Effect of Pooled Human Intravenous Globulin (IVIG) on the Reversal of Cholinergic Inhibition of Smooth Muscle by Immunoglobulins (IgGs) from Patients with Scleroderma (SSc)

Poster presented at: Digestive Disease Week (DDW) International meeting in San Diego, California. Backgrounds and Aims: The gastrointestinal (GI) tract is the most common internal organ system affected in SSc. We and others have shown before that the SSc immunoglobulins (IgGs) cause selective blockade of muscarinic type-3 cholinergic (M3-R) in the GI tract. Presently, there is no effective treatment for SSc although numerous cytotoxic and immunomodulatory agents have been employed with limited success and are marred with serious side effects. Present studies investigated the reversibility of SScIgGs-caused M3-R blockade by the pooled Intravenous immunoglobulins (IVIG)

Effects of scleroderma antibodies and pooled human immunoglobulin on anal sphincter and colonic smooth muscle function.

BACKGROUND & AIMS: Patients with systemic sclerosis (SSc) have impairments in gastrointestinal smooth muscle function. The disorder has been associated with circulating antibodies to cholinergic muscarinic the type-3 receptor (M(3)-R). We investigated whether it is possible to neutralize these antibodies with pooled human IgGs (pooledhIgG). METHODS: We studied the effects of IgGs purified from patients with SSc (SScIgGs) on cholinergic nerve stimulation in rat colon tissues. We also examined the effects of SScIgGs on M(3)-R activation by bethanechol (BeCh), M(3)-R occupancy, and receptor binding using immunofluorescence, immunoblot, and enzyme-linked immunosorbent analyses of human internal anal sphincter (IAS) smooth muscle cells, before and after administration of pooledhIgG. Functional displacement of M(3)-R occupancy by the SScIgGs was compared with that of other IgGs during the sustained phase of BeCh-induced contraction of intact smooth muscles from rats. RESULTS: SScIgG significantly attenuated neurally mediated contraction and acetylcholine release in rat colon as well as BeCh-induced sustained contraction of the IAS smooth muscle. In immunofluorescence analysis, SScIgG co-localized with M(3)-R. In immunoblot and enzyme-linked immunosorbent analyses, M(3)-R loop-2 peptide and human IAS SMC membrane lysates bound significant amounts of SScIgG, compared with IgGs from healthy individuals and pooledhIgG. Binding was attenuated significantly by application of pooledhIgG, which by itself had no significant effect. Incubation of samples with pooledhIgG, or mixing pooledhIgG with SScIgG before administration to tissues, significantly reduced binding of SScIgG, indicating that pooledhIgG prevents SScIgG blockade of M(3)-R. CONCLUSIONS: In studies of rat and human tissues, pooled human IgG prevent and reverses the cholinergic dysfunction associated with the progressive gastrointestinal manifestations of SSc by neutralizing functional M(3)-R antibodies present in the circulation of patients with SSc

Boerhaave\u27s syndrome as an initial presentation of eosinophilic esophagitis: A case series

Background Prior studies report esophageal rupture following endoscopy or bolus impaction in eosinophilic esophagitis (EoE). The purpose of this study is to add new information to available evidence defining the clinical spectrum of spontaneous rupture (Boerhaave\u27s syndrome) associated with vomiting in EoE. Methods A retrospective search of inpatient and outpatient records was conducted from January 2001 to January 2011. A faculty member in pathology blindly reviewed all esophageal biopsy specimens. EoE was defined as 15 or more eosinophils in at least 2 high-power fields (hpfs) or 25 or more eosinophils in any single HPF. Results In ten years, 447 patients were identified with a diagnosis of EoE. Of these, four patients presented with Boerhaave\u27s syndrome in the setting of EoE. None of the patients had an established diagnosis of EoE prior to presentation. All cases presented with a triad of vomiting, chest pain and pneumomediastinum. In two patients, water-soluble contrast extravasation prompted surgical intervention (50%). Full thickness surgical specimen provides a unique opportunity to show eosinophils in the muscularis propria. Intraepithelial eosinophil infiltration was seen on all mucosal biopsies (\u3e25/hpf) with significant improvement after steroid (topical or systemic) treatment. Conclusions Spontaneous esophageal rupture is a rare (4/447, less than 1%) but critical presentation of EoE manifesting with vomiting, chest pain and pneumomediastinum. Surgery is required if extravasation is seen with water-soluble contrast. We suggest that EoE may be a transmural disease in some patients, thus making the esophageal wall susceptible to spontaneous rupture with vomiting (Boerhaave\u27s syndrome). © 2013 Hellenic Society of Gastroenterology

Effects of scleroderma antibodies and pooled human immunoglobulin on anal sphincter and colonic smooth muscle function

BACKGROUND & AIMS: Patients with systemic sclerosis (SSc) have impairments in gastrointestinal smooth muscle function. The disorder has been associated with circulating antibodies to cholinergic muscarinic the type-3 receptor (M(3)-R). We investigated whether it is possible to neutralize these antibodies with pooled human IgGs (pooledhIgG). METHODS: We studied the effects of IgGs purified from patients with SSc (SScIgGs) on cholinergic nerve stimulation in rat colon tissues. We also examined the effects of SScIgGs on M(3)-R activation by bethanechol (BeCh), M(3)-R occupancy, and receptor binding using immunofluorescence, immunoblot, and enzyme-linked immunosorbent analyses of human internal anal sphincter (IAS) smooth muscle cells, before and after administration of pooledhIgG. Functional displacement of M(3)-R occupancy by the SScIgGs was compared with that of other IgGs during the sustained phase of BeCh-induced contraction of intact smooth muscles from rats. RESULTS: SScIgG significantly attenuated neurally mediated contraction and acetylcholine release in rat colon as well as BeCh-induced sustained contraction of the IAS smooth muscle. In immunofluorescence analysis, SScIgG co-localized with M(3)-R. In immunoblot and enzyme-linked immunosorbent analyses, M(3)-R loop-2 peptide and human IAS SMC membrane lysates bound significant amounts of SScIgG, compared with IgGs from healthy individuals and pooledhIgG. Binding was attenuated significantly by application of pooledhIgG, which by itself had no significant effect. Incubation of samples with pooledhIgG, or mixing pooledhIgG with SScIgG before administration to tissues, significantly reduced binding of SScIgG, indicating that pooledhIgG prevents SScIgG blockade of M(3)-R. CONCLUSIONS: In studies of rat and human tissues, pooled human IgG prevent and reverses the cholinergic dysfunction associated with the progressive gastrointestinal manifestations of SSc by neutralizing functional M(3)-R antibodies present in the circulation of patients with SSc

Adenomas involving the extrahepatic biliary tree are rare but have an aggressive clinical course

Biliary adenomas that are usually found in surgically removed gallbladders are rare, but can also occur in the extrahepatic biliary tree. We present a case series of extrahepatic bile duct adenomas at our institution, along with a review of the literature. All three patients with extrahepatic biliary adenomas (two in the common bile ducts, one in the hepatic duct) were female with a mean age of 74 years. On initial presentation, none of the patients had obstructive jaundice but two of the three patients had symptoms of biliary origin. Case 1 is an 85-year-old woman with an incidental biliary dilation seen on chest imaging; endoscopic ultrasound revealed a sessile adenomatous polyp in the distal bile duct. The patient refused surgery and presented with occlusive biliary stricture and jaundice 5 months after initial presentation, with cytology confirming malignant progression. Case 2 is a 78-year-old woman with a history of primary sclerosing cholangitis and who presented with cholangitis, and Gram-negative sepsis. A polypoid lesion was seen on imaging in the common hepatic duct and direct cholangioscopy with biopsies confirmed the presence of adenoma with high grade dysplasia. The patient underwent successful total bile duct resection and hepaticojejunostomy but represented 1 year later with diffuse metastatic disease to the bone, liver, and peritoneum. Case 3 is a 61-year-old woman who presented with symptoms suggestive of gallbladder pathology and was found to have a polypoid bile duct lesion on intraoperative cholangiogram. Endoscopic retrograde cholangioscopy showed an adenomatous polyp with high grade dysplasia involving the distal common bile duct. The patient underwent distal bile duct resection with choledochojejunostomy but presented with jaundice 4 years after surgery. She was found to have adenocarcinoma involving the small bowel in the Roux limb of jejunum and transverse colon. All three patients in our series presented with interval gastrointestinal malignancy and we therefore recommend aggressive surgical intervention and close postoperative surveillance when diagnosis of extrahepatic bile duct adenoma is made

Boerhaave\u27s Syndrome as a First Presentation of Eosinophilic Esophagitis

Purpose: Prior studies have reported esophageal rupture following endoscopy or bolus impaction in eosinophilic esophagitis. The purpose of this study is to examine the frequency and characteristics of spontaneous rupture (Boerhaave\u27s Syndrome) associated with vomiting S-435 AGA Abstracts in eosinophilic esophagitis. Methods: A retrospective search of inpatient and outpatient records was conducted for the diagnoses Boerhaave\u27s , eosinophilic esophagitis , and esophageal rupture from January 2001 to January 2011 within the gastroenterology division at an urban tertiary care hospital. For each subject identified, medical records, endoscopy reports, biopsy reports and radiographic studies were reviewed. A faculty member of the Department of Pathology blindly reviewed all esophageal biopsy specimens. Eosinophilic esophagitis was defined as 15 or more eosinophils (EOS) in at least 2 high-power fields (HPFs) or 25 or more eosinophils in any single high power field. Results: Over a period of ten years, 447 patients were identified with a diagnosis of eosinophilic esophagitis. Of these, four patients presented with spontaneous esophageal rupture in the setting of eosinophilic esophagitis in the absence of food impaction or endoscopy (4/447, less than 1%). None of the patients had an established diagnosis of eosinophilic esophagitis prior to presentation. All four cases presented with a triad of vomiting, chest pain and pneumomediastinum. Three of the four patients were male (75%), and ages ranged from 22 to 56 (mean 37) years-old. In two of the four patients, water-soluble contrast extravasation was seen on imaging prompting surgical intervention (50%); one of these patients required esophageal resection. The other two patients demonstrated no contrast extravasation. These two patients were observed for resolution. A unique opportunity to examine full thickness surgical specimen showed invasion of eosinophils into the muscularis propria. Intraepithelial eosinophil infiltration was seen on all mucosal biopsies (\u3e30 EOS/HPF) with significant improvement after steroid (topical or systemic) treatment. Conclusion: Spontaneous esophageal rupture is a rare (less than 1%) but critical presentation of eosinophilic esophagitis manifesting with vomiting, chest pain and pneumomediastinum. Surgery is required if extravasation is seen with water-soluble contrast. We suggest that eosinophilic esophagitis is a transmural disease rather than a simple mucosal process, thus making the esophageal wall susceptible to rupture with endoscopy, bolus impaction now spontaneously (Boerhaave\u27s Syndrome)