Your Mouth and Chronic Graft-versus-Host Disease

The mouth is a common target of graft-versus-host disease. Learn the symptoms and treatment options.

Presenter: Nathaniel S. Treister, Chief of the Divisions of Oral Medicine and Dentistry at Brigham and Women’s Hospital and Dana-Farber Cancer Institute and Associate Professor of Oral Medicine, Infection, and Immunity at the Harvard School of Dental Medicine.

This video is a recording of a workshop presented at the 2019 Celebrating a Second Chance at Life Survivorship Symposium

Presentation is 42 minutes, followed by 18 minutes of Q&A


The mouth is a common site for graft-versus-host disease (GVHD) following a transplant with donor cells. It can affect all parts of the mouth and should be followed carefully by a dentist familiar with the signs of GVHD.


• GVHD can occur in the mouth, even if it is not occurring in other parts of the body

• GVHD can affect all parts of the mouth, including the lips

• Oral sensitivity and dry mouth are the most common features of oral GVHD

• Topical steroids are typically used to manage oral GVHD

• Saliva stimulants, moisturizing agents and fluoride are used to manage salivary gland disease

• Routine dental care is important

• Oral GVHD increases the risk of developing cancer in the mouth, although the incidence is small

Transcript of Presentation:

00:00  Overview of Talk: It's really nice to see so many of you here. I think you've probably been to similar sessions so far where I'll give a little bit of information, 25 minutes or so I think is supposed to be about as much as I'm supposed to talk. Then we'll open up for questions. Any questions people have, hopefully, you're comfortable asking in front of everybody.

We'll have an open discussion. I'm obviously happy to answer questions afterwards as well. I generally try to make myself as available as possible through the organization. I'll get emails from Sue and the staff on a pretty regular basis, where somebody somewhere has some sort of question about something and either I can try and help directly or speak with their clinical team.

This is an executive summary overview slide. Ultimately, we're going to talk about everything on this slide, but just as an overview, and I'm sure some of you in this room either are experiencing or have experienced, or are wondering about this condition. But first and foremost, the mouth involvement for GVHD is incredibly common. And oftentimes it can be a very prominent feature of just graft-versus-host-disease overall.

Again, we're primarily talking about chronic graft-versus-host disease. I'm not going to talk about acute forms in this talk at all. If anyone has any questions, by all means, I'm happy to answer, but for the most part, it's not nearly as relevant and typically something that comes and goes and doesn't become a long term problem, compared with a chronic form, which again, I think many of you are well aware, is something that can last for potentially many, many years.

01:44  There’s a wide range of severity in patients who have chronic GVHD in their mouth: There's a wide range of severity; so every single patient that has graft-versus-host disease in the mouth doesn't have the same condition. Even when it looks the same in one person versus another, it doesn't necessarily mean that they're suffering from the same degree of symptoms or not. There's just a great amount of variability for reasons we don't understand very well. It's not necessarily that unique to graft-versus-host disease. There's other conditions that I see as an oral medicine specialist where I see one patient, and I need to treat them much more aggressively, and I see another patient, and I might think that this person would be in much worse condition, and they're actually not complaining at all. In which case, I take my foot off the gas pedal because there's no reason to treat it so aggressively.

02:27  The most common feature of graft-versus-host disease in the mouth is lichenoid inflammation:  The most common feature is what we call lichenoid inflammation. That's generally related to symptoms of mouth sensitivity. Again, I'll show pictures, and I'll explain what all this is. But this is the rash like eruption that can develop in the mouth, typically with red and white changes. It's certainly the most prominent feature of graft-versus-host disease. It's recognized by a patient or by a clinician. But it can also affect the lips. Oftentimes, it's initially thought that the lips are just dry or getting chapped, but it can actually be really a primary target of the graft-versus-host disease.

Interestingly, for reasons that I, and I don't think anyone can explain very well, the lips tend to be an extension of the mouth rather than a component of the skin involvement. Someone may have very prominent involvement of the lips as well as mouth, but then the face really isn't affected. Other parts of the body might be, but not necessarily the face.

03:22  Salivary glands can be affected by graft-versus-host disease:  When the salivary glands are affected... So you have these glands, that for the most part you don't really think about: prodded submandibular, sublingual and you have minor salivary glands all throughout the mouth. These produce saliva, which we generally take for granted until we don't have enough saliva. Chronic graft-versus-host disease very frequently will affect the salivary glands. I think of that as almost the silent attack on the mouth; because you can't really see it. The mouth doesn't even always look tremendously dry, despite the fact that the mouth can feel very dry. In some cases, we actually see complications related to dryness changes, before there have been any symptoms.

04:04  Graft-versus-host disease can cause cavities and recurrent yeast infections in the mouth:  Again, without getting too far ahead, we'll talk about that. But in particular, certain patterns of dental cavities, and recurrent yeast infections in the mouth. 

04:13 Patients with graft-versus-host disease in the mouth are at risk for developing mouth cancer:  Then the last thing we'll talk about- which by no means is what I want to be the take home for today's talk, I don't want anyone not being able to go to sleep tonight or thinking, what did I do or what can I do differently - but there is a significantly increased risk of mouth cancer in patients who have undergone an allogeneic bone marrow stem cell transplantation, and in particular with a history of chronic-graft-versus-host disease, and in particular, with a history of mouth chronic-graft-versus-host disease. I'll talk about that a little bit at the end. I just want to make that statement now that even when we talk about an increased risk, we're talking about a significantly increased risk [compared] to your spouse, friend, partner, brother, sister who has not undergone a transplant; but still in the big picture, it's a very, very, very rare event. When we talk about increased risk, this isn't an increased risk where it's a 50% chance that if you step into the street, you look both ways and take a step forward that the bus is going to hit you. Nothing like that.

05:23  70-90% of patients with chronic GVHD have it on the skin and in the mouth:  I'm not going to show you a whole lot of data and charts, but I think that this is a really nice figure that works for a group like you or a group of dentists or group of physicians. This is data from, now nearly 20 years ago, from Seattle, from the Fred Hutch Cancer Research Center. This is looking at the various presentations, areas of involvement in the body with patients with chronic graft-versus-host disease. You can see that we go from high to low and skin and mouth are the two most frequent. Approaching anywhere from 70 to 90% of patients who actually develop any form of chronic GVHD. So very common for the mouth to be affected. We'll talk about these features first.

06:18  GVHD in the mouth resembles other oral problems sometimes seen in people who did not have a transplant: With the mouth, it's interesting that what we see with chronic graft-versus-host disease really resembles conditions that we otherwise see in the general population in patients who have not otherwise undergone a transplant. As I'm sure all of you are well aware, and some have probably experienced personally, we have immune mediated disorders, we have autoimmune disorders. I mean, there's all sorts of things that can go wrong with the body, despite not having been treated for a type of cancer or other hematologic problem.

06:50  The rash-like changes essentially resemble almost exactly a condition that we see routinely in oral medicine called oral lichen planus. The clinical features are essentially exactly the same with maybe some tiny little nuance differences.

07:07 When the salivary glands are affected it essentially resembles a condition called Sjogren syndrome, which is an autoimmune disease where the body essentially attacks the glands that supply the fluid to the mouth and to the eyes.

07:22  Tightening of and thickening of skin in the mouth is similar to what is seen in patients with scleroderma:  Then there's autoimmune condition called scleroderma, or progressive systemic sclerosis. Again, not a common condition by any means; but still a condition that just developed spontaneously. The condition where we see chronic graft-versus-host disease causing the tightening and thickening of the skin in particular making movement difficult is really almost identical to what we see in patients with scleroderma. It's as if all of these three conditions in one way or another can affect the mouth. Again, these are conditions that we see in other situations.

07:59  In most cases the impact of chronic graft-versus-host disease in the mouth has to do with maintaining overall oral health and quality of life, versus contributing to potentially an early death. Now, that being said, obviously, if someone develops an aggressive mouth cancer, unfortunately, that can potentially be something that that can be fatal. It's by no means something common, and by no means anything that we think about and worry about on a daily basis. At the same time, when I talk about it later, there is reason why of course, we will at least want to be alerted to it so: we don't miss the diagnosis when we should.

08:35  GVHD problems in the mouth can persist after GVHD in other parts of the body resolve:  The other important thing to keep in mind is with the mouth oftentimes, even when we start with systemic therapy - so somebody might present with new onset disease, as some of you are probably well aware, usually in the six to 12 months or so after transplant, maybe the liver enzymes come up, there's a full body rash, and the mouth is starting to become uncomfortable, the eyes are getting dry. The patient goes on prednisone, the liver normalizes, the skin clears up, maybe it needs a little bit of topical treatment and oftentimes the mouth just really doesn't change. It's not to say that it never responds to systemic therapy, but it's not that uncommon that it ends up requiring more attention than just the general approach.

09:22  Also, in many cases, the condition chronic graft-versus-host disease can be limited to the mouth. So it's just in the mouth and nowhere else. Even if it's really bad in the mouth, if we can, we try to avoid using systemic treatment initially, if we think we can get by without it. Obviously, it points to a really important role for what we call ancillary care, or types of topical or localized treatments that we provide as a specialist.

09:49  Pictures of GVHD in the mouth:  The next few slides are going to show clinical examples, but just so you can see what we're looking at here, these are these typical red and white changes. They have these lacy or reticular pattern. Sometimes the white changes coalesce and almost look like a plaque of white, and you can see the redness. There's areas where it's least, I think pretty distinctly red compared with for example, maybe back here where it looks a little bit more normal pink.

Then this area here that has a somewhat irregular, but otherwise well defined yellowish area, this is all what we refer to as ulceration. This is basically what we call the mucosa, the covering lining surface is basically completely denuded, similar to the way alterations can develop in the skin so you get this big open raw sore. These tend to be the most uncomfortable.

Symptoms tend to be very uncomfortable when there's ulcers present. But again, I've had patients like this that tell me that they can eat hard crust pepperoni pizza and it doesn't make their eyes tear, and I have patients like this where if you showed them a glass of orange juice they'd start crying because they just want to think about drinking it and they couldn't. I can't determine a treatment plan just by looking in someone's mouth. I'm always going to have taken a history before I look in the mouth anyways. 

Just some more examples. Here you can see, first and foremost, it can affect anywhere in the mouth. The cheeks and the tongue tend to be the most common, but it doesn't really matter what's most common. It can be anywhere. Roof of the mouth is actually quite common as well, as are these little recurrent blisters that you can see here. We call them superficial mucoceles. This is actually caused by inflammation of minor salivary glands which are all throughout the mouth, but in particularly in the roof of the mouth.

Generally when they get stimulated and they're inflamed they cause these little spit bubbles to form. Some of you I'm sure have experienced this. They tend to be more of a nuisance than painful, but in a very small subset of patients, they can actually be really, really uncomfortable, but they tend to just come and go. Sometimes they respond to treatment, sometimes they don't, they tend to burn out with time.

12:08  GVHD can affect the lips:  Here you can see the prominent involvement of the lips, both in this case, as well as in this case, and you can see that all those same features you see in the mouth can also be on the lips. So in this case, it looks just very dry, but it's this very prominent white changes. Here, much more inflamed where it's actually broken down into ulcers on the lips as well which could obviously be very uncomfortable. Just other examples of, you can see areas of ulceration again. These areas that are yellow along with the red and white. Again, very, very common pattern in the buccal mucosa.

12:45  Oral GVHD can occur with GVHD in other parts of the body or by itself:  I like to include this actually written quote. This was one of the first really significant publications that described graft-versus-host disease in the mouth, going back to 1990. The first author was really the person that I think of as the father or grandfather of mouth graft-versus-host disease. Somebody who really put a lot of time and effort into studying and understanding and becoming an expert in managing and somebody actually is still a very good colleague of mine. He's been in Seattle at the Fred Hutch in University of Washington for his entire career.

I'll just read this out loud, but it really nails home some of the key principles of this condition. "While oral lesions are most common in patients with extensive chronic graft-versus-host disease - that means that it's more common to see mouth, skin, other areas- patients in our and other centers have been described who 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.

I see patients where it's sometimes only the mouth from the start, and that's really our focus of what we're managing. I have patients who are 12, 15 years, 20 years out of transplant, and they have nothing else going on. They've been off of their immunosuppressive therapy for years. They're otherwise doing great and the mouth just continues to be active. There's no absolute rhyme or reason. Obviously, there's outliers on either side. But we can see just about anything.

14:29  Slide showing signs and symptoms of GVHD in the mouth:  This slide, I think, is more helpful to have outline, and you can look through in more detail. I think, I'm not entirely sure, but I think that this is a paper that you can actually download from PubMed for free at this point, I think. And if anyone really wanted it, and they couldn't find it that way, if you communicate through the organization, by all means, I'm happy to provide it.

But what I've done is break down the disease into this three separate conditions so to speak. So talking about what are the signs and associated symptoms of the mucosal disease, versus the salivary gland disease, versus the sclerotic or fibrotic disease. 

most cases, the symptoms of GVHD in the mouth are sensitivity:  Again, in most cases, it's that problem of sensitivity, the mouth being uncomfortable and not tolerating certain foods that otherwise would be tolerated. Sometimes a sensation of tightness can all be associated with the mucosal disease.

15:27  Symptoms of GVHD of the salivary glands:  With salivary gland disease, it's much more dryness, mouth feeling dry, sticky, difficulty eating, difficulty swallowing, difficulty speaking, problems with dental cavities, we'll talk about. But in some cases, the dry mouth symptoms can also cause sensitivity, very similar to the sensitivity caused by the rash like changes.

15:49  GVHD can cause tightness and difficulty opening the mouth There's a little bit of overlap there. Then finally, with a sclerotic disease, like I said, incredibly, incredibly rare, fortunately. But we'll talk about it a little bit more details or the ways in which it can affect the mouth. It's typically difficulty with opening, difficulty with being able to open widely, difficulty with being able to adequately brush the teeth or have dental care provided just because of the limitations in opening.

16:18 GVHD Can cause mucosal disease:  Mucosal disease, we've talked about this a little bit. When we call something lichenoid, that's that red and white pattern. Like we see here, we call this lichenoid inflammation because it all refers back to this condition I referred to called lichen planus. It has typically white, red changes and the ulcerations.

Again, sensitivity is the leading symptom. It's rare. I'm not going to say impossible, because some patients do have some discomfort at rest, but not usually disabling discomfort. It might be just a little bit of low-grade discomfort. But with that being said, it's actually much more common that someone like this at rest would actually say my mouth doesn't hurt at all. But when they go to actually do something functionally, then it becomes very uncomfortable. Something as simple as brushing the teeth can actually become very difficult. We'll talk about ways of managing that. But I can tell you now, something as simple as just using a children's toothpaste, generally, will keep that problem from being an issue.

17:23 GVHD can make it hard to open the mouth: Then some cases limited mouth opening and that's only because of the amount of that white change inside the mouth. Without getting too technical, it looks white because the tissue actually becomes thicker than normal. It's just a response to the inflammation. You can imagine if your arm was twice as thick with a thick coating over it, everything would just feel kind of tighter as you moved it, despite the fact that it's not actually fibrotic; because it's something that with treatment will just go away.

17:53 First line treatment for GVHD in the mouth is topical steroids:  As far as management goes, our mainstay for management, unless we absolutely need systemic therapy, which maybe a consideration, is primarily topical corticosteroids. We think, chronic graft-versus-host disease can be treated with steroids. The skin is often treated with steroids, for the eyes we can use topical steroids, [and the] mouth responds very well to topical steroids as well.

We generally use either gels or solutions. Solutions tend to work the best, especially when there's widespread involvement like most people have; because the mouth works very well from a treatment standpoint. It's essentially a vessel, you can put a liquid in, keep your lips closed, swish it around, and you actually get very good contact delivery.

18:38 Topical gels to treat oral GVHD:  Gels have a very good penetration into the tissue. They can work well for treating one area here or there; but not for treating the entire mouth. But oftentimes, what we'll do, as I explained here with gauze, is for example, if we were trying to treat this patient with this ulcer, and they were already doing a rinse, and yet the ulcer was still causing significant symptoms, we might then use something like clobetasol gel, a very high potency topical steroids applied to gauze. You put some on the gauze and then basically put the gauze against the ulcer, let it sit there for another five or 10 minutes after doing the rinse. It's basically a secondary treatment that just can further help to get the inflammation down and potentially get the area healing.

19:32  Key to using solutions to treat oral GVHD is using them as frequently as possible:  With solutions, the key with using the solutions as much as frequency is the overall contact time. We don't have good evidence that five minutes is a magic number; but we know that five minutes generally is correlated with a good response for most of the conditions we treat in oral medicine. If you treat someone for one minute versus five minutes, the difference can be remarkable. Three minutes versus five minutes, we've never done studies. But if someone can only get to three minutes, it's still going to be a lot better than 30 seconds or one minute and then the frequency is important too. Maybe if someone can only manage one minute, but they can do it six times during the day, that's probably pretty good delivery of the medicine. 

20:21 Dexamethasone should be swished and spit out, not swallowed:  Dexamethasone, and some of you are probably familiar with this prescription, is what we use the most widely. It's essentially because it's a commercially available corticosteroid in solution form. Nothing we use in oral medicine is actually intended to be used in the mouth, so we have to be creative with all the different available resources. These solutions are intended to be swallowed so it's actually important that the prescription is clear, because if the physician just says, "Oh, I'll give you dexamethasone solution", and they enter it from their electronic health system, the prescription will go in as take by mouth, and I've had patients before they come back and they're doing great for whatever condition because they were given a prescription and not told to swish and spit, and we have to change that.

21:06  Clobetasol and budesonide are higher potency topical steroids:  These other two that I have listed here, clobetasol and budesonide, these are both higher potency topical steroids that sometimes I have to go to if dexamethasone isn't working effectively enough. And these have to be compounded. That's why I have that in italics. They're not commercially available otherwise in solution form.

21:25  Topical tacrolimus is not a steroid and works well for GVHD on the lips:  Topical tacrolimus, so tacrolimus is not a steroid, but it's another immunomodulatory agent. I'm sure many of you are familiar with it's called a calcineurin inhibitor. It can work very well for managing areas of the skin. It works very well for the lips. 

We generally like to avoid using topical steroids on the lips, at least for any long periods of time, because it can actually cause irreversible changes and thinning atrophy in lips much, much, much more quickly than even other parts of the skin. It's why if any of you have had to treat your face with topical steroids, generally, if you're using a high potency topical steroids, it's generally used somewhat sparingly. Sort of an on, off or together with something like topical tacrolimus. We can also have tacrolimus compounded. So sometimes we use that as a solution as well. If I've gone to one of those higher potency, topical steroids solutions, and I still need to push a little bit further on the gas pedal, I can add topical tacrolimus, and basically have those two solutions being used together at the same time. Just like you might take more than one systemic immunosuppressive agent. These are actually, when I say combination, truly just mixing the two so that both agents are being delivered at the same time.

22:42  Sometimes steroids are injected into mouth ulcers caused by GVHD:  Then finally, in some cases will use what we call intralesional steroid therapy. This is basically an injection of steroids into an area where there's one of these ulcers that just isn't healing, especially if it's an area that's really driving symptoms.

Intralesional steroid therapy generally is very effective. I have a number of patients that I see every one or two months, not necessarily for the rest of their lives, but during periods where it's active and in some cases for a year, two years, where on top of their normal regimen, coming in and having various areas that just tend to pop up, helps really control the disease in ways that we wouldn't be able to control otherwise.

23:21  Pictures of patients with oral GVHD before and after treatment:  These are a couple of examples of patients before and after treatment. I think in both of these cases, this is roughly one month of treatment. Just rinsing with topical therapy, or in this case using topical tacrolimus for managing lip involvement. I would hope that even to non-clinician eyes, you can see there's really a significant difference in the before and after. This is without any change in systemic treatment, without needing any injections or anything like that.

23:53  Treating oral GVHD with topical steroids can lead to a yeast infection in the mouth:  Really the only potential complication that we encounter with treating mucosal disease, with topical steroids in particular, is the risk of developing a yeast infection in the mouth. I'm going to talk about infections in the next couple slides. But this is a really nice example.

This is a patient who was diligently using their topical treatment and came back and felt a little bit better, but also noted that things were still uncomfortable and noticed some other little changes. I'm not showing you a before and after, but I can tell you that in this case, the mouth overall looked better. But you see this area here, these areas here and here, where it looks much different than here, which is the typical graft-versus-host disease changes. Instead, you see what looks like, we oftentimes describe it as a cottage cheese like appearance where it's just this splattered accumulation of these generally white plaques. Very typical for how yeast a infection appears, and we'll talk about treating that in just a minute.

But when we use a topical steroids in the mouth, it basically suppresses the local immune system locally. And for somebody who's otherwise susceptible, it basically allows the yeast infection to develop. We can treat the yeast infection very effectively with either topical or systemic treatment and still treat the mouth. It's just a matter of being aware that this is something that could happen.

25:20 A dry mouth can increase the risk of infection in the mouth: The infections that we can encounter are candidiasis, which is a yeast infection. It can obviously affect other parts of the body, but very common in the mouth, and in particular related to the use of topical treatment. Overall level of immunosuppression. A dry mouth can also contribute significantly, because the saliva plays an important role in controlling various aspects of infection risk in the mouth. Actually, if anyone has a removable, full or partial denture, a denture can also potentially act as a risk factor. It's really important that the dentures are really well cleaned and disinfected or that can be contributing.

26:03 Anti-fungal medications can control infections in the mouth:  Antifungal therapy, again topical and systematic can work well. I generally favor systemic therapy only because unless there's a reason we absolutely have to avoid it, it does tend to be more effective, and it tends to be just easier to be compliant with. We might initially treat somebody with a daily course for seven days or 10 days. But if that infection just keeps coming back, oftentimes with just once a week or twice a week dosing with fluconazole, so just a single pill once a week or twice a week, that can actually prevent the infection from coming back. That tends to be a much easier regimen to keep up with than a topical that needs to be applied four or six times a day.

26:47  Immunosuppression can cause the herpes simplex virus to recur:  With herpes simplex virus recrudescence, this is a viral infection. Most people are familiar with herpes causing cold sores around the lips; but they can actually commonly occur inside the mouth in patients after transplant. Really any patients that I see in my practice that are really significantly immunosuppressed or immunocompromised, and sometimes...

The primary driver of risk for recrudescence of HSV infection is just general immunosuppression. It's not the amount of graft-versus-host disease in the mouth or how aggressively we're topical steroids. It really doesn't have any impact. It's just a general risk factor.

But we can see what are called breakthrough infections and breakthrough means simply that the patient's taking their antiviral prophylaxis. If it's 400 milligrams twice a day or three times a day of acyclovir, been taking it regularly, and then just for whatever reason the lesions break out. And treatment is generally effective with antiviral therapy. Even if someone's already been taking their acyclovir, we generally switch to valacyclovir, and we go to a higher dose, and that will generally get it under control, and then at some period of time, we'll try stepping back to the prophylactic regimen. Very rarely, these are more complicated cases, but it's not even worth getting into that.

28:11  Pictures of patients who had herpes simplex virus recur in the mouth:  This is another example of candidiasis. You're experts on that from the last image. This is an example of a patient who's developed HSV recrudescence. I think probably the most important thing to be aware of with this is, especially if you or whoever you're here with has graft-versus-host disease in the mouth, or even if there have been areas with the ulcerations, but they tend to be in the same place, maybe they come and go a little bit, and symptoms have been fairly stable, then all of sudden some small ulcers develop somewhere that just seem to be much, much, much more painful than what the graft-versus-host disease symptoms were, that should raise an alarm that this is potentially what's going on, and you can see it's not always so simple.

Here's the patient that I've been following (again, with persistent graft-versus-host disease for many years.) There's changes on the tongue that are absolutely consistent with long standing graft-versus-host disease. But then develop these little punctate ulcers, you can see here and here, very round, very focal, also inside the mouth along the inner part of the lip. Without the typical red and white changes, just this very focal irregular ulceration. Very, very painful. And we can confirm this with culture or some other tests, but we typically just start treatment regardless.

29:38 GVHD can cause salivary gland disease which may lead to cavities and infection: Salivary gland disease, we've talked about a bit. Without going into detail - and you have this handout, so you can read as much or as little about this as you like - but understanding the importance and the various functions of saliva really points to the problems that potentially develop when we don't have enough saliva or the quality of the saliva becomes compromised. 

Saliva plays all these critical, critical roles, in addition to the things that we're aware of it also has anti-microbial activity, has these qualities that are called buffering and remineralization. The teeth to some extent are in this constant flux of breakdown and building back up on the outer surface. The saliva plays an important role in constantly providing that remineralization. You can imagine like anything, you affect one side of an equation and things tend to tip the other direction.

Really, from a health standpoint, what can be really problematic is when dental cavities start to develop, and especially when they develop rapidly. Sometimes before we can get ahead of them. Then also, like I talked about before, this risk of recurrent yeast infections based on salivary changes.

30:56 Salivary gland graft-versus-host disease can lead to cavities:  This is the type of pattern that we can see. This is a patient who developed these early changes, and you can see along the gum line, it has a white frosty appearance, and that's demineralization of the teeth. Over a period of time, you can see that this demineralization actually turns into cavities. They have these yellowish, sometimes brownish appearance. And in this patient, (this patient had active mucosal graft-versus-host disease, just mostly redness in this case) here you can see the typical white little bit of red changes. Again, this pattern of affecting the teeth along the gum line, because you don't have the normal cleansing. After eating, little food particles basically stay in that area; and that's what the bacteria utilize to eventually cause the changes that lead to cavities.

There's a number of ways to treat the symptoms of salivary gland graft-versus-host disease. There are various saliva substitutes, stimulants, over the counter products. All sorts of things that you can experiment with. There's also prescription medication, we call sialogogue therapy like pilocarpine or cevimeline. These are actually prescription medications that can help the salivary glands produce more saliva. It's not immunosuppressive and it doesn't interfere with any of the immunosuppressive medications.

32:20  What to do to prevent cavities:  There's the importance of prevention of dental cavities. I mean, everyone in the population should be brushing and flossing; but obviously in this case it's really important that there's regular brushing, especially after meals whenever possible. Flossing at least once a day, avoiding foods that are potentially, what we call, cariogenic like sugar drinks, a lot of sticky, sugary type foods- things that are just potentially going to stick around in the teeth provide the sugars that the bacteria use to eventually cause cavities.

32:54 Fluoride to prevent cavities:  We have fluoride, so prescription fluoride that you can actually apply at home. Patients who are at very high risk, we generally have a prescription fluoride that's applied by just basically placing it on the teeth at night before going to sleep. There's fluoride that can be applied in the office. There's traditional fluoride treatments, there's something called fluoride varnish as well where you actually paint this very intense fluoride product onto the teeth. 

Then there's also something else referred to as remineralizing agents. Probably not as important as the fluoride, but something that certainly can be incorporated into management when somebody is at very high risk.

It can be a lot of work, and so at the same time we try not to make things too complicated, but at the same time, if somebody's already presenting with cavities like this, even if we can get them well restored, ideally, without having to extract any teeth, we know that that person is going to be at a very high risk. So to some extent you do have to implement these types of measures.

34:06  Seeing a dentist regularly is also really important. You can't expect that everyone's just going to diagnose and figure out what to do here. Oftentimes, these are cavities you can't see obviously clinically, or that what you see clinically is only part of what's going on. That's because the area in between the teeth or what we call the inner proximal region, we need X-rays to be able to see some of these changes. We don't want to see this in an X-ray like this, but all these dark areas in between the teeth, these much larger areas like here, unfortunately, in this case, this is a tooth that clearly would need to be extracted just from the image on the radiograph. But this is the pattern that we can see. If there's cavities, they should be treated. We don't want to just leave them because they can progress much more rapidly than in other patients. We already talked about antifungal medication.

34:58  GVHD can make it difficult to open your mouth:  Last piece and again, I don't have a whole lot to talk about this. Fortunately, it's not very common, and I don't want anyone in this room, assuming that you're not already experiencing this, thinking that this is going to be the end result if I have graft-versus-host disease in the mouth. But when the sclerotic form develops, it can cause significant problems with mouth opening. And it can happen in a few different ways. 

The most traditional way we would think of is when there's that tightening and fibrosis of the skin and it ends up affecting this part of the body and secondarily affects the mouth just because the face becomes so tight. But it can also happen inside the mouth where there's actually no fibrosis and also somebody may have complete mobility everywhere else, but as a long term result of the inflammation in the mouth and again, why this happens in some people and not others, you can get scarring to form and especially in the back part of the cheek, and especially if there have been long standing ulcers.

36:00 Picture of sclerotic GVHD in the mouth:  What you see in this image are these scar bands and this patient... It has limitations, in their opening. I mean, they can obviously open widely enough from a functional standpoint, but they have tightness because these areas that used to be very inflamed have now left behind what almost feels like piano wire. And very, very difficult to manage.

In some cases, we can also see what we call periodontal defects. Areas where there seems to be really, really excessive recession, because of areas where there's not as much flexibility and basically just from normal mouth function, there's basically tugging and pulling away of these otherwise very sensitive areas, or what we call loss of vestibule. 

So if somebody were wearing full upper and lower dentures, they may actually have difficulty wearing the dentures because the amount of that, what we call the gutter space, becomes less and less and you actually need that space for a denture to be able to sit. There can be pain in association with this but in most cases it's not really pain, it's usually the problem is more having to do with function and just dealing with daily activities.

Management, I don't want to go into too much detail, but if somebody had specific questions I'd be happy to discuss afterwards. But there are physical therapy type approaches that can be done that certainly have the potential to help for some patients. Rarely, we even think about potential surgical interventions. But again, the outcomes are so variable, that it's not something that I typically want to start thinking about up front.

37:38  GVHD in the mouth increases the risk of developing cancer in the mouth: Last thing to talk about briefly, is just the fact again, I mentioned that this risk of secondary cancers, unfortunately, tends to develop a few years after transplant, but then that solid black line that's for solid tumors, as far as we know, it basically just keeps going up. The longer anyone lives, great; but unfortunately, it's not so different for me. I mean, the longer I live, there's greater likelihood of something bad happening. 

But in this case, it's a very specific complication. I think, as I mentioned before, the skin and the mouth are the two most common sites- obviously, my focus is on the mouth. The important thing is just recognizing that that risk is there so that you don't potentially have something going on and you just keep rationalizing "yeah, it's just the graft-versus-host disease", which unfortunately, we see this happens sometimes.

38:32  Summary review of photos:  You're all experts in graft-versus-host disease now. You've looked at a lot of pictures, you know, at least what some of your mouths look like and in all these cases, there's something abnormal going on. Here there's this cleft like ulcer, it doesn't look very clean, it's really well defined. There's no other changes around it. 

Here, there's just this funny mass of white changes, really doesn't look... There's nothing else surrounding it. 

Here, there's this red and white speckled growth arising from the gingiva. Really, you can't even really appreciate where it starts and stops. 

Similarly, here, there's this deep penetrating ulcer, incredibly painful, but also with this mass, it's firm, almost rock hard. Again, you don't want to let something like this, get to the point where, you've been trying to figure out for the last six months why something isn't getting better, because at six months it really does make a difference. It's not to say that if we diagnose every one of these cancers, the day it developed, that we can change everybody's outcome, but there's no question that diagnosing these earlier and getting the treatment that it needs earlier will contribute to better outcomes.

39:48  Summary of presentation:  This is a summary slide, and then we'll have time for some questions. Again, graft-versus-host disease in the mouth, it's common. It may be the initial sight of GVHD, and it may persist for months if not years after it first presents. 

Oral sensitivity and dry mouth are the most common symptoms: not the only, but by far the most common symptoms.

Management, in large part is actually going to be driven by the symptoms, the type of symptoms, the intensity of the symptoms. But basic management we talked about, avoiding irritating foods and drinks. Finding a toothpaste that is tolerable, generally any children's toothpaste. The use of topical, we call it immunomodulatory agents like corticosteroids and tacrolimus, in particular for the mucosal disease. And then the various salivary stimulants, moisturizing agents, and prescriptions and fluoride for managing the salivary gland disease.

The importance of routine dental care, so you shouldn't be running away from the dentist, you should be going to the dentist. Importance of getting dental radiographs. Don't be worried about radiation from dental radiographs. It's nothing compared with what we all get exposed to on a daily basis. Good preventive care and being aware of the risk of cancer.

I'm not going to go through these next slides. But just to orient you, because you have these in your handouts, this is just a summary of common prescriptions for mucosal disease, and some of the best practices we talked about. This is common prescriptions for salivary gland disease, and again, common best practices. This a table that just summarizes guidelines for screening and prevention and management of late complications. Again, all things we've talked about.

And then this is a slide that just makes you aware of various other resources that are available through BMT InfoNet, but also through other organizations. I'll stop there. We have at least 15 minutes. I know, I didn't leave 30 minutes, but I'm happy to speak with you guys afterwards or if you have questions during lunch, so questions.

Question and Answer Period

41:55  Clotrimazole troches. Yeah, the little things to suck on instead, right? The question started out, this individual is saying that he's using a mix of dexamethasone solution and nystatin solution, which is actually quite common. What I don't know yet, but I'll just bring up is: it's common. This is just given as an upfront prophylaxis. The idea of combining nystatin together with dexamethasone because somebody may be at risk for developing yeast infection. So whether you developed a yeast infection in the past or not. But it may or may not be essential, but it doesn't do harm. Clotrimazole troches will also effectively work as a preventive agent.

 [audience] Yeah, so I was wondering what the difference between nystatin and clotrimazole?

42:50  [Treister] Yeah, so without getting overly technical, they have different mechanisms of action, which is actually a good thing because in some cases when we're dealing with really difficult- I mean, this is not what we're talking about right now, but when we're dealing with really difficult to treat yeast infections - sometimes we actually use that to our advantage of using two different topical agents potentially even with systemic therapy. Because they're basically, approaching the condition from two different directions. But I'd say from a patient standpoint and for a topical prophylaxis for oral candidiasis, whether it's my nystatin or clotrimazole really shouldn't make a difference. I'll just leave it at that.

[audience] One other thing. So I used to mix those two together. Now one is liquid and one is a pill. What's the right [crosstalk 00:43:41]?

43:43 [Treister] Yeah. Yeah, right, right. The idea again, of mixing them together is that, like how do you lower the bar in any way possible because it's not just your mouth. You may have, "and I've got to do this for my skin, I have to do this for my eyes. I've got to take these other medications because of my blood pressure," and it becomes a really complicated daily regimen. In that case, they're just trying to make it easier for you. It's just a matter of however many times a day they want you doing it. So if you haven't had an infection, probably one or two times a day would be sufficient. Even if you're being told to do it four to six times a day with the troches, but what time of the day it really doesn't matter. It's just that it's getting that exposure at some point.

44:25 [audience]With the clobetasol versus dexamethasone and things like that, does it matter which one you're on? Like the dexamethasone, does it work like clobetasol does. Is that an indicator that things are worse for you or [crosstalk 00:44:41]- for one [crosstalk 00:44:43].

44:42 [Treister] The question was, if somebody were being treated with dexamethasone versus clobetasol solutions, and if they respond or don't respond, what does that potentially tell us about the underlying disease or prognosis or anything, and the short answer is nothing, despite the fact that coming from an expert, I will put someone on clobetasol because it's a more potent topical steroid and should be more effective. Both in my graft-versus-host disease patient population as well as other patients I see outside of oncology. I absolutely have patients that start on clobetasol and they told me it makes their mouth worse. They go back to dexamethasone and they think it's better. I don't know what to make of it and I just leave it at that. Who knows? Maybe they do have some weird unexpected response.

 [inaudible 00:45:44] five years post. Long term use of dexamethasone is that [crosstalk 00:45:49].

45:50  It's a really good question. I didn't mention. The question was, are there any potential concerns with long term use of dexamethasone, or I would say for any topical steroids in the mouth. 

As far as we know: short answer is no. We see very little, if any, systemic uptake from topical use in the mouth. There's few and far between cases that are outliers, like you could imagine, but for the most part we just don't see it. Even somebody who's not on systemic immunosuppression, we don't see that there's systemic effects of being on a steroid by using even four times a day for five minutes, indefinitely. 

Some of those problems that you potentially either have heard about or I even mentioned the problems with steroids and the skin, we don't see it in the mouth. It's not to say that potentially there's some degree of change, maybe some thinning of the mucosal in some areas over long periods of time. But even if that happens, it's nothing that we see that actually leads to any problem. If that makes sense. We never hold back on the use of topical steroids because we're concerned about the effects of intensive use or of long term use.

47:07 [audience] Within the last couple of years, all of sudden my teeth really deteriorated and I'm getting fewer and fewer teeth and actually [inaudible 00:47:20] so many cavities in between the teeth that they're suggesting this whole new teeth process [inaudible 00:47:27] I'm just wondering about the whole stress of that.

47:36 [Treister] She had a question that in the last couple of years, there's been somewhat of a rapid decline in her dental health. It's been advised perhaps to have all teeth extracted and perhaps to have implants placed and the question was from just an overall stress and health standpoint would that be acceptable? 

I guess the short answer is first, really make sure that a really drastic treatment plan is essential, versus potentially picking and choosing where the problems are, and just extracting select teeth, but preserving other teeth, because that might be an option. Again, I don't know and I haven't looked at radiographs and in your mouth. But sometimes, especially for someone who hasn't worked with more complex patients like this, not a little bit of noise, but even a significant amount of noise leads to a bigger reaction than is necessarily warranted. And in particular, if you haven't been having any symptoms, you're not in any pain, you're overall functioning well, I mean, these are all considerations that I would be thinking about and advising someone about a treatment plan.

The other thing is, is that even missing many teeth, if not all the teeth, that implants are generally discussed, just because that's where dentistry is today. But the reality is that implants aren't necessarily a necessity. And for every person, I'm not sure that it's always necessarily the best option. 

With that being said, there's really nothing specific about having chronic graft-versus-host disease that would preclude from being able to safely have dental implants placed. Now, it's a very short and focused answer. There's certainly other things that I would think about. For example, in some patients, even within the graft-versus-host disease world, there might be higher risk. So, if I were speaking to someone with a history of multiple myeloma, and they've been on bone strengthening agents, then I would probably advise perhaps against doing implants just because of the potential risk of complications. But even then it's not a hard recommendation.

 I can't give you a really, really clear directive answer; but I can say that it can be done safely, but it also may not be absolutely essential and or the time frame of how essential it might be, might be up for debate.

50:24 [audience] I'm on the higher slide [inaudible 00:50:32] but you mentioned that also [crosstalk 00:50:35].

50:35  [Treister] There's something called fluoride varnish. I don't think there's any really hard guidelines on how frequently it can be applied. It's something that for the most part entered into the dental world for preventing cavities in high risk children but obviously, we can apply in any situation.

So for somebody who's at very high risk, it might be reasonable coming in and having us apply it on a monthly basis. There's no harm; and it can actually have a significant impact in either reversing or at least arresting the dental decay. Again, there's a lot of things to consider, but even if what clinically looks bad, is otherwise functional, and there haven't been any issues with infections, abscesses, anything like that, there's a lot of things that I might think about, but I do have patients where we have ideal things that we would like to do. But at the same time, they're so stable that it just doesn't make sense to jump in at that point.

51:41  [audience] just one [inaudible 00:51:44].

51:52 [audience] If the children's toothpaste is still too irritating do you have any other suggestions?

51:59  Short answer is it shouldn't be. It just shouldn't be. As long as it's not minty, you go for the bubblegum flavor or the fruity flavor, it will not be uncomfortable. If there's an issue with the toothbrush, then making sure that it's the softest toothbrush you can find like super, super soft and even running that under warm water beforehand [would help]. But there shouldn't be anything about one of those toothpastes that causes any sort of discomfort. It's usually the combination of either the flavoring or the cleansing detergent.


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