United European Gastroenterology guideline: How to manage immunoglobulin G4-related digestive diseases

Immunoglobulin G4 (IgG4)-related disease is an entity that emerged in the 20th century. Prior to this nomenclature, different systemic lesions, such as Mikulicz’s disease, interstitial pneumonia, sclerosing cholangitis, idiopathic pancreatitis, ¹ retroperitoneal fibrosis, and interstitial nephritis, were considered independent inflammatory diseases. However, these lesions commonly demonstrate abundant IgG4-positive plasmacytic infiltration (>10/high power field), with high ratios of IgG4-positive cells (>40% in IgG4/IgG-positive cells) and raised serum IgG4 levels (>135 mg/dL), and they mostly respond to steroid therapy. ² Subsequently, they were recognized as subtypes of IgG4-related systemic lesions and were initially categorized as “IgG4-positive multiorgan lymphoproliferative syndrome (IgG4(+)-MOLPS)” ³ or “IgG4-systemic plasmacytic syndrome (IgG4-SIPS),” ³ and then ultimately called “IgG4-related disease.”^2,3

IgG4-related digestive diseases (IgG4-DDs) ⁴ include various inflammatory disorders in the hepato-pancreato-biliary organs^5–7 and digestive tract. ⁸ They mostly develop in middle-aged to elderly people (median age 58–65 years) with a male sex predominance,^2,3,7 but they rarely occur in children. ⁴ IgG4-DDs usually show elevated serum IgG4 and typical images, sometimes accompanied with other organ involvement (OOI).^3,5 However, images can occasionally be atypical, without OOI or increased serum IgG4. So, they require careful differentiation from malignancies.^6,9 Endoscopic ultrasonography-guided fine-needle aspiration biopsy is fairly important in cases suspected to be autoimmune pancreatitis (AIP), both to exclude malignancies and to achieve a conclusive histological diagnosis.^4,9 Similarly, transpapillary biliary biopsy is effective in cases of IgG4-related sclerosing cholangitis (IgG4-SC). ⁶ Although the histological items for IgG4-SC cannot be fully obtained by bile-duct biopsy (0–88%), ⁶ exclusion of biliary cancer is feasible to some extent. The serum IgG4 is often within the normal level in cases of isolated IgG4-SC. ⁶ Therefore, recognition of the continuous mucosal layer of the bile duct and observation of a steroid response are critical. The international consensus diagnostic criteria (ICDC; 2011), which exempt from endoscopic retrograde pancreatography (ERP), have been widely used over the world for the diagnosis of AIP. ⁵ To date, Japanese groups have provided the most up-to-date diagnostic criteria and guidelines for IgG4-related diseases,^2,3,5,6,8 and now no longer obligate ERP and accept magnetic resonance pancreatography. ⁵ Today, and in the future, safety, simplification, and utilization are required in the diagnosis of IgG4-DDs.

Information about the treatment is limited for IgG4-DDs other than AIP. Corticosteroid is the standard AIP treatment and has an initial response rate of 97–100%. ⁹ Rituximab and immunomodulators (azathioprine) can be applied in steroid-refractory or repeatedly relapsed cases. Corticosteroid is generally associated with aggravation of glycemic control and can induce diabetes. However, in cases of AIP, steroid therapy instead improves glucose tolerance by reducing pancreatic inflammation and promoting β-cell function during the long treatment period. ⁹ One therapeutic issue is the high relapse rate (24–52%) in type 1 AIP during the long clinical course.^9,10 The relapse rate tends to differ among countries, depending on the use of low-dose maintenance steroids. ¹⁰ A prolonged steroid dosage increases the risk of side effects, such as infection, vertebral fracture, femoral head necrosis, and myopathy. ¹⁰ Hence, maintenance therapy is indicated for patients with recurrence risks such as high serum IgG4, diffuse pancreatic swelling, or OOIs (especially dacryoadenitis/sialadenitis, proximal bile duct stenosis, and retroperitoneal fibrosis^3,4,9). In cases with life-span-overdosed steroids, rituximab and immunomodulators can be used as steroid-sparing agents. ³

Interval malignancies have been reported in cases of AIP or IgG4-RDs. However, whether the standardized incidence ratio is significantly increasing in the cohort of AIP remains controversial. ⁹ The increase may reflect a bias due to intensive systemic examinations at the initial diagnosis, as malignancies are predominantly discovered shortly after diagnosis of AIP. The concept of paraneoplastic syndrome has also been reported, whereby IgG4-related lesions may develop as responses to subclinical malignancies. Physicians must remain alert for tumor development during the clinical course.

The United European Gastroenterology (UEG) guideline working group published the European guideline for IgG4-DD⁴ based on the most up-to-date information drawn from a large number of studies. The authors strongly believe this guideline will support clinicians working in relevant fields. However, the current guideline still lacks evidence for entire categories of IgG4-DDs, especially those of the liver and digestive tract and those in children. The UEG guidelines and ours differ mainly in therapeutic aspects; that is, the UEG guideline recommends a year or less of maintenance steroid therapy ⁴ in contrast to the prolonged (three-year) maintenance therapy recommended in Japan. ¹⁰ The authors believe that low-dose maintenance steroid therapy ¹⁰ is effective, at least in AIP patients with recurrence risks. Further accumulation of clinical and basic data is necessary to determine the optimal treatment strategy for IgG4-DD.