Mesalamine for refractory celiac disease: an old medicine for a new disease.

Celiac disease (CD) is an autoimmune disease affecting the small bowel, which results in malabsorption, diarrhea, and myriad extraintestinal symptoms. This autoimmune disease is triggered by the ingestion of gluten in a fraction of individuals with the human leukocyte antigen haplotypes, DQ2 and DQ8. Earlier thought to be rare in the United States, CD is now known to be common, with a prevalence of nearly 1%. Nevertheless, CD remains underdiagnosed and is generally underrecognized, with a ratio of undiagnosed to diagnosed individuals of 20:1 in the United States, a much higher ratio than that observed in European nations. A successful case-finding initiative in the United States shows that these undiagnosed CD patients are ‘‘out there,’’ many of whom are symptomatic and treatable with a gluten-free diet. Why is CD underrecognized in the United States? In this country, much disease awareness on the part of physicians and patients is driven by the pharmaceutical industry. The research and development of this industry pay off great dividends; the United States leads the world in the development of new pharmaceutical agents and is at the vanguard of innovation in health care. But there is a flip side. Disease awareness has become dependent on the pharmaceutical industry’s awareness-raising activities. A recent analysis showed that the introduction of tegaserod was associated with an immediate rise in patient visits and new diagnoses of irritable bowel syndrome. In this regard, CD has been left behind. It is a disease that is treated primarily with a diet. The diet can be difficult, expensive, and potentially unhealthy if not prescribed with close nutritional guidance, but for the majority of patients it is effective, and can result in a dramatic alleviation of the presenting signs and symptoms of CD. Although there are many steps in the pathogenesis of CD, which could be the targets of potential drug therapies, only 2 steps are currently under development. CD remains largely a disease without a drug, and therefore keeps a low profile. Not all patients with CD respond to the gluten-free diet. Some never respond in the first place, whereas others lose reponsiveness. The frequency of this phenomenon is unknown, and estimates of the prevalence of poorly responsive CD vary widely from 7% to 30% of all individuals with CD. More recently, our understanding of refractory celiac disease (RCD) has been shaped by the crucial dichotomy between RCD types 1 and 2, the latter of which has a poor short-term prognosis and is closely associated with enteropathy-associated T-cell lymphoma. These 2 types of RCD are differentiated by the T-cell make-up in the intestinal epithelium. A monoclonal T-cell receptor rearrangement and a loss of the normal CD3 surface expression and loss of CD4 and CD8 are indicative of RCD type 2, whereas a polyclonal T-cell receptor and normal expression of CD3/CD4/CD8 denote RCD type 1. As such, the use of immunohistochemistry, flow cytometry, and T-cell receptor polymerase chain reaction on intestinal biopsies has emerged as a valuable diagnostic and prognostic tool for assessing individuals with RCD. Despite this advance and well-performed studies of the prognosis of RCD types 1 and 2 at referral centers, we remain ignorant of the prevalence of these conditions. Much of this uncertainty stems from the fact that patients who do not respond to the gluten-free diet do not necessarily have RCD. Some may not have CD to begin with, and others may have one of several conditions associated with CD, such as small intestinal bacterial overgrowth, microscopic colitis, and pancreatic exocrine insufficiency. Such conditions should be evaluated before the labeling of patients with RCD. Nevertheless, in 1 cohort of patients with or without symptoms undergoing follow-up biopsy, the proportion of patients with persistent abnormalities was found to be 34% in 5 years. In that cohort, the lack of histologic recovery was associated with an increased risk of death, though this did not meet statistical significance.