Article

IgG4-related Disease Subject of Increasing Referrals, Questions Among Rheumatologists

Multiorgan inflammatory condition first described in 1888

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IgG4-related disease (IgG4-RD), a chronic, multi-organ inflammatory condition, was recognized only about 15 years ago as a distinct pathologic entity, receiving its designation in 2012 as “IgG4-RD” by an international multidisciplinary research panel in 2012. IgG4-RD now comes up more frequently in conversations about the diagnosis of patients with puzzling systemic illnesses and results in more referrals to rheumatologists as its characteristics and treatment options become better understood.

The pathology of this chronic disease is characterized by the infiltration of tissues with lymphocytes and plasma cells, fibrosis in a cartwheel shaped pattern, and an abundance of IgG4-secreting plasma cells. Lymphocytes are among the cellular components of the immune system that generate specific responses against invading pathogens, while plasma cells produce IgG4 and other antibodies. Recent studies implicate suggest that a specific subtype of lymphocyte, a cytotoxic CD4 T cells, as are a potentially critical mediator of the disease. However, the role of IgG4 antibodies in causing IgG4-RD remains a mystery.

Early diagnosis and treatment of IgG4-RD are the keys to avoid organ damage and related complications. The disease may present clinically in one or more body systems—orbital, neurologic, cardiovascular, respiratory, gastrointestinal, and urologic—with multiple manifestations in different organ systems.  Since pancreatitis and biliary disease are among the most common of its presentations, gastroenterologists are gaining familiarity with this disease.   

Clinical suspicion is triggered when tumefactive (tumor-like) lesions are found during physical exam or detected on radiologic imaging, says E. William St. Clair, chief of the Duke Division of Rheumatology and Immunology and an expert on the condition. Elevated serum levels of IgG4 are a key diagnostic marker, but this finding may only be present in three-quarters of patients. Interpreting serum IgG4 levels presents challenges because of limits in the sensitivity and specificity of this test. “The diagnosis of this disease usually requires clinical judgment and a tissue biopsy to reach the correct diagnosis,” St. Clair says.

With a peak onset at ages 60 through 70s and primarily affecting men, IgG4-RD is relatively rare. Although good epidemiologic studies are lacking, this condition has approximately the same prevalence as scleroderma, says St. Clair.

“The disease is old, but its description as a pathologic entity is new, and we understand it better today because of its association with both elevated IgG4-levels in blood and IgG4 plasma cells in tissue,” says St. Clair.

The diagnosis of this disease usually requires clinical judgement and a tissue biopsy to reach the correct diagnosis,” says William St. Clair, MD, chief of the Duke Division of Rheumatology and Immunology. “The disease is old, but its description as a pathologic entity is new, and we understand it better today because of its association with both elevated IgG4-levels in blood and IgG4 plasma cells in tissue.
William St. Clair, MD, Chief of the Duke Division of Rheumatology and Immunology

Clinical Spectrum of IgG4-RD

  • Dacryoadenitis/sialadenitis: Mikulicz disease, Kuttner tumor, sclerosing dacryoadenitis
  • Orbital: Orbital myositis, enlargement of orbital nerves, sclerosing orbital inflammation
  • Pulmonary: Inflammatory pseudotumor, interstitial involvement, bronchial involvement, hilar/mediastinal lymphadenopathy, pleural thickening/effusions
  • Hepatobiliary: Sclerosing cholangitis, IgG4-related hepatic disease
  • Pancreas: Type 1 autoimmune pancreatitis
  • Renal/urinary tract: Tubulointerstitial nephritis, retroperitoneal fibrosis, prostatitis
  • Endocrine: Riedel’s thyroiditis, diabetes (chronic pancreatitis)
  • Central Nervous System: Pachymeningitis, dural thickening, hypophysitis, intracranial lesions
  • Lymphatic: IgG4-associated lymphadenopathy
  • Cardiovascular: Periaortitis, coronary artery involvement
  • Other: Arthritis, skin disease

What was likely the first description of IgG4-RD was made in 1888 by a Polish pathologist who wrote an article about a patient with salivary gland enlargement, and for a time called Mikulicz disease in his honor.  Mikulicz disease was later believed to be a subset of Sjögren’s syndrome, which is also associated with salivary gland enlargement, and only in the last decade or so has this clinical presentation been widely appreciated to be a frequent manifestation of IgG4-RD.   

The 2012 classification of IgG4-RD as a distinct pathological entity changed physicians’ approach to the disease and resulted in a more targeted autoimmune therapy approach to treatment, St. Clair says.

“Management is as much an art as a science and must be tailored to the individual’s disease severity and organ system involvement,” he says. Although glucocorticoid therapy remains the mainstay of drug treatment,

“The recent evidence that rituximab can effectively treat the condition has revolutionized treatment,” St. Clair says. “It’s been particularly important because patients typically present with more than one organ or organ system involved. Before rituximab was accepted as a therapeutic agent, our treatment options were limited to oral steroids and a few other steroid-sparing drugs such as azathioprine.”

Existing treatments are effective and can cause the disease go to into remission, but relapse is frequent. “We can’t predict when patients will relapse or require more prolonged therapy. That’s uncharted territory right now,” St. Clair says, adding that rituximab is effective in managing the disease for most patients.

“Management is as much an art as a science and must be tailored to the individual’s disease severity and organ system involvement,” he concludes.