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First Classification Criteria Developed for IgG4–Related Disease

Key findings

  • Classification of IgG4–related disease follows a three-step process that sequentially considers entry, exclusion and inclusion criteria
  • The American College of Rheumatology and the European League Against Rheumatism have funded the development of the first classification criteria for IgG4–related disease (IgG4-RD). This effort was led by Massachusetts General Hospital Rheumatology Division investigators
  • The process of classifying a patient as having IgG4-RD or not does not always require a biopsy or an elevated serum IgG4 level
  • The classification criteria were created for research purposes rather than for use in clinical practice to establish the diagnosis of IgG4–related disease

IgG4-related disease (IgG4-RD) is an immune-mediated condition in which fibroinflammatory lesions affect nearly any organ—and often multiple organs at the same time. It was not recognized as a distinct disease until 2003. IgG4-RD is sometimes confused with malignancy, infection and other immune-mediated conditions such as forms of vasculitis, systemic lupus erythematosus, Sjögren’s syndrome and others.

The American College of Rheumatology and the European League Against Rheumatism recently funded the creation and validation of the first classification criteria for IgG4-RD. Zachary S. Wallace, MD, MSc, a physician in the Rheumatology Unit at Massachusetts General Hospital, and John H. Stone, MD, MPH, director of Rheumatology and the Edward A. Fox chair in medicine at Mass General, led the international working group that developed the criteria, published in Annals of the Rheumatic Diseases and Arthritis & Rheumatology.

Development of the Criteria

Eighty-six physicians from North and South America, Europe and Asia submitted 1,879 cases for use in three cohorts:

  • Derivation cohort (272 IgG4-RD cases, 214 mimickers)
  • First validation cohort (493 cases, 415 mimickers)
  • Second validation cohort (321 cases, 164 mimickers)

Through a series of consensus-building exercises, Likert ratings and an in-person meeting, a steering committee selected entry criteria as well as preliminary inclusion and exclusion criteria. The criteria were assessed in the derivation cohort, then revised to best distinguish IgG4-RD cases from mimickers.

At a threshold of ≥20 points for inclusion criteria, the revised classification elements were 99% specific and 86% sensitive for IgG4-RD in the first validation cohort. In the second validation cohort the respective figures were 98% specific and 82% sensitive for IgG4-RD.

The Classification Process

The article provides detail about the three-step classification process:

  1. Determine if there is clinical, radiologic or pathologic evidence that at least one of 11 typical organs is involved in a manner consistent with IgG4-RD
  2. Consider the exclusion criteria (32 items). The presence of any exclusion criterion eliminates the patient from classification as an IgG4-RD subject. An example of an exclusion criterion encountered frequently by Rheumatologists is a positive antineutrophil cytoplasmic antibody assay
  3. Consider eight weighted inclusion criteria domains (clinical, serologic, radiologic and pathologic findings; ≥20 points needed)

Notable Criteria Features:

  • No biopsy is required when the diagnosis of IgG4-RD is straightforward on the basis of clinical, serological and radiologic findings
  • An elevated serum IgG4 level is not essential to the diagnosis of IgG4-RD. Certain organ systems and anatomic regions are less likely than others to be associated with elevated IgG4, so IgG4 is normal in a substantial percentage of patients who have a clinicopathologic diagnosis of IgG4-RD

Using the Criteria

The working group created the classification criteria so that more homogeneous groups of subjects can be included in clinical trials and epidemiologic studies. The criteria are not to be used in clinical practice to establish the diagnosis of IgG4-RD.

However, the criteria are a useful framework; for example, they clarify that radiologic findings alone are never sufficient in making the diagnosis of IgG4-RD. They also highlight findings that increase the likelihood of IgG4-RD and those that suggest alternative diagnoses.

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