IgG4-related disease is a chronic relapsing fibro-inflammatory disorder of autoimmune etiology. It lacks an established and validated diagnostic criterion, although EULAR/ACR 2019 and the revised comprehensive diagnostic criteria 2020 (RCD) are valiant attempts at classifying the disease, but while the earlier criteria lack sensitivity (77-82%), the latter are oversimplified and lack specificity (50%) and validation. Thus, it’s important for a rheumatologist to have a comprehensive evaluation before making a diagnosis.

Raised serum IgG4 is not diagnostic.

A raised serum IgG4 level is often suggestive of IgG4RD but is neither sensitive nor specific enough to be considered diagnostic. Fibrosis-predominant IgG4RD-like pachymeningitis, orbital, thyroid, and retroperitoneal diseases frequently do not have a significant IgG4 elevation. Other diseases like multicentric Castleman disease, ANCA vasculitis, lymphoma, and chronic infections (syphilis and tuberculosis) can have a significant IgG4 elevation. However, an elevation more than five times limit of normal is generally considered more specific for IgG4RD.

Histology Over Numbers: The Deciding Factor.

A compatible clinical and radiological picture along with serological tests may suggest the diagnosis, but histology with immunohistochemistry on biopsy specimens is what confirms the diagnosis in most instances. The classical triad of dense lymphoplasmacytic aggregates, storiform fibrosis, and obliterative phlebitis is not always present, but the combination of these features in the absence of features of significant necrosis, granulomas, neutrophil- or histiocyte-rich infiltrates, and malignant cells clinches diagnoses. The IgG4:IgG4 ratio of more than 40% is usually seen, and diagnosis is moving away from actual IgG4-positive plasma cell numbers in a field. This is often because of the small size of tissue often received from core biopsies rather than excision or surgical approaches.

Mimics you must exclude first.

IgG4RD diagnosis should always be made after careful exclusion of conditions with similar clinical, radiologic, serological, or histologic pictures. One must carefully consider and rule out solid and hematologic malignancies, chronic infections, other autoimmune diseases like vasculitis, sarcoidosis, histiocytic and other proliferative disorders like Erdheim-Chester, Rosai-Dorfman, and multicentric Castleman disease.

Steroid Response Can Mislead.

The EULAR/ACR 2019 criteria consider improvement with steroids as a favoring clinical feature in classification. This may lead to more therapeutic trials of steroids in clinical practice. One must remember that diagnosis of malignancies in patients of IgG4RD is elevated in the first three years after diagnosis owing predominantly to wrong initial diagnosis. One must not try steroids unless they have confirmed the diagnosis or exhausted all options of confirming after ruling out alternative etiologies. Lymphomas, Castleman disease, and even infections like tuberculosis may initially show improvement in symptoms and radiologic and clinical signs with corticosteroid use.

Red Flags Against IgG4-Related Disease

Rapid and aggressive course, significant constitutional findings (except weight loss in pancreatitis), and lack of significant response with steroids are the clinical red flags. Radiological findings of lytic or destructive lesions and rapid progression are also against IgG4RD. Histological features of necrosis, atypical cells and neutrophil or histiocytic inflammation are few other red flags.

Suggested reading:

1. Peyronel, F., Della-Torre, E., Maritati, F. et al.IgG4-related disease and other fibro-inflammatory conditions. Nat Rev Rheumatol 21, 275–290 (2025). https://doi.org/10.1038/s41584-025-01240-x.
2. John H Stone, IgG4-related disease: lessons from the first 20 years, Rheumatology, Volume 64, Issue Supplement_1, March 2025, Pages i24–i27, https://doi.org/10.1093/rheumatology/keaf008.