Immunohistochemical and T-cell receptor gene rearrangement analyses as predictors of morbidity and mortality in refractory celiac disease

J Clin Gastroenterol. 2013 Aug;47(7):593-601. doi: 10.1097/MCG.0b013e31828a3c44.


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.

Goals: To investigate the contribution of IEL parameters toward mortality and morbidity in RCD.

Study: 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.

MeSH terms

  • Adolescent
  • Adult
  • Aged
  • Aged, 80 and over
  • CD3 Complex / immunology*
  • CD8 Antigens / immunology*
  • Celiac Disease / diagnosis*
  • Celiac Disease / genetics
  • Celiac Disease / immunology
  • Celiac Disease / mortality*
  • Disease Progression
  • Female
  • Follow-Up Studies
  • Gene Rearrangement, T-Lymphocyte / genetics*
  • Humans
  • Immunohistochemistry
  • Kaplan-Meier Estimate
  • Male
  • Middle Aged
  • Polymerase Chain Reaction
  • Prognosis
  • Proportional Hazards Models
  • Receptors, Antigen, T-Cell / genetics*
  • Risk Factors
  • Survival Rate
  • Young Adult


  • CD3 Complex
  • CD8 Antigens
  • Receptors, Antigen, T-Cell