Type 1 Autoimmune Pancreatitis in Europe: Clinical Profile and Response to Treatment.

BACKGROUND & AIMS: Autoimmune pancreatitis (AIP) is an immune-mediated disease of the pancreas with distinct pathophysiology and manifestations. Our aims were to characterize type 1 AIP in a large pan-European cohort and study the effectiveness of current treatment regimens. METHODS: We retrospectively analyzed adults diagnosed since 2005 with type 1 or not-otherwise-specified AIP in 42 European university hospitals. Type 1 AIP was uniformly diagnosed using specific diagnostic criteria. Patients with type 2 AIP and those who had undergone pancreatic surgery were excluded. The primary end point was complete remission, defined as the absence of clinical symptoms and resolution of the index radiologic pancreatic abnormalities attributed to AIP. RESULTS: We included 735 individuals with AIP (69% male; median age, 57 years; 85% White). Steroid treatment was started in 634 patients, of whom 9 (1%) were lost to follow-up. The remaining 625 had a 79% (496/625) complete, 18% (111/625) partial, and 97% (607/625) cumulative remission rate, whereas 3% (18/625) did not achieve remission. No treatment was given in 95 patients, who had a 61% complete (58/95), 19% partial (18/95), and 80% cumulative (76/95) spontaneous remission rate. Higher (≥0.4 mg/kg/day) corticosteroid doses were no more effective than lower (<0.4 mg/kg/day) doses (odds ratio, 0.428; 95% confidence interval, 0.054-3.387) and neither was a starting dose duration >2 weeks (odds ratio, 0.908; 95% confidence interval, 0.818-1.009). Elevated IgG4 levels were independently associated with a decreased chance of complete remission (odds ratio, 0.639; 95% confidence interval, 0.427-0.955). Relapse occurred in 30% of patients. Relapses within 6 months of remission induction were independent of the steroid-tapering duration, induction treatment duration, and total cumulative dose. CONCLUSIONS: Patients with type 1 AIP and elevated IgG4 level may need closer monitoring. For remission induction, a starting dose of 0.4 mg/kg/day for 2 weeks followed by a short taper period seems effective. This study provides no evidence to support more aggressive regimens.

Prevalence of autoimmune pancreatitis in pancreatic resection for suspected malignancy: a systematic review and meta-analysis.

BACKGROUND/OBJECTIVES: Autoimmune pancreatitis (AIP) is a diagnosis-challenging disease that often mimics pancreatic malignancy. Pancreatic resection is considered to be a curative treatment for pancreatic ductal adenocarcinoma (PDAC). This meta-analysis aims to study the incidence of AIP in patients who have undergone pancreatic resection for clinical manifestation of cancer. METHODS: A comprehensive search was conducted in three databases, PubMed, Embase and the Cochrane Library, using the terms 'autoimmune pancreatitis' and 'pancreatic resection' and supplemented by manual checks of reference lists in all retrieved articles. RESULTS: Ten articles were included in the final analysis. 8917 pancreatic resections were performed because of a clinical suspicion of pancreatic cancer. AIP accounted for 140 cases (1.6%). Type 1 AIP comprised the majority of cases, representing 94% (132 cases), while type 2 AIP made up the remaining 6% (eight cases) after further classification. AIP accounted for almost 26% of all cases of benign diseases involving unnecessary surgery and was overrepresented in males in 70% of cases compared to 30% in females. The mean age for AIP patients was 59 years. Serum CA 19 - 9 levels were elevated in 23 out of 47 (49%) AIP patients, where higher levels were detected more frequently in patients with type 1 AIP (51%, 22 out of 43) than in those with type 2 AIP (25%, 1 out of 4). The sensitivity of IgG4 levels in type 1 AIP was low (43%, 21/49 patients). CONCLUSION: Even with modern diagnostic methods, distinguishing between AIP and PDAC can still be challenging, thus potentially resulting in unnecessary surgical procedures in some cases. Serum CA 19 - 9 levels are not useful in distinguishing between AIP and PDAC. Work must thus be done to improve diagnostic methods and avoid unnecessary complicated surgery.

Autoimmune pancreatitis: Biopsy interpretation and differential diagnosis.

Autoimmune pancreatitis (AIP) is classified into type 1 (IgG4-related) and type 2 (IgG4-unrelated) and the interpretation of pancreatic biopsy findings plays a crucial role in their diagnosis. Needle biopsy of type 1 AIP in the acute or subacute phase shows a diffuse lymphoplasmacytic infiltrate, storiform fibrosis, obliterative phlebitis, and the infiltration of many IgG4-positive plasma cells. In a later phase, changes become less inflammatory and more fibrotic, making interpretations more challenging. Confirmation of the lack of 'negative' findings that are unlikely to occur in type 1 AIP (e.g., neutrophilic infiltration, abscess) is important to avoid an overdiagnosis. The number of IgG4-positive plasma cells increases to >10 cells/high-power field (hpf), and the IgG4/IgG-positive plasma cell ratio exceeds 40 %. However, these are minimal criteria and typical cases show >30 positive cells/hpf and a ratio >70 % even in biopsy specimens. Therefore, cases with a borderline increase in this number or ratio need to be diagnosed with caution. In cases of ductal adenocarcinoma, the upstream pancreas rarely shows type 1 AIP-like changes; however, the ratio of IgG4/IgG-positive plasma cells is typically <40 %. Although the identification of a granulocytic epithelial lesion (GEL) is crucial for type 2 AIP, this finding needs to be interpreted in conjunction with a background dense lymphoplasmacytic infiltrate. An isolated neutrophilic duct injury can occur in peritumoral or obstructive pancreatitis. Drug-induced pancreatitis in patients with inflammatory bowel disease often mimics type 2 AIP clinically and pathologically. IL-8 and PD-L1 are potential ancillary immunohistochemical markers for type 2 AIP, requiring validation studies.

A Better Understanding of Pediatric Autoimmune Pancreatitis: Over 13 Years of Experience.

OBJECTIVES: Pediatric autoimmune pancreatitis (P-AIP) is an uncommon disease whose diagnosis requires strong clinical suspicion. Late diagnosis increases morbidity. We aimed to compare the usefulness of the 2011 International Consensus Diagnostic Criteria (ICDC) for Autoimmune Pancreatitis with the 2018 INSPPIRE (INternational Study Group of Pediatric Pancreatitis: In search for a cuRE) criteria. METHODS: We retrospectively analyzed demographics and clinical, laboratory, radiological, and histological findings at diagnosis and during long-term follow-up in children diagnosed with AIP in 2 tertiary hospitals between 2008 and 2021. RESULTS: We included 11 patients [6 girls; median age at diagnosis, 12.5 (range 2.8-15.7) years]. The most common symptom was abdominal pain. Pancreatic enzymes were elevated in 10 patients, and serum immunoglobulin G4 was elevated in 1. Magnetic resonance imaging showed enlargement of the pancreatic head in 10 patients and general pancreatic enlargement in 1. Pancreatic and papilla tissue were obtained from 9 patients. All patients received corticosteroids (prednisolone), and 4 also received azathioprine. According to the ICDC, all patients were classified as probable or non-otherwise specified AIP. According to INSPPIRE criteria, all patients were classified as AIP. Using the INSPPIRE criteria would have avoided biopsies in 6 patients who responded well to corticosteroids. CONCLUSIONS: The INSPPIRE criteria are useful. Using the ICDC in pediatric patients can delay diagnosis and result in unnecessary invasive tests.

Differential Diagnosis of IgG4-related Pancreatitis and Pancreatic Cancer by MRI Features and Its Correlation with Serum IgG4 Level.

It was to analyze the diagnostic value of MRI in immunoglobulin G (IgG4)-related autoimmune pancreatitis (AIP) and pancreatic cancer (PC) and its relationship with serum IgG4 level. 35 patients with IgG4-related AIP (group A1) and 50 patients with PC (group A2) were enrolled. MRI was performed to determine serum IgG4 levels. Spearsman was used to analyze the relationship between MRI characteristics and serum IgG4 level. It was found that patients in group A1 showed double duct sign (DDS), pancreatic duct (PD) perforation sign, the proportion of main PD truncation, and main PD diameter/pancreatic parenchymal width ratio, which were different from those of patients in group A2 (P < 0.05). MRI had a sensitivity (Sen) of 88%, specificity (Spe) of 91.43%, accuracy (Acc) of 89.41%, positive predictive value (PPV) of 0.936, and negative predictive value(NPV) of 0.842 for the diagnosis of IgG4-related AIP and PC. Serum IgG4 levels were significantly negatively correlated with DDS and main PD truncation, significantly positively correlated with PD penetration sign, and extremely significantly negatively correlated with main PD diameter/pancreatic parenchymal width (P < 0.001). The results showed that MRI had high sensitivity and specificity for differentiating IgG4-related AIP from PC, and the diagnostic effect was good, which had a high correlation with serum IgG4 levels in patients.

Recent progress on the treatment of type 1 autoimmune pancreatitis and IgG4-related disease.

IgG4-related disease (IgG4-RD) is a fibroinflammatory disorder recognized as a novel clinical entity with either synchronous or metachronous multiorgan involvement. Autoimmune pancreatitis (AIP) is classified into two types: type 1 AIP as a pancreatic manifestation of IgG4-RD and type 2 AIP with granulocytic epithelial lesion and occasional association with ulcerative colitis. Although the pathogenic mechanism still remains unclear, possible multipathogenic factors such as genetic factors, disease-specific or related antigens, and abnormal innate or adaptive immunity may be involved in the development of IgG4-RD. Many immunocytes including M2 macrophages, plasmablasts, B cells, and T-cells (Th2-CD4+T, follicular helper T-cells, and CD4+SLAMF7+cytotoxic T-cells) play important roles in the pathogenesis. Conventional induction and maintenance therapies with glucocorticoid or rituximab are recommended in all symptomatic patients with active IgG4-RD. In those at risk for irreversible damage in any organs, this should be done urgently, regardless of symptoms. As no randomized clinical trials other than glucocorticoid maintenance therapy for type 1 AIP have been performed, the comprehensive management for IgG4-RD has not been established yet. Targeted treatment approaches against the plasmablast to B cell lineage and the CD4+ SLAMF7+ cytotoxic T-cell seem to be promising for the future-directed treatment.

Is Surgery in Autoimmune Pancreatitis Always a Failure?

Autoimmune pancreatitis is a rare form of chronic pancreatitis of presumed autoimmune etiology. Due to significant overlap in clinical and imaging characteristics, misdiagnosis as a pancreatic malignancy is common. As a result, a significant number of patients undergo a major pancreatic resection, associated with considerable morbidity, for a disease process that generally responds well to corticosteroid therapy. In the past ten years, important advances have been made in understanding the disease. Several diagnostic criteria have been developed to aid in diagnosis. Despite this, pancreatic resection may still be required in a subset of patients to reliably exclude pancreatic malignancy and establish a definite diagnosis of autoimmune pancreatitis. This article aimed to define the role of surgery in autoimmune pancreatitis, if any. For this purpose, published case series of patients with a diagnosis of autoimmune pancreatitis, based on the histopathological examination of surgical specimens, were reviewed and patients' clinical, radiological and serological details were assessed. At the end, histopathologic examinations of patients who underwent pancreatic resection at our department in the last 10 years were retrospectively reviewed in order to identify patients with autoimmune pancreatitis and assess their clinical characteristics.

Diagnostic Utility of Serum IgG4 in Autoimmune Pancreatitis: An Updated Comprehensive Systematic Review and Meta-analysis.

OBJECTIVES: Despite many studies suggesting an association between serum immunoglobulin G4 (sIgG4) and autoimmune pancreatitis (AIP), the evidence of utility in differentiation between AIP and pancreatic cancer (PC) remain uncertain. METHODS: The analysis based on published studies. Data were pooled by means of a random-effects model, and sensitivity, specificity, diagnostic odds ratios (DOR), areas under summary receiver operating characteristic curves were calculated. RESULTS: In the included thirteen studies, sIgG4 were measured in 594 patients with AIP and 958 patients with PC. The pooled sensitivity, specificity, DOR, and area under the curve were 0.72 [95% confidence interval (CI): 0.68-0.75], 0.93 (95% CI: 0.92-0.95), 51.37 (95% CI: 23.20-113.74), and 0.91 (95% CI: 0.87-0.95). Subgroup analyses of the DORs for region and year: Asia, (112.10; 95% CI: 27.72-453.32), non-Asia (26.01; 95% CI: 12.38-54.65), and year before 2011 (107.61; 95% CI: 39.30-294.68), year after 2011 (26.96; 95% CI: 9.78-74.32). Overall, sIgG4 was associated with AIP, the result revealed a moderate sensitivity 0.72 and high specificity 0.93. In the meta-analysis, the pooled DOR of sIgG4 levels of 2-fold upper limit 50.44 was similar with the DOR 51.37 when 1-fold cut-off value, but the summary receiver operating characteristic was 0.755 and 0.91. The higher specificity (from 93% to 98%) derived from the cut-off value (from 130-140 to 260-280 mg/dL) for sIgG4 occurred at a significant reduction in sensitivity (from 72% to 43%). CONCLUSIONS: The study revealed sIgG4 is a good marker of AIP. Screening of sIgG4 may help clinicians differentiate between AIP and PC, and the best cut-off value should be 140 rather than 280 mg/dL.

Autoimmune Pancreatitis: From Pathogenesis to Treatment.

Autoimmune pancreatitis (AIP) is a rare disease. The diagnosis of AIP is difficult and should be made by a comprehensive evaluation of clinical, radiological, serological, and pathological findings. Two different types of AIP have been identified: autoimmune pancreatitis type 1 (AIP-1), which is considered a pancreatic manifestation of multiorgan disease related to IgG4, and autoimmune pancreatitis type 2 (AIP-2), which is considered a pancreas-specific disease not related to IgG4. Although the pathophysiological conditions seem to differ between type 1 and type 2 pancreatitis, both respond well to steroid medications. In this review, we focused on the pathogenesis of the disease to develop a tool that could facilitate diagnosis and lead to the discovery of new therapeutic strategies to combat autoimmune pancreatitis and its relapses. The standard therapy for AIP is oral administration of corticosteroids. Rituximab (RTX) has also been proposed for induction of remission and maintenance therapy in relapsing AIP-1. In selected patients, immunomodulators such as azathioprine are used to maintain remission. The strength of this review, compared with previous studies, is that it focuses on the clear difference between the two types of autoimmune pancreatitis with a clearly delineated and separate pathogenesis. In addition, the review also considers various therapeutic options, including biologic drugs, such as anti-tumor necrosis factor (TNF) therapy, a well-tolerated and effective second-line therapy for AIP type 2 relapses or steroid dependence. Other biologic therapies are also being explored that could provide a useful therapeutic alternative to corticosteroids and immunosuppressants, which are poorly tolerated due to significant side effects.

Serum free light chain assessment in type 1 autoimmune pancreatitis.

BACKGROUND: /Object: Some patients with type 1 autoimmune pancreatitis (AIP), the pancreatic manifestation of IgG4-related disease, have normal serum IgG4. The aim of this study is to investigate the diagnostic value of measuring serum free light chains (FLCs) in type 1 AIP. MATERIALS AND METHODS: Thirty-seven patients with type 1 AIP, and 21 healthy, 17 alcoholic chronic pancreatitis (ACP), 21 idiopathic chronic pancreatitis (ICP) and 20 pancreatic cancer (PC) patients were enrolled. Serum IgG4 and FLC concentrations were measured using sFLC Freelite assays on a nephelometric analyzer. RESULTS: Active AIP patients have significantly higher serum levels of κ (median 30.97 (12.3-227.0) mg/L) and λFLC (median 20.53 (12.36-102.7) mg/L)) than healthy controls (κFLC; median 12.5 (3.1-52.1) mg/L), λFLC: median 12.45 (5.4-39.5) mg/L) (p < 0.05) correlating with raised serum IgG4, and significantly higher summated FLCs (∑) (median 53.09 (25.0-218.0) mg/L) than ICP patients (median 26.77 (15.0-89.2) mg/L) and healthy controls (median 24.43 (8.5-91.6) mg/L) (p < 0.05). AIP patients (median 1.43 (0.84-3.24)) showed significantly higher κ/λ ratios than ACP (median 0.83 (0.42-1.18)), ICP (median 0.87 (0.47-2.16)), PC patients (median 0.90 (0.48-1.27)) and healthy controls (median 0.963 (0.51-1.32)). There was a correlation between increased κ and λ FLCs levels and the number of affected organs involved in IgG4 related disease. CONCLUSION: Patients with type 1 AIP have increased serum k and λ FLC concentrations, Σ FLC, and κ/λ ratios. These novel biomarkers may be useful in the diagnosis of type 1 AIP and in monitoring disease activity.

Probe-based confocal laser endomicroscopy for the diagnosis of pancreatic ductal structures.

BACKGROUND AND AIM: The image-based diagnosis of pancreatic diseases can be difficult and requires pathological evaluation. Probe-based confocal laser endomicroscopy (pCLE) enables real-time observation of the microscopic tissue pattern of lesion and may be a useful assistance for the diagnosis. This study aimed to evaluate the feasibility and utility of pCLE for the diagnosis of pancreatic diseases. METHODS: Thirty patients who underwent endoscopic retrograde cholangiopancreatography with pCLE for the evaluation of indeterminate pancreatic diseases from June 2015 to October 2018 were included in this study. The pCLE findings were interpreted according to the Miami Classification. RESULTS: Among a total of 30 patients, 12, 10, 4, and 4 patients received the definitive diagnoses of pancreatic ductal adenocarcinoma (PDAC), main duct intrapapillary mucinous neoplasm, autoimmune pancreatitis, and chronic pancreatitis, respectively. The diagnostic accuracy of pCLE for PDAC and pancreatitis (96.7% and 93.3%, respectively) was higher than that of cytology (76.7% and 63.3%, respectively) (P = 0.0227 and 0.0048, respectively). The sensitivity of pCLE for PDAC was significantly higher (91.7%) than that of cytology (41.7%) (P = 0.0094). Moreover, the specificity of pCLE for pancreatitis was significantly higher than that of cytology (90.9% vs 50%; P = 0.0029). However, the diagnostic accuracies of pCLE and cytology for main duct intrapapillary mucinous neoplasm did not differ significantly (96.7% and 86.7%, respectively). CONCLUSIONS: Probe-based confocal laser endomicroscopy may be effective for the diagnosis of pancreatic diseases as adjunct modality. It requires technical learning and further evaluation of its usefulness.

Clinical Usefulness of Serum Autotaxin for Early Prediction of Relapse in Male Patients with Type 1 Autoimmune Pancreatitis.

BACKGROUND: Serum IgG4 level is a useful diagnostic marker for autoimmune pancreatitis (AIP), but it is difficult to use to predict relapse. AIMS: We investigated whether serum autotaxin (ATX) level is predictive of AIP relapse after steroid therapy. METHODS: Fifty-six patients with type 1 AIP were investigated. We measured serum ATX at the time of diagnosis. We selected 24 males for whom serum samples during steroid therapy had been obtained and measured serum ATX at steroid therapy for induction of remission and at maintenance therapy. In the relapse group, we also measured ATX at the time of relapse. RESULTS: ATX was significantly higher in female patients than in male patients. In order to clarify changes in ATX during steroid therapy, we focused on 24 male patients. We found that ATX decreased significantly during steroid therapy for induction of remission and at the time of maintenance therapy. In half of all patients who relapsed during maintenance therapy, ATX was significantly elevated at the time of relapse compared with that of induction therapy (P = 0.039). When we compared ATX at the time of maintenance therapy between patients with relapse and without, we observed significantly higher ATX in the former (P = 0.024). We found that the combination of ATX and elastase-1 could predict relapse with high accuracy (95%). CONCLUSIONS: Preliminary evidence suggests that serum ATX might serve as a candidate biomarker to predict relapse of AIP as well as to monitor the effect of steroid therapy.

Pitfalls of diagnosing autoimmune pancreatitis.

The diagnosis of the rare disease autoimmune pancreatitis (AIP) is demonstrated in the case of a patient who underwent a series of examinations that were unable to unequivocally prove the diagnosis of benignity. The disease as a form of chronic pancreatitis, and the most important and first objective of the examination is to exclude malignant disease of the pancreas and biliary tract. While imaging led to suspicion of malignancy, repeated histological examinations did not confirm it. After we were able to exclude suspected carcinoma according to the available diagnostic criteria, AIP was confirmed, and a diagnosis of type I was made, which belongs to the group of diseases characterized by high levels of immunoglobulin G4 (IgG4) in the blood serum. Successful treatment with glucocorticoids was initiated with induction of disease remission. However, AIP shows frequent relapses and this should also be borne in mind during treatment. Our case report also describes such a case.

Impact of diet and genes on murine autoimmune pancreatitis.

The impact of environmental factors, such as diet, and the genetic basis of autoimmune pancreatitis (AIP) are largely unknown. Here, we used an experimental murine AIP model to identify the contribution of diet to AIP development, as well as to fine-map AIP-associated genes in outbred mice prone to develop the disease. For this purpose, we fed mice of an autoimmune-prone intercross line (AIL) three different diets (control, calorie-reduced and western diet) for 6 months, at which point the mice were genotyped and phenotyped for AIP. Overall, 269 out of 734 mice (36.6%) developed AIP with signs of parenchymal destruction, equally affecting mice of both sexes. AIP prevalence and severity were reduced by approximately 50% in mice held under caloric restriction compared to those fed control or western diet. We identified a quantitative trait locus (QTL) on chromosome 4 to be associated with AIP, which is located within a previously reported QTL. This association does not change when considering diet or sex as an additional variable for the mapping. Using whole-genome sequences of the AIL founder strains, we resolved this QTL to a single candidate gene, namely Map3k7. Expression of Map3k7 was largely restricted to islet cells as well as lymphocytes found in the exocrine pancreas of mice with AIP. Our studies suggest a major impact of diet on AIP. Furthermore, we identify Map3k7 as a novel susceptibility gene for experimental AIP. Both findings warrant clinical translation.

Prevalence of histological features resembling autoimmune pancreatitis in neoplastic pancreas resections.

AIMS: Types 1 and 2 autoimmune pancreatitis (AIP) can mimic pancreatic neoplasia. Due to the small quantity of tissue in mass-targeted pancreas biopsies, inflammatory features may raise the differential of AIP. However, the frequency of AIP-like histology in neoplastic pancreas is not well characterised. Therefore, the specificity of inflammatory lesions on biopsy with respect to the diagnosis of AIP is uncertain. METHODS AND RESULTS: Neoplastic pancreas resections performed at our institution between 2008 and 2019 were retrospectively reviewed. Features of AIP types 1 and 2 were assessed in the non-neoplastic areas. If features of immunoglobulin (Ig)G4-associated AIP were seen, IgG4 immunohistochemistry was performed. We identified 163 neoplastic pancreas resections. Of these, 34 had one or more types of inflammatory lesions in non-neoplastic pancreatic tissue. Dense lymphoplasmacytic inflammation mimicking type 1 AIP was found in six cases with mild to moderately increased IgG4-positive plasma cells. Neutrophilic infiltrates in small intralobular ducts were found in 20 cases. Mild extralobular ductitis or duct microabscess was found in 10 specimens. Marked neutrophilic duct destruction that resembled granulocytic epithelial lesions was found in 12 cases. Some cases showed multiple features. CONCLUSION: Approximately 20% of neoplastic pancreas resections showed focal areas that could raise the differential of AIP. More cases showed neutrophilic predominant inflammation as seen in type 2 autoimmune pancreatitis, compared to dense lymphoplasmacytic infiltrates seen in type 1 AIP. Pathologists must be cautious when making a diagnosis of AIP on biopsy tissue based on histological findings alone.

The use of immunohistochemistry for IgG4 in the diagnosis of autoimmune pancreatitis: A systematic review and meta-analysis.

BACKGROUND: The diagnosis of autoimmune pancreatitis (AIP) remains challenging, especially when serum IgG4 is normal or imaging features are indeterminate. We performed a systematic review and meta-analysis to evaluate the performance of IgG4 immunostaining of pancreatic, biliary, and ampullary tissues as a diagnostic aid for AIP. METHODS: A comprehensive literature search of the PubMed, EMBASE, and Ovid MEDLINE databases was conducted until February 2020. The methodological quality of each study was assessed according to the Quality Assessment of Diagnostic Accuracy Studies checklist. A random-effects model was used to summarize the diagnostic odds ratio and other measures of accuracy. RESULTS: The meta-analysis included 20 studies comprising 346 patients with AIP and 590 patients with other pancreatobiliary diseases, including 371 pancreatobiliary malignancies. The summary estimates for tissue IgG4 in discriminating AIP and controls were as follows: diagnostic odds ratio 38.86 (95% confidence interval (CI), 18.70-80.75); sensitivity 0.64 (95% CI, 0.59-0.69); specificity 0.93 (95% CI, 0.91-0.95). The area under the curve was 0.939 for tissue IgG4 in discriminating AIP and controls. Subgroup analysis revealed no significant difference in diagnostic accuracy according to control groups (pancreatobiliary cancer versus other chronic pancreatitis) and sampling site (pancreas versus bile duct/ampulla). CONCLUSIONS: Current data demonstrate that IgG4 immunostaining of pancreatic, biliary, and ampullary tissue has a high specificity but moderate sensitivity for diagnosing AIP. IgG4 immunostaining may be useful in supporting a diagnosis of AIP when AIP is clinically suspected, but a combination of imaging and serology does not provide a conclusive diagnosis.

Significance of peripheral eosinophilia for diagnosis of IgG4-related disease in subjects with elevated serum IgG4 levels.

OBJECTIVES: In this study, we aim to assess the diagnostic utility of elevated serum IgG4 (sIgG4) concentration alone and in combination with peripheral eosinophilia (PE) for IgG4-related disease (IgG4-RD). METHODS: From the Mayo Clinic, Rochester electronic medical record database we identified 409 patients with above normal levels of sIgG4 (reference range 121-140 mg/dL) who had sIgG4 measured to differentiate IgG4-RD from another disease. RESULTS: Among 409 patients with any elevation in sIgG4 levels, 129 (31.5%) had a definite diagnosis of IgG4-RD. The prevalence of PE increased with increasing sIgG4 levels and was more likely to be seen in subjects with IgG4-RD vs. non-IgG4-RD at ≥1X (n = 35/120, 29.2% vs. n = 23/258, 8.9%; p < 0.001), ≥2X (n = 23/64, 35.9% vs. n = 5/54,9.3%; p = 0.001) and ≥3X (n = 18/42, 42.9% vs. n = 0/9, 0%; p = 0.015) of sIgG4 upper limit of normal (ULN), respectively. After adjusting for gender and age, sIgG4 levels ≥ 2X ULN with PE as a predictor, had a higher positive predictive value in predicting IgG4-RD (72.2% vs. 65.9%) with an Area Under the Receiver Operatic Characteristic Curve (AUC) of 0.776, compared to sIgG4 ≥ 2X ULN without PE predictor (AUC = 0.74), p = 0.016. PE, sIgG4≥2X ULN, male gender, and age independently predicted the disease with odds ratio of 4.89 (95% CI:2.51-9.54), 3.78 (95% CI:2.27-6.28), 2.78 (95% CI:1.55-4.97), and 1.03 (95% CI:1.02-1.05), respectively. CONCLUSION: Even in subjects in whom IgG4-RD is suspected, only a minority (∼30%) with elevated sIgG4 levels have IgG4-RD. sIgG4 by itself is more specific at higher levels, though never diagnostic. PE increases with increasing sIgG4 and adds diagnostic value at higher sIgG4 levels.

Efficacy and limitations of the histological diagnosis of type 1 autoimmune pancreatitis with endoscopic ultrasound-guided fine needle biopsy with large tissue amounts.

OBJECTIVES: We examined the efficacy and limitations of acquiring large specimens by endoscopic ultrasound-guided fine needle biopsy (EUS-FNB) for diagnosing type 1 autoimmune pancreatitis (AIP). METHODS: Patients from 12 institutions with non-neoplastic diseases or pancreatic ductal adenocarcinoma (PDAC) with large EUS-FNB specimens were investigated. Slides stained with hematoxylin-eosin, elastic, IgG4, and IgG stains were evaluated. The IgG4- and IgG-positive cell numbers were counted in three foci. The diagnoses were based on the Japan Pancreas Society 2011 (JPS 2011) criteria and the International Consensus Diagnostic Criteria (ICDC). RESULTS: We analyzed 85 non-neoplastic (definite type 1 AIP in 73/85 based on the ICDC) cases and 64 PDAC cases. IgG4-positive cells were numerous (>10 in 85.9%), and the IgG4/IgG ratios were high (>40% in 81.2%). Plasma cell crushing by an artifact caused unsuccessful immunostaining, notably in smaller samples. Tissue lengths were an important factor for the presence of storiform fibrosis and obliterative phlebitis, but storiform fibrosis was equivocal even in large tissues. A definite or possible histological diagnosis was achieved in 45.9% (39/85) and 41.2% (35/85), respectively, and contributed to the definite final diagnosis of type 1 AIP in 33.3% (ICDC) and 55.6% (JPS 2011) in cases with segmental/focal lesions. In the PDAC group, >10 IgG4-positive cells was rare (2/58), but elastic stains revealed fibrous venous occlusions in 10.3% (6/58). CONCLUSIONS: EUS-FNB with large tissue amounts was useful for diagnosing type 1 AIP, notably by facilitating successful IgG4 immunostaining, but definite diagnosis may not be achieved even in cases with large specimens.

Comparison of a 22-gauge Franseen-tip needle with a 20-gauge forward-bevel needle for the diagnosis of type 1 autoimmune pancreatitis: a prospective, randomized, controlled, multicenter study (COMPAS study).

BACKGROUND AND AIMS: Histologic diagnosis of autoimmune pancreatitis (AIP) using EUS-guided FNA (EUS-FNA) is difficult. To address this issue, new fine-needle biopsy (FNB) needles were recently developed. Here, we prospectively evaluated 2 newly designed EUS-FNB needles for histologic evaluation in patients with type 1 AIP. METHODS: This was a prospective, randomized, multicenter trial comparing biopsy specimens obtained with a 22-gauge Franseen needle or a 20-gauge forward-bevel needle in patients with suspected type 1 AIP. AIP was diagnosed according to international consensus diagnostic criteria. The primary endpoint was the sensitivity of EUS-FNB needles, and secondary endpoints were the amount of specimen obtained, histology of the pancreas based on evaluation of lymphoplasmacytic sclerosing pancreatitis (LPSP), and contribution of histologic findings to the diagnosis of AIP. RESULTS: One hundred ten patients were randomly assigned to the Franseen group (22-gauge Franseen needle) or the forward-bevel group (20-gauge forward-bevel needle). EUS-FNB sampling was successful in all patients. Nine patients were excluded because of diagnoses other than AIP. Compared with the forward-bevel needle, the Franseen needle obtained a significantly greater number of high-power fields. Of 101 patients, 39 patients (78%) in the Franseen group and 23 patients (45%) in the Forward-bevel group were diagnosed with level 1 or 2 LPSP (P = .001). Thirty-six patients could not be diagnosed with type 1 AIP without EUS-FNB specimen results. CONCLUSIONS: The 22-gauge Franseen needle should be routinely used for histologic diagnosis of type 1 AIP. (Clinical trial registration number: UMIN 000027668.).

A Nondilated Main Pancreatic Duct Predicts Type 2 Autoimmune Pancreatitis: Comparative Study of Resected Pancreatic Head Masses.

BACKGROUND: Chronic pancreatitis (CP), pancreatic cancer (PCa), and autoimmune pancreatitis (AIP) often present as a pancreatic mass. Accurate diagnosis is not always possible; up to 8% of surgical procedures are performed in benign pancreatic masses presumed to be malignant. OBJECTIVES: We aimed to compare clinical and imaging characteristics of resected focal type 2 AIP, CP, and PCa and identify factors that could improve preoperative differential diagnosis. METHODS: Charts from patients that underwent pancreatic resection under suspicion of PCa between 2000 and 2014 were reviewed. Clinical and imaging data were recorded. Subjects were grouped as type 2 AIP, CP, and PCa. RESULTS: We included 79 cases; 41 men, mean age of 57.3 years/old ± 15.6 SD. Pathology report was type 2 AIP (20%), CP (10%), and PCa (70%). According to international consensus criteria for AIP 11 cases were deemed probable type 2 and 5 as unspecific pancreatic mass. A nondilated main pancreatic duct (MPD) was associated with AIP (OR 9.3; 95% CI 3.05-28.7), p < 0.001; obstructive jaundice (OR 28.5; 95% CI 8.18-79.5); and a dilated MPD (OR 5.21; 95% CI 1.9-14.6) suggested malignancy. CONCLUSIONS: In the setting of undetermined pancreatic focal mass, a nondilated MPD suggests the diagnosis of type 2 AIP.