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S1280 Serum IgG4 Levels and Extrapancreatic Lesions in Autoimmune Pancreatitis
AGA Abstracts
sclerosing cholecystitis, sclerosing sialadenitis, and retroperitoneal fibrosis) and clinical factors were retrospectively assessed. Results: The mean serum IgG4 level of the 40 AIP patients was 411±448 mg/dl. Based on the ROC curve data (Fig. 1), the optimal cutoff value for the serum IgG4 to distinguish between AIP patients with and without extrapancreatic lesions was 220 mg/dl; 18 (78%) of 23 patients whose serum IgG4 was ≥ 220 mg/dl had extrapancreatic lesions, while 4 (24%) of 17 patients whose serum IgG4 was < 220 mg/dl had extrapancreatic lesions (p=0.0011). No significant differences between the 2 groups in age, gender, frequency of pancreatic enlargement or obstructive jaundice, and associated sialadenitis, retroperitoneal fibrosis, and diabetes mellitus were identified. Sclerosing cholangitis and cholecystitis were more frequent in patients with serum IgG4 levels higher than 220 mg/dl than in those with lower serum IgG4 levels (p=0.0002 and p=0.0204, respectively). The number of associated extrapancreatic lesions was significantly greater in patients with high serum IgG4 level (p=0.0003). Conclusions: AIP patients with serum IgG4 levels ≥ 220 mg/ dl frequently have extrapancreatic lesions. In differentiating AIP from pancreatic cancer, recognition of the presence of extrapancreatic lesions in patients with serum IgG4 levels ≥ 220 mg/dl strongly supports the diagnosis of AIP.
S1278 Is the Search for Serum Antibodies to Carbonic Anhydrase II Helpful for the Diagnosis of Auto-Immune Pancreatitis? Frédérique Maire, Catherine Johanet, Hélène Voitot, Yann Lebaleur, Thibaud Lefebvre, Vinciane Rebours, Eric Ballot, Olivia Hentic, Marie-Pierre Vullierme, Philippe Levy, Philippe B. Ruszniewski, Pascal Hammel Background : Auto-immune pancreatitis (AIP) should be suspected in patients with unexplained pancreatitis. AIP is recognized according to HISORt criteria (including histology, pancreatic imaging, elevated serum IgG4 level and response to steroid therapy) as recently proposed by the Mayo Clinic. These criteria are highly selective and often difficult to fulfill. Previous studies suggested that carbonic anhydrase (CA) II is a target antigen in AIP. The aim of the present study was to evaluate the prevalence of serum antibodies to CA II in patients with AIP. Patients and Methods : 21 patients with AIP fulfilling HISORt criteria were retrospectively studied. An enzyme-linked immunosorbent assay was used to quantify serum antibodies to CA II. The concentrations of serum IgG4 were measured by nephelemetry with a cut-off of 2 g/L. Thirty two patients with pancreatic adenocarcinoma or non-auto immune pancreatitis, and 96 healthy subjects served as controls. Results : 21 patients (13 males), median age 37 years [21-70] had AIP, histologically defined (57%) or with typical pancreatic imaging and response to steroids (43%). Pancreatic imaging revealed mass or irregular ducts in 71% and 48% of the cases, respectively. Four patients had ulcerative colitis. Serum IgG4 were elevated in 1 patient (5%). Serum antibodies to CA II were present in 2 patients (10%). Both had a pancreatic mass, and underwent pancreaticoduodenectomy. They developed post-operative, steroid-sensitive cholangitis. Serum antibodies to CA II were present in 3 healthy controls (3%) and in 1 subject with alcoholic chronic pancreatitis (3%). No patient with pancreatic cancer had serum antibodies to CA II. The sensitivity, specificity, positive and negative predictive values of antibodies to CA II for the diagnosis of AIP were 10%, 97%, 33%, et 87%, respectively. Conclusion : 10% of patients with well-defined AIP have serum antibodies to CA II in an European center. This prevalence is in accordance with previously reported studies, but lower than in Japanese series. The high specificity of CA II antibodies might be helpful for AIP diagnosis, particularly when serum IgG4 is normal.
S1281 Prednisolone Maintenance Therapy Reduces the Relapse Rate of Autoimmune Pancreatitis Takayoshi Nishino, Fumitake Toki, Keiko Shiratori Background and Aim: Autoimmune pancreatitis (AIP) is a unique form of chronic pancreatitis, and although it responds well to oral prednisolone (PSL) therapy, little is known about the effect of PSL maintenance therapy on the long-term outcome of AIP. This study was undertaken to evaluate the outcome of AIP with and without PSL maintenance therapy, and factors related to the relapse of AIP were analyzed. Patients and Methods: Thirty-six AIP patients, average age 65 years old and average observation period 54.7 months were, divided into a group treated with PSL that also received PSL maintenance therapy (Group A, n=23), a group treated with PSL that did not receive PSL maintenance therapy (Group B, n=6), and a group not treated with PSL at all (Group C, n=7). The initial dose of PSL was 30-40 mg/ day, and it was gradually tapered. The maintenance dose ranged from 2.5 mg/day to10 mg/ day. PSL maintenance therapy was defined as PSL therapy that continued for more than 12 months after the initial PSL therapy. Relapse of AIP was defined as the occurrence of a pancreatic lesion and/or extrapancreatic lesions after remission in response to the initial therapy. Results: 1. AIP relapsed in 4 (17%) of 23 the AIP patients (17%) in Group A and was manifested by pancreatic swelling and bile duct stricture in two patients each. Relapse occurred in 5 (83%) of the 6 patients (83%) in Group B, and was manifested by pancreatic swelling and salivary gland swelling in two patients each and by bile duct stricture in one patient. Relapse occurred in three (43%) of the 7 patients in Group C, and was manifested as pancreatic swelling, salivary gland swelling, and bile duct stricture in one each. 2. The relapse rate in Group A was significantly lower than in Group B (p=0.001) based on the cumulative relapse rates curves. 3. Univariate analysis revealed post treatment serum IgG4 levels above 220 mg/dl was a significant risk factor for relapse of AIP (p=0.04), however, PSL maintenance therapy significantly decreased the relapse rate (p=0.02). A stepwise multivariate analysis confirmed PSL maintenance therapy decreased the relapse rate of AIP (OR=0.045 (95%CI=0.002-0.852), p=0.039). Conclusions: PSL maintenance therapy reduced the overall relapse rate of AIP in various organs. We concluded that PSL maintenance therapy should be taken into consideration as a mean of improving the long-term outcome of AIP.
S1279 Analysis of Pancreatic and Peripheral Regulatory T Cells in Patients with Autoimmune Pancreatitis Kazushige Uchida, Hideaki Miyoshi, Masanori Koyabu, Takeo Kusuda, Norimasa Fukata, Tsukasa Ikeura, Masaaki Shimatani, Toshiro Fukui, Mitsunobu Matsushita, Makoto Takaoka, Kazuichi Okazaki Background & Aim: Autoimmune pancreatitis (AIP) is a newly recognized pancreatic disorder. Patients with AIP have several immunologic and histologic abnormalities specific to the disease. Typical immunological abnormalities are increased levels of serum gammaglobulin, IgG, or IgG4, and the presence of autoantibodies. The histopahtological findings show storiform fibrosis with infiltration of lymphocytes and IgG4-positive plasmacytes. However, the role of IgG4 is unclear. Recently, it has been reported that regulatory T cells (Tregs) are involved in both the development of various autoimmune diseases and the shift of Bcell toward IgG4 producing plasmacytes. To clarify the role of CD4+CD25high Tregs in pathophysiology of AIP, we studied the number of regulatory T cells in the pancreas by immunohistochemistory and IL-10 producing cells in the peripheral blood lymphocytes by flowcytometry. Subjects and Methods: We recruited 37 patients with AIP for this study. Pancreatic tissue was sectioned from 6 AIP patients and 6 patients with pancreatic ductal adenocarcinoma. We studied infiltrating cells in the pancreas by immunohistochemistry. IL10 producing CD4+CD25high Tregs were analyzed from peripheral blood by flow cytometry. Results: There were no significant differences in CD3+, CD4+, or CD79+ cells between the AIP (CD3: 63.1±27.1, CD4: 48.2±32.9, CD79: 24.1±9.2 cells/HPF) and control sections (CD3: 73.6±37.1, CD4: 34.0±23.8, CD79: 14.5±14.6 cells/HPF). On the other hand, CD4+ Foxp3+ cells were increased in the pancreas with AIP (24.6±18.0 cells/HPF) compared with controls (5.1±4.3 cells/HPF). In patients with the untreated AIP, the numbers of CD4+CD25high Tregs and IgG4 are positively correlated (R=0.50, p<0.05). IL-10 producing CD4+CD25high cells and IgG4 also positively correlated (R=0.53, p<0.05). Conclusion: Increased numbers of CD4+CD25high Tregs may influence IgG4 production in AIP.
S1282 Detection of IgG Antibodies Against a Helicobacter pylori-Derived Protein Is Typical of Sera from Patients with Autoimmune Pancreatitis Luca Frulloni, Claudio Lunardi, Chiara Scattolini, Antonio Amodio, Luigi Benini, Italo Vantini, Antonio Puccetti Chronic autoimmune pancreatitis (AIP) is characterized by a chronic inflammatory process in which prominent lymphocyte infiltration with associated fibrosis of the pancreas causes organ dysfunction. The cause of the disease is still unknown. An autoimmune origin for AIP has been suggested but never proven and little is known about its actual pathogenesis. In order to clarify the disease pathogenesis we screened a random peptide library with pooled IgG immunoglobulins derived from 20 patients with AIP. Among the identified peptides, one was recognized by the majority of patients' sera, but not by sera of normal donors and of patients with other autoimmune diseases. The peptide showed homology with an Helicobacter pylori derived protein and with UBR2, a protein ubiquitination enzyme highly expressed in pancreas, and kidney. UBR2 is present in acinar cells of the pancreas
S1280 Serum IgG4 Levels and Extrapancreatic Lesions in Autoimmune Pancreatitis Terumi Kamisawa, Hajime Anjiki, Naoto Egawa Objective: Serum IgG4 levels are frequently elevated in patients with autoimmune pancreatitis (AIP). AIP is sometimes associated with various extrapancreatic lesions. This study examined whether there is a correlation between serum IgG4 levels and associated extrapancreatic lesions in AIP patients. Methods: Serum IgG4 levels were measured in 40 AIP patients before therapy. In these patients, 4 associated extrapancreatic lesions (sclerosing cholangitis,
AGA Abstracts
A-228
sclerosing cholecystitis, sclerosing sialadenitis, and retroperitoneal fibrosis) and clinical factors were retrospectively assessed. Results: The mean serum IgG4 level of the 40 AIP patients was 411±448 mg/dl. Based on the ROC curve data (Fig. 1), the optimal cutoff value for the serum IgG4 to distinguish between AIP patients with and without extrapancreatic lesions was 220 mg/dl; 18 (78%) of 23 patients whose serum IgG4 was ≥ 220 mg/dl had extrapancreatic lesions, while 4 (24%) of 17 patients whose serum IgG4 was < 220 mg/dl had extrapancreatic lesions (p=0.0011). No significant differences between the 2 groups in age, gender, frequency of pancreatic enlargement or obstructive jaundice, and associated sialadenitis, retroperitoneal fibrosis, and diabetes mellitus were identified. Sclerosing cholangitis and cholecystitis were more frequent in patients with serum IgG4 levels higher than 220 mg/dl than in those with lower serum IgG4 levels (p=0.0002 and p=0.0204, respectively). The number of associated extrapancreatic lesions was significantly greater in patients with high serum IgG4 level (p=0.0003). Conclusions: AIP patients with serum IgG4 levels ≥ 220 mg/ dl frequently have extrapancreatic lesions. In differentiating AIP from pancreatic cancer, recognition of the presence of extrapancreatic lesions in patients with serum IgG4 levels ≥ 220 mg/dl strongly supports the diagnosis of AIP.
S1278 Is the Search for Serum Antibodies to Carbonic Anhydrase II Helpful for the Diagnosis of Auto-Immune Pancreatitis? Frédérique Maire, Catherine Johanet, Hélène Voitot, Yann Lebaleur, Thibaud Lefebvre, Vinciane Rebours, Eric Ballot, Olivia Hentic, Marie-Pierre Vullierme, Philippe Levy, Philippe B. Ruszniewski, Pascal Hammel Background : Auto-immune pancreatitis (AIP) should be suspected in patients with unexplained pancreatitis. AIP is recognized according to HISORt criteria (including histology, pancreatic imaging, elevated serum IgG4 level and response to steroid therapy) as recently proposed by the Mayo Clinic. These criteria are highly selective and often difficult to fulfill. Previous studies suggested that carbonic anhydrase (CA) II is a target antigen in AIP. The aim of the present study was to evaluate the prevalence of serum antibodies to CA II in patients with AIP. Patients and Methods : 21 patients with AIP fulfilling HISORt criteria were retrospectively studied. An enzyme-linked immunosorbent assay was used to quantify serum antibodies to CA II. The concentrations of serum IgG4 were measured by nephelemetry with a cut-off of 2 g/L. Thirty two patients with pancreatic adenocarcinoma or non-auto immune pancreatitis, and 96 healthy subjects served as controls. Results : 21 patients (13 males), median age 37 years [21-70] had AIP, histologically defined (57%) or with typical pancreatic imaging and response to steroids (43%). Pancreatic imaging revealed mass or irregular ducts in 71% and 48% of the cases, respectively. Four patients had ulcerative colitis. Serum IgG4 were elevated in 1 patient (5%). Serum antibodies to CA II were present in 2 patients (10%). Both had a pancreatic mass, and underwent pancreaticoduodenectomy. They developed post-operative, steroid-sensitive cholangitis. Serum antibodies to CA II were present in 3 healthy controls (3%) and in 1 subject with alcoholic chronic pancreatitis (3%). No patient with pancreatic cancer had serum antibodies to CA II. The sensitivity, specificity, positive and negative predictive values of antibodies to CA II for the diagnosis of AIP were 10%, 97%, 33%, et 87%, respectively. Conclusion : 10% of patients with well-defined AIP have serum antibodies to CA II in an European center. This prevalence is in accordance with previously reported studies, but lower than in Japanese series. The high specificity of CA II antibodies might be helpful for AIP diagnosis, particularly when serum IgG4 is normal.
S1281 Prednisolone Maintenance Therapy Reduces the Relapse Rate of Autoimmune Pancreatitis Takayoshi Nishino, Fumitake Toki, Keiko Shiratori Background and Aim: Autoimmune pancreatitis (AIP) is a unique form of chronic pancreatitis, and although it responds well to oral prednisolone (PSL) therapy, little is known about the effect of PSL maintenance therapy on the long-term outcome of AIP. This study was undertaken to evaluate the outcome of AIP with and without PSL maintenance therapy, and factors related to the relapse of AIP were analyzed. Patients and Methods: Thirty-six AIP patients, average age 65 years old and average observation period 54.7 months were, divided into a group treated with PSL that also received PSL maintenance therapy (Group A, n=23), a group treated with PSL that did not receive PSL maintenance therapy (Group B, n=6), and a group not treated with PSL at all (Group C, n=7). The initial dose of PSL was 30-40 mg/ day, and it was gradually tapered. The maintenance dose ranged from 2.5 mg/day to10 mg/ day. PSL maintenance therapy was defined as PSL therapy that continued for more than 12 months after the initial PSL therapy. Relapse of AIP was defined as the occurrence of a pancreatic lesion and/or extrapancreatic lesions after remission in response to the initial therapy. Results: 1. AIP relapsed in 4 (17%) of 23 the AIP patients (17%) in Group A and was manifested by pancreatic swelling and bile duct stricture in two patients each. Relapse occurred in 5 (83%) of the 6 patients (83%) in Group B, and was manifested by pancreatic swelling and salivary gland swelling in two patients each and by bile duct stricture in one patient. Relapse occurred in three (43%) of the 7 patients in Group C, and was manifested as pancreatic swelling, salivary gland swelling, and bile duct stricture in one each. 2. The relapse rate in Group A was significantly lower than in Group B (p=0.001) based on the cumulative relapse rates curves. 3. Univariate analysis revealed post treatment serum IgG4 levels above 220 mg/dl was a significant risk factor for relapse of AIP (p=0.04), however, PSL maintenance therapy significantly decreased the relapse rate (p=0.02). A stepwise multivariate analysis confirmed PSL maintenance therapy decreased the relapse rate of AIP (OR=0.045 (95%CI=0.002-0.852), p=0.039). Conclusions: PSL maintenance therapy reduced the overall relapse rate of AIP in various organs. We concluded that PSL maintenance therapy should be taken into consideration as a mean of improving the long-term outcome of AIP.
S1279 Analysis of Pancreatic and Peripheral Regulatory T Cells in Patients with Autoimmune Pancreatitis Kazushige Uchida, Hideaki Miyoshi, Masanori Koyabu, Takeo Kusuda, Norimasa Fukata, Tsukasa Ikeura, Masaaki Shimatani, Toshiro Fukui, Mitsunobu Matsushita, Makoto Takaoka, Kazuichi Okazaki Background & Aim: Autoimmune pancreatitis (AIP) is a newly recognized pancreatic disorder. Patients with AIP have several immunologic and histologic abnormalities specific to the disease. Typical immunological abnormalities are increased levels of serum gammaglobulin, IgG, or IgG4, and the presence of autoantibodies. The histopahtological findings show storiform fibrosis with infiltration of lymphocytes and IgG4-positive plasmacytes. However, the role of IgG4 is unclear. Recently, it has been reported that regulatory T cells (Tregs) are involved in both the development of various autoimmune diseases and the shift of Bcell toward IgG4 producing plasmacytes. To clarify the role of CD4+CD25high Tregs in pathophysiology of AIP, we studied the number of regulatory T cells in the pancreas by immunohistochemistory and IL-10 producing cells in the peripheral blood lymphocytes by flowcytometry. Subjects and Methods: We recruited 37 patients with AIP for this study. Pancreatic tissue was sectioned from 6 AIP patients and 6 patients with pancreatic ductal adenocarcinoma. We studied infiltrating cells in the pancreas by immunohistochemistry. IL10 producing CD4+CD25high Tregs were analyzed from peripheral blood by flow cytometry. Results: There were no significant differences in CD3+, CD4+, or CD79+ cells between the AIP (CD3: 63.1±27.1, CD4: 48.2±32.9, CD79: 24.1±9.2 cells/HPF) and control sections (CD3: 73.6±37.1, CD4: 34.0±23.8, CD79: 14.5±14.6 cells/HPF). On the other hand, CD4+ Foxp3+ cells were increased in the pancreas with AIP (24.6±18.0 cells/HPF) compared with controls (5.1±4.3 cells/HPF). In patients with the untreated AIP, the numbers of CD4+CD25high Tregs and IgG4 are positively correlated (R=0.50, p<0.05). IL-10 producing CD4+CD25high cells and IgG4 also positively correlated (R=0.53, p<0.05). Conclusion: Increased numbers of CD4+CD25high Tregs may influence IgG4 production in AIP.
S1282 Detection of IgG Antibodies Against a Helicobacter pylori-Derived Protein Is Typical of Sera from Patients with Autoimmune Pancreatitis Luca Frulloni, Claudio Lunardi, Chiara Scattolini, Antonio Amodio, Luigi Benini, Italo Vantini, Antonio Puccetti Chronic autoimmune pancreatitis (AIP) is characterized by a chronic inflammatory process in which prominent lymphocyte infiltration with associated fibrosis of the pancreas causes organ dysfunction. The cause of the disease is still unknown. An autoimmune origin for AIP has been suggested but never proven and little is known about its actual pathogenesis. In order to clarify the disease pathogenesis we screened a random peptide library with pooled IgG immunoglobulins derived from 20 patients with AIP. Among the identified peptides, one was recognized by the majority of patients' sera, but not by sera of normal donors and of patients with other autoimmune diseases. The peptide showed homology with an Helicobacter pylori derived protein and with UBR2, a protein ubiquitination enzyme highly expressed in pancreas, and kidney. UBR2 is present in acinar cells of the pancreas
S1280 Serum IgG4 Levels and Extrapancreatic Lesions in Autoimmune Pancreatitis Terumi Kamisawa, Hajime Anjiki, Naoto Egawa Objective: Serum IgG4 levels are frequently elevated in patients with autoimmune pancreatitis (AIP). AIP is sometimes associated with various extrapancreatic lesions. This study examined whether there is a correlation between serum IgG4 levels and associated extrapancreatic lesions in AIP patients. Methods: Serum IgG4 levels were measured in 40 AIP patients before therapy. In these patients, 4 associated extrapancreatic lesions (sclerosing cholangitis,
AGA Abstracts
A-228