IgG4-RD Classification Calculator

IgG4-RD is unique among rheumatic diseases in that it is primarily a histopathologic diagnosis that can affect almost any organ. The three-step process was designed to handle this complexity. Step 1 (entry criteria) ensures the disease involves organs that can actually develop IgG4-RD, preventing the criteria from being misapplied to conditions with no organomegaly or inflammatory mass. Step 2 (exclusion criteria) is critical because the clinical and radiologic phenotype of IgG4-RD overlaps extensively with malignancy, lymphoma, vasculitis, Sjogren's syndrome, and other immune-mediated diseases; some of these (especially lymphoma) are directly dangerous to misclassify. Step 3 (weighted scoring) then quantifies the positive evidence for IgG4-RD using a weighted algorithm developed from 1,879 patients and controls. The architecture was deliberately conservative - specificity (99.2%) was prioritized over sensitivity (85.5%) to ensure that the criteria identify true IgG4-RD cases for research purposes.

Histopathology (Domain A) and immunostaining (Domain B) are complementary but distinct pieces of evidence. Domain A assesses the architectural pattern of the tissue: a dense lymphocytic infiltrate is consistent with but not specific to IgG4-RD (+4 pts); adding obliterative phlebitis (+6) increases specificity; storiform fibrosis alone or with obliterative phlebitis (+13) represents the most characteristic IgG4-RD pathology. Domain B assesses the IgG4+ plasma cell content specifically, combining the percentage of IgG4+ among IgG+ cells (the IgG4+:IgG+ ratio) AND the absolute number of IgG4+ plasma cells per high-power field. The combination is required because: a high ratio with few cells could reflect IgG4-RD in a depleted tissue; many cells with a low ratio suggests non-specific polyclonal plasmacytosis. The highest tier requires both a ratio >71% AND >50 cells/hpf, reflecting that both criteria together provide the most definitive immunohistochemical evidence.

The combination of diffuse pancreatic enlargement (especially with the capsule-like rim/halo sign) AND biliary involvement is the most diagnostically specific finding in IgG4-RD across all domains, reflecting several factors. First, this pattern is essentially pathognomonic for IgG4-related pancreatitis (type 1 autoimmune pancreatitis) and IgG4-related sclerosing cholangitis when they co-occur. Second, the differential diagnosis for isolated biliary disease is broad (PSC, cholangiocarcinoma), but when combined with characteristic pancreatic changes, alternative diagnoses become extremely unlikely. Third, the biliary pattern of IgG4-RD specifically affects the proximal biliary tract (differentiating from primary sclerosing cholangitis which is predominantly distal), and this proximal biliary + diffuse pancreatic pattern was the feature that received the highest expert confidence scores during the Delphi exercises underlying the criteria development.

The 32 exclusion criteria were designed to eliminate mimicking conditions, primarily: Lymphoma and malignancy - the most dangerous mimic because IgG4-RD can present as a mass lesion; pathological features suspicious for malignancy trigger immediate exclusion. Granulomatosis with polyangiitis (GPA/Wegener's) - excluded by positive ANCA and necrotizing vasculitis on pathology. Sarcoidosis - excluded by primary granulomatous inflammation on pathology. Multicentric Castleman disease - can produce elevated IgG4 and lymphadenopathy indistinguishable from IgG4-RD without biopsy. Eosinophilic granulomatosis with polyangiitis (EGPA) - excluded by peripheral eosinophilia >3000/mm3. Sjogren's syndrome - excluded by Ro/La antibodies, relevant because salivary and lacrimal gland involvement can resemble IgG4-RD. SLE - excluded by anti-dsDNA. Erdheim-Chester disease - excluded by characteristic long-bone lesions.

Serum IgG4 elevation is a supportive but not diagnostic feature of IgG4-RD for several reasons. First, organ-specific presentation matters: patients with isolated salivary gland, orbital, or lung involvement tend to have lower serum IgG4 levels than those with pancreatobiliary disease, likely reflecting differences in disease burden and IgG4-secreting plasma cell mass. Second, the serum IgG4 assay has a prozone or hook effect at very high concentrations - extremely elevated IgG4 may falsely read normal due to antigen excess; repeating with dilution can reveal the true value. Third, some disease subtypes - particularly head and neck limited disease and some retroperitoneal cases - are genuinely seronegative. Fourth, prior glucocorticoid treatment dramatically suppresses serum IgG4, so levels drawn after steroid initiation may be misleadingly normal. The 2019 criteria accordingly give IgG4 elevation only moderate weight (+4 to +11) and do not require it for classification.

This exclusion criterion reflects one of the core clinical features of IgG4-RD: most active manifestations respond rapidly and dramatically to glucocorticoid therapy, typically with radiological and clinical improvement within 1-4 weeks of starting prednisolone 30-40 mg/day. Failure to respond to an adequate steroid trial is therefore a major red flag for an alternative diagnosis, particularly malignancy or a steroid-resistant inflammatory condition. However, this exclusion requires careful interpretation: (1) the dose must have been adequate (typically prednisolone 0.6 mg/kg/day or equivalent for at least 2-4 weeks); (2) fibrotic manifestations (retroperitoneal fibrosis with established scarring, pachymeningitis with extensive fibrosis) may show incomplete response even in true IgG4-RD; (3) some patients with biopsy-proven IgG4-RD are treated with rituximab first-line and never receive steroids. The exclusion criterion applies when there is documented failure of an adequate, properly dosed glucocorticoid trial.

The paravertebral band-like soft tissue pattern (Domain E, +10 points) represents one of the most distinctive and underrecognized IgG4-RD manifestations in the thorax. On CT, it appears as bilateral, elongated, band-shaped soft tissue densities running along the vertebral bodies in the thorax, typically bilaterally and following the costovertebral angles. This is different from the common peribronchovascular pattern (+4). The paravertebral pattern reflects inflammation in the perineural and connective tissue spaces along the paravertebral nerves and is thought to represent the thoracic analog of retroperitoneal fibrosis. It was assigned the highest thoracic imaging score (+10 vs +4 for peribronchovascular disease) because it has high specificity for IgG4-RD and is less likely to be seen in mimicking conditions such as sarcoidosis, lymphoma, or idiopathic pulmonary fibrosis. Recognition of this pattern is clinically important because it may not be reported by radiologists unfamiliar with IgG4-RD.

Yes, and this was a deliberate feature of the 2019 criteria. Both histopathology (Domain A) and immunostaining (Domain B) default to a score of 0 if no biopsy was performed or if the biopsy was uninformative. A patient can still reach the classification threshold of 20 points based on: highly characteristic imaging findings (e.g., pancreas + biliary tree involvement = +19), markedly elevated serum IgG4 (≥5x ULN = +11), bilateral glandular involvement (+6 or +14), and/or characteristic retroperitoneal or chest imaging. For example, a patient with the classic autoimmune pancreatitis + IgG4-related sclerosing cholangitis picture (+19), bilateral submandibular and parotid gland involvement (+14), and serum IgG4 ≥5x ULN (+11) would score 44 points - well above threshold - entirely from clinical, serologic, and imaging data without pathology. This reflects real clinical practice where pancreatic biopsy is high-risk and not always performed.