Thalidomide for Recurrent Bleeding Due to Small-Intestinal Angiodysplasia.

BACKGROUND: Recurrent bleeding from the small intestine accounts for 5 to 10% of cases of gastrointestinal bleeding and remains a therapeutic challenge. Thalidomide has been evaluated for the treatment of recurrent bleeding due to small-intestinal angiodysplasia (SIA), but confirmatory trials are lacking. METHODS: We conducted a multicenter, double-blind, randomized, placebo-controlled trial to investigate the efficacy and safety of thalidomide for the treatment of recurrent bleeding due to SIA. Eligible patients with recurrent bleeding (at least four episodes of bleeding during the previous year) due to SIA were randomly assigned to receive thalidomide at an oral daily dose of 100 mg or 50 mg or placebo for 4 months. Patients were followed for at least 1 year after the end of the 4-month treatment period. The primary end point was effective response, which was defined as a reduction of at least 50% in the number of bleeding episodes that occurred during the year after the end of thalidomide treatment as compared with the number that occurred during the year before treatment. Key secondary end points were cessation of bleeding without rebleeding, blood transfusion, hospitalization because of bleeding, duration of bleeding, and hemoglobin levels. RESULTS: Overall, 150 patients underwent randomization: 51 to the 100-mg thalidomide group, 49 to the 50-mg thalidomide group, and 50 to the placebo group. The percentages of patients with an effective response in the 100-mg thalidomide group, 50-mg thalidomide group, and placebo group were 68.6%, 51.0%, and 16.0%, respectively (P<0.001 for simultaneous comparison across the three groups). The results of the analyses of the secondary end points supported those of the primary end point. Adverse events were more common in the thalidomide groups than in the placebo group overall; specific events included constipation, somnolence, limb numbness, peripheral edema, dizziness, and elevated liver-enzyme levels. CONCLUSIONS: In this placebo-controlled trial, treatment with thalidomide resulted in a reduction in bleeding in patients with recurrent bleeding due to SIA. (Funded by the National Natural Science Foundation of China and the Shanghai Municipal Education Commission, Gaofeng Clinical Medicine; ClinicalTrials.gov number, NCT02707484.).

Human Secretory IgM Emerges from Plasma Cells Clonally Related to Gut Memory B Cells and Targets Highly Diverse Commensals.

Secretory immunoglobulin A (SIgA) enhances host-microbiota symbiosis, whereas SIgM remains poorly understood. We found that gut IgM+ plasma cells (PCs) were more abundant in humans than mice and clonally related to a large repertoire of memory IgM+ B cells disseminated throughout the intestine but rare in systemic lymphoid organs. In addition to sharing a gut-specific gene signature with memory IgA+ B cells, memory IgM+ B cells were related to some IgA+ clonotypes and switched to IgA in response to T cell-independent or T cell-dependent signals. These signals induced abundant IgM which, together with SIgM from clonally affiliated PCs, recognized mucus-embedded commensals. Bacteria recognized by human SIgM were dually coated by SIgA and showed increased richness and diversity compared to IgA-only-coated or uncoated bacteria. Thus, SIgM may emerge from pre-existing memory rather than newly activated naive IgM+ B cells and could help SIgA to anchor highly diverse commensal communities to mucus.

Standard of Care Versus Octreotide in Angiodysplasia-Related Bleeding (the OCEAN Study): A Multicenter Randomized Controlled Trial.

BACKGROUND & AIMS: Gastrointestinal angiodysplasias are vascular anomalies that may result in transfusion-dependent anemia despite endoscopic therapy. An individual patient data meta-analysis of cohort studies suggests that octreotide decreases rebleeding rates, but component studies possessed a high risk of bias. We investigated the efficacy of octreotide in reducing the transfusion requirements of patients with angiodysplasia-related anemia in a clinical trial setting. METHODS: The study was designed as a multicenter, open-label, randomized controlled trial. Patients with angiodysplasia bleeding were required to have had at least 4 red blood cell (RBC) units or parental iron infusions, or both, in the year preceding randomization. Patients were allocated (1:1) to 40-mg octreotide long-acting release intramuscular every 28 days or standard of care, including endoscopic therapy. The treatment duration was 1 year. The primary outcome was the mean difference in the number of transfusion units (RBC + parental iron) between the octreotide and standard of care groups. Patients who received at least 1 octreotide injection or followed standard of care for at least 1 month were included in the intention-to-treat analyses. Analyses of covariance were used to adjust for baseline transfusion requirements and incomplete follow-up. RESULTS: We enrolled 62 patients (mean age, 72 years; 32 men) from 17 Dutch hospitals in the octreotide (n = 31) and standard of care (n = 31) groups. Patients required a mean number of 20.3 (standard deviation, 15.6) transfusion units and 2.4 (standard deviation, 2.0) endoscopic procedures in the year before enrollment. The total number of transfusions was lower with octreotide (11.0; 95% confidence interval [CI], 5.5-16.5) compared with standard of care (21.2; 95% CI, 15.7-26.7). Octreotide reduced the mean number of transfusion units by 10.2 (95% CI, 2.4-18.1; P = .012). Octreotide reduced the annual volume of endoscopic procedures by 0.9 (95% CI, 0.3-1.5). CONCLUSIONS: Octreotide effectively reduces transfusion requirements and the need for endoscopic therapy in patients with angiodysplasia-related anemia. CLINICALTRIALS: gov, NCT02384122.

In small-intestinal angiodysplasia with recurrent bleeding, thalidomide reduced bleeding episodes at 1 y.

SOURCE CITATION: Chen H, Wu S, Tang M, et al. Thalidomide for recurrent bleeding due to small-intestinal angiodysplasia. N Engl J Med. 2023;389:1649-1659. 37913505.

In transfusion-dependent, angiodysplasia-related anemia, adding octreotide to usual care reduced transfusions at 1 y.

SOURCE CITATION: Goltstein LC, Grooteman KV, Bernts LH, et al. Standard of care versus octreotide in angiodysplasia-related bleeding (the OCEAN study): a multicenter randomized controlled trial. Gastroenterology. 2024;166:690-703. 38158089.

Endoscopic therapy for gastrointestinal angiodysplasia.

OBJECTIVES: This is a protocol for a Cochrane Review (intervention). The objectives are as follows: To assess the benefits and harms of the different endoscopic management approaches for gastrointestinal angiodysplasia in symptomatic adults.

Effectiveness of aortic valve replacement in Heyde syndrome: a meta-analysis.

AIMS: Heyde syndrome is the co-occurrence of aortic stenosis, acquired von Willebrand syndrome, and gastrointestinal bleeding. Aortic valve replacement has been demonstrated to resolve all three associated disorders. A systematic review and meta-analysis were performed to obtain best estimates of the effect of aortic valve replacement on acquired von Willebrand syndrome and gastrointestinal bleeding. METHODS AND RESULTS: A literature search was performed to identify articles on Heyde syndrome and aortic valve replacement up to 25 October 2022. Primary outcomes were the proportion of patients with recovery of acquired von Willebrand syndrome within 24 h (T1), 24-72 h (T2), 3-21 days (T3), and 4 weeks to 2 years (T4) after aortic valve replacement and the proportion of patients with cessation of gastrointestinal bleeding. Pooled proportions and risk ratios were calculated using random-effects models. Thirty-three studies (32 observational studies and one randomized controlled trial) on acquired von Willebrand syndrome (n = 1054), and 11 observational studies on gastrointestinal bleeding (n = 300) were identified. One study reported on both associated disorders (n = 6). The pooled proportion of Heyde patients with acquired von Willebrand syndrome recovery was 86% (95% CI, 79%-91%) at T1, 90% (74%-96%) at T2, 92% (84%-96%) at T3, and 87% (67%-96%) at T4. The pooled proportion of Heyde patients with gastrointestinal bleeding cessation was 73% (62%-81%). Residual aortic valve disease was associated with lower recovery rates of acquired von Willebrand syndrome (RR 0.20; 0.05-0.72; P = 0.014) and gastrointestinal bleeding (RR 0.57; 0.40-0.81; P = 0.002). CONCLUSION: Aortic valve replacement is associated with rapid recovery of the bleeding diathesis in Heyde syndrome and gastrointestinal bleeding cessation. Residual valve disease compromises clinical benefits.

Heyde Syndrome Unveiled: A Case Report with Current Literature Review and Molecular Insights.

Heyde syndrome, marked by aortic stenosis, gastrointestinal bleeding from angiodysplasia, and acquired von Willebrand syndrome, is often underreported. Shear stress from a narrowed aortic valve degrades von Willebrand factor multimers, leading to angiodysplasia formation and von Willebrand factor deficiency. This case report aims to raise clinician awareness of Heyde syndrome, its complexity, and the need for a multidisciplinary approach. We present a 75-year-old man with aortic stenosis, gastrointestinal bleeding from angiodysplasia, and acquired von Willebrand syndrome type 2A. The patient was successfully treated with argon plasma coagulation and blood transfusions. He declined further treatment for aortic stenosis but was in good overall health with improved laboratory results during follow-up. Additionally, we provide a comprehensive review of the molecular mechanisms involved in the development of this syndrome, discuss current diagnostic and treatment approaches, and offer future perspectives for further research on this topic.

Gastrointestinal Angiodysplasia in Patients with Severe Aortic Stenosis: The Endoscopic Features of Heyde's Syndrome.

INTRODUCTION: Aortic stenosis (AS) is sometimes associated with gastrointestinal bleeding, and this phenomenon is known as Heyde's syndrome. Such bleeding is most often considered to originate from gastrointestinal angiodysplasias, but the frequency and endoscopic features of such bleeding remain unclear. This study aimed to determine the frequency and endoscopic features of gastrointestinal angiodysplasia in patients with severe AS. PATIENTS AND METHODS: In this multicenter, retrospective study, we evaluated consecutive patients who underwent transcatheter aortic valve implantation (TAVI) with severe AS from May 2016 to December 2019. We extracted the data on the clinicopathological features according to the status of anemia, the proportion of patients who underwent gastrointestinal endoscopic examinations and demonstrated gastrointestinal angiodysplasia, and identified the endoscopic features associated with such patients. RESULTS: In 325 patients, the rates of moderate/severe anemia (hemoglobin < 11 g/dL) were 52%. Regarding medicine, there were no significant differences between the patients with and without moderate/severe anemia. Patients were examined by esophagogastroduodenoscopy (21%), colonoscopy (12%), and balloon-assisted enteroscopy or small bowel capsule endoscopy (1.5%). Patients with moderate/severe anemia had significantly more angiodysplasia (38.3% vs. 7.7%; p < 0.0001) and active bleeding (23.4% vs. 0%; p < 0.01). Angiodysplasia was detected in 21 patients (stomach, n = 9; small intestine, n = 5, and colon, n = 10). CONCLUSIONS: The results suggest, for the first time, that patients with severe AS who underwent TAVI and moderate/severe anemia frequently had gastrointestinal angiodysplasia and active bleeding throughout the entire gastrointestinal tract.

Diagnostic accuracy of artificial intelligence-aided capsule endoscopy (TOP100) in overt small bowel bleeding.

BACKGROUND: Capsule endoscopy (CE) is the first-choice exploration in case of overt small bowel bleeding (SBB). An early CE is known to increase diagnostic yield, but long reading times may delay therapeutics. The study evaluates the diagnostic performance of the artificial intelligence tool TOP100 in patients with overt SBB undergoing early CE with Pillcam SB3. METHODS: Patients who underwent early CE (up to 14 days from the bleeding episode) for suspected overt SBB were included. One experienced endoscopist prospectively performed standard reading (SR) and a second blind experienced endoscopist performed a TOP100-based reading (TR). The primary endpoint was TR diagnostic accuracy for lesions with high bleeding potential (P2). RESULTS: A total of 111 patients were analyzed. The most common clinical presentation was melena (64%). CE showed angiodysplasias in 40.5% of patients (45/111). In per-patient analysis, TR showed a sensitivity of 90.48% (95% CI 82.09-95.80), specificity of 100% (95% CI 87.23-100) with a PPV of 100% (95% CI 94.01-100), NPV of 77.14% (95% CI 63.58-86.71) and diagnostic accuracy of 92.79 (86.29-96.84). At multivariate analysis, adequate intestinal cleansing was the only independent predictor of concordance between TR and SR (OR 2.909, p = 0.019). The median reading time for SR and TR was 23 min (18.0-26.8) and 1.9 min (range 1.7-2.1), respectively (p < 0.001). CONCLUSIONS: TOP100 provides a fast-reading mode for early CE in case of overt small bowel bleeding. It identifies most patients with active bleeding and angiodysplasias, aiding in the prioritization of therapeutic procedures. However, its accuracy in detecting ulcers, varices and P1 lesions seems insufficient.

Causes of gastrointestinal bleeding in oral anticoagulant users compared to non-users in a population-based study.

BACKGROUND/AIMS: Causes of gastrointestinal bleeding (GIB) in patients on oral anticoagulants (OACs) are not well established. The aims of the study were to compare the causes of GIB in patients on OACs and those not on OAC therapy. METHODS: A nationwide study of all GIB events in patients on OACs in Iceland from 2014-2019 was conducted. Bleeding events were obtained through ICD-10 codes and review of endoscopy databases, confirmed by review of medical records. For comparison, patients not on OACs from previous Icelandic population-based studies were used. RESULTS: Among 752 GIB events in 12,005 patients on OACs, 273 (1.9%) had verified upper and 391 (2.7%) had verified lower GIB. For lower GIB, multivariate analysis showed that OAC users were more likely to have colonic polyps (OR 6.6, 95% CI: 2.4 - 17.8, p < .001) or colorectal cancer (OR 3.7, 95% CI: 2.0 - 7.0, p < .001) but less likely to have ischemic colitis (OR 0.11, 95% CI: 0.04 - 0.26, p < .001). For upper GIB, bleeding from mucosal erosions (OR 4.0 95% CI: 2.5 - 7.9, p < .001) and angiodysplasia (OR 3.6, 95%CI: 1.5 - 8.6, p = .003) were more common in OAC users. CONCLUSIONS: A high proportion of GIB caused by colonic polyps and colorectal cancer among OAC patients indicates that OACs treatment may facilitate cancer diagnosis. The low proportion of ischemic colitis among those on OACs suggests that OACs provide a protective effect against ischemic colitis. OACs seem to increase the bleeding from angiodysplasia and mucosal erosive disease.

Evaluation and Validation of a New Score to Measure the Severity of Small Bowel Angiodysplasia on Video Capsule Endoscopy.

INTRODUCTION: Angiodysplasias are responsible of 50% of small bowel bleeding. An endoscopic method that allows measuring its severity is not available. AIMS: The aim of the study was to validate a new endoscopic score with VCE to measure the severity of small bowel angiodysplasias (SBAD). METHODS: Four endoscopists independently reviewed VCE videos of 22 patients with SBAD. The score graded 3 variables: A - extent of lesions: E1, located in one half of the intestine and E2, in both halves; B - number of lesions: N1, <5; N2, 5-10; and N3, >10 lesions; C - probability of bleeding: P1, pale red spots; P2, bright red spots; P3, bleeding stigmata; and P4, active bleeding. Capsule Endoscopy Small Bowel Angiodysplasia Activity Index (CESBAI) was calculated as follows: E × 1 + N × 2 + P × 3. Interobserver variability was analyzed by Spearman's correlation and agreement Kappa statistic tests. RESULTS: The mean CESBAI scores by observers were O1= 11.6 ± 4.1; O2 = 11.3 ± 4.8; O3 = 11.1 ± 4.9; and O4 = 11.8 ± 4.2 (p > 0.05). Spearman's correlation values of CESBAI between every 2 observers were from 0.61 to 0.94 (p < 0.001) with a global correlation of 0.73 among all observers. Kappa values of CESBAI between every 2 observers ranged from 0.42 to 0.87 (p < 0.001) with a global agreement of 0.57 among all observers. All evaluators stated that the method was easy to use. CONCLUSIONS: CESBAI is a reliable and reproducible score. Nevertheless, these results must be validated in other studies with larger population before assessing its power for predicting bleeding recurrence.

Systemic bevacizumab to facilitate anticoagulation in antiphospholipid syndrome and bleeding gastrointestinal angiodysplasia.

Bleeding gastrointestinal angiodysplasia may occur in patients with vasculitis and can be challenging to treat. We describe the novel use of bevacizumab therapy to treat bleeding gastrointestinal angiodysplasia and severe anemia in a patient with eosinophilic granulomatosis with angiitis complicated by antiphospholipid antibody syndrome requiring indefinite warfarin therapy. Studies confirmed multiple bleeding jejunal angiodysplasias unamenable to endoscopic intervention, and the patient required ongoing support with iron infusions and blood transfusions to maintain a minimally acceptable hemoglobin. Given the severe anemia, need for continued, indefinite antiplatelet and anticoagulation therapy, and failure of standard treatment approaches, the patient was initiated on systemic bevacizumab therapy, on the basis of prior documented success of bevacizumab to manage gastrointestinal telangiectasias in patients with hereditary hemorrhagic telangiectasia. Bevacizumab was highly effective, with rapid resolution of bleeding, normalization of hemoglobin, liberation from hematologic support and no adverse events, including no thromboembolic events. Vascular endothelial growth factor (VEGF-A) rose paradoxically after initiation of bevacizumab and normalized after its discontinuation. Given these findings, use of systemic bevacizumab to manage bleeding angiodysplasia in patients with acquired vascular disorders merits further study.

Experimental modeling of selective photodestruction of skin angiodysplasia by laser radiation with a wavelength of 525 nm.

Until now, the problem of effective treatment of skin angiodysplasia remains relevant. To solve it and improve the results of the treatment of this vascular pathology of the skin, photodestruction by laser radiation is considered, which provides a selective effect on the skin with minimal damage to the surrounding tissues. For selective photodestruction in the treatment of angiodysplasia of the skin, one can consider laser radiation with a wavelength of 520 ± 5 nm in the "green" spectral range, located close to the absorption peaks of hemoglobin and oxyhemoglobin chromophores. An experimental study in vivo on the combs of live white chickens was carried out to clarify the features of damage and the regeneration process in the zone of exposure to this radiation. We used an experimental sample of a solid-state laser apparatus based on semiconductor diodes, generating laser radiation with a wavelength of 520 ± 5 nm. The results of an experimental study in vivo confirmed the selectivity of the effect of "green" laser radiation of 520 ± 5 nm on subepithelial vascular structures with minimal damage to the epithelium, including the area of its growth. In irradiated areas, one could see whitening and smoothing of the surface due to closure of vessel lumens in the subepithelial zone and formation of collagenosis layer there, as well as epithelialization of wound surface in physiological term without any formation of cicatricial deformation of the skin. The prospect of using "green" laser radiation of 520 ± 5 nm for the purposes of selective photodestruction of angiodysplasia of the skin, which should ensure the achievement of a good clinical and aesthetic result of treatment, has been effective for selective destruction of angiodysplasia.

Strange coincidence in the gut: pseudomelanosis duodeni diagnosed by capsule endoscopy and active bleeding due to angiodysplasia.

We present the case of an 82-year-old male with a medical history of hypertension, dyslipidemia, diabetes mellitus, chronic renal failure, ischemic heart disease and iron deficiency anemia. He was under therapy with hydralazine, furosemide, amlodipine, valsartan, nitroglycerin patches, bisoprolol, omeprazole, doxazosin, human insulin and oral iron. The patient presented at our institution with melena. Initial gastroscopy showed fresh blood and a gastric angiodysplasia that was treated with argon plasma coagulation (APC). Three months later, he suffered a new episode of bleeding and a small bowel capsule endoscopy (SBCE) was subsequently indicated.