Insight in the diagnosis and treatment of coeliac disease in general practice: A survey and case vignette study among 106 general practitioners.

BACKGROUND: Coeliac disease (CD) is a highly prevalent (∼1%) disease that allegedly remains undiagnosed in over 80% of the cases because of atypical symptoms or silent disease. Currently, it is unknown how GPs deal with (suspected) CD. OBJECTIVES: This study aimed to better understand the diagnostic approach and the clinical reasoning process of GPs concerning CD and concurrently address diagnostic pitfalls. METHODS: A questionnaire with case vignettes to assess the knowledge, diagnostic reasoning pattern and practice for CD by GPs was developed. It was sent through academic GP research networks (encompassing over 1500 GPs) in two large cities and to smaller practices in rural areas. The questionnaire was composed of seven background questions, 13 questions related to four case vignettes and six additional CD-related questions. RESULTS: Responses were received from 106 GPs. Knowledge on risk factors for CD and appropriate testing of at-risk populations was limited. Twenty-two percent would diagnose CD in adults exclusively based on serology, without histopathological confirmation. In total, 99% would refer a newly diagnosed patient to a dietitian to initiate a gluten-free diet (GFD). In the absence of symptoms, only 33% would initiate a GFD. CONCLUSION: The results of this study have given us insight into the diagnostic process of GPs encountering patient with gluten-related complaints. Multiple serology test is available and used, while a positive serology test is not always followed up by a gastroduodenal biopsy to confirm the diagnosis. Most GPs would refer a symptomatic CD patient to a dietician for a GFD.

Safety and efficacy of AMG 714 in patients with type 2 refractory coeliac disease: a phase 2a, randomised, double-blind, placebo-controlled, parallel-group study.

BACKGROUND: Refractory coeliac disease type 2 is a rare subtype of coeliac disease with high mortality rates; interleukin 15 (IL-15) is strongly implicated in its pathophysiology. This trial aimed to investigate the effects of AMG 714, an anti-IL-15 monoclonal antibody, on the activity and symptoms of refractory coeliac disease type 2. METHODS: This was a randomised, double-blind, placebo-controlled, phase 2a study of adults with a confirmed diagnosis of refractory coeliac disease type 2. Patients were randomly assigned at a 2:1 ratio to receive seven intravenous doses over 10 weeks of AMG 714 (8 mg/kg) or matching placebo. Biopsy samples were obtained at baseline and week 12 for cellular analysis and histology. The change in the proportion of aberrant intraepithelial lymphocytes from baseline to week 12 with respect to all intraepithelial lymphocytes was the primary endpoint and was quantified using flow cytometry. Secondary endpoints were the change in aberrant intraepithelial lymphocytes with respect to intestinal epithelial cells; intestinal histological scores (villous height-to-crypt depth ratio; VHCD); intraepithelial lymphocyte counts; Marsh score; and patient-reported symptom measures, including the Bristol stool form scale (BSFS) and gastrointestinal symptom rating scale (GSRS). Main analyses were done in the per-protocol population of patients who received their assigned treatment, provided evaluable biopsy samples, and did not have major protocol deviations; only patients with non-atypical disease were included in the analyses of aberrant intraepithelial lymphocytes, including the primary analysis. Safety was assessed in all patients who received at least one dose of study drug. This study is registered at ClinicalTrials.gov (NCT02633020) and EudraCT (2015-004063-36). FINDINGS: From April 13, 2016, to Jan 19, 2017, 28 patients were enrolled and randomly assigned to AMG 714 (n=19) and placebo (n=9). Six patients were not included in the primary analysis because of protocol deviation (one in the AMG 714 group), insufficient biopsy samples (one in the AMG 714 group), and atypical intraepithelial lymphocytes (three in the AMG 714 group and one in the placebo group). At 12 weeks, the least square mean difference between AMG 714 and placebo in the relative change from baseline in aberrant intraepithelial lymphocyte percentage was -4·85% (90% CI -30·26 to 20·56; p=0·75). The difference between the AMG 714 and placebo groups in aberrant intraepithelial lymphocytes with respect to epithelial cells at 12 weeks was -38·22% (90% CI -95·73 to 19·29; nominal p=0·18); the difference in change in Marsh score from baseline was 0·09% (95% CI -1·60-1·90; nominal p=0·92); the difference in VHCD ratio was 10·67% (95% CI -38·97 to 60·31; nominal p=0·66); and the difference in change in total intraepithelial lymphocyte count was -12·73% (95% CI -77·57-52·12); nominal p=0·69). Regarding symptoms, the proportion of patients with diarrhoea per the BSFS score decreased from ten (53%) of 19 at baseline to seven (37%) of 19 at week 12 in the AMG 714 group and increased from two (22%) of nine at baseline to four (44%) of nine at week 12 in the placebo group (nominal p=0·0008); and the difference between the groups in change in GSRS score was -0·14 (SE 0·19; nominal p=0·48). Eight (89%) patients in the placebo group and 17 (89%) in the AMG 714 group had treatment-emergent adverse events, including one (11%) patient in the placebo group and five (26%) in the AMG 714 group who had serious adverse events. The most common adverse event in the AMG 714 group was nasopharyngitis (eight [42%] patients vs one [11%] in the placebo group). INTERPRETATION: In patients with refractory coeliac disease type 2 who were treated with AMG 714 or placebo for 10 weeks, there was no difference between the groups in terms of the primary endpoint of aberrant intraepithelial lymphocyte reduction from baseline. Effects on symptoms and other endpoints suggest that further research of AMG 714 may be warranted in patients with refractory coeliac disease type 2. FUNDING: Celimmune and Amgen.

Gamma-Delta T Lymphocytes in the Diagnostic Approach of Coeliac Disease.

GOALS: To validate cut-off values of CD3 T-cell receptor gamma-delta chain (TCRγδ) intraepithelial lymphocyte (IEL) in the (differential) diagnosis of celiac disease (CD). BACKGROUND: CD is characterized by an increase in gamma-delta IEL (CD3TCRγδ IEL). STUDY: Percentages were determined by flow cytometric analysis of IELs from small bowel biopsies in 213 CD and 13 potential CD (PCD) patients and in total 112 controls. A cut-off value for percentages of CD3TCRγδ IEL to differentiate active CD and controls was obtained from a receiver operating characteristic curve and implemented in controls and PCD patients. RESULTS: Percentage of CD3TCRγδ IEL was significantly increased in the majority of CD patients, irrespective of the presence of villous atrophy. A cut-off value of 14% for CD3TCRγδ IEL resulted in 66.3% sensitivity and 96.6% specificity for CD diagnosis (area under the curve, 88.6%). CONCLUSIONS: A percentage of ≥14% CD3TCRγδ IEL has a high specificity for CD diagnosis and can be of diagnostic help in cases where diagnosis is not straightforward.

NKp46 is a diagnostic biomarker and may be a therapeutic target in gastrointestinal T-cell lymphoproliferative diseases: a CELAC study.

OBJECTIVES: Primary GI T-cell lymphoproliferative diseases (T-LPD) are heterogeneous entities, which raise difficult diagnosis and therapeutic challenges. We have recently provided evidences that lymphomas complicating coeliac disease (CD) arise from innate-like lymphocytes, which may carry NK receptors (NKRs). DESIGN: NKRs expression was compared by flow cytometry in intraepithelial lymphocytes (IEL) from CD, type I or type II refractory CD (RCD). NKp46 was next assessed by immunohistochemistry in paraffin-embedded biopsies from 204 patients with CD, RCDI, RCDII or GI T-cell lymphomas and from a validation cohort of 61 patients. The cytotoxic properties of an anti-NKp46 monoclonal antibody conjugated to pyrrolobenzodiazepine (PBD) was tested ex vivo in human primary tumour cells isolated from fresh duodenal biopsies. RESULTS: NKp46 (but not CD94, NKG2A, NKG2C, NKG2D) was significantly more expressed by malignant RCDII IEL than by normal IEL in CD and RCDI. In paraffin biopsies, detection of >25 NKp46+ IEL per 100 epithelial cells discriminated RCDII from CD and RCDI. NKp46 was also detected in enteropathy-associated T-cell lymphomas (EATL, 24/29) and in monomorphic epitheliotropic intestinal T-cell lymphomas (MEITL, 4/4) but not in indolent T-LPD (0/15). Treatment with anti-NKp46-PBD could efficiently and selectively kill human NKp46+ primary IEL ex vivo. CONCLUSION: NKp46 is a novel biomarker useful for diagnosis and therapeutic stratification of GI T-LPD. Strong preclinical rationale identifies anti-NKp46-PBD as a promising therapy for RCDII, EATL and MEITL.

Risks for lymphoma and gastrointestinal carcinoma in patients with newly diagnosed adult-onset celiac disease: Consequences for follow-up: Celiac disease, lymphoma and GI carcinoma.

BACKGROUND: The association between celiac disease (CD) and the development of lymphoid and gastrointestinal (GI) malignancies have been reported. However, data are scarce yet needed to develop evidence-based follow-up programs. OBJECTIVE: The objective of this article is to assess relative (RR) and absolute risks of lymphoma and GI carcinoma for newly diagnosed patients. METHODS: A case-control design to determine RR was performed with cases (lymphoma or GI carcinoma) and controls (melanoma or basal cell carcinoma) diagnosed 1994-2014, retrieved from the Dutch nationwide population-based pathology database (PALGA). Within this population, individuals with histologically proven CD before or simultaneously diagnosed with the malignancy were identified. RESULTS: A total of 349/301,425 cases (0.1%) and 282/576,971 (0.05%) controls were diagnosed with CD. Risk of T-cell lymphoma, predominantly enteropathy-associated T-cell lymphoma (EATL), was strongly associated with CD diagnosis (RR = 35.8 (95% CI 27.1-47.4)). Although most often synchronously diagnosed, T-cell lymphoma RR ≥ 1 year after CD diagnosis was still elevated (RR = 12.7 (95% CI 7.6-21.3)). Other CD-associated malignancies were small bowel adenocarcinoma (RR = 11.9 (95% CI 8.2-17.2)) and esophageal squamous cell carcinoma (RR = 3.5 (95% CI 2.1-5.8)). Absolute risks were relatively low. Other types of lymphomas and GI carcinomas were not associated with CD. CONCLUSION: Increased risk for specific malignancies in CD should alert physicians for EATL (both intestinal and extraintestinal) and small bowel adenocarcinoma in patients with CD diagnosed at age ≥ 50 years.

The daily practice of (suspected) coeliac disease management by general practitioners: A qualitative approach.

BACKGROUND: General practitioners (GPs) play a crucial role in diagnosing coeliac disease (CD). However, data on GP management of (suspected) CD patients is sparse. OBJECTIVES: To provide insights into the daily practice of diagnosis, treatment, and follow-up of CD by GPs. METHODS: A qualitative study using topic list-based semi-structured in-depth interviews with Dutch GPs with more than five years' experience carried out between January and March 2017. GPs were purposively sampled. The number of GPs interviewed depended on when data saturation was reached. We applied content analysis to the semi-structured interviews. RESULTS: Seven GPs were interviewed, five of whom were female. Analysis of the interviews resulted in three main themes: 'awareness,' 'diagnostics' and 'management.' Vague gastrointestinal symptoms and diarrhoea were often mentioned as a possible presentation of CD. Antibodies were used in CD diagnosis, although some GPs would start a gluten-free diet as a first diagnostic tool. Some GPs diagnosed CD only based on positive antibodies without referring to secondary care or duodenal biopsy analysis. GPs mentioned no role for primary care physicians in the follow-up of CD and noted the important role of dieticians in CD management. CONCLUSION: The different views of GPs on how to diagnose and monitor CD could be a basis for further research to improve CD detection rate and CD care.

Self-reported oral health and xerostomia in adult patients with celiac disease versus a comparison group.

OBJECTIVES: This study aimed to assess the impact of celiac disease (CD) on oral health and xerostomia. STUDY DESIGN: Members of the Dutch Celiac Society (n = 5522) were invited to complete an online questionnaire based on the Oral Health Impact Profile 14 (OHIP-14) and Xerostomia Inventory (XI). Acquaintances and partners of the CD respondents served as the comparison group. In total, data of 740 patients with CD and 270 comparison participants were evaluated. RESULTS: The median age of the responding patients with CD (55 years) was similar to the median age in the comparison group (53 years). Oral health problems, including aphthous stomatitis, painful mouth, and gingival problems, were more frequently reported by patients with CD. Mean OHIP-14 score (4.9 vs 2.6; P < .001) and the mean XI score (22.2 vs 17.2; P < .001) were higher in the CD group than in the comparison group. No significant effects of gender, age at CD diagnosis, or time on a gluten-free diet in mean OHIP-14 and XI scores were observed. CONCLUSIONS: This study showed that oral health problems are more commonly experienced in adult patients with CD than in the comparison group. Collaboration between dentists and gastroenterologists is recommended to increase detection of undiagnosed CD.

Splenic volume differentiates complicated and non-complicated celiac disease.

BACKGROUND: Studies in small groups of patients indicated that splenic volume (SV) may be decreased in patients with celiac disease (CD), refractory CD (RCD) type II and enteropathy-associated T-cell lymphoma (EATL). OBJECTIVE: The objective of this article is to evaluate SV in a large cohort of uncomplicated CD, RCD II and EATL patients and healthy controls. METHODS: The retrospective cohort consisted of 77 uncomplicated CD (of whom 39 in remission), 29 RCD II, 24 EATL and 12 patients with both RCD II and EATL. The control group included 149 healthy living kidney donors. SV was determined on computed tomography. RESULTS: The median SV in the uncomplicated CD group was significantly larger than in controls (202 cm3 (interquartile range (IQR): 154-275) versus 183 cm3 (IQR: 140-232), p = 0.02). After correction for body surface area, age and gender, the ratio of SV in uncomplicated CD versus controls was 1.28 (95% confidence interval: 1.20-1.36; p < 0.001). The median SV in RCD II patients (118 cm3 (IQR 83-181)) was smaller than the median SV in the control group (p < 0.001). CONCLUSION: This study demonstrates large inter-individual variation in SV. SV is enlarged in uncomplicated CD. The small SV in RCD II may be of clinical relevance considering the immune-compromised status of these patients.

CD4 T-cell cytokines synergize to induce proliferation of malignant and nonmalignant innate intraepithelial lymphocytes.

Refractory celiac disease type II (RCDII) is a severe complication of celiac disease (CD) characterized by the presence of an enlarged clonal population of innate intraepithelial lymphocytes (IELs) lacking classical B-, T-, and natural killer (NK)-cell lineage markers (Lin-IELs) in the duodenum. In ∼50% of patients with RCDII, these Lin-IELs develop into a lymphoma for which no effective treatment is available. Current evidence indicates that the survival and expansion of these malignant Lin-IELs is driven by epithelial cell-derived IL-15. Like CD, RCDII is strongly associated with HLA-DQ2, suggesting the involvement of HLA-DQ2-restricted gluten-specific CD4+ T cells. We now show that gluten-specific CD4+ T cells isolated from CD duodenal biopsy specimens produce cytokines able to trigger proliferation of malignant Lin-IEL lines as powerfully as IL-15. Furthermore, we identify TNF, IL-2, and IL-21 as CD4+ T-cell cytokines that synergistically mediate this effect. Like IL-15, these cytokines were found to increase the phosphorylation of STAT5 and Akt and transcription of antiapoptotic mediator bcl-xL Several small-molecule inhibitors targeting the JAK/STAT pathway blocked proliferation elicited by IL-2 and IL-15, but only an inhibitor targeting the PI3K/Akt/mTOR pathway blocked proliferation induced by IL-15 as well as the CD4+ T-cell cytokines. Confirming and extending these findings, TNF, IL-2, and IL-21 also synergistically triggered the proliferation of freshly isolated Lin-IELs and CD3-CD56+ IELs (NK-IELs) from RCDII as well as non-RCDII duodenal biopsy specimens. These data provide evidence implicating CD4+ T-cell cytokines in the pathogenesis of RCDII. More broadly, they suggest that adaptive immune responses can contribute to innate IEL activation during mucosal inflammation.

Celiac Disease in The Netherlands: Demographic Data of Members of the Dutch Celiac Society.

BACKGROUND AND AIMS: Celiac disease is an autoimmune disease induced by the intake of gluten with a female to male ratio of 2-4:1. Female predominance has not been recognized in serological mass screening studies. Limited data are available on gender and age distribution in the daily clinical practice of celiac disease. The aim of this study is to describe differences in gender and age at the time of celiac disease diagnosis in the Netherlands. METHODS: Data was obtained from a prospectively maintained database of members of the Dutch Celiac Society in whom celiac disease was diagnosed between 1980 and August 2015. DESIGN: retrospective database study; Setting: database of members of the Dutch Celiac Society; Participants: out of the total number of 26,986 current and ex-members, the data of 7,886 members could be used for analysis. RESULTS: Age at celiac disease diagnosis ranged between 0 and 88 years; the minority (36%) were diagnosed in childhood. In children, the majority (52%) were diagnosed before the age of 4 years. Median age did not differ in children when compared for gender (3 years). In adults, median age differed between males (52 years, IQR 41-61) and females (44 years, IQR 32-56), p<0.001. Female to male ratio was 2.4:1. CONCLUSION: The majority of celiac disease patients are diagnosed during adulthood, with males diagnosed at an older age. Only one-third of the patients were diagnosed at childhood. Celiac disease is less frequently diagnosed in young adult males.

Prevalence and Characterization of Self-Reported Gluten Sensitivity in The Netherlands.

BACKGROUND: A growing number of individuals reports symptoms related to the ingestion of gluten-containing food in the absence of celiac disease. Yet the actual prevalence is not well established. METHODS: Between April 2015 and March 2016, unselected adults visiting marketplaces, dental practices and a university in The Netherlands were asked to complete a modified validated questionnaire for self-reported gluten sensitivity (srGS). RESULTS: Among the 785 adults enquired, two had celiac disease. Forty-nine (6.2%) reported symptoms related to the ingestion of gluten-containing food. These individuals were younger, predominantly female and lived more frequently in urban regions compared with the other respondents. Symptoms reported included bloating (74%), abdominal discomfort (49%) and flatulence (47%). A total of 23 (47%) srGS individuals reported having had tried a gluten-free or gluten-restricted diet. Abdominal discomfort related to fermentable oligosaccharide, disaccharide, monosaccharide and polyol (FODMAP)-containing food was more often reported in srGS individuals compared with the other respondents (73.5% vs. 21.7%, p < 0.001). CONCLUSION: Self-reported GS is common in The Netherlands, especially in younger individuals, females and urban regions, although the prevalence was lower than in a comparable recent UK study. It cannot be excluded that FODMAPs are in part responsible for these symptoms.

Serendipity in Refractory Celiac Disease: Full Recovery of Duodenal Villi and Clinical Symptoms after Fecal Microbiota Transfer.

Treatment of refractory celiac disease type II (RCD II) and preventing the development of an enteropathy associated T-cell lymphoma in these patients is still difficult. In this case report, we describe a patient with RCD II who received fecal microbiota transfer as treatment for a recurrent Clostridium difficile infection, and remarkably showed a full recovery of duodenal villi and disappearance of celiac symptoms. This case suggests that altering the gut microbiota may hold promise in improving the clinical and histological consequences of celiac disease and/or RCD II.

The first cases of collagenous sprue successfully treated with thioguanine.

OBJECTIVE: Collagenous sprue (CS) is a rare form of small bowel enteropathy characterised by a thickened basement membrane and is, in most of the literature, reported as part of coeliac disease. Multiple treatment strategies are suggested in CS, but there is no standardised therapy. The aim of this series is to describe 4 cases of CS and to propose thioguanine (6-TG) treatment. DESIGN: We reviewed 4 cases of CS. Data were obtained from our prospective database of patients referred to our coeliac centre. Evaluation of small bowel biopsies was performed by an expert pathologist. RESULTS: None of the patients had ever had coeliac-specific antibodies, and all were negative for HLA-DQ2 and HLA-DQ8 phenotype. Three patients were treated with a combination of 6-TG and budesonide, and 1 patient received 6-TG only. All patients improved remarkably. Normalisation of the thickened basement membrane was found in 2 patients and complete histological improvement including full recovery of villi was found in 1 patient. In the third patient, the thickened basement membrane was only very focally recognised. The thickened membrane persisted in the last patient, probably because of the short time of follow-up. CONCLUSIONS: CS should be separated from coeliac disease. Based on the lack of typical HLA phenotyping and the absence of coeliac-specific antibodies, there seems to be no relation with coeliac disease in these 4 cases. A promising treatment option might be 6-TG with or without budesonide. Research in a larger cohort is needed to standardise treatment for CS.

Mechanisms and management of refractory coeliac disease.

A small subset of patients with coeliac disease become refractory to a gluten-free diet with persistent malabsorption and intestinal villous atrophy. The most common cause of this condition is inadvertent gluten exposure, but concomitant diseases leading to villous atrophy should also be considered and excluded. After exclusion of these conditions, patients are referred to as having refractory coeliac disease, of which two categories are recognized based on the absence (type I) or presence (type II) of a clonal expansion of premalignant intraepithelial lymphocyte population with a high potential for transformation into an overt enteropathy-associated T-cell lymphoma. Type I disease usually has a benign course that can be controlled by mild immunosuppressive treatment, but type II can be more severe with cladribine with or without autologous stem cell transplantation effective as treatment. Patients who fail to respond to cladribine therapy, however, still have a high risk of malignant transformation. Insights into the immunophenotype of these cells and the recognition that type II disease is a low-grade, no-mass lymphoma opens avenues for new treatment strategies, including chemotherapeutic and immunomodulating strategies. This Review will provide an overview of refractory coeliac disease, discussing mechanisms, diagnosis and management.