Sparked by inexplicable symptoms in one patient, an intrepid physician’s investigation led to the discovery of a new disease that afflicts many worldwide.
John Stone, MD, MPH, director of  Clinical Rheumatology, led the search for a new disease.
John Stone, MD, MPH, director of Clinical Rheumatology, led the search for a new disease.

Breathing heavily, Noor Khan, MD, trudged down the hallway one late afternoon to a Mass General laboratory followed by his wife and son. Leading the way was John Stone, MD, MPH, director of Clinical Rheumatology at Mass General, who was armed with a strong suspicion and a handful of microscope slides. He hoped to discover why Dr. Khan, a physician from Long Island, had been suffering with strange symptoms.

The group gathered around a microscope and over the next hour, Dr. Stone invited Mass General pathologists, medical residents, fellows, and Rheumatology clinic staff to view Dr. Khan’s case and discuss what they saw. Finally, they agreed on a firm conclusion.

“This is a slam dunk!” Dr. Khan recalls Dr. Stone saying, “It’s IgG4-related disease.”

If you’ve never heard of IgG4-related disease, it’s because no one else had either – until recently.

A Case from Casablanca

That changed in 2008, when a young woman from Casablanca with swelling in her neck visited Mass General, setting in motion a “series of epiphanies,” as Dr. Stone says. Combining the clinical skills of a physician with the investigatory instincts of a scientist, he led the way to the description of a new disease, the identification of a novel white blood cell, and a broader understanding of the human immune system that could help in treating patients with IgG4-related disease and other conditions.

The discovery of IgG4-related disease underscores the history of Mass General breakthroughs, grown out of the tradition of physician-scientists.

The discovery of IgG4-related disease underscores the history of Mass General breakthroughs, grown out of the tradition of physician-scientists. In the mid-20th century, for example, Fuller Albright, MD, helped create the field of endocrinology—the study of hormones—by observing his patients closely and delving into their conditions with the best scientific tools of his day.

More recently, Bruce Walker, MD, now director of the Ragon Institute of MGH, MIT and Harvard, noticed a patient with the AIDS virus whose immune response was protecting him from becoming ill. Dr. Walker began a line of investigation that helped define the key components of an effective immune response that are the basis for vaccine development and new immune therapies.

“John Stone is part of a great tradition of physician-scientists at Mass General that dates back 200 years,” says Katrina Armstrong, MD, Mass General’s physician-in-chief. “The ability of a physician to look and learn from a patient whose symptoms don’t fit with conventional wisdom can lead to a whole new line of research, changing how we define disease.”

Discovery Rooted in Experience

Dr. Stone’s perspective is rooted in his growing up years, when he watched his mother cope with scleroderma, a condition that, like the newly-discovered IgG4-related disease, causes fibrosis—a form of scarring resulting from inflammation. His mother’s brave struggle with scleroderma and her death at age 54 shaped Dr. Stone, a third-generation physician. He became a doctor who closely observes a patient’s physical condition, rather than relying solely on tests and scans.

Bich Na (Shine) Lee suffered years of unexplained pain until she was treated for IgG4-related disease.  She is pictured with her daughter, Maya Zoe.
Bich Na (Shine) Lee, pictured with her daughter, Maya Zoe, suffered years of unexplained pain until she was treated for IgG4-related disease.

His interest in unusual physical findings in patients helped him recognize a unique form of fibrosis in the woman from Casablanca. Fibrosis – the medical term for scarring – contributes to approximately 45 percent of deaths around the world. But this woman’s case didn’t look like anything he’d seen. He studied the medical literature and spent many hours at the microscope with Mass General pathologist Vikram Deshpande, MD.  They compared the case to others described in the medical journals—particularly from Japan, where scientists had begun to make similar observations. The tissues of patients with this condition were infiltrated by cells making an antibody called immunoglobulin 4, or “IgG4,” for short.

Misdiagnosed Patients, Unnecessary Treatments

After much research, Dr. Stone and his colleague concluded that this form of painful and disabling fibrosis appears in many organs—the pancreas, liver, kidneys, salivary glands, eyes, lymph nodes and others. The condition had been misdiagnosed for decades as a variety of diseases, particularly cancer. What all cases had in common, however, was the presence of the IgG4 antibody. It is a player in a large-scale attack by the immune system on healthy tissues, similar to other autoimmune diseases.

Patients started coming out of the woodwork, including those who had been misdiagnosed with cancer.

Dr. Stone and colleagues had identified a new disease. They published their work in The New England Journal of Medicine in 2012.

“The disease was like a crow flying in the dark night of medical history,” Dr. Stone says, invoking a metaphor used by Japanese colleagues also working on IgG4-related disease.

Patients started coming out of the woodwork, including those who had been misdiagnosed with cancer. Some had undergone unnecessary surgery, radiation or other ineffective treatments when what they really needed was a drug that would shrink the inflammation and fibrosis. And Dr. Stone knew of one.

The work of pathologist Vikram Deshpande, MBBS, was crucial in identifying the new disease.
The work of pathologist Vikram Deshpande, MBBS, was crucial in identifying the new disease.

Treatment for a New Disease

In 2011, a young Korean woman named Bich Na (Shine) Lee visited Dr. Stone. Since her teens, Shine had suffered immense pain behind her nose and one eye. She had been referred to Mass General for treatment of a sarcoma – a lethal cancerous tumor – that was eating through her facial bones.

The bridge of her nose had collapsed and if she survived, she would need plastic surgery, as well.

Before proceeding with radiation therapy for her tumor, Dr. Stone and Dr. Deshpande reviewed Shine’s biopsy and, instead of cancer, saw exactly the same kinds of cells with IgG4 antibodies they had seen in the patient from Casablanca.

Dr. Stone treated Shine with rituximab, a drug he had used for other diseases of the immune system.  Shine’s tumor shrank away. She had successful plastic surgery, married and recently gave birth to a daughter, Maya Zoe.

“Dr. Stone has been warm and caring and has treated me like a daughter,” Shine says.

“Dr. Stone has been warm and caring and has treated me like a daughter,” Shine says.

With IgG4-related disease patients now pouring through the door, Dr. Stone says, the most exciting phase of the journey of discovery was yet to come.

Another Step of Discovery

Enter Dr. Khan who, in 2012, had been suffering with unexplained symptoms for three years. The physician was singularly determined to figure out the cause of his breathing problems, neck swelling, weight loss and muscle pain. Specialists he had seen had provided a variety of confusing and frightening diagnoses, including cancer. Luckily, one doctor had read Dr. Stone’s papers and sent him to Mass General. After establishing the correct diagnosis, Dr. Stone also treated Dr. Khan with rituximab.  Within days, the illness that had plagued Dr. Khan began to lift.  Within weeks, he felt normal again.

Noor Khan, MD
Noor Khan, MD

Dr. Stone added Dr. Khan’s blood and tissue samples to the growing collection of cell lines from patients with IgG4-related disease being studied by colleagues at the Ragon Institute in the lab of immunologist Shiv Pillai, MD, PhD. Using a cutting edge technique known as “next-generation sequencing,” Dr. Pillai and his colleagues Hamid Mattoo, PhD, and Vinay Mahajan, PhD, identified a new T lymphocyte cell, or “T-cell.” That discovery began to turn accepted wisdom on its head.

“My case became the Rosetta Stone of this disease!” Dr. Khan exclaims about the role his case played in the unraveling mystery.

A Barrage Unleashed

Dr. Stone was in Florida to give a medical talk when he received an email from Dr. Pillai reporting that analysis of Dr. Khan’s blood demonstrated “an enormous expansion of one particular T-cell.” This previously unknown cell was multiplying wildly, driving the storm of inflammation and fibrosis.

The work that began in IgG4-related disease is now rapidly expanding to other conditions associated with fibrosis.

Researchers soon found the same T-cell in the blood of every patient with IgG4-related disease, revealing that its cause was not the IgG4 antibodies but the result of a powerful and destructive immune response orchestrated by the T-cell now called the “CD4 killer T-cell.” The IgG4 antibodies were merely part of that response, a bit player that appears when the T-cells unleash a barrage of chemicals and inflammation.

Today, phone calls and emails continue to stream into Dr. Stone’s office from clinicians around the world seeking his help in diagnosing patients. The work that began in IgG4-related disease is now rapidly expanding to other conditions associated with fibrosis.  Sitting at his desk recently, Dr. Stone turned to his computer where the image of a large bird appeared on the screen. “That’s the crow flying through the night of medical history,” he said – a reminder of how a now-recognized disease had flown unseen for many years.

To learn more about Dr. Stone’ research and how you can support it, please contact us.