Dr John H Stone: a physician–investigator’s journey with IgG4-related disease
Looking down a microscope in 2007, Dr John H Stone was astonished to find a clue pointing to the existence of a multi-organ condition. At that time, the disease—IgG4-related disease (IgG4-RD)—was unheard of in the United States, but soon afterwards many other cases were found. Here John describes the journey of discovery that has taken place since then
Written by Geoff Case, digital editor, RARE Revolution Magazine
Interview with John H Stone MD, MPH, senior clinical consultant in rheumatology, Massachusetts General Hospital, and professor of medicine at Harvard Medical School
My journey with IgG4-related disease began in late 2007 at Massachusetts General Hospital. One of the very first patients I evaluated there was a 26-year-old woman from Morocco. She was referred to me because she had two swellings below her chin on either side, and her physicians thought she might have Sjögren’s syndrome (a chronic autoimmune disease). She’d been to one physician after another for about three months; it was also thought she might have tuberculosis, some kind of infection, maybe lymphoma, maybe cancer.
I had been a practising rheumatologist for a dozen years and I had never knowingly seen anything like this before, so I was intrigued. I presented her case to my colleagues, and we decided that though it didn’t really look like a classic case of Sjögren’s syndrome, she might have had a lymphoma, which Sjögren’s patients are at risk for. So we asked for a biopsy (tissue sample) of her submandibular glands, which were the source of the swelling below her chin.
rheumatologist – a doctor who diagnoses and manages chronic (long-lasting or recurrent) conditions that cause inflammation
submandibular glands – glands that make saliva
pathologist – a doctor who specialises in pathology: the study of disease processes with the aim of understanding their nature and causes
histology – the study of the structure of tissues by means of special staining techniques combined with light and electron microscopy
pancreatitis – inflammation of the pancreas, a large gland that lies behind the stomach
Two weeks later, the laboratory results were still not back, so I went to the lab and sat down with the pathologist at the microscope. We were astonished to see a histological picture in the submandibular gland that resembled pancreatitis—i.e. inflammation in an entirely different organ. I’ll never forget the pathologist’s statement: “It looks like she has autoimmune pancreatitis in her submandibular gland”. This was the first clue that I might be dealing with a multi-organ disease, and my first insight about one of this disease’s characteristics: the pathology—the changes in the organ caused by the disease—looks the same in every affected organ. This suggested that problems in multiple organs might have a single unifying cause.
With this clue that perhaps we were dealing with a disease that could affect multiple organs, I began to read up on it. At the library I dug out some papers and I found two things. One: it didn’t seem to be a new disease. Going back to the 1890s, in fact, there were patients described in the German medical literature who looked just like my patient: they had dramatically swollen submandibular glands. Two: Japanese colleagues had recognised this as being a unified condition about four years earlier. For several years, they had been writing about it and referring to the condition as IgG4-related sclerosing disease, but the rest of the world basically hadn’t heard of it; almost no one in the United States had any knowledge about these developments when I saw my first patient in 2007.
Once we had become aware of this emerging condition, we began to see more and more patients. There was a patient we’d been following for seven or eight years who had been diagnosed with Sjögren’s syndrome but there were a number of atypical features about his case. It all finally made sense when we realised that he had IgG4-related disease. There were patients who had undergone surgeries to remove most of their pancreas because it was thought they had cancer, but the pathology ultimately confirmed that they had IgG4-related disease of the pancreas rather than cancer.
Now, not a day goes by when I don’t hear from someone across the world, a patient or a physician, about a patient with IgG4-related disease. Today, we have at least 600 patients at my hospital whom we follow with this disease. We estimate, based on a study of insurance claims databases, that in the United States there may be at least 40,000 people with the disease.1 This means it fulfils the definition of being an “orphan” disease, but it’s certainly not vanishingly rare.
orphan disease – in the United States an orphan disease is defined as a condition that affects fewer than 200,000 people nationwide2
It’s been difficult, however, to understand how widespread IgG4-related disease is because it has not had a single name or its own ICD-10 code (a list of diseases used for healthcare recording around the world). We know that IgG4-related disease is a multi-organ disease—there are 10 to 12 organs that it tends to affect commonly.3 A patient might, therefore, have a thyroid diagnosis, such as Riedel’s thyroiditis, or an eye diagnosis, such as proptosis (bulging), or a pancreas diagnosis, such as chronic pancreatitis, when the underlying cause, in fact, for all of these clinical presentations is IgG4-related disease. Yet IgG4-RD is not recorded because an ICD-10 code for that diagnosis does not exist. But in October 2023, more than 15 years after I saw my first patient, it will.
“It’s been like the parable in which the blind men are touching separate parts of an elephant and come to different conclusions about what it is. The first person, whose hand is on the trunk, says it’s a snake. Another, whose hand is on its leg, says it’s a tree, and so on.”
If physicians know that there is a code for IgG4-related disease and the existence of this code is publicised appropriately, that will help them code the disease properly. That will help us understand how common it is and make the case that this is an important disease because it affects a lot of people in substantial ways, having a major impact on patients’ lives. Then there will be more attention focused on it with regard to research, more emphasis on the development of new therapies, the creation of educational programmes for patients, their family members, and healthcare providers, and so on.
Early diagnosis is critical because one of the characteristics of IgG4-related disease is that it’s slow—it’s not detected for months, or years. And the entire time that the disease is smouldering undetected, it’s causing damage. When we fail to make the diagnosis early, we lose the opportunity to prevent the damage.
And the disease is very treatable: if we’re able to diagnose the disease on day one, or week one or month one, the patient would never develop long-term problems. But with disease, patients generally have undiagnosed inflammation in one or more organs for many months, or even years. And by the time patients even realise they’re sick, they may already have major damage to multiple organs.
Having an ICD-10 code and increasing the awareness of the disease will help this potential diagnosis occur to physicians earlier. Early diagnosis and treatment will prevent a lot of problems for patients that are chronic and irreversible but avoidable with more timely recognition of this disease.
“Japanese physicians who described this disease came up with a wonderful metaphor. They referred to the disease as being like a black crow flying through the night. 100 years ago, the disease was there, but physicians did not detect it. When I was in medical school and years before I recognised my first case, the disease was already there, but we missed it.”
One of the greatest unmet needs is getting a prompt diagnosis—and I think we’re making progress with that: we’re educating the world about the disease.
The second need is an effective therapy to control the disease. The cornerstone of therapy for IgG4-related disease around the world is glucocorticoids (steroids). Glucocorticoids work very well in controlling the disease, but they don’t cure it. And when they are stopped, the disease comes back. Typically patients need to be on steroids chronically, so the toxicities from them accumulate. Also, IgG4-related disease tends to affect middle-aged or elderly people who may already have “comorbidities”—other conditions—that make treatment with steroids highly problematic. These include obesity, hypertension, type 2 diabetes, hyperlipidaemia (high cholesterol) or osteoporosis.
IgG4-related disease leads to pancreatic failure for many patients. When the pancreas is damaged, it makes less insulin, leading potentially to diabetes. But the steroids used to treat IgG4-related disease tend to elevate the blood sugar and that contributes to diabetes. The condition of diabetes, of course, leads to the need for additional medications and can have multiple long-term complications.
The third thing that patients really need is education about their disease. Presently, there is not a single source of truth about this disease for patients, so they don’t know where to go to get good information. Where there is not a reliable source of information, misconceptions spread.
We’ve come a long way in 15 to 20 years from a situation in which virtually no one in the world had heard of this disease. It’s gone from individual physicians publishing reports about unusual things they’d seen but did not yet understand, to laboratory collaborations in which clinicians and scientists established bedside-to-bench collaborations, to clinical trials now studying new medications that will someday be approved for patient use. The clinical trials we’ve developed have stemmed directly from the bedside-to-bench collaborations: blood samples from patients with well-defined IgG4-related disease have been examined by talented immunologists, who then used cutting-edge techniques to identify cells that are critically important for this disease (such as B cells and certain T cells).
B cells – white blood cells that are part of the body’s immune system
T cells – another type of white blood cell. These are also an important part of the immune system
Armed with our laboratory knowledge, we’ve been able to go back from the bench to the bedside with knowledge about what treatments might work. Through international collaborations we have begun to develop targeted therapies for treating this disease that may, I hope, give us additional treatment options in the future.
IgG4 is an ideal disease to study in the lab because it is slow-moving. You can collect samples from patients before they’ve received any therapy, and then you can observe what happens after a targeted therapy to understand the impact that treatment has had on the immune system. We’ve been able to discover a lot about this disease through this approach.
Another big accomplishment in research has been development of classification criteria for the disease. These criteria help us ensure that patients who are thought to have IgG4-related disease don’t have some other diagnosis. These were developed in an effort funded by the American College of Rheumatology (ACR) and the European League Against Rheumatism (EULAR). They are now used as inclusion criteria for clinical trials and other studies.
From the research we’ve also learned more about how checking the levels of IgG4 in blood serum can help physicians to diagnose IgG4-related disease. (IgG4 is a particular type of immunoglobulin; immunoglobulins, which are also called antibodies, are proteins the body makes to fight infection.) We now know that an increased level of IgG4 is not by itself diagnostic of the disease—there are other things that can cause this—but it does help make a diagnosis. IgG4 concentrations are part of the ACR–EULAR classification criteria.
serum – the fluid that separates from clotted blood or blood plasma that is allowed to stand
It is a rare privilege to work in this area. I think it’s every physician–investigator’s dream to focus on a disease for which much progress can be made, leading both to important ways to help patients and, more broadly, to lessons that are applicable to other diseases and the field of human immunology. I often say that it’s one thing to help describe a new disease, it’s quite another to actually help develop therapies for it.
A number of insights about how the disease works have moved us very quickly to the development of therapies that may potentially alleviate patients’ suffering and reduce damage from the disease. So it is a remarkable journey we’re on.
Early on, there was a new “Eureka!” moment almost every week as we realised something else about this disease: here is IgG4-related disease in yet another organ! Look at how this patient has responded to therapy! Those moments have made this a remarkably interesting and rewarding field to work in.
The important steps towards meeting the unmet needs—earlier diagnosis, better treatments and better education for patients—are all moving forward now and very fast.
We had the first IgG4-related disease symposium in Boston, United States, in 2011 and I’m pleased to say that we’ll have the fifth International Symposium on IgG4-related disease In Milan, Italy, in the spring of 2024. I’m sure that symposium will be the biggest yet. We may even have to have a virtual or a hybrid symposium because we’ll have so many people coming together. Earlier diagnosis comes down to education of physicians and other healthcare providers, and this symposium will be a great forum for continued collaboration and exchange of ideas.
We can also spread knowledge about the disease among care providers through peer-reviewed publications. There are clinical trials in multiple centres internationally that are ongoing. When these finish and the results are published, that will lead to publicity about the disease. If there are new tools for treating these diseases, clinicians will know about them.
Education for patients is important too. They need to know how they can live well with their disease, the treatments that are available and how to use them, the complications of the disease or of the treatments they might need to look out for, how to deal with the complications of the disease that may have already happened to them by the time they’re diagnosed. With electronic media, we can really begin to get the word out more quickly.
Another exciting movement is the idea of consented communities, which capitalises on the electronic communication we use in society. They are important because they help patients contribute to our understanding of what it’s like to have a particular diagnosis, and they help us to identify areas of unmet need, and ultimately to facilitate progress in those areas.
A strong patient advocacy group is going to be critical going forward. In this context, I am delighted to announce that I recently became the executive chairman of a newly established international patient advocacy group known as the IgG4ward! Foundation. The exclamation point is a key part of the name of this organisation, the motto of which is “Paving a path 4ward!”. There is much to do in the interest of improving the lives of people with IgG4-RD and IgG4ward! is eager to tackle the big work ahead.
 Wallace ZS, Miles G, Smolkina E, et al. Incidence, prevalence and mortality of IgG4-related disease in the USA: a claims-based analysis of commercially insured adults. Ann Rheum Dis. 2023;82(7):957-962. doi:10.1136/ard-2023-223950
 Rare Diseases at FDA. FDA. Published December 13, 2022. Accessed August, 2023. https://www.fda.gov/patients/rare-diseases-fda
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