IGg4-related disease is a systemic, immune-mediated disorder characterised by inflammation and progressive fibrosis. The condition was first described in the literature in 2003, and in 2011 the concept IgG4-related disease was defined. A review article on IgG4-related disease was published in the Journal of the Norwegian Medical Association in 2017 (2).
The typical patient with IgG4-related disease is a middle-aged or elderly man. Autoimmune pancreatitis type 1 is the most common manifestation and accounts for 60 % of cases. It is followed by affection of salivary glands, kidneys, lacrimal glands and retroperitoneal fibrosis. In half of the patients, two or more organs are affected (6).
Characteristic tissue biopsy findings obtained by immunohistochemical analysis, with lymphoplasmacytic inflammation, storiform fibrosis and a ratio of IgG4- to IgG-positive plasma cells of over 0.4 are regarded as the gold standard, but the diagnosis must be based on a combination of radiological, pathological and serological findings (6). The most widely used sets of diagnostic criteria are the HISORt criteria (histology, imaging, serology, other organ involvement and response to steroid therapy), which were developed for diagnosing autoimmune pancreatitis and later modified for IgG4-related sclerosing cholangitis (7).
Serum-IgG4 levels are neither sufficiently sensitive nor specific, and have no established cut-off value (6). Elevated IgG4 may be seen in association with malignancy and other inflammatory disease, for example in 10–15 % of patients with primary sclerosing cholangitis (8). Elevated serum IgG4 must therefore be interpreted with caution. An elevated serum IgG4/IgG1 ratio (> 0.24) and IgG4/total-IgG ratio (> 0.1) is indicated to have higher specificity than serum IgG4 alone (8). The IgG4/IgG-RNA ratio has shown promising results as a more accurate marker, but is not available for clinical use (9).
The plasmablast cell count per millilitre is often elevated and may have a diagnostic value in combination with serum IgG4 (10). Serum plasmablasts are assayed today at Oslo University Hospital, Rikshospitalet. Elevated IgE and eosinophilia are common, and increased CRP and sedimentation rate may be seen. If systemic IgG4-related disease is suspected, a PET-CT scan can be performed to assess the extent of the disease and to evaluate response to treatment (6).
Patients with IgG4-related sclerosing cholangitis are known to present with jaundice, weight loss and abdominal pain, as in the case of our patient. It may be difficult to distinguish IgG4-related sclerosing cholangitis from primary sclerosing cholangitis because MRCP and ERCP findings may be completely identical. Differential diagnosis is very important because it has consequences for therapy, follow-up and prognosis (6).
Our patient was found to have IgG4-related disease affecting the pancreas, bile ducts and salivary glands. Ηis clinical history began with the detection of chronic pancreatitis, and it is probable that the patient has had recurring IgG4-related autoimmune pancreatitis, even though the diagnostic imaging results were not typical of this disease at the time of diagnosis.
The liver resection specimen revealed that the patient had an IgG4-related inflammatory pseudotumour of the liver hilum, which may explain the ineffective biliary drainage. IgG4-related inflammatory pseudotumour of the liver is rarely reported and is most frequently described in the orbit, kidney and lungs. Tissue biopsy of perihilar strictures is largely avoided because of the fear of tumour dissemination and due to the risk of pancreatitis and cholangitis (3).
The case history shows the importance of broad differential diagnosis assessment, if the map does not agree with the terrain. In our patient's case, the combination of ineffective biliary drainage and affection of several organs directed the diagnosis towards systemic disease. Analysis of serum IgG4 concentrations was not carried out during the workup phase, but is of limited diagnostic value as a single diagnostic marker because it may also be elevated in malignancy. Normal biliary brush cytology and normal serum CA19–9 measurements cannot be emphasised due to the low sensitivity of these tests. If IgG4-related disease had been considered prior to surgery, it would have been relevant to obtain a tissue sample from the enlarged submandibular glands and attempt steroid therapy. The dilemma in this period would be the risk of the patient developing a non-resectable cholangiocarcinoma.
IgG4-related disease is believed to be underdiagnosed because of lack of awareness of the condition (6). The disease must be regarded as a differential diagnosis when malignancy in pancreas or bile duct strictures is suspected. In a study from the Netherlands, 15 % of the patients who underwent surgery for suspected perihilar cholangiocarcinoma had a benign stricture, and 42 % of them had IgG4-related disease (11).
Early treatment is important to prevent the development of fibrosis and irreversible organ damage. In 2015, an international group of experts introduced recommendations for treating IgG4-related disease (12). The first choice of treatment is peroral prednisolone (30–40 mg daily) for two to four weeks, followed by gradual tapering (13). Most patients respond well to this, but relapse during tapering and discontinuation is common, and long-term prednisolone treatment (5–7.5 mg daily) reduces the risk of recurrence (13). Practice regarding second-line treatment varies internationally. There are no prospective studies on traditional steroid-sparing drugs such as azathioprine, methotrexate and mycophenolate mofetil, and there is limited data supporting the efficacy of these drugs for IgG4-related disease (12).
Rituximab is a monoclonal antibody for the B-cell marker CD20 and has shown promising results (14). Rituximab selectively reduces the number of CD20-positive B-lymphocytes, which in turn reduces the number of circulating plasma cells that produce IgG4. This is reflected in the fact that the number of plasmablasts (a cell stage between mature B-lymphocytes and differentiated plasma cells) per millilitre is significantly reduced after rituximab therapy (6). Treatment with rituximab in the form of two 1000 mg intravenous infusions separated by 2 weeks has proved effective in inducing remission, and the drug is usually tolerated very well (14). Clinical experience indicates that rituximab should be offered to patients who do not tolerate prednisolone, or for whom it does not have the desired efficacy. Documentation of rituximab maintenance therapy is scarce (14, 15). The pathogenesis of IgG4-related disease is only partly defined, but the good response to rituximab indicates that B-lymphocytes play a central part.