Search

An association between celiac disease and IgA nephropathy (IgAN) has been suggested. In celiac disease, in addition to circulating in serum, IgA-class tissue transglutaminase (tTG) autoanti-bodies are deposited in the small bowel mucosa and extraintestinal organs. In this case series of IgAN patients with or without celiac disease, we studied whether celiac disease-type IgA-tTG deposits occur in kidney biopsies. The study included nine IgAN patients, four of them with celiac disease. At the time of the diagnostic kidney biopsy serum tTG autoantibodies were measured and colocalization of IgA and tTG was investigated in the frozen kidney biopsies. Three IgAN patients with celiac disease had IgA-tTG deposits in the kidney even though in two of these the celiac disease diagnosis had been set years later. These deposits were not found in a patient with already diagnosed celiac disease following a gluten-free diet. Of the five non-celiac IgAN patients, three had IgA-tTG deposits in the kidney. We conclude that tTG-targeted IgA deposits can be found in the kidney biopsies of gluten-consuming IgAN patients but their specificity to celiac disease seems limited. publishedVersion

Non-biopsy diagnosis of celiac disease is possible in children with anti-transglutaminase 2 antibodies (TGA) &gt, 10&times, the upper limit of normal (ULN) and positive anti-endomysial antibodies (EMA). Similar criteria have been suggested for adults, but evidence with different TGA assays is scarce. We compared the performance of four TGA tests in the diagnosis of celiac disease in cohorts with diverse pre-test probabilities. Serum samples from 836 adults with either clinical suspicion or family risk of celiac disease were tested with four commercial TGA assays, EmA and celiac disease-associated genetics. The diagnosis was set based on duodenal lesion or, in some cases, using special methods. 137 (57%) patients with clinical suspicion and 85 (14%) of those with family risk had celiac disease. Positive predictive value (PPV) for 10&times, ULN was 100% in each TGA test. The first non-diagnostic investigations were encountered with ULN 1.0&times, &ndash, 5.1&times, in the clinical cohort and 1.3&times, 4.9&times, in the family cohort, respectively. Using the assays&rsquo, own cut-offs (1&times, ULN) the PPVs ranged 84&ndash, 100%. Serology-based diagnosis of celiac disease was accurate in adults using different commercial kits and pre-test probabilities using 10&times, ULN. The results also suggest that the ULN threshold for biopsy-omitting approach could be lower.

Dermatitis herpetiformis (DH), a cutaneous manifestation of coeliac disease, is characterized by transglutaminase (TG) 3-targeted dermal immunoglobulin A (IgA) deposits. The treatment for DH is the same as for coeliac disease, namely a life-long gluten-free diet. DH patients typically have gluten-dependent circulating autoantibodies targeting TG3 and TG2, and plasma cells secreting such autoantibodies have been detected in the small intestinal mucosa. This study investigates the gluten-responsiveness of intestinal TG3 and TG2 antibody-secreting plasma cells in 16 treated DH patients undergoing a gluten challenge. The frequency of both plasma cell populations increased significantly during the challenge, and their frequency correlated with the corresponding serum autoantibody levels at post-challenge. TG3-specific plasma cells were absent in all 18 untreated coeliac disease patients and seven non-coeliac control subjects on gluten-containing diets. These findings indicate that, in DH, both intestinal TG3- and TG2-antibody secreting plasma cells are gluten-dependent, and that TG3-antibody secreting plasma cells are DH-specific.

Coeliac disease and dermatitis herpetiformis (DH) are characterized by autoantibodies targeting transglutaminase (TG)2 and TG3, respectively. Previous studies show that TG2 antibodies are produced in the gut and can be assessed in organ culture of small-intestinal biopsies from patients with coeliac disease. Thus far, no studies have investigated TG3 antibodies in organ culture of biopsies from patients with DH, or exploited the method in DH. The aim of this study was to investigate TG3 and TG2 antibody responses in serum and small-intestinal biopsies from patients with DH with active disease, and from those in remission. The majority of patients with DH were negative for both serum and organ culture medium TG2-targeting antibodies. Surprisingly, patients with active DH secreted TG3 antibodies into the culture medium despite seronegativity. In patients secreting high levels of TG3 antibodies into the culture medium, we also detected TG3-antibody-positive cells in the small-intestinal mucosa. These findings suggest that TG3 antibodies can be investigated in the organ culture system and that their secretion occurs in the small intestine, especially in active DH.

BACKGROUND AND AIMS It remains unclear as to what are the clinical characteristics associated with the presence of anemia at celiac disease diagnosis, and how these are affected by a gluten-free diet. We investigated these issues in a prospective study. METHODS Clinical and demographic data, small-bowel mucosal histology, serology, and laboratory parameters, body mass index (BMI), and bone mineral density (BMD) both at diagnosis and after 1 year on a gluten-free diet were investigated in 163 adults with celiac disease. Gastrointestinal symptoms and psychological well-being were evaluated by validated Gastrointestinal Symptom Rating Scale and Psychological General Well-Being questionnaires. All study variables were compared between participants with and without anemia at celiac disease diagnosis. RESULTS Altogether, 23% of the patients had anemia at diagnosis. Anemic patients were more often women (P=0.001) and had more gastrointestinal symptoms (P=0.004) and were less often screen detected (P=0.009). Further, they had higher celiac antibody values (P=0.007) and a lower total iron (P

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.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.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.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.

GOALS To test the accuracy of serology-based criteria for diagnosing celiac disease utilizing quantitative histomorphometry. BACKGROUND The revised European pediatric guidelines allow noninvasive celiac disease diagnosis for a subgroup of children. However, in some of the studies on this issue, the positive predictive value (PPV) of serology has remained suboptimal, possibly because of challenges of histopathology as the reference standard. STUDY Prospectively enrolled children with transglutaminase 2 antibodies (TGA) above the upper limit of normal (ULN) underwent blood sampling and duodenal biopsy in Finland and Romania. Those with TGA ≥10× ULN, positive endomysium antibodies (EmA), and disease-associated genetics were considered to fulfill triple criteria for celiac disease. Initial histopathologic analysis was conducted using grouped classification, whereupon centralized morphometry was performed. RESULTS Altogether 88 (54%) children were triple positive. In local evaluation, 99% of triple-positive children and 73% of children with TGA

Widespread use of endomysial autoantibody (EmA) test in diagnostics of celiac disease is limited due to its subjectivity and its requirement of an expert evaluator. The study aimed to determine whether machine learning can be applied to create a new observer-independent method of automatic assessment and classification of the EmA test for celiac disease. The study material comprised of 2597 high-quality IgA-class EmA images collected in 2017–2018. According to standard procedure, highly-experienced professional classified samples into the following four classes: I - positive, II - negative, III - IgA deficient, and IV - equivocal. Machine learning was deployed to create a classification model. The sensitivity and specificity of the model were 82.84% and 99.40%, respectively. The accuracy was 96.80%. The classification error was 3.20%. The area under the curve was 99.67%, 99.61%, 100%, and 99.89%, for I, II, III, and IV class, respectively. The mean assessment time per image was 16.11 seconds. This is the first study deploying machine learning for the automatic classification of IgA-class EmA test for celiac disease. The results indicate that using machine learning enables quick and precise EmA test analysis that can be further developed to simplify EmA analysis. publishedVersion

Background: Alveolar hemorrhage is a potentially life-threatening condition which is usually managed by the pulmonologist. When considering its etiology, there is a rare association that sets the disease into the hands of the gastroenterologist. Case presentation: We report the case of a 48 year-old female who was admitted to the intensive care unit for severe anemia and hemoptysis. On imaging, diffuse pulmonary infiltrates suggestive of alveolar hemorrhage were detected and a diagnosis of pulmonary hemosiderosis was made. She received cortisone therapy and hematologic correction of anemia, with slow recovery. In search of an etiology for the pulmonary hemosiderosis, an extensive workup was done, and celiac disease specific serology was found positive. After confirmation of celiac disease by biopsy, a diagnosis of Lane-Hamilton syndrome was established. The patient was recommended a gluten-free diet and at 6 months follow-up, resolution of anemia and pulmonary infiltrates were observed. Conclusion: Although the association is rare, celiac disease should be considered in a patient with idiopathic pulmonary hemosiderosis. In our case, severe anemia and alveolar infiltrates markedly improved with glucocorticoids and gluten-free diet. Abbreviations: APTT: activated partial thromboplastin time; BAL: bronchoalveolar lavage; CD: celiac disease; Cd: crypt depth; GFD: gluten-free diet; GI: gastrointestinal; IEL: intraepithelial lymphocyte; INR: international normalized ratio; IPH: idiopathic pu

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

Dermatitis herpetiformis (DH) is an extraintestinal manifestation of celiac disease causing an itchy, blistering rash. Granular IgA deposits in the skin are pathognomonic for DH, and the treatment of choice is a lifelong gluten-free diet (GFD). Preliminary evidence suggests that there are patients with DH who redevelop gluten tolerance after adherence to a GFD treatment. To evaluate this, we performed a 12-month gluten challenge with skin and small-bowel mucosal biopsy samples in 19 patients with DH who had adhered to a GFD for a mean of 23 years. Prechallenge biopsy was negative for skin IgA and transglutaminase 3 deposits in 16 patients (84%) and indicated normal villous height-to-crypt depth ratios in the small bowel mucosa in all 19 patients. The gluten challenge caused a relapse of the rash in 15 patients (79%) in a mean of 5.6 months; of these 15 patients, 13 had skin IgA and transglutaminase 3 deposits, and 12 had small-bowel villous atrophy. In addition, three patients without rash or immune deposits in the skin developed villous atrophy, whereas one patient persisted without any signs of relapse. In conclusion, 95% of the patients with DH were unable to tolerate gluten even after long-term adherence to a GFD. Therefore, lifelong GFD treatment remains justified in all patients with DH.

Background The revised paediatric criteria for coeliac disease allow omission of duodenal biopsies in symptomatic children who have specific serology and coeliac disease-associated genetics. It remains unclear whether this approach is also applicable for adults with various clinical presentations. Aim To evaluate the accuracy of serology-based criteria in adults with variable pre-test probabilities for coeliac disease. Methods Three study cohorts comprised adults with high-risk clinical coeliac disease suspicion (n = 421), moderate-risk family members of coeliac disease patients (n = 2357), and low-risk subjects from the general population (n = 2722). Serological and clinical data were collected, and "triple criteria" for coeliac disease comprised transglutaminase 2 antibodies >10x the upper limit of normal, positive endomysium antibodies, and appropriate genetics without requirement of symptoms. The diagnosis was based on intestinal biopsy. Results The diagnosis of coeliac disease was established in 274 subjects. Of these, 59 high-risk subjects, 17 moderate-risk subjects, and 14 low-risk subjects fulfilled the "triple criteria". All had histologically proven coeliac disease, giving the criteria a positive predictive value of 100%. Altogether, 90 (33%) of all 274 newly diagnosed patients could have avoided biopsy, including 37% among high-risk, 20% among moderate-risk, and 48% among low-risk patients. No histological findings other than coeliac disease were found in the biopsies of "triple positive" subjects. Conclusions Coeliac disease can reliably and safely be diagnosed without biopsy in adults fulfilling the "triple criteria" regardless of the pre-test probability. Revised criteria would enable the number of endoscopies to be reduced by one-third.

Guidelines recommend regular follow-up in coeliac disease, but effect of this on long-term outcomes remains unclear.To evaluate predictors and significance of long-term follow-up.677 previously diagnosed coeliac patients were recruited for a nationwide health survey. Medical data were gathered through interviews and patient records. Current symptoms and quality of life were assessed by validated questionnaires and blood samples were drawn for serology. All variables were compared between patients with and without long-term (2 years) follow-up.15% had long-term follow-up, median duration 10 years. Predictors (p 0.05) for the follow-up were immunological (35% vs. 24%) and circulatory (20% vs. 12%) comorbidities, whereas it was less common in subjects with musculoskeletal (23% vs. 34%) comorbidity and those not belonging to any at-risk group (16% vs. 27%). Patients with or without follow-up had comparable age, adherence and ability to manage a gluten-free diet and frequency of seropositivity. Also questionnaire scores paralleled, but those without follow-up reported more overall symptoms (16% vs. 26%). Most patients wished for follow-up.Only a minority of patients had regular follow-up. However, patients with and without the follow-up were comparable in most long-term outcomes, indicating that it might not be always necessary. The results call for more personalized follow-up policies in coeliac disease.

In celiac disease, a follow-up biopsy taken 1 year after diagnosis is considered important in monitoring histological recovery. In many cases, recovery is incomplete, and the clinical significance of this is poorly understood. We now investigated associated factors and the significance of imperfect histological recovery in patients in whom the follow-up had been completed.Two hundred sixty-three biopsy-proven patients were divided into two groups: histological recovery and incomplete recovery after 1 year on gluten-free diet. Serology, laboratory values, bone mineral density, and different clinical variables were measured at diagnosis and after 1 year. Gastrointestinal symptoms and quality of life were assessed by validated questionnaires. Further, long-term follow-up data on mortality, malignancies, and other severe complications were collected.The incomplete recovery group had more severe mucosal damage (P=0.003), higher antibody values (P=0.017), and more signs of malabsorption (P0.001) at diagnosis. There was no difference in gender, symptoms or quality of life, family history of celiac disease, or comorbidities. At follow-up, there was still a difference in antibodies (P=0.018) and femoral T-scores (P=0.024). Histologically recovered patients showed better dietary adherence, although it was excellent in both groups (97% vs. 87%, P0.001). There was no difference in long-term outcomes between groups.The presence of more severe disease in terms of histology, serology, and signs of malabsorption was associated with histological non-response. In patients with high dietary adherence, incomplete villous recovery after 1 year does not affect the clinical response or long-term prognosis. A personalized approach is required to decide the optimal timing of the follow-up biopsy.

Background & Aims The guidelines of the European Society of Pediatric Gastroenterology, Hepatology, and Nutrition allow for diagnosis of celiac disease without biopsies in children with symptoms and levels of immunoglobulin A against tissue-transglutaminase (TGA-IgA) 10-fold or more the upper limit of normal (ULN), confirmed by detection of endomysium antibodies (EMA) and positivity for HLA-DQ2/DQ8. We performed a large, international prospective study to validate this approach. Methods We collected data from consecutive pediatric patients (18 years or younger) on a gluten-containing diet who tested positive for TGA-IgA from November 2011 through May 2014, seen at 33 pediatric gastroenterology units in 21 countries. Local centers recorded symptoms; measurements of total IgA, TGA, and EMA; and histopathology findings from duodenal biopsies. Children were considered to have malabsorption if they had chronic diarrhea, weight loss (or insufficient gain), growth failure, or anemia. We directly compared central findings from 16 antibody tests (8 for TGA-IgA, 1 for TGA-IgG, 6 for IgG against deamidated gliadin peptides, and 1 for EMA, from 5 different manufacturers), 2 HLA-DQ2/DQ8 tests from 2 manufacturers, and histopathology findings from the reference pathologist. Final diagnoses were based on local and central results. If all local and central results were concordant for celiac disease, cases were classified as proven celiac disease. Patients with only a low level of TGA-IgA (threefold or less the ULN) but no other results indicating celiac disease were classified as no celiac disease. Central histo-morphometry analyses were performed on all other biopsies and cases were carefully reviewed in a blinded manner. Inconclusive cases were regarded as not having celiac disease for calculation of diagnostic accuracy. The primary aim was to determine whether the nonbiopsy approach identifies children with celiac disease with a positive predictive value (PPV) above 99% in clinical practice. Secondary aims included comparing performance of different serological tests and to determine whether the suggested criteria can be simplified. Results Of 803 children recruited for the study, 96 were excluded due to incomplete data, low level of IgA, or poor-quality biopsies. In the remaining 707 children (65.1% girls; median age, 6.2 years), 645 were diagnosed with celiac disease, 46 were found not to have celiac disease, and 16 had inconclusive results. Findings from local laboratories of TGA-IgA 10-fold or more the ULN, a positive result from the test for EMA, and any symptom identified children with celiac disease (n = 399) with a PPV of 99.75 (95% confidence interval [CI], 98.61–99.99); the PPV was 100.00 (95% CI, 98.68–100.00) when only malabsorption symptoms were used instead of any symptom (n = 278). Inclusion of HLA analyses did not increase accuracy. Findings from central laboratories differed greatly for patients with lower levels of antibodies, but when levels of TGA-IgA were 10-fold or more the ULN, PPVs ranged from 99.63 (95% CI, 98.67–99.96) to 100.00 (95% CI, 99.23–100.00). Conclusions Children can be accurately diagnosed with celiac disease without biopsy analysis. Diagnosis based on level of TGA-IgA 10-fold or more the ULN, a positive result from the EMA tests in a second blood sample, and the presence of at least 1 symptom could avoid risks and costs of endoscopy for more than half the children with celiac disease worldwide. HLA analysis is not required for accurate diagnosis. Clinical Trial Registration no: DRKS00003555.

Background & Aims Celiac disease (CeD) provides an opportunity to study autoimmunity and the transition in immune cells as dietary gluten induces small intestinal lesions. Methods Seventy-three celiac disease patients on a long-term, gluten-free diet ingested a known amount of gluten daily for 6 weeks. A peripheral blood sample and intestinal biopsy specimens were taken before and 6 weeks after initiating the gluten challenge. Biopsy results were reported on a continuous numeric scale that measured the villus-height–to–crypt-depth ratio to quantify gluten-induced intestinal injury. Pooled B and T cells were isolated from whole blood, and RNA was analyzed by DNA microarray looking for changes in peripheral B- and T-cell gene expression that correlated with changes in villus height to crypt depth, as patients maintained a relatively healthy intestinal mucosa or deteriorated in the face of a gluten challenge. Results Gluten-dependent intestinal damage from baseline to 6 weeks varied widely across all patients, ranging from no change to extensive damage. Genes differentially expressed in B cells correlated strongly with the extent of intestinal damage. A relative increase in B-cell gene expression correlated with a lack of sensitivity to gluten whereas their relative decrease correlated with gluten-induced mucosal injury. A core B-cell gene module, representing a subset of B-cell genes analyzed, accounted for the correlation with intestinal injury. Conclusions Genes comprising the core B-cell module showed a net increase in expression from baseline to 6 weeks in patients with little to no intestinal damage, suggesting that these individuals may have mounted a B-cell immune response to maintain mucosal homeostasis and circumvent inflammation. DNA microarray data were deposited at the GEO repository (accession number: GSE87629; available: https://www.ncbi.nlm.nih.gov/geo/)., Graphical abstract

Coeliac disease is hallmarked by an abnormal immune reaction against ingested wheat-, rye- and barley-derived gluten and the presence of transglutaminase 2 (TG2)-targeted autoantibodies. The small-bowel mucosal damage characteristic of the disorder develops gradually from normal villus morphology to inflammation and finally to villus atrophy with crypt hyperplasia. Patients with early-stage coeliac disease have TG2-autoantibodies present in serum and small-intestinal mucosa and they may already suffer from abdominal symptoms before the development of villus atrophy. Previously, we have shown that intraperitoneal injections of coeliac patient-derived sera or purified immunoglobulin fraction into mice induce a condition mimicking early-stage coeliac disease. In the current study, we sought to establish whether recombinantly produced patient-derived TG2-targeted autoantibodies are by themselves sufficient for the development of such an experimentally induced condition in immune-compromised mice. Interestingly, mice injected with coeliac patient TG2-antibodies had altered small-intestinal mucosal morphology, increased lamina propria cellular infiltration and disease-specific autoantibodies deposited in the small bowel, but did not evince clinical features of the disease. Thus, coeliac patient-derived TG2-specific autoantibodies seem to be sufficient for the induction of subtle small-bowel mucosal alterations in mice, but the development of clinical features probably requires additional factors such as other antibody populations relevant in coeliac 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 glutenfree 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 recombinantgluten-specificproteasesgivenorally,toprotectpatients 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 ¼ 20) or placebo (n ¼ 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 ¼ .0007; density of CD3 þ intraepithelial lymphocytes changed from 61 to 91 cells/mm after challenge; P ¼ .0003). However, no significant mucosal deterioration was observed in biopsies from the ALV003 group. Between groups, morphologic changes and CD3 þ intraepithelial lymphocyte counts differed significantly from baseline to week 6 (P ¼ .0133 and P ¼ .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.

Dermatitis herpetiformis (DH) is an extraintestinal manifestation of coeliac disease. Untreated coeliac disease patients are known to have transglutaminase 2 (TG2)-targeted IgA deposits in the small bowel mucosa. To evaluate whether similar intestinal IgA deposits are also present in DH and whether the deposits disappear with gluten-free diet, 47 untreated and 27 treated DH patients were studied. Seventy-nine percent of untreated and 41% of the treated DH patients had TG2-specific IgA deposits in the small bowel, and the presence of the deposits showed a significant association with the degree of small bowel villous atrophy (p < 0.001). Other coeliac-disease related inflammatory markers were also investigated, and the density of small bowel mucosal intraepithelial γδ(+) T cells was increased in 91% of untreated and 73% of treated DH patients. The results show that the majority of untreated DH patients have similar gluten-dependent TG2-specific IgA deposits the small bowel mucosa as coeliac disease patients.

Aim To evaluate whether coeliac disease (CD) can be diagnosed by measuring autoantibodies without small-intestinal mucosal biopsies in children with type 1 diabetes. Methods Case finding of CD was undertaken in 181 consecutive IgA-competent children with type 1 diabetes using transglutaminase 2 (TG2) and endomysial IgA antibody (EMA) tests in serum and the rapid point of care test in fingertip whole-blood sample. Endoscopy with intestinal biopsies was recommended for patients with high TG2-IgA titres (>96 U) and in children with lower positive tests if either the EMA test or the rapid point of care test was additionally positive. The duodenal mucosal biopsies were graded according to the Marsh classification. Results The TG2-IgA test had a 15.5% and the EMA test a 6.0% seropositivity. All seven biopsied high-titre TG2-IgA-positive children were symptom free and found to have CD (Marsh 3 type lesion). These patients were also positive for EMA and in the rapid point of care test. Lower titre TG2-IgA-positive children had histological Marsh 1 to 3a lesions. Conclusions None of the type 1 diabetes children with high TG2-IgA titres would have needed endoscopy with duodenal biopsies to reach a CD diagnosis. Lower TG2-IgA-positive patients need to be biopsied.

SummaryBackground A repeat biopsy is recommended, but often omitted in coeliac disease patients on a gluten-free diet. The effect of performing or not performing repeat biopsies is currently unknown. Aim To identify factors associated with and the significance of lacking biopsy for long-term outcome. Predictors and the importance of incomplete histological recovery after 1 year was investigated in re-biopsied patients. Methods A total of 760 patients participated in a nationwide follow-up study. Medical data were gathered via interviews and patient records, and blood samples were drawn for serology. Current symptoms and well-being were assessed by validated PGWB, SF-36 and GSRS questionnaires. Results Malabsorption was more common among those with a repeat biopsy (46%) than those without repeat biopsy (33%), P

Dermatitis herpetiformis (DH) is a blistering skin disease, which is regarded as an extra-intestinal manifestation of coeliac disease. Refractory cases of coeliac disease, that do not respond to a gluten-free diet and which carry an increased risk of lymphoma, are well-known in coeliac disease. To determine whether refractory cases of DH with active rash and persistent small bowel atrophy occur we analysed our series of 403 patients with DH. Seven (1.7%) patients, who had been on a gluten-free diet for a mean of 16 years, but who still required dapsone to treat the symptoms of DH, were identified. Of these, one patient died from mucinous adenocarcinoma before re-examination. At re-examination skin immunoglobulin A (IgA) deposits were found in 5/6 refractory and 3/16 control DH patients with good dietary response. Small bowel mucosa was studied at re-examination from 5 refractory and 8 control DH patients and was normal in all 5 refractory and 7/8 control DH patients. One refractory DH patient died from adenocarcinoma, but no lymphoma developed in any of the patients. This study documents for the first time refractory DH, in which the rash is non-responsive to a gluten-free diet, but the small bowel mucosa heals. This differs from refractory coeliac disease, in which the small bowel mucosa does not heal on a gluten-free diet.

Objectives A variety of neurological and psychiatric disorders have recently been linked to coeliac disease and gluten sensitivity. We here explored whether persistently positive gliadin antibodies (AGA) and coeliac-type HLA increase the risk of gluten sensitivity-related neurological and psychiatric manifestations. The study was carried out in an older population who had consumed gluten for decades but who had no previous coeliac disease diagnosis. Materials and Methods The original study population comprised 4272 randomly selected older individuals, of whom 2089 had AGA and transglutaminase 2 antibodies (antiTG2) measured twice within a 3-year interval. Forty-nine persistently AGA-positive but antiTG2-negative subjects with coeliac-type HLA and 52 randomly selected persistently AGA- and antiTG2-negative age- and sex-matched controls were clinically examined for neurological disorders. The Psychological General Well-Being (PGWB) questionnaire, the SF-36 health survey questionnaire and the Depression Scale (DEPS) were employed to evaluate psychological well-being. The medical files of all the study subjects were analysed for previous illnesses. Results Persistently AGA-positive but antiTG2-negative older subjects carrying coeliac disease-type HLA did not evince significantly more neurological symptoms or diseases than AGA-negative control subjects (P = 0.682, P = 0.233). There were no statistically significant differences between AGA-positive and AGA-negative groups in psychological well-being and quality of life when measured by PGWB (P = 0.426), SF-36 questionnaires (P = 0.120) and DEPS (P = 0.683). Conclusions At population level, persistent AGA positivity did not indicate gluten sensitivity-related neurological and psychiatric disorders.

Demonstration of small-bowel mucosal damage has been the basis of celiac disease diagnosis, but the diagnostic approach is undergoing changes. The European Society for Pediatric Gastroenterology, Hepatology, and Nutrition recently stated that in a subgroup of children, high positive transglutaminase 2 antibody (TG2ab) values may be sufficient for the diagnosis. The utility of these new criteria was evaluated by applying the human red blood cell TG2 antibody test (RBC-TG2ab) to a large cohort of children and adults belonging to at-risk groups.RBC-TG2ab and endomysial antibodies (EmA) were measured in 3031 family members or other relatives of patients with celiac disease. The RBC-TG2ab values were classified as weak (20-29 U), moderate (30-99 U), and strong (≥100 U) positive. Seropositive subjects were further tested by human recombinant TG2ab (Hr-TG2ab) and for the presence of celiac disease-associated human leukocyte antigen-DQ alleles. Gastroscopy was recommended for all with positive RBC-TG2ab, EmA, or Hr-TG2ab, or weak positive RBC-TG2ab and symptoms.Strong positive RBC-TG2ab has good correlation with EmA and Hr-TG2ab and positivity of DQ2/8, and the diagnosis was established in 94% of both children and adults. In contrast, moderately positive (≥30 U) RBC-TG2ab showed poor correlation with the other tests, and celiac disease was diagnosed in 69% of children and 86% of adults. Most participants with weak positive RBC-TG2ab were negative for EmA and Hr-TG2ab.In accordance with the new European Society for Pediatric Gastroenterology, Hepatology, and Nutrition criteria, strong positive RBC-TG2ab showed good accuracy and excellent correlation with the other antibodies and celiac-type human leukocyte antigen. In contrast, low or moderately positive RBC-TG2ab values were of unsatisfactory prognostic value for a subsequent diagnosis.

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.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.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.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.

Background It has been suggested that antibodies against transglutaminase (TG) 6 could serve as a biomarker to identify a subgroup of gluten-sensitive patients who may be at risk of developing neurological disease. We here investigated whether TG6-targeted autoantibodies are a characteristic feature of celiac patients, especially those with neurological symptoms, and further, whether such antibodies are gluten-dependent. Methods Serum IgA-class TG6 autoantibodies were measured in untreated and treated celiac patients with and without neurological manifestions and in non-celiac controls. The results were compared to TG2 autoantibody levels. Results During a gluten-containing diet the number of TG6 autoantibody-positive celiac patients with neurological problems (25%) did not significantly differ from that of TG6-seropositive patients without neurological impairment (16%) or from non-celiac controls (15%). This was in contrast to our finding in TG2 autoantibody-positive individuals, whose numbers differed significantly between all three study groups. On a gluten-free diet the levels of TG6 autoantibodies remained unchanged. Conclusions We conclude that the serum IgA-class TG6 autoantibody assay is not able to distinguish gluten-sensitive patients with neurological manifestations from celiac patients without neurological problems or from control subjects, and further, that TG6 autoantibodies are not gluten-dependent.

The autoantigen of celiac disease, transglutaminase 2 (TG2), adopts an open conformation during enzymatic activation. We studied diagnostic accuracy of serodiagnostic assays using TG2 in its open and closed conformation as antigens in patients with diagnostic difficulties. The open TG2 antibody (TG2ab) test identified 93% of untreated celiac patients in contrast to 44%, 27%, and 68% detected by closed and conventional TG2ab and endomysial antibody (EmA) tests, respectively. The assay was able to detect 60% of non-responding celiac patients seronegative for conventional TG2ab and EmA. The titers of the open TG2abs were higher than those of the closed TG2abs. The serological test utilizing TG2 in an open conformation was more accurate than the other assays in finding active celiac disease even in patients having negative or borderline conventional celiac autoantibodies and in revealing poor dietary response non-invasively. It thus offers a promising tool in the diagnostics and follow-up of celiac disease.

Background and aims The diagnosis of coeliac disease is problematic in individuals not responding to a gluten-free diet. Small-bowel villous atrophy occurs in other enteropathies and non-responsive patients are often seronegative. We investigated whether small-bowel mucosal transglutaminase-2 specific autoantibody deposits distinguish non-responsive coeliac disease from other enteropathies. Methods Small-bowel mucosal autoantibody deposits were determined in 27 non-responsive, 28 responsive coeliac patients and 10 controls with other enteropathies. Of the non-responsive coeliac patients six were adhering poorly and 21 strictly to the diet; six of the 21 had enteropathy-associated lymphoma, five refractory coeliac disease and 10 otherwise persistent villous atrophy. The presence of mucosal autoantibody deposits was compared to serology, villous morphology, densities of intraepithelial lymphocytes (IELs) and markers of refractory coeliac disease. Results Twenty out of 21 well-adhering, all six poorly adhering non-responsive and all 28 untreated responsive coeliac patients had small-bowel mucosal autoantibody deposits present, while controls with other enteropathies were negative. Small-bowel mucosal autoantibody deposits were more accurate in detecting coeliac disease than serology or IEL densities. Refractory coeliac markers revealed only cases with the most severe condition. Conclusions Small-bowel mucosal autoantibody deposits differentiate coeliac disease from other enteropathies, enabling the design of appropriate therapeutic strategies.

Serum immunoglobulin A-class tissue transglutaminase (tTG-ab) and endomysial antibody (EMA) tests play a key role in the diagnostic evaluation of celiac disease. Recently, a novel whole blood rapid test based on self-tissue transglutaminase (tTG) was developed for celiac disease case finding. Based on the same principle, a whole blood self-tTG enzyme-linked immunosorbent assay (ELISA), especially applicable to large-scale screening of celiac disease, has been produced. We assessed the value of this new test in celiac disease antibody detection.The new test uses endogenous tTG found in red blood cells of whole blood in IgA-class tTG-ab measurement by detecting tTG-tTG-ab complexes formed after hemolysis of the whole blood sample. Stored whole blood samples from 150 untreated celiac disease patients and 107 control individuals without celiac disease were evaluated, and the test results were compared with those of the whole blood rapid test, 2 conventional serum-based tTG-ab ELISA tests, and 2 EMA tests.A total of 15 whole blood samples were found to be clotted or dried after storage and were excluded from further evaluation. The whole blood ELISA test had a specificity (98%) comparable to that of the conventional serological tests, the sensitivity (91%) being slightly lower. The test was concordant with the whole blood rapid test in 92% of cases, with 2 serological ELISA tests in 91% and 94% of cases and with EMA tests in 94% and 93% of cases.Whole blood self-tTG-based testing is accurate in celiac antibody detection, also when an ELISA method is applied. The testing requires no serum separation or external tTG.

Background. In coeliac disease endomysial and transglutaminase autoantibodies are directed against the human autoantigen, transglutaminase. The conventional coeliac antibody tests are performed from serum samples in centralized laboratories. Aims. To evaluate a rapid and easy immunoglobulin A-class whole blood point-of-care test and its commercial application, the Biocard test, in coeliac autoantibody detection. Methods. In the whole blood point-of-care test transglutaminase is liberated from the red blood cells by haemolysis. Transglutaminase antibodies, if present, complex with the liberated antigen, and are visualized. Altogether 51 biopsy-proven untreated coeliac adult patients, 48 of the same patients after treatment, and 36 controls were tested. The point-of-care test results were compared with serum endomysial and transglutaminase antibody and Biocard test results and histology. Results. The whole blood point-of-care test was as sensitive (82%) as the serum endomysium test (80%) in detecting untreated coeliac disease while the serum transglutaminase antibody test was superior (88%). The tests had 100% specificity. A positive point-of-care test result seroconverted or the test reaction weakened in 90% of the treated coeliac patients. Biocard test-positive were 22 of the 24 tested untreated coeliac patients. Biocard test-negative were 15 of 19 controls. Conclusions. The whole blood rapid tests are as reliable as the conventional serological tests in detecting untreated coeliac disease and in coeliac disease diet monitoring. © 2007 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.

SUMMARY Background The number of coeliac disease diagnoses has increased in the recent past and according to screening studies, the total prevalence of the disorder is around 1%. Aim To establish whether the increased number of coeliac disease cases reflects a true rise in disease frequency. Methods

Circulating antibodies against naive, whole gliadin have been replaced by more accurate endomysial and tissue transglutaminase antibody tests in the diagnosis of coeliac disease. The purpose of this study was to compare these serological tests with a new test recognizing antibodies against deamidated and defined gliadin peptides.The study population comprised selected coeliac disease patients in a tertiary clinic: newly detected patients before and after a gluten-free diet, patients with persistent small-bowel mucosal villous atrophy despite a strict gluten-free diet and non-coeliac controls reporting abdominal symptoms after ingestion of cereals. Comparisons were made between serum IgA-class gliadin peptide, endomysial, tissue transglutaminase and conventional gliadin antibodies.The deamidated gliadin peptide antibody test showed a sensitivity of 91% and a specificity of 98% in coeliac disease. The tissue transglutaminase antibody test performed equally well. The specificity of endomysial antibody was just as high, but its sensitivity was lower, 80%. The conventional gliadin antibody test showed poor sensitivity and specificity. Combination of the deamidated gliadin peptide and tissue transglutaminase tests offered the best sensitivity without loss of specificity in the diagnosis of coeliac disease. All antibody levels declined in line with mucosal recovery. The deamidated gliadin peptide antibody test showed six of the nine cases with small-bowel mucosal damage persisting on a gluten-free diet, whereas tissue transglutaminase detected only two cases and endomysial antibody none.The new gliadin peptide antibody test proved highly accurate in the diagnostic work-up and follow-up of coeliac disease and can be endorsed in combination with the tissue transglutaminase test.

Background: Some patients with untreated coeliac disease are negative for serum endomysial autoantibodies (EmA) targeted against transglutaminase 2 (TG2). Aims: To evaluate the clinical and histological features of EmA-negative coeliac disease, and to examine whether EmA-equivalent autoantibodies against TG2 can be seen in the small-bowel mucosa when absent in serum. Patients: Serum EmA was studied in 177 biopsy-proved specimens from adult patients with coeliac disease. 20 patients with intestinal diseases served as non-coeliac controls; three had autoimmune enteropathy with villous atrophy. Methods: Clinical manifestations, small-bowel mucosal morphology, intraepithelial inflammation and TG2-specific extracellular immunoglobulin A (IgA) deposits were investigated in both serum EmA-negative and EmA-positive patients. Results: 22 patients with IgA-competent coeliac disease were negative for serum EmA. Three of these had small-bowel lymphoma. Patients with EmA-negative coeliac disease were older, had abdominal symptoms more often, and the density of γδ+ intraepithelial lymphocytes in their intestinal mucosa was lower than in EmA-positive patients; otherwise the histology was similar. All serum EmA-negative patients with coeliac disease, but none of the disease controls, had gluten-dependent mucosal IgA deposits alongside TG2 in the small-bowel mucosal specimens. In vivo deposited IgA was shown to be TG2-specific by its ability to bind recombinant TG2. Conclusions: Negative serum EmA might be associated with advanced coeliac disease. TG2-targeted autoantibodies were deposited in the small-bowel mucosa even when absent in serum. This finding can be used in the diagnosis of seronegative coeliac disease when the histology is equivocal. It may also be helpful in the differential diagnosis between autoimmune enteropathy and coeliac disease.

Reliable markers of early developing coeliac diseases are needed. Coeliac autoantibodies in the serum or Marsh I inflammation may be indicators of subsequent coeliac disease.To investigate whether determination of intestinal transglutaminase 2-targeted autoantibody deposits would detect early developing coeliac disease better than previous methods.The study investigated patients previously excluded for coeliac disease: 25 had positive serum coeliac autoantibodies (endomysial), 25 antibody-negative had Marsh I, and 25 antibody-negative had Marsh 0 finding. Seven (median) years after baseline investigation, new coeliac cases were recorded, and small bowel biopsy was offered to the rest of the patients. Serum and intestinal coeliac autoantibodies and intraepithelial lymphocytes were assessed as indicators of developing coeliac disease.Seventeen patients had developed coeliac disease: 13 in the autoantibody-positive group, three in the Marsh I group and one in the Marsh 0 group. At baseline, intestinal coeliac autoantibody deposits had a sensitivity and specificity of 93% and 93% in detecting subsequent coeliac disease, CD3+ 59% and 57%, gammadelta+ 76% and 60%, and villous tip intraepithelial lymphocytes 88% and 71%, respectively.Endomysial antibodies with normal histology indicates early developing coeliac disease. Transglutaminase 2-targeted intestinal autoantibody deposits proved the best predictor of subsequent coeliac disease.

The conventional coeliac disease antibody tests require patient's sera, and are laborious and time-consuming.To evaluate a newly developed rapid whole blood test in coeliac disease antibody detection, and its suitability for office use.Endogenous tissue transglutaminase found in red blood cells in a whole blood fingertip or venous sample is liberated upon haemolysis and complexes with tissue transglutaminase antibodies, if present. The complexes, captured by a lateral flow system, are visualized within 5 min. Stored samples from 121 untreated, 106 treated coeliac disease patients and 107 controls were evaluated and compared with serum endomysium and tissue transglutaminase antibody tests and histology; 150 patients were prospectively tested on site in the doctor's office.The rapid test showed sensitivity (96.7%) comparable with the serum endomysium and tissue transglutaminase antibody tests from stored samples; specificity was slightly lower (93.5%). When tested on site the results were concordant in 96.7% of cases compared with endomysium and tissue transglutaminase antibody results. The test recognized the disappearance of tissue transglutaminase antibodies on a gluten-free diet.The self tissue transglutaminase-based rapid test can be easily carried out from a fingertip blood sample on site in the physician's office for both coeliac disease case finding and dietary monitoring purposes.

Background. Nephropathia epidemica (NE) is the Scandinavian type of haemorrhagic fever with renal syndrome. Usually heavy transient proteinuria is present at the onset of the disease. Methods. We investigated glomerular permeability in eight patients with acute NE and in eight healthy controls. Six patients were followed for 1 year. The glomerular filtration rate (GFR) was determined by inulin clearance and effective renal plasma flow v (ERPF) by para-aminohippurate clearance. Results. GFR and ERPF were significantly reduced in NE patients during the acute phase compared with those in controls (P < 0.001 and P < 0.001, respectively). The filtration fraction (FF) was thus high, 0.37. The fractional clearances of albumin. IgG, and IgG 4 were markedly increased. As a sign of tubular dysfunction, increased urinary excretion of α 1 -microglobulin was observed in all patients. After 1 year, the GFR of the patients no longer differed from that of the controls. ERPF was lower and FF higher than those in controls (P = 0.014 and P = 0.009, respectively). The fractional clearances of albumin, IgG. and IgG4 remained increased. The high-molecular fractional dextran clearances in the patients were significantly increased compared with controls during the acute phase. Computed analysis of glomerular membrane-pore structure showed that the shunt-flow' was increased in the patients during the acute phase compared with the controls. There was a positive correlation between the FF and the shunt (r = 0.768, P = 0.026). In addition, fractional clearances of albumin and IgG correlated significantly with the shunt (r = 0.810, P = 0.015 and r = 0.762, P = 0.028, respectively). Conclusions. Renal involvement in the acute phase of NE is characterized by a markedly decreased GFR and ERPF. Increased glomerular permeability is associated with impairment of both the size- and charge-selectivity properties of the glomerular filter.

Typical features of celiac disease are small-bowel villus atrophy, crypt hyperplasia, and inflammation which develop gradually concomitant with ingestion of gluten. In addition, patients have anti-transglutaminase 2 (TG2) autoantibodies in their serum and tissues. The aim of this study was to establish whether celiac disease can be passively transferred to mice by serum or immunoglobulins. Serum aliquots or purified immunoglobulins (Ig) were intraperitoneally injected into Hsd:Athymic Nude-Foxn1nu mice for 8 or 27 days. As mice do not have proper IgA transport from peritoneum to blood, sera with a high content of IgG class anti-TG2 antibodies from untreated IgA-deficient celiac patients were used. Mouse sera were tested for celiac disease-specific autoantibodies, and several tissues were analyzed for autoantibody deposits targeted to TG2. Morphological assessment was made of the murine small intestinal mucosa. Injection of celiac disease patient sera or total IgG led to a significant delay in weight gain and mild diarrhea in a subset of mice. The mice injected with celiac patient sera or IgG had significantly decreased villus height crypt depth (Vh/CrD) ratios and celiac disease-specific autoantibody deposits targeted to TG2 in several tissues, including the small intestine. None of these features were observed in control mice. We conclude that administration of IgA-deficient celiac disease patient serum or total IgG induces both deterioration of the intestinal mucosa and clinical features of celiac disease in mice. The experimentally induced condition in the mice injected with patient serum or IgG resembles early developing celiac disease in humans.Celiac disease patient sera or total IgG was injected into athymic mice. A significant delay in weight gain and mild diarrhea was observed. Mice evinced significantly decreased villus height crypt depth ratios. Celiac disease-specific autoantibody deposits were present in several tissues. The condition in mice resembles early stage celiac disease in humans.

Background & Aims: Tissue transglutaminase has been reported to be the target for endomysial antibodies in celiac disease. We sought to establish whether immunoglobulin (Ig) A class tissue transglutaminase autoantibodies can be considered specific for celiac disease. Methods: Serum samples from 136 patients with untreated celiac disease (diagnosed according to the criteria of the European Society for Pediatric Gastroenterology, Hepatology and Nutrition) and 207 disease controls were studied. Enzyme-linked immunosorbent assay (ELISA) and Western blots were performed using calcium-treated and untreated tissue transglutaminase as antigen. Reticulin, endomysial, and mouse monoclonal tissue transglutaminase antibodies were studied by an indirect immunofluorescence method and gliadin antibodies with ELISA. Results: The calcium-activated tissue transglutaminase autoantibody ELISA was highly sensitive (129 of 136) and specific (194 of 207) in detecting celiac disease. The new autoantibody ELISA test correlated well with the endomysial antibody test. Tissue transglutaminase autoantibody ELISA showed a clearly better predictive potential than the IgA class gliadin antibody ELISA. Immunoblots and ELISA blocking studies showed that calcium is needed for the specific antigen-antibody reaction to occur. Double immunofluorescence staining in human umbilical cord with sera from patients with celiac disease and with monoclonal tissue transglutaminase antibodies showed complete overlap. Conclusions: Calcium-activated tissue transglutaminase autoantibody ELISA is highly accurate in detecting untreated celiac disease. Tissue transglutaminase seems to be the target self-antigen for endomysial antibodies. GASTROENTEROLOGY 1998;115:1322-1328

We investigated whether screen-detected and apparently asymptomatic adults with endomysial antibodies (EmA) benefit from a gluten-free diet (GFD).We performed a prospective trial of 3031 individuals at risk for celiac disease based on screens for EmA. Of 148 seropositive individuals, 40 fulfilled inclusion criteria and were assigned randomly to groups placed on a GFD or gluten-containing diets. We evaluated ratios of small-bowel mucosal villous height:crypt depth, serology and laboratory test results, gastrointestinal symptom scores, physiologic well-being, perception of health by a visual analog scale, bone mineral density, and body composition at baseline and after 1 year. Thereafter, the group on the gluten-containing diet started a GFD and was evaluated a third time; subjects in the GFD group remained on this diet.After 1 year on the GFD, the mean mucosal villous height:crypt depth values increased (P .001), levels of celiac-associated antibodies decreased (P .003), and gastrointestinal symptoms improved to a greater extent than in patients on gluten-containing diets (P = .003). The GFD group also had reduced indigestion (P = .006), reflux (P = .05), and anxiety (P = .025), and better health, based on the visual analog scale (P = .017), than the gluten-containing diet group. Only social function scores improved more in the gluten-containing diet group than in the GFD group (P = .031). There were no differences between groups in laboratory test results, bone mineral density, or body composition. Most measured parameters improved when patients in the gluten-containing diet group were placed on GFDs. No subjects considered their experience to be negative and most expected to remain on GFDs.GFDs benefit asymptomatic EmA-positive patients. The results support active screening of patients at risk for celiac disease. Clinicaltrials.gov no: NCT01116505.

Summary We aimed to study intestinal immune activation status in juvenile idiopathic arthritis (JIA) by assessing intestinal human leucocyte antigen (HLA) class II expression and the mRNA expression levels of the pro- and anti-inflammatory mediators and pattern recognition receptors. HLA-D-related (HLA-DR) expression was assessed using immunohistochemical staining of frozen sections in 11 children with JIA and 17 controls. The gene expression levels of the anti- and proinflammatory cytokines, lymphocyte recognition receptors and pattern recognition receptors were studied with reverse transcription–polymerase chain reaction (RT–PCR) in 14 children with JIA and 12 controls. All subjects had various gastrointestinal (GI) symptoms indicating endoscopic examinations, but eventually were not diagnosed with GI disease. In JIA patients, the expression of HLA-DR was increased in the crypt epithelial cells and in the epithelial basement membrane of the ileum when compared with the controls. Positive HLA-DR staining in the ileal mucosa was associated with the presence of high clinical disease activity of JIA and low mRNA expression of anti-inflammatory mediators, such as forkhead box protein P3 (FoxP3), glucocorticoid-induced tumour necrosis factor receptor-related protein (GITR) and transforming growth factor (TGF)-beta. Low ileal expression of interleukin (IL)-10, TGF-β, FoxP3, Toll-like receptor 2 (TLR-2) and TLR-4 transcripts correlated significantly with a high clinical disease activity in the JIA patients. The increased HLA-DR expression suggests enhanced intestinal antigen presentation in JIA. A correlation between clinical disease activity and low gene expression of tolerogenic mediators in the ileum supports the hypothesis that a link exists between the gut immune system and JIA.

Aims: Diagnostics and follow-up of celiac disease have gradually shifted from tertiary centers to secondary and primary health care. In order to establish whether this has affected the success of treatment, and to identify predictors for dietary non-adherence, we carried out a study in a nationwide cohort of treated celiac patients. Patients and Methods: 843 biopsy-proven patients, 94 children and 749 adults, were enrolled and interviewed. Adherence to a gluten-free diet was determined by means of an interview and serological testing. Results: Altogether, 88% were on a strict gluten-free diet; the rest had occasional dietary transgressions. Younger age at diagnosis, being currently a teenager, and current symptoms were associated with non-adherence. There was no association between non-adherence and place of diagnosis, gender, disease phenotype or severity of symptoms before diagnosis, presence of comorbidities, family history of celiac disease, smoking, duration of diet, use of oats, self-efficacy for the diet or lack of follow-up. Conclusions: Good dietary adherence can be achieved also in patients diagnosed and followed in primary health care. In a country with a high prevalence and good general knowledge of celiac disease, only age at diagnosis and age at present would appear to be major determinants for adherence.

Background The utility of serologic screening for celiac disease is still debatable. Evidence suggests that the disorder remains undetected even in the older population. It remains obscure whether screening makes good or harm in subjects with long-standing gluten ingestion. We evaluated whether older subjects benefit from active detection and subsequent gluten free dietary treatment of celiac disease. Methods Thirty-five biopsy-proven patients aged over 50 years had been detected by serologic mass screening. We examined the disease history, dietary compliance, symptoms, quality of life and bone mineral density at baseline and 1-2 years after the commencement of a gluten-free diet. Symptoms were evaluated by gastrointestinal symptom rating scale and quality of life by psychological general well-being questionnaires. Small bowel biopsy, serology, laboratory parameters assessing malabsorption, and bone mineral density were investigated. Results Dietary compliance was good. The patients had initially low mean serum ferritin values indicating subclinical iron deficiency, which was restored by a gluten-free diet. Vitamin B12, vitamin D and erythrocyte folic acid levels increased significantly on diet. Celiac patients had a history of low-energy fractures more often than the background population, and the diet had a beneficial effect on bone mineral density. Alleviation in gastrointestinal symptoms was observed, even though the patients reported no or only subtle symptoms at diagnosis. Quality of life remained unchanged. Of all the cases, two thirds would have been diagnosed even without screening if the family history, fractures or concomitant autoimmune diseases had been taken carefully into account. Conclusions Screen-detected patients benefited from a gluten-free diet. We encourage a high index of suspicion and active case-finding in celiac disease as an alternative to mass screening in older patients.

Background The specificity of the conventional gliadin antibody test is considered low. Aims We explored whether gliadin antibody(AGA)-positivity without tissue transglutaminase antibodies (tTGA) is persistent in the elderly population and whether such positivity indicates overt or potential coeliac disease in genetically predisposed individuals. Methods AGA and tissue transglutaminase antibody were measured in 2089 elderly individuals twice with a three-year interval. AGA-positive but tissue transglutaminase antibody-negative subjects with coeliac-type human leucocyte antigen (HLA) were examined and underwent gastroduodenal endoscopy (cases). Small-bowel mucosal villous morphology and densities of CD3+ and γδ+ intraepithelial lymphocytes and the occurrence of tissue transglutaminase-specific IgA deposits were analysed. Randomly selected persistently AGA-negative age- and sex-matched subjects served as controls. Results AGA-positivity was persistent in 81% of those initially positive. Amongst the 49 clinically studied and 36 endoscopied cases only one (2.8%) had coeliac disease. Many (54%) showed signs of inflammation in the biopsy, without villous atrophy. Coeliac-type HLA was not over-represented in the persistently AGA-positive compared to the general population. Persistently AGA-positive coeliac-type HLA-positive subjects had more gastrointestinal symptoms than AGA-negative controls. Conclusions AGA-positivity is often persistent. Overt coeliac disease is seldom found behind persistent AGA-positivity, but this characteristic is associated with mucosal inflammation and gastrointestinal symptoms at least in HLA-positive individuals.

Objective: The aim of this study was to evaluate performance of serumantibodies against deamidated gliadin peptides (a-DGPs) in detecting com-pliance with gluten-free diet (GFD) in children with celiac disease (CD).Patients and Methods: Serum samples were collected the same day ofendoscopy in 95 children with CD and 106 controls. We preliminarilycalculatedthecutoffofa-DGPimmunoglobulinA(IgA)anda-DGPIgAþGin our population by receiver operating characteristic (ROC) curves. Of 95children with CD, 28 were studied during the first year after GFDintroduction, with interview and serum collection every 3 months. Inaddition, serum samples were collected in 106 children with CD on GFDfor more than 1 year (range 1–14). In both groups of children with CD onGFD, we compared a-DGP IgA and IgAþG performance in monitoringcompliance with GFD with anti-tissue transglutaminase antibodies (anti-tTG) IgA and anti-gliadin antibody (AGA) IgA.Results: The cutoff resulted in 13.1 arbitrary units (AU) for a-DGP IgA(sensitivity 87.4, 95% confidence interval [CI] 79%–92%, specificity 97.2,95% CI 92%–99%) and 16.5 for a-DGP IgAþG (sensitivity 94.7, 95% CI88%–98%,specificity89.6,95%CI84%–95%).Inthefirst yearofGFD,at6 to 8 months prevalence of positive a-DGPs was significantly higher inpartially versus strictly compliant children, and at 9 to 12 months onlyprevalence of positive a-DGP IgAþG remained significantly higher.Moreover, at 9 to 12 months sensitivity to detect transgressions to GFDwas44%fora-DGPIgAand100%fora-DGPIgAþG(P¼0.03).Inthe106children on GFD for more than 1 year, sensitivity to detect transgressions toGFD was 60% for a-DGP IgA and 76% for a-DGP IgAþG. Anti-tTG IgAandAGAIgAsensitivitywasmuchlower(24%and4%,respectively).The4tests showed comparable high specificity.Conclusions: Both a-DGPsshowedhighersensitivitythananti-tTG IgA andAGAIgAinmonitoringcompliancewithGFD,buta-DGPIgAþGseemedtoperform better. a-DGPs did not outperform anti-tTG IgA for CD screening.Key Words: anti-gliadin, anti-tissue transglutaminase, celiac disease,gluten-free diet