Novel treatments for celiac disease: glutenases and beyond.

Currently, the only effective treatment for celiac disease is a strict lifelong gluten-free diet. However, gluten-free dieting is restrictive, difficult to maintain and nutritionally less than optimal. The improved knowledge on celiac disease pathogenesis has enabled researchers to suggest alternative strategies to treat the disorder. The drug development poses a challenge as any novel drug for celiac disease should be simultaneously effective and as safe as the gluten-free diet. The rationale behind enzyme supplementation therapy as a future treatment option for celiac patients lies in the fact that gluten is only poorly digested by gastrointestinal proteases. Due to incomplete degradation in the gastrointestinal tract, fairly long gluten peptides enter the small-intestinal lumen and come into contact with the mucosal epithelium, and in celiac disease patients this encounter launches deleterious downstream effects. Enzyme supplement therapy using either bacterial or fungal endopeptidases or proteases from germinating cereals has been proposed to promote complete digestion of prolamins and destroy disease-inducing gluten peptides. A major advantage of these glutenases is that they work in the lumen of the small intestine and do not themselves take part in the immunological cascade of events in the lamina propria, thus being unlikely to cause harmful side effects to the host. Studies to test this rationale, e.g. with Aspergillus niger prolyl endoprotease and a combination enzyme product ALV003, are already ongoing. The development of a novel medication for celiac disease is still in its early days, and thus the conventional dietary treatment will hold its place for the time being.

Burden of illness and use of health care services before and after celiac disease diagnosis in children.

OBJECTIVES: Prevalence of celiac disease in children is approximately 1%, but most patients remain unrecognized by reason of variable clinical presentation. Undetected patients may have an increased burden of illness and use of health care services because of nonspecific complaints. We investigated these issues prospectively in newly detected patients with celiac disease before and after diagnosis in a large nationwide cohort of children. METHODS: A validated questionnaire was sent to consecutive families whose children had been diagnosed as having celiac disease within 1 year. The survey contained questions about the use of medical consultations, on-demand drugs, vitamins and herbal products, children's absenteeism from day care or school and, parents' work absenteeism. A follow-up questionnaire was sent after 1 year of receiving a gluten-free diet. RESULTS: A total of 132 families responded. A total of 44 children were diagnosed because of gastrointestinal and 88 because of extraintestinal symptoms or by risk-group screening. On treatment, outpatient visits to primary health care decreased from a mean of 3.0 to 1.3 visits per year (P < 0.001), the number of hospitalizations from 0.2 to 0.1 (P = 0.008), and antibiotic prescriptions from 1.0 to 0.5/year (P < 0.001). Visits to secondary and tertiary health care increased from 0.6 to 1.4 (P < 0.001), mostly for celiac surveillance. Use of vitamins, micronutrients, and herbal products increased from 7.3 to 10.2 pills per month (P = 0.028). CONCLUSIONS: Implementation of a gluten-free diet resulted in reduced use of health care services and antibiotic prescriptions in children. Our findings support active case-finding and risk-group screening for celiac disease.

Use of health care services and pharmaceutical agents in coeliac disease: a prospective nationwide study.

BACKGROUND: Approximately 1% of the population suffer from coeliac disease. However, the disease is heavily underdiagnosed. Unexplained symptoms may lead to incremented medical consultations and productivity losses. The aim here was to estimate the possible concealed burden of untreated coeliac disease and the effects of a gluten-free diet. METHODS: A nationwide cohort of 700 newly detected adult coeliac patients were prospectively evaluated. Health care service use and sickness absence from work during the year before diagnosis were compared with those in the general population; the data obtained from an earlier study. Additionally, the effect of one year on dietary treatment on the aforementioned parameters and on consumption of pharmaceutical agents was assessed. RESULTS: Untreated coeliac patients used primary health care services more frequently than the general population. On a gluten-free diet, visits to primary care decreased significantly from a mean 3.6 to 2.3. The consumption of medicines for dyspepsia (from 3.7 to 2.4 pills/month) and painkillers (6.8-5.5 pills/month) and the number of antibiotic courses (0.6-0.5 prescriptions/year) was reduced. There were no changes in hospitalizations, outpatient visits to secondary and tertiary care, use of other medical services, or sickness absence, but the consumption of nutritional supplements increased on treatment. CONCLUSIONS: Coeliac disease was associated with excessive health care service use and consumption of drugs before diagnosis. Dietary treatment resulted in a diminished burden to the health care system and lower use of on-demand medicines and antibiotic treatment. The results support an augmented diagnostic approach to reduce underdiagnosis of coeliac disease. TRIAL REGISTRATION: ClinicalTrials.gov NCT01145287.

Small- bowel mucosal changes and antibody responses after low- and moderate-dose gluten challenge in celiac disease.

BACKGROUND: Due to the restrictive nature of a gluten-free diet, celiac patients are looking for alternative therapies. While drug-development programs include gluten challenges, knowledge regarding the duration of gluten challenge and gluten dosage is insufficient.We challenged adult celiac patients with gluten with a view to assessing the amount needed to cause some small-bowel mucosal deterioration. METHODS: Twenty-five celiac disease adults were challenged with low (1-3 g) or moderate (3-5g) doses of gluten daily for 12 weeks. Symptoms, small-bowel morphology, densities of CD3+ intraepithelial lymphocytes (IELs) and celiac serology were determined. RESULTS: Both moderate and low amounts of gluten induced small-bowel morphological damage in 67% of celiac patients. Moderate gluten doses also triggered mucosal inflammation and more gastrointestinal symptoms leading to premature withdrawals in seven cases. In 22% of those who developed significant small- intestinal damage, symptoms remained absent. Celiac antibodies seroconverted in 43% of the patients. CONCLUSIONS: Low amounts of gluten can also cause significant mucosal deterioration in the majority of the patients. As there are always some celiac disease patients who will not respond within these conditions, sample sizes must be sufficiently large to attain to statistical power in analysis.

Serum fatty acid profile in subjects with irritable bowel syndrome.

OBJECTIVE: Irritable bowel syndrome (IBS) is a fluctuating disorder of the gastrointestinal tract, characterized by abdominal pain and change in bowel habit. We wanted to investigate subjects with IBS for signs of disturbed intestinal absorption of fatty acids, as reflected in serum composition. MATERIAL AND METHODS: Serum samples were obtained from 32 adults with IBS, and from 59 controls. Serum fatty acids were analyzed by capillary gas-liquid chromatography. RESULTS: Especially the proportions of arachidonic acid (20:4 n-6) and the long-chain polyunsaturated fatty acids of the n-3 family docosapentaenoic acid (22:5 n-3) and docosahexaenoic acid (22:6 n-3) were decreased in subjects with IBS. The proportions of unsaturated and monounsaturated fatty acids were generally increased in IBS compared to controls. CONCLUSIONS: Although organic disease has been ruled out in patients with IBS, they presented signs of inadequate supply of long-chain fatty acids. Supplementation with n-3 fatty acids may be implicated.