Georgia Malamut (editor) - Refractory Celiac Disease

Coeliac disease (CD) has customarily a benign outcome after gluten-free diet with symptoms that resolve within a few weeks while normal epithelial architecture is recovered within one to two years (see text by S Varma, S Krishnareddy). Yet, iterative follow-up of biopsies has revealed that histological recovery is delayed in some patients. Notably one population-based study led in 7648 celiac patients in Sweden showed persistent villous atrophy in 43% cases among individuals biopsied one to two years and two to five years after diagnosis [].

Authentic refractory coeliac disease (RCD) refers to persistence of malnutrition and intestinal villous atrophy for more than one to two years despite strict gluten-free diet in coeliac patients having initially serum detectable coeliac antibodies and coeliac susceptibility haplotype HLA-DQ2 or -DQ8. Ascertaining diagnosis remains difficult and impacts treatment and follow-up. RCD has been subdivided into two subgroups according to the normal (RCDI) or abnormal phenotype of intraepithelial lymphocytes (IEL) (RCDII). RCDII is considered as a low-grade intraepithelial lymphoma and has a poor prognosis due to gastrointestinal and extra-intestinal dissemination of the abnormal IELs, and high risk of overt lymphoma []. Open capsule budesonide appears as the first line treatment in RCDII: it is generally efficacious to obtain villous recovery and to decrease the number of abnormal lymphocytes while having much lower iatrogenic effects than more aggressive drugs such as cladribine and fludarabine, two purine analogs that are used in RCDII refractory to steroids particularly in association with autologous stem cell transplantation. Recent advances in RCDII pathogenesis have opened the path to targeted therapy (see text by S. Cording, S. Berrabah, G. L. Lhermitte, Malamut, N. Cerf-Bensussan). A clinical trial using a blocking anti-IL-15 led two years a ago showed disappointing efficacy. Following identification of recurrent somatic mutations in the JAK1/STAT3 pathway in RCDII lymphocytes, JAK inhibitors are currently tested in a Phase 2 clinical trial with the goal to inhibit the growth and activation of malignant cells that is driven by the inflammatory cytokines upregulated in the celiac intestine (see text by k G. Bouma and T. Dieckman). Besides specific therapy, prognostic scores demonstrated the needs to restore serum albumin and hemoglobin levels, in order to improve long term survival.

We thank the authors of the present book, who are all specialized in refractory celiac disease and have accepted to share their expertise in order to provide an exhaustive presentation of epidemiological, diagnostic, pathogenic and therapeutic aspects of refractory coeliac disease.