Immunohistochemical and T-Cell Receptor Gene Rearrangement Analyses as Predictors of Morbidity and Mortality in Refractory Celiac Disease

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.