Bret T. Petersen

Immunoglobulin G4–Associated Cholangitis: Clinical Profile and Response to Therapy

BACKGROUND & AIMS Immunoglobulin (Ig)G4-associated cholangitis (IAC) is the biliary manifestation of a steroid-responsive multisystem fibroinflammatory disorder in which affected organs have a characteristic lymphoplasmacytic infiltrate rich in IgG4-positive cells. We describe clinical features, treatment response, and predictors of relapse in IAC and compare relapse rates in IAC with intrapancreatic vs proximal bile duct strictures. METHODS We reviewed clinical, serologic, and imaging characteristics and treatment response in 53 IAC patients. RESULTS IAC patients generally were older (mean age, 62 y) men (85%), presenting with obstructive jaundice (77%) associated with autoimmune pancreatitis (92%), increased serum IgG4 levels (74%), and abundant IgG4-positive cells in bile duct biopsy specimens (88%). At presentation, biliary strictures were confined to the intrapancreatic bile duct in 51%; the proximal extrahepatic/intrahepatic ducts were involved in 49%. Initial presentation was treated with steroids (n = 30; median follow-up period, 29.5 months), surgical resection (n = 18; median follow-up period, 58 months), or was conservative (n = 5; median follow-up period, 35 months). Relapses occurred in 53% after steroid withdrawal; 44% relapsed after surgery and were treated with steroids. The presence of proximal extrahepatic/intrahepatic strictures was predictive of relapse. Steroid therapy normalized liver enzyme levels in 61%; biliary stents could be removed in 17 of 18 patients. Fifteen patients treated with steroids for relapse after steroid withdrawal responded; 7 patients on additional immunomodulatory drugs remain in steroid-free remission (median follow-up period, 6 months). CONCLUSIONS IAC should be suspected in unexplained biliary strictures associated with increased serum IgG4 and unexplained pancreatic disease. Relapses are common after steroid withdrawal, especially with proximal strictures. The role of immunomodulatory drugs for relapses needs further study.

A lexicon for endoscopic adverse events: report of an ASGE workshop

Patients and practitioners expect that their endoscopy procedures will go smoothly and according to plan. There are several reasons why they may be disappointed. The procedure may fail technically (eg, incomplete colonoscopy, failed biliary cannulation). It may seem to be successful technically but turn out to be clinically unhelpful (eg, a diagnosis missed, an unsuccessful treatment), or there may be an early relapse (eg, stent dysfunction). In addition, some patients and relatives may be disappointed by a lack of courtesy and poor communication, even when everything otherwise works well. The most feared negative outcome is when something ‘‘goes wrong’’ and the patient experiences a ‘‘complication.’’ This term has unfortunate medicolegal connotations and is perhaps better avoided. Describing these deviations from the plan as ‘‘unplanned events’’ fits nicely

Value of serum IgG4 in the diagnosis of autoimmune pancreatitis and in distinguishing it from pancreatic cancer.

OBJECTIVES:To determine the sensitivity and specificity of elevated serum IgG4 level for the diagnosis of autoimmune pancreatitis (AIP) and its ability to distinguish AIP from pancreatic cancer, its main differential diagnosis.METHODS:We measured serum IgG4 levels (normal 8–140 mg/dL) in 510 patients including 45 with AIP, 135 with pancreatic cancer, 62 with no pancreatic disease, and 268 with other pancreatic diseases.RESULTS:Sensitivity, specificity, and positive predictive values for elevated serum IgG4 (>140 mg/dL) for diagnosis of AIP were 76%, 93%, and 36%, respectively, and 53%, 99%, and 75%, respectively, for IgG4 of >280 mg/dL. Among subjects with elevated IgG4, non-AIP subjects (N = 32) differed from AIP subjects (N = 34) in that they were more likely to be female (45% vs 9%, P < 0.001), less likely to have serum IgG4 >280 mg/dL (13% vs 71%, P < 0.001), or elevation of total IgG (16% vs 56%, P < 0.001). Serum IgG4 levels were elevated in 13/135 (10%) pancreatic cancer patients; however, only 1% had IgG4 levels >280 mg/dL compared with 53% of AIP. Compared with AIP, pancreatic cancer patients were more likely to have CA19-9 levels of >100 U/mL (71% vs 9%, P < 0.001).CONCLUSION:Elevated serum IgG4 levels are characteristic of AIP. However, mild (<2-fold) elevations in serum IgG4 are seen in up to 10% of subjects without AIP including pancreatic cancer and cannot be used alone to distinguish AIP from pancreatic cancer. Because AIP is uncommon, IgG4 elevations in patients with low pretest probability of having AIP are likely to represent false positives.

Quality indicators for colonoscopy.

Colonoscopy is widely used for the diagnosis and treatment of colonic disorders. Properly performed, colonoscopy is generally safe, accurate, and well tolerated by most patients. Visualization of the mucosa of the entire large intestine and distal terminal ileum is usually possible at colonoscopy. In patients with chronic diarrhea, biopsy specimens can help diagnose the underlying condition. Polyps can be identified and removed during colonoscopy, thereby reducing the risk of colon cancer. Colonoscopy is the preferred method to evaluate the colon in most adult patients with bowel symptoms, iron deficiency anemia, abnormal radiographic studies of the colon, positive colorectal cancer screening tests, postpolypectomy and postcancer resection surveillance, surveillance in inflammatory bowel disease, and in those with suspected masses. The use of colonoscopy has become accepted as the most effective method of screening the colon for neoplasia in patients over the age of 50 years and in younger patients at increased risk (1). The effectiveness of colonoscopy in reducing colon cancer incidence depends on adequate visualization of the entire colon, diligence in examining the mucosa, and patient acceptance of the procedure. Preparation quality affects the ability to perform a complete examination, the duration the procedure, and the need to cancel or reschedule procedures (2, 3). Ineffective preparation is a major contributor to costs (4). Longer withdrawal times have been demonstrated to improve polyp detection rates, (5–7) and conversely, rapid withdrawal may miss lesions and reduce the effectiveness of colon cancer prevention by colonoscopy. The miss rates of colonoscopy for large (≥1 cm) adenomas may be higher than previously thought (8, 9) Thus, careful examinations are necessary to optimize the effectiveness of recommended intervals between screening and surveillance examinations. Finally, technical expertise will help prevent complications that can offset any cost benefit ratio gained by removing neoplastic lesions. The following quality indicators have been selected to establish competence in performing colonoscopy and help define areas for continuous quality improvement. The levels of evidence supporting these quality indicators were graded according to Table 1. PREPROCEDURE

Differences in Clinical Profile and Relapse Rate of Type 1 Versus Type 2 Autoimmune Pancreatitis

BACKGROUND & AIMS Autoimmune pancreatitis (AIP) has been divided into subtypes 1 (lymphoplasmacytic sclerosing pancreatitis) and 2 (idiopathic duct centric pancreatitis). We compared clinical profiles and long-term outcomes of types 1 and 2 AIP. METHODS We compared clinical presentation, relapse, and vital status of 78 patients with type 1 AIP who met the original HISORt criteria and 19 patients with histologically confirmed type 2 AIP. RESULTS At presentation, patients with type 1 AIP were older than those with type 2 AIP (62 +/- 14 vs 48 +/- 19 years; P < .0001) and had a greater prevalence of increased serum levels of immunoglobulin G4 (47/59 [80%] vs 1/6 [17%]; P = .004). Patients with type 1 were more likely than those with type 2 to have proximal biliary, retroperitoneal, renal, or salivary disease (60% vs 0; P < .0001). Inflammatory bowel disease was associated with types 1 and 2 (6% vs 16%; P = .37). During median clinical follow-up periods of 42 and 29 months, respectively, 47% of patients with type 1 and none of those with type 2 experienced a relapse. In type 1 AIP, proximal biliary involvement (hazard ratio [HR], 2.12; P = .038) and diffuse pancreatic swelling (HR, 2.00; P = .049) were predictive of relapse, whereas pancreaticoduodenectomy reduced the relapse rate (vs the corticosteroid-treated group; HR, 0.15; P = .0001). After median follow-up periods of 58 and 89 months (types 1 and 2, respectively), the 5-year survival rates for both groups were similar to those of the age- and sex-matched US population. CONCLUSIONS Types 1 and 2 AIP have distinct clinical profiles. Patients with type 1 AIP have a high relapse rate, but patients with type 2 AIP do not experience relapse. AIP does not affect long-term survival.

Small-bowel imaging in Crohn's disease: a prospective, blinded, 4-way comparison trial

BACKGROUND With the introduction of new techniques to image the small bowel, there remains uncertainty about their role for diagnosing Crohns disease. OBJECTIVE To assess the sensitivity and specificity of capsule endoscopy (CE), CT enterography (CTE), ileocolonoscopy, and small-bowel follow-through (SBFT) in the diagnosis of small bowel Crohns disease. METHODS Prospective, blinded trial. SETTING Inflammatory bowel disease clinic at an academic medical center. PATIENTS Known or suspected Crohns disease. Exclusion criteria included known abdominal abscess and non-steroidal anti-inflammatory drug (NSAID) use. Partial small-bowel obstruction (PSBO) at CTE excluded patients from subsequent CE. INTERVENTIONS Patients underwent all 4 tests over a 4-day period. MAIN OUTCOME MEASUREMENTS Sensitivity, specificity, and accuracy of each test to detect active small-bowel Crohns disease. The criterion standard was a consensus diagnosis based upon clinical presentation and all 4 studies. RESULTS Forty-one CTE examinations were performed. Seven patients (17%) had an asymptomatic PSBO. Forty patients underwent colonoscopy, 38 had SBFT studies, and 28 had CE examinations. Small-bowel Crohns disease was active in 51%, absent in 42%, inactive in 5%, and suspicious in 2% of patients. The sensitivity of CE for detecting active small-bowel Crohns disease was 83%, not significantly higher than CTE (83%), ileocolonoscopy (74%), or SBFT (65%). However, the specificity of CE (53%) was significantly lower than the other tests (P < .05). One patient developed a transient PSBO due to CE, but no patients had retained capsules. LIMITATION Use of a consensus clinical diagnosis as the criterion standard-but this is how Crohns disease is diagnosed in practice. CONCLUSIONS The sensitivity of CE for active small-bowel Crohns disease was not significantly different from CTE, ileocolonoscopy, or SBFT. However, lower specificity and the need for preceding small-bowel radiography (due to the high frequency of asymptomatic PSBO) may limit the utility of CE as a first-line test for Crohns disease.

Do consensus indications for resection in branch duct intraductal papillary mucinous neoplasm predict malignancy? A study of 147 patients

BACKGROUND AND AIMS:Recent consensus guidelines suggest that presence of ≥1 of the following is an indication for resection (IR) of branch duct intraductal papillary mucinous neoplasm (IPMN-Br): cyst-related symptoms, main pancreatic duct diameter ≥10 mm, cyst size ≥30 mm, intramural nodules, or cyst fluid cytology suspicious/positive for malignancy. Among a cohort of patients with IPMN-Br we determined if the consensus IR (CIR), presence of multifocal IPMN-Br, or growth of cyst size on follow-up predict malignancy.METHODS:We identified 147 patients with IPMN-Br of whom 66 underwent surgical resection at diagnosis and 81 were followed conservatively, of whom 11 were resected during follow-up. Clinical, imaging, histological, and cyst fluid characteristics from all 147 patients with IPMN-Br were obtained from clinical records and/or by contacting the patients. In all cases, presence of CIR at baseline and during follow-up (N = 66), presence of multifocal cysts (N = 57), and increase in cyst size (N = 38) were noted.RESULTS:Among the 77 resected IPMN-Brs, at initial evaluation 61 had at least one CIR and 16 had none. Malignancy was present in 9/61 (15%) with CIR and 0/16 without IR (P = 0.1). When presence of any one of the CIR was taken as an indicator of malignancy, the CIR had a sensitivity, specificity, positive predictive value, and negative predictive value of 100%, 23%, 14%, and 100%, respectively. Prevalence of malignancy in those with single versus multifocal IPMN-Br was similar (13% vs 11%). No patient has developed malignancy after a median follow-up of 15 months. So far, none of the 38 patients with increase in cyst size on follow-up has developed malignancy related symptoms.CONCLUSIONS:Suggested consensus indications for resection identify all patients with malignancy; however, their specificity is low. In the short term it would be safe to follow patients without these features.

A Diagnostic Strategy to Distinguish Autoimmune Pancreatitis From Pancreatic Cancer

BACKGROUND & AIMS Autoimmune pancreatitis (AIP) and pancreatic cancer (PaC) have similar presentations; a diagnostic strategy is needed to distinguish the 2 diseases. METHODS We compared computed tomography images (for pancreas and other organ involvement), serum IgG4 levels, histology data, and the response to steroids between patients with AIP (n = 48) and those with PaC (n = 100). RESULTS Pancreatic imaging findings stratified patients into 3 groups. Group 1 was highly suggestive of AIP, with diffuse pancreatic enlargement without group 3 features (n = 25, 100% AIP). Group 2 was indeterminate, with normal-sized pancreas or focal pancreatic enlargement without group 3 features (n = 20, 75% AIP). Group 3 was highly suggestive of PaC, with presence of >1 low-density mass, pancreatic duct cutoff, or upstream pancreatic atrophy (n = 103, 92% PaC). Although all patients in group 1 had AIP, only 20 of the 25 patients had increased serum IgG4 levels and/or other organ involvement. Of the patients in groups 2 and 3 who did not have cancer, all those with serum IgG4 levels >2-fold the upper limit of normal or a combination of increased serum IgG4 levels and other organ involvement (n = 15) had AIP. In AIP subjects without supportive serologic evidence or other organ involvement (n = 14), diagnosis required pancreatic core biopsy (n = 7), steroid trial (n = 5), or resection (n = 2). CONCLUSIONS PaC can be distinguished from AIP by pancreatic imaging, measurement of serum IgG4 levels, and determination of other organ involvement. However, a pancreatic core biopsy, steroid trial, or surgery is required for diagnosis in approximately 30% of patients with AIP.

Treatment of relapsing autoimmune pancreatitis with immunomodulators and rituximab: the Mayo Clinic experience

Background There is a paucity of data on long-term management of type 1 autoimmune pancreatitis (AIP), a relapsing steroid-responsive disorder. Objective We describe our experience with treatment of relapses and maintenance of remission using steroid-sparing immunomodulators (IMs) and induction of remission using rituximab (RTX). Methods We obtained details of disease relapse and treatment in 116 type 1 AIP patients from clinic visits, medical records and telephone interviews. We compared relapse free survival in those treated with IMs versus those treated with steroids alone, assessed patients’ response to RTX, and identified treatment-related complications. Results During a median follow-up of 47 months, 52/116 AIP patients experienced 76 relapse episodes. The first relapse was treated with another course of steroids in 24 patients, and with steroids plus IM in another 27 patients; subsequent relapse-free survival until a second relapse was similar in the two groups (p=0.23). 38 patients received an IM for >2 months; failure or intolerance of IM therapy occurred in 17 (45%). 12 patients with steroid or IM intolerance/resistance were treated with RTX, an antiCD20 antibody; 10 (83%) experienced complete remission and had no relapses while on maintenance therapy. Treatment-limiting side effects related to RTX were uncommon. Conclusions In type 1 AIP relapses are common. Relapse-free survival is similar in those treated with steroids plus IM compared to those treated with steroids alone. Nearly half the patients on IMs will relapse during treatment. RTX is effective in the treatment of both IM resistant and steroid intolerant patients.

Safety and outcome of endoscopic snare excision of the major duodenal papilla

BACKGROUND The optimal management of adenoma of the major duodenal papilla is not established. Options include surgical excision, endoscopic ablative techniques, snare excision, and observation with periodic biopsies. The aims of this retrospective study were to determine the safety and outcome of snare excision of the papilla. METHODS Twenty-eight snare excisions of the papilla were performed in 26 patients. Sixteen had familial adenomatous polyposis. In 22 procedures, a minisnare was used, and in 6 cases a prototype snare was designed for excision of the papilla. Pancreatic stents were placed as a prophylactic measure at the discretion of the endoscopist (n = 10). RESULTS Histopathologically, resected tissue included 25 adenomas, 1 inflammatory polyp, 1 invasive malignancy, and 1 normal papilla. Immediate complications were minor bleeding (n = 2), mild pancreatitis (n = 4) and a duodenal perforation (n = 1). The presence (n = 10) or absence (n = 18) of a pancreatic stent did not correlate with subsequent pancreatitis (2 in each group, p = NS). Follow-up was available for 21 patients (median, 9 months; range, 2-32 months). Pancreatic duct stenosis at the papillectomy site resulted in pancreatitis in 2 patients (17%) at, respectively, 4 months and 24 months. Follow-up endoscopy revealed recurrent/residual adenomatous tissue in 2 (10%). CONCLUSIONS Snare excision of the major duodenal papilla was well tolerated. Most complications were mild except for a small duodenal perforation. Stenosis of the pancreatic duct orifice with pancreatitis may be a late complication.