First recognized as a distinct disease in 2003, IgG4-related disease (IgG4-RD) has since evolved from the field of rheumatology to general medicine and other subspecialties, making its mark worldwide. With clinical trials underway, an international multispecialty group decided it was time to issue rigorous inclusion and exclusion classification criteria for this disease. The guidance, released by the American College of Rheumatology (ACR) and the European League Against Rheumatism (EULAR), also provides insights into the usefulness of serum IgG4 levels and why this measurement still plays an important role in classification criteria.

“It is essential that studies include patients who truly merit classification as an IgG4-RD patient. These rigorous ACR/EULAR classification criteria will help guide us through some of the most important challenges of studying this disease,” John H. Stone, MD, MPH, professor of medicine at Harvard Medical School and director of the international panel of experts who developed the criteria, told CLN Stat.

Responsive to treatment if caught early, this inflammatory condition can lead to serious organ damage, organ failure, and death if it remains undetected, affecting the pancreas, kidneys, orbits, and other organs. According to Stone, an alarmingly high percentage of patients with IgG4-RD experience major pancreatic damage, leading to diabetes, exocrine pancreatic failure, or both conditions.

“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,” Stone said. However, many physicians still aren’t familiar with IgG4-RD, which has a tendency to mimic a host of other diseases such as lupus and pancreatic cancer.

Investigators from Japan, North America, and Europe had previously collaborated on research to better understand IgG4-RD pathology, codify its nomenclature, develop consensus around disease management, and create an IgG4-RD responder index, Stone said. Draft criteria were unveiled at the 2018 ACR/ARP (Association of Rheumatology Professionals) Annual Meeting in Chicago. In a second validation study, which led to the final ACR/EULAR criteria, 86 IgG4-RD multispecialty experts from five continents took part in a multicriteria decision analysis, facilitated by a powerful software called 1000Minds. 

Stone and his team recruited about 2,000 IgG4-RD patients and those with mimicking conditions and conducted two independent validation studies of the draft IgG4-RD classification criteria. The two studies demonstrated remarkably consistent results: an extremely high specificity (>98%) and a high sensitivity (85%). According to 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.”

Specifically, the criteria classify IgG4-RD patients through a three-step process: demonstration that at least 1 of 11 organs have been involved in a manner suggestive of disease; an exclusion criteria assessment of 32 clinical, serologic, radiologic, and pathologic items; and eight weighted inclusion criteria domains involving clinical, serologic, radiologic, and pathologic findings.

Few, if any other ACR/EULAR classification efforts have used exclusion criteria, so this was a unique feature, Stone commented. “For a disease that is as protean as IgG4-RD and as capable of mimicking (and being mimicked by) so many other conditions, exclusion criteria were an important part of our effort,” he added. As an example of how comprehensive this process was, the serologic exclusion criteria included five elements: leukopenia and thrombocytopenia without alternative explanation; peripheral eosinophilia; positive antineutrophil cytoplasmic antibody (ANCA); positive antibodies; and cryoglobulinemia.

A quick glance through the exclusion criteria reveals a great deal about IgG4-RD, Stone said. This condition does not generally cause fevers, is not associated with necrotic lesions on pathology, and does not have granulomatous features. “Specific autoantibodies such as ANCA and anti-Ro antibodies are highly atypical and point in other directions,” he said. Stone and his colleagues found that when they employed the exclusion measures, specificity of the overall  ACR/EULAR classification criteria improved by 10%.

In their guidance, the authors made an interesting point about serum IgG4 concentration, one of the inclusion criteria domains. Many patients with IgG4-RD diagnoses actually have normal levels of this marker, calling its utility into question, they wrote. Serum IgG4 is no longer considered a necessary element for diagnosing this disease. However, this analyte continues to have relevance as a criterion, Stone emphasized. A serum IgG4 concentration >5 times the upper limit of normal is associated with a weight of 11, for example. While that’s not enough to fulfill criteria in the absence of other disease features, it is a substantial weight, nevertheless, Stone said.

“Serum IgG4 concentrations are useful as diagnostic biomarkers and as longitudinal markers of disease activity, even though serum IgG4 elevations are not present universally in these patients. The higher the level at baseline the more likely it is that the patient has IgG4-RD,” he continued. “Moreover, if the serum IgG4 is elevated before treatment begins, it normally declines nicely after the start of treatment, and if it rises again can be a useful clue that the disease is once again active.”

Stone anticipates that multicenter clinical trials and other types of investigations focusing on IgG4-RD will use the new criteria. “I’m anticipating major advances in this field in the years to come, triggered in part by the strength of having sound classification criteria.”