Lupus, TB, and IgG4

Motivation: Recently, I have heard increasing whispers about IgG4 related disease.  In the  list of diseases that are hard to diagnose with widely varying symptoms, long time residents like TB and lupus are being joined by IgG4.  Of course, I have yet to see a single patient with IgG4 related disease personally.  But, when mentioned, I do not know how to fend off the possibility.  So, how do patients with IgG4 typically present?

As way of background, IgG4 related disease has become the topic of much discussion only since 2001, when autoimmune pancreatitis related to IgG4 was first described.  Pathologically, IgG4 related disease is characterized by extensive IgG4+ plasma cell infiltration.

Paper: Zen, Y and Nakanuma, Y. "IgG4-Related Disease: A Cross-Sectional Study of 114 Cases" Am J. Surg. Pathol. (2010); 34: 1812.

Methods: Between 1990 and 2009, pathological samples with diffuse IgG4 plasma cell infiltration were retrieved from case files at Kanazawa University Hospital and affiliated hospitals in Japan.  Clinical features of patients meeting criteria were retrospectively reviewed from medical records.

Results: 
Location: Total of 114 patients with IgG4 related disorder were identified.  Location of disease is as follows:

• 23 patients (20.1%) with head and neck lesions - primarily salivary gland and lacrimal gland
• 16 patients (14.0%) with thoracic lesions found in lung, pleura, and breast
• 27 patients (23.6%) with hepatobiliary lesions in pancreas, bile duct, gallbladder, and liver
• 13 patients (11.4%) with retroperitoneal disease presenting with retroperitoneal fibrosis and aortitis
• 35 patients (30.7%) with diffuse systemic manifestations

Demographics: Median age of presentation is 64 with youngest aged 42.  Male and females were almost evenly distributed for the head and neck group.  On the other hand, >70% of the patients were male with thoracic lesions and >80% were male with hepatobiliary, retroperitoneal, and systemic presentations.

Associated Autoimmune Diseases: In the cohort, 22 patients had history of allergy while only 2 had a clinical history of autoimmune disease - one with sarcoidosis and one with rheumatoid arthritis.  Enlarged lymph nodes were found in 47 patients (41%) by physical and radiologic examination.

Serum Concentration of IgG4: IgG subset information was available in 58 patients.  Serum IgG4 was elevated in 50 of 58 patients (86%).  Serum levels of IgG4 were highest in patients with systemic and head & neck disease.

Lesion Features: Of the biopsied lesions, all except one lesion was macroscopic - could be identified by physical exam or by radiology.  When IgG4 related disease affected a solid organ, the pattern of infiltration was either diffuse or as mass-like lesion.

Malignancy: Of 114 patients, 3 patients in the systemic group presented with malignancy during follow-up: small cell carcinoma (1 year after IgG4 diagnosis), adenocarcinoma (2 years later), and B cell lymphoma (4 years later).

Discussion: What I take away from this cross-sectional description is that this oft invoked but little understood disease is very different from traditional auto-immune diseases.  IgG4 related disease can occur in just about any part of the body, but the likely presentation is a macroscopically visible diffusely infiltrative or mass-like lesion.  Besides testing for IgG subsets, there is little to distinguish it (at least in this survey) at first glance from neoplastic disease.  Importantly, the disease does not appear correlated with other auto-immune phenomenon such as lupus or rheumatoid arthritis or paraneoplastic disease.  I think that in the future, we will learn more about historical features, but for now, IgG4 related disease remains hard to diagnose with protean manifestations - just like lupus and TB.