DISPATCHES FROM THE GUILD CONFERENCE, SERIES #23 DISPATCHES FROM THE GUILD CONFERENCE, SERIES #23

Uma Mahadevan MD, Series Editor guildconference.com IgG4-related Sclerosing Cholangitis

Raj A. Shah Kris V. Kowdley

IgG4-related disease, characterized by IgG4-rich inflammatory infiltrates and variable degrees of fibrosis, encompasses a variety of disorders involving multiple organs. IgG4-related sclerosing cholangitis (IgG4-SC) is frequently associated with autoimmune . The disease is associated with a clinical presentation of obstruction, , weight loss and abdominal pain. IgG4-SC is typically diagnosed in middle- aged and older men and therefore may lead to a suspicion of cholangiocarcinoma or primary sclerosing cholangitis. The association with autoimmune pancreatitis and an elevated IgG4 level (>135 mg/dl) should increase the clinical suspicion of IgG4-SC. There are typical histological features of an IgG4-rich infiltrate on liver histology as well as storiform fibrosis and obstructive phlebitis. Cholangiographic changes in IgG4-SC are distinct from PSC and four types of IgG4-SC have been described. All diagnostic modalities should be used to evaluate patients with suspected IgG4-SC including imaging, endoscopic methods and biopsy as well as a thorough history, physical examination and laboratory assessment to evaluate for extrahepatic disease. are the mainstay of therapy, with a starting dose of prednisone of 0.6 mg/kg/day. Other immunosuppressive therapies can be used for steroid-intolerant or refractory patients. This review describes the epidemiology, diagnosis and management of IgG4-SC.

Epidemiology gG4-related disease (IgG4-RD) is a involvement.2 The incidence and prevalence of fibroinflammatory process with multiorgan AIP in Japan was estimated to be 1.4 and 4.6 per Imanifestations, of which IgG4-related 100,000 of the population, respectively.3 Of this sclerosing cholangitis (IgG4-SC) is a known biliary population with AIP, 23.5% had IgG4-SC within complication.1 IgG4-SC is frequently accompanied the intrahepatic ducts and 10.3% had disease at by autoimmune pancreatitis (type I AIP) as found the porta hepatis. by a cohort in UK, which showed that 87% of cases IgG4-SC has a three to five-fold higher diagnosed with IgG4-SC also had intrapancreatic prevalence in men than women, and the mean age of presentation is in the sixth decade.3,4 In one study, Raj A. Shah, MD Liver Care Network and Organ 92% of cases had a medical history of AIP, 77% Care Research Swedish Medical Center, Seattle WA had obstructive jaundice on presentation, and 74% Kris V. Kowdley, MD, FACP, FACG, AGAF, FAASLD had increased serum IgG4 levels on presentation.4 Director of the Liver Care Network and Organ Care Research, Swedish Medical Center, Seattle, WA Occupational exposure may play a role as 61% of

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patients in a cohort had worked ‘blue collar’ jobs field on immunofluorescence staining, obliterative for at least one year prior to diagnosis and 52% phlebitis, and storiform fibrosis. Imaging, while reported prolonged exposure to solvents, industrial for AIP would reveal pancreatic abnormalities, dusts, pesticides, industrial oils, or polymers.5 for IgG4-SC should reveal biliary structures This is in contrast to a 14% reported history of either in intrahepatic ducts, proximal extrahepatic blue collar occupation in those diagnosed with ducts, or intrapancreatic ducts.12 Serologic criteria primary sclerosing cholangitis (PSC).5 History of include IgG4 levels ≥ 135 mg/dL.15 Other organ allergy and atopy has been noted in 63% and 40% involvement may include pancreatic, renal, of patients with IgG4-RD, respectively.6 In fact, salivary or lacrimal, or retroperitoneal fibrosis. the study also observed IgE-positive mast cells and Response to steroid therapy would be demonstrated eosinophilia in biliary tissue in these cases. IgG4- by either radiologic improvement of stricturing or SC is often accompanied by other autoimmune by biochemical response. disorders, the most common being inflammatory Japanese clinical guidelines15 support bowel disease afflicting 10% and thyroid disease cholangiographic classification of IgG4-SC into in 7%.2 four types, characterized by location and pattern of The presence of IgG4-SC is an important biliary strictures, and used to inform the clinician prognostic indicator in IgG4-RD, predicting regarding potential alternative diagnoses that relapse after discontinuation of must be considered. Type 1 involves stenosis in therapy.2,4 IgG4-SC may impart an increased the distal bile duct. (PC) and risk of all-cause mortality,2 though this may be cholangiocarcinoma may mimic this presentation at least partially attributable to the advanced age and would therefore warrant consideration prior of those diagnosed.7 Increased risk of malignancy to diagnosis of IgG4-SC.16 Type 2 is characterized has been associated with diagnosis of IgG4-SC in by diffusely distributed stenosis both in the intra- some studies,2,8 though another cohort did not find and extrahepatic ducts, due to which PSC must be a significant difference in incidence of malignancy ruled out. Type 3 includes hilar biliary strictures from the general population.9 One proposed along with distal stenosis. Type 4 involves only the hypothesis for an increased risk is the chronic hilar strictures. Cholangiocarcinoma may present inflammation caused by the disease.7 The K-ras ­ similarly to either type 3 or 4. mutation is frequently found in the , bile The differentiation of IgG4-SC from PC, duct, and gallbladder of patients with AIP.10 The cholangiocarcinoma, and PSC remains a diagnostic relative risk of cancer at the time of diagnosis of challenge and requires a multimodal approach. IgG4-RD has been found to be 4.9, which decreases Serologic examination of the secretory mucin to 1.5 in subsequent years.8 This finding indicates MUC5AC along with CA19-9 has shown a malignancy may be a cause, rather than the result, sensitivity of 83% and specificity of 80% in of IgG4-RD. Increased B-cell secretion of IgG- diagnosis of PC.17 Imaging modalities such as 4 has been observed in malignancy, specifically CT, MRI, and EUS have different contexts for melanoma.11 use and limitations in diagnosis of PC, and are discussed elsewhere.18 EUS-guided fine needle Diagnosis aspiration may be required if clinical suspicion IgG4-SC is diagnosed in patients with AIP in 87- remains high.18 92%2,4 of cases. As the disease process is similar, Cholangiocarcinoma can also be assessed the diagnostic criteria of AIP have therefore with serologic testing of CA 19-9 and duke been adapted for the diagnosis of IgG4-SC.12 pancreatic monoclonal antigen type 2, both of Diagnostic criteria for AIP, proposed in 2006,13,14 which are significantly more elevated with this involve five criteria: histology, imaging, serology, disease compared to IgG4-SC.19 As IgG4-SC is other organ involvement, and response to steroid nearly always associated with AIP,2,4,19 pancreatic therapy (HISORt criteria). Histology involves involvement on imaging can be a sign of the the findings of periductal lymphoplasmacytic disease. Serum IgG4 levels can be elevated in infiltrate with > 10 IgG4+ cells per high power cholangiocarcinoma, and increased specificity of

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87% can be obtained with a higher cutoff at 157.5 specific for IgG4-SC, with a specificity of 90.2%,27 mg/dL20. Serologic tumor markers that may be is a ratio of IgG4+ plasma cells to IgG+ plasma elevated in cholangiocarcinoma include CA 19-9, cells that is > 40%. Research has also shown that CA 242, and carcinoembryonic antigen (CEA).20 determination of dominant IgG4+ B-cell receptor EUS may be a useful tool to differentiate imaging clones via next-generation sequencing may be characteristics. In one study, a thickened wall was accurate in differentiating IgG4-SC from PSC or detected on EUS in 94% of patients with IgG4- cancer.28 Moreover, the same study identified a SC as opposed to 30% with cholangiocarcinoma, cutoff of 5% for the ratio of IgG4 to IgG RNA while a space occupying lesion was seen in only using quantitative PCR that yielded a sensitivity 6% of those with IgG4-SC versus 80% with of 94% and specificity of 99% in identification cholangiocarcinoma.20 Obtaining biopsy samples of IgG4-SC. Other assays, such as IgG4:IgG1 for histopathologic assessment may be useful as ratio, continue to be studied to develop robust storiform fibrosis and obliterative phlebitis are biochemical parameters that can be used to present in IgG4-SC but not in cholangiocarcinoma.21 diagnose and prognosticate this illness.1 Immunofluorescence may be of limited utility in this context as 16% of cholangiocarcinoma cases Treatment and 17% of cases with PC can have ≥ 20 IgG4+ Corticosteroid therapy is the cornerstone of plasma cells on histologic assessment.22 therapy for IgG4-SC12,15,25 and leads to rapid and Serologic evaluation in PSC may show durable remission in 90% of patients.29 The dose is elevation of serum titers of IgM, anti-smooth muscle dependent on the center but commonly used is either antibody, anti-nuclear antibody, and anti-neutrophil a dose of 0.6 mg/kg/day of prednisolone or 30-40 cytoplasmic antibody but none of these are specific mg daily.30 This was usually continued for four for the disease.23 IgG4 elevation is also present in weeks followed by a taper whereby the dose would 9-15% of those with PSC, and the extent of any be decreased by 5 mg every 1-2 weeks predicated relationship between this subset of PSC and IgG4- on the patient’s clinical response.29,30 Standard SC remains undetermined.24 While type 2 IgG4- practice in Europe and North America has been SC may mimic characteristics of PSC on imaging, to subsequently discontinue steroid therapy in three cholangiography can detect certain features that months without maintenance dosing.30 By contrast, favor IgG4-SC such as multifocal strictures, bile in Asia, prednisolone is tapered to a maintenance duct wall thickness > 2.5 mm, and the lack of dose of 5 mg daily, which is continued for three hepatic parenchymal changes.25 Characteristics years prior to consideration for discontinuation15. of PSC on cholangiography include a beaded As the disease responds swiftly to steroid therapy, appearance or the presence of diverticulum-like obstructive jaundice without acute cholangitis outpouchings.15 Patient history may be helpful in may be safely managed without biliary drainage differentiating PSC from IgG4-SC. Average age at under close clinical monitoring, thereby avoiding diagnosis of PSC is 41 years old26 compared to 62 the risks associated with endoscopic retrograde years old at diagnosis of IgG4-SC.4 IBD is present cholangiopancreatography (ERCP).30 in 70-80% of patients with PSC26 as opposed to Relapse of IgG4-RD after a course of steroid 10% of those with IgG4-SC.2 Furthermore, PSC therapy is common, occurring in 45% of cases is not associated with pancreatic disease whereas with AIP in a cohort at Mayo Clinic.31 In this IgG4-SC coexists with AIP in up to 92% of cases.4 cohort, those who relapsed received either a repeat Histologically, the fibroinflammatory process of course of steroids or a combination of steroids IgG4-SC exhibits a transmural distribution whereas and steroid-sparing immunomodulators, such as PSC demonstrates mucosal damage.25 , 6-mercaptopurine, mycophenolate While a criterion of > 10 IgG4+ plasma cells mofetil, or methotrexate. The two groups had a per high powered field is included in diagnostic similar rate of relapse-free survival, with a total criteria, other disease processes such as PSC, PC, of 77% achieving remission. The remainder, who and cholangiocarcinoma can mimic this finding.22 were either intolerant or resistant to treatment, Another criterion that has been shown to be more (continued on page 30)

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(continued from page 28) References received , which achieved remission in 1. Culver EL, Chapman RW. IgG4-related hepatobiliary 83% of the remaining patients. Rituximab, an anti- disease: An overview. Nat Rev Gastroenterol Hepatol CD20 antibody causing B-cell depletion, has been 2016;13(10):601–612. 2. Huggett MT, Culver EL, Kumar M, et al. Type 1 auto- tested in an open-label pilot trial for treatment of immune pancreatitis and IgG4-related sclerosing chol- IgG4-RD with disease response observed in 97% angitis is associated with extrapancreatic organ failure, of participants and complete remission achieved malignancy, and mortality in a prospective UK cohort. 31 Am J Gastroenterol 2014;109(10):1675–1683. in 47% at 6 months. 3. Kanno A, Masamune A, Okazaki K, et al. Nationwide Elucidation of the pathophysiology of IgG4- epidemiological survey of autoimmune pancreatitis in SC and the overarching diagnosis of IgG4-RD has Japan in 2011. Pancreas 2015;44(4):535–539. opened avenues to explore for targeted treatments. 4. Ghazale A, Chari ST, Zhang L, et al. Immunoglobulin G4-Associated Cholangitis: Clinical Profile The IgG4 molecule has a uniquely unstable hinge and Response to Therapy. Gastroenterology region that allows dissociation to two ‘hemi-IgG4’ 2008;134(3):706–715. molecules that can then reassociate with other hemi- 5. Buy Wenniger LJM de, Culver EL, Beuers U. Exposure to occupational antigens might predispose to IgG4- IgG4 molecules to form antibodies that are specific related disease. Hepatology. 2014;60(4):1453–1454. to two different antigens, but that have poor affinity 6. Culver EL, Sadler R, Bateman AC, et al. Increases for both Fc receptors and complement.32 Hence, the in IgE, Eosinophils, and Mast Cells Can be Used in Diagnosis and to Predict Relapse of IgG4-Related molecule is considered anti-inflammatory due to Disease. Clin Gastroenterol Hepatol 2017;15(9):1444– its competitive binding of antigenic sites without 1452.e6. subsequent activation of inflammatory response. 7. Ikeura T, Miyoshi H, Shimatani M, Uchida K, Takaoka M, Okazaki K. Long-term outcomes of autoimmune This is indeed observed in its role in blunting pancreatitis. World J. Gastroenterol. 2016;22(34):7760– immune response to malignancy33 and moderating 7766. allergic reactions.34 The discovery of the role of 8. Shiokawa M, Kodama Y, Yoshimura K, et al. Risk of + cancer in patients with autoimmune pancreatitis. Am J circulating CD19 plasmablasts, progenitors of Gastroenterol 2013;108(4):610–617. plasma cells, in disease activity35 has led to clinical 9. Hirano K, Tada M, Sasahira N, et al. Incidence of investigation of targeted drug therapy. XmAb5871, Malignancies in Patients with IgG4-related Disease. Intern Med 2014;53(3):171–176. a monoclonal antibody for CD19 with an Fc domain 10. Kamisawa T, Tsuruta K, Okamoto A, et al. Frequent that binds to the inhibitory receptor of B-cells, is and significant k-ras mutation in the pancreas, the bile currently in phase II of development for treatment duct, and the gallbladder in autoimmune pancreatitis. 36 Pancreas 2009;38(8):890–895. of IgG4-RD. 11. Karagiannis P, Gilbert AE, Josephs DH, et al. IgG4 In summary, IgG4-SC is a protean disease subclass antibodies impair antitumor immunity in mela- that remains a diagnostic challenge requiring a noma. J Clin Invest 2013;123(4):1457–1474. 12. Barnes E, Phil D. IgG4-Related Sclerosing Cholangitis. holistic approach. While more specific markers Clin Liver Dis 2017;10(1):9–16. are on the horizon, the HISORt criteria remain the 13. Chari ST, Smyrk TC, Levy MJ, et al. Diagnosis of most studied diagnostic tools to assist the clinician. Autoimmune Pancreatitis: The Mayo Clinic Experience. Clin Gastroenterol Hepatol 2006;4(8):1010–1016. Corticosteroid treatment is first-line for the disease 14. Chari ST. Diagnosis of autoimmune pancreatitis using and induces remission in the vast majority of its five cardinal features: Introducing the Mayo Clinic’s patients,12,15 and rituximab may be of benefit in HISORt criteria. J Gastroenterol 2007;42(SUPPL. 37 18):39–41. refractory cases. As the immunologic milieu of 15. Kamisawa T, Nakazawa T, Tazuma S, et al. Clinical this disease process is further illuminated, targets practice guidelines for IgG4-related sclerosing cholan- for future therapy may become more apparent. gitis. J Hepatobiliary Pancreat Sci 2019;26:9–42. 16. Nakazawa T, Naitoh I, Hayashi K, et al. Diagnostic criteria for IgG4-related sclerosing cholangitis based on cholangiographic classification. J Gastroenterol 2012;47(1):79–87. PRACTICAL GASTROENTEROLOGY 17. Kaur S, Smith LM, Patel A, et al. A combination of MUC5AC and CA19-9 improves the diagnosis of pan- creatic cancer: A Multicenter Study. Am J Gastroenterol 2017;112(1):172–183. practicalgastro.com 18. Zhang L, Sanagapalli S, Stoita A. Challenges in diag- nosis of pancreatic cancer. World J. Gastroenterol. 2018;24(19):2047–2060.

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19. Tabata T, Kamisawa T, Hara S, et al. Differentiating immunoglobulin G 4-related disease from primary scle- immunoglobulin G4-related sclerosing cholangitis from rosing cholangitis and biliary/pancreatic malignancies. hilar cholangiocarcinoma. Gut Liver 2013;7(2):234– Hepatology 2016;64(2):501–507. 238. 29. Tanaka A, Tazuma S, Okazaki K, et al. Clinical Features, 20. Du S, Liu G, Cheng X, et al. Differential Diagnosis Response to Treatment, and Outcomes of IgG4-Related of Immunoglobulin G4-associated Cholangitis Sclerosing Cholangitis. Clin Gastroenterol Hepatol from Cholangiocarcinoma. J Clin Gastroenterol 2017;15(6):920–926.e3. 2016;50(6):501–505. 30. Hart PA, Kamisawa T, Brugge WR, et al. Long-term 21. Zen Y. The Pathology of IgG4-Related Disease outcomes of autoimmune pancreatitis: A multicentre, in the Bile Duct and Pancreas. Semin Liver Dis international analysis. Gut 2013;62(12):1771–1776. 2016;36(3):242–256. 31. Hart PA, Topazian MD, Witzig TE, et al. Treatment of 22. Resheq YJ, Quaas A, Renteln D von, Schramm C, relapsing autoimmune pancreatitis with immunomodu- Lohse AW, Lüth S. Infiltration of peritumoural but lators and rituximab: The Mayo Clinic experience. Gut tumour-free parenchyma with IgG4-positive plasma 2013;62(11):1607–1615. cells in hilar cholangiocarcinoma and pancreatic adeno- 32. Della-Torre E, Lanzillotta M, Doglioni C. Immunology carcinoma. Dig Liver Dis 2013;45(10):859–865. of IgG4-related disease. Clin Exp Immunol 23. Lindor KD, Kowdley K V, Harrison ME. ACG clini- 2015;181(2):191–206. cal guideline: Primary sclerosing cholangitis. Am J 33. Karagiannis P, Gilbert AE, Josephs DH, et al. IgG4 Gastroenterol 2015;110(5):646–659. subclass antibodies impair antitumor immunity in mela- 24. Berntsen NL, Klingenberg O, Juran BD, et al. noma. J Clin Invest 2013;123(4):1457–1474. Association between HLA haplotypes and increased 34. Durham SR, Emminger W, Kapp A, et al. Long-term serum levels of IgG4 in patients with primary scleros- clinical efficacy in grass pollen-induced rhinocon- ing cholangitis. Gastroenterology 2015;148(5):924– junctivitis after treatment with SQ-standardized grass 927.e2. allergy tablet. J Allergy Clin Immunol 25. Zen Y, Kawakami H, Kim JH. IgG4-related scleros- 2010;125(1–3):131–138.e7. ing cholangitis: all we need to know. J. Gastroenterol. 35. Mattoo H, Mahajan VS, Della-Torre E, et al. De novo 2016;51(4):295–312. oligoclonal expansions of circulating plasmablasts in 26. Lazaridis KN, LaRusso NF. Primary sclerosing cholan- active and relapsing IgG4-related disease. J Allergy gitis. N Engl J Med 2016;375(12):1161–70. Clin Immunol 2014;134(3):679–687. 27. Deng C, Li W, Chen S, et al. Histopathological diagnos- 36. Perugino CA, Stone JH. Treatment of IgG4-related tic value of the IgG4 +/IgG + ratio of plasmacytic infil- disease. Z Rheumatol 2016;75(7):681–686. tration for IgG4-related diseases. Med (United States) 37. Carruthers MN, Topazian MD, Khosroshahi A, et al. 2015;94(9):e579. Rituximab for IgG4-related disease: A prospective, 28. Doorenspleet ME, Hubers LM, Culver EL, et al. open-label trial. Ann Rheum Dis 2015;74(6):1171– Immunoglobulin G4+B-cell receptor clones distinguish 1177.

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