Classification of refractory celiac disease (RCD) is based on the presence or absence of monoclonal expansions of intraepithelial lymphocytes (IELs) with an aberrant immunophenotype.
To investigate the contribution of IEL parameters toward mortality and morbidity in RCD.
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.
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).
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.