Refractory Celiac Disease Research Articles

Abnormal thymic stromal lymphopoietin expression in the duodenal mucosa of patients with coeliac disease

ObjectiveThe short isoform of thymic stromal lymphopoietin (TSLP), a cytokine constitutively expressed by epithelial cells, is crucial in preserving immune tolerance in the gut. TSLP deficiency has been implicated in sustaining intestinal damage in Crohn's disease. We explored mucosal TSLP expression and function in refractory and uncomplicated coeliac disease (CD), a T-cell-mediated enteropathy induced by gluten in genetically susceptible individuals.DesignTSLP isoforms—long and short—and receptors—TSLPR and interleukin (IL)-7Rα—were assessed by immunofluorescence, immunoblotting and qRT-PCR in the duodenum of untreated, treated, potential and refractory patients with CD. The ability of the serine protease furin or CD biopsy supernatants to cleave TSLP was evaluated by immunoblotting. The production of interferon (IFN)-γ and IL-8 by untreated CD biopsies cultured ex vivo with TSLP isoforms was also assessed.ResultsMucosal TSLP, but not TSLPR and IL-7Rα, was reduced in untreated CD and refractory CD in comparison to treated CD, potential CD and controls. Transcripts of both TSLP isoforms were decreased in active CD mucosa. Furin, which was overexpressed in active CD biopsies, was able to cleave TSLP in vitro. Accordingly, refractory and untreated CD supernatants showed higher TSLP-degrading capacity in comparison to treated CD and control supernatants. In our ex vivo model, both TSLP isoforms significantly downregulated IFN-γ and IL-8 production by untreated CD biopsies.ConclusionsReduced mucosal TSLP expression may contribute to intestinal damage in refractory and untreated CD. Further studies are needed to verify whether restoring TSLP might be therapeutically useful especially in refractory patients with CD.

The composition and differentiation potential of the duodenal intraepithelial innate lymphocyte compartment is altered in coeliac disease

ObjectiveCoeliac disease (CD), a gluten-induced enteropathy, alters the composition and function of duodenal intraepithelial T cells. The intestine also harbours four types of CD3-negative intraepithelial lymphocytes (IELs) with largely unknown...

Celiac Disease, Refractory Celiac Disease, and Tropical Sprue

Celiac disease, often also termed celiac sprue, is an immune-mediated disorder triggered by ingestion of wheat, barley, rye, and triticale gluten proteins in genetically predisposed individuals. The offending glutens induce a characteristic but variable and nonspecific lesion of the small intestinal mucosa that improves following gluten withdrawal. Patients with refractory celiac disease (RCD) have persistent or recurrent symptomatic malabsorption together with biopsy-documented enteropathy that has not responded to 6 to 12 months of strict gluten withdrawal. Tropical sprue is an illness that occurs in individuals living in tropical countries; clinical features include anorexia, diarrhea, and intestinal malabsorption, leading to weight loss accompanied by a characteristic although nonspecific lesion of the mucosa of the small intestine. This review addresses the epidemiology, etiology/genetics, pathophysiology and pathogenesis, diagnosis, differential diagnosis, treatment, complications, and prognosis of these related diseases. Figures show the celiac disease iceberg, duodenal mucosal surface seen at endoscopy, duodenal mucosal biopsies from a patient with celiac disease, higher magnification micrograph of the duodenal mucosal surface from a patient with untreated celiac disease, duodenal biopsies from a patient with refractory celiac disease, and duodenal biopsy obtained from an Indian expatriate with diarrhea, weight loss, and folate deficiency. Tables list selected extraintestinal manifestations of celiac disease, prevalence of celiac disease in selected conditions, disorders with duodenal lesions that may mimic those of celiac diseases, initial treatment for celiac disease, organizations that provide helpful information for gluten-intolerant patients, considerations in a patient not responding to a gluten-free diet, and features that help distinguish tropical sprue from celiac disease. This review contains 6 highly rendered figures, 7 tables, and 96 references.

Refractory celiac disease and EATL patients show severe malnutrition and malabsorption at diagnosis

Refractory celiac disease type II (RCDII) and EATL (Enteropathy Associated T-cell Lymphoma) are (pre)malignant complications of celiac disease (CD). Data on malnutrition and intestinal absorption is lacking in these patients. Therefore, the aim of the study is to comprehensively assess nutritional status and intestinal absorption capacity of patients with RCDII and EATL, compared with data of newly diagnosed CD patients. Observational study in tertiary care setting in RCDII (n=24, 63.8±8.2y), EATL (n=25, 62.3±5.7y) and CD patients (n=43, 45.6±14.8y). At diagnosis, anthropometry (BMI, unintentional weight loss, fat-free mass index (FFMI), handgrip strength (HGS), nutritional intake, fecal losses and Resting Energy Expenditure (REE)) were assessed. Low BMI (<18.5) was more often observed in RCDII patients than in CD or EATL patients (in 33%, 12% and 12%, respectively, p=0.029). EATL patients more frequently had unintentional weight loss (>10%) than CD or RCDII patients (in 58%, 19% and 39% of patients, respectively; p=0.005/0.082). Energy malabsorption (<85%) was detected in 44% and 33% of RCDII and EATL patients, vs 21.6% in CD (NS). Fecal energy losses were higher in RCDII than in CD patients (589±451 vs 277±137kcal/d, p=0.017). REE was underestimated by predicted-REE with>10% in 60% of RCDII, 89% of EATL, and 38% of CD patients (p=0.006). Low FFMI and HGS were detected in one third and two thirds of all patients, respectively. The nutritional status of patients with RCDII and EATL is inferior compared with untreated naïve CD patients at presentation. Both malabsorption as well as hypermetabolism contribute to malnutrition.

Salivary proline-rich proteins and gluten: Do structural similarities suggest a role in celiac disease?

Gluten proteins, the culprits in celiac disease (CD), show striking similarities in primary structure with human salivary proline-rich proteins (PRPs). Both are enriched in proline and glutamine residues that often occur consecutively in their sequences. We investigated potential differences in the spectrum of salivary PRPs in health and CD. Stimulated salivary secretions were collected from CD patients, patients with refractory CD, patients with gastrointestinal complaints but no CD, and healthy controls. PRP isoforms/peptides were characterized by anionic and SDS-PAGE, PCR, and LC-ESI-MS. The gene frequencies of the acidic PRP isoforms PIF, Db, Pa, PRP1, and PRP2 did not differ between groups. At the protein level, PRPs peptides showed minor group differences, but these could not differentiate the CD and/or refractory CDs groups from the controls. This extensive study established that salivary PRPs, despite similarity to gluten proteins, show no apparent correlation with CD and thus will not serve as diagnostic markers for the disease. The structural basis for the tolerance to the gluten-like PRP proteins in CD is worthy of further exploration and may lead to the development of gluten-like analogs lacking immunogenicity that could be used therapeutically.

Sa1282 Attitudes Toward Genetic Testing for Celiac Disease

characteristics at diagnosis and the long-term clinical course of a series of patients attending a referral center. Materials: From 1991 to 2014, all patients diagnosed of UJ were enrolled in this analysis. Diagnosis of UJ was based on the presence of multiple typical ulcerations in the small intestine as shown by enteroclysis, enteroscopy, capsule endoscopy or surgery. Cases with lymphoma at diagnosis were considered if ulcers distant from the malignancy were present. Diagnosis of CD was based on the finding of a characteristic enteropathy (type III of Marsh) and positive CD-specific serology or histological response to the GFD. Type II refractory CD (RCD) was diagnosed if CD8intraepithelial lymphocyte (IEL) count was above 50%. HLA-DQ haplotype was tested in all patients. Survival curves (Mantel-Cox log rank test) were tested for different events. Results: A total of 31 patients (21female; median age: 44yr) fulfilled criteria for diagnosing UJ and the median follow-up was 36 mo./patient (range 4 to 276). Follow-up time was lower in those diagnosed of type II RCD ( pNS). Diagnosis of CD was confirmed in 29 cases. The reminder 2 patients had the characteristic HLA-DQ2 haplotype. According to the immunohistochemistry of biopsy samples, a type II refractory CD was diagnosed in 20 patients. Three of these patients were diagnosed of lymphoma within the first 6 mo. after diagnosing UJ. One additional patient (not type II refractory CD) developed a lymphoma during the follow-up. Mortality (n=7) was produced during the 3 years after diagnosis of UJ. Both 3and 5-years survival were 62% and 91% (pNS) for the type II UJ and non-type II patients, respectively. Sepsis (n=3) and lymphoma (n=2) were the most relevant cause of mortality. Diverse treatment modalities were employed and 17 patients (14 type II) received intensive support + azathioprine for 1 year. Mortality of those treated with azathioprine was 36%. UJ relapsed in 90% of cases at 180 months irrespective of phenotype of RCD (pNS). Conclusions: UJ is a severe complication observed among CD patients. The long-term outcome is affected by the presence of an early mortality in type II refractory cases. A therapeutic conduct cannot be recommended but the addition of azathioprine for 1 year to an intensive treatment strategy was effective and had not shown severe outcomes in type II refractory CD cases. UJ is characterized by a high relapse rate in the long-term.

596 Clinical Outcomes of Inflammatory Bowel Disease Patients With Antibody Deficiencies: A 5-Year Prospective Study

G A A b st ra ct s retrospective observational study was conducted in French tertiary centers from the GETAID, including all consecutive patients who received subcutaneous ustekinumab for refractory CD to conventional and anti-TNF therapy and having a follow-up of more than 3 months. The primary objective was ustekinumab clinical benefit at 3 months, defined by a significant improvement as judged by the physician leading to continue the treatment with complete steroids weaning if given at inclusion. Ustekinumab safety and clinical benefit at 6, 12 months and end of follow-up were also recorded. Results: Ninety-seven CD patients (27 males, mean age 35.1±11.6 years) received at least one subcutaneous ustekinumab injection in 16 centers. At baseline, median (IQR) disease duration was 11.9 (7.3-16.2) years; 97 (100%) patients experienced previous failure or intolerance to thiopurines or methotrexate and to at least one anti-TNF agent (infliximab or adalimumab, with 85 (87%) who received both anti-TNFs) and 59 (61%) patients underwent prior intestinal resection. Ustekinumab was given for luminal CD in 88 (91%) patients and for perianal disease in 9 (9%). Median follow-up duration was 39.2±32.8 weeks. Mean cumulative dose of ustekinumab given for induction from week 0 to 4 was 148.5 ± 65 mg (range: 45-396 mg). At inclusion, 15 patients received corticosteroids and 12 patients concomitant immunosuppressant (IS). Clinical benefit at 3 months was observed in 69 (71%) patients in the whole population and in 8/9 of patients with perianal CD. Among the primary ustekinumab responders, 78% and 86% experienced clinical benefit at 6 and 12 months, respectively. Concomitant IS and absence of corticosteroids at time of ustekinumab introduction were associated, but nonsignificantly, with clinical response to ustekinumab at 3 months (p=0.09). No serious adverse effects related to ustekinumab were reported. Conclusions: In patients with highly refractory CD, a clinical benefit to subcutaneous ustekinumab was observed in 71% at 3 months and was maintained in the majority of patients for up to 12 months. Along this, ustekinumab could be considered as a rescue therapy in CD patients who experienced prior failure or intolerance to conventional IS and to anti-TNF agents. 1 Sandborn WJ, Gasink C, Gao LL, et al. Ustekinumab induction and maintenance therapy in refractory Crohn's disease. N Engl J Med. 2012 Oct 18;367(16):1519-28.

Sa1773 Reduced T-Cell Receptor Variability in Refractory Celiac Disease Type II As Revealed by Next Generation Sequencing

Sa1773 Reduced T-Cell Receptor Variability in Refractory Celiac Disease Type II As Revealed by Next Generation Sequencing

Sa1772 Ilc-Like Lymphomas in Refractory Celiac Disease Type II Respond to Multiple Common γ-Chain Cytokines and Are Sensitive to JAK-Inhibitors

Sa1772 Ilc-Like Lymphomas in Refractory Celiac Disease Type II Respond to Multiple Common γ-Chain Cytokines and Are Sensitive to JAK-Inhibitors

Therapy in RCDII: Rationale for Combination Strategies?

Refractory coeliac disease type II (RCDII) is characterized by a continuous gluten-independent duodenal immune activation with an extremely high risk of malignant transformation. It is therefore considered as an indolent lymphoma. RCDII is characterized by the presence of villous atrophy (Marsh III A-C) in combination with an aberrant intra- epithelial lymphocyte (IEL) population consisting of >20% sCD3-CD7+iCD3+ IELs. The sCD3-CD7+iCD3+ IELs are a heterogeneous lineage-negative cell population, consisting of cells that do or do not express CD127/IL7Rα. Experiments using IEL from non-RCDII patients have indicated that while the CD127- cells are IL-15 responsive, the CD127+ cells are not. Together with the observation that some patients express an aberrant (monoclonal) TCRγδ phenotype, this confirms the heterogeneity of the aberrant IEL population in RCDII and suggests that the aberrant cells are heterogeneous with respect to their response to common γ-chain cytokines. Although cladribine with or without autologous stem cell transplantation is effective in the treatment of signs and symptoms of RCDII and improves survival as compared to symptomatic topical steroid therapy, cladribine failures still bear a high risk of malignant transformation, and the rate of enteropathy-associated T-cell lymphoma (EATL) development in this subgroup is extremely high. It might be hypothesized that the heterogenous nature of aberrant IEL and the high risk of malignant transformation require a treatment strategy which is effective despite this heterogeneity. RCDII should be seen more in the light of a low-grade/no mass lymphoma or pre-EATL. We would suggest an upfront combination therapy approach integrating inhibition of downstream Jak-STAT signalling pathways with conventional therapy (2-CDA) to hopefully effectively treat signs and symptoms of RCDII and accomplish a more effective EATL prevention.

Food, the Immune System, and the Gastrointestinal Tract

Food, the Immune System, and the Gastrointestinal Tract

The role of bilateral adrenalectomy in the treatment of refractory Cushing's disease.

Cushing's syndrome (CS) results from sustained exposure to excessive levels of free glucocorticoids. One of the main causes of CS is excessive adrenocorticotropic hormone (ACTH) secretion by tumors in the pituitary gland (Cushing's disease [CD]). Cushing's disease and its associated hypercortisolism have a breadth of debilitating symptoms associated with an increased mortality rate, warranting urgent treatment. Currently, the first line of treatment for CD is transsphenoidal surgery (TSS), with excellent long-term results. Transsphenoidal resections performed by experienced surgeons have shown remission rates ranging from 70% to 90%. However, some patients do not achieve normalization of their hypercortisolemic state after TSS and continue to have persistent or recurrent CD. For these patients, various therapeutic options after failed TSS include repeat TSS, radiotherapy, medical therapy, and bilateral adrenalectomy (BLA). Bilateral adrenalectomy has been shown to be a safe and effective treatment modality for persistent or recurrent CD with an immediate and definitive cure of the hypercortisolemic state. BLA was traditionally performed through an open approach, but since the advent of laparoscopic adrenalectomy, the laparoscopic approach has become the surgical method of choice. Advances in technology, refinement in surgical skills, competency in adrenopathology, and emphasis on multidisciplinary collaborations have greatly reduced morbidity and mortality associated with adrenalectomy surgery in a high-risk patient population. In this article, the authors review the role of BLA in the treatment of refractory CD. The clinical indications, current surgical and endocrinological results reported in the literature, surgical technique (open vs laparoscopic), drawbacks, and complications of BLA are discussed.

Myoclonus ataxia and refractory coeliac disease.

BackgroundCortical myoclonus with ataxia has only rarely been reported in association with Coeliac Disease (CD). Such reports also suggested that it is unresponsive to gluten-free diet. We present detailed electro-clinical characteristics of a new syndrome of progressive cortical hyperexcitability with ataxia and refractory CD. At our gluten/neurology clinic we have assessed and regularly follow up over 600 patients with neurological manifestations due to gluten sensitivity. We have identified 9 patients with this syndrome.ResultsAll 9 patients (6 male, 3 female) experienced asymmetrical irregular myoclonus involving one or more limbs and sometimes face. This was often stimulus sensitive and became more widespread over time. Three patients had a history of Jacksonian march and five had at least one secondarily generalised seizure. Electrophysiology showed evidence of cortical myoclonus. Three had a phenotype of epilepsia partialis continua at onset. There was clinical, imaging and/or pathological evidence of cerebellar involvement in all cases. All patients adhered to a strict gluten-free diet with elimination of gluten-related antibodies in most. However, there was still evidence of enteropathy in all, suggestive of refractory celiac disease. Two died from enteropathy-associated lymphoma and one from status epilepticus. Five patients were treated with mycophenolate and one in addition with rituximab and IV immunoglobulins. Their ataxia and enteropathy improved but myoclonus remained the most disabling feature of their illness.ConclusionsThis syndrome may well be the commonest neurological manifestation of refractory CD. The clinical involvement, apart from ataxia, covers the whole clinical spectrum of cortical myoclonus.Electronic supplementary materialThe online version of this article (doi:10.1186/2053-8871-1-11) contains supplementary material, which is available to authorized users.

Early lymphoid lesions: conceptual, diagnostic and clinical challenges.

There are no "benign lymphomas", a fact due to the nature of lymphoid cells to circulate and home as part of their normal function. Thus, benign clonal expansions of lymphocytes are only rarely recognized when localized. Recent studies have identified a number of lymphoid proliferations that lie at the interface between benign and malignant. Some of these are clonal proliferations that carry many of the molecular hallmarks of their malignant counterparts, such as BCL2/IGH and CCND1/IGH translocations associated with the in situ forms of follicular lymphoma and mantle cell lymphoma, respectively. There are other clonal B-cell proliferations with low risk of progression; these include the pediatric variants of follicular lymphoma and marginal zone lymphoma. Historically, early or incipient forms of T/NK-cell neoplasia also have been identified, such as lymphomatoid papulosis and refractory celiac disease. More recently an indolent form of T-cell lymphoproliferative disease affecting the gastrointestinal tract has been described. Usually, CD8(+), the clonal cells are confined to the mucosa. The clinical course is chronic, but non-progressive. NK-cell enteropathy is a clinically similar condition, composed of cytologically atypical NK-cells that may involve the stomach, small bowel or colon. Breast implant-associated anaplastic large cell lymphoma is a cytologically alarming lesion that is self-limited if confined to the seroma cavity. Atypical lymphoid proliferations that lie at the border of benign and malignant can serve as instructive models of lymphomagenesis. It is also critical that they be correctly diagnosed to avoid unnecessary and potentially harmful therapy.

Serum regenerating islet-derived 3-alpha is a biomarker of mucosal enteropathies.

The clinical presentation of organic and functional intestinal disorders can overlap and clinicians often rely on invasive and time-consuming procedures to make a final diagnosis. Regenerating islet-derived 3-alpha (Reg3α) is detectable in the circulation of patients with intestinal graft-versus host disease and patients with inflammatory bowel disease (IBD). To determine whether serum Reg3α testing is useful for discriminating mucosal enteropathies from functional intestinal disorders. We prospectively included 47 patients with active coeliac disease (ACD), 13 patients with refractory coeliac disease (RCD), seven patients with common variable immunodeficiency (CVID), 72 patients with active Crohn's disease, 22 patients with active ulcerative colitis (UC) and 28 patients with irritable bowel syndrome (IBS)-related diarrhoea. Sera were also taken from 10 CD patients before and after 6-12months of a gluten-free diet (GFD) and from 14 patients with IBD before and after induction therapy with Infliximab (IFX). Sera of 119 healthy volunteers were used to determine the cut-off value. Reg3α levels were measured by a commercial ELISA kit. Levels of Reg3α exceeded the cut-off value of the assay in 43/47(91%) ACD patients, 13/13(100%) RCD patients, 7/7(100%) CVID patients, 65/72(90%) Crohn's disease patients, 17/22(77%) UC patients and one patient with IBS(4%). Reg3α levels distinguished mucosal enteropathies from IBS with a sensitivity of 90% and a specificity of 96%. Reg3α levels significantly decreased in CD patients following a GFD and in IBD patients after treatment with IFX. Reg3α is a serum biomarker of intestinal damage that, combined with clinical data, identifies patients who should undergo invasive tests for diagnosing enteropathies.

Diagnosis and management of adult coeliac disease: guidelines from the British Society of Gastroenterology

A multidisciplinary panel of 18 physicians and 3 non-physicians from eight countries (Sweden, UK, Argentina, Australia, Italy, Finland, Norway and the USA) reviewed the literature on diagnosis and management of...

PTH-117 Thymic Stromal Lymphopoietin Is Primarily Reduced In Refractory Coeliac Disease Duodenal Mucosa

IntroductionThymic stromal lymphopoietin (TSLP), a cytokine released by enterocytes and gut dendritic cells, promotes the development of Foxp3+ regulatory T cells and at the same time inhibits the development of...

PTH-120 Coeliac Disease And Double-balloon Enteroscopy: What Can We Achieve? The Experience Of Two European Tertiary Referral Centres

IntroductionThe indications for and efficacy of device-assisted enteroscopy is not standardised in coeliac disease (CD). We present the largest study to date to evaluate the clinical role of double-balloon enteroscopy...

Increased IgA glycoprotein-2 specific antibody titres in refractory celiac disease.

In most cases celiac disease (CD) is successfully treated with a gluten-free diet (GFD). However, some patients become refractory to the GFD. Refractory CD (RCD) patients have an increased risk for developing enteropathy associated T-cell lymphoma and early diagnosis is therefore of importance. Currently, RCD diagnosis relies on endoscopy and adequate serological markers are lacking. Antibodies against glycoprotein-2 (GP2A) were described in Crohn's disease (CrD) and active CD but not in ulcerative colitis (UC), suggesting this is a specific marker for small intestinal lesions. Sera obtained from patients visiting our outpatient clinic for routine serological tests for diagnosis and/or follow-up of inflammatory bowel disease (n=78), active CD (n=45), GFD (n=34) and RCD (n=15) were analysed for GP2A titres. Increased GP2A-IgA levels in CrD and active CD as compared to controls (p<0.001) and lack thereof in UC was confirmed. However, we could not confirm the association with small bowel localization within the CrD patient group. Within CD patients, we demonstrated a significant decrease of GP2A-IgA titres upon a GFD and increased levels in RCD patients as compared to patients on a GFD. Although GP2A-IgA was not associated with the degree of villous atrophy, GP2A-IgA levels were able to distinguish RCD patients from GFD patients (ROC AUC=0.79, p=0.002). Follow-up of GP2A-IgA titres in CD patients on a GFD may help to identify patients at risk for developing RCD.

PTH-112 A Single Centre Experience Of Treatment Of Refractory Celiac Disease Type 2

IntroductionRefractory celiac disease (RCD) is a persistent malabsorption and villous atrophy despite adhering to a strict gluten-free diet (GFD) for at least 6–12 months in the absence of other cause...