Efficacy of Antiobesity Medications in Patients With Celiac Disease on a Gluten-free Diet: A Retrospective Matched Cohort Study.

GOALS: We aim to describe the weight loss outcomes of patients with celiac disease (CeD) taking antiobesity medications (AOMs) and compare it with the weight loss outcomes of patients without CeD taking AOMs. BACKGROUND: Increasing rates of obesity and obesity-associated comorbidities have been previously reported in patients with CeD on a gluten-free diet. The effectiveness of AOMs in this population has not been previously described. METHODS: In our retrospective cohort study, we matched 39 patients with treated CeD to 78 patients without CeD based on sex and AOM. We assessed the weight loss outcomes at 3, 6, and 12 months after starting the AOM in both cohorts and analyzed if there was a differential response when comparing by type of AOM [injectable glucagon-like peptide 1 (GLP-1) receptor agonists vs. oral non-GLP-1 AOMs]. RESULTS: Both cohorts had similar baseline demographic and anthropometric characteristics. At 12 months, the CeD cohort had a nonsignificantly inferior total body weight loss percentage compared with the cohort without CeD (6.5% vs. 9.5%, P=0.13). The CeD cohort had a similar proportion of patients achieving a total body weight loss percentage of ≥5% than the cohort without CeD (72.7% vs. 72.1%, P=1.00). No significant difference was observed when comparing the weight loss outcomes of injectables (GLP-1 receptor agonists) to oral AOMs. The proportion of patients reporting side effects was similar for both groups, regardless of the type of AOM. CONCLUSION: Patients with CeD taking AOMs had similar weight loss outcomes to patients without CeD. Hence, AOMs can be a safe and effective therapy for weight management in patients with CeD.

Susceptibility of nucleotide-binding oligomerization domain 2 mutations to Whipple's disease.

OBJECTIVES: Whipple's disease (WD) results from infection of the bacteria Tropheryma whipplei (TW). This disease is characterized by macrophage infiltration of intestinal mucosa and primarily affects Caucasian males. Genetic studies of host susceptibility are scarce. Nucleotide-binding oligomerization domain containing protein 2 (NOD2) is an innate immune sensor, resides mainly in monocytes/macrophages and contributes to defense against infection and inflammatory regulation. NOD2 mutations are associated with autoinflammatory diseases. We report the association of NOD2 mutations with TW and WD for the first time. METHODS: A multicenter, retrospective study of three patients with WD was conducted. Patients received extensive multidisciplinary evaluations and were cared for by the authors. NOD2 and its association with infection and inflammation were schematically represented. RESULTS: All patients were Caucasian men and presented with years of autoinflammatory phenotypes, including recurrent fever, rash, inflammatory arthritis, gastrointestinal symptoms, and elevated inflammatory markers. All patients underwent molecular testing using a gene panel for periodic fever syndromes and were identified to carry NOD2 mutations associated with NOD2-associated autoinflammatory disease. Despite initially negative gastrointestinal evaluations, repeat endoscopy with duodenal tissue biopsy ultimately confirmed WD. After initial ceftriaxone and maintenance with doxycycline and/or hydroxychloroquine, symptoms were largely controlled, though mild relapses occurred in follow up. CONCLUSION: Both NOD2 and TW/WD are intensively involved in monocytes/macrophages. WD is regarded as a macrophage disease. NOD2 leucin rich repeat-associated mutations in monocytes/macrophages cause functional impairment of these cells and consequently may make the host susceptible for TW infection and WD, especially in the setting of immunosuppression.

Latiglutenase Protects the Mucosa and Attenuates Symptom Severity in Patients With Celiac Disease Exposed to a Gluten Challenge.

BACKGROUND & AIMS: Gluten ingestion in patients with celiac disease can lead to gastrointestinal symptoms and small intestinal mucosal injury. METHODS: This gluten challenge phase 2 trial was double blind and placebo controlled, and it assessed the efficacy and safety of a 1200-mg dose of IMGX003 in patients with celiac disease exposed to 2 g of gluten per day for 6 weeks. The change in the ratio of villus height to crypt depth was the primary endpoint. Secondary endpoints included density of intraepithelial lymphocytes and symptom severity. These endpoints were evaluated by analysis of covariance. Additional endpoints included serology and gluten-immunogenic peptides in urine. RESULTS: Fifty patients were randomized, and 43 patients completed the study (IMGX003, n = 21; placebo, n = 22). The mean change in the ratio of villus height to crypt depth (primary endpoint) for IMGX003 vs placebo was -0.04 vs -0.35 (P = .057). The mean change in the density of intraepithelial lymphocytes (secondary endpoint) for IMGX003 vs placebo was 9.8 vs 24.8 cells/mm epithelium (P = .018). The mean change (worsening) in symptom severity in relative units (secondary endpoint) for IMGX003 vs placebo was 0.22 vs 1.63 (abdominal pain, P = .231), 0.96 vs 3.29 (bloating, P = .204), and 0.02 vs 3.20 (tiredness, P = .113). The 3 × 2-week trend line significance values for these symptoms, respectively, were P = .014, .030, and .002. CONCLUSIONS: IMGX003 reduced gluten-induced intestinal mucosal damage and symptom severity. (ClinicalTrials.gov, Number: NCT03585478).

Mortality and cancer in eosinophilic gastrointestinal disorders distal to the esophagus: nationwide cohort study 1990-2017.

BACKGROUND: Eosinophilic gastrointestinal disorders (EGIDs) include inflammatory conditions with enteric infiltration of eosinophils and resulting symptoms. This study aims to examine a population-based sample of patients for prevalence, mortality, and cancer risk in EGIDs distal to the esophagus. METHODS: Nationwide, population-based cohort study. EGID was identified through relevant biopsy codes from Sweden's all 28 pathology departments through the ESPRESSO cohort. Individuals with EGID were then matched to general population reference individuals with similar age and sex. Study participants were linked to Swedish healthcare registers. Through Cox regression, we calculated adjusted hazard ratios (aHRs) adjusting for sex, age, county, calendar period, and education. RESULTS: In total, 2429 patients (56% female) were found to have EGID distal to the esophagus, representing a prevalence of about 1/4800 in the Swedish population. Mean age was 44 years with 11% children at the time of diagnosis. Mortality was increased 17% in patients with EGIDs compared to reference individuals (aHR = 1.17; 95%CI = 1.04-1.33). Excess mortality was seen in gastric and small bowel eosinophilic disease, but not colonic disease (aHR = 1.81; 95%CI = 1.32-2.48, aHR = 1.50; 95%CI = 1.18-1.89, and aHR = 0.99; 95%CI = 0.85-1.16, respectively). Cause specific mortality was driven by cancer-related death (aHR = 1.33; 95%CI = 1.05-1.69). However, this study failed to show an increase in incident cancers (aHR = 1.14; 95%CI = 0.96-1.35). Comparison of EGID individuals with their siblings yielded similar aHRs. CONCLUSIONS: This study found an increased risk of death in patients with EGIDs distal to the esophagus, with cancer death driving the increase. Proximal gut disease seems to confer the greatest risk. There was no increase in incident cancers.

Cryptogenic multifocal ulcerous stenosing enteritis (CMUSE): a 20-year single-center clinical and radiologic experience.

OBJECTIVE: The purpose of this article is to describe clinical and imaging characteristics of confirmed cases of cryptogenic multifocal ulcerous stenosing enteritis (CMUSE). METHODS: Retrospective review of electronic medical records identified patients considered for a diagnosis CMUSE over 20-years in a single large tertiary center. Clinical data were abstracted and diagnosis was confirmed based on published criteria. Two GI radiologists reviewed CT and MR enterography (CTE/MRE) exams in consensus of confirmed patients to characterize the imaging features of CMUSE. RESULTS: Eight patients with confirmed CMUSE diagnosis were included for image review, and 9 CTEs and 1 MRE were analyzed. Most patients were males (75%) with a median age at diagnosis of 59.5 years (25-71) presenting with iron deficiency anemia (75%). Patients were commonly refractory (87.5%) to their first therapy, including steroids, with half being refractory to surgical intervention. Major imaging features included multiple (≥ 5; 88%; 7/8), short (< 2 cm; 100%; 8/8), circumferential (100%; 8/8) strictures with moderate wall thickening (6-9 cm), and stratified hyper enhancement (100%; 8/8) located in the ileum (100%; 8/8). Median proximal small bowel dilation was 2.95 cm (2.5-4.1 cm). No CMUSE cases demonstrated penetrating disease (e.g., abscess, fistula). CONCLUSION: CT and MR enterography are invaluable tools in the multidisciplinary diagnostic evaluation of CMUSE, a rare cause of small bowel strictures with overlapping clinical and imaging features of Crohn's disease and NSAID enteropathy.

TAK-101 Nanoparticles Induce Gluten-Specific Tolerance in Celiac Disease: A Randomized, Double-Blind, Placebo-Controlled Study.

BACKGROUND & AIMS: In celiac disease (CeD), gluten induces immune activation, leading to enteropathy. TAK-101, gluten protein (gliadin) encapsulated in negatively charged poly(dl-lactide-co-glycolic acid) nanoparticles, is designed to induce gluten-specific tolerance. METHODS: TAK-101 was evaluated in phase 1 dose escalation safety and phase 2a double-blind, randomized, placebo-controlled studies. Primary endpoints included pharmacokinetics, safety, and tolerability of TAK-101 (phase 1) and change from baseline in circulating gliadin-specific interferon-γ-producing cells at day 6 of gluten challenge, in patients with CeD (phase 2a). Secondary endpoints in the phase 2a study included changes from baseline in enteropathy (villus height to crypt depth ratio [Vh:Cd]), and frequency of intestinal intraepithelial lymphocytes and peripheral gut-homing T cells. RESULTS: In phase 2a, 33 randomized patients completed the 14-day gluten challenge. TAK-101 induced an 88% reduction in change from baseline in interferon-γ spot-forming units vs placebo (2.01 vs 17.58, P = .006). Vh:Cd deteriorated in the placebo group (-0.63, P = .002), but not in the TAK-101 group (-0.18, P = .110), although the intergroup change from baseline was not significant (P = .08). Intraepithelial lymphocyte numbers remained equal. TAK-101 reduced changes in circulating α4ß7+CD4+ (0.26 vs 1.05, P = .032), αEß7+CD8+ (0.69 vs 3.64, P = .003), and γδ (0.15 vs 1.59, P = .010) effector memory T cells. TAK-101 (up to 8 mg/kg) induced no clinically meaningful changes in vital signs or routine clinical laboratory evaluations. No serious adverse events occurred. CONCLUSIONS: TAK-101 was well tolerated and prevented gluten-induced immune activation in CeD. The findings from the present clinical trial suggest that antigen-specific tolerance was induced and represent a novel approach translatable to other immune-mediated diseases. ClinicalTrials.gov identifiers: NCT03486990 and NCT03738475.

Certolizumab Trough Levels and Antibodies in Crohn Disease: A Single-Center Experience.

Background: Certolizumab pegol (CZP) has been successfully used for the treatment of Crohn disease (CD); however, real-world data regarding the utility of CZP trough levels (CTLs) are lacking. We aimed to correlate CTL with CD outcomes and to determine frequency of CZP antibodies. Methods: Retrospective evaluation of all CD patients on maintenance CZP with CTL obtained between 2016 and 2019. Outcomes included: median CTL, presence of anti-CZP antibodies, biochemical response (BR), clinical response (CR), radiologic response (RR), radiologic healing (RH), and mucosal healing (MH). Results: Seventy-seven CD patients were included. Median CTL was 18.9 µg/mL (interquartile range, 7.6-35.4). Twenty-three patients (27.3%) had positive antibody levels, with lower median CTL compared to patients with no antibodies (0.0 vs 29.8; P < 0.0001). Median CTL levels were higher in patients with vs without CR (30.4 vs 10.3 µg/mL; P = 0.0015) and RR (29.6 vs 5.8 µg/mL; P = 0.006). CZP dosing at least every 2 weeks was associated with higher odds of achieving MH (odds ratio, 3.2; 95% confidence interval, 1.03-9.97). CTL resulted in change in clinical management in 62.7% of cases and presence of CMZ antibodies was associated with an odds ratio of 5.83 (95% confidence interval, 1.57-21.73) of change in management. Receiver operating characteristic curve and quartile analysis suggested that CTL >19 µg/mL is associated with increased rates of CR and RR. Conclusions: Higher CTL was significantly associated with CR and RR. The rate of CZP antibodies was 27.3%. Our data suggest maintenance CTL of ≥19 µg/mL should be achieved in order to optimize outcomes in clinical practice.

Anti-Siglec-8 Antibody for Eosinophilic Gastritis and Duodenitis.

BACKGROUND: Eosinophilic gastritis and duodenitis are characterized by gastrointestinal mucosal eosinophilia, chronic symptoms, impaired quality of life, and a lack of adequate treatments. Mast-cell activity may contribute to the pathogenesis of the conditions. AK002 (lirentelimab) is an anti-Siglec-8 antibody that depletes eosinophils and inhibits mast cells and that has shown potential in animal models as a treatment for eosinophilic gastritis and duodenitis. METHODS: In this phase 2 trial, we randomly assigned adults who had symptomatic eosinophilic gastritis, eosinophilic duodenitis, or both conditions in a 1:1:1 ratio to receive four monthly infusions of low-dose AK002, high-dose AK002, or placebo. The primary end point was the change in gastrointestinal eosinophil count from baseline to 2 weeks after the final dose; to maximize statistical power, we evaluated this end point in the placebo group as compared with the combined AK002 group. Secondary end points were treatment response (>30% reduction in total symptom score and >75% reduction in gastrointestinal eosinophil count) and the change in total symptom score. RESULTS: Of the 65 patients who underwent randomization, 43 were assigned to receive AK002 and 22 were assigned to receive placebo. The mean percentage change in gastrointestinal eosinophil count was -86% in the combined AK002 group, as compared with 9% in the placebo group (least-squares mean difference, -98 percentage points; 95% confidence interval [CI], -121 to -76; P<0.001). Treatment response occurred in 63% of the patients who received AK002 and in 5% of the patients who received placebo (difference, 58 percentage points; 95% CI, 36 to 74; P<0.001). The mean change in total symptom score was -48% with AK002 and -22% with placebo (least-squares mean difference, -26 percentage points; 95% CI, -44 to -9; P = 0.004). Adverse events associated with AK002 were similar to those with placebo, with the exception of higher percentages of patients having mild-to-moderate infusion-related reactions with AK002 (60% in the combined AK002 group and 23% in the placebo group). CONCLUSIONS: In patients with eosinophilic gastritis or duodenitis, AK002 reduced gastrointestinal eosinophils and symptoms. Infusion-related reactions were more common with AK002 than with placebo. (Funded by Allakos; ENIGMA ClinicalTrials.gov number, NCT03496571.).

Micronutrient Deficiencies Are Common in Contemporary Celiac Disease Despite Lack of Overt Malabsorption Symptoms.

OBJECTIVE: To evaluate micronutrient deficiencies in a contemporary cohort of adult patients with newly diagnosed celiac disease (CD). PATIENTS AND METHODS: This is a retrospective study of prospective adults newly diagnosed with CD from January 1, 2000, through October 31, 2014, at Mayo Clinic. Micronutrient data were collected for tissue transglutaminase IgA, zinc, 25-hydroxy vitamin D, ferritin, albumin, copper, vitamin B12, and serum folate. Data were analyzed for absolute number of deficiencies and associations with age, sex, body mass index, presenting symptoms, and tissue transglutaminase IgA; each deficiency was assessed using logistic regression. Deficiencies were compared with age- and sex-matched controls from the National Health and Nutrition Examination Survey. RESULTS: In total, 309 patients with CD (196 women and 113 men; mean age, 46.1±15.1 years; mean body mass index, 25.9 kg/m2) were included. Weight loss was seen in only 25.2% (78/309) of patients. Zinc was deficient in 59.4% (126/212) of patients with CD compared with 33.2% (205/618) of controls (P<.001). Albumin was low in 19.7% (24/122) compared with 1.1% of controls (P<.001). Copper was low in 6.4% (13/204) compared with 2.1% (13/618) of controls (P=.003). Vitamin B12 was low in 5.3% (13/244) compared with 1.8% (11/618) of controls (P=.004). Folate was low in 3.6% (6/159) compared with 0.3% (2/618) of controls (P=.002). 25-Hydroxy vitamin D was low in 19.0% (44/213) compared with 18% (111/618) of controls (P=.72). Ferritin was low in 30.8% (66/214) of patients; no NHANES controls were available for comparison for ferritin. CONCLUSION: Micronutrient deficiencies remain common in adults with CD despite increased nonclassic presentation. This study provides support for micronutrient assessment at the time of CD diagnosis.

Phenotype and Clinical Course of Inflammatory Bowel Disease With Co-existent Celiac Disease.

BACKGROUND AND AIMS: Inflammatory bowel diseases, principally Crohn's disease and ulcerative colitis, and celiac disease are among the most common immune-mediated gastrointestinal diseases. We aim to elucidate the clinical course and outcomes of patients with concomitant inflammatory bowel disease and celiac disease, a unique population that remains scarcely studied to date. METHODS: A retrospective matched case-control study of adults with co-existent inflammatory bowel disease [IBD] and celiac disease was performed at a tertiary referral institution in North America. Logistic regression and Kaplan-Meier curves compared disease characteristics and clinical outcomes of the two groups. RESULTS: A total of 342 inflammatory bowel disease patients were included in this study, of whom 114 had co-existent celiac disease and 228 did not. Patients with co-existent inflammatory bowel disease and celiac disease had higher rates of primary sclerosing cholangitis [19.3% vs 5.7%; odds ratio, 4.4; 95% confidence interval, 2.1-9.4; p <0.001], extensive ulcerative colitis [78.1% vs 59.0%; odds ratio, 2.8; 95% confidence interval, 1.5-5.5; p =0.002], and family history of celiac disease [10.5% vs 3.5%; odds ratio 3.2; 95% confidence interval, 1.3-8.2; p =0.01], compared with patients without concomitant celiac disease. CONCLUSIONS: Patients with inflammatory bowel disease with concomitant celiac disease have unique phenotypic features compared with non-celiac inflammatory bowel disease, with higher risks for colitis-related hospitalisations, extensive colitis, and primary sclerosing cholangitis. Increased recognition of co-existent IBD and celiac disease can prompt clinicians to investigate for concomitant disease sooner, particularly in patients with seemingly refractory disease.

Colon Ischemia: An Update for Clinicians.

Colon ischemia (CI) is an underrecognized entity associated with high morbidity and mortality. Establishing the diagnosis and initiating appropriate and timely treatment is critical for improving outcomes. Colon ischemia is a disease spectrum that requires a full understanding for recognition and treatment. This review outlines the full spectrum of CI management from initial presentation to medical and surgical treatment.

Anxiety states induced by post-weaning social isolation are mediated by CRF receptors in the dorsal raphe nucleus.

Post-weaning social isolation of rats is utilized as a model of early life stress. We have previously demonstrated that rats exposed to post-weaning social isolation exhibit greater anxiety-like behaviors as adults. Furthermore, these rats exhibit greater density of corticotropin-releasing factor (CRF) type 2 receptors in the dorsal raphe nucleus. Therefore, we examined whether antagonism of CRF(2) receptors in the dorsal raphe nucleus reverses the effects of post-weaning social isolation on anxiety states. Male rats were reared in isolation or in groups from day of weaning (postnatal day [PND] 21) to mid-adolescence (PND42) and then allowed to develop to early adulthood housed in groups. At PND62, rats were either infused with vehicle, the CRF(1) receptor antagonist antalarmin (0.25-0.5 µg) or the CRF(2) receptor antagonist antisauvagine-30 (2 µg) into the dorsal raphe nucleus, 20 min prior to being introduced to the elevated plus maze. Isolation-reared rats showed reduced open arm behavior compared to group-reared rats, confirming the anxiogenic effects of post-weaning social isolation. Infusion of the CRF(2) receptor antagonist, but not the CRF(1) receptor antagonist, into the dorsal raphe nucleus of isolation-reared rats increased open arm behavior when compared to that of group-reared rats. Overall, the findings suggest that CRF(2) receptors within the dorsal raphe nucleus mediate anxiety-like states following post-weaning social isolation, and CRF(2) receptors may represent an important target for the treatment of anxiety disorders following early life stressors.