CD8 IELs were considered abnormal. Time to worsening of clinical symptoms and predictors of worsening were calculated by Kaplan-Meier and Cox proportional hazard analyses.
  
  
  RESULTS
  Fewer than 50% CD3 CD8 IELs were detected in 30 patients and monoclonal TCR rearrangements in 6. Three patients died and 40 suffered clinical worsening despite treatment. Estimated 5-year survival rates decreased from 100% in patients with >50% CD3 CD8 IELs and polyclonal TCR to 88% and 50% in patients with <50% CD3 CD8 IELs and monoclonal TCR, respectively. Clinical worsening was more frequent (100%) among patients harboring a monoclonal TCR gene rearrangement with <50% CD3 CD8 IELs. These patients also showed shorter median time to clinical worsening (11 mo) when compared to patients with <50% CD3 CD8 IELs alone (21 mo), polyclonal TCR (38 mo), or >50% CD3 CD8 IELs alone (66 mo). After adjusting for age and gender, only the presence of <50% CD3 CD8 IELs was associated with increased risk for clinical worsening despite negative celiac serologies (hazard ratio=4.879; 95% confidence interval, 1.785-13.336; P=0.002).
  
  
  CONCLUSIONS
  Presence of <50% CD3 CD8 IELs is a risk factor for clinical worsening in RCD and combined with a monoclonal TCR gene rearrangement result is associated with increased mortality. IEL phenotype and TCR gene rearrangement analyses provide differential information regarding morbidity and mortality in RCD.
authors.affiliation: Celiac Disease Center, Columbia University, Columbia University Medical Center, New York, NY, USA.
authors.forename: Carolina
authors.initials: C
authors.lastname: Arguelles-Grande
authors.forename: Pardeep
authors.initials: P
authors.lastname: Brar
authors.forename: Peter H R
authors.initials: PH
authors.lastname: Green
authors.forename: Govind
authors.initials: G
authors.lastname: Bhagat
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D017252:CD3 Complex / Q000276:immunology*; D016827:CD8 Antigens / Q000276:immunology*; D002446:Celiac Disease / Q000175:diagnosis* / Q000235:genetics / Q000276:immunology / Q000401:mortality*; D018450:Disease Progression; D005260:Female; D005500:Follow-Up Studies; D015329:Gene Rearrangement, T-Lymphocyte / Q000235:genetics*; D006801:Humans; D007150:Immunohistochemistry; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D016133:Polymerase Chain Reaction; D011379:Prognosis; D016016:Proportional Hazards Models; D011948:Receptors, Antigen, T-Cell / Q000235:genetics*; D012307:Risk Factors; D015996:Survival Rate; D055815:Young Adult
chemical_list: D017252:CD3 Complex; D016827:CD8 Antigens; D011948:Receptors, Antigen, T-Cell