IgG4-related disease, an immune-mediated fibroinflammatory disorder that can affect multiple organs, has only been recognized as a distinct disease since 2003. The varied manifestations and organ systems involved make it a difficult disease to study and have necessitated the creation of an international set of classification criteria, endorsed by both the American College of Rheumatology (ACR) and EULAR.

A group of 86 physicians from North America, Europe, Asia and Australia worked together to identify potential classification criteria and to provide derivation and validation cohorts of patients with IgG4-related disease (n = 1,086) and diseases that mimic this condition (n = 793).

“The research group included rheumatologists, internists, ophthalmologists, pathologists, gastroenterologists, allergists, pulmonologists, radiologists, neurologists, nephrologists, and a variety of other subspecialists,” says principal investigator John Stone. “The enthusiasm and collegiality among investigators was a source of inspiration to the group overall, and a major contributor to the overall success of the effort.”

An initial set of 51 exclusion criteria and 27 inclusion criteria was refined by the ability of each criterion to distinguish between IgG4-related disease and mimicking conditions. The use of exclusion criteria was particularly remarkable, as most classification criteria rely on inclusion criteria alone.

“For a disease that is as protean as IgG4-related disease and as capable of mimicking (and being mimicked by) so many other conditions, exclusion criteria were an important part of our effort,” explains Stone. “The specificity of the overall ACR–EULAR classification criteria were improved by about 10% simply by the use of exclusion criteria.”

The final inclusion criteria were designed to avoid the absolute need for a biopsy to reach a conclusion of IgG4-related disease, although most patients will require one. A patient must have either characteristic involvement (clinical or radiological) or pathological evidence of inflammation in a typically affected organ, not meet any of the exclusion criteria and accrue a total of 20 points or more from the weighted inclusion criteria to be classified as having IgG4-related disease. Typical organs include the pancreas, salivary glands, lungs, kidneys, bile ducts, aorta, retroperitoneum, thyroid gland, orbits and pachymeninges.

“The two independent validation studies we performed demonstrated remarkably consistent results: an extremely high specificity (>98%) and a high sensitivity (85%),” enthuses Stone. “The final criteria set is easy to use and lends itself well to adaptation in an electronic format, which we have already instituted at my hospital.”

Stone and colleagues are keen to remind researchers that the ACR–EULAR classification criteria, while informative in a clinical setting, are not designed for diagnosis. Not all patients with IgG4-related disease will be captured by the criteria owing to their design, but the authors hope that they can be successfully used to recruit cohorts of patients with relatively homogeneous disease for clinical and epidemiological studies, which will aid research efforts.

“It is essential that studies include patients who truly merit classification as having IgG4-related disease. These rigorous ACR–EULAR classification criteria will help guide us through some of the most important challenges of studying this disease well,” concludes Stone.