A Randomized Trial of a Transglutaminase 2 Inhibitor for Celiac Disease.

BACKGROUND: In celiac disease, small intestinal transglutaminase 2 causes deamidation of glutamine residues in gluten peptides, which enhances stimulation of T cells and leads to mucosal injury. Inhibition of transglutaminase 2 is a potential treatment for celiac disease. METHODS: In a proof-of-concept trial, we assessed the efficacy and safety of a 6-week treatment with ZED1227, a selective oral transglutaminase 2 inhibitor, at three dose levels as compared with placebo, in adults with well-controlled celiac disease who underwent a daily gluten challenge. The primary end point was the attenuation of gluten-induced mucosal damage, as measured by the ratio of villus height to crypt depth. Secondary end points included intraepithelial lymphocyte density, the Celiac Symptom Index score, and the Celiac Disease Questionnaire score (for assessment of health-related quality of life). RESULTS: Of the 41 patients assigned to the 10-mg ZED1227 group, the 41 assigned to the 50-mg group, the 41 assigned to the 100-mg group, and the 40 assigned to the placebo group, 35, 39, 38, and 30 patients, respectively, had adequate duodenal-biopsy samples for the assessment of the primary end point. Treatment with ZED1227 at all three dose levels attenuated gluten-induced duodenal mucosal injury. The estimated difference from placebo in the change in the mean ratio of villus height to crypt depth from baseline to week 6 was 0.44 (95% confidence interval [CI], 0.15 to 0.73) in the 10-mg group (P = 0.001), 0.49 (95% CI, 0.20 to 0.77) in the 50-mg group (P<0.001), and 0.48 (95% CI, 0.20 to 0.77) in the 100-mg group (P<0.001). The estimated differences from placebo in the change in intraepithelial lymphocyte density were -2.7 cells per 100 epithelial cells (95% CI, -7.6 to 2.2) in the 10-mg group, -4.2 cells per 100 epithelial cells (95% CI, -8.9 to 0.6) in the 50-mg group, and -9.6 cells per 100 epithelial cells (95% CI, -14.4 to -4.8) in the 100-mg group. Use of the 100-mg dose may have improved symptom and quality-of-life scores. The most common adverse events, the incidences of which were similar across all groups, were headache, nausea, diarrhea, vomiting, and abdominal pain. Rash developed in 3 of 40 patients (8%) in the 100-mg group. CONCLUSIONS: In this preliminary trial, treatment with ZED1227 attenuated gluten-induced duodenal mucosal damage in patients with celiac disease. (Funded by Dr. Falk Pharma; CEC-3 EudraCT number, 2017-002241-30.).

Effect of Early Feeding on Intestinal Permeability and Inflammation Markers in Infants with Genetic Susceptibility to Type 1 Diabetes: A Randomized Clinical Trial.

OBJECTIVES: To assess whether weaning to an extensively hydrolyzed formula (EHF) decreases gut permeability and/or markers of intestinal inflammation in infants with HLA-conferred diabetes susceptibility, when compared with conventional formula. STUDY DESIGN: By analyzing 1468 expecting biological parent pairs for HLA-conferred susceptibility for type 1 diabetes, 465 couples (32 %) potentially eligible for the study were identified. After further parental consent, 332 babies to be born were randomized at 35th gestational week. HLA genotyping was performed at birth in 309 infants. Out of 87 eligible children, 73 infants participated in the intervention study: 33 in the EHF group and 40 in the control group. Clinical visits took place at 3, 6, 9, and 12 months of age. The infants were provided either EHF or conventional formula whenever breastfeeding was not available or additional feeding was required over the first 9 months of life. The main outcome was the lactulose to mannitol ratio (L/M ratio) at 9 months. The secondary outcomes were L/M ratio at 3, 6, and 12 months of age, and fecal calprotectin and human beta-defensin 2 (HBD-2) levels at each visit. RESULTS: Compared with controls, the median L/M ratio was lower in the EHF group at 9 months (.006 vs .028; P = .005). Otherwise, the levels of intestinal permeability, fecal calprotectin, and HBD-2 were comparable between the two groups, although slight differences in the age-related dynamics of these markers were observed. CONCLUSIONS: It is possible to decrease intestinal permeability in infancy through weaning to an extensively hydrolyzed formula. This may reduce the early exposure to dietary antigens. TRIAL REGISTRATION: Clinicaltrials.gov: NCT01735123.

Dietary Factors and Mucosal Immune Response in Celiac Disease Patients Having Persistent Symptoms Despite a Gluten-free Diet.

GOALS: The aim of this study was to investigate the role of dietary factors, distinct small-bowel mucosal immune cell types, and epithelial integrity in the perpetuation of gastrointestinal symptoms in treated celiac disease patients. BACKGROUND: For unexplained reasons, many celiac disease patients suffer from persistent symptoms, despite a strict gluten-free diet (GFD) and recovered intestinal mucosa. STUDY: We compared clinical and serological data and mucosal recovery in 22 asymptomatic and 25 symptomatic celiac patients on a long-term GFD. The density of CD3 and γδ intraepithelial lymphocytes (IELs), CD25 and FOXP3 regulatory T cells, and CD117 mast cells, and the expression of tight junction proteins claudin-3 and occludin, heat shock protein 60, interleukin 15, and Toll-like receptor 2 and 4 were evaluated in duodenal biopsies. RESULTS: All subjects kept a strict GFD and had negative celiac autoantibodies and recovered mucosal morphology. The asymptomatic patients had higher mean fiber intake (20.2 vs. 15.2 g/d, P=0.028) and density of CD3 IELs (59.3 vs. 45.0 cell/mm, P=0.045) than those with persistent symptoms. There was a similar but nonsignificant trend in γδ IELs (17.9 vs. 13.5, P=0.149). There were no differences between the groups in other parameters measured. CONCLUSIONS: Low fiber intake may predispose patients to persistent symptoms in celiac disease. There were no differences between the groups in the markers of innate immunity, epithelial stress or epithelial integrity. A higher number of IELs in asymptomatic subjects may indicate that the association between symptoms and mucosal inflammation is more complicated than previously thought.

At-Risk Screened Children with Celiac Disease are Comparable in Disease Severity and Dietary Adherence to Those Found because of Clinical Suspicion: A Large Cohort Study.

OBJECTIVE: To assess whether children at risk for celiac disease should be screened systematically by comparing their baseline and follow-up characteristics to patients detected because of clinical suspicion. STUDY DESIGN: Five hundred four children with celiac disease were divided into screen-detected (n = 145) and clinically detected cohorts (n = 359). The groups were compared for clinical, serologic, and histologic characteristics and laboratory values. Follow-up data regarding adherence and response to gluten-free diet were compared. Subgroup analyses were made between asymptomatic and symptomatic screen-detected patients. RESULTS: Of screen-detected patients, 51.8% had symptoms at diagnosis, although these were milder than in clinically detected children (P < .001). Anemia (7.1% vs 22.9%, P < .001) and poor growth (15.7% vs 36.9%, P < .001) were more common, and hemoglobin (126 g/l vs 124 g/l, P = .008) and albumin (41.0 g/l vs 38.0 g/l, P = .016) were lower in clinically detected patients. There were no differences in serology or histology between the groups. Screen-detected children had better dietary adherence (91.2% vs 83.2%, P = .047). The groups showed equal clinical response (97.5% vs 96.2%, P = .766) to the gluten-free diet. In subgroup analysis among screen-detected children, asymptomatic patients were older than symptomatic (9.0 vs 5.8 years of age, P = .007), but the groups were comparable in other variables. CONCLUSIONS: More than one-half of the screen-detected patients with celiac disease had symptoms unrecognized at diagnosis. The severity of histologic damage, antibody levels, dietary adherence, and response to treatment in screen-detected cases is comparable with those detected on a clinical basis. The results support active screening for celiac disease among at-risk children.

Anemia and Iron Deficiency in Children With Potential Celiac Disease.

OBJECTIVES: Active screening for celiac disease frequently detects seropositive children with normal villous morphology (potential celiac disease). It remains unclear whether these subjects should be treated. We here investigated the prevalence of anemia and iron deficiency in children with potential and mucosal atrophy celiac disease. METHODS: The prospective study involved 19 children with potential disease, 67 with partial or subtotal villous atrophy (P/SVA), and 16 with total villous atrophy (TVA). Twenty-three healthy children comprised the control group. The groups were compared for various clinical, histological, and laboratory parameters and hepcidin. RESULTS: The prevalence of abnormal parameters was as follows (controls, potential celiac disease, P/SVA, and TVA, respectively): anemia 0%, 15%, 22%, and 63%; low iron 5%, 0%, 14%, and 50%; increased transferrin receptor 1 5%, 16%, 20%, and 47%; low ferritin 0%, 21%, 35%, and 87%; and low transferrin saturation 10%, 11%, 41%, and 71%. One subject had low folate and none had low vitamin B12. The median values for hemoglobin, total iron, ferritin, and transferrin saturation were significantly lower and transferrin receptor 1 values higher in TVA group compared with other groups. After a median of 7 months on a gluten-free diet hemoglobin, total iron, ferritin, and albumin in children with P/SVA exceeded the baseline values in the potential celiac disease group. CONCLUSIONS: The development of anemia and iron deficiency in celiac disease is a continuum and may already be present in children with normal villous morphology, advocating an early diagnosis and possible dietary treatment of these patients.

Coeliac patients detected during type 1 diabetes surveillance had similar issues to those diagnosed on a clinical basis.

AIM: Screening children with type 1 diabetes for coeliac disease is controversial, because they often appear asymptomatic. Our aim was to establish whether active screening should be recommended. METHODS: This study focused on 22 children whose coeliac disease was detected by serological screening during diabetes surveillance and 498 children diagnosed because of a clinical suspicion. We compared the clinical and histological data at diagnosis and the children's adherence and responses to a gluten-free diet. RESULTS: The serological screening group suffered less from decreased growth (p = 0.016) and clinical symptoms (p < 0.001) at diagnosis than the clinical group. The groups did not differ in terms of age at diagnosis (p = 0.903), gender (p = 0.353), anaemia (p = 0.886), endomysial antibody titres (p = 0.789) and the severity of small-bowel mucosal atrophy (p = 0.104). They also showed equal adherence (p = 0.086) and clinical responses (p = 0.542) to a gluten-free diet after a median follow-up of 13 months. CONCLUSION: Coeliac patients detected during diabetes surveillance had signs of malabsorption and advanced mucosal damage that was similar to those diagnosed on a clinical basis. They often suffered from unrecognised gluten-dependent symptoms and showed excellent adherence and responses to a gluten-free diet. Our findings support active screening for coeliac disease in patients with type 1 diabetes.

A Prospective Study on the Usefulness of Duodenal Bulb Biopsies in Celiac Disease Diagnosis in Children: Urging Caution.

OBJECTIVES: Several recent celiac disease guidelines recommend the acquisition of duodenal bulb biopsies for diagnostics. This is in conflict with previously reported evidence and routine practice from the 1960s onward. We reopened the issue in a prospective multicenter study and used morphometric variables in evaluating the usefulness of bulb biopsies in children. We further sought to establish whether deposits of IgA targeting bulb transglutaminase 2 (TG2) could be of diagnostic help. METHODS: Diagnoses of celiac disease were based on clinic and distal duodenal histopathology statements. Centralized reading of villous height (VH) to crypt depth (CrD) ratios and IgA deposits was performed on anatomical duodenal bulb specimens. All children participating also underwent routine investigations for other diseases. RESULTS: Twenty-two children had celiac disease, and another 22 served as non-celiac disease controls. The quality of the anatomical bulb specimens was unsatisfactory for reliable morphometric measurements in 20 out of 44 (45%) patients even after recuttings. All celiac disease patients had VH:CrD<2.0 (mean 0.2) but also 10 out of 13 (77%) non-celiac control patients had an injured bulb mucosal lining (mean 1.3) even up to false-positive "flat lesion". Bulb IgA deposits were able to separate celiac disease from disease controls. CONCLUSIONS: Morphological injury is common in the anatomical bulb even without celiac disease, increasing the risk of false-positive diagnoses. Premature conclusions might have been drawn on current care guidelines as to celiac disease diagnosis based solely on anatomical bulb specimens. Bulb mucosal IgA targeting TG2 in poor quality biopsy specimens is a powerful clinical tool in finding celiac disease patients.

Glutenase ALV003 attenuates gluten-induced mucosal injury in patients with celiac disease.

BACKGROUND & AIMS: Gluten 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. METHODS: We established the optimal daily dose of gluten to be used in a 6-week challenge study. Then, in the intervention study, adults with biopsy-proven celiac disease were randomly assigned to groups given ALV003 (n = 20) or placebo (n = 21) together with the daily gluten challenge. Duodenal biopsies were collected at baseline and after gluten challenge. The ratio of villus height to crypt depth and densities of intraepithelial lymphocytes were the primary end points. RESULTS: A daily dose of 2 g gluten was selected for the intervention study. Sixteen patients given ALV003 and 18 given placebo were eligible for efficacy evaluation. Biopsies from subjects in the placebo group showed evidence of mucosal injury after gluten challenge (mean villus height to crypt depth ratio changed from 2.8 before challenge to 2.0 afterward; P = .0007; density of CD3(+) intraepithelial lymphocytes changed from 61 to 91 cells/mm after challenge; P = .0003). However, no significant mucosal deterioration was observed in biopsies from the ALV003 group. Between groups, morphologic changes and CD3(+) intraepithelial lymphocyte counts differed significantly from baseline to week 6 (P = .0133 and P = .0123, respectively). There were no statistically significant differences in symptoms between groups. CONCLUSIONS: Based on a phase 2 trial, the glutenase ALV003 appears to attenuate gluten-induced small intestinal mucosal injury in patients with celiac disease in the context of an everyday gluten-free diet containing daily up to 2 g gluten. Clinicaltrial.gov, NUMBERS: NCT00959114 and NCT01255696.

Presentation of Celiac Disease in Finnish Children Is No Longer Changing: A 50-Year Perspective.

OBJECTIVES: To chart trends in the presentation of celiac disease in a large cohort of Finnish children diagnosed over a period of 48 years. STUDY DESIGN: Clinical and serologic data, severity of small-bowel mucosal damage, and presence of associated conditions were gathered from 596 children diagnosed with celiac disease in 1966-2013. The children were divided into 4 groups based on the year of diagnosis (before 1980, 1980-1999, 2000-2009, and 2010-2013), and the variables were compared between the periods. The incidence of celiac disease autoimmunity in 2001-2013 was calculated based on the number of new antibody-positive cases in each year. RESULTS: Age at diagnosis rose from median 4.3 years before 1980 to between 7.6 and 9.0 years in the later periods. The severity of clinical presentation, in general, became milder and poor growth less common during the entire study period of 50 years. Percentages of children with classical gastrointestinal presentation decreased, and those with atypical or subclinical presentation increased after the 1990s, these changes leveling off in 2000-2013. Similarly, the severity of small-bowel mucosal damage was milder after the 1990s. The incidence of celiac disease autoimmunity increased in the early 2000s but then fluctuated without a clear trend. There were no significant secular changes in sex distribution, presence of anemia, levels of celiac antibodies, or celiac disease-associated conditions. CONCLUSIONS: The clinical and histologic presentation of celiac disease in children became milder, especially in the 1980s and 1990s. However, most of these changes have reached a plateau in recent years.

Altered duodenal microbiota composition in celiac disease patients suffering from persistent symptoms on a long-term gluten-free diet.

OBJECTIVES: A significant fraction of celiac disease patients suffer from persistent symptoms despite a long-term gluten-free diet (GFD) and normalized small bowel mucosa. The commonly suggested reasons, such as inadvertent gluten-intake or presence of other gastrointestinal disease, do not explain the symptoms in all these patients. Recently, alterations in intestinal microbiota have been associated with autoimmune disorders, including celiac disease. This led us to test a hypothesis that abnormal intestinal microbiota may be associated with persisting gastrointestinal symptoms in treated celiac disease patients. METHODS: Duodenal microbiota was analyzed in 18 GFD-treated patients suffering from persistent symptoms and 18 treated patients without symptoms by 16S rRNA gene pyrosequencing. The celiac disease patients had been following a strict GFD for several years and had restored small bowel mucosa and negative celiac autoantibodies. Their symptoms on GFD were assessed with Gastrointestinal Symptom Rating Scale. RESULTS: The results of several clustering methods showed that the treated celiac disease patients with persistent symptoms were colonized by different duodenal microbiota in comparison with patients without symptoms. The treated patients with persistent symptoms had a higher relative abundance of Proteobacteria (P=0.04) and a lower abundance of Bacteroidetes (P=0.01) and Firmicutes (P=0.05). Moreover, their microbial richness was reduced. The results indicated intestinal dysbiosis in patients with persistent symptoms even while adhering to a strict GFD. CONCLUSIONS: Our findings indicate that dysbiosis of microbiota is associated with persistent gastrointestinal symptoms in treated celiac disease patients and open new possibilities to treat this subgroup of patients.

Degree of damage to the small bowel and serum antibody titers correlate with clinical presentation of patients with celiac disease.

BACKGROUND & AIMS: In patients with celiac disease, gluten-induced lesions of the small-bowel mucosa develop gradually. However, it is not clear whether clinical presentation correlates with the degree of mucosal damage based on histology analysis. We investigated whether the degree of mucosal damage to the small bowel correlates with clinical presentation and serum markers of celiac disease. METHODS: We collected results from serology tests and mucosal biopsy samples from 638 consecutive patients with celiac disease and compared them with reported gastrointestinal symptoms, health-related quality-of-life scores, results from laboratory tests, and bone mineral densities of patients. We assessed mucosal injury based on the ratio of villous height to crypt depth, numbers of intraepithelial CD3(+) cells, and semiquantitative Marsh classification criteria. Correlations were established based on the Pearson or Spearman coefficients. RESULTS: The ratio of the villous height to crypt depth correlated with the severity of gastrointestinal symptoms, quality-of-life scores, laboratory test results, numbers of intraepithelial CD3(+) cells, and serum levels of antibodies associated with celiac disease. There was no correlation between the ratio of villous height to crypt depth and bone mineral density. The number of intraepithelial CD3(+) cells was not associated with symptoms, whereas the Marsh classification and serum levels of antibodies associated with celiac disease correlated with gastrointestinal symptoms, laboratory test results, and numbers of intraepithelial CD3(+) cells. CONCLUSIONS: The ratio of small-bowel villous height to crypt depth and results from serology tests correlate with reported symptoms and quality of life of patients with celiac disease. Patient-reported outcomes are therefore of value, in addition to histology findings, in assessing patients with celiac disease.

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.

Peptide hormones in infants with feeding disorders.

The prevalence of eating problems in otherwise healthy infants is a common problem in Western countries. Peptide hormones such as adiponectin, ghrelin and resistin have been shown to play an important role in the regulation of satiety and hunger in several diseases and states. The aim of this study was to evaluate the peptide hormone levels in children with eating problems. In this study, 12 otherwise healthy infants (mean age 10.4 months) with eating problems and 12 healthy controls were studied. At their first hospital visit samples for analysis of adiponectin, ghrelin and resistin were obtained and a careful physical examination was carried out. To exclude any possible anatomic or metabolic reason for eating problems necessary investigations were also performed. Adiponectin levels were significantly higher in the cases than in the controls (p = 0.033), and the difference was still significant after adjustment for weight (p < 0.05). Resistin and ghrelin concentrations showed no significant differences. Conclusions. For the first time we were able to show in this pilot study that adiponectin concentrations were elevated in the infants with eating problems. Cross-sectional association does not necessarily imply causal relationship. Thus, further studies with larger number of cases will be needed to clarify the role of adiponectin in the eating problems in infants.

Burden of illness in screen-detected children with celiac disease and their families.

OBJECTIVES: Because of a variable clinical picture, most children with celiac disease remain unrecognized without active serologic screening. Because, however, many patients are asymptomatic, the justification for screening remains unclear. We assessed health and well-being and the effect of a 1-year gluten-free diet in a nationwide cohort of children with celiac disease detected by screening in at-risk groups. METHODS: A total of 222 newly detected children received a validated questionnaire covering aspects of the burden caused by the undiagnosed celiac disease. After 1 year, adherence to the diet and difficulties attending this, attitudes toward and effects of disease and diet on daily life, and parents' satisfaction with the diagnosis were inquired about. The children's health and parents' concern for it were asked about at diagnosis and on treatment. The outcomes of screen-detected children were compared with those of children diagnosed on the basis of clinical symptoms. RESULTS: Forty-three screen-detected and 88 symptom-detected children responded. Also, 65% of the screen-detected patients experienced symptoms; these, however, being less troublesome and of shorter duration than in symptom-detected subjects. There were no differences between the groups in dietary adherence (71% vs 84% strict diet), management of the diet (80% vs 80%), alleviation of symptoms (78% vs 86%), and improvement in daily life (73% vs 69%), or in satisfaction with the diagnosis (93% vs 88%). Improved health and reduced parental concern were observed in both groups. CONCLUSIONS: Screen-detected children with celiac disease can attain satisfactory dietary adherence and benefit from treatment similarly to symptom-detected patients. The results support intensified screening for celiac disease in at-risk children.

Gluten-sensitive hypertransaminasemia in celiac disease: an infrequent and often subclinical finding.

OBJECTIVES: Earlier studies suggest that 40-50% of untreated celiac disease patients have elevated transaminase levels. Celiac disease can also be the underlying reason for unexplained hypertransaminasemia or even liver failure. We investigated the prevalence and gluten dependency of hypertransaminasemia in celiac patients also diagnosed with minor or atypical symptoms. METHODS: In the cross-sectional study, serum aspartate (AST) and alanine (ALT) transaminase levels were measured in 313 untreated and 339 treated adult celiac patients and 237 non-celiac controls. In the prospective part, transaminase levels were investigated in 130 celiac patients at diagnosis and after 1 year on a gluten-free diet and in 25 treated celiac patients in clinical remission before and after gluten challenge. RESULTS: The proportion of subjects with elevated serum AST values in the untreated celiac disease group (11%) did not differ significantly from that in the treated celiac disease (8%) or non-celiac control groups (9%) (P=0.587). Although the serum transaminase values were within normal range in the majority of untreated patients, initially normal liver enzyme levels decreased significantly on a gluten-free diet. In treated celiac disease, gluten challenge led to mild and transient hypertransaminasemia. CONCLUSIONS: In our area, where the prevalence of celiac disease is high, hypertransaminasemia is less frequent in untreated celiac disease patients than previously reported. The regular screening of transaminases in celiac disease needs to be re-evaluated. Although the liver enzyme levels were within the reference values in the majority of celiac patients, an obvious gluten dependence of transaminase levels was observed even in these subjects.

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.

[Mastocytosis as the cause of childrens' abdominal discomforts]. / Mastosytoosi lasten vatsavaivojen aiheuttajana.

In mastocytosis the number of mast cells is increased, and the most common manifestation is urticaria pigmentosa. We describe four children, of which two developed ulceration of the upper gastrointestinal tract. Main symptoms in the other children were vomiting, heartburn and abdominal pains, which were manifested as intense crying spells. The symptoms are caused by mediators such as histamine being released from the mast cells, and blockers of the histamine receptor thus play a central role in their treatment. The childrens' condition was significantly alleviated by adequate medication: the ulceration healed, symptoms were relieved and growth was normalized.

Rotavirus Vaccination Does Not Increase Type 1 Diabetes and May Decrease Celiac Disease in Children and Adolescents.

BACKGROUND: Rotavirus (RV) infection has been proposed to trigger type 1 diabetes mellitus (DM1) and celiac disease (CD) by molecular mimicry in genetically susceptible children. If so, a live attenuated oral RV vaccine could also trigger these autoimmune diseases, or else, prevent the effect of wild-type RV infection. METHODS: In Rotavirus Efficacy and Safety Trial, conducted between 2001 and 2003, the participant children received RotaTeq (Kenilworth, NJ) vaccine or placebo in 1:1 ratio. The surveillance was extended as Finnish Extension Study. A questionnaire was sent in 2015 to the parents of 19,133 Finnish Extension Study participants and 5764 (30%) returned the questionnaire. Diagnosis of DM1, biopsy-proven CD and other autoimmune disease over the 11-14 year period were inquired. RESULTS: At the time of questionnaire, the prevalence of DM1 was similar in both groups, 0.97% (25 of 2580 children) in the placebo group and 1.04% (33 of 3184 children) in the vaccine group (P = 0.810). The prevalence of CD was significantly higher in placebo recipients (1.11%; confidence interval: 0.78%-1.6%) than in vaccine recipients (0.60%; confidence interval: 0.38%-0.93%) (P = 0.027). CONCLUSIONS: RV vaccination using RotaTeq did not alter the occurrence of DM1 but decreased the prevalence of CD in childhood and adolescence. We propose that wild-type RV may trigger CD and the triggering effect can be prevented or reduced by RV vaccination.

Daily Life Restrictions are Common and Associated with Health Concerns and Dietary Challenges in Adult Celiac Disease Patients Diagnosed in Childhood.

The prevalence and associated factors of daily life restrictions due to a gluten-free diet in adult celiac disease patients diagnosed in childhood are poorly known. We investigated these issues by collecting the medical data of 955 pediatric patients and sending questionnaires evaluating various health outcomes to the 559 patients who had reached adulthood. Of the 231 respondents, 46% reported everyday life restrictions caused by dietary treatment. Compared with those without restrictions, they more often had anemia at diagnosis (37% vs. 22%, p = 0.014), but the groups were comparable in other diagnostic features. In adulthood, patients with restrictions reported more overall symptoms (32% vs. 17%, p = 0.006), although the symptoms measured with the Gastrointestinal Symptom Rating Scale questionnaire were comparable. Despite strict dietary adherence in both groups, the experience of restrictions was associated with dietary challenges (34% vs. 9%, p < 0.001), health concerns (22% vs. 13%, p = 0.050), and lower vitality scores in the Psychological General Well-Being questionnaire. The groups did not differ in their current age, socioeconomic status, family history of celiac disease, general health or health-related lifestyle, the presence of co-morbidities, or regular follow up. Our results encourage healthcare professionals to discuss the possible health concerns and dietary challenges with patients to avoid unnecessary daily life restrictions, especially when young patients start to take responsibility for their treatment.

Safety and efficacy of AMG 714 in adults with coeliac disease exposed to gluten challenge: a phase 2a, randomised, double-blind, placebo-controlled study.

BACKGROUND: Interleukin 15 (IL-15) is implicated in the pathophysiology of coeliac disease. AMG 714 is the first anti-IL-15 monoclonal antibody to be investigated for the treatment of coeliac disease. We aimed to investigate the effects of AMG 714 in patients with coeliac disease who underwent gluten challenge. METHODS: This randomised, double-blind, placebo-controlled, parallel-group, phase 2a trial was done at three clinical sites in Finland. Inclusion criteria included age 18-80 years, a confirmed diagnosis of coeliac disease, and adherence to a gluten-free diet for at least 12 months before screening. Patients were randomly assigned (1:1:1) to 150 mg AMG 714, 300 mg AMG 714, or placebo using permuted blocks and stratified by study site and sex. Patients and study staff were masked to treatment assignment. Treatments were administered by two subcutaneous injections every 2 weeks for 10 weeks (total six doses). Patients without severe villous atrophy at baseline received a gluten challenge (2-4 g daily) during weeks 2-12. Small bowel biopsy samples were obtained for histological assessments at baseline and week 12. The primary efficacy endpoint was the percentage change from baseline to week 12 in villous height-to-crypt depth (VHCD) ratio. Secondary endpoints were CD3-positive intraepithelial lymphocyte density; clinical symptoms measured by gastrointestinal symptom rating scale (GSRS), coeliac disease GSRS, and Bristol stool form scale (BSFS); and changes in anti-tTG and anti-DGP antibodies from baseline. The primary analysis was done in the per-protocol 1 population of patients who received at least one dose of study drug and who underwent the gluten challenge. Safety analyses were done in all patients who received at least one dose of study drug. This trial is registered at ClinicalTrials.gov, NCT02637141 and EudraCT, 2015-003647-19. FINDINGS: Between April 13, 2016, and Nov 22, 2016, 64 patients were enrolled and randomly assigned to either the 150 mg AMG 714 group (n=22), the 300 mg AMG 714 group (n=22), or the placebo group (n=20). Two patients did not start treatment and two did not provide post-treatment biopsy samples. 49 patients underwent the gluten challenge (per-protocol 1 population) and 11 patients did not because of baseline villous atrophy. AMG 714 did not prevent mucosal injury due to gluten challenge. The least square mean difference in the relative change from baseline in VHCD ratio was -2·49% (95% CI -16·82 to 11·83; p=0·73) between 150 mg AMG 714 and placebo and 6·39% (-7·07 to 19·85; p=0·34) between 300 mg AMG 714 and placebo. Neither comparison was statistically significant. The density of CD3-positive intraepithelial lymphocytes increased in all groups, with smaller increases in the 300 mg group (-41·24% [95% CI -79·28 to -3·20] vs placebo, nominal p=0·03) but not the 150 mg group (-14·32% [-54·39 to 25·74], nominal p=0·47). Clinical symptoms were ameliorated with AMG 714 treatment between baseline and week 12, particularly diarrhoea as measured by the BSFS (nominal p=0·01 for 150 mg vs placebo, and nominal p=0·0002 for 300 mg vs placebo). Serum antibody titres for anti-tTG and anti-DGP antibodies increased in all three treatment groups, with no significant difference between AMG 714 and placebo. Treatment-emergent adverse events occurred in 21 (95%) patients in the 150 mg AMG 714 group, 0 (95%) in the 300 mg AMG 714 group, and 19 (100%) in the placebo group. The most common treatment-emergent adverse events were gastrointestinal disorders (17 [77%] participants in the 150 mg AMG 714 group, 16 [76%] in the 300 mg AMG 714 group, and 13 [68%] in the placebo group). Injection site reactions were the most common individual adverse event, reported in eight (36%) patients in the 150 mg AMG 714 group, 11 (52%) in the 300 mg group, and five (26%) in the placebo group. No serious adverse events occurred. INTERPRETATION: The primary endpoint, change in VHCD ratio from baseline after 12 weeks of treatment in patients with coeliac disease undergoing gluten challenge, was not significantly different between placebo and AMG 714 at either 150 mg or 300 mg. Effects on intraepithelial lymphocyte density and symptoms suggest that further research of AMG 714 may be warranted in patients with non-responsive coeliac disease. FUNDING: Celimmune and Amgen.