Diagnosing and managing IgG4-related disease (IgG4-RD) requires a systematic and multidisciplinary approach to patient care. Learn how patients with IgG4-RD generally present across practice settings, the importance of ruling out key mimicking diseases and assessing multiorgan involvement, as well as evidence-based treatment strategies to prevent relapse and irreversible organ damage.
The key to effective IgG4-related disease (IgG4-RD) management is early recognition, accurate diagnosis, and timely treatment to prevent irreversible organ damage. Listen in to learn from expert faculty about recognizing common disease manifestations, distinguishing IgG4-RD from key mimicking conditions, assessing multiorgan involvement, and applying evidence-based treatment strategies to reduce relapse risk and improve patient outcomes.
Presenters
Yasmin G. Hernandez-Barco, MD
MGB Director of the Center for Pancreatic Disease
AMC Division of Gastroenterology, Hepatology, and Endoscopy
Outpatient Director, Complicated Pancreatitis Treatment Center
Assistant Professor of Medicine
Harvard Medical School
Boston, Massachusetts
Guy Katz, MD, MS
Associate Physician, Division of Rheumatology, Inflammation, Immunity
Mass General Brigham
Instructor, Harvard Medical School
Boston, Massachusetts
Arezou Khosroshahi, MD
Professor of Medicine
Director of Clinical Trials
Rheumatology Division
Emory University School of Medicine
Atlanta, Georgia
Jai Radhakrishnan, MD, MS
Professor of Medicine
Clinical Director, Nephrology
Columbia University Vagelos College of Physicians and Surgeons
New York, New York
Chuck Vega, MD, FAAFP
Health Sciences Clinical Professor
UC Irvine Department of Family Medicine
Director, UCI Program in Medical Education for the Latino Community
Assistant Dean for Culture and Community Education
UC Irvine School of Medicine
Irvine, California
Link to full program:
https://bit.ly/4k6oQOe
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This transcript was automatically generated from the audio recording and may contain inaccuracies, including errors or typographical mistakes.
Dr. Arezou Khosroshahi (Emory University): Before we get to our discussions, I just wanted to go over the results of a presurvey that Decera Clinical Education had done among clinicians. I looked at the demographics of the clinicians who participated in the survey, and the majority were rheumatologists, gastroenterologists, primary care, internal medicine doctors, nephrologists, other subspecialties; most of them physicians, some APPs who participated in this survey.
IgG4‑RD: Diagnostic Confidence and Recognition
The questions were around diagnostic treatment, and monitoring of IgG4‑RD. About 56% of the learners reported that they were only somewhat to moderate confident in recognizing IgG4‑RD features; about 67% said multi‑organ involvement was the most recognized feature raising suspicion or bringing the diagnosis in the radar, and recognition gaps remain around distinguishing IgG4‑RD from malignancy and other mimickers, and that was the most challenging part for majority of the clinicians.
IgG4‑RD: Diagnostic challenges
The other questions of the survey were, as I mentioned, around the diagnostic challenges: about 56% had challenges differentiating IgG4‑RD from malignancy, 45% coordinating diagnostic evaluation across specialties, 45% recognizing multisystem disease, and 67% current diagnostic approaches varied, and this suggests need for more standardized, evidence‑based evaluation pathway.
The challenge is not only recognizing IgG4‑RD, but mostly making sure that we are excluding all the mimickers. That is something that we will be discussing today.
IgG4‑RD: Multidisciplinary Collaboration and Evaluation.
There were some questions around the multidisciplinary collaboration and evaluation of patients with IgG4‑related disease, and learners reported collaborating with rheumatology, gastroenterology, and radiology the most. After that, pathology was the most frequently collaboration subspecialty.
There were lower recorded collaborations with nephrology, pulmonary and ophthalmology, but definitely mentioned.
No mention of sending patients with IgG4‑RD to allergy immunology in this group. This actually highlights opportunities to improve multidisciplinary care when people are seeing patients with IgG4‑RD, and that could support definitely the need for earlier specialty coordination.
We know IgG4‑RD crosses organ systems. It is a multisystemic disease, so an effective diagnosis usually requires care across the subspecialty, and sending patients to different specialty groups.
IgG4‑RD: Treatment and Long‑Term Management Gaps
Questions around treatment and long‑term maintenance gap also had interesting results. About 44% mentioned glucocorticoid toxicity and 33% mentioned disease severity influenced their decision to initiate steroid‑sparing therapy most often.
Learners varied in their use of biologics and steroid‑sparing treatment approaches, and usually had challenges in long‑term management that included tapering therapy, how to monitor the response to their treatments, and how to identify patients who are at risk and require maintenance treatment to prevent relapse.
Usually, monitoring included imaging in 56%. Some learners reported they monitor serum IgG4 in 56% of cases and clinical symptoms. Uncertainty extends beyond treatment selection, so even if you choose what treatment you want to do for patients with IgG4‑RD, people do not know how to taper them, how to monitor for response or relapse, and how to keep the disease under control long term.
Identifying and Addressing Unmet Needs in IgG4‑RD Diagnosis and Long‑Term Management
Now that we know the unmet needs, at least based on this survey, what people need to know more about IgG4‑RD, it is time to start discussing it.
Overview of IgG4‑RD
So a little bit of overview of IgG4‑RD. The way that we define it is IgG4‑related disease is a systemic, immune‑mediated fibroinflammatory condition that can progress if it is not treated.
It is usually characterized by a tumor‑ or mass‑like organ enlargement. Most of the symptoms that these patients have are related to the pressure of that mass or infiltration of the tissue to the adjacent organ, or dysfunction of the organ due to the infiltration. What is that infiltrate? It usually includes a dense lymphoplasmacytic infiltrate very rich in IgG4 plasma cells. There is a component of fibrosis that happens that has a typical pattern; we call it storiform fibrosis, but it does not happen in all patients. There are different phases, so the first inflammatory phase, you may have more lymphoplasmacytic infiltrate, and longer the disease goes on you may have more storiform fibrosis.
In some cases, in the pathology, you will see obliterative phlebitis, which is a vein that has been occluded with the inflammatory infiltrate. Also, you may have eosinophils in the tissue. Regardless of which organ you take the biopsy, these are the features that you should see. This has the analogy with other systemic diseases, for example, sarcoidosis. When you do a biopsy of sarcoidosis, no matter if it is a lymph node, it is a nervous system, or a part of the lung, you see the same histology. It is the same for IgG4‑related disease.
The true epidemiology of the disease is unknown, and the reason is we did not know about IgG4‑RD 20‑25 years ago. Really, the point of systemic IgG4‑RD as a disease was coined in 20, 2003, and then 2006. The name was given to the disease in 2011, and an ICD code was assigned to this disease in 2024. Prior to that, getting the real estimation of the prevalence of the disease was very difficult.
What we know from the cohorts of the patients that around the world we have collected is it is more common in middle age and elderly. The most common age is between 50 to 70. It is more predominant in men, and there are certain features of the disease that have more presentation in women, for example, head and neck‑limited disease. no other organ involvement is more common in females.
I am going to hand it over to Guy.
Clinical Manifestations of IgG4‑RD
Dr. Katz: Thanks, Arezou. To follow up on what Arezou was saying, I think it would be helpful to talk about what are the clinical manifestations of the disease, really focusing on how multisystem it is, and then talk a little bit about the classification criteria and how we can use that to help with the diagnostic process.
I will say that this is not exhaustive; there are definitely organs that can be affected. For example, the coronary arteries and the prostate that are involved relatively commonly, but this is a great representation of how multisystem this disease really is and that there is a lot of differences between different patients. You will notice that some of the organs are relatively common; some of them are infrequent. They can all happen together, or patients can have just one or two organs. There are certain patterns of organs that tend to be associated with each other, but no patient reads the textbooks, and we have all seen patients that have unusual combinations of organs involved.
I think this is one of the biggest challenges in getting to the diagnosis is that It is very rare to have skin involvement in IgG4‑related disease. Similarly, We do not see inflammatory arthritis as a feature of IgG4‑related disease, which makes it challenging because, even though this is a disease that we typically think of as rheumatologists will manage it because it is a systemic autoimmune disease, it does not present with joint pain and rash like many of the other autoimmune diseases that often get sent over to rheumatology.
I think it is an added challenge for clinicians in all specialties to be able to recognize that these are manifestations that pop up in different organs, whether it is the eye or the structures around the eye, the meninges, the thyroid, the lungs, the aorta. These are all very unrelated organs to each other, and it is the clinician who detects that, who is responsible to recognize that that is a potential manifestation of IgG4‑related disease. I say clinician, but I am also including radiologists and pathologists who are really essential in being able to recognize this because a pathologist who is reviewing a salivary gland biopsy should know that a submandibular gland that is being inflamed, IgG4‑related disease is on the differential and looking for the typical features of that disease.
Clinical Heterogeneity Creates Diagnostic Challenges in IgG4‑RD
As I was just mentioning, the clinical heterogeneity of this disease is part of what makes it difficult to come to a diagnosis. There is a wide differential diagnosis for just about every manifestation that we see in IgG4‑related disease. If we think about the pancreas and biliary system, when we see the combination of pancreatic disease and biliary disease, IgG4‑related disease is highest on our differential. However, we also see cases of type 2 autoimmune pancreatitis, which is not IgG4‑related disease and can be associated with primary sclerosing cholangitis, so even that very specific finding that we think of as highly specific for IgG4‑related disease can in some cases be seen in other diseases.
We talked about the salivary and lacrimal glands having a wide differential diagnosis, including Sjögren's disease and sarcoidosis; metabolic sialosis is another element of that differential diagnosis. The lung disease that we see in IgG4‑related disease overlaps in clinical presentation with the lung disease of probably 150 or 200 other conditions and even retroperitoneal fibrosis, which we think of as really specific to IgG4‑related disease. There are some patients that have idiopathic retroperitoneal fibrosis. There are patients that have retroperitoneal fibrosis that is due to Erdheim‑Chester disease or even cancers, and these can look very, very similar to the RPF that we see in IgG4‑related disease. Of course, with lymph node involvement, the list of organs that can lead to lymphadenopathy is a mile long.
It is a challenge for the clinician to be able to take all of the different manifestations that they find, and the more manifestations that suggest IgG4‑related disease, the higher the likelihood of the disease is. That is why getting imaging to look for other organs involved, including organs that might be completely asymptomatic, is a really important part of the diagnostic process. At the same time, when there is no very clear diagnosis based on imaging, labs, and symptoms, a biopsy is very important in being able to come to the right diagnosis, and even more importantly, to rule out mimicking conditions.
I think we talked about the utility and the pitfalls related to serum IgG4 concentration and how it is really not a diagnostic test. Unfortunately, we do not have a diagnostic test for this disease. We do not have a test that is positive in just about everyone with the disease and negative in just about everyone without the disease. It really is a clinical‑pathologic diagnosis that requires the clinician to incorporate all of the data ranging from pathology to symptoms and imaging, and ultimately it is the clinician, not anyone else, who will need to make the diagnosis.
ACR/EULAR criteria for IgG4‑RD
I think particularly for clinicians who do not see this on a daily basis, the ACR/EULAR classification criteria are a really helpful framework for how to think about the diagnosis. Before talking about the classification criteria in more detail, I have to make a really important disclaimer, which is that they are classification criteria and not diagnostic criteria. That is for a very important reason; we do not have any way that we can say with certainty, based on certain clinical features, that someone has IgG4‑related disease. That is because we do not know what causes it. We do not have a perfect diagnostic test. It is really a clinical syndrome that we have described.
The classification criteria were designed to be able to identify a homogeneous group of patients that have the disease with near certainty, so that when we study them in clinical trials and observational research, we know that we are studying the right disease. What that means is that the classification criteria were, by design, made to prioritize specificity at the cost of sensitivity. There are many patients who have IgG4‑related disease, including in our cohort, and, Arezou, I am sure, in your cohort as well; there are many patients who have IgG4‑related disease, and we are confident that they have it, but they do not fulfil classification criteria.
It is important to recognize that while the classification criteria are a really helpful way to think about how to make the diagnosis, they should not be used as a diagnostic test. They should not be used to say definitively this patient does or does not have the disease.
With that disclaimer aside, let us talk about the classification criteria themselves. They require four steps. The first is to recognize typical organ involvement, and that is either through clinical manifestations or through a biopsy that shows the typical histopathologic findings of IgG4‑related disease that are as reviewed earlier in one of the typical sites.
The next and probably the most important part of the classification criteria are the exclusion criteria. Regardless of how much evidence there is to support a diagnosis of IgG4‑related disease, if someone has features that are really strongly suggestive of alternative diagnoses, things that we do not see in IgG4‑related disease, then it almost does not matter how strong the evidence is. Otherwise, they are very likely to have that other diagnosis, and important examples of that are things like fever, which we really do not see in IgG4‑related disease unless there is an infection that is a consequence of the disease.
Certain serologies like a positive ANCA, particularly a PR3 or an MPO, would be strong evidence against the diagnosis of IgG4‑related disease. Granulomas on a biopsy or necrotizing vasculitis. Those are things that we really do not see in IgG4‑related disease.
For the clinician that does not have day‑to‑day experience with IgG4‑related disease, looking at the exclusion criteria is probably the most important part of making the diagnosis correctly of IgG4‑related disease, because if elements of the exclusion criteria are present, then it should really send the clinician down the road of trying to look for those other diagnoses.
After excluding the exclusion criteria, the next step in the classification criteria is inclusion criteria, which includes weighted domains that include how high the serum IgG4 concentration is, whether there is dense lymphoplasmacytic infiltrate on biopsy, storiform fibrosis, obliterative phlebitis, and how high the IgG4 staining is, so there is different amounts of points that are given for all of those features.
Then there is a list of clinical features ranging from head and neck disease to kidney disease to pulmonary disease and retroperitoneal fibrosis and pancreatobiliary disease; there are different point values assigned to those different clinical manifestations.
To fulfil classification criteria, a patient has to meet the entry criteria, not have any exclusion criteria, and then have at least 20 points from the inclusion criteria, but again, I would just emphasize that that is not how we should be using them. Clinically, patients can have IgG4‑related disease and not meet the 20‑point threshold.
Dr. Khosroshahi: I just wanted to add something before we move ahead with the case presentation here.
The reason that the items, the eight weighted criteria domains, were selected and the items below each domain were to emphasize on a specific presentation of each domain, so either a histology IgG4 staining or specifically in the clinical domains.
That is the most important one that I think I agree with Guy. I do have patients with lots of patients, actually, in my cohort, about 40% of my cohort at the beginning of their presentation did not meet the classification criteria. When I followed them, now that I have accumulated more organ manifestations, they meet the criteria. When they came, they only had one organ involvement; they did not make it. It is very important.
For example, the two sets of glands, lacrimal or salivary glands, would give you much higher suspicious for IgG4 than if it was just one submandibular gland, or things that Jai knows much better than me would be bilateral renal cortex, low densities. If you see it on the CT scan, what are the other differential diagnoses that you consider, especially if you see some IgG4 is elevated and you have those densities in the kidney? I just wanted to bring up that not calculating the classification criteria. That is okay not to do that, but know the items, and that helps for the differential diagnosis.
Yasmin, do you want to start with the case?
Weighing the Evidence: Efficacy and Safety of Current and Emerging Therapies in IgG4‑RD
Dr. Hernandez‑Barco: Happy to. We are going to go over a case that really has multi‑organ involvement and then talk about the treatment approach to this patient.
Patient 2: Daniel, 64‑yr‑old man
This is Daniel. He is a 64‑year‑old gentleman. He presented with weight loss and loose bowel movements. He also mentioned to his primary care that he was having trouble urinating for the last few months. His physical exam showed enlarged submandibular glands, and there was a biopsy performed that showed diffuse lymphoplasmacytic infiltrate.
He had imaging of the chest, abdomen, and pelvis, and he was noted to have a pair of vertebral mass, thoracic aortic wall thickening, a pancreatic mass with intra‑ and extrahepatic biliary duct dilation, and with thickening of the bile duct wall.
He had bilateral wedge‑shaped cortical hypodensities with soft tissue encasing the ureters and prostate enlargement and enhancement. His blood work was notable for a very elevated IgG4 level of 550 and an elevated IgE level to 326. Both ESR and CRP were elevated. His complement levels and eosinophils were normal. His CA 19‑9 was also elevated, and his creatinine was 2.3, with the urinary sediment was bland. He had elevations in his liver function test. On the biopsy sample, there were greater than 40 IgG4‑positive cells per high‑power field and also an elevated IgG4 to IgG ratio.
Patient 2: Daniel, 64‑yr‑old man (Cont'd)
In this patient, because he had multi‑organ involvement, steroids prednisone was initiated to really rapidly control the disease, but also at the same time we started the process for B‑cell‑depleting therapy, because, as we will discuss in a few moments, the risk for relapse in a patient like this is actually very high. In his case, steroids alone and then giving him a chance to relapse is not ideal.
Patient 2: Faculty Discussion
Perhaps I can open it up to the group. In a patient like this, would you have necessarily done a biopsy, or like our first case with the imaging, did you feel confident in the diagnosis of IgG4‑RD?
Dr. Radhakrishnan: I can say, as a nephrologist, when you see a retroperitoneal process causing renal decline, which it seems to be progressive, it is imperative to establish a tissue diagnosis as quickly as possible, because, as Guy said, there are many contenders to the diagnosis. We do not want to be treating a lymphoma with inappropriate therapy. The idea here is which tissue. The most accessible tissue is what we should aim for since the mass is retroaortic; the IR interventional radiology people might say, "Look, it is a little dangerous. Maybe focus on the pancreas or the kidneys, and all that is reasonable. We need to work very closely with our radiology colleagues to choose the site that is most amenable to the biopsy, and then get the diagnosis as soon as possible, like you said, Yasmin, and get on with therapy.
Dr. Hernandez‑Barco: Arezou, when you see a patient like this with multi‑organ involvement, how do you assess disease activity, relapse rate once you have initiated therapy?
Dr. Khosroshahi: That is a great question. I agree with Jai. When you have these typical patterns of organ involvement and elevated IgG4, the diagnosis is pretty confident, but you want to make sure that you are not dealing with anything, but go ahead and start treatment because without treatment, this patient will develop end‑organ damage, not only in the liver and kidney and other places. Usually, people with multisystem involvement; it is just the burden of the disease. The number of plasma cells with IgG4 that they have is so high that you require to treat them not only with induction with eight weeks of steroid treatment, but think about long‑term because this disease will come back.
We do have studies looking at the risks of flare, and one of the most important ones that has come up in every cohort that we have looked at in different parts of the world is multi‑organ involvement. Patients who have multiple organs at the time of the presentation, which is about 60% of the patients now diagnosed with IgG4‑RD, when you do CT scan, you find asymptomatic involvement of IgG4‑RD in their other organs. Those are the ones that are at higher risk that, as soon as you taper their prednisone, they will flare.
Long‑term studies have shown that IgG4‑RD patients, if they are followed for three years after their steroid taper, 90% of them will have a flare. The person that we are just talking about, as soon as they are down on their 5 mg of their prednisone, their disease is going to come back. That is why the clinician decided very early on, as soon as you see the patient and start the prednisone, make sure that you evaluate for the infectious workup in terms of hepatitis B, tuberculosis, and things like that, and get them started on the B‑cell depletion therapy, which is something that we have as a standard of care now in the US.
Other risk factors that, in addition to the multi‑organ involvement, will help me to know that this is a patient who will flare is elevated IgG4, which is very directly related to the number of organs involved, elevated IgE level, low complements and eosinophilia. These are very important.
There is one specific that has been standing out in some of the series that have been followed for risk of flare, and that is proximal bile duct involvement that I am not expert to talk about. I can give it back to you, Yasmin, to mention why you think that is something that patients flare more often if they have involvement.
Dr. Hernandez‑Barco: I think that isolated bile duct involvement is not always necessarily a risk for flare on its own, but the presence of proximal bile duct involvement with pancreatic involvement suggests that there are two organs involved, as you were saying, because what you can see with a pancreatic mass, you can certainly see the bile duct is involved, and that is the distal bile duct, but you do not always know, is it just because the pancreatic mass is compressing the bile duct, making it look or appear that it is involved, or is there true primary involvement of the bile duct. However, that is a very, very good point.
Jai, I wanted to ask you something as a nephrologist. The second question here, and I am curious everyone's thoughts. When is glucocorticoid monotherapy appropriate, and what is the patient phenotype that you see as a nephrologist where you might consider steroids alone?
Dr. Radhakrishnan: When you look at kidney involvement, the spectrum is from acute inflammatory interstitial nephritis, which you have a fairly rapid rise in creatinine, to a smoldering, more of a fibrotic phenotype. In those patients, you may see a few active areas of inflammation on the kidney biopsy, and in those patients, a monotherapy may be appropriate and not expose the patients to heavy‑duty steroid‑sparing therapy and see how it goes.
The tactic I have taken recently is, if the insurance approves, I do a PET scan in some of my patients to make sure I have not missed extrarenal areas of activity. If it lights up in one patient, actually the entire mediastinum, although the nodes were small, was very, very active. In such a patient, I would go straight to a B‑cell therapy in addition to steroids versus someone who just comes in with a very slowly progressive, and on biopsy shows a predominantly fibrotic phenotype.
Dr. Hernandez‑Barco: I wanted to ask because you brought up a great point earlier on that as a primary care physician, you really are the front line for all these patients, and so in somebody like this, you were mentioning you would start steroids in the process of sending to a subspecialist. Can you touch upon how other primary care doctors can feel confident doing this for patients that present like this?
Dr. Vega: I actually would not start steroids for most patients because when they come to us, they are not going to have the broad workup done. That is going to take at least weeks, and I would not want the steroids; they are harmful in a lot of ways. There are some significant side effects, particularly for 63‑year‑olds. No, I do want to start them promptly once we are confident in the diagnosis. You guys did a great job of describing how to try to cinch and get us as close as possible to make that specification.
However, what we end up doing many times is managing the consequences of steroids, such as hyperglycemia and higher risk of infection, so we really want to pay ‑ if they have heart failure, that could be a big issue, so we want to manage those and be there to support, because it is rare to have a patient especially when they are 63, with IgG4 disease and no other or one other diagnosis. Usually, they are tagging along with several things, and so we are still going to be there. I do not think we are going to be running that care in primary care. I would really encourage colleagues because there are newer therapies I am sure we are going to talk about available that can make a profound difference. What we need to do is support and make sure that we are giving the specialists everything we can and supporting mostly the patient and their families, their supporters as well, through this process.
Dr. Khosroshahi: Thank you. That is actually a very important point, if I may. I have seen the patients that their IgG4‑RD has been considered, but the primary care started them on a steroid right away without sending the right labs, without doing appropriate workup, and delayed the diagnosis because of the steroid that was started. As much as I agree that the prompt treatment, especially for bile ducts, for kidney involvement, for pachymeningitis is very, very important, but premature start of a steroid is going to delay the diagnosis and as you mentioned, tons and tons of side effects for these people who are elderly, have their pancreas affected to more prone to get diabetes. That just tips them over to have a full diabetes.
Dr. Katz: If I may add, I agree with all of that. I also agree that in rare situations, the patient does need to be started on prednisone because they have critical organ involvement, and even days of delay could mean long‑term damage. Fortunately, that is rare, but when that happens, it is so critical for whether it is the primary care doctor or other specialist, whoever it may be, whoever is starting that steroid to actually reach out and have a conversation with someone who can accept that patient and take over the management because as soon as the steroids are started, it starts the timer for how long it will take before the diagnostic workup is going to be ‑ the yield of it will be reduced. It is so important for these patients to have direct communication between the different providers on the team so that they can be seen quickly and so that the evaluation can be done expeditiously.
Dr. Hernandez‑Barco: I will just expand on what you all said. The reason why steroids could delay the diagnosis is because immediately once you start steroids, because it is such a steroid‑responsive disease, the IgG4 and IgE levels in the blood will drop. If you do a biopsy, a lot of the features that you would see on biopsy are no longer there. That is part of the concern with delaying the diagnosis. If not all of the blood work and potential biopsies have been done.
Guy, could you talk about your approach to determine the conventional immunosuppressants versus biologic therapy? Then maybe as a team, we can talk about the newer drugs that either have been approved or are about to be approved.
Dr. Katz: Sure. There is still fairly widespread use of conventional immunosuppressive agents like mycophenolate, azathioprine, leflunomide, and methotrexate around the world for IgG4‑related disease. There is clinical trial‑level data that shows that those agents can reduce the risk of relapse.
Many of the trials that support their use allowed for 5 mg to 10 mg of prednisone as maintenance, in addition to the conventional immunosuppressive agents. We just do not see the same remarkable degree of responsiveness to those agents as we do with B‑cell targeted therapies.
For those reasons, and in light of recent phase III trials that have come out, I agree with Arezou that at least in the United States, the standard of care really is to move on to B‑cell targeted therapies as the first‑line steroid‑sparing agent in IgG4‑related disease.
There is still use of those other agents. I just think it is important to recognize that they are not universally effective, and truthfully, in my experience, they tend to have a lot more side effects and are much less well tolerated by patients compared to B‑cell targeted therapies.
In my practice, I really almost never use them. It is only if someone has a really odd reason that they cannot get B‑cell targeted therapies. Those cases are few and far between. Otherwise, when I am using something other than steroids, it is one of the newer agents, the B‑cell targeted therapies.
Dr. Hernandez‑Barco: Are there scenarios where you do not use steroids at all and go straight to B‑cell therapy? Can you talk about what that a patient might look like?
Dr. Katz: I would actually say that I do that very frequently. One of the nice things about IgG4‑related disease, is also a reason that there is often delay in diagnosis, but one of the nice things about it from a management perspective is that it tends to be a slow disease. It is not a disease that patients are typically doing great one day and are in the hospital the next week. Very often when we meet these patients, they have had what we, in hindsight, can recognize as active disease for at least months, if not several years, without any treatment. These are patients that can wait a little bit to have the disease fully under control for the most part.
There are data, at least in rituximab, that we can achieve glucocorticoid‑free remission with the exception of the steroid pre‑medication that they get before each rituximab dose. Many patients, if not most patients, actually do just fine with that. The only difference is that it takes a little bit longer for the disease to get under control. With steroids, they will be under control within days to weeks, whereas with B‑cell depletion, it takes a few weeks for them to get their infusions, then it takes a few more weeks, if not a couple of months, for those infusions to fully kick in. You can expect it to be an extra two to four months between when you make the decision to start to when they are likely to be fully in remission. Which again, I think most patients’ disease can actually tolerate that, but for patients who have organ involvement, that really needs to be controlled more quickly. Those are the patients that I will use the combination of B‑cell depletion plus a taper of glucocorticoids.
Dr. Hernandez‑Barco: Thank you. Before I go on, are there any other comments?
Dr. Khosroshahi: I just wanted to add. I completely agree with Guy. There are certain patients that we do that, and it is more common than we do, that we can wait. However, because of the importance of some specific organs, including bile ducts and kidneys, that can develop damage even with a few weeks of delay, that should not be something that we consider for all patients.
There are many factors involved, depending on how soon you can get their insurance approve the medication, how soon your infusion center can schedule the patient, how soon they can have their vaccines.
One thing that I wanted to talk also to have a discussion about hopefully in the next few items we can talk about that are the significant increased risk of infection that we have in these patients, not only because of the steroid use, but because of the B‑cell depletion, so we have to make sure the primary care doctor is involved with us, take care of the vaccinations and everything before they get their B‑cell depletion, or orchestrate that during their B‑cell depletion.
Dr. Vega: Yes, I can just really briefly address vaccines. One great thing is that now patients can get them at the pharmacy and are often encouraged to do so. Hopefully, if they have a good primary care, they are already up to date on their vaccines. If they cannot get in with their primary care clinician for a few weeks, they can oftentimes go to pharmacy and pick them up there.
Dr. Hernandez‑Barco: I agree that before the end of our talk, we should definitely talk about what should be sent, as you were mentioning: hepatitis B, tuberculosis, and also talk about vaccines because those are important considerations before initiation of therapy.
A Comprehensive Approach to IgG4‑RD Management
Just to review what we have already discussed, but what is a common theme that we are discussing is that it is very important once the diagnosis have been made, patients need induction therapy to go into remission. Then the question becomes, is this a patient that is going to need maintenance therapy, or is this a patient where we feel comfortable observing because they either have single organ involvement or very mild disease?
As you can tell from our conversations with each other, really there is a lot to consider for each patient, and even though we certainly have broad guidelines and consensus of how to treat, it really is an individualized decision for each patient.
Glucocorticoids Remain a Mainstay of Initial Therapy for IgG4‑RD
When we do use steroids, it is typically 0.5 mg to 1 mg per kilo, which is approximately 20 mg to 40mg for most individuals. You keep them on that higher dose for about two to four weeks, and then you taper it slowly for the next two to three months. 97% of patients are going to respond to steroids, but when you follow them long enough, up to 50% of patients will have a relapse, especially as they taper if there is multi‑organ involvement.
As Chuck was mentioning, steroids are not benign. When we need them, we need them, but we really do have to consider alternative therapy for patients because diabetes, metabolic bone disease, all of these things are very serious complications that are difficult to manage once they set in.
Latest Treatments Target IgG4‑RD Pathophysiology
I am only going to touch upon this briefly because Arezou is going to go through this but this is a pretty comprehensive overview of the pathophysiology of IgG4‑related disease, where we have really two major cell types. Those of the B‑cell lineage: B‑cells and plasmablasts, and those of the T‑cell lineage. It is really this antigen presentation to the T‑cells that drives a lot of the inflammation and fibrosis that we see and damage in the different organs. What is pretty amazing is you can see there is a medication here for almost every single target. This is an exciting time where before we only had steroids, now there is a lot of good rationale for different therapies. I will hand this over.
B‑Cell Targeting Biologics in IgG4‑RD
Dr. Khosroshahi: Thank you, Yasmin. I just want to touch on, as Yasmin mentioned, we are fortunate enough to live in a time that we have all these targeted treatments rather than suppressing the whole immune system as a rheumatologist. It is like the best time to be able to target really the pathogenic cells that are causing the disease. What we have learned in the past 15 years or so from IgG4‑related disease is targeted treatment works.
Although there was no randomized controlled clinical trial. The only thing we had to base our treatment on was these prospective open‑label trial that had about 30 patients and multiple case series from around the world that showed B‑cell depletion works for IgG4‑RD.
The real‑world experience has been that as soon as we have the diagnosis, we move on to rituximab, and many of our patients do not require to get it every six months. They may need to get it as soon as the disease is active, but they have a pretty good response to the treatment.
Thankfully, there was a phase III double‑blind, placebo‑controlled trial of inebilizumab, which is, again, another B‑cell‑targeted monoclonal antibody, but it targets CD19 instead of CD20 that rituximab does. CD19 is actually present on the wider range of B‑cells. From pre‑B‑cells to the plasmablasts, we have CD19. When you treat the patient with inebilizumab, you get rid of the wider range of B‑cells and plasmablasts that are involved in mechanism of developing IgG4‑RD.
In this trial, which was called MITIGATE, 135 patients were randomized the results were pristine. They were one of the best results that we have seen in rheumatic diseases. 86% annualized flare rate reduction in between inebilizumab arm and the placebo arm happened. Higher rates of flare‑free, glucocorticoid‑free, and complete remission in the inebilizumab group, and serious adverse events were as expected: 18% with inebilizumab versus 9% with placebo, mostly infection; not serious infection, but infections.
This drug got FDA approval in April of 2025, which was a huge milestone for IgG4‑RD and put the IgG4‑RD really on the stage for a lot of other targeted treatments that Yasmin just mentioned. Now, since it is FDA‑approved, our patients have the option of actually getting it easier through the insurance, although we all have the challenges that now that the insurances that we are seeing, rituximab was experimental. Now, when you apply for an inebilizumab, sometimes they allow rituximab to be given to the patients.
Emerging Treatments in IgG4‑RD
With that introduction, I just wanted to mention that there are multiple emerging targeted treatments in IgG4‑RD, but I just want to mention a couple of them not go into the details.
The results of a phase III placebo‑controlled trial of obexelimab, which is a B‑cell inhibitory molecule that again targets CD19, but in addition to that has a bifunctional co‑ligation to the FcγRIIb receptors ‑ it does not kill the B‑cells, but it inhibits the function of the B‑cells ‑ has been also published it is an FDA for evaluation. It definitely showed a significant improvement in patients who received obexelimab with a similar design with mitigated study. Pretty soon we will have another option. Not only B‑cell depletion, but B‑cell inhibition.
There are multiple other drugs in the clinical trials, including BTK inhibitor, which is again another B‑cell signaling target. There are a few other T‑cell co‑stimulator molecules that are being considered, and this is exciting time. Hopefully we have more options with more modalities; just mentioning that inebilizumab is very similar to rituximab. It is every six months infusion, so the B‑cells are gone for more than six months. Obexelimab is a subcutaneous injection. It is weekly, so when your patient has an infection, your patient needs to get a vaccination, you can hold the medication. The B‑cell function can come back to normal, and then you can restart that.
With this brief review of the emerging studies, I am going to just hand it over. Chuck, do you want to take it from here?
Determining Clinical Relevance: Multidisciplinary, Patient‑Centered Care in IgG4‑RD.
Patient 2: Faculty Discussion (Cont'd)
Dr. Vega: Yes, of course. This is a great discussion, and I am just going to close with some of the main thoughts we had.
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I actually learned a lot. It was wonderful to see all the experts coming together.
Key Takeaways
My takeaways for me personally were that we cannot let these patients who have presenting findings, who have concerning symptoms go. You do need to do a broad workup that includes other autoimmune diseases that includes malignancy, among other things.
However, biopsy is very important. Generally, you do not need to do multiple biopsies. You can biopsy the most accessible area, the safest biopsy, especially when you have already done your serologic workup, and you have done your rule‑outs for those other chronic illnesses, and your imaging too; then you are probably likely to clinch the diagnosis, particularly if they have findings that are typical, such as those lymphoplasmacytic infiltrates on the biopsy.
Now there are criteria to help guide us. Guy did a great job of describing those, how they keep us in the ballpark, although there is not one singular criteria that we can say this is IgG4‑related disease. However, they do have a high specificity, so the more characteristics that are accounted for and that are positive, the much more likely it is that they have IgG4‑related disease, and we make that diagnosis, and therefore we can proceed to treatment avoiding significant organ dysfunction, which is fairly common with these diseases.
Certainly, we know that corticosteroids can work; they do have their downside. And so now we have inebilizumab as FDA‑approved, and there is a very great pipeline of other drugs that should be coming along that can provide even more treatment options for a diverse group of patients.
Overall, the future looks bright.