Celiac Disease (CD) is an autoimmune enteropathy which occurs in genetically susceptible individuals carrying the prerequisite genetic markers HLA DQ2 or DQ8. These genetic markers are present in approximately 30% of the population, and the worldwide prevalence of CD is estimated to be approximately 1-2%. Currently a gluten-free diet is the only treatment for CD, but novel therapies aimed at gluten modification are underway. This review will discuss gluten based therapies including wheat alternatives and wheat selection, enzymatic alteration of wheat, oral enzyme supplements, and polymeric binders as exciting new therapies for treatment of Celiac Disease.
BACKGROUND & AIMS
Patients with celiac disease have been reported to be at increased risk for pancreatitis and pancreatic insufficiency, but the risk might have been overestimated because of patient selection and limited numbers of patients for analysis. Furthermore, no distinction has been made between patients with gallstone-related and non gallstone-related pancreatitis. We performed a nationwide study to determine the risk for any pancreatitis or subtype of pancreatitis among patients with biopsy-verified celiac disease.
We analyzed data from patients in Sweden with celiac disease (n=28,908), identified based on small intestinal biopsy records from 28 pathology departments (those with villous atrophy, Marsh 3). Biopsies were performed from 1969 to 2008 and biopsy report data were collected from 2006 to 2008. Patients with pancreatitis were identified based on diagnostic codes in the Swedish Patient Register and records of pancreatic enzyme use in the Swedish Prescribed Drug Register. Data were matched with those from 143,746 individuals in the general population; Cox regression was used to estimate hazard ratios (HRs) for pancreatitis.
We identified 406 individuals with celiac disease who were later diagnosed with pancreatitis (and 143 with expected pancreatitis) (HR=2.85; 95% confidence interval [CI], 2.53–3.21). The absolute risk of any pancreatitis among patients with celiac disease was 126/100,000 person-years with an excess risk of 81/100,000 person-years. The HR for gallstone-related acute pancreatitis was 1.59 (95% CI, 1.06–2.40), for non-gallstone-related acute pancreatitis was 1.86 (1.52–2.26), for chronic pancreatitis was 3.33 (95% CI, 2.33–4.76), and for supplementation with pancreatic enzymes was 5.34 (95% CI, 2.99–9.53). The risk of any pancreatitis within 5 years of diagnosis was 2.76 (95% CI, 2.36–3.22).
Based on an analysis of medical records in Sweden, patients with celiac disease were at an almost 3-fold increase in risk of developing pancreatitis.
Coeliac Disease; Celiac Disease; Cohort study; Inflammation; Pancreatitis; Epidemiology; retrospective analysis; gluten intolerance; complication
Small intestinal diseases are a common, though often overlooked cause of diarrhoeal illness. Fully 1% of the Caucasian population are affected by coeliac disease and a substantial portion of children living in poverty in the developing world are affected by environmental enteropathy. These are but two examples of the many diseases that cause mucosal injury to the primary digestive and absorptive organ in our body. While diarrhoea may be a common, though not universally seen symptom of small bowel mucosal disease, the consequent malabsorption can lead to substantial malnutrition and nutrient deficiencies. The small intestine, unlike the colon, has been relatively inaccessible, and systematic evaluation is often necessary to identify and treat small intestinal mucosal diseases that lead to diarrhoea. Immunodeficiency states, including HIV enteropathy, adult autoimmune enteropathy, drug-associated enteropathy, and tropical sprue continue to occur and require specific therapy. All patients with severe diarrhoea or diarrhoea associated with features suggestive of malabsorption may have a disease of the small intestinal mucosa that requires careful evaluation and targeted management.
Autoimmune enteropathy; Coeliac disease; HIV enteropathy; Malabsorption; Tropical sprue steatorrhoea
Major histocompatibility complex (MHC) class II alleles HLA-DQ8 and the mouse homologue I-Ag7 lacking a canonical aspartic acid residue at position β57 are associated with coeliac disease1,2 and type I diabetes3,4. However, the role of this single polymorphism in disease initiation and progression remains poorly understood. The lack of Asp 57 creates a positively charged P9 pocket, which confers a preference for negatively charged peptides. Gluten lacks such peptides, but tissue transglutaminase (TG2) introduces negatively charged residues at defined positions into gluten T-cell epitopes by deamidating specific glutamine residues5,6 on the basis of their spacing to proline residues7. The commonly accepted model, proposing that HLA-DQ8 simply favours binding of negatively charged peptides, does not take into account the fact that TG2 requires inflammation for activation8 and that T-cell responses against native gluten peptides are found9,10, particularly in children11. Here we show that β57 polymorphism promotes the recruitment of T-cell receptors bearing a negative signature charge in the complementary determining region 3β (CDR3β) during the response against native gluten peptides presented by HLA-DQ8 in coeliac disease. These T cells showed a crossreactive and heteroclitic (stronger) response to deamidated gluten peptides. Furthermore, gluten peptide deamidation extended the T-cell-receptor repertoire by relieving the requirement for a charged residue in CDR3β. Thus, the lack of a negative charge at position β57 in MHC class II was met by negatively charged residues in the T-cell receptor or in the peptide, the combination of which might explain the role of HLA-DQ8 in amplifying the T-cell response against dietary gluten.
Between 1980 and 2010 there were 1 million homicides in Brazil. Dramatic increases in homicide rates followed rises in inequality, more young men in the population, greater availability of firearms, and increased drug use. Nevertheless, disarmament legislation may have helped reduce homicide rates in recent years. Despite its very high rate of lethal violence, Brazil appears to have similar levels of general criminal victimization as several other Latin American and North American countries. Brazil has lower rates of drug use compared to other countries such as the United States, but the prevalence of youth drug use in Brazil has increased substantially in recent years. Since 1990, the growth of the Brazilian prison population has been enormous, resulting in the fourth largest prison population in the world. Through a systematic review of the literature, we identified 10 studies assessing the prevalence of self-reported offending in Brazil and 9 studies examining risk factors. Levels of self-reported offending seem quite high among school students in Brazil. Individual and family-level risk factors identified in Brazil are very similar to those found in high-income countries.
•Between 1980–2010 the Brazilian homicide rate rose to one of the highest worldwide.•Levels of non-lethal victimization in Brazil seem similar to other American nations.•Rates of self-reported offending are quite high among school children in Brazil.•Individual and family risk factors are similar to those in high-income countries.•More systematic official and self-report crime data collection is needed in Brazil.
Crime; Violence; Systematic review; Prevalence; Risk factors; Middle-income country
Background & Aims
Adherence to a gluten-free diet is the only effective treatment for celiac disease. It has been recommended that patients be followed, make regular visits to the clinic, and undergo serologic analysis for markers of celiac disease, although a follow-up procedure has not been standardized. We determined how many patients with celiac disease are actually followed.
We collected data on 122 patients with biopsy-proven celiac disease, diagnosed between 1996 and 2006 in Olmsted County, Minnesota (70% women, median age of 42 years) for whom complete medical records and verification of residency were available. We determined the frequency at which patients received follow-up examinations, from 6 months to 5 years after diagnosis. The Kaplan-Meier method was used to estimate event rates at 1 and 5 year(s). Patients were classified according to categories of follow-up procedures recommended by the American Gastroenterology Association (AGA).
We estimated that by 1 and 5 year(s) after diagnosis with celiac disease, 41.0% and 88.7% of the patients had follow-up visits, 33.6% and 79.8% were assessed for compliance with a gluten-free diet, 3.3% and 15.8% met with a registered dietitian, 2.5% and 18.1% had an additional intestinal biopsy, and 22.1% and 65.6% received serologic testing for markers of celiac disease. Among 113 patients (93%) who were followed for more than 4 years, only 35% received follow-up analyses that were consistent with AGA recommendations.
Patients with celiac disease are not followed consistently. Follow-up examinations are often inadequate and do not follow AGA recommendations. Improving follow-up strategies for patients with celiac disease could improve management of this disease.
food allergy; therapy; long-term; assessment
Celiac disease (CD) is an increasingly common disease that may affect as many as 1% of the North American population. Recent population-based data suggest a substantial increase in the prevalence of CD over the last several decades. Several factors are hypothesized as possible disease triggers including intercurrent illnesses, such as gastroenteritis, surgeries, and trauma. We used the active duty US military, a unique healthy worker population with essentially complete medical diagnostic coding, as an opportunity to describe trends in CD and deployment-related risk factors.
Using electronic medical encounter data (1999–2008) on active duty US military (over 13.7 million person-years), a matched, nested case–control study describing the epidemiology and risk determinants of CD (based on ≥2 ICD-9 medical encounters) was conducted. Incidence and duration of CD-related medical care were estimated, and conditional logistic regression was utilized to evaluate CD risk following infectious gastroenteritis (IGE) occurring within 3 years before CD diagnosis while controlling for other risk factors.
A total of 455 incident cases of CD were identified and age, gender, and time matched to 1,820 controls. The incidence of CD increased five-fold from 1.3 per 100,000 in 1999 to 6.5 per 100,000 in 2008, with the highest rates of increase among those over 34 years of age (average annual increase of 0.8 cases per 100,000). A total of 172 IGE episodes, predominately of “viral etiology” (60.5%), were documented. In multivariate models, a significant association between IGE and CD was found (Odds ratio (OR): 2.06, 95% confidence interval (CI) 1.43, 2.97). Risk generally increased with temporal proximity to, and non-viral etiology of, exposure. Other notable risk factors for CD in multivariate models were Caucasian race (OR: 3.1, P < 0.001), non-Army service (OR: 1.5, P = 0.001), and greater than a high-school education (OR: 1.3, P = 0.05).
Incidence of CD diagnosis in the US military is increasing, particularly among those in the fourth and fifth decades of life and appears higher than other population-based estimates. An association between antecedent IGE and risk of CD was noted, but the potential for exposure misclassification cannot be ruled out and further study is needed to link pathogen-specific exposure to incident CD anti-gluten antibody development or symptom onset.
The initial development and maintenance of tolerance to dietary antigens is a complex process that, when prevented or interrupted, can lead to human disease. Understanding the mechanisms by which tolerance to specific dietary antigens is attained and maintained is crucial to our understanding of the pathogenesis of diseases related to intolerance of specific dietary antigens. Two diseases that are the result of intolerance to a dietary antigen are celiac disease (CD) and dermatitis herpetiformis (DH). Both of these diseases are dependent upon the ingestion of gluten (the protein fraction of wheat, rye, and barley) and manifest in the gastrointestinal tract and skin, respectively. These gluten-sensitive diseases are two examples of how devastating abnormal immune responses to a ubiquitous food can be. The well-recognized risk genotype for both is conferred by either of the HLA class II molecules DQ2 or DQ8. However, only a minority of individuals who carry these molecules will develop either disease. Also of interest is that the age at diagnosis can range from infancy to 70–80 years of age. This would indicate that intolerance to gluten may potentially be the result of two different phenomena. The first would be that, for various reasons, tolerance to gluten never developed in certain individuals, but that for other individuals, prior tolerance to gluten was lost at some point after childhood. Of recent interest is the concept of non-celiac gluten sensitivity, which manifests as chronic digestive or neurologic symptoms due to gluten, but through mechanisms that remain to be elucidated. This review will address how animal models of gluten-sensitive disorders have substantially contributed to a better understanding of how gluten intolerance can arise and cause disease.
Case reports and case series studies suggest a positive association between intussusception and celiac disease (CD).
We contacted Sweden’s 28 pathology departments and obtained data on 29,096 patients with biopsy-verified CD (equal to Marsh stage 3) through biopsy reports. Patients with CD were matched for age, sex, calendar period and county of residence with up to five reference individuals from the general population (n = 144,522). Cases of intussusception were identified from nationwide inpatient, hospital-based outpatient and day-surgery data from the Swedish Patient Register.
Odds ratios (ORs) for future CD in patients with intussusception were estimated using conditional logistic regression.
34 (0.12%) individuals with CD had a diagnosis of intussusception vs. 143 (0.10%) reference individuals, suggesting that intussusception was not a risk factor for later CD (OR = 1.17; 95% confidence interval (CI) = 0.82–1.67). The OR for CD in patients with at least two records of intussusception was 0.40 (95% CI = 0.06–2.99).
In contrast, a post-hoc analysis showed that CD was associated with a statistically significantly increased risk of intussusception after CD diagnosis (hazard ratio = 1.95; 95% CI = 1.01–3.77); however, this analysis was based on only 12 cases with both CD and intussusception.
We found no association between intussusception and future CD; and a mostly modest increased risk of intussusception after a diagnosis of CD.
Celiac; Coeliac, Gluten; Inflammation; Intussusception; Population-based
This study aimed to review evidence on the prevalence of and risk factors for conduct problems in Brazil.
We searched electronic databases and contacted Brazilian researchers up to 05/2012. Studies were included in the review if they reported the prevalence of or risk factors for conduct problems, conduct disorder, or oppositional defiant disorder for 100 + Brazilian children aged ≤18 years, systematically sampled in schools or the community. Prevalence rates and sex differences were meta-analysed. Risk factor studies were reviewed one by one.
The average prevalence of conduct problems in screening questionnaires was 20.8 %, and the average prevalence of conduct disorder/oppositional defiant disorder was 4.1 %. There was systematic variation in the results of screening studies according to methodology: recruitment location, informants, instruments, impairment criterion for case definition, and response rates. Risk factors previously identified in high-income countries were mainly replicated in Brazil, including comorbid mental health problems, educational failure, low religiosity, harsh physical punishment and abuse, parental mental health problems, single parent family, and low socioeconomic status. However, boys did not always have higher risk for conduct problems than girls.
Studies using screening questionnaires suggest that Brazilian children have higher rates of conduct problems than children in other countries, but diagnostic studies do not show this difference. Risk factors in Brazil were similar to those in high-income countries, apart from child sex. Future research should investigate developmental patterns of antisocial behaviour, employ a variety of research designs to identify causal risk mechanisms, and examine a broader range of risk factors.
Conduct disorder; Oppositional defiant disorder; Risk factors; Middle income country; Systematic review
By targeting surface antigens expressed on tumor cells, monoclonal antibodies have demonstrated efficacy as cancer therapeutics. Recent successful antibody-based strategies have focused on enhancing anti-tumor immune responses by targeting immune cells, irrespective of tumor antigens. We discuss these innovative strategies and propose how they will impact the future of antibody-based cancer therapy.
Background & Aims
Celiac disease (CD) is associated with an increased risk of lymphoma. However, relatively few studies have assessed the outcome of patients diagnosed with both CD and lymphoma. We evaluated the temporal association between lymphoma and CD, along with clinical presentation, response to therapy, and prognosis.
Patients diagnosed with both CD and lymphoma were identified retrospectively in a tertiary referral center. Clinical characteristics and survival were analyzed.
Sixty-three patients (36 men) were identified who had been diagnosed with lymphoma and CD. Thirty-six (57%) were diagnosed with CD before they were diagnosed with lymphoma. The most common histologic entity was diffuse, large, B-cell lymphoma, which affected 18 (29%) patients. Complete information for staging was available in 59 patients; 24 (38%) had stage IV disease. Only chemotherapy or only radiation therapy was used for 43 (68%) and 11 (17%) patients, respectively. The 5- and 10-year cumulative survival rates for the entire cohort were 58% and 39%, respectively. Survival of patients with T-cell lymphoma was shorter than for all other lymphomas (119.4 vs 22.8 mo; P = .02).
CD is associated with B- and T-cell lymphomas. Patients with B-cell lymphomas had a better prognosis than those with T-cell lymphoma. Therapy is unsatisfactory for enteropathy-type T-cell lymphoma.
Cancer; Enteropathy; GI Disease; Gluten
The US CDC estimates over 2 million foodborne illnesses are annually caused by 4 major enteropathogens: non-typhoid Salmonella spp., Campylobacter spp., Shigella spp. and Yersinia enterocoltica. While data suggest a number of costly and morbid chronic sequelae associated with these infections, pathogen-specific risk estimates are lacking. We utilized a US Department of Defense medical encounter database to evaluate the risk of several gastrointestinal disorders following select foodborne infections.
We identified subjects with acute gastroenteritis between 1998 to 2009 attributed to Salmonella (nontyphoidal) spp., Shigella spp., Campylobacter spp. or Yersinia enterocolitica and matched each with up to 4 unexposed subjects. Medical history was analyzed for the duration of military service time (or a minimum of 1 year) to assess for incident chronic gastrointestinal disorders. Relative risks were calculated using modified Poisson regression while controlling for the effect of covariates.
A total of 1,753 pathogen-specific gastroenteritis cases (Campylobacter: 738, Salmonella: 624, Shigella: 376, Yersinia: 17) were identified and followed for a median of 3.8 years. The incidence (per 100,000 person-years) of PI sequelae among exposed was as follows: irritable bowel syndrome (IBS), 3.0; dyspepsia, 1.8; constipation, 3.9; gastroesophageal reflux disease (GERD), 9.7. In multivariate analyses, we found pathogen-specific increased risk of IBS, dyspepsia, constipation and GERD.
These data confirm previous studies demonstrating risk of chronic gastrointestinal sequelae following bacterial enteric infections and highlight additional preventable burden of disease which may inform better food security policies and practices, and prompt further research into pathogenic mechanisms.
To report the response to discontinuation of olmesartan, an angiotensin II receptor antagonist commonly prescribed for treatment of hypertension, in patients with unexplained severe spruelike enteropathy.
Patients and Methods
All 22 patients included in this report were seen at Mayo Clinic in Rochester, Minnesota, between August 1, 2008, and August 1, 2011, for evaluation of unexplained chronic diarrhea and enteropathy while taking olmesartan. Celiac disease was ruled out in all cases. To be included in the study, the patients also had to have clinical improvement after suspension of olmesartan.
The 22 patients (13 women) had a median age of 69.5 years (range, 47-81 years). Most patients were taking 40 mg/d of olmesartan (range, 10-40 mg/d). The clinical presentation was of chronic diarrhea and weight loss (median, 18 kg; range, 2.5-57 kg), which required hospitalization in 14 patients (64%). Intestinal biopsies showed both villous atrophy and variable degrees of mucosal inflammation in 15 patients, and marked subepithelial collagen deposition (collagenous sprue) in 7. Tissue transglutaminase antibodies were not detected. A gluten-free diet was not helpful. Collagenous or lymphocytic gastritis was documented in 7 patients, and microscopic colitis was documented in 5 patients. Clinical response, with a mean weight gain of 12.2 kg, was demonstrated in all cases. Histologic recovery or improvement of the duodenum after discontinuation of olmesartan was confirmed in all 18 patients who underwent follow-up biopsies.
Olmesartan may be associated with a severe form of spruelike enteropathy. Clinical response and histologic recovery are expected after suspension of the drug.
Background & Aims
Studies on pregnancy characteristics and mode of delivery and risk of later celiac disease in offspring are inconsistent. In recent decades rates of cesarean delivery and preterm birth survival have increased while at the same time the prevalence of celiac disease has doubled.
In this population-based case-control study we examine the risk of celiac disease in individuals exposed to cesarean delivery and adverse fetal events (i.e. low Apgar score, small for gestational age, low birth weight, preterm birth, and neonatal infections). Prospectively recorded pregnancy data were obtained from the Swedish Medical Birth Register between 1973 and 2008. Study participants consisted of 11,749 offspring with biopsy-verified celiac disease identified through histopathology reports from Sweden’s 28 pathology departments and 53,887 age- and sex-matched controls from the general population.
We found a positive association between elective cesarean delivery and later celiac disease (adjusted odds ratio (AOR) = 1.15; 1.04-1.26; p = 0.005), but no increased risk of celiac disease following emergency (AOR = 1.02; 0.92-1.13; p = 0.749) or any cesarean delivery (AOR = 1.06; 0.99-1.13; p = 0.074). Infants born small for gestational age were at a 21% increased risk of celiac disease (95% CI = 1.09-1.35; p = 0.001), whereas other pregnancy exposures did not increase the risk of future celiac disease.
The positive association with elective, but not emergency, cesarean delivery is consistent with the hypothesis that the bacterial flora of the newborn plays a role in the development of celiac disease.
cesarean section; prematurity; register
We investigated whether treatment with gliadin induces a paracellular permeability defect that enhances bacterial translocation to mesenteric lymph nodes (MLN) via resident dendritic cells (DC) expressing TLR-2 or 4 in HCD4/HLA-DQ8 transgenic mice.
HLA-DQ8 transgenic mice were sensitized and subsequently gavaged with gliadin, in the presence or absence of AT1001 (paracellular permeability inhibitor). Non-sensitized mice were gavaged with indomethacin (permeability inducer) or rice cereal. CD11c and CD103 (DC markers) and TLR-2 and 4 were investigated by immunostaining. Intestinal permeability was assessed by paracellular flux of 51Cr-EDTA in Ussing chambers. Bacterial translocation to MLN was performed by plate counting on aerobic and anaerobic conditions.
In gliadin-treated mice, both 51Cr-EDTA flux in jejunal mucosa and aerobic and anaerobic bacterial counts in MLN were increased (p < 0.05) compared to indomethacin-treated mice and controls. The inhibitor AT1001 normalized 51Cr-EDTA flux, but had no effect on bacterial translocation in gliadin-treated mice. In addition, changes in mucosal DC marker distribution such as increased (p < 0.05) trans-epithelial CD103+ cells and reduction (p < 0.05) of CD11c immunostaining were detected in gliadin-treated mice. Moreover, changes in DC markers and TLR-2 or 4 immunophenotypes were not associated.
Pharmacological restoration of paracellular permeability was not sufficient to prevent bacterial translocation in gluten-sensitive mice. We hypothesize that transcellular mechanisms involving CD103+DC and CD11c+DC may explain in gluten-sensitive HCD4/HLA-DQ8 transgenic mice the sustained increased bacterial translocation observed in the absence of a significant inflammatory response.
Celiac disease; Dendritic cells; Toll-like receptors; Intestinal permeability; HCD4/HLA-DQ8 transgenic mice
Nonresponsive celiac disease (CD) is defined by persistent or recurrent symptoms, common after treatment with a gluten-free diet (GFD).
To evaluate the utility of capsule endoscopy (CE) in nonresponsive CD.
Forty-two consecutive patients with nonresponsive CD and 84 age- and sex-matched CD-free controls who underwent CE were included. In addition, capsules taken after treatment with a GFD were retrospectively evaluated in 30 patients with uncomplicated CD.
Main Outcome Measurements
Diagnostic accuracy of CE for the detection of mucosal abnormalities in nonresponsive CD.
Macroscopic features of villous atrophy were detected in 13 of 42 patients (31%) with nonresponsive CD compared with none among 84 CD-free controls and 14 of 30 patients (47%) with uncomplicated CD. Among nonresponsive CD cases, the overall sensitivity and specificity of CE for the detection of any degree of villous atrophy as graded by histology were 56% and 85%, respectively. Single or multiple erosions/ulcerations of the gut were observed in 19% of nonresponsive CD patients, 18% of CD-free controls, and 31% of patients with uncomplicated CD (P = .35). The presence of erosions/ulcerations was associated with increased aspirin/nonsteroidal anti-inflammatory drug use in nonresponsive CD (P =.05). Two severe complications (ulcerative jejunitis and adenocarcinoma) were detected by CE in nonresponsive CD.
Single-center, retrospective study.
Mucosal abnormalities were observed by CE in patients with both nonresponsive CD and uncomplicated CD. CE can detect severe complications in patients with nonresponsive CD.
To investigate the effects of socioeconomic changes from birth to 11 years of life on emotional, conduct, and attentional/hyperactivity problems in 15-year-old adolescents, from the 1993 Pelotas (Brazil) birth cohort study.
The original cohort was composed of 5,249 hospital-born children whose mothers answered a questionnaire. We conducted interviews with 87.5% and 85.7% of the original cohort in 2004–2005 and 2008, respectively. We divided family income changes into nine possible categories based on two assessment points (birth and 11 years of age) and three income levels. To assess the psychopathology of the adolescents at 15 years of age, 4,423 mothers answered the Strengths and Difficulties Questionnaire.
Adolescents who were always poor or who became poor between birth and 11 years of age had greater conduct problems at 15 years of age. There was no consistent association between poverty and emotional and attentional/hyperactivity problems.
The effects of income change were more specific to conduct problems than to emotional and attentional/hyperactivity problems, similar to what has been previously described in developed countries.
Psychopathology; Income; Poverty; Socioeconomic status; Conduct disorders; Emotional disorders; Attention deficit/hyperactivity disorder adolescence
BACKGROUND & AIMS
Collagenous sprue (CS) is characterized by the presence of a distinctive band of subepithelial collagen deposition in the small bowel. We evaluated the clinical characteristics, treatments, and outcomes of patients with CS.
Thirty patients with CS were identified at the 3 Mayo Clinic sites between 1993 and 2009. Clinical data from medical records were reviewed.
The study cohort was 70% female (age range, 53–91 years). Most patients had severe diarrhea and weight loss. Hospitalization to treat dehydration was necessary in 16 (53%) patients. Associated immune-mediated diseases were noted in 70% of the patients; celiac disease was the most frequent. Other associated diseases were microscopic colitis, hypothyroidism, and autoimmune enteropathy. The median thickness of the layer of subepithelial collagen deposition in the small bowel was 29 μm (20 –56.5 μm). Subepithelial collagen deposition in the colon or stomach was noted in 8 patients. A clinical response was observed in 24 (80%) patients after treatment with a combination of a gluten-free diet and immunosuppressive drugs. Histologic improvement was confirmed in 9 patients, with complete remission in 5. Two patients died (1 of complications of CS and 1 of another illness).
Most patients with CS are treated effectively with a combination of gluten-free diet and steroids. CS is often associated with collagen deposition or chronic inflammation in other segments of the gastrointestinal tract as well as other immune-mediated disorders.
Sprue; Microscopic Colitis; Celiac Disease; Duodenum; Collagen; Fibrosis
Celiac disease (CD) is frequently diagnosed in patients with type 1 diabetes (T1D), and T1D patients can exhibit Abs against tissue transglutaminase, the auto-antigen in CD. Thus, gliadin, the trigger in CD, has been suggested to have a role in T1D pathogenesis. The objective of this study was to investigate whether gliadin contributes to enteropathy and insulitis in NOD-DQ8 mice, an animal model that does not spontaneously develop T1D. Gliadin-sensitized NOD-DQ8 mice developed moderate enteropathy, intraepithelial lymphocytosis, and barrier dysfunction, but not insulitis. Administration of anti-CD25 mAbs before gliadin-sensitization induced partial depletion of CD25+Foxp3+ T cells and led to severe insulitis, but did not exacerbate mucosal dysfunction. CD4+ T cells isolated from pancreatic lymph nodes of mice that developed insulitis showed increased proliferation and proinflammatory cytokines after incubation with gliadin but not with BSA. CD4+ T cells isolated from nonsensitized controls did not response to gliadin or BSA. In conclusion, gliadin sensitization induced moderate enteropathy in NOD-DQ8 mice. However, insulitis development required gliadin-sensitization and partial systemic depletion of CD25+Foxp3+ T cells. This humanized murine model provides a mechanistic link to explain how the mucosal intolerance to a dietary protein can lead to insulitis in the presence of partial regulatory T cell deficiency.
The repertoire of gastrointestinal (GI) symptoms is finite; however, the etiologies and mechanisms underlying symptom generation and perception are diverse and, in many cases, unknown. This review examines the clinical and experimental evidence exploring the putative relationship between gluten sensitivity (GS) and the generation of GI symptoms. It explores the hypothesis that, in a proportion of patients, GS causes functional bowel disorder (FBD)-like symptoms. We propose a model for investigating and understanding the induction of GI symptoms and dysfunction by gluten in FBD and organic disease. We hypothesize that, even in the absence of fully developed celiac disease, gluten can induce symptoms similar to FBD. We discuss the hypothesis that GS and post-infectious irritable bowel syndrome (IBS) provide two triggers that can explain at least part of the spectrum that constitutes IBS, further advancing an understanding of the role of mucosal responses to luminal factors in FBDs. We propose that the animal model of GS in human leukocyte antigen (HLA)-DQ8 mice allows investigation of mucosal pathophysiological changes that occur before the onset of full-blown inflammation in a GS host. A better understanding of how gluten can cause symptoms in sensitive individuals will illuminate the interaction between host genotype, diet, and intestinal microbiota in generating one of the most common GI conditions.
Active delivery of recombinant autoantigens or allergens at the intestinal mucosa by genetically modified Lactococcus lactis (LL) provides a novel therapeutic approach for the induction of tolerance. Celiac disease is associated with either HLA-DQ2 or HLA-DQ8 restricted responses to specific antigenic epitopes of gliadin, and may be treated by induction of antigen-specific tolerance. We investigated whether oral administration of LL-delivered DQ8-specific gliadin epitope induces antigen-specific tolerance.
was engineered to secrete a deamidated DQ8 gliadin epitope (LL-eDQ8d) and the induction of antigen-specific tolerance was studied in NOD AB° DQ8 transgenic mice. Tolerance was assessed by delayed-type hypersensitivity reaction, cytokine measurements, eDQ8d-specific proliferation and regulatory T cell analysis. Oral administration of LL-eDQ8d induced suppression of local and systemic DQ8 restricted T-cell responses in NOD AB° DQ8 transgenic mice. Treatment resulted in an antigen-specific decrease of the proliferative capacity of inguinal lymph node cells and lamina propria cells. Production of IL-10 and TGF-β and a significant induction of Foxp3+ regulatory T-cells were associated with the eDQ8d-specific suppression induced by LL-eDQ8d.
These data provide support for the development of effective therapeutic approaches for gluten-sensitive disorders using orally administered antigen-secreting LL. Such treatments may be effective even in the setting of established hypersensitivity.
Background & Aims
Refractory celiac disease (RCD) occurs when both symptoms and intestinal damage persist or recur despite strict adherence to a gluten-free diet. In RCD, the immunophenotype of intraepithelial lymphocytes may be normal and polyclonal (RCD I) or abnormal and monoclonal (RCD II). The aim is to describe the clinical characteristics, treatment, and long-term outcome in a large single-center cohort of patients with RCD.
We compared the clinical characteristics and outcome in 57 patients with RCD: 42 with RCD I and 15 with RCD II.
The overall 5-year cumulative survival is 70, 80 and 45 percent in the entire cohort, RCD I, and RCD II respectively (p = 0.07, among subtypes). The drop in survival was more evident during the first two years after the diagnosis. Fifteen (26%) patients died (n=8 with RCD I and n=7 with RCD II). The refractory state itself and enteropathy-associated T-cell lymphoma (EATL) were the most common causes of death, respectively. A new staging system is proposed based on the cumulative effect of five prognostic factors investigated at the time of the refractory state diagnosis: for patients in stages I, II, and III, the 5-year cumulative survival rate was 96, 71, and 19 percent, respectively (p<0.0001).
RCD is associated with high mortality with RCD II having an especially poor prognosis because of the development of EATL. A new staging model is proposed that may improve the precision of prognosis in patients with RCD.
refractory sprue; corticosteroids; lymphoma; intraepithelial lymphocyte; capsule endoscopy; body imaging
To investigate a possible association between celiac disease (CD) and systemic lupus erythematosus (SLE). Case series have indicated a possible association, but population-based studies are lacking.
We compared the risk of SLE in 29,048 individuals with biopsy-verified CD (villous atrophy, Marsh 3) from Sweden’s 28 pathology departments with that in 144,352 matched individuals from the general population identified through the Swedish Total Population Register. SLE was defined as having at least 2 records of SLE in the Swedish Patient Register. We used Cox regression to estimate hazard ratios (HR) for SLE.
During followup, 54 individuals with CD had an incident SLE. This corresponded to an HR of 3.49 (95% CI 2.48–4.90), with an absolute risk of 17/100,000 person-years and an excess risk of 12/100,000. Beyond 5 years of followup, the HR for SLE was 2.54 (95% CI 1.57–4.10). While SLE was predominantly female, we found similar risk estimates in men and women. When we restricted our outcome to individuals who also had a dispensation for a medication used in SLE, the HR was 2.43 (95% CI 1.22–4.87). The HR for having 2 records of SLE diagnoses, out of which at least 1 had occurred in a department of rheumatology, nephrology/dialysis, internal medicine, or pediatrics, was 2.87 (95% CI 1.97–4.17).
Individuals with CD were at a 3-fold increased risk of SLE compared to the general population. Although this excess risk remained more than 5 years after CD diagnosis, absolute risks were low.
AUTOIMMUNE; CELIAC; GLUTEN; SYSTEMIC LUPUS ERYTHEMATOSUS