The American College of Rheumatology and the European League Against Rheumatism have released the first classification criteria for IgG4-related disease.

Although it was first recognized as a distinct disease in 2003, investigators have since learned that IgG4-related disease (IgG4-RD) is not particularly rare. Specialists across many different fields of medicine now treat IgG4-RD, which affects multiple organ systems, and the pancreas, kidneys, and orbits are most commonly affected by severe disease.

“IgG4-RD has proven to be a remarkable window into human immunology, and the insights investigators have made from studying this disease have already led to important discoveries in other rheumatic diseases, such as scleroderma,” John H. Stone, MD, professor of medicine at Harvard Medical School and director of clinical rheumatology at Massachusetts General Hospital, both in Boston, said in an interview.

To develop the classification criteria, 86 experts from five continents across various subspecialties including rheumatology, internal medicine, ophthalmology, pathology, gastroenterology, allergology, pulmonology, radiology, neurology, nephrology, and others met as a working group in 2016, achieving consensus on 79 criteria. They then narrowed down the number of items to 8 domains and 29 items within a set of inclusion and exclusion criteria for the draft classification criteria. For the final classification criteria, the working group applied weighting to each inclusion criteria item within a domain on a Likert scale (–5 to 5 range), removing items that were not significantly attributable to IgG4-RD classification (those with –2 to 2 scores).

The final IgG4-RD criteria are divided into three classification steps: entry criteria, exclusion criteria, and inclusion criteria. Patients who meet the entry criteria should have clinical or radiologic involvement of one or more organs consistent with IgG4-RD, such as the pancreas, salivary glands, bile ducts, orbits, kidney, lung, aorta, retroperitoneum, pachymeninges, or thyroid gland. Patients could alternatively meet the entry criteria by having “pathologic evidence of an inflammatory process accompanied by a lymphoplasmacytic infiltrate of uncertain etiology in one of these same organs,” the authors wrote.

If a patient meets the entry criteria, their case is examined against 32 clinical, serologic, radiologic, and pathologic items and specific disease inclusions. Any exclusion criteria present in a case means the patient does not meet the criteria for IgG4-RD classification.

The third step is to evaluate whether a patient meets inclusion criteria consisting of clinical findings, serologic results, radiology assessments, and pathology interpretations across eight domains: immunostaining, head and neck gland involvement, chest, pancreas and biliary tree, kidney, and the retroperitoneum. Each criterion has a weight, and if a patient has a score of 20 or higher, they meet the classification criteria for IgG4-RD.

“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,” said Dr. Stone, who is also director of the international panel of experts who created the criteria.

Two cohorts were used to validate the IgG4-RD classification criteria. In the first cohort, investigators used 771 patients (85% of the total cohort) in whom they were “confident” or “very confident” of a diagnosis of IgG4-RD or a mimicker to assess the test performance with a classification threshold of 20 points. The researchers found the criteria had a specificity of 99.2% (95% confidence interval, 97.2%-99.8%) and a sensitivity of 85.5% (95% CI, 81.9%-88.5%). The experts used a second validation cohort of 402 additional patients (83% of the total cohort) with suspected IgG4-RD or a mimicker using the same confident and very confident metric. The panel assembled this cohort because of minor definition changes in inclusion and exclusion criteria that had been made after the derivation set of patients had been collected, but the definitions of inclusion and exclusion criteria used in the two validation cohorts were exactly the same. Overall, the specificity of the criteria was 97.8% (95% CI, 93.7%-99.2%) and the sensitivity was 82.0% (95% CI, 77.0%-86.1%) for IgG4-RD classification in this second group.

Dr. Stone said that more investigations, including multicenter clinical trials, are being organized for patients with IgG4-RD, and these classification criteria will help to identify which patients to include in these studies.

“These rigorous ACR/EULAR classification criteria will help guide us through some of the most important challenges of studying this disease well,” Dr. Stone said. “I’m anticipating major advances in this field in the years to come, triggered in part by the strength of having sound classification criteria.”

The authors reported no relevant conflicts of interest.

SOURCE: Wallace ZS et al. Arthritis Rheumatol. 2019 Dec 2. doi: 10.1002/art.41120.