Study Seeks FDA-approved Therapy for IgG4-related Disease

Massachusetts General Hospital's Rheumatology Division and scientists at the Ragon Institute are conducting an NIH-funded clinical trial to develop an FDA-approved therapy to treat IgG4-related disease.

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"We're looking at repurposing a drug from the oncology space to treat an autoimmune disease. We want to meet a need for a group of patients that are often overlooked," says Mass General rheumatologist Cory A. Perugino, DO. "A secondary goal of the study is to identify a potential biomarker to further understand disease activity."

Limitations of IgG4-related Disease Treatment

According to Dr. Perugino, estimates suggest 50,000–60,000 Americans have IgG4-related disease but the exact prevalence is still unknown. Prednisone has proven to be an effective treatment to induce remission, but often causes side effects and is not a safe long-term treatment option. The IgG4-related disease team at Mass General has demonstrated rituximab to be an effective remission maintenance therapy for this disease, but most community-based rheumatologists report difficulty in obtaining insurance approval for this treatment for patients with IgG4-related disease.

Mass General's IgG4-related Disease Program has been exploring new treatment options for several years. The FDA approval of additional therapeutics to treat IgG4-related disease will change how patients are treated and give them better access to care, says Dr. Perugino.

Testing Elotuzumab as Treatment for IgG4-related Disease

The major inflammatory cell populations in tissues affected by IgG4-related disease are B cells and CD4+ cytotoxic T cells. In the laboratory of Shiv Pillai, MD, PhD, at the Ragon Institute, Mass General researchers discovered that SLAMF7 protein is highly expressed on the surface of CD4+ cytotoxic T cells and many disease-associated B cells in this disease. Elotuzumab, traditionally used to treat multiple myeloma, is a humanized monoclonal antibody that targets SLAMF7.

In 2015, elotuzumab was the first drug given a breakthrough indication by the FDA to treat multiple myeloma. Multiple myeloma is a plasma cell malignancy and plasma cells express SLAMF7, Dr. Perugino noted.

"Our background work led to the idea of targeting this protein to deplete multiple cell types we think drive IgG4-related disease," Dr. Perugino says. "We are taking what we've learned in the lab and targeting SLAMF7 with elotuzumab to hopefully arrest the disease process."

Changing Cells in Patients Blood, Tissue

Patients enrolled in the clinical trial will receive elotuzumab infusions over several months. Researchers based dosage on what is traditionally administered to patients with multiple myeloma but will adjust dosage as needed. Patients with IgG4-related disease may need less medication than those with multiple myeloma.

Dr. Perugino's team will collect blood samples throughout treatment, categorize the immune cells at baseline and track them over time.

"We're using a large, comprehensive flow cytometry panel that encompasses more than just the CD4+ cytotoxic T cells," he says. "We are looking at a wide collection of other cell types that we think also contribute to the process of IgG4-related disease."

Paired tissue and blood studies are a unique aspect of the trial. Mass General researchers will obtain glandular tissue samples and blood samples from patients with salivary gland involvement before and after administering elotuzumab to assess changes in the immune cell populations expanded pre-treatment. Dr. Perugino says biopsy of the gland—which is frequently affected by IgG4-related disease—is considered a low-risk procedure.

"We're pairing those tissue studies with blood samples on the same day. It is going to be a potential avenue for advancement and understanding of the disease," Dr. Perugino adds. "We still don't know what antigens are driving the T cells in this disease. Through these paired tissue and blood studies, we're hoping to gain more insight."

Identifying Biomarkers of IgG4-related Disease

IgG4-related disease often goes undetected, says Dr. Perugino, causing significant damage to the body. Identifying a biomarker that tracks tightly with disease activity will allow clinicians to monitor the disease more precisely and prevent damage over time.

Utilizing the flow cytometry panel, Mass General researchers aim to capture patients with relapsing disease during the trial. By identifying what cells are expanding, they aim to define a collection of cell types that correlate with disease activity.

"Identifying a biomarker that could be used to track disease activity would be a huge gain for providers and patients. It would be a quick way to tell whether the disease is active or not, and this is something that would greatly complement the bedside clinical assessment," he notes.

Researchers will also measure soluble SLAMF7. Dr. Perugino says it would be an appealing biomarker because measuring protein levels (like that of soluble SLAMF7) is a far easier task that implementing flow cytometry into clinical practice.

Mass General Advancing IgG4-related Disease Treatment

This clinical trial is one of several being conducted by Mass General researchers, all of which aim to uncover new treatments for IgG4-related disease. Researchers are also studying inebilizumab and rilzabrutinib.

The program's large cohort of patients presents a unique opportunity to study this rare disease. Mass General's IgG4-Related Systemic Disease Program follows more than 400 patients with confirmed diagnoses and treatment plans.

Mass General has earned a Clinical Research Autoimmunity Center of Excellence (ACE) award from the NIH to study IgG4-related disease, which is led by John Stone, MD, MPH, director of Clinical Rheumatology at Mass General. The hospital is one of only two centers awarded a Clinical Research ACE and a Basic Research ACE, the latter led by Dr. Pillai, MD, PhD.

"Having both these ACE awards reflects the richness of the bedside-to-bench collaboration we have had at Mass General for many years now," says Dr. Perugino. "Between those two funding sources from the NIH, we're able to facilitate these clinical trials and pursue important discovery work in defining new therapeutic options, insights into the underlying disease mechanisms, and biomarkers to assist in the longitudinal care of patients with IgG4-related disease."

Learn more about Mass General's IgG4-Related Systemic Disease Program

Refer a patient to the Department of Rheumatology