John Stone, MD, MPH
John Stone, MD, MPH

John Stone, MD, MPH
Professor of Medicine, Harvard Medical School
The Edward A. Fox Chair in Medicine
Director, Clinical Rheumatology, Massachusetts General Hospital
Clinical and Translational Research Center

Dr. Stone is recognized as the world’s leading clinical investigator in IgG4-related disease (IgG4-RD), a multi-organ immune-mediated condition that can cause inflammation and fibrosis (the formation of excessive connective tissue) in various organs and tissues throughout the body. IgG4-RD can cause swelling of the organs in a way that can be mistaken for cancer—and many of his patients have misdiagnosed as having cancer before coming to Massachusetts General Hospital. He is collaborating with Xencor to test a novel treatment strategy for this disease that may also have relevance to other inflammatory conditions.

Research Institute (RI): What problem are you trying to solve?

John Stone (JS): I am currently working on IgG4-related disease (IgG4-RD), a condition I recognized only about eight years ago in one of the very first patients I evaluated at Mass General. Since then, I’m almost embarrassed to admit, the work has been a virtually continuous series of “Eureka" moments and exciting collaborations both within Mass General, and among a growing network of colleagues abroad.

We have identified new clinical features of this condition; made great strides in unraveling its immunology; discovered a novel T lymphocyte that appears critical as a driver of the disease; and—most importantly—found therapies that really seem to be effective. In fact, over a very short period of time, Mass General has become the center for research on this disease. Most remarkably, perhaps, the entire program began because of a single patient interaction.

We are currently conducting an important single-center clinical trial that I believe will lead to an innovative treatment approach for multiple immune-mediated (“autoimmune”) diseases. The trial started after a pharmaceutical company, Xencor, read about the work we had published and realized their drug might be highly effective in IgG4-RD. Our initial results—both in the laboratory and in the clinic with this new therapy—have been striking.

As a rheumatologist, it is immensely gratifying to control an immune-mediated process without having to use steroids.

RI: Did you have institutional support from Mass General in setting up your trial?

JS: Yes. The staff of the new Translational and Clinical Research Center (TCRC) is terrific. From the very start, they have joined us on teleconferences with Xencor. They have been present at meetings, helped develop a budget for the trial and also helped with the IRB approval.

RI: This must be a valuable resource for investigators.

JS: Right, absolutely, helping to negotiate the budget with the company has been very important. The TCRC staff has been wonderful, and this is only one of several collaborations that I have had with them.

RI: How did you learn about the TCRC?

JS: I first spoke with Mason Freeman, MD, (Director of the TCRC) about the same time I saw my first patient with IgG4-RD—not long after I came to Mass General. Mason and I talked about a variety of projects that I was working on related to IgG4-RD, vasculitis and other autoimmune conditions. We narrowly missed on our first effort at a major collaboration, but I’m delighted that the Xencor trial is working out so well.

RI: Has Mass General's expanding translational research effort helped to bridge the gap with industry?

JS: It is essential, because investigators—both basic and clinical—don’t have the time to do everything that is required to pull together collaborations with industry. We really need the support of the institution to do that. It’s important that we play an important role in cultivating those opportunities, but we need the support of others within the institution.

RI: Can you tell me more about how you first recognized IgG4-RD?

JS: It all started with one patient that was referred to me to rule out Sjogren's syndrome, another well-known autoimmune disease. After examining the patient, I realized that I had never seen a patient with Sjogren’s syndrome who presented in that way.

I thought there was a possibility that she may have lymphoma, so her submandibular gland—a salivary gland just below her jaw—was biopsied. I reviewed the gland with a pathologist, who made the very curious statement that “it looks like she has autoimmune pancreatitis in her submandibular gland!” It was at that point that I started deeply investigating this in the literature.

Through this research, I discovered that Japanese investigators have been writing about this emerging condition for a few years, and that identification of the disease was starting to take shape.

RI: Is this disease more prevalent in people of Asian descent?

JS: No, it is a worldwide disease. We have subsequently found it in patients from all over the world—every continent on the planet save Antarctica (so far).

RI: Prior to your discoveries, what kind of care plan were these patients on?

JS: Patients were misdiagnosed and often mistreated with inappropriate surgeries and damaging therapies. Many suffered end-organ failure or simply died without a diagnosis.

As an example, I evaluated a patient earlier this week whose pancreas is failing. He is sliding toward diabetes and pancreatic deficiency. Prior to the discovery of IgG4-RD, he would have been thought to have idiopathic pancreatic failure, and just wasted away from the ravages of diabetes mellitus and exocrine pancreatic insufficiency (the inability to digest multiple kinds of food). We would never have understood why, and called his problem “idiopathic.”

RI: What is your success rate with the therapies you are developing?

JS: This is a very treatment-responsive disease if it is diagnosed at an early stage. As I’ve indicated, we are working on therapies that permit steroid-free disease remissions. Even more exciting is the possibility that my collaborative work with Dr. Shiv Pillai and his colleagues at the Ragon Institute of MGH, Harvard, and MIT may lead to a treatment approach that targets a novel T lymphocyte that we discovered in the course of investigating IgG4-RD.

RI: Speaking of discovery, if you were at a different institution would you have access to same patient population, research collaborators and research environment?

JS: The environment of Mass General has been enormously enabling—no question about it. There are few places anywhere else in the world where such a productive “bedside-to-bench” collaboration could have happened.

In Boston we not only have Mass General, but also Harvard Medical School, MIT, and—most importantly—patients who come from all over the world to get care. Moreover, in addition to the scientific firepower of Mass General, we have the Ragon Institute, the Broad Institute and all of the world’s major pharmaceutical companies located just across the river in Kendall Square or otherwise nearby.

There is no better place in the world for this kind of discovery to happen. All of the ingredients are here.

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