Your Mouth and Chronic Graft-versus-Host Disease

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Your Mouth and Chronic Graft-versus-Host Disease

Wednesday, May 4, 2022

Presenter: Nadarajah Vigneswaran BDS, DMD, FAAOMP, DABOMP, Professor of Oral and Maxillofacial Pathology, UTHealth School of Dentistry, Houston, Texas

Presentation is 54 minutes long with 12 minutes of Q & A.

Summary: Approximately 60% of patients with chronic graft-versus-host disease (GVHD) have GVHD in their mouth. Patients, as well as dentists, often confuse oral GVHD with other mouth problems.  Seeking treatment from a dentist familiar with chronic GVHD is important.

Many thanks to Kadmon, a Sanofi Company. whose support, in part, made this presentation possible.

Highlights:

• GVHD can destroy the salivary gland and cause dry mouth. Dry mouth can lead to infection, tooth decay, gum disease, lack of taste, and persistent sores. Saliva substitutes and some prescription medications can help with dry mouth.
• If you have a dry mouth, avoid carbonated beverages. Even those without sugar can increase your risk of developing cavities.
• If severe mouth pain doesn’t respond to topical corticosteroids or a dexamethasone rinse, systemic steroids may be used. Since these may trigger yeast infections, antifungal medications may also be necessary.

Many thanks to Kadmon, a Sanofi Company, whose support, in part, made this presentation possible.

Key Points:

(01:58): Common symptoms of oral GVHD are mouth pain, ulcerations, chapped lips and dry mouth, which increase the risk of infections

(03:51): Lichen planus, characterized by red and white striations, is a common expression of oral GVHD. Unless it is causing pain, it is left untreated since it cannot be cured and usually resolves on its own.

(08:43): Most bacterial infections in the mouth are gram positive and will not clear with antibiotics like Bactrim that doctors prescribe to prevent gram negative infections in other areas of the body.

(10:50): Topical steroid gels, rather than topical creams, are preferred to treat pain in the mouth due to GVHD, since saliva can wash creams away. In more severe cases, a dexamethasone rinse or systemic steroids may be needed to treat oral GVHD.

(17:01): Hairy or coated tongue can occur in GVHD patients and is often mistaken for thrush. Patients with hairy tongue should avoid mouthwashes with alcohol that can reduce saliva.

(28:22): A variety of saliva substitutes and stimulants, and some prescription medications may help with dry mouth.

(39:12): If you wear dentures, both your mouth AND the dentures should be treated to avoid reinfection when dentures are put back into the mouth.

(49:05): Without proper treatment GVHD related gingivitis can also promote bacterial infection and even severe periodontal disease. A custom tray with gel medication can treat gingivitis from GVHD.

(51:50): Oral cancer can sometimes be mistaken for GVHD so accurate diagnosis by an expert clinician in mouth diseases is essential.

(52:55): Mouth ulcers caused by other problems are often confused with GVHD. Getting a proper diagnosis is important before starting treatment.  

Transcript of Presentation:

(00:01): [Marla O’Keefe]  Introduction. Hi, my name is Marla O’Keefe O'Keefe. Today's workshop is Your Mouth and Chronic Graft-versus-Host Disease. I'd like to thank Kadmon, a Sanofi company, whose support helped make this workshop possible.

(00:16): It is my pleasure to introduce Dr. Vigneswaran. Dr. Vigneswaran is a professor of oral and Maxillofacial pathology at the UT Health School of Dentistry in Houston. He specializes in the diagnosis and treatment of oral mucosal and salivary gland and jawbone diseases. Please join me in welcoming Dr. Vigneswaran.

(00:43): [Dr. Nadarajah Vigneswaran] Overview of Talk. Thank you, Marla O’Keefe. First of all, thank you for the [BMT] InfoNet, inviting me to give this presentation. And I've been working with the MD Anderson clinic with a number of patients with GVHD, and I hope I can answer some of your questions. If I don't know the answer, I will ask other experts and get back to you.

(01:13): Approximately 60% of patients with chronic graft-versus-host disease (GVHD) have GVHD in their mouth.  So, with that introduction, I want to start my presentation. And so, as you can see [with] chronic GVHD, the most common area in our body that [is] affected is our skin. The second most common site, [in] about 60% of the patients with chronic GVHD, their mouth gets affected. Most of the mouth issues are very minor, most of the time, but occasionally it can be cause severe pain and other complications. So we are going to go through some of the common. as well as some of the rare, but more serious complications that can be seen in patients with GVHD.

(01:58): Common symptoms of oral GVHD are mouth pain, ulcerations, chapped lips and dry mouth, which increase the risk of infections. So, the second most common site that [is] affected by GVHD is the mouth. So that's what we are going to talk about. So what are the common problems patients with chronic GVHD encounter in the mouth? Typically, they will feel pain, ulcerations, or sores. They will explain that it is painful, especially while eating some crunchy food or hard or spicy food, [it] bothers them. Or even in the throat they can have [it]. And frequently, they also have chapped lips like a cracking and dry lips, dry mouth. And when you have a dry mouth that increases the risk of developing decay of the teeth.

And infection is frequently seen. We are going to talk about some of the common infections that we can see. And most of you might have a prophylactic treatment for antiviral and antifungal, but there are some infections [that] may overcome that, and you may present. And the last topic I'm going to talk about, the risk of oral cancer is slightly increased over that seen in the general population.

(03:08): A fungal infection called yeast or thrush, and viral infections such as herpes simplex and herpes zoster are common in patients with oral GVHD. So what are the problems that are commonly seen in patients with the chronic GVHD. Frequently we see infection. Commonly seen is a fungal infection, called yeast or thrush. Sometimes thrush can look red or white., And of course, viral infections, commonly the herpes simplex virus, or herpes zoster virus, are rare. Most of the patients are on antifungal prophylactics and antivirals, so usually you won't see that. But if they stop the antiviral or antifungal treatment, then these can end up coming back because of the immunosuppressed status of the patient.

(03:51): Lichen planus, characterized by red and white striations or lesions, is a common expression of GVHD. The most, very common condition that we see in patients with GVHD, is oral lichen planus, or lichenoid changes. This is a very common condition we see in non-GVHD patients, a condition we call lichen planus, which is red and white patches of striations. And similar lesions also occur frequently in transplant patients. And that's what we call lichenoid. They look exactly the same, even microscopically in the biopsy, they look the same. But the only difference is, in patients with GVHD, the bone marrow transplant triggers it - that is, somebody else's immune cells are attacking the mouth, whereas in the general population it is their own immune cell, so they're called autoimmune. In the case of GVHD, it's called graft-versus-host disease.

Another common problem is very minor hairy or coated tongue. I'm going to show you a lot of pictures.

(04:57): Gingivitis and dry mouth can develop from GVHD as well. And frequently also we see the gingival inflammation, what we call gingivitis. As you know, gingivitis is most commonly caused by bacterial gingivitis, so plaque related. But in some patients with GVHD they develop gingivitis due to GVHD.

And that's what we call discriminative gingivitis, which is not plaque related. So even with brushing and cleaning your mouth, still, the gum is going to be inflamed, and we'll talk about it, what the treatment is for that. And that last one is dry mouth. It's another common complication because the GVHD affects your salivary glands, or medications that you are taking that can also cause dry mouth.

(05:42): There are different types of lichen planus. Unless it is causing pain, it does not require treatment. So, there are different types of the lichen planus, and I'm going to show you the pictures. This is a very common lesion that we see in patients with chronic GVHD affecting the oral cavity. We call them lichenoid keratosis. What is keratosis? It is an increase, almost like a callous-like white patch, occurring on the lips, on the tongue or on the cheek. And on the top of your tongue, it'll be more like a white plaque.

Fortunately, these lesions, these white areas, rarely cause pain, unless they're mixed with the red areas. So these are called lichenoid keratosis, and frequently if they're not hurting, or if they're not painful, if you're not feeling any pain while eating spicy or acidic food, we just leave them alone. We don't treat them because they’re not causing pain, because we cannot cure it. And with time they will become less and less prominent and become not cosmetically bothersome. So unless if it is painful, we do not treat these conditions called lichenoid keratosis.

(06:56): Lichenoid mucositis is likely to be painful and require treatment. The pain and sensitivity comes with these types of lichenoid mucositis. We call them mucositis because there is definitely inflammation and thinning of the epithelium. So that's where the skin of your mouth becomes very thin and inflamed. It looks red with some white patches like that on the tongue. The top of the tongue will be very smooth and red, and the side of the tongue will have white patches with redness. And these patients will have a lot of sensitivity to spicy food, hot food, or even a crunchy food will be bothersome. So this is what we call lichenoid mucositis. Again, patients with this condition may need to be treated and we'll explain in a minute what the treatment is that we usually prescribe for these patients.

(07:51): Ulcerative mucositis is the most painful lesions of the mouth. And the last form of lichenoid mucositis, these types of lesions, these are called ulcerative. These are the worst ones. They are the most painful. So you have open sores like that, and you will have a yellowish dead tissue in the middle - large areas, either in the cheek or in the tongue. In patients with GVHD, because of their immunosuppressed condition, these can get infected by bacteria. And some of the bacterial antibiotics that your doctors will be prescribing for you, like a Bactrim, those antibiotics will not protect against oral bacteria. So in those instances, we sometimes have to treat you with amoxicillin or antibiotics that will work for the oral microbial flora.

(08:43): Most bacterial infections in the mouth are gram positive and will not clear with antibiotics, like Bactrim, that doctors prescribe to prevent infection in other areas of the body. So when you have a very large open sore, when you have a dry mouth - and every one of us has bacteria in our mouth, we cannot get it out, that is normal microbial flora. But when a patient has GVHD and stays in the hospital for a long time, that microbial flora changes. Some bad bacteria gets into your mouth too. So those bacteria utilize the opportunity of the patient being immunosuppressed - you may be taking prednisone or some of the other immunosuppressive medication - -so those bacteria can overgrow and get rid of the good bacteria.

And then, if you have an open sore, then they become infected. I will show you pictures in a minute. So keep in mind that these bacterial infections will not clear with the Bactrim that your doctors will be prescribing for your GI or other areas, for gram negative bacteria. Most of the bacterial infections that occurs in that mouth are gram positive. So it’s important to keep in mind that you may be taking antibiotics, but those antibiotics may not work for infections in the mouth.

(09:51): In people with darker skin, lichenoid lesions can become pigmented and darker. Another thing you may see, especially in people with darker skin, are these inflammatory lichenoid lesions that can become pigmented. So you may see some gray or blackish discoloration in addition to red and white areas. That is the normal response of the body. When we have a dark skin individual, when there is an irritation and inflammation, it's like when you go in the sun, you tan more, in the same way an inflammation makes them darker. We call them post inflammatory melanosis or pigmentation. That is the normal response. It is not a melanoma or anything like that. That typically occurs in dark skinned individuals with longstanding inflammation. The inflammation is coming from the GVHD or lichenoid mucus condition.

(10:50): Topical gels, rather than topical creams, are preferred to treat pain in the mouth due to GVHD, since saliva can wash creams away. So how do we manage that? So this is a very common condition. As I said, when you have white areas, no pain, we just leave it alone. But if you have a pain, depending on the severity of the pain and extent of the lesion, we start with a very conservative method, using a topical corticosteroid, like Clobetasol gel. We always use the gel medication. Usually in the mouth we do not use anything like a cream because mouth has saliva, it's watery. So you want to use the gel that can be applied to the mucosa, or cream that doesn't spread out. So the gel is the best form t use to treat oral lesions.

(11:37): Another thing to keep in mind when you buy these tubes of gel, it that is will state that it's for external use only. The reason is, the FDA has not approved any topical corticosteroid to be used in the mouth. But remember, mucosa is similar to skin. As long as you don't unnecessarily swallow your spit, you can apply these to the mouth mucosa. Since it's kind of an off-label use - the FDA has not stated that this can be used in the mouth - you are going to see it stated on the tube that it is for external use only, but you can use it in the mouth. But when you're putting it in the mouth, if you have to spit. Do not swallow the spit, try to spit it out, or take a paper towel and wipe it away so that you don't swallow it. If you swallow it, it's not poisonous or anything like that. It's only that you are unnecessarily taking systemic steroids, and that's not what your doctors meant when they prescribed the topical one. So it is either Clobetasol, which is stronger, or clobetasol plus fluocinonide gel which is a little more intermediate. So either one, depending on how extensive the disease is.

(12:49): A dexamethasone rinse can treat larger areas. If you have a lot of areas affected like a cheek, tongue and other places, it's very hard to put a gel on topically. So we can prescribe a rinse form. The most common one that we use is dexamethasone. So you would just put it in your mouth, one teaspoon, keep it in a minimum of two minutes, maximum five minutes, and kind of move it around the areas. Then you are going to spit it out. After you spit it out, do not immediately rinse your mouth. Wait at least 15 minutes, 10 to 15 minutes longer. After that you can rinse your mouth out and you go on with your life. So make sure to not rinse immediately. Keep it in as long as possible.

 (13:35): If you have a large ulcer, like the one that I showed earlier on the tongue, in order to make them heal faster, we sometimes give an intralesional steroid injection. Rather than give you systemic medication, which has its own side effects, [we give it] around the ulcer. That will help the ulcer heal faster. So if you have one deep ulcer like that, or even two of them, we can, under the local anesthesia, inject around the ulcer, and that makes the ulcers heal faster.

(14:07): If severe conditions don’t respond to other treatments, systemic steroids may be used. If there is a severe condition and it's not responding to the other treatments we just talked about, that's when we're going to start the systemic steroids. Sometimes doctors will prescribe prednisone. I prefer dexamethasone because it has a topical effect as well as systemic effect. We use a tapering dose. That means we'll start with the higher dose and slowly, gradually reduce it. We need to reduce it very gradually every week, slowly, and not typically use the Medrol dose pack.  I like to use it longer term to get your immune system tamed down so that it slowly stops attacking your mouth.

(14:56): But sometimes your doctors might say, you have other complications: you have thinning of the bone, osteoporosis, you have other conditions and they do not want to use steroids systemically. There are other options such as Tacrolimus cream. Or sometimes you want to make an oral solution out of the capsule. so you can rinse it and spit it out. The same capsule you'll be using for your GVHD, we make it as a solution, and you can use it to rinse your mouth and spit it out as a topical treatment.

(15:30): There is ointment available. Unfortunately, they don't make gel for Tacrolimus, so that's one reason I don't like to use it as a gel. I will compound that as a solution and use it for that purpose for the mouth.

(15:48): Steroids may cause yeast infections so antifungal medications may also be utilized. So one other thing to keep in mind: If your doctors prescribe prednisone or dexamethasone, or even a rinse and spit it out, if you are not taking any antifungal medication like fluconazole or Diflucan, you may have a risk of developing yeast infections, because the steroids suppress the immune system in your mouth. We have yeast in the [mouth], but it doesn't cause infection. It lives in our mouth. But as soon as we suppress the immune system, then that’s going to cause thrush or yeast infection. So make sure you're taking an antifungal. Then you won't have the problem. If you're not [taking an anti-fungal], and if you started taking prednisone or any immunosuppressive medication, you have a greater likelihood of developing yeast infection, thrush. So, you may think, ‘oh, this is due to my GVHD but that may not be the case. And I will show you some pictures in a minute.

(17:01): Hairy or coated tongue can occur in GVHD or non-GVHD patients and is often mistaken for thrush. Here is another common mistake a lot of patients make. So here you see, in the two [pictures], the top of the tongue looks white in one, and in the other one it looks brownish white. We call this hairy or coated tongue. It occurs in both non-GVHD patients as well as GVHD patients. We see it frequently in GVHD patients because of their mouth dry. So because our saliva keeps our mucosa healthy and cleaned up, when you have a dry mouth and some altered microbial flora, which I talked about earlier, that irritates the top of the tongue and makes those, we call them Filiform papillae, grow it a little higher and then get coated by bacteria, And that's why it's white.

(17:51): So a lot of times, not only patients, even the medical doctors mistake this as a thrush. This is not thrush. This is actually a bacterial coating of your dorsal tongue., Especially with a thrush or a yeast infection, when it occurs in the dorsal tongue, it'll look more red. I'll show you pictures in a minute. So if you have a tongue like that, this is called coated tongue. And I'll explain to you how you treat that in a minute.

Sometimes it also can get pigmented if you're drinking coffee or taking certain medications. And certain bacteria can make chromogenic substrate, and then the [tongue] become more blackish or white. And this can also cause some mal odor, halitosis. And it also can cause some irritation in your throat when you swallow. So these are some of the complications that you can see, but it's a very benign condition and it can be easily taken care of, and I will come back to that minute.

 (18:47): So it is typically on the top of the tongue and looks white or brownish or blackish. Sometimes, rarely, it can cause halitosis. It can cosmetically look ugly, Rarely, it also can cause irritation or a gagging sensation in your throat. It can cause some altered taste in your mouth and always make your mouth feel very dry. A coated tongue makes your mouth feel more dry.

(19:25): Immunosuppression and dry mouth can cause hairy tongue. Using mouthwashes with alcohol will cause more dehydration. So who gets it? It occurs in both non-GVHD patients and GVHD patients. The major risk factor for developing it is dry mouth and severely ill patients, which some of you are because you had a bone marrow transplant. You had a lot of medications given to you that altered your microbial flora, and you may be still taking many medications that make your mouth dry, that suppress your immune system. So longstanding antibiotic [use], longstanding steroid treatments or other immunosuppressive treatments, all these things can cause coated tongue or hairy tongue.

The most important thing is to avoid using any mouthwash with alcohol in it because that's going to dehydrate more. So the only thing that you want to do is drink enough water. Mix salt and baking soda in eight ounces of water, that's the easiest, and rinse your mouth frequently. And we will talk about dry mouth treatment later on. So never ever use any mouthwashes that have alcohol in them. Okay?

(20:38): So this is where I want you to see the difference. A lot of time, even your doctors will tell that you have thrush when they see a white area on the tongue. This is coated tongue. This is bacterial coating, where you have excess growth of those Filiform papillae. This is not a yeast infection. When a yeast infection occurs in GVHD patients or anyone who is immunosuppressed, this is how the tongue will look: very red, not white. Sometimes you may have a little bit of white patches that can be wiped away easily. So this kind of red, it's almost like a bold tongue like that. You won't see the Filiform papillae that fill a granular like this area. So when you see that, then you know, and this will be very sensitive, will burn with spicy food or acidic food.

 (21:27): It’s important to recognize the difference between thrush and hairy tongue. So that's how you will differentiate. This is a very frequent mistakes patients make. When they see this white, they think that they have thrush or a yeast infection, and sometimes it gets reinforced by the doctor. So I want to highlight this important difference, that thrush only occurs on the top of the tongue, and when it occurs it looks more reddish, not white like that.

(21:59): Hairy tongue can be treated in several ways. So how do we treat the hairy and coated tongue? This is another common complication I see in patients with chronic GVHD. So there are different oral antimicrobial rinses. One is called chlorhexidine. Unfortunately they stopped making the alcohol free one, so it still contains alcohol. But I'm not going to ask you to rinse your mouth with that. You pour it in a cup and use these tongue scrapers that you can buy it commercially. Dip them in chlorhexidine, and every time after you brush your teeth, just scrape your tongue with that. Okay? That's the best way to kill those bacteria that are coated on the top of the tongue.

 (22:38): If some patients, even with that, they don't get better. Sometimes we use a kind of diluted Clorox, basically. So, 125% and you dilute it. And you basically dip the same tongue brush and scrape it. And this basically takes care of all the bacteria. It kills them. So, these are the two best ways to kill the bacteria that are growing on your dorsal tongue and causing the coated tongue.

(23:13): And you can see here a in patient who has a very dry mouth with thick, less watery saliva, that bacteria gets coated. I'm just showing a picture here - this is called a Velscope. When there is bacteria, it produces a fluorescence. It looks like a red color. I sometimes use this to demonstrate to the patients, this is not a yeast. You have a lot of bacterial coating, that's what makes this white area. So remember, the coated tongue is, the, majority of the time, a bacterial coating with keratin builds up and other things. Cleaning the tongue, brushing the tongue with antimicrobials will take care of that.

(23:56): GVHD can destroy salivary glands and cause dry mouth. Some medications can also cause dry mouth. The third complication is dry mouth. Some of you might already know that it is mainly caused by two things. One, the GVHD, the immune cells that are grafted into you, the allogeneic graft, they can affect your salivary glands and cause a disease, similar to Sjogren syndrome. Sjogren syndrome is an autoimmune disease in non-GVHD patients. In GVHD patients, graft-versus-host disease affects the salivary glands. It destroys the glands so that they cannot make spit, and you develop dry mouth. Even in the absence of GVHD, a lot of patients take many medications such as an antipsychotic, anti-inflammatory medication, blood pressure medication.... There are a number of medications that have, as one of their side effects, dry mouth. So medications and GVHD are the main cause of dry mouth, and we see a higher proportion of patients with GVHD who have a dry mouth. So we need to treat initially conservatively with an over-the-counter medication. If it doesn't get better, we prescribe other medications. I'll come back to that in a bit.

(25:19): Anxiety can also contribute to dry mouth. The third, and not least common [cause of dry mouth] is anxiety. You have gone through a lot: a cancer diagnosis, a bone marrow transplant, a lot of medications and that really causes severe anxiety and stress. And that can also cause dry mouth. So you have the medications, the Sjogren syndrome-like effect, as well as anxiety, all three of them combined, or even in isolation, can cause dry mouth. And that causes dehydration because you may not be drinking a lot of water because of the pain or other things. All these factors also add to the severity of dry mouth.

 (26:05): Patients with dry mouth have to continuously drink water. So how does it feel? A lot of patients with dry mouth have to continuously drink water. They have to get up in the night and drink water. Their mouth feels parched, it's almost like a scorched, burn, almost sandpaper like sensation. The tongue and everything sticks. They don't move. And in fact, if you have a lichenoid mucositis, it’s going to be worse because your tongue and cheeks have lost their moisture, and there's not a lot of friction. So the dry mouth gets aggravated, it makes it worse. You may have a bitter taste, a metallic taste. You will have difficulty talking or chewing food and have choking. All of these complications that are seen in patients with severe dry mouth. So definitely you have to treat it to improve the moisture in your mouth.

(27:01): Dry mouth can cause persistent sores, affect taste and lead to tooth decay and gum disease. So what other complications can dry mouth can cause? There are the long-term complications. In addition to the discomfort we just talked about, dry mouth increases the risk of developing tooth decay. And I will show you the type of decay that you see in patients with severe dry mouth.

 It also increases gum disease. So there is a higher risk of more severe tooth decay and gum disease when you have a dry mouth because saliva protects ... it has an immune system. It protects against bacterial infection, even fungal infection. So if you have a dry mouth, it causes gum disease, decay, and more frequent yeast infections in your mouth if you are not taking anti-fungal medication.

 (27:44): Dry mouth can affect taste and cause persistent sores. It's also important to taste food. When you don't have [enough saliva] you may not be able to taste the food or [you may have] altered taste. And the last, not the least, it's going to aggravate mucositis and ulceration, because of the friction.

(27:57): Number two, saliva has growth factors. It facilitates the healing of open wounds. And when you have a dry mouth, that function is lost. So you are going to have persistent sores, which are not healing because of the dry mouth. Even though we don't appreciate it, it's very critical to make more spit to help to reduce some of these complications.

(28:22): Saliva substitutes and some medications may help with dry mouth. So how do we treat patients with dry mouth? There are a number of saliva substitutes you might have heard of. Many of you know Biotene. I do give it to some patients, but there are more [saliva substitutes] than Biotene. There are a lot of different products. I have a picture [of them] in a minute, so I will tell you when I show you the pictures. So, these are stimulating ones that stimulate [saliva production].

(28:45): And definitely we can prescribe medications to make more spit. They don't have major side effects. A very old medication, like a pilocarpine, it makes you sweat a little bit. Other than that it's tolerated well by a lot of my patients. So that can help you to make more spit. It also keeps your salivary glands active. If you don't use them, you lose them. If you don't make your salivary glands work, they slowly die. So that's another reason to treat you, to make you spit, and to make your salivary glands continuously work, and become more active.

(29:19): Cavity prevention is basically fluoride, flossing and using fluoride prescription gel. And sometimes we use varnish to prevent carries [cavities].

(29:32): Finding a regular dentist who is comfortable treating patients with GVHD is important. And of course you have to get regular dental care. Some dentists are a little hesitant to treat you. You have to find a dentist who's comfortable treating patients with GVHD. And you’re not like any other patients who have immunosuppressant treatment. There are no contraindications to have fillings or anything like that, or getting your teeth cleaned. If your GVHD doctor tells you that you can have dental treatment, you should be able to go to any dental office and get your teeth cleaned, caries protection, fluoride gel.

(30:04): Several antifungal medications and sprays can be used for yeast infections. If you have a yeast infection, of course, we have to treat you with an antifungal infection. So these are some of the things that I prescribe. These are over-the-counter treatments. You can buy them online or you can buy them from any pharmacy. And a lot of patients use Biotene, but there are many, many products available. And many of my patients like this product, Xylimelts. You should get mint-free, with no flavoring. So this is more like a tablet that is stuck between your gum and the cheek. And you can put two in the bottom or in the top gums and just leave them there. They will stimulate you to make more spit. And they also protect your teeth against cavities. It has Xyalactin in it. It's not sugary. So a lot of my patients like that.

(30:56): There is another one, same chemical as Xylimelts, called Sparks. It's like a candy that you put it in your mouth and let it dissolve. And it also stimulates [saliva], it also protects it. You don't need to use both. You can try either one, and whichever one you like, you can use.

(31:12): Then you have sprays. A new one is called Salivamax. There are a number of over-the-counter products. Why do we have many of these? Because it's a personal preference. Some patients like one product, the other patient will say, no, I don't like it. So you are the best person to try them. Whichever one works best for you, just stick with that. You don't need to use many of them, but you select one that works for you, the best.

(31:38): The other medications that require a prescription are NeutraSal and Salivamax. They will send it to your home. You mix it and rinse your mouth frequently. The easiest one is to use is a half a teaspoon of salt and half a teaspoon of baking soda in eight ounces of warm water, and you use that to rinse your mouth frequently or gargle frequently.

(32:04): There are two other medications, Cevimeline and Pilocarpine. These are two prescription medication that are currently approved by FDA for dry mouth, which I frequently use in patients with severe dry mouth. As I said, these other ones we just talked about are symptomatic relief, only. But these two medications are going to stimulate your salivary glands to make more spit. So we are making the salivary glands continue to work. If they stop working, they're going to die. So that's another reason that we prescribe this medication if you can tolerate it. There are no major side effects, there is no harm in using that medicine so that your salivary glands still continue work. As you know, if we don't use our muscle, we lose it. It's the same way with salivary glands. If they are not stimulated, they're going to slowly undergo atrophy.

(32:58): Prophylactic antifungal medications can prevent yeast infections. Again, this is a very common infection I see in patients, especially if you are not on antifungal prophylaxis. So a lot of time patients may have yeast infection, but they may assume that they have GVHD affecting the mouth. They can look the same. They tend to look red and white, painful, burns. So you won't be able to tell, even some of the physicians may not be able to tell, whether it's a yeast infection or lichenoid mucositis. So the first thing I want to find out is, if you're not on antifungal prophylaxis, I need to do a scraping to test for a yeast or empirically treat with an antifungal medication to make sure it's not a yeast infection. It's very common because of the dry mouth, and some of the immunosuppressed medications.

(33:50): Here is the common way yeast and thrush look. You might know, these white areas. If you're wearing dentures, and if you don't take them out in the night when you have a dry mouth and you are on immunosuppression, you'll see red areas underneath the dentures. That is always a yeast infection, not dentures dermatitis or anything like that, no denture irritation. You always have to take out dentures when you go to sleep, or you may have the corners of your mouth cracking. That is also commonly caused by yeast infection and crusting, and the red areas like that. So it's very, very common in patients with GVHD. If you're taking an antifungal prophylaxis to prevent [fungal infections] like Posaconazole, then you may not develop that. But otherwise this is something we commonly see.

(34:44): Cheilitis or inflamed and chapped lips is another common problem. This is another common thing that we see in patients. This is called cheilitis. Cheilitis means lip inflammation and chapped lips. The patients will see a thickening, almost peeling of the skin on the lips. Sometimes the lips build up a lot thicker, and when you build up a thick area, it becomes an area for bacteria or fungal overgrowth., Those thick surface areas are dead tissue sticking to your mucosa because you don't have a lot of saliva. So the lip is very dry. So the dead tissue is sticking more and more, and it becomes an area for overgrowth of bacteria and fungus.

 (35:30): This can cause dead skin which prevents antibiotic and antifungal medications from working. So you may be taking a yeast medication. You’re taking an antibacterial, so [you think] that should not be the cause, even doctors will think like that. But remember, when you have dead tissue on the lips there, there is no blood flow to the dead tissue. So then the antibiotics that you are taking systemically or antifungal medication you are taking systemically, the blood is the one that brings the medication to the area where it's supposed to work. But if you have dead tissue, then they are not going to be effective. Those antibiotics will not work. So we have to use some topical antimicrobial cream. So antibiotic, antifungal creams, that can kill the top. Because for the dead tissue, the systemic antibiotics and antifungal medication will not work. And I will tell you the common one that we use for these problems.

(36:26): So it's important to keep in mind that if you're wearing dentures, which can be removed, you always have to take them out when you are going to sleep. The other condition that can cause dry mouth, is if you're using corticosteroid inhalers., Poor dental hygiene, all of these increase the risk of developing yeast infection and bacterial infection. So you have to clean up your dentures and take the dentures out at night. And a lot of time patients will develop uncontrolled diabetes, these are some of the other causes for developing infection, especially a yeast infection.

(37:19): Several topical treatments can help with yeast infections. So what are the different ways we treat yeast infection? There is Nystatin oral rinse, which most of you know about. But one thing that I want to make sure you understand is, if we are using Nystatin, it has a topical effect. So, say, you have dentures. You have to use it underneath the dentures where you have the red area. If you use the Nystatin with the denture in, the medicine is not going to work because it's supposed to touch the area where there's infection. So you always have to take your dentures out when you are using the rinse and swallow medication.

(37:52): Or Clotrimazole, it’s like a lozenge that you would use. These two, Nystatin and Clotrimazole have a topical effect. So this medicine has to touch the skin of your mouth to kill the bacterial or fungal infection. If you have coverage, like a denture or something, it won't work.

(38:11): More systemic medications like fluconazole may also be used. Otherwise we have to prescribe some systemic medication, like Fluconazole or Diflucan, which is what I prefer to use because it's very easy for patients to use. So start at two tables, once a day for two weeks. We have to be mindful that some medications like a blood thinners or cholesterol medication, or seizure medications or certain blood pressure medications, these can interact with fluconazole. Some medications you can stop, like if you are on a cholesterol medication, you can take a two week break. But you don't want to stop the blood thinners. So you want to check with your doctor, whether any of those medication can be stopped for a short period while you use this medicine. Otherwise, we have to keep you on a Nystatin or Clotrimazole. So then you have to use them more frequently, you have to take your dentures out, because those medicines you have to use at least five times a day.

(39:12): Dentures should be carefully cleaned to prevent reinfection. The other times patients make a mistake - I don't know how many of you use dentures- you not only have to treat your mouth when you have a yeast infection, you also have to treat your dentures. Otherwise, after your mouth get cleared of yeast, when you put the dentures back in, you're going to reinfect. So you always have to treat the backside of your denture with some kind of an antimicrobial substance, like such as Chlorhexidine. Or the best treatment, if you have an acrylic denture - that's the pink ones, not metal dentures, the metallic dentures you want to use the paradex or chlorhexidine - but if you have an acrylic, pink denture, there are two ways you can clean it. You can just use a household bleach, one percent, usually the 10% you dilute it one to 10, and you put your denture in that for 10 minutes, and you take an old toothbrush and scrape your dentures, clean them up, and then let the denture sit in running water for about two, three minutes to get rid of all the Clorox, and that will kill everything that grows on your back of the dentures.

(40:15): Or you can even microwave it. Put it in water and heat it at 800 watts, for about six minutes. That will kill it. So that's only for acrylic, pink dentures. If you have metal dentures, don't try that. For metal dentures you need to use chlorhexidine.

(40:39): Even without GVHD, dry mouth can cause ulcers and promote bacterial infections. Even without having GVHD, if you have a dry mouth because of the lack of moisture, and the lack of the increased friction, you're going to end up with ulcers in your mouth. So dry mouth itself can cause ulcerations. So keep in mind, even if you don't have GVHD, having dry mouth increases the risk of developing ulcers like that. So when ulcers occur on the tongue, when they go very deep and kill some of those muscles, then these ulcers will not heal because there is dead tissue. And usually it gets infected by bacteria.

(41:35): Traumatic ulcerative granuloma is an ulcer that does not heal without more aggressive treatment to remove dead tissue. We have a technical term called traumatic ulcerative granuloma, it's kind of a long-term, we call them TUGSE. They usually occur on the tongue, in the posterior portion of the tongue, like a deep ulcer, not healing. They can last for months and months and can look very similar to a cancer. The reason why this ulcer is not healing is, one, there is a lot of dead muscle. The tongue is full of muscles under the skin of your tongue. So if you accidentally bite on it, or if you have a trauma that goes a little deeper and damages the muscle underneath, the muscle dies. So when there's dead tissue underneath [the tongue], it will not allow the wound to heal on its own. So in that case, always we have to go and clean it up and biopsy it to remove the dead tissue.

 (42:29): And sometimes if it is infected by bacteria, we have to prescribe some antibiotics. That infection is a gram-positive infection. So we have to put you on an amoxicillin to kill the bacteria, and remove the dead tissue so the ulcers can heal. So this is not the lichenoid ulceration I just talked about. These are basically caused by traumatic ulcers that are going too deep They can occur in patients with GVHD due to dry mouth, which we see not infrequently. And unfortunately, sometimes it gets mistaken for GVHD, and it's not. It is actually something that we see in non-GVHD patients because of the non-healing ulcer due to dead tissue underneath, and it needs to be biopsied to make sure there is no cancer. Also, the biopsy helps to remove the dead tissue and make fresh bleedings to facilitate the healing.

(43:31): Chronic ulcers can cause herpes infections that can also become chronic. Other ulcerations, very frequently, are chronic ulcers. When you have chronic non-healing ulcers, these multiple ulcers, that is a typical cause of herpes infection. I know you may be taking some antiviral medication, but even with that, there are certain viruses that can become resistant. And I know that your GVHD and infectious doc will be speaking about those. So even though you may be on antivirals, still, you can develop chronic hepatic ulcers, unlike non-GVHD patients. These herpes infections will not heal on their own. They will persist. So that's a reason that sometimes you may want to make sure that [ your doctor] is either doing a culture test or a biopsy to test whether these ulcers are herpetic infection or not. In that case, they have to change your antiviral medication. I will let your infectious docs speak about the different other options that are available for these medications.

(44:41): Drug resistant herpes virus is higher in patients who had an allogeneic transplant. If there are other non-healing ulcers, always think about chronic herpes. Important thing to remember is that the prevalence of drug-resistant herpes virus is higher in patients who had an allogeneic stem cell transplant and GVHD than in non-GVHD patients. Even though you may be on Valacyclovir, you still can develop chronic herpetic infection. Your doctors know that, and they will test for it. In that case, they'll have to prescribe some different medications. So keep that in mind, even if you are taking antiviral medication, you can have it. Foscarnet is the one that is usually given. Kidney toxicity is beyond my expertise. Other doctors will talk about that later on.

(45:36): Cavities from dry mouth tend to affect the front teeth and should be filled promptly. The type of caries that you're going to see in dry mouth are typically around the gum level and also the top of the front teeth. So it tends to affect your front teeth and you don't want to lose your front teeth. So it's important to make sure that when you develop these dark areas, or in the gum level you see brownish areas, those are decay. You really need to go to a dentist and get that area filled, because you don't want it to go too deep, and end up needing a root canal or you may lose the teeth. Frequently we see them in the front teeth, and you don't want to lose them. So this type of decay on the top of the teeth and the gum level are always seen in patients with dry mouth.

(46:20): Avoiding carbonated drinks minimizes dental problems. The important thing to remember is that if you have a dry mouth and this type of decay, please avoid drinking any carbonated drinks, like a diet Coke. You may think it's ok because it’s diet Coke. It's not, because any carbonated water is acidic. So it's going to dissolve your enamel and protection. Never ever drink anything carbonated if you have dry mouth, because that's going to increase your risk of developing caries, okay? Saliva neutralizes everything we drink. When you have a dry mouth, you won't neutralize. So please do not drink any carbonated water if you have a severe dry mouth.

(47:02): So the cavities occur in the cemental junction. And this is an x-ray., I don't know what shows up. You may have a crown; you may not even see there is decay. And then you go, after six months, one year after all your treatments finished, and your dentist take a radiograph and says, ‘oh, you have a lot of decay under your crown. You're going to lose the tooth’. Because it always occurs at the margin of the crown, and your tooth or cemental junction. That's where the decay occurs when you have a dry mouth. So it’s important to keep your mouth moist, prevent carries and frequently get tested, or x-rayed, to make sure that you don't develop cavities.

(47:38): One thing you can do to prevent decay when you have a dry mouth is use a fluoride gel, neutral pH. PreviDent solid. This is more like a toothpaste. you put a small amount on your toothbrush and just brush your teeth before you go to bed, and that typically protects against decay. Your dentist can prescribe this. You can get a non-flavored one, if you have a dry mouth, so that it doesn't bother you., Mint sometimes can cause burning.

(48:13): Gingivitis caused by GVHD and not bacteria should be treated with topical corticosteroids. This is the other problem that we see in patients with GVHD. So this is gingivitis caused by GVHD. It's not due to bacteria. It's something we also see in patients with lichen planus, another autoimmune disease. So we need to treat this inflammation so that you can brush your teeth and dentures. You want to let the dentist know that you have GVHD affecting your gums, and that's keeping you from brushing your teeth. This inflammation is not caused by bacteria, but your GVHD causing inflammation of the gingiva. We call them non-bacteria or non-plaque related gingivitis. We have to treat it like GVHD using topical corticosteroids.

(49:05): Without proper treatment GVHD related gingivitis can also promote bacterial infection and even severe periodontal disease. So it is basically a two way process. When you have GVHD affecting your gums, you can't brush your teeth. Then you have bacterial build up, and that makes it worse. So we have to treat the GVHD affecting your gum, and at the same time, your dentist has to clean your teeth, and you have to brush your teeth. If we leave both of them alone, it's going to make it worse. You're both going to have GVHD causing inflammation, then bacterial build up, and that causes more inflammation, and then you have severe periodontal disease.

(49:38): A custom tray with gel medication can treat gingivitis from GVHD. The way we treat gingivitis due to GVHD, is we make a sub tray, a custom tray for your gums, similar to a bleaching tray. The bleaching tray is mainly to bleach your teeth. But this is to apply medication to your gums. If you have an area on your skin, you can put a gel or cream, leave it there. You cannot do that on the gums. It's going to be wiped away by spit. So basically we make this custom tray, then you can put the gel medication inside and you wear it in touch with the gums. That that keeps the medicine in touch with the gums for 30 minutes, then you take it out. And 10 minutes later, you rinse your mouth and do that for two to three weeks. That will clear the inflammation of the gums. Then you go to your dentist to get your teeth cleaned. That's how we manage the gum involvement of GVHD. So we call them medication application trays. Your dentist can make it as a sub tray to do that.

(50:44): So always use a soft brush or a water pick to very gently remove your plaque. And this is a very common, another complication, not as common as the other ones we talked about. These are small blisters showing up on the roof of your mouth, especially the junction of the posterior part of the roof of the mouth. These typically occur just before you eat, or even while eating, they break up and release some fluid. Sometimes, during that time, they may be a little sore. It's a very benign condition. Unless it's very bothersome just leave it.

(51:21): These are called superficial mucoceles. The salivary glands in that area get blocked up by keratin buildup and these blisters form, especially when you're eating. The saliva is trying to come out, but the keratin blocks it. So it just swells up like a blister and it breaks up and produces a little soreness. It's something we see in patients with GVHD. These are called superficial mucoceles.

 (51:50): Oral cancer can sometimes be mistaken for GVHD so accurate diagnosis by an expert clinician in mouth diseases is essential. The last, not the least, is cancer that occurs in the mouth. Patients with GVHD have a higher risk than the general population. The most common problem that we encounter is that patients, sometimes even doctors, may mistake when you have a non-healing ulcer with red area. They may think the patient has GVHD. This is what many of my patients, who have developed cancer in the mouth, initially assumed, that they had GVHD. 'Oh, I have to put up with that. Oh, there is no treatment ever. I'll have to put up with that.'

Don't do that. At least go see somebody who knows what GVHD looks like, knows what cancer looks like, how herpes looks, because that way you won't miss the cancer. Cancer, chronic traumatic ulcer, GVHD all can look very similar in the mouth, not only to the patient, but also for a clinician who is not used to seeing mouth problems.

(52:55): Do not assume mouth problems are GVHD when they could be something else. Getting an accurate diagnosis and even a biopsy may be important.  So whenever you have an ulcer that doesn't heal, see an expert clinician who knows mouth diseases. They can look at it and say whether you need a biopsy, or whether you have a herpes infection, or you have a TUGSE or it really is GVHD causing the problem. That's the last, but the most important message I want to convey. Do not assume everything in your mouth is GVHD because sometimes the other bad ones can show up and look similar to GVHD.

(53:26): So definitely you have to go and see your dentist or oral medicine doctor or expert in oral diseases and have periodic biopsies. There's no harm in doing the biopsy. When in doubt, whenever you have a ulcer that's not healing on its own after the treatment, that is a danger sign in the mouth, that needs to be further worked up. So there are different ways we can do an oral cancer screening. This is for general population as well. So there are ways that you can use the lights and things like that. That's not very critical. So at this stage, I'm going to stop and answer your questions.

(54:10): [Marla O’Keefe] Q & A. Thank you. Thank you, Dr. Vigneswaran, for that very excellent presentation. We are now going to go to the questions. The first question is, “I have many episodes of multiple canker stores. I just started having these after my unrelated donor transplant. Could this be a form of GVHD? What kind of doctor can treat this?”

(54:42): [Dr. Nadarajah Vigneswaran] Okay. That's a very good question. Remember, canker sores rarely occur if you don't have a history of previous canker sores, and they always occur in younger kids. So a lot of patients assume, when you have an ulcer, you have a canker sore. And your doctor might also think that. Never, ever think that.

Ulcers occurring in people who are 30 or 40 years old are not canker sores. They are either GVHD or are due to medication. Drugs can cause ulcers, or herpes or TUGSE. Dry mouth can cause ulcers. They're not really canker sores. Canker sores are typically seen in high school kids, young, healthy patients. They develop and they heal on their own. The other important thing is canker sores don't persist. They usually heal within two weeks’ time. If you have an ulcer that doesn't heal within three weeks, that's not a canker sore.

(55:42): So those are chronic ulcers. And they can be GVHD affecting your mouth, or it can be chronic herpes, or it can be TUGSE, a traumatic ulcer, this long name I mentioned. Or in very rare cases it can be cancer. So definitely, oral medicine doctors are the ones who are oral pathology, oral medicine. Orr there are some larger centers that will have expert GVHD doctors who manage oral problem. So you want to look at a long list of doctors listed in BMT InfoNet's GVHD directory to find a doctor in your area. I work at MD Anderson, and most of the academic institutions are going to have experts who can manage this condition in the mouth.

(56:32): [Marla O’Keefe] Thank you. Next question. “I have mouth GVHD, and recently very tight lips. Any advice for relief? I'm using hydrocortisone 25 milligrams, five grams, but not much improvement.”

(56:46): [Dr. Nadarajah Vigneswaran] Yeah. The tight lips and even the mouth can become kind of an opening of the [inaudible 00:56:55] and these are some of the other complications we see, though rare, that are due to fibrosis. That also makes you a GVHD. It's not scleroderma-like, but it kind of mimics that. Skin doctors will talk about that when your skin becomes very firm and it's not flexible. The same thing can happen to the skin on the lip. A lot of fibrosis can happen in your cheek, as well as on your lips. That makes opening the mouth harder. Lips become stiffer, something like that. Even the topical steroids can help because that's the only way we are going to reduce the inflammation and fibrosis. But sometimes when you put steroids on the skin of your lips too often, that causes atrophy of the skin. So you're making it worse.

 (57:47): So occasionally, I give a steroid injection deep into that area to relieve the inflammation inside that deeper tissue, rather than using a topical, because as I said, when you have a keratin buildup or fibrosis, the topicals won't penetrate. So sometimes we do use a steroid injection to do that. Some of you might have experience on your skin or your skin specialists will talk about scleroderma-like skin changes that happen in GVHD. The same thing can happen in the cheek that makes the mouth opening harder. And the same thing can happen on the lips that makes the skin fibrotic. We don't have a lot of good treatment for that, unfortunately. Steroid injection is the best option.

(58:44): [Marla O’Keefe] Next question. “I have heard that some medications for osteoporosis, such as Fosamax have negative side effects for the bones in the jaw and the mouth. Is there any truth to this?”

(58:56): [Dr. Nadarajah Vigneswaran] Yes. 100% truth. Yes, that's a very, very good question. So I know that most of you are on long-term steroids and you are going to have a higher risk of developing osteoporosis. Your doctors are going to say, you need to take Fosamax or the other newer medications. So what that does is delay your bone remodeling. The other bones are not a problem. Sometimes you may get a femoral fracture, but in the jaw bones we have decay going on there, infection, gum infection or they take a tooth out, the bone heals by remodeling. But when you put the patient on this medication, the remodeling of the bone, the regeneration of the bone is not effective, so it gets infected and the bone dies because of the medication-related osteonecrosis.

(59:57): So how do you prevent that? Your doctor's going to determine if you really need to take this medication to prevent you losing bone., You may still have to take it, but there are precautions you can take. You have a higher risk of developing gum disease. You have higher risk of developing decay. So the best option is prevention. You prevent decay by cleaning your teeth, checking frequently, using fluoride, getting teeth cleaned. And if you have GVHD affecting your gums, treat that with the topical steroid, with the medication application tray, and don't do any invasive treatment in your jaw bones. Then you won't develop it.

(01:00:39): The most important thing is preventing infections going into the jawbone, either from the teeth or from the gums, so that you don't need to have a tooth extraction. That is the worst part. So if you don't have those problems, then you don't need to worry about it. But if your doctor is telling you may or may not need it, if you have GVHD, I would recommend avoiding that, but I will let your doctors to decide whether you need it or not. If it was my mother or my sister, she has GVHD, if you have a borderline osteoporosis, I would say don't take it.

(01:01:15): [Marla O’Keefe]  Thank you. Next question. “Is there a correlation between high dose chemo ahead of an auto transplant and teeth crumbling, or disintegrating five to 10 years later?”

(01:01:26): [Dr. Nadarajah Vigneswaran] Not directly, because the teeth, when they form and when they erupt, they the enamel and dentin are mostly formed already. So whatever you are going to do, any medication you use, that's not going to affect your teeth. Teeth, unlike bone don't remodel. So that's why we can't treat the teeth by giving more hormones or anything like that. Teeth are formed and they're going to stay. The enamel is permanently deposited. But when you have a dry mouth and you drink a lot of Cokes and lot of carbonated drinks, that can remove some of the enamel and make the teeth more fragile. So the most important thing is keeping the mouth moist and preventing decay by using the fluoride. And most importantly, avoid any acidic drink in your mouth, including wine.

(01:02:27): [Marla O’Keefe] Okay, thank you. Next question. “Does the use of baking soda-based mouth washes daily cause any problem with the enamel breaking down or tooth decalcification?”

(01:02:39): [Dr. Nadarajah Vigneswaran] Very good question. It's the opposite. The enamel is broken down by acid. Bicarbonates are alkaline. So the reason we use salt and bicarbonate is to neutralize the acid. How do we get acid in the mouth? Bacteria make acid, drinks make an acid. So there are many different things that can make your mouth feel acidic. So the bicarbonate is basically a neutralizer. And in fact, saliva contains a lot of bicarbonate. That's why saliva is important for neutralizing. Since we have a dry mouth, we use the sodium bicarbonate, that is the baking soda with salt. An excellent question. The opposite is true. It actually neutralizes things so that your enamel is not going to get dissolved.

(01:03:30): [Marla O’Keefe] Okay. I think we have time for one or two more questions. The next one is, how should I replace saliva? My tongue is all white and sometimes is painful and irritated by food. How can that be improved?

(01:03:43): Dr. Nadarajah Vigneswaran] Yes, that's a good question. I know you can go through this handout and I have inserted a lot of pictures in there. Some of the over-the-counter one you can order are Xylimelts, or Sparks. Those are ones that my patients like that also protect your teeth. You can try them on your own. You don't need a prescription for that. And also, salt and baking soda mixed. Or there's the one called NeutraSal, and Salivamax, that your doctor can order. But if you have a very severe dry mouth, I would definitely ask your doctor to prescribe the medication that's going to make more spit. That's Pilocarpine, or cevimeline or Salagen. They have very minimal side effects. So if your saliva glands are sleeping, these drugs are going to wake them up and start them making more spit.

(01:04:45): If you wait too long, then the salivary glands are dead. You have never had radiation, some of you might, but they are usually not in the head and neck area. That's where your salivary glands are. So important thing is to start the treatment early, so the salivary glands are not dead. If they're dead, or if they're what we call an atrophic, then you can't help by giving those medication. But if you start early with the severe dry mouth, then definitely those medications will work. And if, when you are taking them, you get side effects, then you want to stop it. And then you will use the other ones that I just mentioned. There are a number of different over-the-counter medications.  You want to try different ones and pick the one that works for you.

(01:05:32): And especially for the soreness and pain, make sure that you don't have a yeast infection, you're taking antifungal medication, and definitely make sure that you don't have a GVHD affecting your mouth. If that's the case, then we need to treat for that. So those are the major reasons for being in pain, especially on the tongue, or whenever you eat spicy food or acidic food. If it burns, you have inflammation in your mouth. A lot of my patients will say, ‘I avoid spicy food.’ No, I say, eat it. That's the way you're going to find out what your problem is. So if spicy foods don't make your GVHD to get worse, it will tell you that you have inflammation in your mouth.

(01:06:16): [Marla O’Keefe] Closing. Well, that's going to have to be our last question. On behalf of BMT InfoNet and our partners, I'd like to thank you, Dr. Vigneswaran, for your very helpful remarks. And thank you, the audience, for your excellent questions. Please contact BMT InfoNet if we can help you in any way and enjoy the rest of the symposium.