Your Mouth and Chronic Graft-vs-Host Disease

Summary:

Chronic GVHD can affect the mouth and lips in a variety of ways. Learn how to manage the symptoms of GVHD in the mouth and prevent future problems from arising.

Presenter: Nathaniel Treister, DMD, DMSc, Chief of the Divisions of Oral Medicine and Dentistry at Brigham and Women's Hospital and Dana-Farber Cancer Institute in Boston, Massachusetts

30-minute presentation followed by a 15-minute Q & A session.

Highlights:

• Chronic graft-versus-host disease in the mouth (oral GVHD) is common after a bone marrow or stem cell transplant using donor cells (allogeneic transplant)
• Chronic GVHD can affect both the inside of the mouth as well as the lips, causing a variety of problems
• Patients who have had chronic graft-versus-host disease in the mouth have an increased risk of later developing cancer in the mouth, and should be checked regularly by a dentist

Key points:

02:21  Typical pattern of inflammation in mouth due to chronic GVHD

03:06  How chronic GVHD affects lips

06:22  GVHD in the mouth resembles other diseases dentists see such lichen planus and Sjogren’s syndrome

09:18  Blisters on the roof of the mouth are a common feature of chronic GVHD in the mouth

11:10  Chronic GVHD can cause a very dry mouth and food sensitivity

14:21  Topical steroids are an effective treatment for chronic GVHD in the mouth

18:07  There is a risk of infection when treating graft-versus-host disease in the mouth with steroids, but it is manageable.

21:43  Chronic GVHD can affect the quantity and composition of saliva

25:56  Chronic GVHD can cause tightness (fibrosis) around the mouth

27:24  Patients who have had chronic GVHD in the mouth have an increased risk of later developing cancer in the mouth

30:29  Resources for patients about prescriptions for oral GVHD, late complications and recommended screenings 

This recording was made possible, in part, by support from Pharmacyclics and Janssen, Incyte Corporation and the Meredith A. Cowden Foundation. 

Transcript of Presentation

00:00  Introduction:  So, I never know who here is a patient, who is a family member, who might be a care giver, or actually a provider. But I assume everyone knows that they are here for the mouth: the oral graft-versus-host disease oral health session. So, I'll try to make this as interesting and relevant for everyone here. This will not be a really high level technical talk like I would give if it was a room full of providers; but, even then I always try and make things as tangible and understandable as possible. I also don't want to talk about anything that's going to make anyone too upset or be scary. But, at the same time, I do want to talk about some of the real things that can happen and some of the things that we can actually do to hopefully prevent or minimize complications, especially as time goes on.

00:49  Mouth is commonly affected by chronic graft-versus-host disease (GVHD):  First and foremost, and I'll show you this in the next slide, the mouth is one of the most commonly effected sites with graft-versus-host disease. So, anyone in this room who has experienced or is experiencing graft-versus-host disease is very common, very likely that the mouth has been affected to some extent. It might be the first place where it presents, it may persist when other areas tend to   quiet down or respond to other treatments and it also may be an area that persists for years afterwards even when somebody is able to be taken off of systemic immunosuppression. So, I've got some patients that I'm following now 15, even 20 years after transplant that still have active enough disease that we have to actively treat it—It's symptomatic without management.

01:38  Chronic graft-versus-host diseases in the mouth (oral chronic GVHD) may have minimal impact on life or be debilitating:  Like, graft-versus-host disease affecting any part of the body, there's not a one size package. Somebody who has graft-versus-host disease of the eyes, some of you will hear about, or graft-versus-host disease of the skin. Everybody doesn't experience the same thing. In some cases, it might be something that's, it's there, doctors noticed it, or patients notice something that feels a little bit different in the mouth. But, for the most part, they're able to eat, drink, do everything, have a normal life. Other patients, it can be so debilitating that there's significant weight loss, significant reduction in quality of life, just because things as simple as being able to drink water actually become uncomfortable.

02:21  Typical pattern of inflammation in mouth due to chronic graft-versus-host disease (GVHD): The lichenoid inflammation, this term if any have heard, is a term we use to describe the most typical pattern of inflammation that we see clinically in the mouth. But, also it's used to describe inflammation patterns on the skin. I don't remember if somebody was talking about genital mucosa, but especially in, well men and women, it is the same type of pattern that we can see on that tissue. And so, it has in the mouth a   very distinct red and white type of pattern to it. And in particular the white pattern that most people are aware of: it's actually considered a diagnostic criteria. We see somebody with these very characteristic features in the mouth, which I'll show you, we can actually make a diagnosis of graft-versus-host disease based on that alone.

03:06  How chronic graft-versus-host disease (GVHD) affects lips:  The lips are very often affected. And I point that out here in this first slide just because, with graft-versus-host disease the lips are really part of the mouth, much more than part of the skin. It's this area where we leave the mouth and get to skin. But, interestingly it tends to be active in association with the mouth; whereas, it may stop at the edge of the lips and the skin of the face may not be affected at all. And we'll talk a little bit about that and how we manage it.

03:35  Dry mouth is a common feature oral chronic graft-versus-host disease (GHVD):  Dry mouth is another really important feature of graft-versus-host disease, and how it affects the mouth and oral cavity. So, the salivary glands, we don't see, we take for granted, I think, most of the time. But, we have major salivary glands that are here in the cheek, underneath the mandible as well, under the tongue. And these get targeted by the graft-versus-host disease, actually, very similarly to the way that the glands of the eyes can be targeted. And it causes basically changes in the saliva, but also decreased saliva. And this can cause some significant problems in the mouth: in particular, increasing in the risk of cavities.

So, I'm   laying the groundwork for a lot of things that we'll talk about more specifically in just a minute. But, this is obviously an important area where we can actually do a lot to help prevent complications and eventually prevent tooth loss.

04:31  There is an increased risk of mouth cancer due to oral chronic graft-versus-host disease (GVHD):  And then finally, this is something that I never want to put too much emphasis on, but, it is important to be aware of. Anyone who has any involvement with a patient with graft-versus-host disease in the mouth, and really anybody who is managing, dealing with a patient who has any history of graft-versus-host disease, unfortunately, there is this increased risk of cancer just related to the history of the graft-versus-host disease, the treatments for the graft-versus-host disease. And the mouth is one the most high risk sites. So, what that means is that this is still a very low risk event from the standpoint of anyone who has gone through transplant, even someone who has had very active graft-versus-host disease in the mouth. The likelihood of developing cancer is still very low. But, compared to the general population, it's actually very high. It's just that when you have risks that are very low, the relative risk, sometimes it's hard to reconcile in someone's head. So, nobody should consider that they are at very high risk for cancer. But, again, it's something that we always want to be aware of so that if there's changes we can actually identify and do something early.

05:38  Incidence of chronic graft-versus-host disease (GVHD) in the mouth:  So, I mentioned that the mouth is one of the most common sites. This is data that's been reported for many years now. There's actually updated data as well, but, it really hasn't changed at all. So, I like to refer back to more classic work. And what this shows is that the areas of involvement and the proportion of patients with involvement. And what you can see is that, like I had said before, skin and mouth are the two most frequently affected. And these are upwards in 80 to 90% of patients, so really very common. And then as we get to other areas, they tend to be   less frequently affected. Although, again, in a large population of patients with graft-versus-host disease, we see a combination of all these areas being affected.

06:22  GVHD in the mouth (oral GVHD) resembles other diseases dentists see such lichen planus, Sjogren’s syndrome:  So, with the mouth, and similar to the way graft-versus-host disease is really anywhere in the body, it resembles other diseases that we otherwise see. So, in my non-transplant, non-cancer population I see patients with a condition called lichen planus, which is very common. And it really looks almost identical to the way chronic graft-versus-host disease will look in the mouth: with this pattern of lichenoid inflammation. So, I talked about these white lacy changes. Oftentimes red changes as well. And then, this is all ulceration. Ulcers tend to be very painful. So, some of you may be familiar with a canker sore, a tiny little, maybe the size of the back of a pencil eraser, and that can cause really significant pain. Imagine this is all ulceration. So, it can potentially be a very uncomfortable condition.

Sjogren’s syndrome, it's an autoimmune condition that affects the salivary glands and the glands of the eyes, the lacrimal glands. Again, in the context of this, we see a condition that almost exactly resembles it. And then scleroderma, again, a potentially very serious autoimmune condition that also can have the same kind of effects with graft-versus-host disease: affecting the skin, the tissue   under the skin, but sometimes the skin around the face and the neck. And sometimes even inside the mouth we see that same type of tightening and fibrosis. It is not very common, but I will talk about it a little bit towards the end.

07:52  Graft-versus-host disease (GVHD) in the mouth can impact quality of life:  So, with all the potential ways in which the mouth can be affected, it can have potentially a quite profound impact on quality of life. Simple things like being able to eat, eat comfortably, drink, brush your teeth, just basic activities where it can impact. And importantly, the mouth oftentimes not only may not respond as well to systemic therapies as other areas might, but really it responds very well to more local focused localized therapies. So, whenever possible, we really try to take advantage of the various treatment modalities that we have.

08:37  Images of oral chronic graft-versus-host disease (GVHD):  These are just some clinical images just to orient everybody again. So, here again, we see these typical   white lacy changes. In some cases it can get actually quite thick. It almost looks like it's like a plaque-like formation. You can see how the lips are very prominently affected here; but, really just to the edges of the lips. And how sites are affected can vary tremendously. So, I may see one patient and they have very prominent involvement of the palette. I may see another patient that has very prominent involvement of the cheeks, but not involvement of the palette. And we have no idea why one area gets targeted more than another.

09:18  Mucoceles, blisters of saliva on roof of mouth, are a common feature of chronic graft-versus-host disease (GVHD) in the mouth:  Another common feature, which I'll talk about a little bit when I talk about the salivary gland component, are these mucoceles, or little spit bubbles that will pop up on the roof of the mouth. And any of you that have experienced this condition have probably experienced this to some extent. This is related to minor salivary gland tissue that's actually all throughout the mouth. And these can get plugged and inflamed, and cause these little blisters of saliva. They don't actually tend to be very painful, but they can be pretty alarming when they're all over the place. Again, we saw this in the other picture, but another example where we have this focal area of ulceration in the cheek or what we call the buccal mucosa. And then surrounded by these very prominent red and white changes .And again you can see very similar involvement with the tongue but also the lips.

10:12  Graft-versus-host disease (GVHD)  in the mouth can be first sign of GHVD and may persist for a long time:  I've almost said this I think verbatim already, but I like to include this quote because it was written   in the early days when some of the first literature was first coming out describing graft-versus-host disease in detail. And this was from the group in Seattle. Dr. Schubert is an oral medicine specialist, someone I've known for many years, and still sees patients there. But, they said, "While oral lesions are most common in patients with extensive chronic GVHD ..." (so, that means where many, many areas tend to be affected, not just one area) "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 resolution of chronic GVHD affecting other sites." So, this really can be the first, the middle, and the last area of involvement. And sometimes it might be the only area of involvement.

11:10  Chronic graft-versus-host disease (GVHD) can cause dry mouth and food sensitivity:  I know you have hand-outs, and I'm not going to go through this in a lot of detail. This was a figure that we had published a few years ago in this review article. But, we can think of, as I've already sort outlined, we can think of the disease in the mouth as three different diseases. One is the disease affecting the mucosa. And the primary symptom with that tends to be what we call sensitivity.

So, even with one of these mouths that I showed you that look like they would have to be incredibly painful, if it were me, I would actually be fine, right now, talking if my mouth weren't dry. And I wouldn't necessarily have a dry mouth just because the inflammation. But, as soon as I went to have breakfast, and I tried to eat those potatoes, I'd probably go from being as comfortable as possible to tears coming out of my eyes just because of the texture, let alone the flavor, the little bit of spice. And things that we would never even think would bother somebody immediately can become something that they just can't even tolerate. So, the idea of going out to dinner, let alone having someone else cook for you, going to somebody's house for dinner, ends up becoming really very difficult.

12:21  Risk of cavities and infection due to chronic graft-versus-host disease (GVHD):  With the salivary gland disease, it's much more the dry mouth, the problem with increased risk of cavities. With a dry mouth there's also increased risk of recurrent yeast infections in the mouth. And I think many of you know that's a common complication also related to just systemic immunosuppression. But, some of the symptoms can be similar. So, sometimes when somebody just has a very dry mouth, the mouth can actually become very sensitive even though we don't see the typical lichenoid, lacy inflammation patterns.

12:53  Chronic graft-versus-host disease (GVHD) can cause tightness around mouth (sclerotic form of oral GVHD):  And then with the sclerotic or the scleroderma form, this is generally tightness, difficulty opening the mouth, difficulty being able to   just do normal things like brush or receive dental care. In rare cases I've seen patients where similarly we can see with the skin, where there can actually be deep inflammation into the muscle, and chronic spasm of muscles which can be very painful. But, again, this is not very common.

13:22  Chronic graft-versus-host disease (GVHD) can affect eating, drinking and tooth brushing:  So, with the mucosal disease, again, that lichenoid pattern of inflammation is really classic. The cheeks and the tongue are most common, lips are really frequently affected. Again, the sensitivity tends to be the main feature. This affects eating and drinking; in particular tooth brushing. Simply using a children's toothpaste rather than an adult toothpaste for most patients is enough to make things comfortable. So, as long as there's not a minty flavor or any   real strong flavor. There's also adult formulated toothpaste like the Biotene toothpaste, some of the Tom's toothpaste that can so be tolerated well. In some cases, some patients may note that the mouth seems tighter than normal. It may seem like they can't open it. And it's not because there's the sclerotic changes like we talked about, but simply those white changes actually make the tissue thicker than normal; and so it actually will restrict opening a little bit. And simply by treating the mouth, if we can treat it effectively, it can actually treat that very well.

14:21  Topical steroids are an effective treatment for GVHD in the mouth (oral GVHD):  So, for managing the mouth, topical steroids, just like the way we treat the skin with topical steroids, tends to be very effective. We can use gels and we can use solutions. In most cases, especially for the cases I showed you, we would tend to use solutions just because they're easier to treat the mouth. You can put it all in your mouth, swish around everywhere. We generally recommend upwards of five minutes of swishing, because the contact time is really important. Otherwise, it's just going on for a minute and then it gets washed away, and then whatever saliva the patient has basically washes everything else away.

The solution that we typically start with, and I think is used most widely throughout this country, is called dexamethasone. Dexamethasone is not actually approved for topical use. So, this is a steroid that's provided in a solution form, so that somebody who otherwise can't swallow pills, for example little children, can swallow this nicely flavored medicine. And we repurpose that as a topical agent. It works very well. It's widely available. So, basically, no matter where somebody lives, it's very easy to get from the pharmacy. It works well for most patients, but not for all patients. So, sometimes we have to go to these other agents that I have in italics. I have them in italics because they require compounding. These are not commercially available. I can't just prescribe clobetasol as an oral solution for somebody. But, again, for any of you who are familiar with some of these names or have treated skin disease, we use generally the same medications for different areas. For the skin, we have many formulations of clobetasol. For the mouth, all we have, for example a gel formulation. We can use to treat one area focally. Sometimes I'll use gauze to maybe treat an ulcer very specifically. But, even that is usually in combination with doing a rinse as well.

16:15  Tacrolimus (Protopic®) can be used to treat GVHD on lips:  Tacrolimus is also available topically. There's a commercial formulation called Protopic®. Some of you, again, may be familiar with this if you've treated the skin. And we use that to treat the lips very effectively. The lips are an area that we try to avoid using topical steroids extensively on, because it can cause irreversible thinning. And the lips are obviously an area that's very sensitive. That can be a problem with the skin, fortunately it's not something we typically see in the mouth. So, we can actually treat the mouth as aggressively as we need to for extended periods of time. On occasion, we'll actually have this compounded into a solution as well.

16:53  Intralesional steroid therapy – injecting steroids into the area in the mouth affected by chronic graft-versus-host disease (GVHD):  And then the last thing to mention is what we call "intralesional steroid therapy". And this is actually, this is what we see here. This is actually injecting an injectable steroid directly into the area where the inflammation is. And if you can imagine, going back to here, imagine if all the patient’s symptoms, in this case, were really focused here, intralesional steroid therapy, if this is an area in, particular, that hasn't otherwise responded well to at least several weeks of intensive topical treatment, can work very, very well. So, basically the idea is I'm injecting just next to this ulcer, delivering the steroid right to the area. And I have many patients that just require this on an ongoing basis; but, manages the condition very well.

17:42  Photos of patients before and after treatment for GVHD in the mouth (oral GVHD):  And so, these are some examples of treatment before and after. Here's somebody before they've started doing rinses, after doing the rinses. They had a sense of tightness, some discomfort. Now their symptoms are significantly improved. Similarly, you can imagine this lip would be very uncomfortable any time anything is touching it. And this is after a few weeks of treatment with a topical tacrolimus; and you can see how well it can respond.

18:07  There is a risk of infection when treating graft-versus-host disease in the mouth (oral GVHD) with steroids, but it is manageable:  Really the primary complication that we see when we're treating the mouth, especially using topical steroids, is the risk of developing a secondary yeast infection, or thrush, or candidiasis. Use of a topical steroid increases the risk, because it locally suppresses the immune system in the mouth. For patients who are also on systemic immunosuppressive therapy it's an additive effect, so they're already at risk to some extent. And then if the salivary glands aren't functioning completely normally, it's potentially another contributing factor. So, this is a fairly common complication. But, one that we can actually treat very easily, in most cases actually prevent from developing once it's happened.

18:53  Removable dentures can increase risk of infection:  Candidiasis, I mentioned these already. The other potential risk factor is if somebody has a removable denture, that can also contribute to the risk of the infection coming back. So, disinfecting the denture on a regular basis can be very important, making sure that it's out at night. Management is with antifungal therapy. We have topical and systemic agents. I tend to favor systemic agents. There's always some potential interactions depending on what systemic medication somebody is on. But, especially with fluconazole, which is the most commonly used systemic antifungal agent, that risk is relatively small and it's something that we can monitor. For the prevention, in most cases I can have somebody on a once a week dose, sometimes twice a week. And that once or twice a week dose will not typically have a significant impact on interacting with other medications. But, it can be very effective in keeping the infection from coming back. And this is something that once I have a patient who has had thrush come back a couple of times, we'll pretty much go to a prophylaxis.

20:01  Herpes simplex infections (cold sores) in the mouth are common after transplant:  The other infection that is fairly common in patients after transplant is herpes simplex virus. So, herpes cold sores that I think most people are aware of. The primary risk factor is immunosuppression. So, most patients, even fairly young patients, this is an infection that most people are exposed to in childhood, teenage, early adulthood. By the time we're 50/60 years old, the overwhelming majority of the population has been exposed to this virus. Once you're exposed, you have it forever. It can reactivate under certain conditions, usually stress, but in particular, suppression of the immune system. And important to remember: that for somebody who is taking their acyclovir regularly, which is supposed to suppress this, we can still, if there's enough suppression, otherwise get what is called a breakthrough infection. So, you're taking the medicine but you still develop an infection. And so, we have to go up to a higher dose of medication or potentially change the medication.

And so, it's not always the easiest diagnosis to make, especially when somebody has generalized graft-versus-host disease changes. But, if somebody develops fairly acute onset really, really painful symptoms, especially just painful at rest, there's a little ulcer here, and an ulcer here, it probably looks very subtle to you. But it's very painful for this patient, and also this funny, irregular ulcer here on the inner aspect of the lip without any typical associated white changes like we talked about before.

21:43  Function of saliva in the mouth:  Salivary gland disease. So, the important thing to realize is that saliva isn't purely just water. I think we tend to think of that way. It feels like we have wetness in our mouth. But saliva, and I'm not going to through this, you have this in your slides, it's somewhat of a technical table, but, it talks about all the various properties and the components of the saliva. So, it provide lubrication, it has antimicrobial, and actually controls bacteria and fungus in the mouth. There's growth factors, various proteins in the saliva that we don't even really understand exactly what it does. It plays a role in maintaining mucosal integrity. Plays actually an important role in maintaining the health of the teeth. Has buffering capacities, and actually remineralization. So that just like bone, the teeth are in this constant flux of being broken down and built back up.

22:36  Chronic graft-versus-host disease (GVHD) can change the composition of saliva in the mouth:  And importantly, like I mentioned earlier, there's potentially not just that there's not enough saliva, but the composition has changed. So in some cases, a patient may not even notice that the mouth feels dry. And yet over a period of time, we may actually start to see changes where we can see that there's cavities developing. Typical symptoms can be dry mouth, some discomfort, sometimes difficulty eating and swallowing just because saliva plays an important role in being able to chew up food and swallow food. But, what I'll show you in the next slide—and what we're most concerned about—is the risk of caries, dental cavities developing. And they tend to follow a fairly distinct pattern. Areas where food and debris would tend to collect, like along the gum lines and in between the teeth. And then again, this is an important factor for recurrent yeast infections in the mouth.

23:26  Photo of cavities beginning to develop:  So, what you see here is very early changes. But, you can see it has almost like a frosted appearance along the gum line. And this is what demineralization looks like. So, even though there aren't actual cavities formed at this point, the hard tissue is actually very undermined. And this is after just not a very long, unfortunately, period of time where we can see the progression of this to the actual cavity. Cavities will tend to have this yellowish/brownish appearance. And with an instrument this would be very soft. And then this is, again, typical pattern. These are more advanced cavities at this point. But, this is very typical pattern of along the gum line, and with almost all teeth being affected. So, obviously we want to be able to intervene at a point before this. But even if it's at this point, it's still a time at which as long as the teeth are salvageable, we want to be aggressive and go in there and treat the teeth, and try and prevent any further advancement.

24:30  Treatment for salivary gland disease:  So, we have ways to treat the salivary gland disease from a symptomatic standpoint. There are actually some medications that can help stimulate the saliva.

 But, making sure that there's just good hydration, things like sugar free chewing gum or candy, can help just keep the saliva flowing. Brushing and flossing, having a diet that doesn't promote dental caries is important; avoiding sugary foods, sticky foods. Use of fluoride, both sometimes being applied at the office, like something like fluoride varnish, but, also prescription fluoride at home. We always struggle a little bit about how much to push this on all transplant survivors, because we know that not every patient is at the same level of risk. And it's difficult to keep up with all of these preventive instructions that you're given. But, for somebody who has significant dry mouth symptoms, any evidence that there have been changes already with the teeth, we obviously really reinforce this. Simply seeing the dentist on a regular basis. Bitewing radiographs for screenings, so this is a bitewing radiograph. This is unfortunately showing a lot of dental disease. This is all decay that we're looking at. But, we can do these early on; six months, 12 months after transplant. And if we actually see someone who is starting to develop cavities, we know that this is someone that we need to pay more attention to.

25:56  Mouth can become tight (fibrosed) from chronic graft-versus-host disease (GVHD):  This is just one slide just to talk briefly about the changes that can affect the mouth when it becomes tight or fibrosed. So, here what you're looking at is a patient who has had, previously, actually very active graft-versus-host disease in the mouth. They would have had sores, ulcers like we saw before. Now it's all resolved, but in the areas where it was very active there are these very tight bands of fibrosis, and it's making opening difficult. And when they open it pulls in these areas and becomes very uncomfortable. And so, the reduced mouth opening can actually be because of these types of bands forming inside the mouth or because of changes around the skin on the outside.

And this can lead to very localized changes around the gums and teeth. We've seen some areas of very severe recession. Sometimes actual sores and ulcers just due to the actual tightness pulling of the tissue. For somebody who potentially would be wearing a denture, the what we call the vestibule or the gutter space, will tend to get lost because the tissue gets tighter. And so, it can become very difficult to be able to place a denture. Management is really challenging. And we have some physical therapy type approaches, sometimes surgical approaches. But, fortunately this is not a common complication.

27:24  The risk of developing cancer in the mouth following chronic graft-versus-host disease (GVHD):  And the last thing I want to talk about briefly, which I mentioned in the beginning, is the increased risk of cancer in the mouth. We know that there's a significant association with both chronic graft-versus-host disease and also specifically chronic graft-versus-host disease in the mouth. But, patients who have not had chronic graft-versus-host disease in the mouth are still going to be at risk for potentially developing cancer in the mouth at some point after transplant. And the important thing to understand is, this tends to be a late complication, many years after transplant. And as far as we understand, this risk actually never goes down, it just continues to go up. So, again, overall the risk is still very low. No one should think that they're at high risk for developing cancer in the mouth. But, it is something that we have to have our alerts up on.

And in most cases, it should look very different from the way chronic graft-versus-host disease looks. Even when there is still active chronic graft-versus-host disease, there should be something distinct about the changes that are related to cancer. So, here you can see there is   this ill-defined red and white mass along the tissue. This is very distinct: it's raised. It has a funny pattern texture to it. It's white, so yeah, you could say "graft-versus-host disease looks white." But, this looks very different. Again, it's very distinct. Similarly here, very distinct deep ulcer with very firm surrounding borders. Graft-versus-host disease, the tissue should always feel soft. There's not going to be this firmness around an ulcer. Similarly here, very very well defined ulcerative lesion extending deep into that pocket between the teeth and the gums, but without any other changes that look like graft-versus-host disease in the surrounding area.

29:26  Summary of Talk:   So, I'm going to wrap up and then we've got time for questions. As I said, the way we started out, graft-versus-host disease in the mouth is common. It may be the first place, it may be the last place of involvement. Wide range of symptoms. We have some fairly standard approaches to management. There's some very simple things, like avoiding things that would be bothersome. There's active treatments for both treating the mucosal disease as well as for treating the salivary gland disease and symptoms. The importance of seeing a dentist regularly, as soon as ideally six months after transplant. Ideally that is a good time and it's important to return to the dentist, assuming there aren't other complicating factors that would keep someone from going. And then the oral cancer surveillance, and I think it's important for patients to be aware. So, a patient knows their mouth in most cases better than anyone else. They know what things feel like, they know what's normal. If something just doesn't seem normal, they would want to make sure that they let someone know.

30:29  Resources for patients about prescriptions for chronic graft-versus-host disease in the mouth (oral GVHD), late complications and recommended screenings:  These next few slides, I'm not going to go through. I just have this as   just a resource. These are some of the more common prescriptions, and it might be helpful depending on how and where you're being managed. This is a table that we just reproduced from our publication that just talks about some of these potential late complications and some of our recommended guidelines for screening, prevention, management. And then, you've probably seen this slide previously, but there's a number of other resources including this book; which I played role in in providing some review and material for. So, this talks about graft-versus-host disease in the mouth a little bit. There's some other good resources.

And we'll stop there. And we have, 25 minutes for questions.

Thank you, Dr. Treister. And we'll just open the floor to questions. And if we ask that you could speak to the mic; and if you can't get to mic we can bring the mic to you.

Question from audience: [inaudible)      

31:29  Resources about GVHD in the mouth (oral GVHD) for community dentists:  So, very good question. I try to serve as a resource and obviously we try to put materials together like this, and publish materials, and so on. The reality is as you're probably aware, most dentists will not know a whole lot about stem cell transplantation. My hope would be that especially once they have a patient, that they take that opportunity to spend a little bit of time and seek out some resources. So, for example, I believe that paper that I referenced a couple of times, anyone could go to Google, look it up and download it. Because, it's available open. But, I think as long as they have a way to communicate back to the transplant center, and there's some information being provided... every center works a little bit differently. Most centers, unfortunately, don't have at least as strong of an oral health resource as we do. But, obviously we have resources. We have resources on our website. I would even say, someone could certainly come to our website even just to look for those resources.

But, the reality is, for the most part the dental aspect of things, it's really the basic principles of dentistry don't change because you or somebody has had a transplant. Somethings may seem a little bit different, like "I haven't had a patient who has had this problem with such dry mouth before, and this problem with cavities." But, reality is, maybe they have. Because, I mentioned, this condition, Sjogren syndrome, it's a fairly common autoimmune disease. So, we do see other, sometimes there's other cancer therapies that can result in a similar situation. So, somebody who has been treated for head and neck cancer, not to talk about more cancers, but someone who has had radiation therapy, they often times have as similar but even worse complications related to salivary changes. So, it's a long-winded answer to that there are resources out there, and I would hope that they understand and seek that out, and/or reach out to look for it.

32:35  Question from audience:   [Inaudible]

33:38  Metal fillings in teeth are safe:  No, that's not necessary. There's no reason to be replacing metal fillings unless they're actually breaking down. So, anyone who has heard anything about anything related, from cancer to I don't even know what conditions have been associated, but silver fillings in the mouth are safe. They don't need to be replaced. Often times they would still be our filling of choice. The material of choice depending on   the where and the what of what's being restored.

34:11  Community dentists can manage GVHD in the mouth (oral GVHD) with help:  The other thing I wanted to mention, is when it comes to managing not the teeth, but the actual mucosal disease, the sores, unfortunately that is also an area where most dentists just don't have most of the basic education and experience in managing mucosal conditions. It doesn't mean that they're not capable. And again, for the most part, most of what we do to manage this, it's not really, really high-level complex medicine. It's just understanding how to connect the dots and explain to someone what to do effectively. So, again, there's resources out there they can be prescribing. We want to make sure that somebody is hopefully paying attention.

34:55  Contact Dr. Treister via email or through BMT InfoNet:  Email, yeah. One thing I would say is I try to make myself as available as possible, just because there aren't that many resources like me. By all means, if somebody gets, has a way to get a hold of me, I'm happy to receive emails. But, also, I make myself available through the BMT InfoNet. So, probably four or five times a year, I get a question that's come through whatever the portal is to BMT InfoNet, and then to me. So, it's kind of a nice way of doing it because I think that way they know also that they're serving as that clearing house resource, at least.

35:28   Finding dentists in Colorado familiar with GVHD:  So, it's a good question. Depending on where you live in Colorado, my guess would be is that it ... What's that? Yeah, you're probably not going to find a dentist who specifically ... You're not going to find someone that has my type of training, for example, oral medicine training out in anywhere except or Denver. And even in Denver, there's one or two people. So, there's not a lot out there. Again, they should be comfortable with the basic management of things; and at least the more basic aspects of managing the dry mouth aspect of things, and/or working together with the transplant team.

36:19  Pilocarpine and cevimeline stimulate production of saliva:  So, for example, one of the medications, it's on the list but I didn't talk about specifically, when I talked about, it's called sialogogues.  But, some of you may be aware of these. There are two medications we have available. One is called pilocarpine, and the other is called cevimeline. And these basically stimulate the salivary glands to produce more saliva. They're not immunosuppressive, so, it's not like you're adding on another immunosuppressive medication. It's just doing a very specific action. Sometimes that can be prescribed by a dentist, or it could be prescribed by a primary care physician or it could be prescribed by a transplant physician. Probably more often than not, in the transplant world, it's going to be prescribed by the transplant physician. Whereas, at our center, our team is generally writing those prescriptions. But, a dentist can write a prescription for that. So, even as a patient being an advocate you can say, "I was at this talk, and I've heard about this medication pilocarpine." And they say, "Oh yeah, I've never even prescribed it before, but seems reasonable. Let's give it a try."

37:27  Treatment for mouth that won’t open wide:  I mean, there's nothing that will actually stretch it like that. I mean, obviously I think, basic trick is at least putting some Vaseline to make it more comfortable. Also, depending on what is being done, the length of the procedure, there's something called a bite block that can just make it a lot more comfortable for you. So, even if it's not opening it wider, it's easier to keep it open for longer. So, it's just a little triangular piece of rubber that goes between the teeth and kind of holds things open. But, if it's really limited, like for instance you were able to open a certain amount to eat or do something, and now it's becoming difficult, there's some simple stretching exercises. Sometimes people do something as simple as using tongue depressors, Popsicle sticks and stacking them and adding them in between to get a certain opening. There are some physical therapy devices too; I didn't go into any detail, we don't use them very often. But, there's actually devices that are bio-engineered to open the mouth. But, again, most of these treatments we don't have big studies demonstrating who is going to benefit, who is not going to benefit.

38:37  Tooth brushing is important:  So, you probably don't want to hear this, but there's no substitute for brushing. So, if that's really what you're trying to accomplish, and I would say for anyone ... I mean, for any of my patients, especially that I really feel are at risk for the dental problems, it's try to brush after every meal. Even if you're doing somewhat of a cursory brushing and you know that you spend longer in the morning and at night, you're still doing something. So, brushing: there's no substitute. Other than that, there's a rinse if the mouth is really dry and food tends to collect, then certainly a rinse would be helpful. But, at that point just water or a basic salt water rinse. It doesn't need to be anything more. I mean, some patients use, for instance, the Biotene rinse. I think it's just a taste pleasant; but there's nothing magic about it.

39:26  Xylamelts and xylitol can keep saliva flowing:  Yeah. You've got a lot of good questions. So, the only things are these medications I mentioned, which will actually help produce more saliva. So, it's like squeezing more out of them. Or something to just help keep saliva flowing, like sugar free gum or sugar free candy. There's little, they're called Xylimelts. A lot of patients like these. Some people have heard the term xylitol, it's a type of sugar that doesn't promote decay in the mouth. So, there's these little discs that apparently, some patients find they just help kind of keep the saliva flowing. But, that's pretty much it. There's no ... There's some saliva substitute type agents out there: for the most part they're not really widely accepted. They're just .... Yeah, no they shouldn't. Not that I'm aware of.

40:14  Mouth gels are helpful for dry mouth:  The other type of product that can be really helpful for somebody who has got really, really dry mouth, and there's two out there that I'm aware of—and I have no reason to think that one is any better than the other—but, there are these dry mouth gels. So, it's essentially a lubricant for the mouth. And as far as dry mouth treatments go, topical treatments, for anyone who has used something like Biotiene rinse, or even like a spray type product, these are an extra level of intensity. And so, Biotene makes a product, it's called Oral Balance Dry Mouth Gel. And it comes in a tube. It looks like a tube of toothpaste.

And then there's a company also, it's a European company, called Xerostom. And their products are available online through Amazon and others. A lot of patients really like them. Again, we don't receive any  support from either company. We let people know these are out there, they're available, you should probably try one of the two of them. But, Xerostom also makes, I think it's almost an identical type product. [It] comes in a tube and it's a gel. And that's something you just put a little bit in your mouth and it just kind of melts into the mouth. You can have it at the bed at night, so you're not drinking water. It'll actually provide better relief than water. And won't make you have to keep getting up and go to the bathroom.

41:12  Question from audience [inaudible] and Dr. Treister’s response about when to use dexamethasone, clobetasol:  So, obviously I haven't examined you and I can't see everything ... And one thing I always want to make sure is that there is no chance that there's potentially also a yeast infection component. Just because that can always complicate things. But, if you're taking systemic medication for that or whatever, we'll assume that's not the case. Depending on  the where and what, I would typically continue doing the dexamethasone. And then if you're using clobetasol, I assume you have a cream or gel? Yeah. Right, so it has to be compounded. But, there's compounding pharmacies throughout the country. So, it's really just a matter of understanding that's a prescription that can be sent in. And then your doctor communicating with the pharmacy so they actually understand what it is that they're ordering.

So, if you're treating a wide spread condition, and you've been on dexamethasone for let's say at least six to eight weeks, you've been doing it four times a day, upwards of five minutes and it's stalled out at some level, and there is still very active let's say ulcers on the cheeks or whatever it might be, at that point, that would be justification from my standpoint to go to the compounded clobetasol solution. So, you would basically use that instead of the dexamethasone.

42:28  Question from audience [inaudible] and Dr. Treister’s response:  No, no. So, there's not ... Short answer is no. Yep. We have some good questions this year.  Yeah. We have time for one more question. These are really great questions. And thanks for being so thorough.

43:10 Question from audience [inaudible]

43:18  Topical versus systemic steroids – which to use:  So, they're not interchangeable. So, do you mean topical prednisone or systemic prednisone? So, I'm not usually the one, as an oral medicine specialist, who is making the ultimate decision, especially if it's somebody who is not on any systemic prednisone. Do we need to start prednisone or not? And/or do we need to change the dose of prednisone?

With that being said, I do influence that decision. And I would say that there are few situations where, if it's just the mouth that we're dealing with, there's very few situations where I would recommend starting prednisone without having done anything topically first. Just because the topical tends to be more effective, and often times we just don't really see a significant response with the systemic steroids for the mouth. Some patients will respond, but not everybody. And if we can, we prefer to not use systemic steroids if we can avoid it. And we have some patients where the mouth can even be pretty active to start out, but if nothing else is going on, we can control the mouth. We don't know that doing that has any influence on what might happen later on, and I don't believe that it does. I think if the skin is somewhat programmed to start six weeks later, it's probably going to start no matter what. But, at least we can avoid the onset of steroids. So, it's a good question without an ... I can't give a really clean answer.

Thank you. Thanks everyone for your questions. I'd love everyone to thank again, Dr. Treister for his time today.

Thank all of you for coming, we appreciate it.