Cleveland Clinic aims to speed IgG4-RD diagnosis with AI, registry
Specialists working across departments to develop systems
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Cleveland Clinic specialists across multiple disciplines are working to speed the diagnosis of immunoglobulin G4-related disease (IgG4-RD), a rare and often-missed inflammatory condition. Their efforts include using artificial intelligence (AI) to develop a tool to help assess and manage the disease and create a patient registry.
The specialists — clinicians and researchers focusing on autoimmune and inflammatory diseases, allergies, and gastrointestinal, nervous system, and kidney conditions, as well as those in imaging and tissue analysis — will also promote broader education for primary care clinicians who are less familiar with the disease.
“We want to develop methods for earlier disease identification, combine that with education of clinicians and patients, and put this disease on the radar screen moving ahead,” Leonard Calabrese, director of the R. J. Fasenmyer Center for Clinical Immunology at the Cleveland Clinic, said in a medical center press release.
The Cleveland Clinic is one of the recruiting sites for the Phase 3 RILIEF clinical trial (NCT07190196), which is testing the oral therapy rilzabrutinib in up to 124 adults with IgG4-RD. Recruitment is also ongoing at other sites across the U.S. and in Canada, Europe, South America, and Asia.
IgG4-RD is characterized by infiltration of immune cells, particularly B-cells producing the IgG4 antibody, in tissues. This results in the formation of tumor-like masses or painless enlargements. The disease can affect virtually any organ in the body, most often the pancreas, head and neck, or abdomen.
‘Ability to masquerade’ complicates diagnosis
Because IgG4-RD can mimic cancer, infections, or other immune conditions and because its symptoms vary widely depending on which organs are involved, it’s among the least frequently diagnosed inflammatory diseases. IgG4-RD was first identified in the early 2000s, and international consensus guidelines for diagnosing it were published in 2012.
“It has probably been around forever but was it masquerading as a litany of separate syndromes,” Calabrese said. “We face a challenge in that people with this condition are not being identified because of its capacity to masquerade in virtually any organ system.”
Diagnosing IgG4-RD is challenging because the disease can present with nonspecific symptoms, such as weight loss or back pain. Elevated blood levels of IgG4 can support a diagnosis, but such tests alone are not sufficient.
“Diagnosis requires the appropriate clinical picture combined with supportive laboratory results plus a compatible radiographic imaging appearance and evidence of the [tissue abnormalities] that’s characteristic of [IgG4-RD],” Calabrese said. In most cases, doctors must rule out conditions that mimic IgG4-RD and use a combination of assessments to make an accurate diagnosis, he said.
Primary care and internal medicine clinicians, who are often the first to see patients with early or nonspecific symptoms, may not be familiar with the disease.
For patients with more severe manifestations, including autoimmune pancreatitis (pancreas inflammation), inflammation of large blood vessels, involvement of the area behind the abdominal lining, or kidney disease, “targeted education about IgG4-RD is key for early recognition and prompt therapy,” Calabrese said.
The Cleveland group is evaluating a large language model-based tool designed to assist with IgG4-RD assessment and management using clinical vignettes, which are condensed, story-like case summaries. They will also develop an IgG4-RD patient registry, paired with an AI-based early warning system intended to help flag the disease sooner.
“[IgG4-RD] is a serious disease, but one that can be very well controlled if treated early,” Calabrese said. “The big challenge is identifying patients early enough to benefit from it.”
Glucocorticoids remain the standard first-line treatment for IgG4-RD, but their long-term use can cause serious side effects. Even so, the treatment landscape has progressed last year with the U.S. approval of the first IgG4-RD treatment, Uplizna (inebilizumab). The therapy, administered directly into the bloodstream, works by killing B-cells.
“One recently approved [therapy] already is in use and others are likely to be approved in the near future,” Calabrese said. “This will allow us to spare our patients long-term high dose glucocorticoid exposure which we know carries a significant toll.”
Sanofi’s rilzabrutinib is one of the therapies being evaluated in IgG4-RD. It works by blocking the activity of Bruton’s tyrosine kinase, an enzyme that drives inflammatory activity in B-cells and other immune cells.
Rilzabrutinib is approved as Wayrilz in the U.S., the European Union, and the United Arab Emirates to treat immune thrombocytopenia, a rare autoimmune bleeding disorder.
The therapy has received orphan drug status for IgG4-RD in the U.S., the European Union, and Japan. This status offers incentives and support for companies investing in treatments for rare diseases.
In a Phase 2 trial (NCT04520451) involving 27 adults with IgG4-RD, most (70%) participants treated with rilzabrutinib were free from flares and did not require glucocorticoids or other immunosuppressive treatments after about one year. The ongoing RILIEF study is designed to confirm these benefits in a large patient population.
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