Your Mouth and Chronic Graft-versus-Host Disease

Your Mouth and Chronic Graft-versus-Host Disease

July 15, 2020 Part of the Virtual Celebrating a Second Chance at Life Survivorship Symposium 2020

Presenter: Nathaniel Treister DMD, DMSc, Chief, Division of Oral Medicine and Dentistry, Brigham and Women's Hospital; Clinical Director, Oral Medicine and Oral Oncology, Dana-Farber/Brigham and Women’s Cancer Center

Presentation is 39 minutes with 23 minutes of Q&A.             Download Speaker Slides  

Summary: Graft-versus-host disease in the mouth (oral GVHD) is very common after transplant and manifests itself in many different ways. Treatments are available to manage the discomfort caused by oral GVHD.

Highlights:

• When GVHD affects the mouth, it can cause pain, interfere with a patient’s ability to eat, cause changes in taste, and/or make it difficult to open the mouth or swallow.

• GVHD in the mouth increases the risk of cavities, decay, and infection.

• Patients with oral GVHD have a higher risk of developing mouth cancer, although that risk is still low.

Key Points:

06:27   Oral GVHD may occur by itself, or at the same time GVHD affects other parts of the body, and may persist many months or years after transplant.

07:35   GVHD in the mouth can resemble other autoimmune diseases.

10:15   Systemic treatment with immunosuppressants and steroids that help other manifestations of GVHD is not always successful in treating oral GVHD.

10:56:  Oral GVHD can cause three different problems:  inflammation in the mouth and/or on the lips, dry mouth and/or tightness of skin around the mouth.

12:59:  Oral GVHD can cause discomfort with eating and drinking, particularly with acidic, spicy, crunchy or hard foods.

15:53   Steroids applied directly to the affected area are the usual treatment for oral GVHD when it causes rash or blistering in the mouth and on the lips. Injection of steroids may be needed to help those with extensive ulcers.

19:51   Oral infections are common in patients with oral GVHD.

24:10  Oral GVHD can cause dry mouth, or salivary gland disease, which can make it difficult to talk, eat, swallow and taste. It can also increase the risk of developing cavities.

26:55  Treatment for dry mouth caused by GVHD includes over-the-counter saliva substitutes, saliva stimulants like sugar-free gum or candy, and prescription medications called sialogogues such as pilcarpine.

29:26  Oral GVHD can cause tightening of the mouth which can cause pain, making eating difficult, and make it difficult to put dentures in and out of the mouth.

Transcript or Presentation

00:00     [Moderator] Welcome to the Your Mouth and Chronic Graft-versus-Host Disease workshop. My name is Sue Stewart and I will be your moderator today. It's my pleasure to introduce to you today's speaker, Dr. Nathaniel Treister. Dr. Treister is the chief of the Division of Oral Medicine and Dentistry at Brigham and Women's Hospital, and Clinical Director of Oral Medicine and Oral Oncology at the Dana-Farber/Brigham and Women's Cancer Center in Boston. He is an Assistant Professor of Oral Medicine at Harvard School of Dental Medicine as well.

Dr. Treister specializes in treating patients with oral complications of cancer, and is a nationally, and actually internationally recognized expert on the management of graft-versus-host disease in the mouth after transplant. Please join me in welcoming Dr. Treister.

00:55     [Dr. Treister] Thank you, Sue, and thank you for all of you taking time out of your days to attend this session. I hope everyone is well, and safe, and having a good day so far, regardless of whether it's morning, or evening, or perhaps middle of the night.

I'm going to talk about chronic graft-versus-host disease in the mouth. And I know some of you are patients, some of you may be caregivers, some of you may be family members. So, my intent is for this information to be as clear as possible, but I know we'll have time for questions, and look forward to fielding those questions as they come.

So, graft-versus-host disease in the mouth. It really can affect the mouth and oral health in many different ways. And this is almost like a summary slide to begin with. And we'll touch on all of these points over the next 25 minutes or so.

Mouth involvement is incredibly common and oftentimes very prominent. And I'll show you some examples of that. And actually, not that there's going to be a lot of data here. But I will show you a little bit that I think people will find interesting. There's a very wide range of severity. And especially for those of you that have GVHD and have experienced various complications in the mouth and elsewhere.

02:23     And you probably know other people with a condition, it doesn't affect everybody the same way. Symptoms can also range quite widely. We sometimes see patients that have quite prominent features and have no bother at all. We see other patients with what looked like very minimal features, and yet the clinical impact is very significant.

Symptoms of graft-versus-host disease (GVHD) in the mouth (oral GVHD)

02:49     The hallmark feature of this condition is what we refer to as lichenoid, or lichen planus-like inflammation. And this is what we see inside the mouth. It looks essentially like a rash affecting the lining of the mouth. And the most common symptom associated with that is what we refer to as sensitivity. Meaning that something that stimulates the mouth, like food, or drink, or even just something as simple as brushing the teeth can cause immediate pain that due to the sensitivity. Whereas, in most cases, the mouth is not painful just at rest, occasionally, but not all that often.

Lips are frequently affected, and that's part of that same rash -like change affecting the lips, but causing the lips to sometimes get quite chapped and even blistered with open sores. We'll talk a little bit about how we manage that.

Another really important aspect of how graft-versus-host disease affects the mouth is due to the effects on the salivary glands, and subsequently, dry mouth, or lack of saliva, or we refer to as salivary gland dysfunction. And along with the dry mouth come complications like dental cavities, new cavities, recurrent cavities for teeth that have already been treated, as well as risk of some infections in the mouth. And in particular, recurrent yeast infections.

And finally, in the long term, patients who have graft-versus-host disease, and in particular patients who have graft-versus-host disease in the mouth, are at a significantly increased risk for developing cancer in the mouth. And I'll talk about that towards the end, and how we screen for this, and what some of the features are. But again, I'm going to touch on all of these on all these points as we go through.

Graft-versus-host disease in the mouth is common after a stem cell transplant

So, I mentioned that graft-versus-host disease in the mouth is very common. And this is one of the few data points I'm going to show you. But this is showing the frequency of the various organs being affected across very large population of patients with graft-versus-host disease. And you see that skin and mouth are the two most frequent, followed by many other sites that can be affected. But most patients with chronic graft-versus-host disease will have some degree of involvement in both the mouth and the skin.

This is a quote from one of the classic papers written back in 1990 summarizing the various features of graft-versus-host disease in the mouth. I'll just read it out loud quickly. I know you can read as well. While oral lesions are most common in patients with extensive chronic GVHD, patients in our and other centers have been described to have limited disease involving only the oral cavity. In addition, we've noted that the oral cavity can be the site of persistent activity after the resolution of chronic graft-versus-host disease affecting other sites.

And I really like including this quote in talks like this that I give because it's just stated very clearly and eloquently. And it pretty much defines how this condition exists. So, certainly, quite common in patients who have extensive involvement involving, for example, the skin, and the eyes, and perhaps the liver. But we do see patients that will only have disease in the mouth.

Oral GVHD may appear early or late after transplant, and persistent for a long time.

06:27     And it may be that it first presents in the mouth, and is only in the mouth for a period of time, or in other cases, like stated here, maybe there were other areas of involvement. And now, everything else has quieted down. Maybe this patient doesn't even require a systemic immunosuppression any longer. And yet, the mouth remains very active. It's just a quick example.

I had a call actually yesterday with a dentist colleague of mine in the community in one of the New England states, reaching out to me about a patient who was having some trouble wearing their denture, but also was oral features that they were concerned about. And it was somebody who I had not had follow up with for about six or seven years, had been off of immunosuppression for many years.

And in talking with this dentist and receiving some photographs, it was evident that they still have very active involvement in the mouth. So, this is something that sometimes can stick around for many years, if not even potentially decades.

What does oral GVHD look like?

07:35     So, what are the clinical features? And I try not to be overly technical here. So, anything that sounds technical, I will explain. First and foremost, and like all other features of graft-versus-host disease, it essentially resembles otherwise existing immune mediated and autoimmune conditions that we see in clinical practice. And so, I use that term lichen planus like or lichenoid. And what we see in this picture right now is very typical lichen planus-like inflammation with these red and white changes. The white changes often have a very lazy almost like a spider web-like pattern. And then with these focal areas that look yellow, very well-defined ulceration.

Sjogren syndrome is an autoimmune disease in which the glands that produce fluid to the eyes, and the mouth are specifically targeted, and become dysfunctional. So, the eyes become very dry, the mouth becomes very dry, and then all the secondary complications to that. So, that's an autoimmune disease that we see again in the normal general population. But what we see in graft-versus-host disease is essentially like Sjogren syndrome in the way in which the salivary glands are attacked.

Finally, unfortunately for the mouth and around the mouth, it's not all that common. But some of you are probably experiencing this in the skin is we can see changes just like we see with an autoimmune disease scleroderma or progressive systemic sclerosis, PSS. And again, this is a rare autoimmune disease. But in the context of graft-versus-host disease, we can see those same types of changes affecting the mouth. I'll talk about that a little bit towards the end. Again, fortunately, it's not something that we have to encounter nearly as frequently as the lichen planus-like inflammation, or the Sjogren syndrome like dry mouth component.

GVHD in the mouth can impact quality of life

09:34     These features individually or collectively can have a very significant impact on oral health, and oral health related quality of life. So, we may not think of it that often, but especially for those of us that don't have chronic discomfort in the mouth. When we think about overall quality of life, for somebody who can't eat, for somebody who can't eat the foods that they want to eat, for somebody who maybe doesn't taste them normally, for somebody who can't open their mouth very widely, for somebody who can't swallow food without drinking lots of water, and even then having difficulty swallowing, these things can have a really, really profound impact on one's quality of life.

10:15     And importantly, and we've heard about this in those quotes previously, is that not only can the condition be limited to the mouth, but in some cases, even when systemic therapy is used, and when systemic therapy is effective in for example, resolving an inflammatory skin rash, or resolving abnormal liver function tests, oftentimes, the mouth just doesn't get better. And so, it points to there being a really important role for someone like me, for example, who can help guide more specific organ-targeted ancillary care interventions.

Three types of oral GVHD: Mucosal inflammation, dry mouth and tightness around the mouth

11:03     And I'm not going to go through all the details of this slide. And I'm sure most of you are not all that interested in pulling a publication from our group here. But I know you have these slides available for download. So, you can review this on your own. But what I try and do here is almost think of this condition as three different conditions because one patient may only have the mucosal inflammation, another patient may only have the dry mouth changes, and another patient may only have the tightness complications. But there are unique, and distinct signs, and symptoms for all of these complications, for the three groups of complications.

11:42     And in some cases, there can be some overlap. But again, the most important symptoms that patients will describe that we specifically target is primarily, the sensitivity related to mucosal inflammation, the dry mouth changes, and some of the preventive care that we need to do around that for the salivary gland dysfunction. And largely, physical therapy type interventions for the tightness complications.

What does mucosal disease look like in patients with oral GVHD?

12:44     So, for mucosal disease again, lichenoid is the way we describe that pattern. And you can see in this image that the lips can be affected. And when the lips are affected, it tends to be an extension of what's going on in the mouth. As you see in this picture, there's no skin involvement that goes beyond the border of the lips, yet the lips are affected just like the tongue.

I mentioned that typical pattern of white striations, red changes, and ulceration. Cheeks and tongue are by far the most common sites affected. But anywhere can be affected, including the gums, including the soft palate. And again, lips are actually quite prominent in many cases.

Symptoms of mucosal disease caused by oral GVHD

13:31     The primary symptoms are sensitivity, which is that discomfort we described around eating and drinking. And in particular, with acidic, spicy, hard, crunchy foods, things that just tend to have the potential to be irritating. Also, just brushing the teeth, and it's usually the toothpaste, not the toothbrush that's causing discomfort. And I'll talk about managing that shortly.

In some cases, patients may note a little bit of limited mouth opening and tightness. And that's because of those weight changes inside the mouth. Not because there's actually sclerodermatous changes or tightening, but just because the tissue itself is thicker than normal, and it doesn't stretch as well as it does normally.

And so, here you have some examples. And in all of these features, I hope you can appreciate that you're just looking at different variations of the same thing. I think the lower right is probably the most classic from the standpoint of just the white changes. But in the photo above, you can see those same changes, but then they get very thick up towards the front part of the hard palate. Also, again, in this case with prominent involvement of the lips, and on the left side, you can see in the one with the cheek being retracted on the bottom.

The primary symptoms are sensitivity, which is that discomfort we described around eating and drinking. And in particular, with acidic, spicy, hard, crunchy foods, things that just tend to have the potential to be irritating. Also, just brushing the teeth, and it's usually the toothpaste, not the toothbrush that's causing discomfort. And I'll talk about managing that shortly. In some cases, patients may note a little bit of limited mouth opening and tightness. And that's because of those weight changes inside the mouth. Not because there's actually sclerodermatous changes or tightening, but just because the tissue itself is thicker than normal, and it doesn't stretch as well as it does normally.

Blisters and ulcers cause by GVHD in the Mouth

14:20     Another example with focal areas of ulceration that the mirror is actually sitting over an ulcer right now. And interestingly, like I said before, to do that is not painful for this patient. Just manipulating with my finger with a gloved finger with the mirror like that is not painful. But if they went to have something like a carbonated drink, it would be very painful immediately.

The other thing that you can see in the upper left, if you look carefully, it looks like there's a whole bunch of little bubbles or blisters. And those are what we call superficial mucoceles. And they're essentially little spit blisters that form related to inflammation of what we call minor salivary glands. And these tend to just come and go oftentimes around eating.

Oral GVHD can cause sensitivity to food and drinks

14:48 The primary symptoms are sensitivity, which is that discomfort we described around eating and drinking. And in particular, with acidic, spicy, hard, crunchy foods, things that just tend to have the potential to be irritating. Also, just brushing the teeth, and it's usually the toothpaste, not the toothbrush that's causing discomfort. And I'll talk about managing that shortly. In some cases, patients may note a little bit of limited mouth opening and tightness. And that's because of those weight changes inside the mouth. Not because there's actually sclerodermatous changes or tightening, but just because the tissue itself is thicker than normal, and it doesn't stretch as well as it does normally.

For any of you that are dealing with this condition, you're probably looking at this and saying, "Yep, those are all things I have to avoid." But just to give everyone a sense of the types of things that can be incredibly irritating, even something like orange juice, we don't generally think of it as being all that acidic, but it would be very uncomfortable. Crusty bread, again, it's going to feel for some patients like knife edges in the inside of the mouth. And even just a little bit of salad dressing, just a little bit of spice can be enough to make things very uncomfortable. So, obviously, there's in some cases, some diet modifications that has to be made. And even when we manage this condition very effectively, it still requires some degree of diet modification.

Topical steroids are used to treat mucosal disease caused by GVHD

15:53     But our mainstay of treatment of the mucosal disease is to use topical steroids. And generally speaking, if it's widespread disease, we will tend to use a steroid in a solution form so it can be rinsed all around versus much more focal localized disease, in which case, we can use a gel, and apply that much more directly with gauze like a bandage.

I have listed the most commonly used topical steroids that we use. Sometimes our decisions are made based on what medications are covered by an individual's insurance. Sometimes we have to appeal. But in most cases, we're using steroids that are on the higher level of potency. So, steroids like clobetasol or fluocinonide. For solutions, we typically start with something called dexamethasone, and I'm sure some of you are familiar with this, dexamethasone Decadron. This is a commercially available steroid that's already in solution form. When we need to go to something more potent, anything other than dexamethasone, like clobetasol, which we use in gel form but is not available in solution form, or a medication called budesonide which is only available in a capsule, or actually, in an inhaled form also, those have to be compounded.

And so, we actually do quite a bit of work with compounding pharmacies, and I've helped guide clinicians in other centers and other places around the country as far as how to get these prescriptions filled when they have patients who aren't responding adequately to dexamethasone. Topical tacrolimus, so I'm sure many of you are familiar with tacrolimus or PROGRAF as a systemic agent.

We also have a commercial formulation of topical tacrolimus as Protopic. We typically use the 0.1% ointment. There's also a 0.03% ointment. And we primarily use Protopic for the lips. And that's because we try as much as possible to avoid at least long-term application of steroids to the lips. And some of you who have had to perhaps treat your faces with steroids, it's the same consideration because with longer-term treatment, it can cause thinning and fragility of the skin. And the lips are highly susceptible to that.

We do also sometimes have that compounded into a solution to be used inside the mouth as well. And so, in some cases, we'll do combinations with a solution, for example. If I have to really, really treat someone aggressively, I may have them using, for example, a clobetasol solution and tacrolimus solution together at the same time.

Another treatment that we have that can be very effective, especially, for example, this patient in the lower left who has these two quite extensive ulcers, and maybe those ulcers aren't healing, and other areas have been resolving better, is something called intralesional steroid therapy. And that's where we actually can do an injection of steroids directly into the tissue. And oftentimes, it can really work wonders for some of our patients.

And here's some examples of before and after treatment. In both cases, this is about three or four weeks after starting treatment. In the upper panel, I think everyone can appreciate that the extent and degree of whiteness is just much less to the right. Patient can actually open more comfortably as well.

And similarly, in the lower, showing you the lips, and this is patient who was treated with Protopic ointment, and you see almost complete resolution, just from the topical treatment alone.

Immunosuppressive therapy to treat GVHD can cause oral infections

19:51     So, just a quick side note, as we talk about the mucosal conditions, that oral infections are actually fairly common in the context of chronic GVHD, and in particular oral GVHD. And this is related to both the underlying immunosuppression, as well as the localized immunosuppression from the topical therapy.

20:29      So, candidiasis or thrush is quite common. And there's multiple factors, including the dry mouth component. So, we'll talk a little bit about recurrent candidiasis in the context of the dry mouth as well, using topical steroids. Also, any patient who has removable dentures, that also will increase the risk of having a yeast infection. And we have very effective treatments for this. It can present as these splotchy white changes, sometimes diffuse red changes. So, it's not always the easiest diagnosis to make just from a clinical exam in the context of somebody who has very active GVHD as well. But we have topical and systemic agents. Systemic agents like fluconazole tend to be more reliably effective, and are generally quite safe even in this patient population. And for patients who have continuous recurring infections, where maybe we treat, and then a few weeks later it comes back again, then we'll consider long-term prophylaxis regimens, where in some cases taking a single fluconazole dose once a week will actually be sufficient to keep the infection from coming back.

Herpes simplex virus recrudescence or infection. This is considered a secondary infection. It's rare that somebody in adulthood and especially in the context of after transplant is experiencing a primary herpes infection. This is something that usually happens during infancy, early childhood into teen years. But with herpes simplex virus recrudescence, this can affect anywhere in the mouth.

Lips are still the most common just like we see in the general population with herpes labialis. But we can see inside the mouth as well, which I'll show you.

And the other thing that's important to keep in mind is, is that we can see what we call breakthrough infections. Meaning, a patient is on prophylactic acyclovir. They're taking their medication daily, and yet, they still develop infection. And we treat with antiviral therapy. So, it may be that there needs to be a higher dose, or for somebody who's not on active treatment, starting treatment, active prophylaxis.

So, these are a couple of examples of oral candidiasis. You can see the typical, very splotchy, irregular white changes. You can see it's much more wider, and a little bit more yellow in one image versus the other. And the one on the right side, you can at least get a sense of how it can be difficult to differentiate. So, you can see that ulcer, and the redness, and a little bit of white around it, which is all GVHD. But then all those other white changes, including that funny plaque just in front of the ulcer is all infection.

This is a patient with HSV, herpes simplex virus recrudescence, who had actually been off of acyclovir for some period of time. There were many years out of transplant. I think as you can hopefully see there's still some diffuse graft-versus-host disease-like changes affecting the top part surface of the tongue. But in addition to that, and I don't have a pointer to show you. But you see, there's actually a small ulcer in the far left, upper left lip. And then if you look at the tongue, in the middle, there's a funny area where it looks like there's a little bit of an oblong white plaque. That's actually an ulcer, and then there's two little ulcers behind it. And if you come all the way up towards the front of the tongue, you see another little punched out ulcer right up near the tip. Those are all ulcers that are related to the herpes recrudescence. And inside the lip, same patient, also, you can see that larger abnormal looking ulceration that's all related to the infection.

Oral GVHD can cause dry mouth (salivary gland disease)

24:10      Salivary gland disease, I've already talked about this a few times. The most important really thing to understand is what saliva does for us and how many functions it has. So, in addition to making it possible for me to be able to talk right now, for example, and for us to be able to eat, and swallow, and mediate taste, there are some really important antimicrobial activities.

So, it helps control the microbiota in the mouth. And it also has very important properties, and what we call buffering, and remineralization of the teeth. So, the teeth are in this constant flux of being broken down, and built back up. And when that balance is off, for a number of reasons, and in addition to the lack of antimicrobial activity, patients will be at very high risk for developing dental cavities.

Dry mouth increases the risk for dental cavities and infections.

25:06      And so, it's both not just the dry mouth, and the symptoms around that, but as importantly, the risk of dental cavities. And in particular, cavities developing in places where food, and dental plaque tend to sit. So, along the gum line, and in between the teeth, and even on the top surface of the teeth. And again, for the reasons we talked about, the antimicrobial antifungal aspects of saliva.

Recurred yeast infections are actually quite common for these patients as well. And again, if you imagine somebody who has salivary gland dysfunction, and has active mucosal disease, and is using a topical steroid, and they're on systemic immunosuppression, and they wear a denture, they have multiple, multiple hits against them for putting them at risk for infection.

And this is pretty typical pattern of dental decay that we can see. So, that yellow brown appearance along the gum line is the cavity. That's what we refer to as the cervical part of the tooth. And that's a very high-risk site. Again, it's really important patients brush as frequently as possible, after meals in particular. The X-ray in the bottom, I know most of you are probably not overly familiar with looking at these X-rays. But this is a young patient 13, 14 years old. And if you just look on the left side of your screen, you see where it looks like there was a tooth, but it's just scooped out. That's a tooth that just has extensive decay such that the entire crown is basically wasted away. And nearly all of these teeth have very large cavities present.

Treatment for dry mouth caused by oral GVHD

26:55      So, for managing the salivary gland involvement, there are some good symptomatic relief that can be applied. There's some over-the-counter saliva substitutes. Various stimulants using things like sugar-free gum, sugar-free candy, and then we have prescription medication. We refer to these as prescription sialagogues. And the one that's used most frequently is called pilocarpine. Another one that we use is called cevimeline. I have these listed at the end for common prescriptions, but this is actually medication that's taken that can help stimulate the salivary glands to produce more saliva. And the nice thing about these medications are, is they really don't interact with any medications that are typically used in GVHD, and they're not immunosuppressive

27:49      For the issue with cavities, it's really good oral hygiene. So, brushing after all meals whenever possible, flossing daily, and avoiding certain foods that are considered high risk for dental cavities like sugary drinks and foods, and sticky types of foods. Fluoride, prescription fluoride can be effective in slowing down this process or preventing decay, and that we generally prescribe as a prescription gel that's applied at night before bed. And also, fluoride varnish is something that can be applied on an ongoing basis by the dentist office. There's also something called remineralizing agents, which are used sometimes. And all these things together can help control that risk of cavities.

Seeing a dentist regularly is also very important. And in the context of that, having X-rays taken. So, don't be concerned about radiation from dental X-rays. It's very, very, very small. And those bitewing X-rays, the ones where they have you bite down, and they ask you to smile are really important. We're looking at a bitewing X-ray here on the slide. And if you can see those dark areas of shadowing in between the teeth, that's what these this X-ray picks up particularly well. And obviously, if a patient has dental caries ,dental cavities, or caries, to treat them, and not just sit on them because they can advance quite rapidly in some cases. And again, we've talked about yeast infections already.

GVHD can cause tightening of the skin around the mouth

29:26      I'm going to just briefly talk about this slide. Again, it's fortunately not a very common complication. And even though and despite being uncommon, it's also something that we don't have great evidence base for as far as treatments and the effectiveness of treatments. So, the primary symptom with this tightening of sclerotic disease is that the mouth opening becomes reduced. And that can be due to tightening of the skin on the outside, or as we see here, development of these bands inside them. And these bands can form in areas that were previously very active with GVHD, typically with ulcerations. And how and why some patients heal with this scarring is not clear, but it can have a significant functional and quality of life impact.

 We can see defects inside the mouth because of the tightness. So, oftentimes, we get a loss of we call the vestibule or the gutter area. In particular, if somebody wears a denture, that can make denture wearing, and inserting and taking out the denture, actually very difficult. And sometimes, you could imagine where there's that really tight band forming that where that band essentially connects to the gum tissue.

With all the opening and pulling, that can cause very localized defects with localized recession sometimes with symptoms. It can be a painful condition. It's not typically chronic continuous pain, but in some cases, there can be pain. And again, management is challenging. But physical therapy certainly can help in some cases. And there's a few devices out there on the market that can work well in managing this limited mouth opening.

Patients with GVHD in the mouth have a higher risk of developing an oral cancer

31:19      The last thing I'm going to talk about before we wrap up for questions, is the risk of mouth cancer, or what we call oral squamous cell carcinoma. So, oral cancer can present with a number of different features, but it could be an ulcer, but that's just not going away, and getting worse with time. Oftentimes, with an ulcer or sore, there's some sickness to the tissue, or even induration, where typically, like any of these cases I've showed you so far where I showed you an ulcer, if I put a finger glove against the ulcer, it would feel very soft. Induration is the opposite of that, but there's density and it's very firm. So, if there's an ulcer with some degree of induration around it, around the borders, that's considered a very concerning feature. Just some mass or growth, but it can be challenging because especially early on, these features may appear similar to GVHD.

And so, it may not be obvious until things have progressed. But the important thing to remember is, is that the risk in patients who have had a transplant, have graft-versus-host disease, and in particular have oral graft-versus-host disease is orders of magnitude higher than the general population. It's still a very, very low risk complication, and something that happens in a very low frequency. But for something that otherwise would not be common, it is significantly more common. And so, it's just really important that patients and caregivers are aware so that something isn't ignored for three to six months, when during that time, an earlier diagnosis could have been made, and begin the treatment, and likely outcomes would have been optimized.

So, these are examples of cancers all developing in patients with a history of graft-versus-host disease. And I think the take home here is just that these all look very different. They all look abnormal. None of these actually look like GVHD. And anything presenting like this, and especially if it's evolving and growing, it needs to be biopsied because a biopsy is essential to be able to make the diagnosis.

Summary

33:50     So, in summary, like we started with, oral GVHD is actually very common. It may be the first site of involvement. It may persist for many years, and it may be the last site of involvement. Oral sensitivity and dry mouth are the most common symptoms. They're not the only symptoms, but by far the most common.

And the most important highest-level management guidelines would be to avoid irritating food and drink. Also, irritating toothpaste. So, simply using, for example, a children's toothpaste rather than an adult toothpaste, and anything that's not mint flavored is generally very well tolerated. So, that's very easy to do.

Topical steroids and topical tacrolimus, mainstays of management for the mucosal involvement, and then use of salivary stimulants, moisturizing agents, and prescription sialagogues, as well as preventive care for patients with salivary gland disease.

The importance of seeing a dentist on a regular basis, ideally, within six months of transplant, unless there's over whelming reasons not to, determined by the oncologist. Having regular dental radiographs obtained, and receiving, and practicing good preventive care. And finally, being aware of the risk of oral cancer, and being screened anytime that the mouse is being evaluated otherwise.

So, I'm not going to go through this in detail, but this is a resource that you all have in your handouts that you can print. Talks about the most common prescriptions for managing mucosal disease in the mouth. Common prescriptions for managing salivary gland on a chronic GVHD. This is just a summary of guidelines for screening, prevention, and management of late complications. So, some guidance around screening for squamous cell carcinoma risk, risk of have dental cavities developing, and fibrosis as we discussed.

And lastly, some resources that are available to you, talk about GVHD, and some specific target organs, including the mouth. And with that, we're going to wrap up, and I think I guess that it's just about 30 minutes.

And we should have 20, 25 minutes for questions. So, look forward to seeing what questions people might have. Sorry to not be able to see all you in person, but look forward to the opportunity at some point in the future.

Question and Answer Session

36:41     [Moderator] Thank you, Dr. Treister. That was a great presentation. And I know I learned a lot from it, and I'm sure others did as well. We do have a number of questions. And I'll start with the first one.

I don't live near my transplant center, and I need a local dentist to help me manage GVHD in the mouth. What criteria should I use to select a dentist who will understand and be able to handle my problems?

37:10      [Dr. Treister] So, it's a really good question. And the short answer is, is that most dentists will not have received any specific training in this condition. Many of them will not know very much about it, if at all. But a dentist does understand the principles of a patient who has dry mouth, or salivary gland dysfunction, and can and should be able to effectively manage most of the oral complications around this.

So, I think on the dentist side, it's really their responsibility to educate themselves. There're great resources, I have publications, there's other work out there that's available, there're some online resources. But making sure that they understand enough, and also feeling comfortable with being able to reach out back to the primary transplant center, w here hopefully, even if they don't have someone like me on staff, they have some degree of comfort, and ability in providing guidance.

And/or there may be a dermatologist, for example, that sees some of the patients with mouth involvement, and to provide some guidance. But it's going to be very difficult for somebody anywhere to find a dentist who would actually be able to say, "I specifically have experienced with this and have seen these patients." And so, it really ends up having to be a bit of a teamwork between the patient, the dentist, and either again, their center, or even sometimes reaching out to engage assistance from colleagues elsewhere. It's fortunately not something we have to do on a daily basis, but it's not uncommon that I have outreach from colleagues of mine from other transplant centers, or even through the BMT InfoNet, where there's just questions that need to be answered.

So, I know it's not a perfect answer and it'd be nice if there was a reference or resource you could go to and put in your zip code and get the name of a dentist. And truly, through this organization, I always consider myself as a resource. There're always ways to make connections.

39:30     [Moderator] All right. Before transplant, I was always prone to lip cold sores. And now that I'm two years post-transplant and off antivirals, I found that I still get them. Is there any benefit to taking a lysine supplement or do you have any other suggestions?

39:48     [Dr. Treister] Yeah. Lysine really, it's not effective. I don't know if they've tried topical acyclovir or topical antiviral therapy. For some patients, it can be effective. But depending on how frequent these are, if it's every month for example, I would argue if you haven't discussed that with your transplant physician yet, you should. Because that would seemingly be a good enough reason to go back on prophylactic acyclovir.

So, I see this in patients all the time. I actually just managed somebody who was in very similar situation. Reached their milestone, was taken off of acyclovir, was taken off of their pneumonia prophylaxis, and was given their series of vaccines, and in that context, developed HSV recrudescence, a lot of pain in the mouth. And treated the patient with antiviral therapy.

The question is, is this going to be a recurring problem now that they're off of acyclovir? And if they were to have another episode in a short time frame, I would strongly be pushing towards getting back on prophylaxis. So, acyclovir is a safe medication. And for patients who need to stay on it, I would definitely speak with your physician about it.

41:23     [Moderator] All right. Another question. I'm just two years out from transplant, and my oral GVHD seems to have worsened. The buccal membrane is white and sloughing off especially on the right side. I get firm tiny nodules, which come and go. My transplant doctor suggest that I have an exam, at least annually. What topical medicines alleviate some of the tightness and help heal abrasions?

41:51     [Dr. Treister] Yeah. So, it sounds like what this patient is experiencing is the typical features of the mucosal condition we talked about. And so, the recommendations that I provided, typically starting with dexamethasone solution is a five-minute rinse up to four times a day would be a typical first-line approach.

And as we already talked about, it's important to keep in mind and especially with an intensive regimen, that there's some risk of a secondary yeast infection to develop. So, it's something we always watch out for, especially within the first couple weeks of starting treatment. But if that hasn't been initiated, then that would be the first step is treating with a topical steroid solution.

Doing it regularly, diligently, and giving that initial treatment at least one month to see how, and what improvement is noted before potentially thinking about going to one of the more potent topical steroids like the ones I mentioned that require compounding.

42:56     [Moderator] All right, what do you recommend for dry lips?

43:00     [Dr. Treister] So, it's a good question. Sometimes what seems like dry lips is actually underlying graft-versus-host disease. So, it seems like it's dry and crusted, except what we're actually really seeing is those same fine white reticular lazy changes, but affecting the lip, and causing it to look dry and irritated.

And so, if there's any evidence that there's graft-versus-host disease as a component to this, then Protopic as I discussed, is definitely reasonable, the Protopic ointment. If there's no evidence of GVHD at all, and it's just dry and chapped, generally recommend something like Vaseline, or Aquaphor. Some patients find chap stick to be helpful.

So, as long as it's not irritating, really any of those. But definitely, if just trying to use moisturizer is not really all that effective, and even if it's not all that clear, is this GVHD or not., it's worth just trying to treat that empirically with Protopic ointment. Because if that improves, then there's most likely some underlying inflammatory component.

44:23     [Moderator]  Next question, does rinsing the mouth with saltwater after brushing help with cavities?

44:30     [Dr. Treister]  Not that I'm aware of. So, as long as the mouth is rinsed really well after brushing the teeth, and everything is cleared out, rinsing with one brief rinse with salt water isn't going to do anything. I can't imagine that's going to be effective. Rinsing just after eating, if you don't have the opportunity to brush your teeth can certainly help to some extent. But I'm not sure that it would matter if it's salt water, or just a regular water.

45:03     [Moderator] All right. I currently wear a mouth guard prescribed by my dentist. I'm pre transplant. When I have the transplant, should I continue to wear in use the mouth guard?

45:14     [Dr. Treister] It should be fine. There sometimes might be institutional standards that are just different for whatever reason, but there's no reason why they can't wear the nightguard during transplant. The main concern would just simply be that somehow it gets lost, because things that go in and out of the mouth. It's not uncommon for dentures to get misplaced sometimes, just because they get put one place, and then they get taken away, and nobody knows what happened. But I think if you can take good care of it, there's no risk. And whatever you would normally do with it during the day, or in the morning, or whenever to clean or disinfect it, just to continue doing that during your hospitalization.

45:58     [Moderator] Next question, I got AML, which led to a haploidentical transplant last July. Recently, I had a molar pulled. Is there any GVHD issue associated with obtaining an implant as a replacement?

46:13     [Dr. Treister] No, there's really not. It's a good question. There's really not. Even if the gum tissue in that area were affected by GVHD and there were some red and white changes, it still wouldn't be a reason not to place an implant. If the patient has been exposed to what are referred to as antiresorptive therapies, like Fosamax for low bone density or osteoporosis, then that increases some risk of poor healing.

But most of the complications we see in patients who have been on what I refer to as antiresorptive therapies, it's usually actually in cancer patients who are receiving very high doses of those related to metastatic disease. And really, from the standpoint of transplant, the only patient population that overlaps a little bit with what I'm talking about is patients who have multiple myeloma. And so, these are typically going to be autologous transplants. But patients with multiple myeloma are very frequently treated with these antiresorptive agents. And so, if a tooth needs to be extracted and/or an implant was considering to be placed, then we consider there could be some risk. But just from the GVHD immunosuppression, even long-term steroid exposure, there's really no evidence that an implant would be less successful.

47:58     [Moderator] All right, next question. I'm three years out of transplant and have had a chronic cough, which is not related to my lungs. Is there any possibility it could be related to GVHD of the mouth?

48:09     [Dr. Treister] As a cough, I have trouble believing that unless there's very prominent involvement of the back part of the soft palate. I haven't seen that presenting as someone with a cough, but it's possible. The other possibility is if the mouth is very dry, then related to the effect on the salivary glands, that could be contributing to a cough. But I probably need a little bit more information on that. But just GVHD with those red and white changes in the mouth should not be related to a chronic cough. But again, there's more questions I'd want to ask including some questions around swallowing.

48:58     [Moderator] All right. Is GVHD of the mouth common in autologous transplantation?

49:04     [Dr. Treister] No. No graft-versus-host disease is not common in autologous transplant. It almost doesn't exist, except that there are a few funny reports here and there. That has something to do with what we call the immune reconstitution, and it causing some reaction. But almost by definition, when somebody receives an autologous transplant, meaning it's their own cells, there's no functional basis for the onset development, and onset of chronic graft-versus-host disease, mouth or elsewhere.

49:40     [Moderator] Is there any issue with kissing if you have mouth GVHD?

49:45     [Dr. Treister] No. Not at all. If the mouth is dry, then it may make things a little less comfortable, but there's ways of getting around that, and drinking water, and some other things. But there's no issues whatsoever. And even for somebody who's had some recurrent infections, especially with someone you're kissing, and you have a relationship with, you're not introducing anything new or dangerous into their mouth. Similarly, with herpes simplex virus infection, again, assuming what we're talking about is somebody who is in an otherwise long term and monogamous relationship. Both partners have been exposed to the virus previously.

50:34     [Moderator] Next question, are there any over-the-counter products to stimulate saliva flow at night? And if not, what prescriptions would you recommend?

50:43     [Dr. Treister] Yeah. That's a good question. So, for night time dryness, which for some patients is the number one complaint. So, I can see where that question is coming from. Some patients, even if they say a mouth is pretty dry, but just during the day, they're fine with it. It's just at night that it's so bothersome. Things that we generally recommend, and I almost feel like I'm a like a broken record player because we talk about this so much with our patients, is two things. I'm mentioning a couple of specific products, but I have no relationship whatsoever with these manufacturers.

First is I'm sure many of you are familiar with the Biotene line of products. And some people find the mouth rinse to be soothing. Some people like to spray. Most people are not aware that they make something called dry mouth gel. It's called Oralbalance dry mouth gel. And this comes in a tube, and it's squeezed out like lubricant, it's a semi solid just clear, and it's fairly tasteless, odorless, and you put a little bit in the mouth, and it just melts into the mouth, and it can provide really good long-lasting relief unlike their other products.

And I'm sure there's some other products you can find out there. There's another company, again, no direct relationship with, but who also has a very nice product like this that some patients prefer. Their products are not available in the store, but they are over-the-counter. So, if you go to amazon.com, you can order. It's called Xerostom, X-E-R-O-S-TO-M, Xerostom. It's a Spanish company. And they also make a dry mouth gel that's very similar to the Biotene gel.

The other product that patients really swear by are called XyliMelts, and that's X-Y-L-I-M-E-L-T-S, XyliMelts. They're almost like little candies. They contain xylitol so they don't cause cavities. And they somehow help stimulate the mouth to produce saliva. And throughout the evening, they can actually act over a long period of time.

So, those really tend to be the two most effective. I only mention, because someone was talking about this recently, there is actually an FDA-cleared electro-stimulating device that apparently can help with saliva in some patients. It's not anything we have experienced with that I felt real strongly about based on reading about this.

But talking about medication, we talked about the medication pilocarpine. And some patients will take a dose of that before bed. Sometimes rather than three times a day, we have patients on a four-times-a-day regimen, and one is taken just before bed. Some patients, also, who only take it before bed and not throughout the day.

And most of these are not going to be magic cures. It's not going to go from whatever the current state is to being completely normal. But for many patients, just something that's better than what it was, again, getting back to quality of life can have a really significant impact.

54:20     [Moderator] I am six months out of my BMT, and in the last three months, I've had extreme gum recession to the point where all of my roots are showing. How do I protect those roots?

54:32     [Dr. Treister] So, very good question. And just firstly, the basis for that and how and why, we don't really understand. And I think sometimes, it seems maybe it becomes an observation that is not necessarily happening as quickly. But bottom line is we do hear this, and I have had patients absolutely convinced that over a fairly short period of time, these changes occur.

So, as far as prevention, there's really nothing that I can say that I know is going to be effective and just keeping it from happening, other than just not brushing really hard. The gums don't need to be brushed hard, just brushed effectively. As far as what to do to protect, it gets back to all the hygiene things we talked about, good tooth brushing, flossing.

And if there's considerable root exposure, probably a good idea is to have a prescription fluoride as mentioned previously, by either your transplant team or by your dentist, and to use that nightly. Because once the root surface is exposed, that area is at much higher risk for a cavity to develop than on the crown part of the surface. Because it's a less dense material, cavities develop there much easier and much faster.

56:00     [Moderator] Next question. I'm three years out, and I've had chronic GVHD. Currently, most issues are under control. However, I occasionally just choke upon swallowing. I do have less saliva, but do have some saliva. What would you recommend?

56:16     [Dr. Treister]  Well, so I guess first is, is there any way to predict? Are there certain types of foods, or certain situations in which it's more likely to happen than others? And if so, is there anything that can be changed or modified? Not necessarily to avoid that food entirely. But to avoid, for example, the size of the bite, or how long it's chewed.

I'll just throw that out there without knowing the specifics, as a consideration. Otherwise, if there's not a good explanation, and it happens unexpectedly and sudden, probably needs to be discussed with the transplant team, and there should be evaluation with a gastroenterologist, whether they need to actually examine the area, or they start with a swallowing study to look for any abnormality.

I would recommend that, just so that nothing is otherwise missed. Beyond that, it certainly can be related to the amount of saliva. And if it's dry enough, things just don't necessarily go down that well. But it would be less likely for there to be a sudden-type event with that being the underlying problem. In some cases, there can just be active GVHD in the esophagus. And because of the inflammation, food won't go through as well.

And sometimes we use a swallowed version of budesonide to help to try and address that as a localized swallowed topical therapy. And then, the other possibility is in some cases, there can be scarring and fibrosis in the esophagus. But when that happens, it's typically something that, like if there's a problem with swallowing, it's noticed all the time, not just on occasion. So, I can't answer specifically, but I hope that helps at least guide the patient to what they might do next.

58:15     [Moderator] All right. And this will have to be our last question. I know there are several out there. If you need a response to the question, you can email us, but are taste buds permanently destroyed by GVHD?

58:26     [Dr. Treister] So, it's incredibly variable. And what even the cause is when patients have taste changes is not entirely clear. So, my short-short answer would be no. No reason to think that it's permanent. And that with time, things can improve and get back to normal. But what the actual underlying cause is, is really, really hard to know. We see some patients that tell us that there are taste-related changes, whether it's lack of taste, or altered taste, or uncomfortable, or bitter taste.

Many patients will report that it started during transplant, and then it just never got better. And then, I have other patients that didn't have anything until mouth GVHD started. So, it's one of the things we don't have a whole lot of really good evidence base on. But I can say that most of my patients, either with treating the GVHD, or with time, and resolution that when these symptoms do present, they don't typically last indefinitely.

59:40     [Moderator] And with that, I'm afraid we'll have to wrap it up.

59:43     [Dr. Treister] All right.

59:43     [Moderator] Thank you, Dr. Treister for an excellent presentation. And thank you to everyone who submitted questions. They were excellent questions that helped a lot of us, I believe.