Raised levels of serum IgG4 have historically been used in diagnostic criteria of AIP, with >95% specificity reported in early studies [8]. More recent studies in AIP have suggested a much lower sensitivity (30–70%) and specificity (62–83%). Serum IgG4 level has been used to attempt to distinguish IgG4-SC from primary sclerosing cholangitis (PSC) and cancer (both pancreatic and cholangiocarcinoma). One study attempted to establish the optimal cut-off of IgG4 levels in order to differentiate between the subgroups of IgG4-SC, identifying a cut-off of 182 mg/dL and greater than 207 mg/dL for distinguishing types 3 and type 4 IgG4-SC from CCA with a specificity of 97% and 100%, respectively [9]. Another study described the utility of a serum IgG1/IgG4 ratio of 0.24 in differentiating IgG4-SC from PSC patients with an elevated serum IgG4 level between 140 mg/dL and 2.8 mg/dL [10]. However, serum IgG4 levels alone are not a sufficiently sensitive or specific tool to be able to reliably distinguish IgG4-SC from PSC or HPB malignancy.

Tissue acquisition and a formal pathological diagnosis are increasingly viewed as a central focus of establishing the diagnosis of IgG4-RD, and the same is true of IgG4-SC. This is particularly important given the extent to which clinical and radiological features of IgG4-SC may mimic those of other benign and malignant conditions, including PSC and CCA, and the divergent treatment approaches to each. Cytological samples, whether from brush cytology of biliary strictures or endoscopic ultrasound (EUS)-guided fine-needle aspiration (FNA) may be important in excluding malignancy (albeit with sensitivity for biliary cytology of only 20–50% for malignancy) but rarely allow a definitive diagnosis of IgG4-SC to be made. Intrabiliary biopsies may be obtained at the time of ERCP through either fluoroscopy-directed biopsies or more recently via the use of cholangioscopy, allowing visually directed biopsies [11]. Ampullary biopsies may advance the diagnosis of IgG4-SC, in the setting of an IgG4-positive lymphoplasmacytic infiltrate, but other diagnostic features are rarely present [12].

A similar pathological lesion is seen in all tissues affected in IgG4-RD and is central to the recently agreed international consensus on the diagnosis of IgG4-RD [13]. Tissue IgG4 and IgG immunostaining should be performed on biopsy and resection specimens, and a mean IgG4 count (in three high-power fields (HPF)) and ratio of IgG4 to total IgG should be calculated. For IgG4-SC, >10 IgG4+cells/HPF in a biopsy specimen, or >50 IgG4+cells/HPF in a resection specimen, and an IgG4/IgG ratio >40%, in the context of two of three classical features, are considered diagnostic in the appropriate clinical context. However, tissue sampling can be patchy and not all features may be seen in a single specimen [14].

Differentiating IgG4-SC from other benign and malignant causes of biliary stricturing is of fundamental importance. PSC appears to be particularly associated with raised levels of serum IgG4, occurring in 9%–18% of patients, compared with <1% of other biliary conditions [15]. Although there is considerable disease overlap between IgG4-SC and PSC [16], IgG4+ PSC appears to be distinct, with different HLA associations and carries a higher risk of disease progression than IgG4-ve PSC [17]. In this instance, a ratio of IgG1/IgG4 may be useful in distinguishing IgG4+ PSC from IgG4-SC [10]. CCA may occur in up to 30% of patients with PSC and also be a de novo cause of biliary stricturing and a hilar mass. An inflammatory ‘pseudotumour’ may be seen in IgG4-SC, with imaging features that may mimic malignancy. In a retrospective study of patients who had undergone liver surgery for presumed CCA, 8% were found to have histology on resection consistent with IgG4-SC [18].

The mainstay of medical treatment in IgG4-SC is the use of systemic corticosteroids, despite the absence of randomised placebo controlled trials. Current approaches to medical therapy are largely extrapolated from the treatment of other manifestations of IgG4-RD, and AIP in particular. Although spontaneous remission can occur in AIP, steroids have been shown to induce remission quicker, more consistently and have a lower relapse rate. Significant spontaneous cholangiographic improvement of type 1 IgG4-SC may be seen (with stricture improvement probably correlating with reduced pancreatic inflammation around the low bile duct), but in types 2–4 IgG4-SC an improvement without treatment is unusual.

International consensus regarding the role of oral corticosteroids in initiation therapy in IgG4-RD has recently been reached [19], and a starting dose of prednisolone 30-40 mg daily for 4 weeks, before reducing by 5 mg every subsequent 14 days, is widely employed. Patients are reviewed regularly, given steroid-induced side effects and the increased risk of cholangitis/sepsis with use of steroids and biliary obstruction. Improvement in bile duct stricturing and normalisation of liver enzymes following the introduction of steroid therapy have been shown [1]. In the setting of biliary obstruction and hilar or dominant extrahepatic strictures, biliary stenting at ERCP is usually indicated, even if a response to steroids is expected. A clinical and cholangiographic improvement should be seen within 4–6 weeks of starting treatment and be seen on repeat imaging (MRCP, ERCP or CT). Non-response to steroid therapy may be representative of a less inflammatory ‘burnt-out’ disease, and a more fibrotic phenotype, or an alternative diagnosis.

Patients with IgG4-SC are at high risk of relapse, either after stopping steroid treatment or during the initial taper. In a study of patients with IgG4-SC and AIP, 57% (13 of 23) of patients relapsed [20]. In a further study of 53 patients with IgG4-SC, a similar relapse rate was reported in patients that underwent surgery (n = 18) or treatment with steroids (n = 30) (44% vs 54%, p = 0.1). Factors predictive of relapse included the presence of proximal strictures (IgG4-SC type 2–4) and increased IgG4 levels [1]. Relapses that occur after steroid withdrawal/reduction may be treated with a further course of steroids followed by additional immunomodulatory drugs, e.g. azathioprine (target dose 2 mg/kg/day). However the benefits of the addition of immunomodulators over low-dose steroids alone in reducing time to further relapses are uncertain [21]. Predictors of resistance to immunomodulator therapy include evidence of other organ involvement other than IgG4-SC and retroperitoneal fibrosis (p < 0.03).

Certain patients may be intolerant of immunomodulatory drugs and become dependent on high-dose steroids in order to maintain remission. Rituximab, a monoclonal antibody depletion therapy directed against the CD20 antigen on B cells, has been described in case series and a prospective open-label study of patients with AIP and IgG4-RD [21, 22]. In the Mayo study, complete radiographic remission was achieved in 80% of AIP patients, at a median of 4.5 months, although all these patients required additional maintenance therapy with rituximab. Rituximab may find a role in the treatment of patients with Ig4-SC who have failed previous steroid therapy or immunomodulatory therapy or perhaps in a more ‘top-down’ approach for sparing of long-term steroid-related side effects.

Long-term outcome in patients with IgG4-SC is lacking. However, in a UK study of 116 patients with IgG4-RD, with 34 months of follow-up, cirrhosis in the setting of IgG4-SC occurred in 5% of patients [23]. An increased risk of CCA in patients with IgG4-SC is not proven, although there have been case reports suggesting an association. An all-cause increased risk of malignancy in IgG-SC and AIP patients, including HPB cancers, has been shown [23].

Although the pathogenic mechanisms underlying IgG4-SC are poorly understood, insights into the genetic and immunological aspects of the disease have increased over the last decade. Most of these studies have focused on patients with AIP and/or IgG4-related sialoadenitis, and thus the findings are extrapolated to IgG4-SC. Disease pathways believed to be involved in the disease are shown in Fig. 12.2.

Studies have identified human leukocyte antigen (HLA) molecules and other immune-regulatory genes as determinants of disease susceptibility to AIP, disease relapse after steroid therapy and extra-pancreatic disease [24–26].

There has been a sustained quest to find an antigen initiating and/or driving AIP/IgG4-SC, and although no specific antigen has yet been identified, the presence of oligoclonal plasmablasts and B cells in peripheral blood and tissues supports an antigen-mediated response [30–32].