Guidelines for best practices in monitoring established coeliac disease in adult patients.

Coeliac disease (CeD) is an immunological disease triggered by the consumption of gluten contained in food in individuals with a genetic predisposition. Diagnosis is based on the presence of small bowel mucosal atrophy and circulating autoantibodies (anti-type 2 transglutaminase antibodies). After diagnosis, patients follow a strict, life-long gluten-free diet. Although the criteria for diagnosis of this disease are well defined, the monitoring phase has been studied less and there is a lack of specific guidelines for this phase. To develop a set of clinical guidelines for CeD monitoring, we followed the Grading of Recommendations Assessment, Development and Evaluation methodology. Statements and recommendations with the level of evidence were developed and approved by the working group, which comprised gastroenterologists, pathologists, dieticians and biostatisticians. The proposed guidelines, endorsed by the North American and European coeliac disease scientific societies, make recommendations for best practices in monitoring patients with CeD based on the available evidence. The evidence level is low for many topics, suggesting that further research in specific aspects of CeD would be valuable. In conclusion, the present guidelines support clinicians in improving CeD treatment and follow-up and highlight novel issues that should be considered in future studies.

Dual X-ray absorptiometry-derived bone status indexes and videocapsule intestinal aspects in celiac disease.

BACKGROUND AND AIM: Celiac disease is a risk factor for osteopenia and osteoporosis. Our aim was to evaluate the possible correlation between villous atrophy extension and dual-energy X-ray absorptiometry (DXA)-derived parameters of bone status. METHODS: We have retrospectively analyzed data of 47 celiac patients (36 women, 52 ± 14 years of age) who underwent video capsule endoscopy and DXA scans within 1 year of interval from 2006 to 2019. Quantitative, qualitative and geometric DXA parameters were collected only from the most recent DXA measurements. RESULTS: . Patients were divided into three categories; the first included those with no lesions at video capsule endoscopy (23 patients), the second those with typical lesions (mucosal atrophy, mosaicism and scalloping) in less than one-third of the small bowel (SB) (16 patients) and the third those with typical lesions in more than one-third of the SB (7 patients). In the third group, bone mineral density seemed to be lower in both the lumbar spine and the hip ( P = 0.026 and P = 0.011, respectively). The deterioration of bone structure in patients with severe and extended SB atrophy was statistically significant ( P = 0.032). Furthermore, bone density, structure and geometry did not correlate with the duration of the gluten-free diet. Notably, autoimmune comorbidities did not affect DXA results. CONCLUSION: Neither endoscopic nor histological atrophy itself can explain the deterioration of bone mineralization and structure, whereas atrophy extension appeared to be responsible for bone impairment.

Mesenchymal stromal cells loaded with Paclitaxel (PacliMES) a potential new therapeutic approach on mesothelioma.

Malignant pleural mesothelioma is an asbestos-related tumor originating in mesothelial cells of the pleura that poorly responds to chemotherapeutic approaches. Adult mesenchymal stromal cells derived either from bone marrow or from adipose tissue may be considered a good model for cell-based therapy, a treatment which has experienced significant interest in recent years. The present study confirms that Paclitaxel is effective on mesothelioma cell proliferation in 2D and 3D in vitro cultures, and that 80,000 mesenchymal stromal cells loaded with Paclitaxel inhibit tumor growth at a higher extent than Paclitaxel alone. An in vivo approach to treat in situ mesothelioma xenografts using a minimal amount of 106 mesenchymal stromal cells loaded with Paclitaxel showed the same efficacy of a systemic administration of 10 mg/kg of Paclitaxel. These data strongly support drug delivery system by mesenchymal stromal cells as a useful approach against many solid tumors. We look with interest at the favourable opinion recently expressed by the Italian Drug Agency on the procedure for the preparation of mesenchymal stromal cells loaded with Paclitaxel in large-scale bioreactor systems and their storage until clinical use. This new Advanced Medicinal Therapy Product, already approved for a Phase I clinical trial on mesothelioma patients, could pave the way for mesenchymal stromal cells use as drug delivery system on other solid tumors for adjuvant therapy associated with surgery and radiotherapy.

Heavy Metal and Rice in Gluten-Free Diets: Are They a Risk?

A gluten-free diet (GFD) is the treatment of choice for gluten-related disorders. It has been associated with macro- and micronutrient deficiencies. Recently, consumption of arsenic-contaminated rice has raised concern because of the potential greater risk that it may represent for people on GFDs, whose rice consumption is high, since it is a fundamental cereal in GFDs. We reviewed the data published over the last 20 years in Medline and Scielo, in English, French and Spanish, on four metals (As, Hg, Cd, and Pb), to assess whether the evidence suggests that celiac disease or consumption of a GFD is associated with increased levels of blood/urinary metal concentrations. The review revealed a few articles that were directly related to the four metals and their relationships with a GFD. The evidence supports that rice-based products are a relevant source of As and other metals. Clinical studies and evaluations based on NHANES have indicated that persons on GFDs have higher As and Hg blood/urinary levels, suggesting that the diet and not the disease is responsible for it. The levels described are statistically significant compared to those of persons on complete diets, but far from toxic levels. The question of whether higher exposure to heavy metals associated with a GFD is biologically relevant remains unanswered and deserves study.

Evaluation of a Single Determination of Gluten Immunogenic Peptides in Urine from Unaware Celiac Patients to Monitor Gluten-Free Diet Adherence.

INTRODUCTION AND AIM: Usually, adherence to the gluten-free diet (GFD) in celiac patients is indirectly assessed through serological analysis, questionnaires, or invasive methods such as intestinal biopsy. The detection of gluten immunogenic peptides in urine (urinary gluten immunogenic peptides-uGIP) is a novel technique that directly evaluates the ingestion of gluten. The aim of this study was to evaluate the clinical efficacy of uGIP in the follow-up of celiac disease (CD). METHODS: From April 2019 to February 2020, CD patients reporting complete adherence to the GFD were prospectively enrolled but were unaware of the reason for the tests. Urinary GIP, the celiac dietary adherence test (CDAT), symptomatic visual analog scales (VAS), and tissue transglutaminase antibodies (tTGA) titres were evaluated. Duodenal histology and capsule endoscopy (CE) were performed when indicated. RESULTS: A total of 280 patients were enrolled. Thirty-two (11.4%) had a positive uGIP test (uGIP+). uGIP+ patients did not show significant differences in demographic parameters, CDAT, or VAS scores. The tTGA+ titre was not related to the positivity of uGIP (14.4% vs. 10.9% in patients with tTGA+ and tTGA-). Regarding histology, 66.7% of the GIP+ patients had atrophy compared to 32.7% of the GIP patients (p-value 0.01). However, the presence of atrophy did not correlate with tTGA. Mucosal atrophy was detected in 29 (47.5%) out of 61 patients by CE. With this method, no noticeable dependence on uGIP results (24 GIP- vs. 5 GIP+) was observed. CONCLUSIONS: The single uGIP test was positive in 11% of CD cases referring a correct GFD adherence. Furthermore, uGIP results significantly correlated with the duodenal biopsy, formerly considered the gold standard for assessing CD activity.

Clinical features of type 1 and 2 refractory celiac disease: Results from a large cohort over a decade.

OBJECTIVES: Refractory celiac disease (RCeD) is a rare complication of celiac disease (CeD) with a severe prognosis. We describe a cohort of patients with RCeD, their clinical and histological features at diagnosis, after therapy and at lymphoma onset, and the rate and causes of death over a 17-year follow-up. METHODS: We retrospectively enrolled RCeD-I and RCeD-II patients attending our center between January 2002 and October 2019. Medical data were collected at diagnosis and during monitoring. Response to therapy, changes in RCeD molecular markers, number of hospitalizations, discharge diagnosis, and cause and date of death were evaluated. The control cohort consisted of 1015 responsive CeD patients. RESULTS: Compared with RCeD-I, RCeD-II more frequently exhibits diarrhea (83 vs 64%), anemia (61 vs 50%), hypoalbuminemia (70 vs 21%), parenteral nutrition need (48 vs 7%), ulcerative jejuno-ileitis (7 vs 39%), and extended small intestinal atrophy (62 vs 21%). One RCeD-I and six RCeD-II patients developed lymphoma. Ten RCeD-II patients died, four from lymphoma progression. Among RCeD-II patients, atrophy extension was the only parameter correlated with hypoalbuminemia and mortality. CONCLUSIONS: Clinical severity, response to therapy, and mortality differ between RCeD-I and RCeD-II. Atrophy extension, evaluated at capsule endoscopy, was associated with disease severity and mortality.

Diagnostic management of patients reporting symptoms after wheat ingestion.

Many patients report symptoms after wheat ingestion experiencing a wide spectrum of clinical manifestations. Three possible diagnoses have been recognized: celiac disease (CD), wheat allergy (WA), and non-celiac (gluten) wheat sensitivity (NCGS/NCWS). CD is a chronic immune-mediated disease of the small bowel caused by exposure to dietary gluten in genetically predisposed individuals, with a prevalence of approximately 1%. It is characterized by mucosal inflammation and atrophy following exposure to gluten and improvement after gluten withdrawal. Food allergies are immunological responses to a food antigen. WA is the expression of an immunologically mediated process that can be immunoglobulin E (IgE) or non-IgE mediated; its many symptoms include urticaria/angioedema, asthma, rhinitis, and anaphylaxis. NCGS/NCWS is characterized by gastrointestinal and/or extra-intestinal symptoms after ingestion of gluten-containing food in subjects not affected by CD or WA. The aim of this review is to help physicians and nutritionists diagnose the cause of symptoms reported after wheat ingestion, thus avoiding patient frustration, inappropriate testing, and incorrect or missed diagnoses. An algorithm for the diagnostic approach in these patients is provided, to help to diagnose CD, WA, NCGS/NCWS or to identify possible functional disorders as the wheat-sensitive irritable bowel syndrome. A personalized approach, regular follow-up, and the help of a skilled healthcare professional are mandatory for patients with symptoms following wheat ingestion is provided. A gluten-free-diet is often recommended for patients with self-reported gluten/wheat-dependent symptoms; for patients with symptoms similar to those of functional diseases while there is evidence that a low-FODMAP diet could be the first option.

Vaccination Status and Attitudes towards Vaccines in a Cohort of Patients with Celiac Disease.

(1) Background: The identification of vaccination status and attitudes towards vaccines among celiac disease (CD) patients is of great importance, but it has not yet been investigated. The aim of this study was to investigate coverage against vaccine-preventable diseases (VPDs), attitudes towards vaccinations, and its determinants among CD patients. (2) Methods: An anonymous web-based validated questionnaire was sent to a mailing list of CD adult patients. Patients were asked to self-report their previous vaccinations and attitudes towards vaccinations, which were defined as positive, negative, and partially positive/negative. The influencing factors towards vaccinations were investigated, and crude and adjusted odds ratios (AdjORs) with 95% confidence intervals (CIs) were calculated. (3) Results: The questionnaire was sent to 412 patients, with a response rate of 31.6% (130 patients, 105 women, median age 40 years, interquartile range 36-51). Patients self-reported vaccination against the following diseases: 73.8% tetanus, 42.3% flu, 20% measles, mumps and rubella, 19.2% meningitis, and 16.2% pneumococcus. Thirty-two people (24.6%) did not remember all of their previous vaccinations. In total, 104 (80%) respondents had a positive attitude towards vaccines, 25 (19.2%) a partially positive/negative one, and 1 a negative one. The determinants significantly influencing the positive attitude were being a graduate (AdjORs 7.49) and a belief in the possible return of VPDs with declining vaccination coverage rates (AdjORs 7.42), while the use of complementary and alternative medicines (AdjORs 0.11) and past negative experience (AdjORs 0.16) were associated with a negative attitude. (4) Conclusions: Despite four out of five CD patients showing a strong positive attitude towards vaccinations, one out of five had a partially negative one. Only a minority (16-20%) reported being vaccinated against some VPDs potentially harmful to their CD because of hyposplenism, such as meningitis and pneumococcus. The low vaccination rate against some VPDs, in spite of the 80% of CD patients stating a positive attitude towards vaccination, may be explained in part by patients' vaccine hesitancy and in part by a possible role of physicians in under-prescribing vaccinations to these patients. These results may be a starting point for developing specific vaccination campaigns to increase vaccination rates against VPDs in CD patients.

Circulating microRNAs Suggest Networks Associated with Biological Functions in Aggressive Refractory Type 2 Celiac Disease.

Despite following a gluten-free diet, which is currently the only effective therapy for celiac disease, about 5% of patients can develop serious complications, which in the case of refractory type 2 could evolve towards intestinal lymphoma. In this study, we have identified a set of 15 microRNAs in serum discriminating between the two types of refractory disease. Upregulated miR-770-5p, miR-181b-2-3p, miR-1193, and miR-1226-3p could be useful for the better stratification of patients and the monitoring of disease development, while miR-490-3p was found to be dysregulated in patients with refractory type 1. Finally, by using bioinformatic tools applied to the analysis of the targets of dysregulated microRNAs, we have completed a more precise assessment of their functions. These mainly include the pathway of response to Transforming Growth Factor ß cell-cell signaling by Wnt; epigenetic regulation, especially novel networks associated with transcriptional and post-transcriptional alterations; and the well-known inflammatory profiles.

Nutrition in Patients with Inflammatory Bowel Diseases: A Narrative Review.

Inflammatory bowel diseases (IBD) affect the gastrointestinal tract: they include Crohn's disease (CD) and ulcerative colitis (UC). Each has a different phenotypic spectrum, characterized by gastrointestinal and extra-intestinal manifestations. People living with IBD are very interested in diet, but little is known about the impact of diet on these patients; no guidelines are available yet. In this review, we analyze the dietary patterns of patients with IBD and the approach to the choices of foods both in adults and pediatric patients. Very often, IBD patients report an intentional avoidance of gluten to manage the disease; furthermore, a proportion of IBD patients believe that dairy products worsen their symptoms and that avoidance may help the disease. They have a low compliance with the Mediterranean Diet, which is considered to have potential benefits but is little used in practice. In conclusion, the review underscores the pivotal role of nutritional counselling in IBD patients, and the importance of future clinical studies to evaluate the beneficial effects of dietary recommendations in the management of IBD.

Anti-SARS-CoV-2 immunoglobulin profile in patients with celiac disease living in a high incidence area.

BACKGROUND AND AIM: How symptoms and antibodies related to SARS-CoV-2 infection develop in patients with celiac disease (CD) is unclear. We aimed to investigate the impact of SARS-CoV-2 infection in CD patients. METHODS: CD patients were interviewed about the development of COVID-19 symptoms, compliance with anti-virus measures and adherence to a gluten-free diet (GFD). The presence of anti-SARS-CoV-2 IgG and IgA (anti-RBD and N proteins) was compared to that in non-CD subjects. Expression of the duodenal ACE2 receptor was investigated. When available, data on duodenal histology, anti-tissue transglutaminase IgA (tTGA), comorbidities and GFD adherence were analyzed. RESULTS: Of 362 CD patients, 42 (12%) reported COVID-19 symptoms and 21% of these symptomatic patients presented anti-SARS-CoV-2 Ig. Overall, 18% of CD patients showed anti-SARS-CoV-2 Ig versus 25% of controls (p = 0.18). CD patients had significantly lower levels of anti-N IgA. tTGA, duodenal atrophy, GFD adherence or other comorbidities did not influence symptoms and/or antibodies. The ACE2 receptor was detected in the non-atrophic duodenal mucosa of patients; atrophy was associated with lower expression of the ACE2 receptor. CONCLUSION: CD patients have an anti-SARS-CoV-2 Ig profile similar to non-celiac controls, except for anti-N IgA. No risk factors were identified among CD parameters and GFD adherence.

Effectiveness of Capsule Endoscopy and Double-Balloon Enteroscopy in Suspected Complicated Celiac Disease.

BACKGROUND & AIMS: Complicated celiac disease (CCD) is a rare but severe condition with a poor prognosis. Guidelines recommend use of capsule endoscopy (CE) to explore the small bowel (SB), followed by a double-balloon enteroscopy (DBE) in selected cases with suspected CCD. Our study aimed to evaluate the diagnostic yield (DY) of CE and DBE in identifying and monitoring CCD. METHODS: Consecutive suspected CCD patients were enrolled prospectively to undergo CE and/or DBE in the presence of: persistent symptoms despite a correct gluten-free diet (GFD), increased anti-transglutaminase antibodies titer, lack of adherence to the GFD, and CCD monitoring. The DY of CE and DBE were calculated. The incidence of neoplastic complications and mortality were assessed. RESULTS: In total, 130 patients (97 women; age, 49 ± 16 y) underwent 151 CEs and 23 DBEs. The DY of CE was 46%. Patients older than age 50 years (at CE examination or at CD diagnosis) with a CD duration shorter than 5 years were at higher risk of positive CE (relative risk, 1.6 and 1.7 in case of enrollement or CD diagnosis after 50 years of age, and 1.5 in case of short CD duration; P < .05) than their counterparts. Up to 40% of SB lesions were unreachable by upper endoscopy. At the end of the diagnostic work-up, 25 patients with premalignant/malignant lesions were identified: 12 type 1 refractory CD (RCD-1), 7 type 2 RCD (RCD-2), and 6 enteropathy-associated T-cell lymphoma (EATL). Six patients died: 2 patients with RCD-2 and 4 patients with EATL. CONCLUSIONS: In case of suspected CCD, CE should be the first-line approach to detect complications and to identify patients deserving DBE. Older and symptomatic patients with suspected CCD deserve a careful evaluation of the SB, especially during the first years after diagnosis.

Clinical Value of Tissue Transglutaminase Antibodies in Celiac Patients over a Long Term Follow-Up.

INTRODUCTION & AIM: Anti-tissue transglutaminase antibody (tTGA) titer is used during the follow-up of celiac patients to evaluate gluten-free diet (GFD) responsiveness. However, no clear data are available on this issue. The aim of this study was to evaluate tTGA significance during celiac disease (CD) monitoring. METHODS: From January 2017 to January 2020, consecutive CD patients on a GFD with persistent positive tTGA were enrolled. Antibody titres were evaluated on a yearly basis from CD diagnosis to the last follow-up. Urinary gluten detection tests, duodenal histology and capsule enteroscopy (CE) were performed. A tTGA-positive cohort was compared with a control group composed of 212 treated CD patients with negative tTGA. RESULTS: 65 patients (12% males, median age at enrollment and CD diagnosis, 37 (14-86) and 31 (1-76), respectively, median follow up 4 (1-26) years) presented with positive tTGA during follow-up. Overall, the tTGA titres were 3 (1-79) fold increased (ULN). Three different tTGA trends were recognized: (I) 36 (55%) patients with a progressive titres decrease; (II) 16 (25%) patients with a fluctuating behavior; (III) 13 (20%) patients with a steady state or increased titres. tTGA+ patients did not present with different clinical and demographic parameters. Duodenal atrophy was present in 10% vs. 36% of the tTGA positive vs. negative group (p < 0.005), respectively. Gluten detection results were positive in 3 (8%) cases, all in the III group. In tTGA+ patients, CE did not identify any CD-related complications. CONCLUSIONS: tTGA positivity during CD follow up did not present a relevant clinical significance without association with autoimmune comorbidities and mucosal damage.

COVID-19 Vaccine: A Survey of Hesitancy in Patients with Celiac Disease.

(1) Background: COVID-19 vaccination campaigns offer the best hope of controlling the pandemic. However, the fast production of COVID-19 vaccines has caused concern among the general public regarding their safety and efficacy. In particular, patients with chronic illnesses, such as celiac disease (CD), may be more fearful. Information on vaccine hesitancy plays a pivotal role in the development of an efficient vaccination campaign. In our study, we aimed to evaluate COVID-19 vaccine hesitancy among Italian CD patients. (2) Methods: an anonymous questionnaire was sent to CD patients followed at our tertiary referral center for CD in Milan, Italy. Patients were defined as willing, hesitant and refusing. We evaluated the reasons for hesitancy/refusal and the possible determinants, calculating crude and adjusted odds ratios [AdjORs] with 95% confidence intervals [CIs]. (3) Results: the questionnaire was sent to 346 patients with a response rate of 29.8%. Twenty-six (25.2%) of the 103 respondents were hesitant, with a total refusal rate of 4.8%. The main reason was fear of adverse events related to vaccination (68.2%). Among hesitant patients, 23% declared that their opinion was influenced by their CD. The determinants positively influencing willingness to be vaccinated against COVID-19 were adherence to a GFD, perception of good knowledge about COVID-19 and its vaccines, and a positive attitude to previous vaccines (AdjOR 12.71, 95% CI 1.82-88.58, AdjOR 6.50, 95% CI 1.44-29.22, AdjOR 0.70, 95% CI 0.11-4.34, respectively). (4) Conclusions: CD patients should be vaccinated against COVID-19 and a specific campaign to address the determinants of hesitancy should be developed.

Nutritional and Gastroenterological Monitoring of Patients With Celiac Disease During COVID-19 Pandemic: The Emerging Role of Telemedicine and Point-of-Care Gluten Detection Tests.

Background and Aims: Since the beginning of the coronavirus disease 2019 (COVID-19) pandemic, telemedicine has been supporting many patients with chronic diseases worldwide. However, data on celiac disease (CeD) nutritional and gastroenterological remote monitoring are scanty. The aims of our study were to verify patients' trust in telemedicine and to evaluate the feasibility of telemedicine in nutritional monitoring. Material and Methods: We used telemedicine in place of the scheduled but not provided follow-up visits during the first lockdown of the COVID-19 pandemic. Patients received a phone call, and televisits were conducted for CeD patients with mild or moderate symptoms and/or with blood alterations. The patient's adherence to the gluten-free diet (GFD) was evaluated according to the Celiac Dietary Adherence Test (CDAT). When gluten contamination was suspected, a point-of-care gluten detection test was prescribed. The patient's trust in telemedicine was assessed, through an adapted version of the Patient Trust Assessment Tool (PATAT) questionnaire, as the percentage of patients giving a score of at least 4 out of 5 on a Likert scale for three selected key statements: "I can trust televisit," "I can trust that possible problems with the telemedicine service will be solved properly," and "I feel at ease when working with this website." Results: One hundred and twelve CeD patients were phone called; among symptomatic patients, 39 out of the 42 scheduled (92.9%) televisits were performed. Among the 39 visits, 34 (87.2%) questionnaires were compiled. The patients included in the study obtained a CDAT score from 7 to 13 (11 ± 2). Gluten detection tests were prescribed to 11 patients, resulting positive in 2. Trust in the telemedicine service was achieved in 94.1, 88.2, and 97.1% for the three selected key statements of the PATAT questionnaire. Conclusion: During the COVID-19 pandemic, telemedicine showed to be feasible and the majority of patients trusted the combined gastroenterological and nutritional televisits. Gluten detection tests demonstrated to be useful tools for the patient and for the caregiver to confirm adherence to the GFD remotely.

Mediterranean Gluten-Free Diet: Is It a Fair Bet for the Treatment of Gluten-Related Disorders?

Gluten-free diet (GFD) is the current treatment of gluten-related disorders. It eliminates wheat, barley, and rye, while the exclusion of oats is still under debate. GFD is based on a combination of naturally gluten-free foods and gluten-free substitutes of cereal-based foods. Although effective as treatment of gluten-related disorders, today there is concern about how to improve GFD's nutritional quality, to make it not only gluten-free, but also healthy. The "Mediterranean diet" (MedD) refers to the dietary pattern and eating habits typical of populations living in the Mediterranean basin, which have been associated with low prevalence of several diet-related pathologies. Here we present a narrative review of the current knowledge about GFD and MedD, their characteristics and central food components. Based on the Mediterranean diet pyramid developed by the Italian pediatric society, we propose a combination between the MedD and the GFD, an attractive alternative to reach a gluten-free state that at the same time is healthy, with a clear benefit to those who practice it.

How to manage celiac disease and gluten-free diet during the COVID-19 era: proposals from a tertiary referral center in a high-incidence scenario.

The outbreak of COVID-19 and SARS-CoV-2 infection is spreading worldwide as the first coronavirus pandemic. The clinical picture is variable but flu-like symptoms are common with bilateral interstitial pneumonia being the most frightening presentation. No specific therapies nor vaccine have been developed to date and the only way to limit the virus diffusion is by modifying one's lifestyle limiting social life and following strict hygienic precautions. No data is available on the risk of COVID-19 and its outcomes in celiac disease (CeD). The restrictions applied to counter COVID-19 can impact on CeD treatment and gluten-free dieting, the only available therapy for CeD. With the present manuscript, we aim to support gastroenterologists and nutritionists in the management of CeD patients in the new pandemic scenario, being conscious that availability and local situations are extremely various.