Treatment considerations and unmet needs for patients with IgG4-related disease
John Stone, MD, MPH, Director of Clinical Rheumatology at the Massachusetts General Hospital and Founder of the IgG4ward! organization, and Emma Culver, BSc, MBChB, DPhil, FRCP, Consultant Hepatologist and Hon Senior Lecturer in the Translational Gastroenterology and Liver Unit at John Radcliffe Hospital in Oxford, discussed the need for better treatment options for patients with IgG4-related disease, a potential FDA approval in 2025, and the unmet needs patients face, chiefly as it relates to education around the disease.
John Stone, MD, MPH:
Emma, welcome. I’m looking forward to the conversation with you today about IgG4-related disease.
Emma Culver, BSc, MBChB, DPhil, FRCP:
Yeah, it’s going to be great to discuss some of these topics.
John Stone, MD, MPH:
Why don’t you start by giving a little overview of your background and work in IgG4-related disease by way of introduction?
Emma Culver, BSc, MBChB, DPhil, FRCP:
Thanks, John. Yeah, my name’s Emma Culver. I’m a consultant, gastroenterologist and hepatologist, and I work in Oxford in the UK at the translational gastroenterology and liver units in the John Radcliffe Hospital. I probably have been working with IgG4-related disease for at least the last 15 years. It was part of my PhD where I was looking very much at the natural history of the condition and also some of the pathogenic mechanisms that drive it. Here in the UK, I’ve set up a national multidisciplinary team meeting and clinic where we would meet with both gastroenterologists and rheumatologists to try and help to diagnose the condition and manage it appropriately. How about you, John, because obviously I know you’ve been involved in the condition even long before myself?
John Stone, MD, MPH:
Well, thank you Emma. I’m John Stone. I’m a professor of medicine at Harvard Medical School and a rheumatologist at the Massachusetts General Hospital in Boston. My involvement with IgG4-related disease began in 2007 when one of the very first patients I evaluated upon moving to Boston and coming to MGH turned out to be a 26-year-old woman who had swelling of what turned out to be her submandibular glands. Dspite being a Board-certified rheumatologist for more than 10 years at that time, I had never knowingly seen anything like that. Long story short, after a workup, which included removal of one of those submandibular glands to make sure she didn’t have a lymphoma or some other kind of cancer, she turned out to have IgG4-related disease.
In reading about what was going on, the currents that were going on with the disease at that time, which still wasn’t even called IgG4-related disease, I came upon literature that was emerging from Japan about this condition. That started me on this exciting journey of the last 17 years. Emma, it’s important, it’s still difficult, despite the fact that the disease has been known for more than 20 years, it’s still so important to make the diagnosis in a timely way. What are some of the things that you look for when trying to ascertain the diagnosis of IgG4-related disease?
Emma Culver, BSc, MBChB, DPhil, FRCP:
Yeah, John, you’re right. I mean diagnosis is still challenging, even sort of 15 years on from when I first saw my first case, and I think there was… A lot of it for me is about some pattern recognition and it’s a combination of features. The majority of patients that I tend to see will present with a mass or a thickening or a stricture, and the mass might be external, so it might be something you can see, like for example, what you’ve just described in the head or the neck, or obviously it can be internal, which is the things that I often see, which includes a mass of the pancreas or a thickening in a stricture in the bile duct, or maybe even an area of enlargement around the retroperitoneum. That mass or that strictural thickening is the first kind of inkling or clue that there’s something abnormal that’s going on.
Obviously one of the big things that we worry about and that we need to distinguish it from is indeed cancer. Cancer can be devastating from a patient’s perspective and it’s important for us not to miss it. That leads to us looking for other things that we might have to look for to try and establish the diagnosis, and that’s a combination of blood markers, so we know that serologically, we can see a serum IgG4 level, which is really just an antibody or protein within the blood that can be elevated in a number of patients who have this condition, and in the patients I often treat with pancreatic biliary disease, that can be elevated in as many as 8 out of 10 patients, but there are still 2 out of 10 whereby it may not be elevated. We also know that actually it can also be risen in other conditions also, so it’s not diagnostic on its own.
Then there’s the typical imaging features that we see in some organs and not others. In the pancreas we may see a typical sort of sausage shaped swollen pancreas with a stricture in the common bile duct, but actually in some other organs there are very nonspecific features and we may just see some nonspecific features within the kidneys or maybe even other organs such as the lungs. Then what we want to think about is also histology. I think lastly, as part of that kind of diagnostic process, we think about needing to take a biopsy. When I think about making a diagnosis, I think of the combination of this mass, the combination of the elevated serum IgG4, the imaging findings, and then lastly some of the histological characteristics.
John Stone, MD, MPH:
By the time patients get to you or to me, they’ve already been processed by lots of other providers, and they’ve typically seen lots of other doctors by the time they get to us. I would add to what you say, sort of thinking about it from the lens of a primary care doctor, reasons to suspect IgG4-related disease. One of them is a mass lesion, absolutely. Masses occur in so many different organs that can be associated with IgG4-related disease.
One other thing that we often see is allergy manifestations. There’s so many different features of atopy; asthma, a mild eosinophilia in the blood, allergic rhinitis, skin rashes. A lot of patients with IgG4-related disease have those as well and sometimes those are present for years before the disease emerges fully. Then every once in a while, for one reason or another, a practitioner orders a serum IgG4 concentration and is struck by how high it is, so that’s another way that these patients come to mind.
But that really is one of the biggest challenges in the field, is the ability to diagnose patients early enough to prevent damage from the disease. Because the disease can be present for many months, even years, smoldering along, damaging the pancreas and other organs before it finally causes enough of a problem to be diagnosed.
Emma Culver, BSc, MBChB, DPhil, FRCP:
I was just interested in what you’re saying, because obviously you talked about the primary care physician, but in your practice do you find that the other physicians will refer to you or they come from other places rather than just primary care?
John Stone, MD, MPH:
It’s very often another subspecialist who refers the patient. Who, in turn, has probably been referred the patient by a primary care doctor very often. Sometimes it’s a nephrologist or very often an ophthalmologist. Rheumatologists see so much orbital inflammatory disease referred by ophthalmologists for diagnosis and management. Sometimes we get these patients from otolaryngologists as well because of disease above the head and neck, and I think that’s a very different profile of the patient that you typically see in gastroenterology and pancreatology.
Emma Culver, BSc, MBChB, DPhil, FRCP:
I think you’re right. I think the other place that they come to for us is also through the emergency department. Through our emergency department or our INE department, we will sometimes see patients who are acutely jaundiced with obviously a risk of what we call cholangitis, so that’s inflammation and infection within the bile ducts. They also come acutely because of the concern of cancer, because they lose vast amounts of weight through the fat soluble vitamin deficiency that they get due to the exocrine and also endocrine involvement with the pancreas.
Then also as you mentioned, other areas that can come to the emergency department include at least our eye casualty will often see our orbital cases or sometimes our sort pachymeningitis cases that will come through, rather than coming to me directly, may go to our neurologist, but can sometimes present through the front door. I think you’re right; a combination of primary care and specialist services, but also the emergency departments, at least with the pancreaticobiliary side, is often overlooked.
John Stone, MD, MPH:
It’s really important to emphasize that this disease is typically very slow moving, and that’s one of the real challenges in diagnosis because it doesn’t really upset anybody’s day for a long time until the disease has been puttering along for… Again, for months or even years and they become jaundiced or their kidneys are found not to be working. It’s that indolent nature that is a real challenge. It is a disease that’s often a multi-organ disease and it really challenges and will continue to challenge our diagnostic abilities, I think, for a long time. Once the diagnosis has been, what is your typical approach now, Emma?
Emma Culver, BSc, MBChB, DPhil, FRCP:
Yeah, it’s a very good question, isn’t it? I guess we have some consensus treatment statements that really date back to 2015, and actually, at least in the world of pancreaticobiliary physicians, we’re still going with our induction and maintenance of remission starting with corticosteroids. We know that systemic steroids have been around since the 1970s, and they’re actually very good in terms of the speed at which they induce, I guess, control of activity of disease in which they will help to shrink a mass, and/or with patients who have acute symptoms like their jaundice actually can start to improve liver function tests and help to take away the jaundice, even though in cases of pancreaticobiliary disease, we sometimes also need to put a small tube or a stent in the actual biliary tree in order to be able to relieve symptoms in the shorter term and prevent infection.
But we still have an approach, at least here, whereby corticosteroids at reasonably high doses, and I know that really varies in different parts of Europe and the US and in the UK, but we tend to use doses in the 30 to 40 mg category in order to be able to induce remission, with a gradual tapering over time, and then a decision with regards to the best possible medical therapy. Can you comment, John, with regards to your approach at the moment? Because obviously we know that steroids have some significant side effects.
John Stone, MD, MPH:
Yes. Steroids continue to be the cornerstone of therapy, really throughout the world. They are readily available, they work very quickly, they work so well in fact that one of the exclusion criteria for the diagnosis is failure to respond to an adequate dose of prednisone or prednisolone. I have never seen a patient with IgG4-related disease who didn’t respond to 40 mg of prednisone a day; at least if they have active inflammatory disease. If they have overwhelming fibrotic disease, then the response may not be that clear. But if they’re a patient with active multi-organ disease, very high serum IgG4 concentrations, they will certainly respond to 40 mg a day.
We often start with that, but it has become clear through the years that there are certain patient characteristics that make them not likely to be able to achieve a remission with a reasonable side effect profile of being treated with steroid monotherapy. You’re acutely aware that this disease targets the pancreas and therefore predisposes patients to glucose intolerance, as does glucocorticoid therapy. We also have learned about the disease, the epidemiology. It tends to affect middle-aged to elderly individuals, men more than women, and so many of the patients have a number of other comorbidities at the time they’re diagnosed, making steroid therapy not a great option for long-term.
In addition, if they have multi-organ disease at diagnosis, then they’re going to require treatment for a long time with just steroids in order to keep the disease under control, and that’s going to lead to a host of problems. In those patients, I certainly look to use a steroid sparing medication from the very beginning. We are on the verge of hopefully having the first drug approval for this disease. We’ve recognized that B-cell depletion is an effective strategy for about 15 years now, but only recently have completed the MITIGATE trial, which is a trial of an anti-CD-19 monoclonal antibody called inebilizumab.
The top-line results of the MITIGATE trial were released in June. The full results will not be presented for another few weeks. But suffice it to say that inebilizumab as a B-cell depletion strategy works very well in terms of helping patients achieve sustained remissions by one year and to be able to not require treatment with other medications, particularly steroids. I hope that inebilizumab will be the first drug approved by regulatory agencies across the world beginning in 2025, but until then, there are some other options as well. In gastroenterology, you’ve got a long history of using other things too, as steroid sparing agents. Maybe you could comment on azathioprine and mycophenolate mofetil briefly?
Emma Culver, BSc, MBChB, DPhil, FRCP:
Yeah, thanks John. I think it’s really exciting news about the potential of a newly approved therapy, and you are completely right; in gastroenterology and hepatology for some time, we have used other what we would call disease-modifying agents or immunosuppressive agents in order to reduce steroid toxicity. That’s because again, those pancreaticobiliary patients particularly suffer with the diabetes that we know that is prevalent in about 50% of patients at diagnosis and you get significant hyperglycemia when starting on corticosteroids. There is probably about a 30% risk of infection, particularly again in those patients who are diabetic, and we know that there are other metabolic complications that can also ensue.
We tend to use a combination or a strategy, depending on the patient in front of us. Mycophenolate is probably at the moment our preferred steroid sparing agent, and we usually give mycophenolate at a good dose, at a gram twice a day, in order to try and reduce the risk of relapse and also allow for steroid tapering and reduction. That’s because in single-center, small, randomized, controlled trials, it seems to have a reduction overall and relapse, even though it was paired with steroid in that particular study. Similarly, we have used things like azathioprine and/or mercaptopurine for many years in the treatment of autoimmune hepatitis, and also in our post-transplant patients and in other inflammatory bowel disease.
With lots of experience of that, we tend to use azathioprine also as a steroid-sparing agent at higher doses than we do in other liver diseases, so closer to 2 mg/kg, but again, with the same rationale of being able to taper off and discontinue steroids. There are a number of other drugs that are not proved for use in this condition but have been used, including things like methotrexate and also cyclophosphamide, and as you mentioned, rituximab.
It’s a little bit of a case of trying to reduce the actual toxicity and the complications that ensue from corticosteroids and trying to maintain steroid-free disease remission, because that’s really important. I guess then we talk a little bit and think about what really disease remission is for us and what we’re trying to achieve overall with regards to that. Because we know that there are other impacts as well, don’t we, with regards to this disease? It’s not just about disease activity, and I think there’s been some lovely work, if I understand from your group, really looking at the impact of the disease on other aspects for the patients. Can you comment on that?
John Stone, MD, MPH:
Yes, that is absolutely right. The disease can affect so many organ systems, and not the least important is the mind, the central nervous system or the brain. It really is the mind that is affected. It’s understandable because the patient journey is really very difficult in this condition. They go from doctor to doctor to doctor without getting a diagnosis, becoming more and more confused about what’s going wrong with them, if something is really going wrong with them.
A great percentage of our patients are told that they have cancer first. Many of them, when they finally hear the word IgG4-related disease, they’re stunned and there is a lot of anxiety and frankly mistrust of the medical profession by that point. This is really a great need of the patient population and something important for providers to remember. I can’t think of another disease where I have appreciated this more keenly than an IgG4-related disease, and that’s of the mental health challenges that patients with this condition have developed.
Another challenge with regard to managing patients, and the mental health issues often require longitudinal management, but hopefully they’ll get better as things go along, is understanding how to maintain disease remission. Steroids are not a great option for that. One of the things, a couple of the things we didn’t really touch on that much is how brittle the diabetes in these patients can be, and the bone health challenges these patients have on steroids. Steroids are not a great drug for maintaining remission, but it’s also challenging to know what drug is truly effective in maintaining remission.
There haven’t been terrific, grade A evidence studies of the classic “steroid-sparing medications” such as mycophenolate mofetil and azathioprine. Then if we’re using B-cell depletion, it’s problematic very often to know when to re-treat patients. We’d like to re-treat them the week or the day before they have a clinical flare, but that’s sometimes hard to predict. What’s your approach, I wonder, Emma to knowing when to retreat patients or maintain remission?
Emma Culver, BSc, MBChB, DPhil, FRCP:
Yeah, I think it’s a little bit like the whole diagnostic challenge; the real question about what is true disease remission and what is importantly steroid-free remission. I use a combination of clinical symptoms and signs, the IgG4 level itself, which in those patients whereby it’s elevated and then falls on treatment can actually be a fantastic biomarker for looking at evidence of resurgence of disease, but not on its own, and I think you have to use that caveat that we do know that some patients will have a high IgG4 and no obvious disease activity. I often pair that with imaging to ascertain whether or not, at least if it’s an internal organ, there is evidence of disease activity. Much easier, obviously, if there is a head and neck organ whereby you can see evidence of an enlarged gland itself.
I think a combination of the three is very helpful, but I guess what we want to do is catch it at the earliest possible opportunity before it has the chance of causing damage. Just like you highlighted within the pancreas, you can get quite significant damage to the pancreas and also the biliary system, but the same is the case for the retroperitoneum aorta and the same is also the case, for example, for the kidneys. Actually, we don’t want to catch the disease too late. I think we have to be mindful of the fact that we want to catch it before there is further damage that occurs. Do you use a similar kind of theme with regards to trying to look for remission or do you have any pointers and tips?
John Stone, MD, MPH:
The one tip that I have found useful is that although some patients don’t have an elevated serum IgG4 concentration at baseline before they’re treated, the majority do. If patients have a really elevated serum IgG4 concentration, it is likely going to be a good biomarker for disease activity. I am guided more by the direction in which the serum IgG4 concentration is moving… Is it going down? Is it going up? Is it remaining stable?… than I am by the absolute value. I’m not bothered too much if it’s still elevated above the upper limit of normal for the lab. But if it is rising and if it’s rising clearly and consistently and fast, then that tells me the disease is active somewhere, even if I haven’t been clever enough to figure out exactly where it is.
If it is declining or stable, then chances are the patient’s disease is under control. They still need to be followed and probably need to have their labs checked every 3 or 4 months, but we all often complain about not having good biomarkers in the inflammatory diseases. Generally that’s true, but for many patients with IgG4-related disease, IgG4 is actually very good. I guess as we close up Emma, I would ask you what you see as a big unmet need in this condition now?
Emma Culver, BSc, MBChB, DPhil, FRCP:
Yeah, and I think that’s a really, again, another good question. I personally think that the patients actually have one of the biggest unmet needs. You’ve obviously highlighted the importance of their mental health, the fear and anxiety associated with the condition, but I think we have to work really hard at making sure that we have appropriate education for our patients, for the physicians that actually treat our patients, and for an ability to be able to spread the information and the word with regards to the condition, its disease mimics, its diagnostic challenges, but also as you’ve nicely highlighted, that there will be new approved therapy that hopefully will allow for steroid sparing. I think that all the patients that we have a responsibility in order to advocate for them and to do that. I think that’s probably in my mind, one of the biggest unmet needs, and also getting that approval through for that new therapy and being able to use it. How about you, John? What do you think is a big unmet need that we haven’t covered?
John Stone, MD, MPH:
I couldn’t agree with you more. Assuming we have an approved therapy soon, that I think the biggest challenge in the field; ultimately, we hope there’ll be even better therapies in the future, but the biggest challenge in the field really will be education. In that context, it needs to be education of patients as well as other providers. In that context, Emma, it is great working with you in the context of the IgG4ward! Foundation, a patient advocacy group that was founded less than a year ago, coming up on the first anniversary of that, and it’s been my pleasure to be the executive chairman and to work with you in your role on the advisory board for the foundation. I think we’ve made great progress so far and look forward to what’s ahead.
Emma Culver, BSc, MBChB, DPhil, FRCP:
Yeah, thank you, John. I think as you’ve said, you have made leaps and bounds with regards to supporting the patients and advocating for the patients, and actually also obviously hosting the IgG4ward Jam that will happen very soon in Virginia, which I think is again, another really important event for patients entirely, trying to spread the word and the importance of… In the education of this disease. Thank you.
John Stone, MD, MPH:
Thank you, Emma. It’s always great to see you and to work with you, and I’m really very excited about the progress we’re making and the steps we’re going to make in the near future.
