Raj A. Shah, MD Liver Care Network and Organ Care Research Swedish Medical Center, Seattle WA Kris V. Kowdley, MD, FACP, FACG, AGAF, FAASLD Director of the Liver Care Network and Organ Care Research, Swedish Medical Center, Seattle, WA.
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 pancreatitis. The disease is associated with a clinical presentation of obstruction, jaundice, 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 plasma cell 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. Corticosteroids 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.
IgG4-related disease (IgG4-RD) is a fibroinflammatory process with multiorgan manifestations, of which IgG4-related sclerosing cholangitis (IgG4-SC) is a known biliary complication.1 IgG4-SC is frequently accompanied by autoimmune pancreatitis (type I AIP) as found by a cohort in UK, which showed that 87% of cases diagnosed with IgG4-SC also had intrapancreatic involvement.2 The incidence and prevalence of AIP in Japan was estimated to be 1.4 and 4.6 per 100,000 of the population, respectively.3 Of this population with AIP, 23.5% had IgG4-SC within the intrahepatic ducts and 10.3% had disease at the porta hepatis.
IgG4-SC has a three to five-fold higher prevalence in men than women, and the mean age of presentation is in the sixth decade.3,4 In one study, 92% of cases had a medical history of AIP, 77% had obstructive jaundice on presentation, and 74% had increased serum IgG4 levels on presentation.4 Occupational exposure may play a role as 61% of patients in a cohort had worked ‘blue collar’ jobs for at least one year prior to diagnosis and 52% reported prolonged exposure to solvents, industrial dusts, pesticides, industrial oils, or polymers.5 This is in contrast to a 14% reported history of blue collar occupation in those diagnosed with primary sclerosing cholangitis (PSC).5 History of allergy and atopy has been noted in 63% and 40% of patients with IgG4-RD, respectively.6 In fact, the study also observed IgE-positive mast cells and eosinophilia in biliary tissue in these cases. IgG4-SC is often accompanied by other autoimmune disorders, the most common being inflammatory bowel disease afflicting 10% and thyroid disease in 7%.2
The presence of IgG4-SC is an important prognostic indicator in IgG4-RD, predicting relapse after discontinuation of corticosteroid therapy.2,4 IgG4-SC may impart an increased risk of all-cause mortality,2 though this may be at least partially attributable to the advanced age of those diagnosed.7 Increased risk of malignancy has been associated with diagnosis of IgG4-SC in some studies,2,8 though another cohort did not find a significant difference in incidence of malignancy from the general population.9 One proposed hypothesis for an increased risk is the chronic inflammation caused by the disease.7 The K-ras mutation is frequently found in the pancreas, bile duct, and gallbladder of patients with AIP.10 The relative risk of cancer at the time of diagnosis of IgG4-RD has been found to be 4.9, which decreases to 1.5 in subsequent years.8 This finding indicates malignancy may be a cause, rather than the result, of IgG4-RD. Increased B-cell secretion of IgG-4 has been observed in malignancy, specifically melanoma.11
IgG4-SC is diagnosed in patients with AIP in 87-92%2,4 of cases. As the disease process is similar, the diagnostic criteria of AIP have therefore been adapted for the diagnosis of IgG4-SC.12 Diagnostic criteria for AIP, proposed in 2006,13,14 involve five criteria: histology, imaging, serology, other organ involvement, and response to steroid therapy (HISORt criteria). Histology involves the findings of periductal lymphoplasmacytic infiltrate with > 10 IgG4+ cells per high power field on immunofluorescence staining, obliterative phlebitis, and storiform fibrosis. Imaging, while for AIP would reveal pancreatic abnormalities, for IgG4-SC should reveal biliary structures either in intrahepatic ducts, proximal extrahepatic ducts, or intrapancreatic ducts.12 Serologic criteria include IgG4 levels ≥ 135 mg/dL.15 Other organ involvement may include pancreatic, renal, salivary or lacrimal, or retroperitoneal fibrosis. Response to steroid therapy would be demonstrated by either radiologic improvement of stricturing or by biochemical response.
Japanese clinical guidelines15 support cholangiographic classification of IgG4-SC into four types, characterized by location and pattern of biliary strictures, and used to inform the clinician regarding potential alternative diagnoses that must be considered. Type 1 involves stenosis in the distal bile duct. Pancreatic cancer (PC) and cholangiocarcinoma may mimic this presentation and would therefore warrant consideration prior to diagnosis of IgG4-SC.16 Type 2 is characterized by diffusely distributed stenosis both in the intra- and extrahepatic ducts, due to which PSC must be ruled out. Type 3 includes hilar biliary strictures along with distal stenosis. Type 4 involves only the hilar strictures. Cholangiocarcinoma may present similarly to either type 3 or 4.
The differentiation of IgG4-SC from PC, cholangiocarcinoma, and PSC remains a diagnostic challenge and requires a multimodal approach. Serologic examination of the secretory mucin MUC5AC along with CA19-9 has shown a sensitivity of 83% and specificity of 80% in diagnosis of PC.17 Imaging modalities such as CT, MRI, and EUS have different contexts for use and limitations in diagnosis of PC, and are discussed elsewhere.18 EUS-guided fine needle aspiration may be required if clinical suspicion remains high.18
Cholangiocarcinoma can also be assessed with serologic testing of CA 19-9 and duke pancreatic monoclonal antigen type 2, both of which are significantly more elevated with this disease compared to IgG4-SC.19 As IgG4-SC is nearly always associated with AIP,2,4,19 pancreatic involvement on imaging can be a sign of the disease. Serum IgG4 levels can be elevated in cholangiocarcinoma, and increased specificity of 87% can be obtained with a higher cutoff at 157.5 mg/dL20. Serologic tumor markers that may be elevated in cholangiocarcinoma include CA 19-9, CA 242, and carcinoembryonic antigen (CEA).20 EUS may be a useful tool to differentiate imaging characteristics. In one study, a thickened wall was detected on EUS in 94% of patients with IgG4-SC as opposed to 30% with cholangiocarcinoma, while a space occupying lesion was seen in only 6% of those with IgG4-SC versus 80% with cholangiocarcinoma.20 Obtaining biopsy samples for histopathologic assessment may be useful as storiform fibrosis and obliterative phlebitis are present in IgG4-SC but not in cholangiocarcinoma.21 Immunofluorescence may be of limited utility in this context as 16% of cholangiocarcinoma cases and 17% of cases with PC can have ≥ 20 IgG4+ plasma cells on histologic assessment.22
Serologic evaluation in PSC may show elevation of serum titers of IgM, anti-smooth muscle antibody, anti-nuclear antibody, and anti-neutrophil cytoplasmic antibody but none of these are specific for the disease.23 IgG4 elevation is also present in 9-15% of those with PSC, and the extent of any relationship between this subset of PSC and IgG4-SC remains undetermined.24 While type 2 IgG4-SC may mimic characteristics of PSC on imaging, cholangiography can detect certain features that favor IgG4-SC such as multifocal strictures, bile duct wall thickness > 2.5 mm, and the lack of hepatic parenchymal changes.25 Characteristics of PSC on cholangiography include a beaded appearance or the presence of diverticulum-like outpouchings.15 Patient history may be helpful in differentiating PSC from IgG4-SC. Average age at diagnosis of PSC is 41 years old26 compared to 62 years old at diagnosis of IgG4-SC.4 IBD is present in 70-80% of patients with PSC26 as opposed to 10% of those with IgG4-SC.2 Furthermore, PSC is not associated with pancreatic disease whereas IgG4-SC coexists with AIP in up to 92% of cases.4 Histologically, the fibroinflammatory process of IgG4-SC exhibits a transmural distribution whereas PSC demonstrates mucosal damage.25
While a criterion of > 10 IgG4+ plasma cells per high powered field is included in diagnostic criteria, other disease processes such as PSC, PC, and cholangiocarcinoma can mimic this finding.22 Another criterion that has been shown to be more specific for IgG4-SC, with a specificity of 90.2%,27 is a ratio of IgG4+ plasma cells to IgG+ plasma cells that is > 40%. Research has also shown that determination of dominant IgG4+ B-cell receptor clones via next-generation sequencing may be accurate in differentiating IgG4-SC from PSC or cancer.28 Moreover, the same study identified a cutoff of 5% for the ratio of IgG4 to IgG RNA using quantitative PCR that yielded a sensitivity of 94% and specificity of 99% in identification of IgG4-SC. Other assays, such as IgG4:IgG1 ratio, continue to be studied to develop robust biochemical parameters that can be used to diagnose and prognosticate this illness.1
Corticosteroid therapy is the cornerstone of therapy for IgG4-SC12,15,25 and leads to rapid and durable remission in 90% of patients.29 The dose is dependent on the center but commonly used is either a dose of 0.6 mg/kg/day of prednisolone or 30-40 mg daily.30 This was usually continued for four weeks followed by a taper whereby the dose would be decreased by 5 mg every 1-2 weeks predicated on the patient’s clinical response.29,30 Standard practice in Europe and North America has been to subsequently discontinue steroid therapy in three months without maintenance dosing.30 By contrast, in Asia, prednisolone is tapered to a maintenance dose of 5 mg daily, which is continued for three years prior to consideration for discontinuation15. As the disease responds swiftly to steroid therapy, obstructive jaundice without acute cholangitis may be safely managed without biliary drainage under close clinical monitoring, thereby avoiding the risks associated with endoscopic retrograde cholangiopancreatography (ERCP).30
Relapse of IgG4-RD after a course of steroid therapy is common, occurring in 45% of cases with AIP in a cohort at Mayo Clinic.31 In this cohort, those who relapsed received either a repeat course of steroids or a combination of steroids and steroid-sparing immunomodulators, such as azathioprine, 6-mercaptopurine, mycophenolate mofetil, or methotrexate. The two groups had a similar rate of relapse-free survival, with a total of 77% achieving remission. The remainder, who were either intolerant or resistant to treatment, received rituximab, which achieved remission in 83% of the remaining patients. Rituximab, an anti-CD20 antibody causing B-cell depletion, has been tested in an open-label pilot trial for treatment of IgG4-RD with disease response observed in 97% of participants and complete remission achieved in 47% at 6 months.31
Elucidation of the pathophysiology of IgG4-SC and the overarching diagnosis of IgG4-RD has opened avenues to explore for targeted treatments. The IgG4 molecule has a uniquely unstable hinge region that allows dissociation to two ‘hemi-IgG4’ molecules that can then reassociate with other hemi-IgG4 molecules to form antibodies that are specific to two different antigens, but that have poor affinity for both Fc receptors and complement.32 Hence, the molecule is considered anti-inflammatory due to its competitive binding of antigenic sites without subsequent activation of inflammatory response. This is indeed observed in its role in blunting immune response to malignancy33 and moderating allergic reactions.34 The discovery of the role of circulating CD19+ plasmablasts, progenitors of plasma cells, in disease activity35 has led to clinical investigation of targeted drug therapy. XmAb5871, a monoclonal antibody for CD19 with an Fc domain that binds to the inhibitory receptor of B-cells, is currently in phase II of development for treatment of IgG4-RD.36
In summary, IgG4-SC is a protean disease that remains a diagnostic challenge requiring a holistic approach. While more specific markers are on the horizon, the HISORt criteria remain the most studied diagnostic tools to assist the clinician. Corticosteroid treatment is first-line for the disease and induces remission in the vast majority of patients,12,15 and rituximab may be of benefit in refractory cases.37 As the immunologic milieu of this disease process is further illuminated, targets for future therapy may become more apparent.