Rituximab Therapy for Refractory Biliary Strictures in Immunoglobulin G4–Associated Cholangitis
2008; Elsevier BV; Volume: 6; Issue: 3 Linguagem: Inglês
10.1016/j.cgh.2007.12.020
ISSN1542-7714
AutoresMark D. Topazian, Thomas E. Witzig, Thomas C. Smyrk, José S. Pulido, Michael J. Levy, Patrick S. Kamath, Suresh T. Chari,
Tópico(s)Gastrointestinal disorders and treatments
ResumoBackground & Aims: Biliary strictures occur in a third of patients with autoimmune pancreatitis and have been termed immunoglobulin G subclass 4 (IgG4) associated cholangitis (IAC). IAC often responds to steroid therapy. Methods: A patient with autoimmune pancreatitis and (IAC) refractory to steroids and 6-mercaptopurine was treated with rituximab, a monoclonal antibody directed against the CD20 antigen on B lymphocytes. Results: The patient’s biliary strictures improved after rituximab therapy, permitting removal of his biliary stents. Systemic manifestations of IgG4-associated disease also improved. Conclusions: Rituximab may be a treatment option for patients with refractory or recurrent autoimmune pancreatitis or IAC. Background & Aims: Biliary strictures occur in a third of patients with autoimmune pancreatitis and have been termed immunoglobulin G subclass 4 (IgG4) associated cholangitis (IAC). IAC often responds to steroid therapy. Methods: A patient with autoimmune pancreatitis and (IAC) refractory to steroids and 6-mercaptopurine was treated with rituximab, a monoclonal antibody directed against the CD20 antigen on B lymphocytes. Results: The patient’s biliary strictures improved after rituximab therapy, permitting removal of his biliary stents. Systemic manifestations of IgG4-associated disease also improved. Conclusions: Rituximab may be a treatment option for patients with refractory or recurrent autoimmune pancreatitis or IAC. See Ghazale AH et al on page 706 for companion article in the March 2008 issue of Gastroenterology.Steroid-responsive biliary strictures occur in autoimmune pancreatitis (AIP), and have been termed immunoglobulin G subclass 4 (IgG4) associated cholangitis (IAC).1Björnsson E. Chari S. Smyrk T. et al.IgG4 associated cholangitis: description of an emerging clinical entity based on review of the literature.Hepatology. 2007; 45: 1547-1554Crossref PubMed Scopus (198) Google Scholar Patients with IAC who relapse after withdrawal of steroids often improve with azathioprine.2Ghazale A. Chari S. Smyrk T. et al.Value of serum IgG4 in the diagnosis of autoimmune pancreatitis and in distinguishing it from pancreatic cancer.Am J Gastroenterol. 2007; 102: 1646-1653Crossref PubMed Scopus (416) Google Scholar This report describes a patient with IAC and refractory hilar biliary strictures who responded to treatment with rituximab, a monoclonal antibody directed against the CD20 antigen on B cells.Case ReportA 64-year-old man developed pancreatitis in the fall of 2004. Serum liver tests were normal except for an alkaline phosphatase level of 130 U/L (normal, 80–120 U/L). History, laboratory evaluation, abdominal ultrasound, and computerized tomography scan did not reveal an etiology. Magnetic resonance imaging showed an irregular main pancreatic duct with a stenosis in the neck. His serum IgG4 level was 568 mg/dL (normal, 8–140 mg/dL). Endoscopic ultrasound showed a hypoechoic, enlarged pancreas. Endoscopic retrograde cholangiopancreatography (ERCP) showed multifocal strictures of the pancreatic duct. Cholangiography was normal. Pancreatic duct brushings were negative for malignancy.Based on the increased serum IgG4 level and compatible pancreatography, a diagnosis of AIP was made and he was treated with an 8-week tapering course of oral prednisone starting with 50 mg/day. His postprandial pain recurred a month after completing steroid therapy, and he was re-treated with a 12-week course of prednisone with immediate symptomatic improvement. Steroid therapy was complicated by ophthalmic herpes zoster.In the fall of 2005 he became jaundiced. His serum alkaline phosphatase level was 378 U/L, his aspartate aminotransferase level was 215 U/L, his total bilirubin level was 12.7 mg/dL, his albumin level was 3.1 g/dL, and his IgG4 level was 993 mg/dL. ERCP showed a stenosis of the biliary confluence and common hepatic duct (Figure 1A). Biliary brushings for cytology, digital image analysis, and fluorescent in situ hybridization (FISH) were negative for malignancy. Intraductal biliary biopsy specimens showed a lymphoplasmacytic inflammatory infiltrate with many IgG4-positive cells, compatible with IAC (Figure 2A and B). Biliary stents were placed and his jaundice resolved. He was treated with a 12-week tapering course of oral prednisone, but repeat ERCP showed a persistent hilar stenosis extending further into the intrahepatic ducts than previously. Intraductal brushings and biopsy specimens again were negative for malignancy. He received another 12-week course of oral prednisone as well as oral 6-mercaptopurine at a dose of 1.5 mg/kg/day. ERCP was repeated 3 months later; the hilar strictures were somewhat improved, and the biliary stents were removed. The patient was hospitalized 2 weeks later with jaundice and cholangitis. Cholangiography again showed a tight stenosis of the biliary confluence, and 3 plastic biliary stents were placed and subsequently exchanged every 3 months.Figure 2(A) Biliary biopsy specimen showing a lymphoplasmacytic infiltrate. (B) IgG4 stain of the biliary biopsy specimen shows abundant positive plasma cells, consistent with IAC. (C) Pancreas Tru-cut biopsy shows features of chronic pancreatitis with a lymphoplasmacytic infiltration and storiform fibrosis, consistent with AIP. (D) Pancreatic IgG4 stain shows abundant positive plasma cells.View Large Image Figure ViewerDownload Hi-res image Download (PPT)In the fall of 2006, after 8 months of 6-mercaptopurine therapy, the patient lost weight and developed steatorrhea with decreased vision in the right eye. His serum bilirubin level increased to 4.4 mg/dL and remained increased despite exchange of his biliary stents. A positron emission tomography scan showed mild to moderate [18F]-2-fluoro-deoxy-D-glucose uptake consistent with inflammatory disease in the hepatic hilum, the pancreas, and the right eye. Ophthalmologic examination revealed deep choroidal infiltrates. Magnetic resonance imaging showed thickening of the pancreatic body and tail with an irregular pancreatic duct, and hilar bile duct thickening. Cholangiography showed worsening of his intrahepatic biliary strictures, and it was difficult to fill his intrahepatic ducts with contrast despite occlusion cholangiography (Figure 1B). Additional biliary biopsy specimens again showed findings of IAC, and biliary brushings were negative for malignancy.EUS was repeated and showed a hypoechoic pancreas. EUS-guided Tru-cut biopsy of the pancreatic body showed chronic pancreatitis with a lymphoplasmacytic infiltrate and storiform fibrosis (Figure 2C). Immunostains showed many IgG4-positive cells, supporting the diagnosis of AIP (Figure 2D). The lymphocytic infiltrate was composed of both CD3- and CD20-positive lymphocytes. Stains for κ and λ light chains did not show light chain restriction. Peripheral blood flow cytometric immunophenotyping showed no monotypic B-cell population. T- and B-cell quantitative markers showed normal CD4 and natural killer cell numbers. The serum IgG4 level was 1480 mg/dL.A diagnosis was made of AIP and IAC with ocular involvement, refractory to steroids and 6-mercaptopurine, which were discontinued. Rituximab immunotherapy was initiated at 375 mg/m2 weekly for 4 doses in November of 2006. Within a month of initiating rituximab therapy the patient’s sense of well being improved steadily; he regained weight and resumed normal activities. Vision in his right eye returned to normal. His jaundice and symptoms of steatorrhea resolved. An upper-gastrointestinal hemorrhage occurred and was attributed to gastric varices; a transjugular liver biopsy in January of 2007 showed cirrhosis with rare, scattered IgG4-positive cells. Oral propranolol was begun. Repeat ophthalmologic examination of the right eye showed the choroidal lesions were now atrophic and inactive. The patient was placed on maintenance rituximab 375 mg/m2 every 3 months. ERCP performed 4 months after initiation of rituximab showed improvement in his hilar biliary strictures (Figure 1C) and his biliary stents were removed. The serum IgG4 level was 1020 mg/dL at the time of stent removal. He remained anicteric and without evidence of cholangitis. Nine months after stent removal his total serum bilirubin level was 1.1 mg/dL, his alkaline phosphatase level was 267 IU/L (normal, 45–115 IU/L), his aspartate aminotransferase level was 58 IU/L, his alanine aminotransferase level was 40 IU/L, and his IgG4 level was 299 mg/dL. The patient consented to review of his medical record for research purposes.DiscussionAIP is an inflammatory disorder characterized by pancreatic enlargement, multifocal pancreatic duct strictures, increased serum IgG4 levels, and a pancreatic IgG4-positive lymphoplasmacytic infiltrate with narrowing of small ducts and obliterative phlebitis. Bile duct strictures are reported in a third of patients with AIP and have been termed IAC.3Nishino T. Toki F. Oyama H. et al.Biliary tract involvement in autoimmune pancreatitis.Pancreas. 2005; 30: 76-82PubMed Google Scholar IAC also may occur in patients without pancreatitis. Stenoses may occur in the intrapancreatic bile duct, biliary confluence, and/or peripheral intrahepatic ducts. Histology of resected IAC shows IgG4-positive lymphoplasmacytic infiltrates in the bile duct wall.4Ghazale A. Chari S. Zhang L. et al.IgG4-associated cholangitis (IAC): clinical profile and response to therapy.Gastroenterology. 2008; 134: 706-715Abstract Full Text Full Text PDF PubMed Scopus (715) Google Scholar Similar infiltrates have been reported in some cases of thyroiditis, Mikulicz’s disease, chronic sialadenitis, retroperitoneal fibrosis, tubulointerstitial nephritis, and autoimmune hypophysitis,5Ohara H. Nakazawa T. Sano H. et al.Systemic extrapancreatic lesions associated with autoimmune pancreatitis.Pancreas. 2005; 31: 232-237Crossref PubMed Scopus (136) Google Scholar, 6Yamamoto M. Takahashi H. Ohara M. et al.A new conceptualization for Mikulicz’s disease as an IgG4-related plasmacytic disease.Mod Rheumatol. 2006; 16: 335-340Crossref PubMed Scopus (313) Google Scholar, 7Chari S. Smyrk T. Levy M. et al.Diagnosis of autoimmune pancreatitis: the Mayo Clinic experience.Clin Gastroenterol Hepatol. 2006; 4: 1010-1016Abstract Full Text Full Text PDF PubMed Scopus (855) Google Scholar and these all may be manifestations of an IgG4-related systemic disease.1Björnsson E. Chari S. Smyrk T. et al.IgG4 associated cholangitis: description of an emerging clinical entity based on review of the literature.Hepatology. 2007; 45: 1547-1554Crossref PubMed Scopus (198) Google Scholar, 8Hamed G. Tsushima K. Yasuo M. et al.Inflammatory lesions of the lung, submandibular gland, bile duct and prostate in a patient with IgG4-associated multifocal systemic fibrosclerosis.Respirology. 2007; 12: 455-457Crossref PubMed Scopus (68) Google ScholarIAC typically responds to oral steroid therapy.1Björnsson E. Chari S. Smyrk T. et al.IgG4 associated cholangitis: description of an emerging clinical entity based on review of the literature.Hepatology. 2007; 45: 1547-1554Crossref PubMed Scopus (198) Google Scholar, 3Nishino T. Toki F. Oyama H. et al.Biliary tract involvement in autoimmune pancreatitis.Pancreas. 2005; 30: 76-82PubMed Google Scholar, 4Ghazale A. Chari S. Zhang L. et al.IgG4-associated cholangitis (IAC): clinical profile and response to therapy.Gastroenterology. 2008; 134: 706-715Abstract Full Text Full Text PDF PubMed Scopus (715) Google Scholar, 9Matsushita M. Yamashina M. Ikeura T. et al.Effective steroid pulse therapy for the biliary stenosis caused by autoimmune pancreatitis.Am J Gastroenterol. 2007; 102: 220-221Crossref PubMed Scopus (13) Google Scholar Relapse after withdrawal of steroids is common, particularly with hilar or intrahepatic duct strictures, and additional steroid or immunomodulator therapy often is successful.4Ghazale A. Chari S. Zhang L. et al.IgG4-associated cholangitis (IAC): clinical profile and response to therapy.Gastroenterology. 2008; 134: 706-715Abstract Full Text Full Text PDF PubMed Scopus (715) Google Scholar The patient described in this report did not respond to steroid or 6-mercaptopurine therapy. Rituximab therapy resulted in cholangiographic improvement and allowed his biliary stents to be removed.Rituximab is a chimeric IgG1 monoclonal antibody directed against CD20, a phosphoprotein expressed on the surface of B lymphocytes. Initially used to treat lymphoma, rituximab has efficacy in some immune-mediated diseases, including rheumatoid arthritis,10Cohen S. Emery P. Greenwald M. et al.Rituximab for rheumatoid arthritis refractory to anti-tumor necrosis factor therapy: results of a multicenter, randomized, double-blind, placebo-controlled, phase III trial evaluating primary efficacy and safety at twenty-four weeks.Arthritis Rheum. 2006; 54: 2793-2806Crossref PubMed Scopus (1399) Google Scholar thrombotic thrombocytopenic purpura,11Scully M. Cohen H. Cavenagh J. et al.Remission in acute refractory and relapsing thrombotic thrombocytopenic purpura following rituximab is associated with a reduction in IgG antibodies to ADAMTS-13.Br J Haematol. 2007; 136: 451-461Crossref PubMed Scopus (212) Google Scholar benign orbital pseudolymphoma,12Witzig T. Inwards D. Habermann T. et al.Treatment of benign orbital pseudolymphomas with the monoclonal anti-CD20 antibody rituximab.Mayo Clin Proc. 2007; 82: 692-699Abstract Full Text Full Text PDF PubMed Scopus (33) Google Scholar and pemphigus vulgaris13Ahmed A. Spigelman Z. Cavacini L. et al.Treatment of pemphigus vulgaris with rituximab and intravenous immune globulin.N Engl J Med. 2006; 355: 1772-1779Crossref PubMed Scopus (423) Google Scholar (a disease characterized by the presence of pathogenic IgG4 antibodies). The mechanism of action of rituximab in these diseases is presumed to be B-cell depletion, resulting in decreased production of pathogenic autoantibodies.Because the patient was treated solely with rituximab, which depletes only B cells, this case suggests that B lymphocytes play a central role in the pathogenesis of IAC and AIP. The lymphoplasmacytic infiltrates that characterize AIP include polyclonal B cells, plasma cells, and T cells.14Kojima M. Sipos B. Klapper W. et al.Autoimmune pancreatitis: frequency, IgG4 expression, and clonality of T and B cells.Am J Surg Pathol. 2007; 31: 521-528Crossref PubMed Scopus (120) Google Scholar In addition to infiltrating affected tissues, B lymphocytes affect the inflammatory response by interaction with regulatory T cells.15Yang Z. Novak A. Ziesmer S. et al.Attenuation of CD8(+) T-cell function by CD4(+)CD25(+) regulatory T cells in B-cell non-Hodgkin’s lymphoma.Cancer Res. 2006; 15: 10145-10152Crossref Scopus (145) Google Scholar The patient’s serum IgG4 level initially remained increased, sharply declining toward normal 7 months after rituximab therapy was begun. The initially persistent increase of IgG4 levels is not surprising because immunoglobulins are secreted by mature plasma cells that are not depleted by rituximab. This phenomenon also has been reported in patients with rheumatoid arthritis10Cohen S. Emery P. Greenwald M. et al.Rituximab for rheumatoid arthritis refractory to anti-tumor necrosis factor therapy: results of a multicenter, randomized, double-blind, placebo-controlled, phase III trial evaluating primary efficacy and safety at twenty-four weeks.Arthritis Rheum. 2006; 54: 2793-2806Crossref PubMed Scopus (1399) Google Scholar and Waldenstrom’s macroglobulinemia16Ghobrial I. Fonseca R. Greipp P. et al.Initial immunoglobulin M ’flare’ after rituximab therapy in patients diagnosed with Waldenstrom macroglobulinemia: an Eastern Cooperative Oncology Group Study.Cancer. 2004; 101: 2593-2598Crossref PubMed Scopus (160) Google Scholar who receive rituximab. The patient’s clinical and cholangiographic response occurred while his serum IgG4 level was increased persistently, suggesting that IgG4 was not directly pathogenic.Cirrhosis in this case most likely was caused by chronic biliary obstruction caused by IAC. A liver biopsy performed 2 months after the initiation of rituximab therapy did show rare, scattered IgG4-positive cells. By improving biliary strictures, rituximab therapy might lead to some reversal of hepatic fibrosis.17Bonis P. Friedman S. Kaplan M. Is liver fibrosis reversible?.N Engl J Med. 2001; 344: 452-454Crossref PubMed Scopus (145) Google Scholar, 18Hammel P. Couvelard A. O’Toole D. et al.Regression of liver fibrosis after biliary drainage in patients with chronic pancreatitis and stenosis of the common bile duct.N Engl J Med. 2001; 344: 418-423Crossref PubMed Scopus (362) Google ScholarCould our patient have a biliary malignancy rather than IAC? Pseudotumors of the biliary tree have been described in association with AIP.19Kurihara T. Itoi T. Sofuni A. et al.Pseudotumor of the bile duct associated with autoimmune pancreatitis.Endoscopy. 2007; (epub ahead of print)Google Scholar The diagnosis of IAC in this case was based on the marked increase of the serum IgG4 levels, the presence of co-existent AIP, and compatible biliary histology. A positron emission tomography scan showed mild to moderate activity suggestive of inflammation rather than malignancy. Histologic and hematologic evaluations for lymphoma were unrevealing. It is unlikely that this patient’s biliary stricture was malignant.The required duration of rituximab therapy is unclear. The short-term efficacy of rituximab therapy has been documented in rheumatoid arthritis10Cohen S. Emery P. Greenwald M. et al.Rituximab for rheumatoid arthritis refractory to anti-tumor necrosis factor therapy: results of a multicenter, randomized, double-blind, placebo-controlled, phase III trial evaluating primary efficacy and safety at twenty-four weeks.Arthritis Rheum. 2006; 54: 2793-2806Crossref PubMed Scopus (1399) Google Scholar and other inflammatory diseases, but the duration of response and the benefit of maintenance therapy is uncertain. Further data are needed in this regard.In conclusion, rituximab therapy was effective in this case of refractory IgG4-associated cholangitis. Rituximab may be a treatment option for patients with refractory or recurrent IgG4-associated disease. Rituximab has few side effects, and may be an attractive therapeutic option in patients who are intolerant of steroids or suffer relapses of IgG4-associated disease, as well as in patients such as this one with AIP and refractory IgG4-associated cholangitis. See Ghazale AH et al on page 706 for companion article in the March 2008 issue of Gastroenterology. See Ghazale AH et al on page 706 for companion article in the March 2008 issue of Gastroenterology. See Ghazale AH et al on page 706 for companion article in the March 2008 issue of Gastroenterology. Steroid-responsive biliary strictures occur in autoimmune pancreatitis (AIP), and have been termed immunoglobulin G subclass 4 (IgG4) associated cholangitis (IAC).1Björnsson E. Chari S. Smyrk T. et al.IgG4 associated cholangitis: description of an emerging clinical entity based on review of the literature.Hepatology. 2007; 45: 1547-1554Crossref PubMed Scopus (198) Google Scholar Patients with IAC who relapse after withdrawal of steroids often improve with azathioprine.2Ghazale A. Chari S. Smyrk T. et al.Value of serum IgG4 in the diagnosis of autoimmune pancreatitis and in distinguishing it from pancreatic cancer.Am J Gastroenterol. 2007; 102: 1646-1653Crossref PubMed Scopus (416) Google Scholar This report describes a patient with IAC and refractory hilar biliary strictures who responded to treatment with rituximab, a monoclonal antibody directed against the CD20 antigen on B cells. Case ReportA 64-year-old man developed pancreatitis in the fall of 2004. Serum liver tests were normal except for an alkaline phosphatase level of 130 U/L (normal, 80–120 U/L). History, laboratory evaluation, abdominal ultrasound, and computerized tomography scan did not reveal an etiology. Magnetic resonance imaging showed an irregular main pancreatic duct with a stenosis in the neck. His serum IgG4 level was 568 mg/dL (normal, 8–140 mg/dL). Endoscopic ultrasound showed a hypoechoic, enlarged pancreas. Endoscopic retrograde cholangiopancreatography (ERCP) showed multifocal strictures of the pancreatic duct. Cholangiography was normal. Pancreatic duct brushings were negative for malignancy.Based on the increased serum IgG4 level and compatible pancreatography, a diagnosis of AIP was made and he was treated with an 8-week tapering course of oral prednisone starting with 50 mg/day. His postprandial pain recurred a month after completing steroid therapy, and he was re-treated with a 12-week course of prednisone with immediate symptomatic improvement. Steroid therapy was complicated by ophthalmic herpes zoster.In the fall of 2005 he became jaundiced. His serum alkaline phosphatase level was 378 U/L, his aspartate aminotransferase level was 215 U/L, his total bilirubin level was 12.7 mg/dL, his albumin level was 3.1 g/dL, and his IgG4 level was 993 mg/dL. ERCP showed a stenosis of the biliary confluence and common hepatic duct (Figure 1A). Biliary brushings for cytology, digital image analysis, and fluorescent in situ hybridization (FISH) were negative for malignancy. Intraductal biliary biopsy specimens showed a lymphoplasmacytic inflammatory infiltrate with many IgG4-positive cells, compatible with IAC (Figure 2A and B). Biliary stents were placed and his jaundice resolved. He was treated with a 12-week tapering course of oral prednisone, but repeat ERCP showed a persistent hilar stenosis extending further into the intrahepatic ducts than previously. Intraductal brushings and biopsy specimens again were negative for malignancy. He received another 12-week course of oral prednisone as well as oral 6-mercaptopurine at a dose of 1.5 mg/kg/day. ERCP was repeated 3 months later; the hilar strictures were somewhat improved, and the biliary stents were removed. The patient was hospitalized 2 weeks later with jaundice and cholangitis. Cholangiography again showed a tight stenosis of the biliary confluence, and 3 plastic biliary stents were placed and subsequently exchanged every 3 months.In the fall of 2006, after 8 months of 6-mercaptopurine therapy, the patient lost weight and developed steatorrhea with decreased vision in the right eye. His serum bilirubin level increased to 4.4 mg/dL and remained increased despite exchange of his biliary stents. A positron emission tomography scan showed mild to moderate [18F]-2-fluoro-deoxy-D-glucose uptake consistent with inflammatory disease in the hepatic hilum, the pancreas, and the right eye. Ophthalmologic examination revealed deep choroidal infiltrates. Magnetic resonance imaging showed thickening of the pancreatic body and tail with an irregular pancreatic duct, and hilar bile duct thickening. Cholangiography showed worsening of his intrahepatic biliary strictures, and it was difficult to fill his intrahepatic ducts with contrast despite occlusion cholangiography (Figure 1B). Additional biliary biopsy specimens again showed findings of IAC, and biliary brushings were negative for malignancy.EUS was repeated and showed a hypoechoic pancreas. EUS-guided Tru-cut biopsy of the pancreatic body showed chronic pancreatitis with a lymphoplasmacytic infiltrate and storiform fibrosis (Figure 2C). Immunostains showed many IgG4-positive cells, supporting the diagnosis of AIP (Figure 2D). The lymphocytic infiltrate was composed of both CD3- and CD20-positive lymphocytes. Stains for κ and λ light chains did not show light chain restriction. Peripheral blood flow cytometric immunophenotyping showed no monotypic B-cell population. T- and B-cell quantitative markers showed normal CD4 and natural killer cell numbers. The serum IgG4 level was 1480 mg/dL.A diagnosis was made of AIP and IAC with ocular involvement, refractory to steroids and 6-mercaptopurine, which were discontinued. Rituximab immunotherapy was initiated at 375 mg/m2 weekly for 4 doses in November of 2006. Within a month of initiating rituximab therapy the patient’s sense of well being improved steadily; he regained weight and resumed normal activities. Vision in his right eye returned to normal. His jaundice and symptoms of steatorrhea resolved. An upper-gastrointestinal hemorrhage occurred and was attributed to gastric varices; a transjugular liver biopsy in January of 2007 showed cirrhosis with rare, scattered IgG4-positive cells. Oral propranolol was begun. Repeat ophthalmologic examination of the right eye showed the choroidal lesions were now atrophic and inactive. The patient was placed on maintenance rituximab 375 mg/m2 every 3 months. ERCP performed 4 months after initiation of rituximab showed improvement in his hilar biliary strictures (Figure 1C) and his biliary stents were removed. The serum IgG4 level was 1020 mg/dL at the time of stent removal. He remained anicteric and without evidence of cholangitis. Nine months after stent removal his total serum bilirubin level was 1.1 mg/dL, his alkaline phosphatase level was 267 IU/L (normal, 45–115 IU/L), his aspartate aminotransferase level was 58 IU/L, his alanine aminotransferase level was 40 IU/L, and his IgG4 level was 299 mg/dL. The patient consented to review of his medical record for research purposes. A 64-year-old man developed pancreatitis in the fall of 2004. Serum liver tests were normal except for an alkaline phosphatase level of 130 U/L (normal, 80–120 U/L). History, laboratory evaluation, abdominal ultrasound, and computerized tomography scan did not reveal an etiology. Magnetic resonance imaging showed an irregular main pancreatic duct with a stenosis in the neck. His serum IgG4 level was 568 mg/dL (normal, 8–140 mg/dL). Endoscopic ultrasound showed a hypoechoic, enlarged pancreas. Endoscopic retrograde cholangiopancreatography (ERCP) showed multifocal strictures of the pancreatic duct. Cholangiography was normal. Pancreatic duct brushings were negative for malignancy. Based on the increased serum IgG4 level and compatible pancreatography, a diagnosis of AIP was made and he was treated with an 8-week tapering course of oral prednisone starting with 50 mg/day. His postprandial pain recurred a month after completing steroid therapy, and he was re-treated with a 12-week course of prednisone with immediate symptomatic improvement. Steroid therapy was complicated by ophthalmic herpes zoster. In the fall of 2005 he became jaundiced. His serum alkaline phosphatase level was 378 U/L, his aspartate aminotransferase level was 215 U/L, his total bilirubin level was 12.7 mg/dL, his albumin level was 3.1 g/dL, and his IgG4 level was 993 mg/dL. ERCP showed a stenosis of the biliary confluence and common hepatic duct (Figure 1A). Biliary brushings for cytology, digital image analysis, and fluorescent in situ hybridization (FISH) were negative for malignancy. Intraductal biliary biopsy specimens showed a lymphoplasmacytic inflammatory infiltrate with many IgG4-positive cells, compatible with IAC (Figure 2A and B). Biliary stents were placed and his jaundice resolved. He was treated with a 12-week tapering course of oral prednisone, but repeat ERCP showed a persistent hilar stenosis extending further into the intrahepatic ducts than previously. Intraductal brushings and biopsy specimens again were negative for malignancy. He received another 12-week course of oral prednisone as well as oral 6-mercaptopurine at a dose of 1.5 mg/kg/day. ERCP was repeated 3 months later; the hilar strictures were somewhat improved, and the biliary stents were removed. The patient was hospitalized 2 weeks later with jaundice and cholangitis. Cholangiography again showed a tight stenosis of the biliary confluence, and 3 plastic biliary stents were placed and subsequently exchanged every 3 months. In the fall of 2006, after 8 months of 6-mercaptopurine therapy, the patient lost weight and developed steatorrhea with decreased vision in the right eye. His serum bilirubin level increased to 4.4 mg/dL and remained increased despite exchange of his biliary stents. A positron emission tomography scan showed mild to moderate [18F]-2-fluoro-deoxy-D-glucose uptake consistent with inflammatory disease in the hepatic hilum, the pancreas, and the right eye. Ophthalmologic examination revealed deep choroidal infiltrates. Magnetic resonance imaging showed thickening of the pancreatic body and tail with an irregular pancreatic duct, and hilar bile duct thickening. Cholangiography showed worsening of his intrahepatic biliary strictures, and it was difficult to fill his intrahepatic ducts with contrast despite occlusion cholangiography (Figure 1B). Additional biliary biopsy specimens again showed findings of IAC, and biliary brushings were negative for malignancy. EUS was repeated and showed a hypoechoic pancreas. EUS-guided Tru-cut biopsy of the pancreatic body showed chronic pancreatitis with a lymphoplasmacytic infiltrate and storiform fibrosis (Figure 2C). Immunostains showed many IgG4-positive cells, supporting the diagnosis of AIP (Figure 2D). The lymphocytic infiltrate was composed of both CD3- and CD20-positive lymphocytes. Stains for κ and λ light chains did not show light chain restriction. Peripheral blood flow cytometric immunophenotyping showed no monotypic B-cell population. T- and B-cell quantitative markers showed normal CD4 and natural killer cell numbers. The serum IgG4 level was 1480 mg/dL. A diagnosis was made of AIP and IAC with ocular involvement, refractory to steroids and 6-mercaptopurine, which were discontinued. Rituximab immunotherapy was initiated at 375 mg/m2 weekly for 4 doses in November of 2006. Within a month of initiating rituximab therapy the patient’s sense of well being improved steadily; he regained weight and resumed normal activities. Vision in his right eye returned to normal. His jaundice and symptoms of steatorrhea resolved. An upper-gastrointestinal hemorrhage occurred and was attributed to gastric varices; a transjugular liver biopsy in January of 2007 showed cirrhosis with rare, scattered IgG4-positive cells. Oral propranolol was begun. Repeat ophthalmologic examination of the right eye showed the choroidal lesions were now atrophic and inactive. The patient was placed on maintenance rituximab 375 mg/m2 every 3 months. ERCP performed 4 months after initiation of rituximab showed improvement in his hilar biliary strictures (Figure 1C) and his biliary stents were removed. The serum IgG4 level was 1020 mg/dL at the time of stent removal. He remained anicteric and without evidence of cholangitis. Nine months after stent removal his total serum bilirubin level was 1.1 mg/dL, his alkaline phosphatase level was 267 IU/L (normal, 45–115 IU/L), his aspartate aminotransferase level was 58 IU/L, his alanine aminotransferase level was 40 IU/L, and his IgG4 level was 299 mg/dL. The patient consented to review of his medical record for research purposes. DiscussionAIP is an inflammatory disorder characterized by pancreatic enlargement, multifocal pancreatic duct strictures, increased serum IgG4 levels, and a pancreatic IgG4-positive lymphoplasmacytic infiltrate with narrowing of small ducts and obliterative phlebitis. Bile duct strictures are reported in a third of patients with AIP and have been termed IAC.3Nishino T. Toki F. Oyama H. et al.Biliary tract involvement in autoimmune pancreatitis.Pancreas. 2005; 30: 76-82PubMed Google Scholar IAC also may occur in patients without pancreatitis. Stenoses may occur in the intrapancreatic bile duct, biliary confluence, and/or peripheral intrahepatic ducts. Histology of resected IAC shows IgG4-positive lymphoplasmacytic infiltrates in the bile duct wall.4Ghazale A. Chari S. Zhang L. et al.IgG4-associated cholangitis (IAC): clinical profile and response to therapy.Gastroenterology. 2008; 134: 706-715Abstract Full Text Full Text PDF PubMed Scopus (715) Google Scholar Similar infiltrates have been reported in some cases of thyroiditis, Mikulicz’s disease, chronic sialadenitis, retroperitoneal fibrosis, tubulointerstitial nephritis, and autoimmune hypophysitis,5Ohara H. Nakazawa T. Sano H. et al.Systemic extrapancreatic lesions associated with autoimmune pancreatitis.Pancreas. 2005; 31: 232-237Crossref PubMed Scopus (136) Google Scholar, 6Yamamoto M. Takahashi H. Ohara M. et al.A new conceptualization for Mikulicz’s disease as an IgG4-related plasmacytic disease.Mod Rheumatol. 2006; 16: 335-340Crossref PubMed Scopus (313) Google Scholar, 7Chari S. Smyrk T. Levy M. et al.Diagnosis of autoimmune pancreatitis: the Mayo Clinic experience.Clin Gastroenterol Hepatol. 2006; 4: 1010-1016Abstract Full Text Full Text PDF PubMed Scopus (855) Google Scholar and these all may be manifestations of an IgG4-related systemic disease.1Björnsson E. Chari S. Smyrk T. et al.IgG4 associated cholangitis: description of an emerging clinical entity based on review of the literature.Hepatology. 2007; 45: 1547-1554Crossref PubMed Scopus (198) Google Scholar, 8Hamed G. Tsushima K. Yasuo M. et al.Inflammatory lesions of the lung, submandibular gland, bile duct and prostate in a patient with IgG4-associated multifocal systemic fibrosclerosis.Respirology. 2007; 12: 455-457Crossref PubMed Scopus (68) Google ScholarIAC typically responds to oral steroid therapy.1Björnsson E. Chari S. Smyrk T. et al.IgG4 associated cholangitis: description of an emerging clinical entity based on review of the literature.Hepatology. 2007; 45: 1547-1554Crossref PubMed Scopus (198) Google Scholar, 3Nishino T. Toki F. Oyama H. et al.Biliary tract involvement in autoimmune pancreatitis.Pancreas. 2005; 30: 76-82PubMed Google Scholar, 4Ghazale A. Chari S. Zhang L. et al.IgG4-associated cholangitis (IAC): clinical profile and response to therapy.Gastroenterology. 2008; 134: 706-715Abstract Full Text Full Text PDF PubMed Scopus (715) Google Scholar, 9Matsushita M. Yamashina M. Ikeura T. et al.Effective steroid pulse therapy for the biliary stenosis caused by autoimmune pancreatitis.Am J Gastroenterol. 2007; 102: 220-221Crossref PubMed Scopus (13) Google Scholar Relapse after withdrawal of steroids is common, particularly with hilar or intrahepatic duct strictures, and additional steroid or immunomodulator therapy often is successful.4Ghazale A. Chari S. Zhang L. et al.IgG4-associated cholangitis (IAC): clinical profile and response to therapy.Gastroenterology. 2008; 134: 706-715Abstract Full Text Full Text PDF PubMed Scopus (715) Google Scholar The patient described in this report did not respond to steroid or 6-mercaptopurine therapy. Rituximab therapy resulted in cholangiographic improvement and allowed his biliary stents to be removed.Rituximab is a chimeric IgG1 monoclonal antibody directed against CD20, a phosphoprotein expressed on the surface of B lymphocytes. Initially used to treat lymphoma, rituximab has efficacy in some immune-mediated diseases, including rheumatoid arthritis,10Cohen S. Emery P. Greenwald M. et al.Rituximab for rheumatoid arthritis refractory to anti-tumor necrosis factor therapy: results of a multicenter, randomized, double-blind, placebo-controlled, phase III trial evaluating primary efficacy and safety at twenty-four weeks.Arthritis Rheum. 2006; 54: 2793-2806Crossref PubMed Scopus (1399) Google Scholar thrombotic thrombocytopenic purpura,11Scully M. Cohen H. Cavenagh J. et al.Remission in acute refractory and relapsing thrombotic thrombocytopenic purpura following rituximab is associated with a reduction in IgG antibodies to ADAMTS-13.Br J Haematol. 2007; 136: 451-461Crossref PubMed Scopus (212) Google Scholar benign orbital pseudolymphoma,12Witzig T. Inwards D. Habermann T. et al.Treatment of benign orbital pseudolymphomas with the monoclonal anti-CD20 antibody rituximab.Mayo Clin Proc. 2007; 82: 692-699Abstract Full Text Full Text PDF PubMed Scopus (33) Google Scholar and pemphigus vulgaris13Ahmed A. Spigelman Z. Cavacini L. et al.Treatment of pemphigus vulgaris with rituximab and intravenous immune globulin.N Engl J Med. 2006; 355: 1772-1779Crossref PubMed Scopus (423) Google Scholar (a disease characterized by the presence of pathogenic IgG4 antibodies). The mechanism of action of rituximab in these diseases is presumed to be B-cell depletion, resulting in decreased production of pathogenic autoantibodies.Because the patient was treated solely with rituximab, which depletes only B cells, this case suggests that B lymphocytes play a central role in the pathogenesis of IAC and AIP. The lymphoplasmacytic infiltrates that characterize AIP include polyclonal B cells, plasma cells, and T cells.14Kojima M. Sipos B. Klapper W. et al.Autoimmune pancreatitis: frequency, IgG4 expression, and clonality of T and B cells.Am J Surg Pathol. 2007; 31: 521-528Crossref PubMed Scopus (120) Google Scholar In addition to infiltrating affected tissues, B lymphocytes affect the inflammatory response by interaction with regulatory T cells.15Yang Z. Novak A. Ziesmer S. et al.Attenuation of CD8(+) T-cell function by CD4(+)CD25(+) regulatory T cells in B-cell non-Hodgkin’s lymphoma.Cancer Res. 2006; 15: 10145-10152Crossref Scopus (145) Google Scholar The patient’s serum IgG4 level initially remained increased, sharply declining toward normal 7 months after rituximab therapy was begun. The initially persistent increase of IgG4 levels is not surprising because immunoglobulins are secreted by mature plasma cells that are not depleted by rituximab. This phenomenon also has been reported in patients with rheumatoid arthritis10Cohen S. Emery P. Greenwald M. et al.Rituximab for rheumatoid arthritis refractory to anti-tumor necrosis factor therapy: results of a multicenter, randomized, double-blind, placebo-controlled, phase III trial evaluating primary efficacy and safety at twenty-four weeks.Arthritis Rheum. 2006; 54: 2793-2806Crossref PubMed Scopus (1399) Google Scholar and Waldenstrom’s macroglobulinemia16Ghobrial I. Fonseca R. Greipp P. et al.Initial immunoglobulin M ’flare’ after rituximab therapy in patients diagnosed with Waldenstrom macroglobulinemia: an Eastern Cooperative Oncology Group Study.Cancer. 2004; 101: 2593-2598Crossref PubMed Scopus (160) Google Scholar who receive rituximab. The patient’s clinical and cholangiographic response occurred while his serum IgG4 level was increased persistently, suggesting that IgG4 was not directly pathogenic.Cirrhosis in this case most likely was caused by chronic biliary obstruction caused by IAC. A liver biopsy performed 2 months after the initiation of rituximab therapy did show rare, scattered IgG4-positive cells. By improving biliary strictures, rituximab therapy might lead to some reversal of hepatic fibrosis.17Bonis P. Friedman S. Kaplan M. Is liver fibrosis reversible?.N Engl J Med. 2001; 344: 452-454Crossref PubMed Scopus (145) Google Scholar, 18Hammel P. Couvelard A. O’Toole D. et al.Regression of liver fibrosis after biliary drainage in patients with chronic pancreatitis and stenosis of the common bile duct.N Engl J Med. 2001; 344: 418-423Crossref PubMed Scopus (362) Google ScholarCould our patient have a biliary malignancy rather than IAC? Pseudotumors of the biliary tree have been described in association with AIP.19Kurihara T. Itoi T. Sofuni A. et al.Pseudotumor of the bile duct associated with autoimmune pancreatitis.Endoscopy. 2007; (epub ahead of print)Google Scholar The diagnosis of IAC in this case was based on the marked increase of the serum IgG4 levels, the presence of co-existent AIP, and compatible biliary histology. A positron emission tomography scan showed mild to moderate activity suggestive of inflammation rather than malignancy. Histologic and hematologic evaluations for lymphoma were unrevealing. It is unlikely that this patient’s biliary stricture was malignant.The required duration of rituximab therapy is unclear. The short-term efficacy of rituximab therapy has been documented in rheumatoid arthritis10Cohen S. Emery P. Greenwald M. et al.Rituximab for rheumatoid arthritis refractory to anti-tumor necrosis factor therapy: results of a multicenter, randomized, double-blind, placebo-controlled, phase III trial evaluating primary efficacy and safety at twenty-four weeks.Arthritis Rheum. 2006; 54: 2793-2806Crossref PubMed Scopus (1399) Google Scholar and other inflammatory diseases, but the duration of response and the benefit of maintenance therapy is uncertain. Further data are needed in this regard.In conclusion, rituximab therapy was effective in this case of refractory IgG4-associated cholangitis. Rituximab may be a treatment option for patients with refractory or recurrent IgG4-associated disease. Rituximab has few side effects, and may be an attractive therapeutic option in patients who are intolerant of steroids or suffer relapses of IgG4-associated disease, as well as in patients such as this one with AIP and refractory IgG4-associated cholangitis. AIP is an inflammatory disorder characterized by pancreatic enlargement, multifocal pancreatic duct strictures, increased serum IgG4 levels, and a pancreatic IgG4-positive lymphoplasmacytic infiltrate with narrowing of small ducts and obliterative phlebitis. Bile duct strictures are reported in a third of patients with AIP and have been termed IAC.3Nishino T. Toki F. Oyama H. et al.Biliary tract involvement in autoimmune pancreatitis.Pancreas. 2005; 30: 76-82PubMed Google Scholar IAC also may occur in patients without pancreatitis. Stenoses may occur in the intrapancreatic bile duct, biliary confluence, and/or peripheral intrahepatic ducts. Histology of resected IAC shows IgG4-positive lymphoplasmacytic infiltrates in the bile duct wall.4Ghazale A. Chari S. Zhang L. et al.IgG4-associated cholangitis (IAC): clinical profile and response to therapy.Gastroenterology. 2008; 134: 706-715Abstract Full Text Full Text PDF PubMed Scopus (715) Google Scholar Similar infiltrates have been reported in some cases of thyroiditis, Mikulicz’s disease, chronic sialadenitis, retroperitoneal fibrosis, tubulointerstitial nephritis, and autoimmune hypophysitis,5Ohara H. Nakazawa T. Sano H. et al.Systemic extrapancreatic lesions associated with autoimmune pancreatitis.Pancreas. 2005; 31: 232-237Crossref PubMed Scopus (136) Google Scholar, 6Yamamoto M. Takahashi H. Ohara M. et al.A new conceptualization for Mikulicz’s disease as an IgG4-related plasmacytic disease.Mod Rheumatol. 2006; 16: 335-340Crossref PubMed Scopus (313) Google Scholar, 7Chari S. Smyrk T. Levy M. et al.Diagnosis of autoimmune pancreatitis: the Mayo Clinic experience.Clin Gastroenterol Hepatol. 2006; 4: 1010-1016Abstract Full Text Full Text PDF PubMed Scopus (855) Google Scholar and these all may be manifestations of an IgG4-related systemic disease.1Björnsson E. Chari S. Smyrk T. et al.IgG4 associated cholangitis: description of an emerging clinical entity based on review of the literature.Hepatology. 2007; 45: 1547-1554Crossref PubMed Scopus (198) Google Scholar, 8Hamed G. Tsushima K. Yasuo M. et al.Inflammatory lesions of the lung, submandibular gland, bile duct and prostate in a patient with IgG4-associated multifocal systemic fibrosclerosis.Respirology. 2007; 12: 455-457Crossref PubMed Scopus (68) Google Scholar IAC typically responds to oral steroid therapy.1Björnsson E. Chari S. Smyrk T. et al.IgG4 associated cholangitis: description of an emerging clinical entity based on review of the literature.Hepatology. 2007; 45: 1547-1554Crossref PubMed Scopus (198) Google Scholar, 3Nishino T. Toki F. Oyama H. et al.Biliary tract involvement in autoimmune pancreatitis.Pancreas. 2005; 30: 76-82PubMed Google Scholar, 4Ghazale A. Chari S. Zhang L. et al.IgG4-associated cholangitis (IAC): clinical profile and response to therapy.Gastroenterology. 2008; 134: 706-715Abstract Full Text Full Text PDF PubMed Scopus (715) Google Scholar, 9Matsushita M. Yamashina M. Ikeura T. et al.Effective steroid pulse therapy for the biliary stenosis caused by autoimmune pancreatitis.Am J Gastroenterol. 2007; 102: 220-221Crossref PubMed Scopus (13) Google Scholar Relapse after withdrawal of steroids is common, particularly with hilar or intrahepatic duct strictures, and additional steroid or immunomodulator therapy often is successful.4Ghazale A. Chari S. Zhang L. et al.IgG4-associated cholangitis (IAC): clinical profile and response to therapy.Gastroenterology. 2008; 134: 706-715Abstract Full Text Full Text PDF PubMed Scopus (715) Google Scholar The patient described in this report did not respond to steroid or 6-mercaptopurine therapy. Rituximab therapy resulted in cholangiographic improvement and allowed his biliary stents to be removed. Rituximab is a chimeric IgG1 monoclonal antibody directed against CD20, a phosphoprotein expressed on the surface of B lymphocytes. Initially used to treat lymphoma, rituximab has efficacy in some immune-mediated diseases, including rheumatoid arthritis,10Cohen S. Emery P. Greenwald M. et al.Rituximab for rheumatoid arthritis refractory to anti-tumor necrosis factor therapy: results of a multicenter, randomized, double-blind, placebo-controlled, phase III trial evaluating primary efficacy and safety at twenty-four weeks.Arthritis Rheum. 2006; 54: 2793-2806Crossref PubMed Scopus (1399) Google Scholar thrombotic thrombocytopenic purpura,11Scully M. Cohen H. Cavenagh J. et al.Remission in acute refractory and relapsing thrombotic thrombocytopenic purpura following rituximab is associated with a reduction in IgG antibodies to ADAMTS-13.Br J Haematol. 2007; 136: 451-461Crossref PubMed Scopus (212) Google Scholar benign orbital pseudolymphoma,12Witzig T. Inwards D. Habermann T. et al.Treatment of benign orbital pseudolymphomas with the monoclonal anti-CD20 antibody rituximab.Mayo Clin Proc. 2007; 82: 692-699Abstract Full Text Full Text PDF PubMed Scopus (33) Google Scholar and pemphigus vulgaris13Ahmed A. Spigelman Z. Cavacini L. et al.Treatment of pemphigus vulgaris with rituximab and intravenous immune globulin.N Engl J Med. 2006; 355: 1772-1779Crossref PubMed Scopus (423) Google Scholar (a disease characterized by the presence of pathogenic IgG4 antibodies). The mechanism of action of rituximab in these diseases is presumed to be B-cell depletion, resulting in decreased production of pathogenic autoantibodies. Because the patient was treated solely with rituximab, which depletes only B cells, this case suggests that B lymphocytes play a central role in the pathogenesis of IAC and AIP. The lymphoplasmacytic infiltrates that characterize AIP include polyclonal B cells, plasma cells, and T cells.14Kojima M. Sipos B. Klapper W. et al.Autoimmune pancreatitis: frequency, IgG4 expression, and clonality of T and B cells.Am J Surg Pathol. 2007; 31: 521-528Crossref PubMed Scopus (120) Google Scholar In addition to infiltrating affected tissues, B lymphocytes affect the inflammatory response by interaction with regulatory T cells.15Yang Z. Novak A. Ziesmer S. et al.Attenuation of CD8(+) T-cell function by CD4(+)CD25(+) regulatory T cells in B-cell non-Hodgkin’s lymphoma.Cancer Res. 2006; 15: 10145-10152Crossref Scopus (145) Google Scholar The patient’s serum IgG4 level initially remained increased, sharply declining toward normal 7 months after rituximab therapy was begun. The initially persistent increase of IgG4 levels is not surprising because immunoglobulins are secreted by mature plasma cells that are not depleted by rituximab. This phenomenon also has been reported in patients with rheumatoid arthritis10Cohen S. Emery P. Greenwald M. et al.Rituximab for rheumatoid arthritis refractory to anti-tumor necrosis factor therapy: results of a multicenter, randomized, double-blind, placebo-controlled, phase III trial evaluating primary efficacy and safety at twenty-four weeks.Arthritis Rheum. 2006; 54: 2793-2806Crossref PubMed Scopus (1399) Google Scholar and Waldenstrom’s macroglobulinemia16Ghobrial I. Fonseca R. Greipp P. et al.Initial immunoglobulin M ’flare’ after rituximab therapy in patients diagnosed with Waldenstrom macroglobulinemia: an Eastern Cooperative Oncology Group Study.Cancer. 2004; 101: 2593-2598Crossref PubMed Scopus (160) Google Scholar who receive rituximab. The patient’s clinical and cholangiographic response occurred while his serum IgG4 level was increased persistently, suggesting that IgG4 was not directly pathogenic. Cirrhosis in this case most likely was caused by chronic biliary obstruction caused by IAC. A liver biopsy performed 2 months after the initiation of rituximab therapy did show rare, scattered IgG4-positive cells. By improving biliary strictures, rituximab therapy might lead to some reversal of hepatic fibrosis.17Bonis P. Friedman S. Kaplan M. Is liver fibrosis reversible?.N Engl J Med. 2001; 344: 452-454Crossref PubMed Scopus (145) Google Scholar, 18Hammel P. Couvelard A. O’Toole D. et al.Regression of liver fibrosis after biliary drainage in patients with chronic pancreatitis and stenosis of the common bile duct.N Engl J Med. 2001; 344: 418-423Crossref PubMed Scopus (362) Google Scholar Could our patient have a biliary malignancy rather than IAC? Pseudotumors of the biliary tree have been described in association with AIP.19Kurihara T. Itoi T. Sofuni A. et al.Pseudotumor of the bile duct associated with autoimmune pancreatitis.Endoscopy. 2007; (epub ahead of print)Google Scholar The diagnosis of IAC in this case was based on the marked increase of the serum IgG4 levels, the presence of co-existent AIP, and compatible biliary histology. A positron emission tomography scan showed mild to moderate activity suggestive of inflammation rather than malignancy. Histologic and hematologic evaluations for lymphoma were unrevealing. It is unlikely that this patient’s biliary stricture was malignant. The required duration of rituximab therapy is unclear. The short-term efficacy of rituximab therapy has been documented in rheumatoid arthritis10Cohen S. Emery P. Greenwald M. et al.Rituximab for rheumatoid arthritis refractory to anti-tumor necrosis factor therapy: results of a multicenter, randomized, double-blind, placebo-controlled, phase III trial evaluating primary efficacy and safety at twenty-four weeks.Arthritis Rheum. 2006; 54: 2793-2806Crossref PubMed Scopus (1399) Google Scholar and other inflammatory diseases, but the duration of response and the benefit of maintenance therapy is uncertain. Further data are needed in this regard. In conclusion, rituximab therapy was effective in this case of refractory IgG4-associated cholangitis. Rituximab may be a treatment option for patients with refractory or recurrent IgG4-associated disease. Rituximab has few side effects, and may be an attractive therapeutic option in patients who are intolerant of steroids or suffer relapses of IgG4-associated disease, as well as in patients such as this one with AIP and refractory IgG4-associated cholangitis.
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