Zebra of the Week: Immunoglobulin G4–related sclerosing disease

Immunoglobulin G4–related disease (IgG4-RD), also known as IgG4-related sclerosing disease, is a chronic, immune-mediated fibroinflammatory disorder capable of affecting virtually any organ system. Although only formally recognized in the early 2000s, it is now understood as a unifying diagnosis underlying a spectrum of previously distinct conditions, including autoimmune pancreatitis, sclerosing cholangitis, and retroperitoneal fibrosis.

Clinical presentation

IgG4-RD is characterized by tumor-like swelling, organ enlargement, and dense fibrosis, often leading to diagnostic confusion with malignancy. Commonly involved sites include the pancreas, salivary and lacrimal glands, lymph nodes, kidneys, lungs, and retroperitoneum, though multiorgan disease is typical.

Symptoms are variable and depend on organ involvement, but classic findings include:

• Painless gland enlargement (e.g., salivary/lacrimal glands)
• Lymphadenopathy
• Abdominal pain or jaundice (pancreatobiliary disease)
• Constitutional symptoms such as weight loss
• Allergic or asthma-like features in some patients

The disease often evolves insidiously, and delayed diagnosis is common, sometimes after invasive evaluation for suspected cancer.

Pathophysiology and diagnosis

The hallmark is infiltration of IgG4-positive plasma cells with associated lymphoplasmacytic inflammation, storiform fibrosis, and often elevated serum IgG4 levels. However, serum IgG4 may be normal, and histopathology remains central to diagnosis.

IgG4-RD likely reflects dysregulated immune activation (particularly B-cell and plasmablast pathways), though the precise etiology remains unknown.

Management

Glucocorticoids are first-line therapy, often inducing rapid remission, particularly in early inflammatory stages. However, relapse is common, and chronic steroid exposure carries substantial toxicity. Steroid-sparing strategies—including rituximab—are frequently used in relapsing or refractory disease.

Despite treatment responsiveness, progressive fibrosis may become irreversible, highlighting the importance of early recognition.

What’s new

In the phase 3 INDIGO trial, obexelimab—a monoclonal antibody that modulates B-cell signaling—significantly reduced the risk of IgG4-RD flare by roughly 50% to 56% compared with placebo while also lowering cumulative glucocorticoid exposure. Treated patients experienced about half the relapse risk, with a safety profile comparable to placebo and potential advantages over B-cell–depleting approaches. These data position obexelimab as a promising steroid-sparing therapy that could shift long-term management of this relapsing, multisystem disease pending regulatory review and durability data.

Sources:

NIH Genetic and Rare Diseases Information Center (GARD). Immunoglobulin G4-related sclerosing disease

Cleveland Clinic. IgG4-Related Disease (IgG4-RD)

Merck Manual Professional/Consumer Editions. IgG4-Related Disease

Chen LYC. IgG4-related disease for the hematologist. American Society of Hematology Education Program. 2024.