Graft-versus-Host Disease: Mouth

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Graft-versus-Host Disease: Mouth

Thursday, May 2, 2024

Presenter: Nathanial Treister DMD, DMSc,  Brigham and Women's Hospital and Dana-Farber Cancer Institute

Presentation is 43 minutes long with 15 minutes of Q & A.

Summary: Chronic graft-versus-host disease (GVHD) of the mouth is a common side-effect of stem cell transplantation. This presentation describes the major types or oral GVHD and discusses the most effective remedies to treat this problem.

Highlights:

• Oral GVHD can affect the salivary glands which can cause yeast infections, make it difficult to eat, and lead to cavities and other dental problems.
• Topical steroids like a dexamethasone solution are often the best treatment for oral GVHD. If they are not effective, corticosteroids with higher potency such as clobetasol and budesonide can be used as well.
• Patients with chronic GVHD of the mouth are at increased risk for cancers of the mouth. If they have persistent sores that do not respond to conventional treatment, follow up care may include a biopsy to screen for oral cancer.

Key Points:

(04:36): The most prominent manifestation of oral GVHD is a rash-like change on the inside of the mouth called lichenoid inflammation, which can be quite painful. Chronic oral GVHD can also affect the lips.

(06:35): When oral GVHD affects the salivary glands, it can produce a very dry mouth that makes eating difficult and can cause cavities.

(10:55): Oral GVHD may last for years, even when GVHD symptoms are no longer occurring in other parts of the body.

(11:44): Symptoms of oral GVHD are often similar to other oral diseases like oral lichen planus, Sjogren’s syndrome, or scleroderma.  

(17:29): Oral  GVHD can cause thickening of tissues inside the mouth, making it difficult to fully open the mouth.

(21:34): Clobetasol and budesonide, more potent steroids than dexamethasone, is sometimes used to treat oral GVHD.

(22:12): Tacrolimus as a topical ointment works well to treat GVHD on the lips.

(26:53): Systemic antifungal medications can often be more effective than topical treatments for chronic oral GVHD.

(32:53): There are several over the counter and prescription medications to hydrate the mouth and stimulate salivary glands.

(34:24): Prescription-strength fluoride gel is one of our best weapons against cavities.

Transcript of Presentation

(00:03): [Steve Bauer]:   Introduction of Speaker. Welcome to the workshop Chronic-Graft-Versus Host Disease in the Mouth. My name is Steve Bauer, and I'll be your moderator for this workshop. I'd like to thank Incyte Corporation, whose support help make this workshop possible.

(00:16): It's my pleasure to introduce today's speaker, Dr. Nathaniel Treister. Dr. Treister is chief of the division of Oral Medicine and Dentistry at Brigham and Women's Hospital, and the clinical director for oral medicine, and oral oncology at Dana-Farber Cancer Institute. He's also an associate professor at Harvard School of Dental Medicine in the Department of Oral Medicine Infection and Immunity.

Dr. Treister's research focuses primarily on oral mucosal diseases, salivary gland diseases, oral facial pain disorders, and oral complications in cancer patients. He is the past president of the American Academy of Oral Medicine, and is a co-principal investigator for National Institutes of Health grant entitled Long-Term Oral Health Outcomes in the Chronic GVHD Consortium. Please join me in welcoming Dr. Treister.

(01:21): [Dr. Nathaniel Treister]:   Overview of Talk. Thank you so much for the kind invitation. Welcome everybody, it's really a pleasure to be here.

(02:05): So, I'm going to go over in hopefully enough detail for everybody, some background and some in-depth detail about what happens with graft-versus-host disease in the mouth, how it impacts the mouth, how we manage some of the potential complications we look out for. And we'll try and keep that within about 25, 30 minutes, and leave plenty of time for question and answers.

(02:32): Chronic graft-versus-host disease (GVHD) of the mouth is actually quite common. I'm going to show you just a little bit of what I would consider data. This is not intended to be a lecture or a course. But I think sharing the type of information that we learn from can be just as important for all of you as well.

(03:16): So the GVHD in the mouth, not only is it very common, but as some of you may even know from your own experiences, if you're experiencing graft-versus-host disease in the mouth as well as other areas, it can be a very prominent site of involvement. Sometimes the most bothersome site of involvement.

(03:33): Chronic GVHD of the mouth has a broad range of severity. But like any area where chronic graft-versus-host disease can affect the body, there can be a broad range of severity. So every patient is not created equally. Every mouth that even looks similar won't necessarily have the same clinical impact on one individual to another. And so the symptoms can range quite a bit. And more often than not, what we're doing is basing our treatment largely around the symptoms that the patient's experiencing.

So not to say that somebody deserves treatment or somebody doesn't deserve treatment, so to speak. But I will approach that very differently from somebody who is really complaining of discomfort, having difficulty functioning, difficulty eating versus another patient who may not look so great when we examine clinically, but if they're otherwise functionally doing very well, my interventions would probably be very different.

(04:36): The most prominent manifestation of oral GVHD is a rash-like change on the inside of the mouth called lichenoid inflammation. The most prominent manifestation of this condition is what we call lichenoid inflammation in the mouth. And this is a rash-like change that can affect the oral mucosa, in some ways very similar to the way that graft-versus-host disease can affect the skin, but it'll look quite different in the mouth. And that condition can be painful on its own. But interestingly for most patients, it's not so much that they experience pain as they experience what we call sensitivity, which means that there has to be some stimulation for the mouth to be bothersome.

(05:12): So I'll show you pictures that might look horrible coming up with a patient with a big ulcer in the mouth. And that ulcer without challenging it with a food or drink may be completely asymptomatic, they can open the mouth, they can put their tongue against it. If I'm examining a patient, I can put a gloved finger or a mouth mirror against it and it's not bothersome. But put something that would cause sensitivity to it, whether it's a rough texture or something that has some spice or acidity or even just a strong flavor, and it can immediately cause significant pain.

(05:51): Chronic oral GVHD can also affect the lips. The lips are commonly involved and oftentimes it'll seem like it's a chapped lip or blistered lip, but it's really an extension of the chronic graft-versus-host disease that's directly affecting the lip. And interestingly, it usually will stop at the outer point of the lip. So it's not that it's affecting the mouth, the lips and then onto the skin of the face. But even when the skin is affected, the face is not so frequently affected. And it's not that it's the skin closing in on the lips, but actually an extension of the mouth. And the lips can actually be quite prominent, so we oftentimes will specifically be targeting the lips for treatment, and we'll talk about that a little bit.

(06:35): Oral GVHD often affects the salivary glands and cause a dry mouth. A really and important manifestation of graft-versus-host disease in the mouth is how it affects the salivary glands, and by extension, the side effect of having a very dry mouth. And this in itself can also be quite bothersome, can actually also contribute to and be a source of sensitivity in the mouth. But it also puts patients at risk for developing dental caries or cavities, and in a fairly unique pattern, I'll show you some pictures of that. And also recurrent yeast infections in the mouth, and I'll talk about that in a couple of contexts. Because when we treat the mouth with topical steroids, it can also predispose to recurrent yeast infections.

(07:25): Patients with chronic GVHD of the mouth are at increased risk of mouth cancer. And then the last thing I have on this slide, and it's not anything that I put here to scare anybody. And for all I know we may have people in attendance today who have experienced graft-versus-host disease, and ultimately have developed another cancer such as a skin cancer or a mouth cancer. But unfortunately, we know that patients who have a history of chronic graft-versus-host disease are at a significantly increased risk for developing cancers in the mouth. And in particular when graft-versus-host disease is affecting the mouth, specifically the mucosa, those lichenoid changes that we talked about, that increases the risk.

(08:09): Now, when we talk about an increased risk, and we're going to come back to this at the end, I don't want anyone coming away from this presentation thinking to themselves, "Wow, I had a transplant. I have chronic graft-versus-host disease. I have chronic graft-versus-host disease in the mouth, and I'm going to develop mouth cancer, and that's going to be a horrible thing." It's still a very low-risk incident, but compared with the general population, so compared with a friend, family member, spouse, partner who presumably has not been through transplant, the risk is very different. So that's just a lot of general background about the condition.

(08:53): Now, I noted that graft-versus-host disease, chronic graft-versus-host disease in the mouth is very common. And you can see this is actually a study that goes back looking at a number of years of patients seen in a very large practice in Seattle, and looking at the various clinical manifestations and the frequency. And you can see that both the skin and mouth are the two most frequently affected sites. So it's very common, despite the fact that a patient may have involvement of many sites, those sites may develop at different points in time, or they may all come on at the same time. But regardless, it is very common for a patient to present with GVH in the mouth.

(09:39): And I really like to include this quotation. This comes from a paper written from a colleague mentor going back to 1990, and it really sort of describes this condition very well. So they note, "While oral lesions are most common in patients with extensive chronic GVHD," meaning that they have maybe chronic GVHD of the skin, the eyes and so on, "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 GVHD affecting other sites."

(10:22): And again, for some of you in the audience, you may have experienced this. Maybe it's the only site that ever developed, but it was really bothersome. Maybe it was the only site that ever developed, and you had to be on systemic therapy because of it. Or maybe you had multiple sites of involvement, and yet the mouth was driving your symptoms. Or you had multiple sites of involvement, and over time while other areas burned out and stopped being bothersome, and stopped requiring any specific therapy.

(10:55): Chronic oral GVHD may last for years, even when GVHD symptoms are no longer occurring in other parts of the body. Chronic oral GVHD may also last for years. Or maybe you no longer needed to be on systemic therapy, yet the mouth continues to be active. And I have patients where I'm still managing mouth disease in some cases 10 to 15 years after transplant, where it never develops that tolerance that we're expecting and settles down. So features of the condition are actually very interesting at least for someone like me who practices the field of oral medicine, because it's a condition that is unique in context of course, because of the transplant setting. And it's unique from the standpoint of that you can have all these different variable features occurring in the same patient at the same time.

(11:44): Symptoms of oral GVHD are often similar to other oral diseases like oral lichen planus, Sjogren’s syndrome, or scleroderma.  But from a clinical standpoint, what I encounter when I'm seeing a patient with chronic GVHD in the mouth is really no different than other patients who I'm seeing for other oral medicine conditions. So for example, the condition affecting the oral mucosa is nearly exactly the same as a condition that we see in the oral medicine clinic all the time called oral lichen planus. Similarly, the condition that affects the salivary glands is in effect no different than a common condition that we see an autoimmune condition called Sjogren's syndrome, where the immune system essentially auto attacks the salivary glands and other glands in the body. So a patient with Sjogren's syndrome will typically have dry eyes and dry mouth. And as many of you know, it's incredibly common in patients with chronic graft-versus-host disease as well.

(12:41): Finally, unfortunately not so common, but sometimes we see fibrosis or sclerosis of the actual oral mucosa, also sometimes the skin around the mouth. And that more or less mimics a condition that we can see, fortunately, not frequently, but many of you're probably aware of the autoimmune condition, scleroderma or progressive systemic sclerosis.

(13:06): And so we can see features of all these conditions, yet all happening at the same time in one patient. It can have a significant impact as you can imagine on a patient's oral health, on a patient's oral function. And by extension overall can have a very significant effect on quality of life, if not actually having a more direct effect on a patient's health from a standpoint of nutrition and oral intake and such.

(13:34): Chronic oral GVHD does not always respond to systemic therapy like steroids. Finally, and importantly, and this was already mentioned to some extent from the quote, it may not respond to systemic therapy. I see patients we put on systemic therapy, so when I talk about systemic therapy, I'm talking about something like prednisone, CellCept, any immunosuppressive agent that's being taken either oral or given by infusion. And sometimes every other part of the chronic GVHD actually has a very good response, the skin rash goes away or gets much better, liver function tests normalize, and yet the mouth continues to be active. So there's a very important role for providing what we call ancillary care, which is very targeted therapy for the oral cavity.

(14:24): This is just a slide, I don't want to go through this in detail. But this is a slide from a figure from a paper we published now over 10 years ago to simply describe these three primary features. And you can see there's some overlapping symptoms, but they're three very different conditions. And one patient may only have features of one or the other, or like I said, in some cases, all. But each of these features either in similar and/or different, or in some situations I would almost argue complementary ways, can all collectively make the mouth uncomfortable, make it difficult to use the mouth the way we do normally, and make it difficult to provide the proper care for the mouth that we normally would, whether it's at home or in a dental office.

(15:18): Oral GVHD can cause lichenoid pattern of inflammation anywhere in the mouth. So just a little bit about each of these features, and again, we'll start with oral mucosal, chronic GVHD, because I think that's what most people really think of when they think of this condition. And again, it has this what we call a lichenoid pattern of inflammation, and this is a combination of these white striations, redness or erythema, it's a fancy medical term for redness and/or ulcerations. And so I don't believe I have an active pointer that you can see here, but if you look at this picture of the tongue, you see areas that look white and streaky. You see areas that look much more red compared with the normal pink.

(15:54): And then you see these areas that have almost a yellowish appearance and they're very well outlined, and those yellowish areas are the areas of ulceration. And you can see in this case this is affecting the patient's tongue and the lips very prominently.

(16:09): As far as anatomic sites, the cheeks and the tongue are very common, but essentially anywhere in the mouth can be affected. It's not so common for it to go to the back of the mouth, so to affect the soft palate in particular, but we do see patients where it affects the hard and soft palates.

(16:28): Patients with oral GVHD often have pain when eating acidic, spicy, crunchy or hard foods. and mint-flavored toothpaste. Sensitivity from chronic oral GVHD may be irritated by toothpaste. Again, lips may present as just seeming dry, sensitive, inflamed. Or they may show these very typical features just like we would see inside the mouth. As far as symptoms are concerned we talked about sensitivity. So patients typically are going to have discomfort with eating and drinking, and in particular items that are either acidic, spicy, hard or crunchy. Brushing teeth can be difficult, not because the gums hurt or are sore, but just because toothpaste itself can be very irritating. And it's because of both minty flavor, and also the detergent in toothpaste, which is called SLS, sodium lauryl sulfate. And so sometimes it's just so simple as changing a toothpaste or switching to a children's toothpaste, and oral hygiene becomes much more tolerable.

(17:29): Chronic GVHD can cause thickening of tissues inside the mouth, making it difficult to fully open the mouth. Some patients will report that the mouth feels tight and/or that they can't open as widely. And in this case it's not because there's actually sclerotic or fibrotic changes, but it's because when you look at these white changes, those white changes are actually thicker than normal tissue. So it's something we call hyperkeratosis, it shouldn't normally have that white appearance. And if the cheek, for example, is not normally keratotic or keratinized, it wouldn't normally have these lacy white changes. And now you have this second almost layer of skin over the mucosa with almost a fence-like pattern, the tissue just doesn't stretch as much and so it'll feel tight. We'll treat the condition and that tightness generally goes away very quickly.

(18:25): So here for examples, you can see again some generalized erythema with the reticular changes. The upper right panel has some very thick reticular changes so to speak, but also with ulceration right nearby if you can appreciate. The bottom left is a patient with some fairly extensive ulcerations. But again, like I said before, you can see I'm not actually causing pain there while I was taking the picture. So having that mirror sitting and stretching against the ulcer in itself is not painful.

(18:57): And then in the lower right you can see the very typical pattern of these reticulations. And this is a slide to just point to all the things that would typically be quite uncomfortable.

(19:15): Chronic, oral GVHD can also cause superficial mucoceles that are just inflamed salivary glands. One other thing I just want to point out on the last slide that I didn't point out so well, but I'll show you again are what we call these superficial mucoceles. And some of you may have experienced this where you get little bubbles that pop up, in particular on the roof of the mouth, and these are just minor salivary glands. You have salivary gland tissue all throughout the mouth, they become inflamed and they just form these little spit bubbles. And they tend to come and go, they don't tend to cause too much discomfort, but sometimes they can be alarming for patients.

(19:47): So again, all these things we talked about already, imagine that all these things that oftentimes bring pleasure to life can actually cause misery in this condition.

(19:59): Topical steroids like a dexamethasone solution are often the best treatment for chronic, oral GVHD. So what do we do for management? I mentioned topical steroids already. We talked about use of overall use of immunosuppressive therapy in treating chronic graft-versus-host disease. Our mainstay of treatment for treating these rash-like changes, the lichenoid changes is topical steroids. We use generally either gels, so a gel is a semi-solid formulation, or vehicle that we're delivering the steroid in, or we use a solution. And a solution oftentimes is our best option because many patients will have not just a limited area or not just one area affected, but really all throughout the mouth. And using a solution is a much more effective way to deliver the steroid to the areas that we're trying to treat.

(20:51): Many of you may have already been treated with a medication called dexamethasone solution. We use this extensively for treating this condition as well as other conditions in oral medicine. It's formulated for oral use, meaning to be swallowed not as a topical medication, but because it's in a solution form, it actually works quite well topically.

(21:14): But again, when I talk to my disclosures about use of medications off-label, using dexamethasone solution for treating mucosal GVHD in the mouth is what we would consider off-label. There's nothing wrong with it and we use it all the time, it just doesn't have a specific approval for that indication.

(21:34): Clobetasol and budesonide are both also corticosteroids with higher potency than dexamethasone, they also both require compounding. I never have a justification to start a patient on anything other than dexamethasone. Because even in a patient where it seems like maybe this is the worst case I've ever seen. As long as I don't think that we need a systemic therapy at least to begin, I can't justify that we skip dexamethasone and go right to one of the others. Because dexamethasone can always have the potential to be very effective in any situation.

(22:12): Tacrolimus can also be used to treat chronic, oral GVHD and it works through a different mechanism than steroids. We also use a medication called tacrolimus. Many of you are familiar with this as an oral medication that you might take for your graft-versus-host disease, and/or it may have been one of the medications used as part of your what's called GVHD prophylaxis at the time of transplant.

Tacrolimus is not a steroid, it has a different mechanism of action. And it is commercially available and formulated as an ointment, which actually works very well for treating lips. And we have reasons to avoid use of topical steroids on the lips, especially the very high potency steroids like I have listed here clobetasol and fluocinonide. But Protopic or topical tacrolimus for the lips is very safe, does not cause changes like skin atrophy, or the atrophy of the lips like steroids can, and it can be a very effective treatment.

(23:07): We also will sometimes compound tacrolimus into an oral solution. And that's in a situation where I've already escalated somebody's topical treatment to clobetasol or budesonide. Maybe we've had some partial response, but I'm really looking for something better. And I still believe that we can achieve that with a topical approach rather than thinking about adding, initiating, and/or adding or changing a patient's systemic regimen.

(23:36): We use combinations of therapy like I already mentioned, and they don't need to be used sequentially. So if I have a patient who has such severe condition that we need to be using clobetasol solution and tacrolimus solution, I'll actually have them use equal parts and they can reduce the volume so you don't have a huge amount, and actually rinse with the two at the same time. Just like you might take all of your pills together at the same time, even though they're working differently once they get into your body.

(24:09): Intralesional steroid therapy can deliver the medication directly to the site of pain. Another treatment that we use is called intralesional steroid therapy, and that's delivering the steroid directly to the sore. So it's an injection of steroid with the intent that that's being delivered locally and acting locally, and it's a treatment that I use all the time in treating symptomatic ulcers. Sometimes we get things under good enough control, but there might be one hotspot that comes and goes, and we can put it at rest sometimes for a period of months just with a single steroid therapy.

(24:41): I mentioned the children's toothpaste consideration already. And again, anybody who's finding that toothpaste causes burning just switch to a children's toothpaste, and a non-mint flavored children's toothpaste, and it should be completely tolerable.

(24:58): So these are examples of treatment both before and after. So in the upper patient has symptomatic chronic GVHD lichenoid changes, they've been rinsing with dexamethasone solution a couple times a day, intensively three four minutes for a month. They come back to the clinic, and you can just see there's a lot less inflammation. The white changes are much less. The little area of ulceration, that little yellow spot has healed and is gone. The redness is much, much, much subdued.

(25:34): Similarly, with that lower panel, here's a patient with typical chronic GVHD in the lips, really bothersome in the lower lip, started the patient on topical tacrolimus, and a month later it's essentially completely cleared out.

(25:50): Immunosuppressive drugs used to treat chronic GVHD can lead to infections in the mouth such as oral candidiasis (thrush) and herpes simplex. We do encounter infections in these patients sometimes, and sometimes the infection can be directly related to our intervention as I already mentioned. First is oral candidiasis or what's referred to as thrush. And there's several risk factors for this that a typical patient, who might be either at risk for developing chronic GVHD would be experiencing, and that is immunosuppression. And it could be the immunosuppression simply related to the transplant, not even medications.

(26:21): Dry mouth, we'll talk about this again in the next couple of slides, but saliva plays a very important role in controlling and maintaining balance in the mouth. So just not having enough saliva will predispose. Use of topical steroids we just talked about that causes a local immune suppression. And if somebody is wearing dentures that go in and out of the mouth, those need to be disinfected very well because otherwise dentures can continuously reinfect so to speak the oral mucosa.

(26:53):. We have topical and systemic antifungal medications. For those of you who are patients, you're probably familiar with these. I underline systemic because in most cases systemic therapy will be more effective, and much more reliably effective than topical therapy. So occasionally, there may be a situation where we really want to avoid the use of a systemic antifungal agent, because of potential complications usually related to interactions with other medications. But in most cases we can use a systemic antifungal agent safely. And to initially treat, we generally only need to treat for about five or seven days.

(27:36): The problem is that if the same risk factors are present, so patient continues to use topical steroids because they have symptomatic graft-versus-host disease, and/or the mouth is dry, in some amount of time the infection is going to come back because all those same risk factors are in place. So we often use a long-term prophylaxis approach and that can be as simple as, and many of you may be familiar with fluconazole, a commonly used oral antifungal agent. And fluconazole at 100 milligrams, basically the lowest dose even just once a week, sometimes twice a week is sufficient to keep an infection from recurring.

(28:22): Herpes simplex virus may also arise from immunosuppression and complicate chronic, oral GVHD. The second important infection to mention is herpes simplex virus, or what we call HSV, or in the mouth and lip area HSV-I. This is largely related to immunosuppression, so this doesn't really matter if the mouth is dry, this doesn't really even matter if there's GVHD in the mouth. This is much more around immunosuppression.

(28:50): And important to keep in mind that patients can develop what we call a breakthrough infection. Meaning, they're on prophylactic antiviral therapy, which is usually acyclovir, sometimes valacyclovir or famciclovir, and despite taking it they develop infection. And that's just because there's just too much of a balance, and it's tipping in the favor of infection. In this case, antiviral therapy is used generally very effective. And rarely do we have situations with either a yeast infection or viral infection, where there's actually true resistance to our standard treatments. And that requires a whole additional workup and approach to management, which I think is outside of the scope of this discussion.

(29:43): So here are a couple of patients with candidiasis in the mouth or thrush, very typical, these are white patchy changes. Sometimes it can just be a redness change or we see a combination of both. And you can see on the right side that ulcer, and you can see some other graft-versus-host disease changes. So here's a patient who's developed what we've consider a secondary yeast infection in the context of intensively exposing neural cavity to topical steroid.

(30:15): These are both examples of herpes simplex virus, what we call recrudescence or reactivation. And these are these little ulcers on the left side. You can see the little collection of ulcers on the tongue, one towards the front, several in the middle looking on the left side, but the patient's right side, towards the right side of the tongue. And these tend to be really, really painful for such a small superficial-appearing ulcer. And they tend to have fairly irregular shape and borders to them like you can see in the bottom right.

(30:52): We talked about salivary gland disease, so I think everyone's fairly aware saliva is important. We use it for lubrication, helps with chewing, helps with breaking down food. It's important for taste. It has antimicrobial properties as we just talked about. It also has some important properties for maintaining the health of the teeth specifically.

(31:14): Oral GVHD can affect the salivary glands, make eating difficult, and lead to cavities. And we know that when the chronic graft-versus-host disease affects the salivary glands, it can lead to changes that cause the mouth to feel dry. It can lead to changes that can make eating difficult. So the food gets stuck or doesn't break down normally. Swallowing can be challenging for some patients. And then again, there's the increased risk of yeast infections, which we already talked about, but now more specifically development of cavities or dental caries. And these tend to follow a very specific pattern because they follow areas where food debris will tend to persist, and this is along the gum line and in between the teeth, and even sometimes on the biting surface of the teeth.

(32:02): So what we don't want to encounter is a situation like this where now a patient has developed cavities. So you can see those yellowish-brown areas near and along the gum line affecting nearly every tooth. This patient has cavities affecting all those teeth. In the lower I'm just showing you a radiograph in a young patient, who in a very short amount of time after transplant also developed extensive caries, including you can see in the patient's lower right side or looking at the screen, the lower left side where it looks like there's a tooth without a tooth. And that's just because the cavity became so deep and extensive that the tooth just fractured off.

(32:53): There are several over the counter and prescription medications to hydrate the mouth and stimulate salivary glands. So for managing salivary gland chronic GVHD, obviously it's really important just to stay well hydrated, and there are some over-the-counter saliva substitutes and sprays out there. We can stimulate the salivary glands with sugar-free gum, sugar-free candies. Some people may have heard of a product called XyliMelts. Many patients are aware of these, they also sort of work in a similar way to help kind of stimulate salivary flow.

(33:24): And then we have prescription sialogogic therapy, these medications are Pylacarpine or Salagen, and Cevimiline or Evoxac. And some of you may have been treated with these. Some of you if treated with these, hopefully, you've benefited. We usually get about a 50% response rate, so maybe a little bit higher than that. So I treat two patients and one patient should do very well with it. And a patient who doesn't respond within two or three months, if we have no reason to stay on the medication, we're not going to stay on it.

(34:00): It’s important to prevent cavities with brushing, flossing, and use of fluoride. Prevention of cavities is also really important and that's basic brushing and flossing, but also being careful about what one eats. So sugary, sticky, tacky foods will put somebody at higher risk because of the amount of sugar exposure or carbohydrate exposure.

(34:24): Fluoride, in addition to brushing and flossing is one of our best weapons against cavities. So this is a prescription strength gel, something that you might get directly from your dentist or that would be prescribed and you get from the pharmacy. Usually, it's noted to have 5,000 parts per million of fluoride. There's also even higher concentration fluoride product called fluoride varnish, this is something that's done in the office. And for somebody who's at high risk, we recommend this probably every three to four months, because fluoride varnish is known to be very effective in preventing cavities.

(35:02): Remineralizing agents can also treat cavities or demineralizing from compromised salivary glands. There's also another agent called remineralizing agents or these calcium phosphate-based agents. They probably don't play nearly as important of a role, but in somebody who's at high risk, and who's demonstrated significant either cavities and/or demineralization. When I say demineralization, that's when the tooth gets almost a funny frosty-like appearance, but it's not actually cavity. Those are the patients we'll probably want to throw everything at them that we can.

(35:35): Just seeing a dentist regularly is very important because the dentist will take what's called bitewing radiographs, which is what you see here. And I know I can't walk you through it, but hopefully you can see that on some of these teeth it looks like there's sort of a Pac-Man bite out. Or in these molars in the bottom towards the right, there's this big, large, shadowed area within the crown part of the tooth, and these areas all represent decay.

(36:07): Sclerotic chronic GVHD involves tightened skin and a reduced mouth opening. The sclerotic chronic graft-versus-host disease as noted, fortunately it's not very common, but it manifests with a reduced mouth opening. And this can be due to tightening of the skin on the outside, or because of what we see here these fibrotic bands that can form. And this is like a long-term complication or reaction to the inflammation of the graft-versus-host disease.

(36:32): And it obviously can have a significant functional impact. It can lead to some mucosal complications or defects, because these tight bands can pull away the gum tissue. It can also completely eliminate what we call the gutters or vestibules in the mouth. And for some patients not a big problem, but for somebody who perhaps wears a denture, without having that space, it'd be impossible to wear the denture. There can be pain but it's multifactorial, so it could be because the mouth doesn't open wide.

(37:10): I've had patients who because of the skin fibrosis sclerosis are actually developing pain related to muscle spasms. And management can be very challenging, we really don't have a good evidence base for this. We have some ways to approach trying to increase mouth opening, but in most cases it's just more of the same or the preventive aspect. And in particular if somebody has significantly limited mouth opening, making sure that there's a plan in place for them to be able to maintain their hygiene well, but also to get into the dentist for routine exams.

(37:49): So last thing I want to talk about before we switch to questions is the risk of Oral Squamous Cell Carcinoma. So oral cancer can present in a number of different ways.

(38:03): Sometimes patients with chronic, oral GVHD have persisting sores that get progressively worse even with treatment. Graft-versus-host disease in itself can be uncomfortable, there can be ulcers that stick around and don't go away. But when something different develops, so maybe there's a sore, but it's not just that it's non-healing, but it's actually progressively getting worse. Or whereas a sore, normally, you touch it with the tongue and it feels smooth and soft, and otherwise not irregular so to speak. In this case, it might be that the edges of the ulcer are thick and hard. So just anything that really points to there being a different process, it could be an ulcer, it could be a mass. There may or may not be induration. So induration is when it gets a hard feeling to it, and that's just because the cells are so dense that it becomes essentially solid. And it can look similar to graft-versus-host disease.

(38:56): When this happens, follow up care may involve a biopsy to screen for oral cancer. So at least early on, sometimes we're not going to make a diagnosis immediately. But at some point when something really differentiates itself, even in a patient who has active graft-versus-host disease, it should be obvious that there's something else going on. This points to the importance of routine follow-up in this patient population. And the importance of obtaining a biopsy in situations where we see something, and maybe we're not really sure what it is, but it looks funny. Also important that the patient is aware of this.

(39:28): So I don't like to put a lot of emphasis on this, but certainly when I'm seeing a patient for the first time for this condition, I give them an information sheet that we put together and I inform them, I say, "I don't want you to be worried about this. I don't want you to think that this is going to happen to you. But you need to be aware so that you don't ignore something that really shouldn't be ignored." And this slide shows that when the risk period for solid cancers develops, as far as we understand that risk just continues to climb as somebody continues to live.

(40:06): The signs of oral cancer are typically quite different than anything caused by chronic, oral GVHD. And here are four examples. And hopefully, without me going back and forth to the previous slides, when you look at these, and these are all in transplant patients, this just doesn't look like graft-versus-host disease. I know none of you are experts yet, but you've gotten fairly comfortable. Each one of these looks very different, but they don't look anything like graft-versus hosts disease. And if you looked in your mouth and you saw something that just looked really weird like this, even if it wasn't painful, you'd want to bring that to the attention of your doctor.

(40:38): So I know we've covered a lot of ground in 30, 35 minutes. Oral GVHD is common, maybe the first site of GVHD, a chronic GVHD, it may persist for months or years. Oral sensitivity and dry mouth are the most common symptoms that patients are going to experience. From a management standpoint there's some simple things that can be done like avoidance of certain foods and drinks, and making a change with toothpaste.

(41:07): We talked about the use of topical steroids and topical tacrolimus. We talked about the various management strategies for dry mouth symptoms. We talked about the importance of routine dental care. Seing a dentist on a routine basis, keeping up with preventive care and the importance of screening with dental radiographs to ensure that there aren't cavities developing. And finally, we just talked about the risk around oral cancer and the importance of awareness, and that this is something that any doctor who's looking in your mouth is potentially screening for.

(41:47): We don't really have guidelines that go above and beyond what we would normally recommend for the general population. Because when you go to see the dentist, or even when you go to see the dentist and it's a dental hygienist, there's always going to be a comprehensive soft tissue exam. So I'm not going to go through these next slides in detail. I think you'll have access to these slides, but this is just a little tip sheet or something you might even share with one of your doctors if they're not familiar. Common prescriptions for the mucosa, some common prescriptions that we use or over-the-counter agents that we might use for salivary gland disease.

(42:24): There are many good sources of information on mouth-related complications of from stem cell transplant and chronic, oral GVHD including at BMTinfonet.org. And then these are the survivorship guidelines from the American Society for Transplant and Cellular Therapy as they pertain to the mouth-related complications. So I will, and then you have the references here to a number of different free and available resources, some of which are provided by BMT InfoNet. And I think I'm going to stop talking and we'll hear the moderator again, or I've been speaking to myself for the last period of time. But I hope this was informative, interesting, it doesn't cause too much anxiety or fear about anything, and I would love to answer some questions.

Question and Answer Session

(43:17): [Steve Bauer]:  Thank you for Dr. Treister for this excellent presentation. We'll now begin the question and answer session. "How to protect my gums against recessing caused by severe mouth dryness. My salivary glands are destroyed by fibrosis caused by oral GVHD, this was diagnosed by unsuccessful salivary gland endoscopy. I need nonstop mouth moisture to open it up. Any help for this please?"

(43:59): [Dr. Nathaniel Treister]: So this is a three-to-four-part sandwich question. I'm going to start with what the question was, although it actually asked I think two to three different questions, or proposed a few different things. The question was what can I do to prevent or slow down the process of gingival recession? As far as I understand, gingival recession is not caused by dryness in the mouth. A patient can have chronic severe dryness, but that won't cause gingival recession. We do see gingival recession sometimes in patients with chronic graft-versus-host disease, probably occurring at a greater rate than we might see in the general population. With that being said, people should keep in mind that gingival recession is somewhat common and expected in the context of aging.

(44:59): And sometimes, especially when there's been a lot happening inside the mouth, and then you get to a period where it feels like, "Oh, things are calming down." That may have been a long enough of a period of time where even just a little bit of recession becomes much more noticeable. With that being said, we definitely will see some patients where we can appreciate recession. Maybe it has to do with some tightening of the tissue like we know can happen anywhere in the skin, or even in the oral mucosa. But unfortunately, my answer to the primary question that was asked is as far as I know, and as far as we know from any experience or evidence, not just with this condition but with other conditions. Unless recession is being caused by something that the patient is doing, for example, brushing too hard consistently in one area.

(45:58): So oftentimes, patients will develop some recession in particular around the canine or eye tooth, and then the premolars. And those are areas where there just tends to be things are more prominent, it's very easy to brush that gum tissue more intensively. And oftentimes people will only do that more on one side than the left side. So making sure that when you're doing oral hygiene, you do it gently with a soft toothbrush. Gently, but effectively that will help reduce the risk of that. But if recession is going to develop, it's going to happen. And as long as the teeth are not particularly becoming sensitive, I would say in most cases other than there being a cosmetic change, it's not necessarily something that requires treatment. So I hope that helped to answer that question.

(46:50): [Lynne Spina]: Does radiation make the skin at the top of your mouth thinner? I seem to burn easily on pizza and the burn causes the whole spot to peel.

(47:03): [Dr. Nathaniel Treister]:  Okay. Anyone can get a piece of burn if other foods are not consistently causing some burn or injury, I would just first off recommend that you're going to have to let your pizza get cooler than normal. It may be that the tissue is a little bit more sensitive than typical than it was before your transplant. But if it's not that all foods are doing this, I would just be careful, because it's easy to burn yourself with pizza. You asked a question about radiation. I'm not sure why the question was focused around radiation versus the effects of chronic graft-versus-host disease.

(47:39): [Lynne Spina]:  The question was does radiation make the skin at the top of the mouth thinner.

(47:42): [Dr. Nathaniel Treister]:   Yeah, no, so the short answer is no. If somebody has received total body irradiation as part of their conditioning for a fully ablative allogeneic stem cell transplant, that radiation doesn't typically have any significant short and/or long-term effects on the oral tissues or the salivary glands. So radiation can cause all sorts of problems in and around the mouth when somebody is treated for a head and neck cancer. But in the setting of total body irradiation conditioning, there shouldn't be any long-term consequences. graft-versus-host disease in the mouth can certainly make the palatial mucosa more sensitive, and could easily become irritated with hot noxious food. But I would just say I would just be cautious.

(48:35): [Lynne Spina]:  Thank you. "Is there any research suggesting a correlation between induction and consolidation chemo ahead of an auto transplant, and teeth crumbling five to 10 years after treatment?"

(48:53): [Dr. Nathaniel Treister]:  No. Short answer is no. And there's a lot of potential explanations for that type of a situation, so I don't really want to speculate in this case. But there shouldn't be any direct lasting effects from those interventions, from those treatments.

(49:12): [Lynne Spina]: Okay, thank you. This person wants to do just a little deeper dive, but still keep it short about your slide 12 that you showed the intensity of oral mucosal GVHD and decline over time. This person is wondering, can you discuss that just a bit?

(49:31): [Dr. Nathaniel Treister]:   So that figure is actually, it's sort of a more general figure for chronic graft-versus-host disease, not the mouth specifically. And what it's pointing to is something that we expect and anticipate, but it's not something that affects each patient equally. And that is the development of what we call immune tolerance. So graft-versus-host disease starts and it may be like a forest fire. But for most people it doesn't remain a forest fire forever, it eventually, as we say it burns out or settles down. And so what that figure was showing is that it starts at a certain level of intensity and it's going to require treatment, but at times it may not require treatment.

(50:26): And that intensity it may not follow that perfect trajectory, but with time it generally gets to be less and less. That's a much more ideal way of thinking about overall chronic GVHD. And while the mouth can and sometimes does track in that pattern, it also can break that pattern as I mentioned before. So it could be that that's happening on a systemic manner. And yet the mouth continues as a dotted line going from near the top of that graph into the right. And maybe it goes down, but it goes down in a much more gradual slope than what was shown in that figure. I hope that makes sense.

(51:15): [Lynne Spina]:  Yes, thank you. "Could any of the medications I take for GVHD have a side effect of dry mouth?"

(51:29): [Dr. Nathaniel Treister]:  Short answer is yes. There's not any of them that are highly xerostomic as we would say, causing dry mouth or dry eye, but certainly they have potential. But just so everyone's aware, the medications that have the greatest potential, and I'm just stating these broadly, not specifically, not even the specific medications within these categories are cardiac medications, and in particular medications used for managing high blood pressure, as well as psychiatric medications and antidepressants in particular.

(52:17): [Lynne Spina]:  Great. The next question, "I was diagnosed with TMJ. I've read that TMJ is typically due to teeth clenching and muscle pain, but X-rays show joint degeneration." This person's wondering if some of the treatments they've had for their disease could cause it, or is there still hope for recovery of TMJ due to joint degeneration?

(52:46): [Dr. Nathaniel Treister]:  I obviously can't really comment on the specifics of this individual person's question. But the finding of joint degeneration may or may not be directly related to what the patient's symptoms are. So with joint degeneration and if there were symptoms around that, that would be very specifically within the joint complex itself. Most people who suffer from what's called a temporomandibular disorder sometimes referred to as TMJ, the temporomandibular joint, it's usually more of a muscle or muscular skeletal condition causing the discomfort.

(53:32): It's also possible that degenerative joint changes were noted incidentally, and it really has nothing to do with it. So it's all speculative. If there's severe joint degeneration, and depending on what an individual's function and symptoms are, there may be specific interventions for that. But again, if it's not actually directly related to the joint degeneration, it may have nothing to do with the overall prognosis. So I'm not really sure how better to answer that. And even from an imaging standpoint, how in what way we image will give us a better understanding of to what extent there are degenerative changes. But I'd say if this person has access to and/or has not already been seen by an oral medicine specialist, or an oral facial pain specialist, that would be in their best interest.

(54:49): [Lynne Spina]:  [That] leads into the next question as it relates to who to see. This person is going to a college dental facility, is that okay for dental checkups post-transplant? And I'm thinking it would be helpful to the audience for you to also expand about when to see a general dentist and when to see a specialist.

(55:17): [Dr. Nathaniel Treister]:   Most people who have had transplant after transplant are going to return to their community dentist, probably the same dentist that they saw for a dental clearance or screening exam before transplant. And for the most part, at least dental management and potential management of dental disease after a transplant, even for somebody who might be at higher risk for developing cavities, or requires management of cavities is well within the scope of a general dentist. General dentists will have very little experience and/or expertise in managing the medical side of graft-versus-host disease in the mouth. So for example, the use of the medications like we talked about for managing the mucosal condition and/or the salivary gland disease.

(56:14): And to see a specialist like me in oral medicine, unfortunately at this point in time it really depends on where you are in the country, because we don't have great penetration of these specialists in all the major cities, let alone non-urban centers. But that's changing and it doesn't help anyone today, but over time we will have more and more oral medicine specialists. But for most dentistry it's going to be a general dentist, or to an appropriate dental specialist if there's a problem, that would require a typical or more standard dental management approach. But for something that's going to be more on the medicine side like what I see on a regular basis in my clinics, it will require some higher level of expertise to see, like I said, an oral medicine specialist. Or I think at some centers there may be dermatologist who's managing chronic graft-versus-host disease, where they may have some degree of comfort of also treating inside of the mouth.

(57:30): [Lynne Spina]:  So post-transplant, if you're not experiencing anything too severe, a dental college or your general dentist is okay?

(57:38): [Dr. Nathaniel Treister]:  Yeah, absolutely. And anyone who wants to go to a dental college or dental school I assume is what they're talking about, perfectly appropriate. Being seen at a dental school won't necessarily provide you a whole lot of expertise onto the medical side of things like I was talking about, because it's really going to depend on the school. Some schools will have very strong oral medicine department and service, and some really may not have much from that standpoint. Some oral surgeons may have some comfort and expertise experience in managing some of the medical side of things, but that's going to be really variable.

(58:22): [Lynne Spina]:  Closing. All right, well, we've run out of time. But before I close up the session, I would like to mention that BMT InfoNet does have a directory of GVHD specialists you can access at bmtinfonet.org/gvhd-directory. thank you to the audience for your excellent questions and thank you Dr. Treister and our partners for a very helpful presentation. Please contact BMT InfoNet if we can help you in any way.