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What is it?
In humans, antibodies are classified into five major groups based on their Fc (fragment crystallizable) region: IgM, IgD, IgE, IgA, and IgG.
IgG itself has four subclasses (IgG1, IgG2, IgG3, and IgG4), ranked by their relative abundance. IgG1 is the most prevalent, followed by IgG2, IgG3, and finally IgG4, which is the least abundant. However, in certain cases—particularly with chronic or repeated antigen exposure—IgG4 can dominate the immune response.
Unlike the other IgG subclasses, IgG4 has distinct properties that have led to its classification as an anti-inflammatory, “benign” antibody with potential benefits in allergic conditions. However, emerging evidence suggests that IgG4 may also contribute to disease pathology in various conditions, including autoimmune diseases (IgG4-AIDs), tumor immunology, and IgG4-related disease (IgG4-RD).
IgG4-related disease (IgG4-RD) is a multi-organ fibro-inflammatory disorder characterized by tumor-like lesions of unknown origin and specific histopathological features.
What are the symptoms?
The most commonly affected organs include the pancreas, kidneys, orbital adnexa, salivary glands, and retroperitoneum.
Symptoms vary depending on the organs involved and the severity of the disease. Multiple organ involvement occurs in 60–90% of cases. The condition typically presents subacutely, often with organ enlargement, and may sometimes be detected incidentally through imaging or laboratory tests (e.g., biochemistry and immunopathology).
IgG4-RD-related tubulointerstitial nephritis may manifest as mass-like lesions on imaging, accompanied by acute or chronic renal failure. A history of allergies is frequently reported, with around 40% of patients experiencing conditions such as atopy, bronchial asthma, or sinusitis. The disease may initially affect one or multiple organs but can later involve additional organs, necessitating close follow-up.
As IgG4-RD can affect nearly any organ, symptom presentation is highly variable. The condition primarily affects elderly males, though pediatric cases—while rare—have been documented. Failure to recognize pediatric cases can delay treatment, potentially leading to poorer outcomes.
How is it diagnosed?
Diagnosis relies on a combination of clinical presentation and histopathological findings. Three main diagnostic criteria are available:
- Mayo Clinic HISORt criteria for diagnosing autoimmune pancreatitis (AIP) (Table 1)
- Japanese Comprehensive Clinical Diagnostic (CCD) criteria for IgG4-RD (Table 2)
- 2019 American College of Rheumatology/European League Against Rheumatism classification criteria for IgG4-RD (Table3)
Approximately 20% of reported pediatric cases meet the IgG4-RD classification or comprehensive diagnostic criteria. Physicians must carefully differentiate IgG4-RD from other conditions with similar presentations.
| Table 1 – The Mayo Clinic HISORt Criteria for the Diagnosis of AIP | |
| Histopathology (one or both criteria required) | Characteristic appearances within biopsy or resection material.* |
| At least ten lgG4-positive plasma cells per high power field within areas of lymphoplasmacytic infiltrate. | |
| Imaging and serology (3 criteria required) | Diffusely enlarged pancreas with delayed and “rim” enhancement. |
| Irregular pancreatic duct. | |
| Increased serum IgG4 concentration. | |
| Response to steroid therapy (3 criteria required) | Unexplained pancreatic disease after a full clinical workup – including the exclusion of cancer. |
| Raised serum IgG4 concentration and/or extrapancreatic organ involvement with increased numbers of tissue lgG4-positive plasma cells. | |
| Resolution or marked improvement in disease with steroid therapy. | |
| *This includes a lymphoplasmacytic infiltrate, “storiform” fibrosis, and obliterative phlebitis; the inflammatory cell infiltrate alone is not sufficient to meet this criterion.(Reproduced from Nambiar S, Oliver TI. IgG4-Related Disease. [Updated 2023 Aug 8]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2025 Jan-) | |
| Table 2 – The Japanese Comprehensive Clinical Diagnostic (CCD) Criteria for IgG-4RD |
| 1. Clinical examination showing characteristic diffuse/localized swelling or masses in single or multiple organs |
| 2. Hematological examination shows elevated serum lgG4 concentrations (greater than 135 mg/dL) |
| 3. Histopathological examination shows: |
| Marked lymphocyte and plasmacytic infiltration and fibrosis. |
| Infiltration of IgG4 + plasma cells: ratio of IgG4 +/ IgG + cells greater than 40% and greater than 10 IgG4 + plasma cells/HPF |
| Definite: 1 + 2 + 3 Probable: 1 + 3 Possible: 1 + 2 |
| (Reproduced from Nambiar S, Oliver TI. IgG4-Related Disease. [Updated 2023 Aug 8]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2025 Jan-) |
| Table 3 – The 2019 American College of Rheumatology/European League Against Rheumatism classification criteria for IgG4-related disease | |
| Step | Categorical assessment or numeric weight |
| Step 1. Entry criteria | Yesb or No |
| Characteristica clinical or radiologic involvement of a typical organ (e.g., pancreas, salivary glands, bile ducts, orbits, kidney, lung, aorta, retroperitoneum, pachymeninges, or thyroid gland [Riedel’s thyroiditis]) OR pathologic evidence of an inflammatory process accompanied by a lymphoplasmacytic infiltrate of uncertain etiology in one of these same organs | |
| Step 2. Exclusion criteria: domains and items c | Yes or Nod |
| Clinical: FeverNo objective response to glucocorticoids | |
| Serologic:Leukopenia and thrombocytopenia with no explanationPeripheral eosinophiliaPositive antineutrophil cytoplasmic antibody (specifically against proteinase 3 or myeloperoxidase)Positive SSA/Ro or SSB/La antibodyPositive double-stranded DNA, RNP, or Sm antibodyOther disease-specific autoantibodyCryoglobulinemia | |
| Radiologic:Known radiologic findings suspicious for malignancy or infection that have not been sufficiently investigatedRapid radiologic progressionLong bone abnormalities consistent with Erdheim-Chester diseaseSplenomegaly | |
| Pathologic:Cellular infiltrates suggesting malignancy that have not been sufficiently evaluatedMarkers consistent with inflammatory myofibroblastic tumorProminent neutrophilic inflammationNecrotizing vasculitisProminent necrosisPrimarily granulomatous inflammationPathologic features of macrophage/histiocytic disorder | |
| Known diagnosis of the following:Multicentric Castleman’s diseaseCrohn’s disease or ulcerative colitis (if only pancreatobiliary disease is present)Hashimoto thyroiditis (if only the thyroid is affected) | |
| If case meets entry criteria and does not meet any exclusion criteria, proceed to step 3. | |
| Step 3. Inclusion criteria: domains and itemse | |
| Histopathology:Uninformative biopsyDense lymphocytic infiltrateDense lymphocytic infiltrate and obliterative phlebitisDense lymphocytic infiltrate and storiform fibrosis with or without obliterative phlebitis | 0+4+6+13 |
| Immunostaining f | 0–16, as follows:Assigned weight is 0 if the IgG4+:IgG+ ratio is 0–40% or indeterminate and the number of IgG4+ cells/hpf is 0–9.g Assigned weight is 7 if the IgG4+:IgG+ ratio is ≥41% and the number of IgG4+ cells/hpf is 0–9 or indeterminate; or 2) the IgG4+:IgG+ ratio is 0–40% or indeterminate and the number of IgG4+ cells/hpf is ≥10 or indeterminate.Assigned weight is 14 if 1) the IgG4+:IgG+ ratio is 41–70% and the number of IgG4+ cells/hpf is ≥10; or 2) the IgG4+:IgG+ ratio is ≥71% and the number of IgG4+ cells/hpf is 10–50.Assigned weight is 16 if the IgG4+:IgG+ ratio is ≥71% and the number of IgG4+ cells/hpf is ≥51. |
| Serum IgG4 concentration:Normal or not checked> Normal but <2× upper limit of normal2–5× upper limit of normal>5× upper limit of normal | 0+4+6+11 |
| Bilateral lacrimal, parotid, sublingual, and submandibular glands:No set of glands involvedOne set of glands involvedTwo or more sets of glands involved | 0+6+14 |
| Chest:Not checked or neither of the items listed is presentPeribronchovascular and septal thickeningParavertebral band-like soft tissue in the thorax | 0+4+10 |
| Pancreas and biliary tree:Not checked or none of the items listed is presentDiffuse pancreas enlargement (loss of lobulations)Diffuse pancreas enlargement and capsule-like rim with decreased enhancementPancreas (either of above) and biliary tree involvement | 0+8+11+19 |
| Kidney:Not checked or none of the items listed is presentHypocomplementemiaRenal pelvis thickening/soft tissueBilateral renal cortex low-density areas | 0+6+8+10 |
| Retroperitoneum:Not checked or neither of the items listed is presentDiffuse thickening of the abdominal aortic wallCircumferential or anterolateral soft tissue around the infrarenal aorta or iliac arteries | 0+4+8 |
| Step 4: Total inclusion points | |
| A case meets the classification criteria for IgG4-RD if the entry criteria are met, no exclusion criteria are present, and the total points is ≥20. | |
| a Refers to enlargement or tumor-like mass in an affected organ except in 1) the bile ducts, where narrowing tends to occur, 2) the aorta, where wall thickening or aneurysmal dilatation is typical, and 3) the lungs, where thickening of the bronchovascular bundles is common.b If entry criteria are not fulfilled, the patient cannot be further considered for classification as having IgG4-related disease (IgG4-RD).c Assessment for the presence of exclusion criteria should be individualized depending on a patient’s clinical scenario.d If exclusion criteria are met, the patient cannot be further considered for classification as having IgG4-RD.e Only the highest-weighted item in each domain is scored.f Biopsies from lymph nodes, mucosal surfaces of the gastrointestinal tract, and skin are not acceptable for use in weighting the immunostaining domain.g ”Indeterminate” refers to a situation in which the pathologist is unable to clearly quantify the number of positively staining cells within an infiltrate yet can still ascertain that the number of cells is at least 10/high-power field (hpf). For a number of reasons, most often pertaining to the quality of the immunostain, pathologists are sometimes unable to count the number of IgG4+ plasma cells with precision yet even so, can be confident in grouping cases into the appropriate immunostaining result category. | |
| (Reproduced from Wallace, Z.S et al., The 2019 American College of Rheumatology/European League Against Rheumatism Classification Criteria for IgG4-Related Disease. Arthritis Rheumatol, 72: 7-19. https://doi.org/10.1002/art.41120) | |
Laboratory Diagnosis
- Elevated serum IgG4 levels (>1.4 g/L) are observed in 70–80% of cases.
- An IgG4 level exceeding twice the upper limit of normal (>280 mg/dL) has a 99% specificity for IgG4-RD.
- However, elevated IgG4 levels are not specific to IgG4-RD; approximately 5% of healthy individuals and 10% of patients with pancreatic-biliary malignancies, infections, or inflammatory disorders may also exhibit elevated IgG4.
- Patients with multiple organ involvement typically have higher IgG4 concentrations, though normal levels do not rule out the disease.
Radiological Diagnosis
- Imaging studies alone cannot reliably distinguish between malignant and benign disease in affected organs.
Endoscopic Procedures
- Endoscopic retrograde cholangiopancreatography (ERCP) and endoscopic ultrasound (EUS) can be useful for obtaining tissue samples for histopathological evaluation.
Histopathology
The hallmark histological features of IgG4-RD include:
- Lymphoplasmacytic infiltration
- Storiform fibrosis (characterized by a swirling pattern of fibrosis)
- Obliterative phlebitis (inflammation and obliteration of small veins)
Differential Diagnoses
It is crucial to differentiate IgG4-RD from:
- Malignant tumors (e.g., cancer, lymphoma)
- Other inflammatory or autoimmune diseases, including:
- Sjögren’s syndrome
- Primary sclerosing cholangitis
- Castleman disease
- Secondary retroperitoneal fibrosis
- Wegener’s granulomatosis (Granulomatosis with polyangiitis)
- Sarcoidosis
- Churg-Strauss syndrome (Eosinophilic granulomatosis with polyangiitis)
How is it treated?
Treatment varies based on organ involvement and disease severity. The main therapeutic strategies include:
- Steroids
- Immunosuppressants
- Surgery
- Biologic agents
Steroid Therapy
Glucocorticoids are the first-line treatment for IgG4-RD. Prednisolone or prednisone is commonly prescribed at doses ranging from 0.5 to 2 mg/kg/day, with tapering protocols lasting between 4 weeks and 6 months. Steroids are highly effective in controlling symptoms and disease progression, but relapses frequently occur, particularly during dose tapering or after discontinuation.
- In cases of relapse, reintroduction of steroids or the addition of an immunosuppressant is considered.
- High-dose steroids (e.g., intravenous methylprednisolone pulse therapy) are reserved for severe or refractory cases.
Immunosuppressants
Used as steroid-sparing agents or in patients who do not respond adequately to steroids.
- Azathioprine (0.5–2.5 mg/kg/day) is the most frequently prescribed immunosuppressant, often combined with steroids.
- Mycophenolate mofetil (MMF) is the second most commonly used agent, particularly for orbital disease. The combination of MMF and steroids is effective for orbital pseudotumors, proptosis, and lacrimal gland involvement, with minimal relapse risk.
- Other less frequently used agents include methotrexate, sirolimus, and cyclosporine.
Surgical Intervention
Surgery is primarily used for localized disease (e.g., orbital pseudotumors, glandular involvement, or soft tissue masses) or for diagnostic purposes. In some cases, surgery alone may lead to complete remission without further pharmacologic treatment.
Biologic Agents
Monoclonal antibodies such as rituximab, adalimumab, infliximab, and intravenous immunoglobulins are used in refractory cases.
Chemotherapeutic Agents
Cyclophosphamide may be considered in severe cases.
References:
Rispens, T., Huijbers, M.G. The unique properties of IgG4 and its roles in health and disease. Nat Rev Immunol 23, 763–778 (2023).
Nambiar, Sudheer. and Tony I. Oliver. “IgG4-Related Disease.” StatPearls, StatPearls Publishing, 8 August 2023.
Hara S, Yoshida M, Sanada H, et al. Pediatric IgG4-related disease: a descriptive review. Expert Rev Clin Immunol. 2024;20(1):97-119.
Sapountzi, E., Kotanidou, E. P., Tsinopoulou, V.-R., Fotis, L., Fidani, L., & Galli-Tsinopoulou, A. (2025). The Management of IgG4-Related Disease in Children: A Systematic Review. Children, 12(2), 213.
Wallace, Z.S., Naden, R.P., Chari, S., Choi, H., Della-Torre, E., Dicaire, J.-F., Hart, P.A., Inoue, D., Kawano, M., Khosroshahi, A., Kubota, K., Lanzillotta, M., Okazaki, K., Perugino, C.A., Sharma, A., Saeki, T., Sekiguchi, H., Schleinitz, N., Stone, J.R., Takahashi, N., Umehara, H., Webster, G., Zen, Y., Stone, J.H. and (2020), The 2019 American College of Rheumatology/European League Against Rheumatism Classification Criteria for IgG4-Related Disease. Arthritis Rheumatol, 72: 7-19.
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