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Celiac Disease Treatment

Gluten-Free Diet and Beyond

Mäki, Markku

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Journal of Pediatric Gastroenterology and Nutrition: July 2014 - Volume 59 - Issue - p S15-S17
doi: 10.1097/01.mpg.0000450397.76521.f9
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Abstract

Treatment of CD is based on excluding all foods containing gluten, the disease-inducing prolamins in wheat, rye, and barley. Dr Willem Karel Dicke, of the Netherlands, discovered the harmful effect of dietary gluten in CD. He demonstrated and wrote in his thesis in 1950 that the harmful effect was specifically caused by wheat flour, also rye elicited or aggravated clinical symptoms and signs; wheat starch did not give rise to the phenomena. In the late 1950s, it became evident that gluten induces small intestinal villous atrophy and crypt hyperplasia; a decade later researchers learned that the mucosa heals on a gluten-free diet and that gluten intolerance in CD is permanent (1). The small-intestinal biopsy histopathology examination became the gold standard for diagnosis and clinical disease recovery. The discussion is still ongoing as to what gluten-free actually means and it has become evident that there is a need for the development of novel therapies.

WHEAT STARCH–BASED GLUTEN-FREE FLOURS

In many European countries, industrially purified wheat starch–based gluten-free flours have been part of the gluten-free diet treatment in CD. It was estimated that starch flours meant for patients with CD had a content of 400 to 600 mg/kg (ppm) of gluten. Later, this level was taken down by authorities to 200 ppm; today, the demand for the end product is <100 ppm (very low gluten) or <20 ppm (gluten-free). As reviewed by Hischenhuber et al (2), evidence-based studies show that a diet including industrially purified gluten-free wheat starch–based flours is safe and the small-intestinal mucosa heals and stays long-term morphologically normal. No differences were observed when comparing the clinical and biopsy results to those patients on a diet that is gluten-free by nature.

Starch hydrolysates of wheat origin—wheat-based glucose syrups, dextrose, and maltodextrins—are found in >50% of European processed food. It was shown that these common foodstuffs and ingredients elicited no harmful effects to patients with CD (3). The wheat origin of these ingredients does not have to be mentioned on the label of the final foodstuff intended to the end consumer (Commission Directive 2007/68/EC).

OATS PART OF THE GLUTEN-FREE DIET

The dogma on oats toxicity for patients with CD was challenged by Janatuinen et al in 1995 (4). Follow-up evidence-based clinical studies, in children and adults, confirmed avenin not to be harmful, neither clinically or at the mucosal level. This holds true also for dermatitis herpetiformis (5). All gluten-intolerant patients in Finland, both children and adults, have been allowed to consume oats for the last decade. Today 86% of all diagnosed patients have a gluten-free diet including oats. In Europe, an allowance of oats that does not contain wheat, rye, or barley and the gluten level does not exceed 20 ppm, may be determined at the national level. In the United States, oats are not included as one of the prohibited grains and can be labeled as gluten-free, as long as the oats contain <20 ppm gluten. Barley is the grain that often contaminates oats. It should be remembered that the so-called R5 Mendez Method heavily overestimates barley contamination in oats (6). The US Food and Drug Administration has stated that for most individuals with CD, oats can add whole-grain options, nutrient enrichment, and dietary variety.

ADJUNCTIVE THERAPIES NEEDED

It has become evident that patients may continue to suffer from symptoms despite adherence to a gluten-free diet and moreover, 20% to 80% of the patients still have a gluten-induced manifest mucosal lesion of Marsh II and III classes, comparable to that found in newly diagnosed patients (7). This means gluten is ingested in hundreds of milligrams if not in grams. In Finland, where we allow both starch products and oats, we see mucosal architectural injury only in 4%, but inflammation in the long-term is still present in 40% to 50% of the patients (7). Clearly, small intestinal mucosal healing in CD is a prerequisite for patients’ long-term well-being (8–10). The described inadequate mucosal healing is most probably caused by inadvertent gluten ingestion. Furthermore, the compliance with the strict lifelong diet is not always optimal. For these reasons, the industry is developing novel therapies on top of an attempted gluten-free diet. The ultimate goal would be a treatment replacing the diet.

OUTCOME MEASURES

The small-intestinal biopsy is the essence of CD clinics and our gold standard for successful treatment is the healing of the small-intestinal mucosa. The behavior of the mucosa is functional and protective against an environmental insult, the ingested gluten. For candidate novel nondietary treatment efficacy outcomes we should apply the same biopsy criteria. The pill, device, or vaccine should be able to prevent or attenuate gluten-induced mucosal injury (Fig. 1). Patient-related outcomes tend to reflect short-term well-being, symptoms should be used as secondary endpoints early on and then as primary ones in phase 3 and 4 trials, when the novel treatment has been shown to be effective. It should be kept in mind that upon gluten challenge, the mucosa often deteriorates earlier than symptoms occur and symptoms are often unspecific (11). Persistent mucosal injury, even in the absence of symptoms, is a risk for the patient in the long run (8–10). Morphometric tools should be used to measure gluten-induced mucosal injury (12,13).

FIGURE 1
FIGURE 1:
Also in children new treatments in celiac disease are to be foreseen. The novel drug, device or vaccine treatment should prevent or attenuate gluten-induced mucosal injury, and thus by definition, similar to a gluten-free diet, sustain health and prevent disease. The net effect of a new treatment, even if not knowing mechanisms in depth, can be measured at a small-intestinal mucosal level.

NOVEL THERAPIES

There are several avenues for novel adjunctive or alternative treatments in CD. The glutenase ALV003 has been sown to attenuate gluten-induced mucosal injury in patients with CD in the context of a gluten-free diet contaminated with 2000 mg gluten per day (14). Phase 2b studies are in progress (Alvine Phatmaceuticals, San Carlos, CA). Similarly, larazotide acetate, an epithelial tight junction regulator, is in phase 2 studies (Alba Therapeutics, Baltimore, MD). Small-intestinal mucosal integrity is not an outcome in this trial (clinicaltrials.gov). The safety of the polymer BL-7010 meant to bind the ingested gluten and sequester it to be eliminated in feces is underway in humans (clinicaltrials.gov). This gluten-binding polymer is also meant as an adjunctive therapy in parallel to a gluten-free diet (BioLineRx, Jerusalem, Israel). Nexvax2 vaccine development, to be used as immunotherapy to induce tolerance towards gluten, is under way and in phase 1 trials (ImmusanT, Cambridge, MA). Other new treatment ideas are in the discovery phase (15).

WHERE ARE WE TODAY?

Nearly 40 review papers have been written by CD researchers on treatments beyond gluten-free diet; however, no novel drugs or new treatments are available on the market. In the future, clinical drug trials are expected, including childhood CD. The ultimate goal is that patients with CD may daily ingest wheat, rye, and barley. New therapeutic approaches should be safe and available ideally at low price, comparable to the gluten-free treatment of today.

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© 2014 by European Society for Pediatric Gastroenterology, Hepatology, and Nutrition and North American Society for Pediatric Gastroenterology,