Management of celiac disease: beyond the gluten-free diet.

EDITORIALS Management of Celiac Disease: Beyond the Gluten-Free Diet See “Glutenase ALV003 attenuates gluten-induced mucosal injury in patients with celiac disease,” by Lahdeaho M-L, Kaukinen K, Laurila K, et al, on page 1649. C eliac disease is a chronic, small intestinal, immune- mediated enteropathy precipitated by exposure to dietary gluten in genetically predisposed individuals 1 esti- mated to affect 1% of the susceptible populations around the world. Currently, the only available management option is a life-long gluten-free diet 2 ; however, the study from Finland by Lahdeaho et al 3 suggests that an oral glutenase to degrade small amounts of dietary gluten can attenuate gluten-induced small intestinal mucosal injury in patients with celiac disease who are consuming a gluten-free diet that contains small amounts of gluten. The need for a treatment above and beyond the gluten-free diet may seem less relevant at a time when gluten-free food products are far more available in stores and restaurants than ever before. However, the explosion of gluten-free offerings has created concerns for individuals who need to adhere to a strict gluten-free diet as treatment for celiac disease. Worldwide, there are varying standards of how much gluten can be present for a product to be deemed gluten free. Typically, the standard is measured as parts per mil- lion of gluten in food, which has been calculated based on what is thought to be a safe daily intake of gluten (10–50 mg/ d) for those with celiac disease. 4 Depending on how much processed food a person consumes on a daily basis, the actual amount of gluten could be over this threshold for those who consume large amounts of gluten-free food. A greater prob- lem is that most meals are consumed outside the home and relying on restaurants to provide truly gluten-free foods often leads to inadvertent gluten exposure. It is also inher- ently difﬁcult to travel and maintain a gluten-free lifestyle. Thus, it is not unexpected that even the most fastidious celiac disease patients are exposed to gluten despite their best efforts. 5 Voluntary compliance with the gluten-free diet is chal- lenging owing to many factors, including the taste and tex- ture of non-gluten alternatives, social reasons, peer pressure, and the inconvenience and expense of obtaining gluten-free foods (3–4 times more costly than their gluten- containing counterparts in the United States, Canada, and Great Britain). 5 A study presented at the 2012 Digestive Disease Week meeting assessing how patients viewed the effectiveness of various treatments indicated that patients with celiac disease rated a gluten-free diet as being more effective for their disease than did patients with other chronic diseases, such as dialysis for chronic renal failure or insulin injections for insulin-dependent diabetes. 6 Some- what surprisingly, patients with celiac disease rated the burden of their treatment at or greater than the level Gastroenterology 2014;146:1594–1605 experienced by individuals who needed dialysis, insulin injections, and other chronic medical treatments. 6 A signiﬁcant percentage of patients with celiac disease who are following a gluten-free diet may have persistent symptoms. The potential causes include continued gluten ingestion, often from trace ingredients not readily recog- nized as sources of gluten in food and from so-called hidden sources in non-food products such as medications and toothpaste. There is an increasing interest with an emerging literature about the factors that may be causing these symptoms, including fermentable starches, sensitivity to other grains often used in gluten-free foods, and the role of small intestinal bacterial overgrowth. Persistent celiac dis- ease activity with elevated celiac disease–speciﬁc autoanti- bodies, inﬂammation, and/or villous atrophy is not unusual in patients taking an ostensibly gluten-free diet. 7,8 There are conﬂicting reports regarding whether such persistent mucosal injury is associated with increased mortality in patients with celiac disease. 9,10 Considering all these issues, other strategies beyond a strict gluten-free diet alone are highly sought after by patients with celiac disease. Despite the promise of new treatments for celiac disease (Table 1), it is only relatively recently that clinical trials of new celiac disease therapies have been published. 11 At the time of writing this editorial, a search of “celiac disease treatment” in clinicaltrials.gov listed 81 studies. After excluding the 37 studies that were unrelated to celiac dis- ease (eg, celiac plexus), of those that remained, only 20 studies focused on treatments for celiac disease beyond a gluten-free diet. Of those 20 studies, 14 have closed to recruitment, 4 are still open to recruitment, and 2 others are listed with an uncertain status regarding recruitment. Some other studies examine the effect of a gluten-free diet on conditions associated with celiac disease and a few trials focus on refractory forms of celiac disease. Only a limited number of experimental therapies for celiac disease have been tested in randomized, controlled clinical trials. Larazotide acetate reduces the paracellular passage of gluten through the epithelial barrier into the lamina propria by inhibiting tight junctions. 12,13 The endopeptidase ALV003 reported in this issue 3 and in prior trials 14 and another endopeptidase, AN-PEP, 15 break down gluten to produce less or non-immunogenic peptide fragments. A therapeutic vac- cine is being tested with the aim of developing tolerance to gluten. 11 Infection with the nematode Necator americanus 16 to shift from a Th1 to a Th2 milieu and treatment with a CCR9 antagonist have also been reported. 11 In this issue of Gastroenterology, the latest study of a celiac disease treatment beyond the gluten-free diet reports the ﬁndings of a randomized, controlled, phase II clinical trial of ALV003, an oral mixture of 2 recombinant gluten-speciﬁc proteases in adult patients with biopsy-proven celiac dis- ease. 3 The goal of the study was to test the ability of ALV003 to protect celiac disease patients from gluten-induced mucosal