IgG4-related disease: presentation, multidisciplinary care, making the diagnosis
Rare Disease 360 brought together 4 clinicians from Massachusetts General Hospital’s IgG4-Related Systemic Disease Program to talk about the current state of care. In part 1 of the video series, they discuss the typical presentation of IgG4-related disease that they have personally experienced, as well as tips for making the correct diagnosis.
John Stone, MD, MPH:
Welcome to our discussion about IgG4-related disease. What an exciting time it is for IgG4-related disease. I’m Dr. John Stone, I’m a professor of medicine at Harvard Medical School, and a rheumatologist at the Massachusetts General Hospital (MGH), and the executive chairman of the IgG4ward! Foundation. I’m joined today by 3 wonderful colleagues from MGH, and before we start our discussion, I’ll let them introduce themselves in turn. Yasmin, would you like to start?
Yasmin G. Hernandez-Barco, MD:
Sure, thank you so much. My name’s Yasmin Hernandez-Barco. I’m a gastroenterologist and a medical pancreatologist at Mass General. I also direct the MGH Pancreas Program, and it’s an honor to work with all the people on this call.
John Stone, MD, MPH:
Thanks, Yasmin. How about you, Cory?
Cory Perugino, DO:
Yeah, thanks John. It’s good to see you all. Cory Perugino, a rheumatologist at Mass General Hospital, with a big interest and expertise in IgG4-related disease. A lot of this is through studying the immunology of the disease in the lab setting. I’ve enjoyed evaluating patients alongside John over the years, and establishing the IgG4ward! Foundation with him over the last year. I’m looking forward to discussing today.
John Stone, MD, MPH:
How about you, Guy?
Guy Katz, MD:
My name is Guy Katz, I’m also a rheumatologist at Massachusetts General Hospital. Also have a strong interest in IgG4-related disease. I do clinical epidemiology and some translational research in the disease, and I’m involved in clinical trials in IgG4-related disease. I’m very much looking forward to the discussion.
John Stone, MD, MPH:
For the discussion, we wanted to tackle 3 broad areas. First, how does the disease present? We might break this down along the lines of, how do patients present to a rheumatologist as opposed to what a pancreatologist is likely to see? Then we want to talk about treatment, the currently available treatment options, including an exciting phase 3 trial that was recently completed and published. Then we wanted to conclude with a discussion about determinants of patient’s long-term prognosis.
Why don’t we start with you, Cory. What are the features of a typical patient, if there is such a thing, that a rheumatologist is likely to see?
Cory Perugino, DO:
Yeah, it’s a difficult disease to quickly encapsulate and summarize I would say, because of the pleiotropic nature of the disease and the diverse organs that can be affected. I commonly think about certain head and neck features, like the classic Mikulicz phenotype with lacrimal and salivary gland involvement that tend to be symmetric and bilateral, as being one very stereotypical manifestation of the disease. These don’t live in discreetly separate buckets per se, but there’s some enrichment for these organs occurring together. This tends to be a painless enlargement of organ type of process and that’s very slow, slowly developing rather than something you may think about with a salivary stone that’s abrupt and painful and self-limited, it’s kind of the opposite of that.
A second bucket I think about is the pancreaticobiliary disease that Yasmin will educate us on more detail about. This has some diverse manifestations on its own, but the pancreas and the bile ducts often are linked when they’re involved in the disease, presenting with autoimmune pancreatitis that comes in a few flavors. Then I often think about retroperitoneal fibrosis as being a third major bucket of manifestation and this can all occur together, these can occur in isolation.
Then there’s a plethora of many other features of the disease, but I think overall relative to all other autoimmune or rheumatologic diseases, I think mostly with IgG4-related disease, I’ve been struck by the relative symptom burden on patients, which is significant and tremendous and still being quantified by us as investigators, but is very different than a lot of other autoimmune diseases that we see. I would often think of this in terms of, how often am I meeting patients that were diagnosed and identified through incidental findings on imaging? It’s a fairly common feature of this disease that we just don’t see that with a lot. You don’t see patients with vasculitis that are incidentally identified, for instance.
John Stone, MD, MPH:
That’s a really good point. I’m often struck by how patients can have multi-organ disease and not really realize that they’re sick. They might have lost 40 pounds, they might have decreased energy, but they might have very little, in terms of symptomatology, yet the disease is raging all the time and damaging organs, sometimes quite irreversibly.
The other thing that I would add to what you said in terms of things that rheumatologist is likely to see, is we’re very often referred patients with orbital disease. Maybe you mentioned that, but orbital disease typically caused by involvement, enlargement of the extraocular muscles and proptosis. I think for some rheumatologists who really specialize in this condition, that is a big part of what they see and it gets back to their referral base.
Cory Perugino, DO:
Yes, absolutely.
John Stone, MD, MPH:
Yasmin, I will toss it over to you then to talk about what a gastroenterologist/pancreatologist is most likely to see, and then give Guy the hardest part by asking him to tie up all the rest. Be prepared, Guy. Yasmin, what is your typical patient like?
Yasmin G. Hernandez-Barco, MD:
I think as a gastroenterologist we typically see patients that have pancreatic and biliary involvement. For most GIs, we don’t always refer to it as IgG4-related disease, but rather autoimmune pancreatitis, type 1 autoimmune pancreatitis and…
John Stone, MD, MPH:
Is that because you’re overlooking all the other organs that the rheumatologists detect?
Yasmin G. Hernandez-Barco, MD:
I don’t because I learned from all of you, but I do think that’s actually an important point that I was going to share towards the end, and perhaps I can just mention it now. That even though we typically think of it as autoimmune pancreatitis with pancreatic or biliary involvement, it is a systemic disease and I think it’s important to look elsewhere because even if patients are presenting primarily with symptoms or signs in one organ, others can be involved and that definitely impacts the type of treatment that you’re going to use for different patients.
When we see patients present, we typically see 2 major features in the pancreas, what I refer to as mass-forming pancreatitis and then diffuse pancreatitis. Mass-forming for us, when a patient comes to us, it really looks like a mass or a tumor, and nobody thinks about anything else until we feel very confident that it’s not pancreatic cancer. These are patients that we’ll usually refer for an endoscopic ultrasound with fine needle biopsy, and it’s important that it’s a core biopsy because you want to look at the tissue. The purpose of that biopsy is usually to exclude a pancreatic cancer, but if you use a core needle, you can actually make the diagnosis of autoimmune pancreatitis if you have a great pathologist that’s thinking about it.
As it relates to the bile ducts, the bile ducts we think of involvement either a distal bile duct involvement, which can be just from inflammation related to the pancreatic disease, or the bile duct itself is also inflamed. Oftentimes, when patients present, depending on where in the country you may be seen, this is usually an indication for a pancreatic stent, but if you can make that diagnosis early, you can sometimes just treat patients with steroids or immunomodulators and actually you’ll see that inflammation improve and so that structure will actually improve.
With diffuse involvement of the pancreas, the differential for that is really any other form of pancreatitis, which can in and of itself be very challenging. But again, to emphasize the multidisciplinary approach, if you have a really wonderful radiologist, there are some key features that you can see on imaging that can point to the diagnosis of autoimmune pancreatitis or IgG4-related disease with pancreatic involvement.
John Stone, MD, MPH:
I know you’re not overlooking the disease in other organs, Yasmin. The radiology is a really interesting point. When we developed the classification criteria, we describe really the classic features of raging active disease. In fact, in practice what we see is sometimes different. If the disease has raged through the pancreas like a forest fire, you’re not going to see a sausage shaped pancreas, it’s going to be quite different. What do you see in those circumstances?
Yasmin G. Hernandez-Barco, MD:
I also see a subset of patients that have essentially been going from doctor to doctor without a diagnosis, just as you mentioned, 40, 50 pounds of weight loss worried about cancer, and by the time that I see them, you actually see diffuse pancreatic atrophy. Many of these patients will have already had some end organ damage, usually in the form of diabetes or exocrine pancreatic insufficiency, where the pancreas is just not making sufficient enzymes for a patient’s nutritional needs, and it can lead to complications like metabolic bone disease and micronutrient deficiency. We do sometimes just see patients with atrophy on imaging, but they still may have IgG4-related disease.
Cory Perugino, DO:
Yeah, just 1 thought or even a question for Yasmin, or a question for our group is, even today in clinic, I saw 2 patients in the same scenario where autoimmune pancreatitis, it’s biopsy, confirm the diagnosis, it’s a concrete diagnosis. Treated with prednisone, disease goes into remission, and then we monitor them, and the IgG4 level just rises. Then they’re monitored with IgG4 levels maybe in the 500s or 600s. The development of exocrine pancreatic insufficiency, is this something that occurs? We used to learn about multiple sclerosis with a flare, patient’s not recovering to their baseline function. This kind of discrete episode and going down and that recovering event.
But I wonder with IgG4-related disease, if there’s a smoldering inflammation in the pancreas that maybe we don’t see a mass or diffuse enlargement and a halo sign around the pancreas and all the classic radiographic features. If we were to get a biopsy in these seeming quiescent interval phases, is there an ongoing cellular infiltrate in the pancreas that’s slowly resulting in the loss of islet cells and the loss of exocrine function? What are your thoughts on that? Do you think it’s like a smoldering low level or superimposed these events that lead to the damage or both?
Yasmin G. Hernandez-Barco, MD:
It could be both, and I think about this in other forms of pancreatic disease. We usually think about pancreatic exocrine function as having a tipping point. As long as you have, and these were very old studies that were done, but 10% of your pancreas functioning, you won’t develop exocrine pancreatic insufficiency or at least signs of this. But if you think about it in patients that have, for example, hereditary pancreatitis or pancreatitis from genetic causes, cystic fibrosis, transmembrane receptor mutation, for example, they may actually have some low-level inflammation all the time, and they do go on to develop exocrine pancreatic insufficiency.
When we think of other forms of pancreatitis, what I will always counsel patients is, we want to know what caused it because we want to prevent it from happening again. Because recurrent acute episodes, which is sort of believe it or not, the smoldering potential ep that you’re describing, low-level inflammation or multiple pancreatitis episodes, can lead to rapid progression of this end organ dysfunction or a very severe episode, such as necrotizing pancreatitis. Again, these are not the more classic presentations in IgG4, but any kind of pancreatic damage, low-level inflammation will probably accelerate the development of these complications.
John Stone, MD, MPH:
That’s an interesting way to think about it as a tipping point and helping patients avoid getting to that tipping point. Suppressing disease, not letting it, doing our best to make sure that it’s not smoldering so they don’t reach the tipping point.
Guy, you have the hardest part that’s summarizing all the other presentations. It’s impossible to summarize them all, but what are some of the other major presentations that stick in your mind? Then we’ll move on to treatment. You can start that one too, but I’ll prompt you.
Guy Katz, MD:
That sounds good. Yeah, in an effort to keep this under 3 hours, I’ll just focus on some of the most salient manifestations, because IgG4-related disease can really affect almost any part of the body. But I’ll kind of go from head down, and I’ll start with hypertrophic pachymeningitis, which is uncommon but certainly something that we see. Very often can be asymptomatic or can present with headaches, with cranial nerve abnormalities, and very often is associated also with inflammation of the pituitary. Hypophysitis, which is another uncommon but very important manifestation because when it happens, the likelihood of developing irreversible damage to the pituitary is actually quite high.
Other manifestations that we see in the head and neck, we see sinusitis that can look very similar to the sinusitis that we see in granulomatosis with polyangiitis. Moving down, the large airways are frequently involved, very often you can see bronchial wall thickening, which often associates with symptoms of asthma. Other tracheobronchitis can occur, other forms of lung disease can occur primarily ground glass opacities throughout the lungs. Fortunately, more fibrotic interstitial lung disease is quite rare in the disease. Also in the neck, the thyroid, what thought to be a distinct entity called Riedel’s thyroiditis is now known to be a manifestation of IgG4-related disease. It can happen on its own or can happen in association with other areas of involvement.
Moving down into the chest and abdomen, tubulointerstitial nephritis is the most common manifestation that we see in the kidneys, and this tends to be a very smoldering, kind of slow-growing inflammation in the kidneys. It’s not very common that we see situations similar to what we see in vasculitis where patients will go from having normal renal function to requiring dialysis over the span of weeks. This is usually something that develops very slowly. On imaging, you can see these cortical hypodensities that are very characteristic of tubulointerstitial nephritis.
Other forms of renal disease can happen as well. Inflammation of the renal pelvis can occur. Rarely, membranous nephropathy can occur. I had also mentioned that IgG4-related disease is a variable vessel vasculitis. Far and away, the most common type of vasculitis that we see is large vessel vasculitis, the aorta, the iliacs, and other major branches. But we also see medium vessel vasculitis, particularly in the coronary artery, this is something that we see and can be quite profound. The vasculitis in IgG4-related disease is a little bit unusual compared to many other types of vasculitis, in that it has a really profound tendency to lead to aneurysms. In these patients with coronary arteritis or peri-arteritis, many of these patients have massive aneurysms, to the point where if you look on imaging and cross-section, the aneurysms almost look like a third atrium.
There are various other manifestations that we could go into. I’ll mention fibrosing mediastinitis, sclerosing mesenteritis, these are very rare but certainly things that we see. Paravertebral mass is something that we can see, which tends to be asymptomatic but is quite suggestive of the diagnosis.
Then the last 1 that I’ll mention is involvement of the prostate, which most patients who have this don’t realize that it’s a part of their disease. But in reality, many men who have the disease will have lower urinary tract symptoms that are quite significant and they’re usually seeing a urologist for this. Many of them have had prostate biopsies or even prostate resections for presumptive prostate cancer for these manifestations. But then when you treat them with prednisone, the lower urinary tract symptoms melt away. That’s something that can be quite profound. Even though it’s not something that we talk about frequently in the disease, it’s one of the manifestations that actually makes a big difference to the patient’s quality of life.
John Stone, MD, MPH:
Agree completely. I think we miss a lot of prostate disease unless we ask patients about whether their BPH symptoms improved after their autoimmune pancreatitis started to be treated.
We spent a lot of time on how the disease presents, and that is appropriate because our failure to diagnose the disease early enough and our lack of familiarity still across the medical community with this disease leads to enormous delays in diagnosis. That is really a big part of our battle in educating both people living with IgG4-related disease and physicians and other healthcare providers. We really have to be able to pick this diagnosis up earlier.
