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Coeliac disease is an immune-mediated enteropathy against dietary gluten present in wheat, rye and barley and is one of the most common lifelong food-related disorders worldwide. Coeliac disease is also considered to be a systemic disorder characterized by a variable combination of gluten-related signs and symptoms and disease-specific antibodies in addition to enteropathy. The ingestion of gluten leads to the generation of harmful gluten peptides, which, in predisposed individuals, can induce adaptive and innate immune responses. The clinical presentation is extremely variable; patients may have severe gastrointestinal symptoms and malabsorption, extraintestinal symptoms or have no symptoms at all. Owing to the multifaceted clinical presentation, diagnosis remains a challenge and coeliac disease is heavily underdiagnosed. The diagnosis of coeliac disease is achieved by combining coeliac disease serology and small intestinal mucosal histology during a gluten-containing diet. Currently, the only effective treatment for coeliac disease is a lifelong strict gluten-free diet; however, the diet is restrictive and gluten is difficult to avoid. Optimizing diagnosis and care in coeliac disease requires continuous research and education of both patients and health-care professionals. Coeliac disease is an immune-mediated enteropathy driven by dietary gluten present in wheat, rye and barley. This Primer discusses the risk factors and immune mechanisms of coeliac disease and highlights future treatment options beyond the gluten-free diet.

Background Undelayed diagnosis is thought to be a major determinant for good prognosis in pediatric inflammatory bowel disease (PIBD). However, factors predicting diagnostic delay and the consequences of this remain poorly defined. We investigated these issues in a well-defined cohort of PIBD patients. Methods Comprehensive electronic data were collected from 136 PIBD patients retrospectively. Diagnostic delay was further classified into < 6 and ≥ 6 months, and < 12 and ≥ 12 months. Logistic regression was used to calculate whether the delay was associated with clinical features and/or risk of complications and co-morbidities at diagnosis. Results The median age of patients was 12.4 years and 43.4% were females. Altogether 35.5% had Crohn´s disease (CD), 59.1% ulcerative colitis (UC) and 6.6% IBD undefined (IBD-U). The median delay before diagnosis was 5.0 months in all, 6.6 months in CD, 4.1 months in UC, and 9.8 months in IBD-U (UC vs. CD, p  = 0.010). In all but IBD-U most of the delay occurred before tertiary center referral. Abdominal pain predicted a delay > 6 months in all PIBD (OR 2.07, 95% CI 1.00–4.31) and in UC patients (3.15, 1.14–8.7), while bloody stools predicted a shorter delay in all PIBD (0.28, 0.14–0.59) patients and in CD (0.10, 0.03–0.41) patients. A delay > 6 months was associated with a higher frequency of complications (2.28, 1.01–5.19). Conclusions Delay occurred mostly before specialist consultation, was longer in children presenting with abdominal pain and in CD and was associated with risk of complications. These findings emphasize the roles of active case-finding and prompt diagnostic evaluations.

The Environmental Determinants of Diabetes in the Young study follows an HLA risk selected birth cohort for celiac disease (CD) development using a uniform protocol. Children under investigation come from 6 different regions within Europe and the United States. Our aim was to identify regional differences in CD autoimmunity and CD cumulative incidence for children born between 2004 and 2010. Children (n = 6,628) with DQ2.5 and/or DQ8.1 were enrolled prospectively from birth in Georgia, Washington, Colorado, Finland, Germany, and Sweden. Children underwent periodic study screening for tissue transglutaminase antibodies and then CD evaluation per clinical care. Population-specific estimates were calculated by weighting the study-specific cumulative incidence with the population-specific haplogenotype frequencies obtained from large stem cell registries from each site. Individual haplogenotype risks for CD autoimmunity and CD varied by region and affected the cumulative incidence within that region. The CD incidence by age 10 years was highest in Swedish children at 3%. Within the United States, the incidence by age 10 years in Colorado was 2.4%. In the model adjusted for HLA, sex, and family history, Colorado children had a 2.5-fold higher risk of CD compared to Washington. Likewise, Swedish children had a 1.4-fold and 1.8-fold higher risk of CD compared with those in Finland and Germany, respectively. There is high regional variability in cumulative incidence of CD, which suggests differential environmental, genetic, and epigenetic influences even within the United States. The overall high incidence warrants a low threshold for screening and further research on region-specific CD triggers.

Assessment of the gluten-induced small-intestinal mucosal injury remains the cornerstone of celiac disease diagnosis. Usually the injury is evaluated using grouped classifications (e.g. Marsh groups), but this is often too imprecise and ignores minor but significant changes in the mucosa. Consequently, there is a need for validated continuous variables in everyday practice and in academic and pharmacological research. We studied the performance of our standard operating procedure (SOP) on 93 selected biopsy specimens from adult celiac disease patients and non-celiac disease controls. The specimens, which comprised different grades of gluten-induced mucosal injury, were evaluated by morphometric measurements. Specimens with tangential cutting resulting from poorly oriented biopsies were included. Two accredited evaluators performed the measurements in blinded fashion. The intraobserver and interobserver variations for villus height and crypt depth ratio (VH:CrD) and densities of intraepithelial lymphocytes (IELs) were analyzed by the Bland-Altman method and intraclass correlation. Unevaluable biopsies according to our SOP were correctly identified. The intraobserver analysis of VH:CrD showed a mean difference of 0.087 with limits of agreement from -0.398 to 0.224; the standard deviation (SD) was 0.159. The mean difference in interobserver analysis was 0.070, limits of agreement -0.516 to 0.375, and SD 0.227. The intraclass correlation coefficient in intraobserver variation was 0.983 and that in interobserver variation 0.978. CD3(+) IEL density countings in the paraffin-embedded and frozen biopsies showed SDs of 17.1% and 16.5%; the intraclass correlation coefficients were 0.961 and 0.956, respectively. Using our SOP, quantitative, reliable and reproducible morphometric results can be obtained on duodenal biopsy specimens with different grades of gluten-induced injury. Clinically significant changes were defined according to the error margins (2SD) of the analyses in VH:CrD as 0.4 and in CD3(+)-stained IELs as 30%.

Background Deep immune receptor sequencing, RepSeq, provides unprecedented opportunities for identifying and studying condition-associated T-cell clonotypes, represented by T-cell receptor (TCR) CDR3 sequences. However, due to the immense diversity of the immune repertoire, identification of condition relevant TCR CDR3s from total repertoires has mostly been limited to either “public” CDR3 sequences or to comparisons of CDR3 frequencies observed in a single individual. A methodology for the identification of condition-associated TCR CDR3s by direct population level comparison of RepSeq samples is currently lacking. Results We present a method for direct population level comparison of RepSeq samples using immune repertoire sub-units (or sub-repertoires) that are shared across individuals. The method first performs unsupervised clustering of CDR3s within each sample. It then finds matching clusters across samples, called immune sub-repertoires, and performs statistical differential abundance testing at the level of the identified sub-repertoires. It finally ranks CDR3s in differentially abundant sub-repertoires for relevance to the condition. We applied the method on total TCR CDR3β RepSeq datasets of celiac disease patients, as well as on public datasets of yellow fever vaccination. The method successfully identified celiac disease associated CDR3β sequences, as evidenced by considerable agreement of TRBV-gene and positional amino acid usage patterns in the detected CDR3β sequences with previously known CDR3βs specific to gluten in celiac disease. It also successfully recovered significantly high numbers of previously known CDR3β sequences relevant to each condition than would be expected by chance. Conclusion We conclude that immune sub-repertoires of similar immuno-genomic features shared across unrelated individuals can serve as viable units of immune repertoire comparison, serving as proxy for identification of condition-associated CDR3s.

Background Various oral manifestations are associated with coeliac disease in children, whereas data on adults are scarce. Moreover, possible individual factors predisposing to these manifestations remain unresolved. The aim of this study was to investigate these issues in a large cohort of adult coeliac disease patients both at diagnosis and while on gluten-free diet (GFD). Methods This population-based study involved 873 adult patients with coeliac disease and 563 non-coeliac controls. Patients and controls were interviewed and structured questionnaires were used to assess the severity of gastrointestinal symptoms and quality of life at the time of the study. All participants were systematically asked about oral manifestations, including dental enamel defects, recurrent aphthous ulceration and glossodynia. Coeliac disease-related data were collected from medical records. Possible individual factors associated with oral manifestations were studied using logistic regression analysis. Results Dental enamel defects were more common among patients than among non-coeliac controls (27% vs. 4%, p  < 0.001). Prior to the coeliac disease diagnosis, 56% of the patients had experienced recurrent aphthous ulceration and GFD brought relief to 69% of them. While on GFD, coeliac disease patients had higher prevalence of recurrent aphthous ulceration than did the controls (17% vs. 13%, p  = 0.040), but this significance disappeared after adjusting for gender. Glossodynia on GFD was more prevalent in the coeliac cohort than in the controls (14% vs 6%, p  < 0.001). Oral manifestations at diagnosis and on GFD were associated with the presence of abdominal symptoms at the time of coeliac disease diagnosis, long diagnostic delay and female gender. At the time of the study, patients with oral symptoms had more severe gastrointestinal symptoms and poorer quality of life than those without these symptoms. Conclusions Oral manifestations were more prevalent, at diagnosis and on GFD, in patients with coeliac disease than in the controls, and they were associated with long diagnostic delay, abdominal symptoms, female gender and impaired quality of life. A GFD was shown beneficial in relieving recurrent aphthous ulcerations in patients with coeliac disease.

Background Vomiting and nausea seem to be relatively specific symptoms related to gluten ingestion in treated celiac disease. However, the overall prevalence and associated factors of these symptoms after chronic gluten exposure at celiac disease diagnosis and acute re-exposure during gluten challenge remain obscure. Methods Medical data on 815 adult celiac disease patients were collected at diagnosis from the medical records and through supplementary interviews. An additional 74 patients underwent a three-day (10 g/day) gluten challenge (wheat, barley, rye or a combination of the three grains) while in remission. Prevalence of vomiting/nausea and associated factors were evaluated in both cohorts. A literature review was conducted to summarize earlier studies. Results Twenty-eight (3%) patients presented with vomiting at diagnosis. They were less often screen-detected and suffered from extra-intestinal symptoms, and had more often abdominal pain (71% vs. 49%, p  = 0.021), diarrhea (61% vs. 40%, p  = 0.031), weight loss (36% vs. 17%, p  = 0.019) and childhood symptoms (61% vs. 33%, p  = 0.002) than those without vomiting ( n  = 787). The groups were comparable in other clinical-demographic data and in genetic, serological, and histological findings. Short-term gluten challenge provoked vomiting/nausea in 14/74 (19%) patients. They consumed gluten-free oats less often than those without these symptoms (64% vs. 92%, p  = 0.017), whereas the groups did not differ in clinical-demographic features at diagnosis, presence of comorbidities, duration of gluten-free diet, or in other symptoms or grain used ingested during the challenge. According to the literature, prevalence of vomiting/nausea at celiac disease diagnosis has varied 3–46% and during gluten challenge 13–61%. Conclusions In chronic gluten exposure at celiac disease diagnosis, vomiting was associated with other gastrointestinal symptoms and onset of symptoms already in childhood, whereas regular consumption of oats may increase the tolerance against vomiting/nausea after acute re-exposure in treated celiac disease.

David van Heel and colleagues report results of a large genome-wide association study of celiac disease. Most of the associated loci contain genes with immune functions, and over half harbor risk variants that are correlated with variation in cis gene expression. We performed a second-generation genome-wide association study of 4,533 individuals with celiac disease (cases) and 10,750 control subjects. We genotyped 113 selected SNPs with P GWAS < 10 −4 and 18 SNPs from 14 known loci in a further 4,918 cases and 5,684 controls. Variants from 13 new regions reached genome-wide significance ( P combined < 5 × 10 −8 ); most contain genes with immune functions ( BACH2 , CCR4 , CD80 , CIITA - SOCS1 - CLEC16A , ICOSLG and ZMIZ1 ), with ETS1 , RUNX3 , THEMIS and TNFRSF14 having key roles in thymic T-cell selection. There was evidence to suggest associations for a further 13 regions. In an expression quantitative trait meta-analysis of 1,469 whole blood samples, 20 of 38 (52.6%) tested loci had celiac risk variants correlated ( P < 0.0028, FDR 5%) with cis gene expression.

The phenotype of coeliac disease varies considerably for incompletely understood reasons. We investigated whether established coeliac disease susceptibility variants (SNPs) are individually or cumulatively associated with distinct phenotypes. We also tested whether a polygenic risk score (PRS) based on genome-wide associated (GWA) data could explain the phenotypic variation. The phenotypic association of 39 non-HLA coeliac disease SNPs was tested in 625 thoroughly phenotyped coeliac disease patients and 1817 controls. To assess their cumulative effects a weighted genetic risk score (wGRS39) was built, and stratified by tertiles. In our PRS model in cases, we took the summary statistics from the largest GWA study in coeliac disease and tested their association at eight P value thresholds ( P T ) with phenotypes. Altogether ten SNPs were associated with distinct phenotypes after correction for multiple testing ( P EMP2  ≤ 0.05). The TLR7/TLR8 locus was associated with disease onset before and the SH2B3/ATXN2 , ITGA4/UBE2E3 and IL2/IL21 loci after 7 years of age. The latter three loci were associated with a more severe small bowel mucosal damage and SH2B3/ATXN2 with type 1 diabetes. Patients at the highest wGRS39 tertiles had OR > 1.62 for having coeliac disease-related symptoms during childhood, a more severe small bowel mucosal damage, malabsorption and anaemia. PRS was associated only with dermatitis herpetiformis ( P T  = 0.2, P EMP2  = 0.02). Independent coeliac disease-susceptibility loci are associated with distinct phenotypes, suggesting that genetic factors play a role in determining the disease presentation. Moreover, the increased number of coeliac disease susceptibility SNPs might predispose to a more severe disease course.

Objective Nationwide prevalence studies on people avoiding gluten without celiac disease (PWAG) are lacking, and in particular, long-term follow-up studies are unavailable. We aimed to evaluate the prevalence, incidence, and characteristics of PWAG in a population-based cohort in 2000 and 2011. Methods Health and diet-related data were collected in nationwide Health 2000 and 2011 surveys, which comprised 5,777 and 3,866 individuals, respectively, representing 2,682,733 and 1,967,876 Finnish adults. Serum samples were taken for the measurement of transglutaminase autoantibodies. In total 3,296 individuals participated in both surveys, forming a prospective cohort. PWAG refers to subjects avoiding gluten without celiac disease or positive autoantibodies. Psychological health was assessed with General Health Questionnaire and the Beck Depression Inventory. Results The prevalence of PWAG increased significantly from 0.2% (2000) to 0.7% (2011) ( p  < 0.001), with the highest prevalence (1.3%) detected in individuals > 70 years old. An annual incidence rate of 42 (95% confidence interval 25–71) per 100,000 persons was noted. The PWAG group was more likely to maintain additional special diets than those not avoiding gluten, including e.g. lactose-free diet (41.7% vs. 12.0% in 2011, p  < 0.001) and food restriction for allergy (12.5% vs. 3.0%, p  = 0.007). Beck Depression Inventory indicated more depression ( p  = 0.023) among PWAG in 2000, while no difference was seen in 2011 or in General Health Questionnaire. Celiac disease-related risk factors, including female gender, anemia, autoimmune diseases or antibody levels near the upper limit of normal in 2000, did not predict later gluten avoidance. Conclusions The prevalence of PWAG multiplied over a decade, reaching 0.7% in 2011 in Finland. The PWAG group maintained more likely additional dietary restrictions than those not avoiding gluten and had signs of psychosocial burden. No predicting factors for the condition were identified.