Management of Celiac Disease: Beyond the Gluten-Free Diet

Abstract

See “Glutenase ALV003 attenuates gluten-induced mucosal injury in patients with celiac disease,” by Lähdeaho M-L, Kaukinen K, Laurila K, et al, on page 1649. See “Glutenase ALV003 attenuates gluten-induced mucosal injury in patients with celiac disease,” by Lähdeaho M-L, Kaukinen K, Laurila K, et al, on page 1649. Celiac disease is a chronic, small intestinal, immune-mediated enteropathy precipitated by exposure to dietary gluten in genetically predisposed individuals1Ludvigsson J.F. Leffler D.A. Bai J.C. et al.The Oslo definitions for coeliac disease and related terms.Gut. 2013; 62: 43-52Crossref PubMed Scopus (1125) Google Scholar estimated to affect ≤1% of the susceptible populations around the world. Currently, the only available management option is a life-long gluten-free diet2Rostom A. Murray J.A. Kagnoff M.F. American Gastroenterological Association (AGA) Institute technical review on the diagnosis and management of celiac disease.Gastroenterology. 2006; 131: 1981-2002Abstract Full Text Full Text PDF PubMed Scopus (608) Google Scholar; however, the study from Finland by Lähdeaho et al3Lähdeaho M.L. Kaukinen K. Laurila K. et al.Glutenase ALV003 attenuates gluten-induced mucosal injury in patients with celiac disease.Gastroenterology. 2014; 146: 1649-1658Abstract Full Text Full Text PDF PubMed Scopus (170) Google Scholar 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 million 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.4Catassi C. Fabiani E. Iacono G. et al.A prospective, double-blind, placebo-controlled trial to establish a safe gluten threshold for patients with celiac disease.Am J Clin Nutr. 2007; 85: 160-166Crossref PubMed Scopus (413) Google Scholar 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 problem 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 inherently 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.5Hall N.J. Rubin G. Charnock A. Systematic review: adherence to a gluten-free diet in 492 adult patients with coeliac disease.Aliment Pharmacol Ther. 2009; 30: 315-330Crossref PubMed Scopus (291) Google Scholar Voluntary compliance with the gluten-free diet is challenging owing to many factors, including the taste and texture 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).5Hall N.J. Rubin G. Charnock A. Systematic review: adherence to a gluten-free diet in 492 adult patients with coeliac disease.Aliment Pharmacol Ther. 2009; 30: 315-330Crossref PubMed Scopus (291) Google Scholar 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.6Shah S, Akbari M, Vanga R, et al. Patient perception that treatment burden is high in celiac disease compared to other common conditions. Am J Gastroenterol. Forthcoming.Google Scholar Somewhat surprisingly, patients with celiac disease rated the burden of their treatment at or greater than the level experienced by individuals who needed dialysis, insulin injections, and other chronic medical treatments.6Shah S, Akbari M, Vanga R, et al. Patient perception that treatment burden is high in celiac disease compared to other common conditions. Am J Gastroenterol. Forthcoming.Google Scholar 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 recognized 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 disease activity with elevated celiac disease–specific autoantibodies, inflammation, and/or villous atrophy is not unusual in patients taking an ostensibly gluten-free diet.7Lanzini A. Lanzarotto F. Villanacci V. et al.Complete recovery of intestinal mucosa occurs very rarely in adult coeliac patients despite adherence to gluten-free diet.Aliment Pharmacol Ther. 2009; 29: 1299-1308Crossref PubMed Scopus (179) Google Scholar, 8Ilus T. Lähdeaho M.L. Salmi T. et al.Persistent duodenal intraepithelial lymphocytosis despite a long-term strict gluten-free diet in celiac disease.Am J Gastroenterol. 2012; 107: 1563-1569Crossref PubMed Scopus (95) Google Scholar There are conflicting reports regarding whether such persistent mucosal injury is associated with increased mortality in patients with celiac disease.9Rubio-Tapia A. Rahim M.W. See J.A. et al.Mucosal recovery and mortality in adults with celiac disease after treatment with a gluten-free diet.Am J Gastroenterol. 2010; 105: 1412-1420Crossref PubMed Scopus (281) Google Scholar, 10Lebwohl B. Granath F. Ekbom A. et al.Mucosal healing and mortality in coeliac disease.Aliment Pharmacol Ther. 2013; 37: 332-339Crossref PubMed Scopus (93) Google Scholar 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.11Schuppan D. Junker Y. Barisani D. Celiac disease: from pathogenesis to novel therapies.Gastroenterology. 2009; 137: 1912-1933Abstract Full Text Full Text PDF PubMed Scopus (468) Google Scholar 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 disease (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.Table 1Treatments for Celiac Disease Beyond the Gluten-Free DietTypes of TreatmentsStatus of InvestigationIntraluminally acting agents Lactobacilli to pretreat flours or doughPreclinical Transamidation of gliadin19Gianfrani C. Siciliano R.A. Facchiano A.M. et al.Transamidation of wheat flour inhibits the response to gliadin of intestinal T cells in celiac disease.Gastroenterology. 2007; 133: 780-789Abstract Full Text Full Text PDF PubMed Scopus (144) Google ScholarPreclinical Prolyl endopeptidasesALV0033Lähdeaho M.L. Kaukinen K. Laurila K. et al.Glutenase ALV003 attenuates gluten-induced mucosal injury in patients with celiac disease.Gastroenterology. 2014; 146: 1649-1658Abstract Full Text Full Text PDF PubMed Scopus (170) Google Scholar, 14Siegel M. Garber M.E. Spencer A.G. et al.Safety, tolerability, and activity of ALV003: results from two phase 1 single, escalating-dose clinical trials.Dig Dis Sci. 2012; 57: 440-450Crossref PubMed Scopus (81) Google ScholarNCT01255696,NCT00959114,NCT01917630,NCT00859391,NCT00626184AN-PEP15Tack G.J. van de Water J.M. Bruins M.J. et al.Consumption of gluten with gluten-degrading enzyme by celiac patients: a pilot-study.World J Gastroenterol. 2013; 19: 5837-5847Crossref PubMed Scopus (97) Google ScholarNCT00810654 Intraluminal polymers to bind gliadin (BL-7010)20Pinier M. Verdu E.F. Nasser-Eddine M. et al.Polymeric binders suppress gliadin-induced toxicity in the intestinal epithelium.Gastroenterology. 2009; 136: 288-298Abstract Full Text Full Text PDF PubMed Scopus (115) Google ScholarNCT01990885 Anti-gluten IgY oral passive antibodyNCT01765647 (not yet recruiting) Study of humanized Mik-beta-1 monoclonal antibody (Hu-Mik-Beta-1)NCT01893775Inhibitors of transepithelial gliadin uptake Zona occludin receptor antagonist AT1001 (larazotide)12Leffler D.A. Kelly C.P. Abdallah H.Z. et al.A randomized, double-blind study of larazotide acetate to prevent the activation of celiac disease during gluten challenge.Am J Gastroenterol. 2012; 107: 1554-1562Crossref PubMed Scopus (133) Google Scholar, 13Kelly C.P. Green P.H. Murray J.A. et al.Larazotide acetate in patients with coeliac disease undergoing a gluten challenge: a randomised placebo-controlled study. Larazotide Acetate Celiac Disease Study Group.Aliment Pharmacol Ther. 2013; 37: 252-262Crossref PubMed Scopus (157) Google ScholarNCT01396213,NCT01255696,NCT00620451,NCT00492960,NCT00889473,NCT00386165,NCT00362856Modulators of the adaptive immune response Inhibitors of transglutaminasePreclinical Inhibitory gluten peptidesPreclinical Blockers of HLA DQPreclinicalImmunomodulation Nectarus americanus (hookworm)16Daveson A.J. Jones D.M. Gaze S. et al.J. Effect of hookworm infection on wheat challenge in celiac disease–a randomised double-blinded placebo controlled trial.PLoS One. 2011; 6: e17366Crossref PubMed Scopus (170) Google ScholarNCT00671138 Gluten vaccineNCT00879749 Regulation of T cells that home to the small intestine CCR9 antagonistPreclinical CCx282-BNCT00540657 Open table in a new tab 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.12Leffler D.A. Kelly C.P. Abdallah H.Z. et al.A randomized, double-blind study of larazotide acetate to prevent the activation of celiac disease during gluten challenge.Am J Gastroenterol. 2012; 107: 1554-1562Crossref PubMed Scopus (133) Google Scholar, 13Kelly C.P. Green P.H. Murray J.A. et al.Larazotide acetate in patients with coeliac disease undergoing a gluten challenge: a randomised placebo-controlled study. Larazotide Acetate Celiac Disease Study Group.Aliment Pharmacol Ther. 2013; 37: 252-262Crossref PubMed Scopus (157) Google Scholar The endopeptidase ALV003 reported in this issue3Lähdeaho M.L. Kaukinen K. Laurila K. et al.Glutenase ALV003 attenuates gluten-induced mucosal injury in patients with celiac disease.Gastroenterology. 2014; 146: 1649-1658Abstract Full Text Full Text PDF PubMed Scopus (170) Google Scholar and in prior trials14Siegel M. Garber M.E. Spencer A.G. et al.Safety, tolerability, and activity of ALV003: results from two phase 1 single, escalating-dose clinical trials.Dig Dis Sci. 2012; 57: 440-450Crossref PubMed Scopus (81) Google Scholar and another endopeptidase, AN-PEP,15Tack G.J. van de Water J.M. Bruins M.J. et al.Consumption of gluten with gluten-degrading enzyme by celiac patients: a pilot-study.World J Gastroenterol. 2013; 19: 5837-5847Crossref PubMed Scopus (97) Google Scholar break down gluten to produce less or non-immunogenic peptide fragments. A therapeutic vaccine is being tested with the aim of developing tolerance to gluten.11Schuppan D. Junker Y. Barisani D. Celiac disease: from pathogenesis to novel therapies.Gastroenterology. 2009; 137: 1912-1933Abstract Full Text Full Text PDF PubMed Scopus (468) Google Scholar Infection with the nematode Necator americanus16Daveson A.J. Jones D.M. Gaze S. et al.J. Effect of hookworm infection on wheat challenge in celiac disease–a randomised double-blinded placebo controlled trial.PLoS One. 2011; 6: e17366Crossref PubMed Scopus (170) Google Scholar to shift from a Th1 to a Th2 milieu and treatment with a CCR9 antagonist have also been reported.11Schuppan D. Junker Y. Barisani D. Celiac disease: from pathogenesis to novel therapies.Gastroenterology. 2009; 137: 1912-1933Abstract Full Text Full Text PDF PubMed Scopus (468) Google Scholar 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 disease.3Lähdeaho M.L. Kaukinen K. Laurila K. et al.Glutenase ALV003 attenuates gluten-induced mucosal injury in patients with celiac disease.Gastroenterology. 2014; 146: 1649-1658Abstract Full Text Full Text PDF PubMed Scopus (170) Google Scholar The goal of the study was to test the ability of ALV003 to protect celiac disease patients from gluten-induced mucosal injury. The authors established the optimal daily gluten dose to be used in the 6-week gluten challenge study using 3 different doses: 1.5, 3, and 6 g of gluten were administered in 3 daily doses over a 6-week period. Based on results of histologic studies as well as patient tolerance, a dose of 2 g was selected. In the subsequent intervention study, adult patients with biopsy-proven celiac disease were randomized 1-to-1 to receive ALV003 or placebo drug along with the daily gluten challenge. 20 Twenty received the study drug and 21 received placebo. Analyses included measurements of villous height to crypt depth ratio, as well as numbers of intraepithelial lymphocytes, which served as primary endpoints. The gluten challenge led to mucosal injury in the placebo group; no significant mucosal changes were noted in the study drug group. Over the 6-week trial, there were significant differences in the morphologic changes that occurred between the 2 groups of subjects. All study subjects had celiac disease serology measured and 4 different instruments assessing quality of life and well-being, as well as gastrointestinal symptoms were assessed. No changes in celiac disease serology were seen between the 2 groups. Gastrointestinal symptoms secondary to gluten ingestion were significantly greater in the placebo group compared with those receiving active treatment. Overall, this study demonstrates that the use of 2 recombinant gluten-specific proteases reduces small intestinal mucosal injury owing to gluten ingestion in celiac disease patients receiving 2 g of gluten per day in an otherwise gluten-free diet. ALV003 contains a prolyl endopeptidase from Sphingomonas capsulate, in combination with another endopeptidase from germinating barley. AN-PEP, an endopeptidase from Aspergillus niger, was tested in a recent pilot study of 16 subjects demonstrating it was well-tolerated, but the primary endpoint was not met.15Tack G.J. van de Water J.M. Bruins M.J. et al.Consumption of gluten with gluten-degrading enzyme by celiac patients: a pilot-study.World J Gastroenterol. 2013; 19: 5837-5847Crossref PubMed Scopus (97) Google Scholar There are some limitations to the current study, including the small sample size consisting of a homogenous population from Finland. It is somewhat surprising that serologic titers did not increase in the placebo group given that a 3 g gluten challenge for 2 weeks was shown to be sufficient to induce histologic changes in intestinal biopsies as well as increased titers of tissue transglutaminase immunoglobulin A.17Leffler D. Schuppan D. Pallav K. et al.Kinetics of the histological, serological and symptomatic responses to gluten challenge in adults with coeliac disease.Gut. 2013; 62: 996-1004Crossref PubMed Scopus (168) Google Scholar Another pharmacologic approach to reduce the uptake of gluten from the intestinal lumen beyond a gluten-free diet is larazotide acetate, a described. In a study to evaluate the efficacy and tolerability of larazotide acetate in protecting against gluten-induced intestinal permeability and gastrointestinal symptom severity in patients with celiac disease,12Leffler D.A. Kelly C.P. Abdallah H.Z. et al.A randomized, double-blind study of larazotide acetate to prevent the activation of celiac disease during gluten challenge.Am J Gastroenterol. 2012; 107: 1554-1562Crossref PubMed Scopus (133) Google Scholar the readout of permeability was sufficiently variable such that an accurate assessment of the effect of larazotide acetate on intestinal permeability was not possible. Some of the lower doses of larazotide acetate seemed to prevent the increase in gastrointestinal symptom severity induced by gluten challenge. A subsequent study of this agent13Kelly C.P. Green P.H. Murray J.A. et al.Larazotide acetate in patients with coeliac disease undergoing a gluten challenge: a randomised placebo-controlled study. Larazotide Acetate Celiac Disease Study Group.Aliment Pharmacol Ther. 2013; 37: 252-262Crossref PubMed Scopus (157) Google Scholar showed similar results despite a lack of effect on permeability. Interestingly, in that study all 3 study drug doses reduced symptoms from the 2.7-g gluten challenge over 6 weeks. In contrast with the current study of ALV-003, TTG IgA levels were reduced in all treatment groups compared with placebo.13Kelly C.P. Green P.H. Murray J.A. et al.Larazotide acetate in patients with coeliac disease undergoing a gluten challenge: a randomised placebo-controlled study. Larazotide Acetate Celiac Disease Study Group.Aliment Pharmacol Ther. 2013; 37: 252-262Crossref PubMed Scopus (157) Google Scholar The variation in results using 2 different agents, both intended to limit immunogenic gluten peptides from reaching the lamina propria, underscores the complexity of the mechanisms of celiac disease. The potential of ALV003 and other therapies for celiac disease is significant given the ongoing exposure to low levels of gluten, persistent symptoms, and chronic intestinal inflammation, which may impact celiac disease morbidity and possibly mortality.9Rubio-Tapia A. Rahim M.W. See J.A. et al.Mucosal recovery and mortality in adults with celiac disease after treatment with a gluten-free diet.Am J Gastroenterol. 2010; 105: 1412-1420Crossref PubMed Scopus (281) Google Scholar, 10Lebwohl B. Granath F. Ekbom A. et al.Mucosal healing and mortality in coeliac disease.Aliment Pharmacol Ther. 2013; 37: 332-339Crossref PubMed Scopus (93) Google Scholar Should the ALV003 endopeptidase come to market, there will likely be issues of availability and cost as a prescription treatment. Given the potential cost of endopeptidases and, for that matter, any new celiac disease therapeutic, who will be eligible to receive such new treatments? Individuals with celiac disease who eat out of their home, travel, and/or purchase prepared foods can never be completely certain of the gluten-free status of their food; as such, the majority with celiac disease could derive benefit from a treatment that reduces exposure to gluten and its potential harm. One can assume that only those with biopsy-proven celiac disease would qualify, whereas those with other forms of gluten sensitivity might not. This could alter emerging recommendations that the diagnosis of celiac disease can be achieved without performing small intestinal biopsies.18Catassi C. Fasano A. Celiac disease diagnosis: simple rules are better than complicated algorithms.Am J Med. 2010; 123: 691-693Abstract Full Text Full Text PDF PubMed Scopus (157) Google Scholar In an era when patients are often asked to use over-the-counter treatments in lieu of more expensive prescriptions, it seems likely that insurance plans will consider the gluten-free diet an over-the-counter agent and access to agents such as endopeptidases could be curtailed. Nonetheless, my patients and I look forward to the day when safe and effective therapies beyond a gluten-free diet are available to improve the health of those with celiac disease. Glutenase ALV003 Attenuates Gluten-Induced Mucosal Injury in Patients With Celiac DiseaseGastroenterologyVol. 146Issue 7PreviewGluten ingestion leads to small intestinal mucosal injury in patients with celiac disease, necessitating strict life-long exclusion of dietary gluten. Despite adherence to a gluten-free diet, many patients remain symptomatic and still have small intestinal inflammation. In this case, nondietary therapies are needed. We investigated the ability of ALV003, a mixture of 2 recombinant gluten-specific proteases given orally, to protect patients with celiac disease from gluten-induced mucosal injury in a phase 2 trial. Full-Text PDF