20-15: IgG₄-Related Disease

GENERAL CONSIDERATIONS

IgG₄-related disease is a systemic disorder of unknown cause marked by highly characteristic fibroinflammation that contains IgG₄ plasma cells and can infiltrate virtually any organ. Elevations of serum IgG₄ levels occur often but are not diagnostic. The disorder chiefly affects men over the age of 50 years.

CLINICAL FINDINGS

A. Symptoms and Signs

IgG₄-related disease can affect any organ of the body, can be localized or generalized, demonstrates the same distinctive histopathology at all sites of involvement, produces protean manifestations depending on location and extent of involvement, and causes disease that ranges in severity from asymptomatic to organ- or life-threatening. The inflammatory infiltration in IgG₄-related disease frequently produces tumefactive masses that can be found during physical examination or on imaging. Some of the common presenting manifestations include enlargement of submandibular glands, proptosis from periorbital infiltration, retroperitoneal fibrosis, mediastinal fibrosis, inflammatory aortic aneurysm, and pancreatic mass with autoimmune pancreatitis. IgG₄-related disease can also affect the thyroid (formerly Reidel thyroiditis), kidney, meninges, pituitary, sinuses, lung, prostate, breast, and bone. Most symptomatic patients with IgG₄-related disease present subacutely; fever and constitutional symptoms are usually absent. Nearly half of the patients with IgG₄-related disease also have allergic disorders such as sinusitis or asthma.

B. Laboratory Findings

The infiltrating lesions in IgG₄-related disease often produce tumors or fibrotic changes that are evident on CT or MRI imaging. However, the cornerstone of diagnosis is the histopathology. The key pathological findings are a dense lymphoplasmacytic infiltrate rich in IgG₄ plasma cells, storiform (matted and irregularly whorled) fibrosis, and obliterative phlebitis. Serum IgG₄ levels are usually, but not invariably, elevated so this finding cannot be used as the sole diagnostic criterion.

DIFFERENTIAL DIAGNOSIS

IgG₄-related disease can mimic many disorders including sarcoidosis, Sjögren syndrome (lacrimal gland enlargement), pancreatic cancer (pancreatic mass), and granulomatosis with polyangiitis (proptosis). Some cases of retroperitoneal fibrosis and mediastinal fibrosis are caused by IgG₄-related disease. Lymphoma can mimic some of the histopathologic features of IgG₄-related disease.

TREATMENT & PROGNOSIS

Patients who are asymptomatic and have no organ-threatening disease can be monitored carefully. Spontaneous resolution can occur. Initial therapy is usually oral prednisone 0.6 mg/kg/day, tapered over weeks or months depending on response. Given that corticosteroid monotherapy may fail to control the disease and can cause significant long-term toxicity, immunosuppressants, such as rituximab, mycophenolate mofetil, or azathioprine, are often used. The degree of fibrosis in ...