New clinical trial offers hope for patients with rare immune disease IgG4-RD

A team led by Mass General Brigham researchers demonstrated that inebilizumab reduced the risk of symptoms by 87% in patients with the rare affliction known as immunoglobulin G4–related disease (IgG4-RD)

An international, phase 3 clinical trial led by investigators at Mass General Brigham could improve the treatment of a rare disease that can cause debilitating symptoms. The study, published in the New England Journal of Medicine, found that treatment with inebilizumab greatly reduced the symptoms of immunoglobulin G4–related disease (IgG4-RD), compared to placebo.

“This is a huge day in the history of this disease,” said lead author John Stone, MD, MPH, a rheumatologist in the Division of Rheumatology, Allergy, and Immunology at Massachusetts General Hospital, a founding member of the Mass General Brigham healthcare system. “We are thrilled to have worked so closely with patients to undertake a trial specifically focused on their disease, with the goal of finding a therapy that we hope will be approved shortly for them.”

IgG4-RD is estimated to affect fewer than 200,000 people in the United States. Although IgG4-RD is an orphan disease first recognized to be a unique condition in 2003, review of the medical literature as far back as the late 1800s confirms that the disease was around even then – and likely much longer. People who have the condition suffer from a build-up of immune cells that produce the IgG4 antibody in certain organs. The disease can affect any organ and frequently involves multiple organs, most commonly the pancreas, bile ducts, salivary glands, abdominal tissue, eyes and lungs. The symptoms are driven by which organs are affected. For example, if the disease affects the eyes, it can cause eye swelling and double vision; if it affects the pancreas, the disease can cause pancreatitis and diabetes; and if it affects the bile ducts, it can cause jaundice. Most patients with IgG4-RD have a long diagnostic journey, and many are misdiagnosed as having cancer before the correct diagnosis is established. Some patients even undergo unnecessary surgery prior to the recognition of IgG4-RD.

As with other immune-mediated conditions, patients typically experience recurrent symptoms – disease “flares” – which require immunosuppressive treatment. Doctors have traditionally treated this condition with steroids, but steroid use is associated with multiple side-effects including weight gain, osteoporosis, anxiety, depression, risk of opportunistic infection, and many others. Moreover, people living with IgG4-RD are often especially at risk to doing poorly on steroids, since the disease targets the pancreas in many patients. “When you have a patient who already has an inflamed pancreas that is functioning poorly on that basis and not making enough insulin, the addition of steroids leads to diabetes mellitus in a high percentage of cases,” said Stone. This underscores the important of a new treatment.

In the study, 135 adults with IgG4-RD were randomized 1:1 to receive inebilizumab or placebo. While 40 patients (59.7%) in the placebo group experienced one or more flares, only 7 participants (10%) in the inebilizumab group experienced at least one flare over the year-long study period. This means the drug reduced the risk of flares by 87%.

Inebilizumab, which is manufactured by the study’s sponsor Amgen, is a medication that depletes CD19-expressing B cells, which researchers believe play a key role in IgG4-RD. While highly effective in the trial, inebilizumab can increase infections by depleting B-cells that produce antibodies, and longer-term data will be needed to establish the treatment’s safety profile. The authors note that one of the challenges with B cell depletion therapies is that responses to vaccines may be impaired, which can lead to serious COVID, flu, or other infections. One way to reduce this risk is to ensure that patients are vaccinated before beginning treatment and to use the new therapy prudently, guided by markers of inflammation in the patient’s blood. 

Stone and his colleagues have advocated for patients with IgG4-RD for many years. In 2011, Mass General Brigham organized the international symposium focused on the disease. Last year, Stone continued his work building international partnerships across IgG4-RD patients and health care providers by founding the IgG4ward! Foundation, a worldwide advocacy group for people living with this disease.

By raising awareness about the disease, Stone hopes that physicians and patient advocates can improve the diagnosis and treatment of IgG4-RD.

With the publication of this phase 3 trial and greater publicity about the condition, greater awareness will lead to earlier diagnoses, contributing to much better patient outcomes.” 

John Stone, MD, MPH, lead author and rheumatologist, Division of Rheumatology, Allergy, and Immunology, Massachusetts General Hospital