Immunoglobulin G4-related disease is an immune mediated condition resulting in disease in various organs of the body such as the pancreas, kidneys, salivary glands, lung, liver, lymph nodes, biliary tract and orbits of the eyes. The disease is recognized by a characteristic pattern of pathological, serological or clinical features shared amongst the organs system that are involved. In some cases, IgG4-RD can mimic malignant, infectious or inflammatory disorders and therefore distinguishing the disease is crucial.
The international consensus statement on IgG4-RD established bases for the diagnosis IgG4-RD from findings in multiple organs. The definitive algorithm for diagnosing IgG4-RD includes: organ swelling (enlargement, mass or nodular lesions) or organ dysfunction in one or more organs on physical examination; hematological studies showing a serum IgG4+ concentration of ≥ 135 mg/dL; histopathology indicating marked lymphocyte and plasmacyte infiltration with fibrosis and IgG4 + plasma cell infiltration (IgG4+/total IgG+ cells > 40% AND > 10 IgG4+ cells on high power field).
Classification Criteria for IgG4-Related Disease
1) Clinical and radiological features
One or more organs show diffuse or localized swelling or a mass or nodule characteristic of IgG4-RD. In single organ involvement, lymph node swelling is omitted.
2) Serological diagnosis
Serum IgG4 levels greater than 135 mg/dl.
3) Pathological diagnosis
Positivity for two of the following three criteria:
- Dense lymphocyte and plasma cell infiltration with fibrosis.
- Ratio of IgG4-positive plasma cells /IgG-positive cells greater than 40% and the number of IgG4-
positive plasma cells greater than 10 per high powered field
- Typical tissue fibrosis, particularly storiform fibrosis, or obliterative phlebitis
- Definite: 1) +2) +3)
- Probable: 1) +3)
- Possible: 1) +2)
Explanatory note 1: Combination of organ-specific diagnostic criteria*.
Patients with a possible or probable diagnosis by comprehensive diagnostic criteria who fulfill the organ-specific
criteria for IgG4-RD are regarded as being definite for IgG4-RD.
*Diagnostic criteria according to the IgG4-related organ:
- International consensus diagnostic criteria for autoimmune pancreatitis
- IgG4-related lacrimal gland, saliva adenitis diagnostic criteria
- Diagnostic criteria for IgG4-related kidney disease
- Clinical diagnostic criteria of IgG4-related sclerosing cholangitis
- Diagnostic criteria for IgG4-related ophthalmic disease
- Diagnostic criteria for IgG4-related respiratory disease
- Diagnostic criteria for IgG4-related large periarteritis/periarteritis and retroperitoneal fibrosis
Explanatory note 2: exclusion diagnosis
1) It is important to acquire tissue samples from each involved organ to distinguish malignant tumors (e.g., cancer,
malignant lymphoma) and similar benign conditions (e.g., Sjögren syndrome, primary sclerosing cholangitis,
multicentric Castleman’s disease, secondary retroperitoneal fibrosis, granulomatosis with polyangiitis, sarcoidosis,
eosinophilic granulomatosis with polyangiitis).
2) It is important to exclude an infectious- or inflammation-related disease in patients with high fever, highly
elevated CRP and neutrophilia.
Explanatory note 3: pathologic diagnosis
1) The numbers of IgG4-positive cells are usually more abundant in resected organs and partially enucleated tissue than in tissue samples obtained by needle biopsy or endoscopic biopsy.
2) Storiform fibrosis is defined as spindle-shaped cells, inflammatory cells and fine collagen fibers forming a flowing
arrangement. Obliterative phlebitis is defined as fibrous venous obliteration with inflammatory cells. Both are
helpful for a diagnosis of IgG4-RD. 1and 3without 2can only be applied in a case with poor IgG4 and/or IgG
Explanatory note 4: steroid reactivity
Steroid trial is not recommended. However, if patients do not respond to initial steroid therapy, the diagnosis should be reconsidered.
- Lanzillotta M, Mancuso G, Della-Torre E. Advances in the diagnosis and management of IgG4 related disease. BMJ. 2020 Jun 16;369:m1067. [Medline]
- Umehara H, Okazaki K, Kawa S, Takahashi H, Goto H, Matsui S, Ishizaka N, Akamizu T, Sato Y, Kawano M; Research Program for Intractable Disease by the Ministry of Health, Labor and Welfare (MHLW) Japan. The 2020 Revised Comprehensive Diagnostic (RCD) Criteria for IgG4-RD. Mod Rheumatol. 2020 Dec 4:1-14. [Medline]
- Vasaitis L. IgG4-related disease: A relatively new concept for clinicians. Eur J Intern Med. 2016 Jan;27:1-9. [Medline]
Created Jan 7, 2021.