Your Mouth and Chronic Graft-versus-Host Disease

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Your Mouth and Chronic Graft-versus-Host Disease

Monday, April 19, 2021

Presenter: Joel Epstein DMD, MSD, FRCD c, RCS (Edin), Medical Director, Dental Oncology Services, City of Hope; Medical Director of Cancer Dentistry, Samuel Oschin Comprehensive Cancer Institute at Cedars-Sinai Medical Center.

Presentation is 37 minutes with 12 minutes of Q & A.

Summary:  Graft-versus-host disease (GVHD) often occurs in the mouth and can cause mouth sores, dry mouth, tooth decay and difficulty swallowing.

Highlights:

• Oral GVHD can affect mouth tissues, the tongue, gums, bone health, and tooth structure. Pain and a dry mouth are typical symptoms.
• Photobiomodulation (low-level laser therapy) can reduce inflammation, help mouth sores heal and reduce pain in patients with oral GVHD.
• Since evaluating and properly treating oral GVHD is more complex than a typical dental exam, patients at risk for developing oral GVHD should be managed by a dentist who has received specialized training in the sub-specialty of dentistry called oral medicine.

Key Points:

(05:29) Oral GVHD can change both the quantity and quality of the saliva in the mouth.

(09:09) If the mouth is the only part of the body affected by GVHD, then local topical therapies can be used that don’t interact with other drugs the patient is taking.

(12:32) Photobiomodulation therapy (low level laser light therapy) helps heal mouth sores and control pain.

(19:32) Increasing saliva production can reduce the risk of developing infections in the mouth.

(21:34) GVHD can cause gum disease.

(22:59) GVHD can reduce the amount of calcium needed to maintain strong teeth.  

(27:50) GVHD can cause skin in and around the mouth to become taut, which can make swallowing difficult.

(28:41) Oral GVHD can cause changes in taste.

(30:55) Certain medications can damage bones and cause dental problems after transplant.

(33:37) Cancer in the mouth can occur as late as 5-10 years after transplant.  

Transcript of Presentation:

(00:00) [Mark Spina]     Introduction. Hello, I'm Mark Spina and I'll be your moderator today. Welcome to the workshop Your Mouth and Chronic Graft-versus-Host Disease. It's my pleasure to introduce Dr. Joel Epstein. Dr. Epstein is the medical director of the dental oncology service in the division of surgery at City of Hope National Medical Center. He is also the medical director of cancer dentistry at the Samuel Oschin Comprehensive Cancer Institute at Cedars-Sinai Medical Center. Dr. Epstein's research interests include the prevention and management of oral complications in transplant recipients, improving taste function and relieving oral pain to improve patient's quality of life. Please join me in welcoming Dr. Epstein.

(01:08) [Joel Epstein]      Overview of talk. Well, good morning everyone. This is Joel Epstein. I'm very happy to be part of the BMT InfoNet Survivorship Symposium. My past activities and current appointments lead me to be highly active in graft-versus-host disease related to oral care issues. What I will plan to do today is speak about and review the oral and dental complications as it is its teeth and gums, but it's much more than that. And as people that are involved in care of patients, but also people experiencing these symptoms realize that it is much more than teeth and gums, but it is that as well. I will be highlighting some of the oral complications that are common and are important in quality of life and oral function and general health as well.

Also, I just thought I would mention at this point that several of us internationally based have completed a review paper on oral care for survivors of transplant and published that in the Journal of the American Dental Association with the goals of informing the community dentists as well about these issues.

(02:34) Let's go to the first slide, which the slides that are the filler slides were taken in a trip I had during a meeting actually in Mexico City. It's interesting how some of the images that I'm going to show really impact and document oral care issues. Of course, all of us wish we would be functioning like the cartoon in this graffiti on the left, and not looking like the person on the right.

Of course, the oral complications of transplant may lead to a very dramatic effects on the quality of life and comfort and function, and that's what we're going to talk about.

(03:18) Graft-versus-host disease can affect teeth, the lining of the mouth, the tongue and gums. Okay. I'm going to show you some examples of what most people would think is the presentation of graft-versus-host disease in the oral cavity. It's really focused mostly on the lining tissues or the mucosal reactions, and this slide shows four cases. On the upper left is a top surface of the tongue, which is lacy and white and partly thinned and atrophic. As you might identify, the normal anatomy of the tongue is absent or changed, and in that normal anatomy are the taste receptors, so just keep that in mind when we talk a bit about taste. The surface of the tongue in this case is thinned, atrophic, and the anatomy and structural changes that have occurred are a common site of involvement by oral graft-versus-host changes.

(04:12) On the upper right, the gum margins are red with some lacy pattern, and unless you're really in the dental world, you won't identify the thinning and the atrophy of the tissues that are around the gum margins, which might have implications for long-term health of the teeth.

(04:32) On the lower left, the gum inflammation is more acute. It is unrelated to plaque control and brushing of teeth, but for example, this may be more difficult when the gums become swollen and more inflamed as they are in these front teeth in this example.

(04:50) Graft-versus-host disease in the mouth can lead to oral cancers. In the next slide on the lower right, there's an area of white patchiness that's more of a plaque-like pattern with some irregularity, and with those pattern changes that requires follow-up. We'll discuss this a little later, but oral cancers can arise in people who have had graft-versus-host disease post-transplant. These are the kinds of changes that need to be evaluated carefully and determine if additional steps are needed for diagnosis and for management.

(05:29) Oral GVHD can change both the quantity and quality of the saliva in the mouth. Another impactful, and maybe the most impactful for some people, are of chronic graft-versus-host disease is salivary gland involvement. I'm going to talk more about some approaches to management, but these slides show in the upper left, the thickened secretions that are on the minor saliva glands that are in the roof of the mouth, which is what those little white rounded areas are reflecting. The surface of the tongue is also affected in this case. It's atrophic, there's some ulcerations on one of the sides of the tongue. The tissues look very dry. The saliva itself can change not only in quantity, but quality and I'll talk a little bit more about that.

(06:11) The minor saliva glands and the roof of the mouth that's on the next slide, upper right, the ducts can become inflamed and that is one of the mechanisms for saliva retention that causes those clear little blister-like lesions. And that's because of both change in saliva, but also a change in inflammation, the salivary ducts. These changes, in addition to dry mouth and really thickened secretions, can also lead to discomfort when the minor glands are swollen due to pressure from excess saliva. There are some direct symptoms in minor salivary glands that are also present.

(06:56) GVHD can cause dry mouth which increases the risk of developing cavities. The lower right corner shows a similar pattern with less change in the hard palate of these salivary gland retentions, and on the lower left corner which I just skipped over, you can see the glistening pattern on the tissue that suggests dry mouth. The fillings that you see on the gum margins of the lower teeth are silver. They're dental amalgam fillings. There's fillings along the upper gum margin on basically all teeth. This person has a high cavity and dental damage risk due to oral dryness, and fillings themselves are there to replace the damage done, but they don't affect the process. I'll talk a little more about affecting the process of cavity risk, but once damage is done, repair to the damaged structure is necessary, and that's what those fillings represent.

(07:52) After transplant, patients may be at risk of developing a human papilloma virus infection in the mouth. Other conditions that occur, and they're less common, but we know that individuals following transplant may be higher risk of human papilloma virus infection. These cause wart-like or grainy surface changes, and they can be detected with special tissue stains following tissue biopsy. Some of these human papilloma viruses represent cancer risk. Knowing the subtype of the virus on tissue study and the nature of the cellular change, meaning pre-cancer or dysplastic change or even squamous cell cancer that can arise in these lesions, needs to be both known and treated early if this is an ongoing, or a developing condition. HPV infection is potentially more common following transplant because of relative immunosuppression in the presence of a virus that's the ubiquitous. Most of those will be benign, but some may not be.

(08:55) Here's another graffiti of an unhappy, uncomfortable potentially a patient in this case, again Mexico City graffiti, but relevant to what we're talking about.

(09:09) If the mouth is the only part of the body affected by GVHD, then local topical therapies can be used that don’t interact with other drugs the patient is taking. I wanted to start just outlining some aspects of management. When the oral changes are the principal side of complaint, then one of the best approaches is to manage a local tissue change with local therapies and thereby, avoid or certainly reduce the potential for drug interactions and, for example, further immunosuppression to control mouth symptoms, when other conditions like liver function, skin and GI are adequately managed or not a significant problem.

(09:44) The cases that people like me see are commonly the ones that haven't responded to systemic medical management and the principal site of complaint is the mouth. When that's the case, we attempt to take topical therapies to manage it locally, and that's the first classification of medicines or anti-inflammatories or topical steroids. I list one name of a compounded product. This is not available in an oral product in North America but it can be compounded.

(10:23) Steroids, such as budesonide, are often applied topically to areas of the mouth affected by GVHD. Budesonide is an interesting steroid with limited general absorption, or close to no absorption, which means we can maintain local therapy at high dose with good effect, without changing any of the systemic effects of those medications. The other two gels listed below are high potency topical steroids which are also commonly used. Again, we have to just be cognizant that there could be some systemic absorption.

(10:54) Occasionally, we will use injection steroids. We'll take an injectable steroid. We'll place it into the soft tissue in an area of a recalcitrant ulcer that we know is benign and we can get enhanced local therapy.

(11:12) Special mouth guards can increase the amount of time the steroid is in contact with the part of the mouth with GVHD The other couple things that can assist in management if the gum margins are highly affected by GVHD, then we can take these topicals and we can add mouth devices that increase contact time on the surface. These are like mouth guards, or other devices that can enhance local contact time of the medications which can be really helpful when the gum margins are affected.

(11:38) Other treatments for oral GVHD include tacrolimus, pimeciolimus, retinoic acid, minocycline and photobiomodulation therapy (PBM). Other agents, basically we use potentially locally and topically with oral application, pretty much any of the agents that are used for immunosuppression of the underlying GVHD. We can use tacrolimus, for example, topically. We also use a couple other products in the mouth, and I list retinoic acid, which is vitamin A, as a topical. It has some evidence of reducing and reversing mild dysplastic, or cellular change that can be pre-cancer, and that may be used on some occasions for these white plaque-like areas, for example. Ulcers that don't resolve quickly, or even at all with therapy can be potentially managed with a topical tetracycline compound, minocycline.

(12:32) Photobiomodulation therapy helps health mouth sores in patients with oral GVHD and control pain. There are good studies in non-GVHD patients in wound healing and in ulcer recovery. I'm going to talk a little bit more in the next couple slides about photobiomodulation therapy, which is otherwise known as low-level laser or red and infrared light therapy. We published in a number of cases of successful management of very difficult to manage oral GVHD with PBM or photobiomodulation therapy, but before I talk a little more about that, I just want to talk a little bit about the discomfort and the symptoms associated with mucosal oral GVHD, and that is pain and discomfort effect on eating and speech.

(13:19) “Magic mouth wash” and other products that contain lidocaine can control the pain associated with oral GVHD. There are a number of local ways to manage pain. Most people are familiar with magic mouthwash, or there's a number of names. They all contain lidocaine and other products, and lidocaine is a local anesthetic. It produces numbness. There are other products that have been used topically and published for oral mucosal ulcers and pain, and these include Doxepin which is a tricyclic analgesic that may have some potential effect on the nerve irritation, as well as pain. Also, topical morphine has been used primarily when somebody is already on systemic morphine due to pain. If it is compounded or put into a liquid and held in the mouth before swallowing, better pain control can be achieved even with the same dose of morphine.

(14:16) Some topical measures can help with the symptoms if the pain is significant in affecting function and quality of life, but we also have to deal with the other compounding complications including dry mouth, which means wetting and lubricating agents can be used and coating agents can also be used. I'm going to talk a little bit more about saliva per se in just a couple minutes.

(14:41) Under symptom management, photobiomodulation is pain relieving and can be beneficial in that setting, and then general pain management requires whatever we might be using for systemic therapies, meaning oral and/or other pain management. This includes the pain relievers that can include morphine and other agents that affect nerve pain as I just quickly mentioned about Doxepin as a pain relieving agent.

(15:16) Photobiomodulation therapy reduces pain and inflammation in the mouth, and accelerates wound healing. Let me just talk briefly about photobiomodulation therapy, or low-level light therapy. This is red and infrared light. It's non-heating, it's non-damaging to tissue, but it has qualities that are desirable in this setting. That includes anti-inflammatory effects, pain effects, or analgesic effects. It accelerates wound healing and also there's a few cases in the literature of significance fibrosis following graft-versus-host disease and the improvement in function that this can produce with extended periods of photobiomodulation therapy. We don't want people's mouths looking and feeling like this paper mache art again from Mexico. It was actually a good trip because there were many examples of art that included focus on oral function.

(16:18)  Oral GVHD can affect the amount, thickness and quality of saliva produced. Too little saliva can result in an abnormally dry mouth. Let’s talk about salivary glands, and that's a big part of the long-term complications. Salivary function depends on how much you make, but also how thick is it and the quality of it. Most people are aware of thinking of quantity or how much saliva do you have, but quality is a considerable feature in symptoms, but also in maintenance of oral and dental health. We can assess the function of saliva by saying how dry is your mouth, and can you eat dry foods without water? Does your dry mouth wake you at night, but we can also measure this and it's easily measured by assessing two main states of saliva function.

(16:56) One is at rest which is a lower flow rate, typically between meals and at night, and a stimulated flow rate which is one where there's a more watery secretion theoretically designed to assist in food wetting, taste function, and swallowing. The measurements allow us a baseline to assess outcome of treatments, and also provide some guidance as to whether stimulation of function is possible. For example, if resting saliva is close to zero and stimulated saliva is close to zero, and we see people with GVHD in this setting, then the ability to stimulate residual function is probably limited, and that can become a long-term problem.

(17:46) There is some evidence the photobiomodulation therapy and acupuncture can help stimulate saliva production. If there's residual function and fluid intake and chewing stimulation, for example, sugar-free gum or candies may be useful, there are systemic medicines that will stimulate normal output of glands if function remains. By normal output, I'm just describing things like the quality of saliva, the presence of antibodies that are in saliva, the tissue protectant molecules, and all the normal function of saliva can be provided by stimulating people's own saliva. Again, in this setting, there's been some studies suggesting photobiomodulation can help with that, as can potentially acupuncture. Limited studies on dry mouth with both of these approaches, the light therapy and acupuncture, but some evidence that it has potential benefit.

(18:42) The other thing that I will mention a little further on is we also have to look at maintenance of dental and periodontal health, because that's an important part of what saliva provides. We'll talk about mineralization and bacterial overgrowth in just a bit. If we cannot stimulate saliva, all we can do is palliate the dryness. There are multiple products that some people like better than others and it really requires treatment trials that will wet the surface, hydrate the cells, so plump them up with fluids and lubricants to reduce friction and trauma. Again, we have to remember about the tooth and dental and periodontal needs that saliva helps to manage when we treat symptomatic dry mouth.

(19:32) Infections In the mouth, such as candida, can be caused by dry mouth, certain antibiotics, diabetes and other health conditions. We also have to treat the biological effects of that secretion. The other issue in GVHD, especially in dry mouth settings is oral infections, and candida, as an example, is very commonly overgrown in individuals that are at risk. The risk factors can include things like dry mouth, can include things like antibiotic use and diabetes and other underlying health conditions. We need to make a diagnosis. We need to do a culture in some cases because some of these organisms are resistant to the commonly used antifungals that we have available. If we do not treat the risk factors, meaning if we can treat the dry mouth and increase saliva, then once we treat the infection, it's much less likely to recur. Otherwise, we have a potential for chronic reinfection by yeast or candida species primarily, and we need to manage that appropriately.

(20:45) Other infections such as a herpes infection can develop in the mouth after transplant. We also see recurrence of herpes virus infections. We need to make a diagnosis, we use antivirals and many people with GVHD may already be on systemic prophylaxis, which may be sufficient. Again, I showed you some examples of human papillomavirus. We need to have an assessment of risk relative to oncologic subtypes that can cause cancer versus the benign ones.

(21:10) On the dental side, here's another photo from Mexico. If you look at the teeth and your dentist, you notice that there's no bone supporting the roots of the lower and really the front teeth. There's some holes or maybe those are actually embedded gemstones, or that some people might like, but it suggests cavities. This is cavities and periodontal disease if you're a dentist.

(21:34) Infections can stimulate or activate GVHD in the mouth. What about gum disease and GVHD? Interestingly, individuals with GVHD are aware that infection can stimulate activation or activity in GVHD, and that applies to periodontal and gum diseases as well, because they're inflammatory conditions. This can lead to one local GVHD, but also systemic aggravation. This is because the periodontal disease and gingivitis presents low-grade chronic immune challenges, and it can stimulate the immune system leading to local, as well as systemic impacts.

(22:16) In other words, management of these infections are also important. That means active periodontal therapy, plaque removal, potential use intermittently of some antibiotics. Mostly, we try and focus on topical or non-systemic therapies.

(22:35) Photobiomodulation may also have an antimicrobial effect and again, it's anti-inflammatory and that's well-documented. That can also have an impact here. And significantly involved teeth present risk of infection. Infection can present risk of bone damage and also pain. We need to deal with the periodontal condition as it presents.

(22:59) Dry mouth can reduce calcium and jeopardize tooth structure. With respect to the tooth structure itself, I mentioned that I was going to talk about it, so this is where I do. This is an example of a dry mouth, young individual, and if you look at the gum margins, particularly in the upper teeth behind the eye tooth, so the molars and the bicuspid teeth, you see a defined white line. This is evidence of demineralization of the tooth structure. In other words, dry mouth is not leading to the calcium source of two structure needs to re-harden. What happens when we eat is the acidity in the mouth increases, and this is in normal hosts. Certainly people with less saliva, the acidity may be much higher. That tends to reduce the remineralization or maintenance of hardening of the tooth structure, and just like bones, calcium is needed to replace the lost calcium due to bacterial activity and lower greater acidity or lower pH.

(24:05) This is an example of where the calcium is lost. It looks more opaque. It looks white, it looks clean. You can see there's no plaque levels in this mouth at all and no active gingivitis, but there is this pre-cavity condition that we can re-mineralize at this point. Once it extends to something like this, you started to see the stain pick up and the brown at the edges of the teeth of the gum line. Again, another person with really pretty good oral hygiene, no visible plaque, and the tips of the teeth that are against the cheek are damaged at areas that are usually resistant to cavities. The classical dry mouth cavity which is basically what this is along the gum lines and at the cusp tip edges.

(24:57) The problem, and you can see it in this slide, the wider areas are actually where the demineralization has been progressing. There isn't really a solid calcified tooth structure to repair to. In other words, you put a filling at the gum line and then right beside it, there's more tooth damage ongoing and that leads to failure of the restoration, and then need to replace it. This is a very difficult situation, and what we need to do is manage the cavity component, the demineralization risk as best as we can before we replace the fillings.

(25:35) Improved oral hygiene, fluoride supplements and managing a person’s diet may help relieve problems caused by dry mouth. How do we do that? If we look down on this slide, the under microbial risk, that's the bacteria. We can improve oral hygiene. We can look to stimulate saliva when we can, that's further down and then we have fluorides as a supplement that increases the density of the calcium crystal in the tooth structure. We often have to provide a calcium source if we can't increase saliva, because the calcium in saliva is what is the calcium source to maintain tooth hardness. We can deal with a diet, frequency of meals, avoiding sugars and whenever possible in a dry mouth situation, saliva is the underlying principal risk factor. We do our best to manage that when possible. Dry mouth is also associated with gum inflammation and more increased difficulty in maintaining oral hygiene. With graft-versus-host disease, there may be atrophy of those gum tissues that are thinned and inflamed, and more gum recession can occur and it's a higher risk in that setting.

(26:46) Transplant recipients need clinical evaluations that are more complex than a regular dental evaluation. The evaluation of people that are a post-transplant is again more complex than a dental evaluation alone, and one of the things that's important to be aware of is we can sometimes identify early signs of recurrence of the primary disease, or other lymphatic changes due to therapy or identify other cancers. We need a clinical evaluation. We often will use adjuncts that help us assess the tissue to identify dysplastic and pre-cancer changes.

(27:22) GVHD can lead to changes in the mouth that look like, or are, cancer. It's more challenging because oral GVHD leads to significant mucosal changes in a lot of people, and the assessment of that change to determine is it benign? Is it inflammatory? Or is it something that could lead to or even represent a cancer risk is challenging? It's harder to do because the tissue is different, and actually I show you a little more about that later just in a couple slides.

(27:50) GVHD can cause skin around and in the mouth to become taut, which can cause difficulty swallowing. The other thing that can occur is you can have sclerodermatitis or fibrotic changes associated with GVHD, and just like any other body site it can affect the mouth and tissues around it. The mouth opening or perioral tissues can become constrained or restricted due to fibrosis in the tissue. Movement of the cheeks, they can become tight. The tongue can become tight and also, you can have restriction in jaw opening.

(28:15) Sclerodermatous and fibrotic changes are present. They can also affect the throat leading to dysphagia and difficulty in swallowing. Again, photobiomodulation has been shown to be useful in established and very challenging cases, but it's an extensive period of time of local therapy to assist.

(28:41) GVHD in the mouth can cause changes in taste which, for many people, are temporary. I also need to mention that there are neurosensory changes. We talked about pain from GVHD, and there may be neuropathic pain when the tissues look normal as well and they're not inflamed, or ulcerated. The other sensory change that occurs is taste change, and taste is both affected by the acute therapy during transplant, but potentially associated with GVHD, which may arise at a much later date one or two years following when then taste is lost or changed. And that can occur probably because of the mucosal change to the taste receptors when the graft-versus-host disease leads to anatomical changes.

(29:28) About taste, again there's multiple causes of taste change in someone following transplant. There's direct damage to the receptors for taste. There's damage to nerve function and nerve signaling, meaning neuropathy. The tissue change itself, the graft-versus-host disease can lead to loss of receptor type.

(29:50) Saliva change also, as the medium for tastes molecules to spread to the receptor and then lead to taste response, can be affected. Infection and bacterial and microbial shifts in the oral cavity can occur and oral hygiene, again it can be more challenging for the dry mouth. These are all components of taste function and we need to assess and manage those conditions as best as we can. But we also have some means of addressing smell and taste change with some systemic and other therapies. This can be associated, though, with weight loss, with food aversions, with nausea. The taste function is a significant impact for many people, but also following transplant, many people gradually recover. There's a subset that just don't, and we have some means to intervene, but we're not as I guess effective in taste management as we would like to be.

(30:55) Certain medications can damage the bones and cause dental problems after transplant. The other thing that I just wanted to highlight is bone damage, due to changes in the bone, can occur, and this is termed osteonecrosis. For individuals, for example, those who have had transplant for myeloma, there are many medications in the myeloma world that can affect bone health that can lead to medication-induced bone necrosis associated usually with pre-existing dental problems. We want to manage the dental issues as best we can before treatments and as early as we can in the course of use of those kinds of medications as possible.

(31:33) A variety of medications and therapies are available to treat damaged bones in the mouth. Diagnosis at an early stage is helpful. Then the management of the necrosis is challenging. It's challenging for all people with this kind of bone damage. We may need antimicrobials. We do use bone healing agents that promote bone repair, and they're listed here. Trental is one with vitamin E. There's a European product called Clodronate that you can mail order that also may help with bone repair. There's new studies on parathyroid hormone, which is teriparatide as an example that show benefit in healing. We're not so sure and we have limited evidence about hyperbaric oxygen therapy and again photobiomodulation or light therapy in this setting. But there's evidence for photobiomodulation therapy that bone healing may be [inaudible 00:32:26], and we may need surgery. We may need reconstruction.

(32:30) I'll show you one example, and this is one of the locations that its highest incidence is. Towards the back of the mouth beside that last molar tooth with a big silver filling is a white area that's semi-circular, and that's exposed jawbone. At this point, it may or may not be painful. Pain is usually related to secondary infection. This doesn't look infected because it's not right around the margins, but this is an exposure that needs to be identified that we can do what is potentially the best therapy to repair, rather than allow this to progress. This is often how they first present, and they're hard to diagnose because they're often in the back of the mouth.

(33:17) Individuals, like people with this, may have no symptoms early on and may have few symptoms, until there's secondary infections. This requires close oral and dental bone evaluation, which is one of the aspects of what a dentist should be doing, but so should people that are being followed at the cancer centers.

(33:37) Cancer in the mouth can occur as late as 5-10 years after transplant.  Again, I mentioned earlier that there are second cancers that can occur after transplant, and they can appear in the mouth. They can be lymphatic or lymphocyte related disorders. The tumor can recur and sometimes, there's oral signs of this.

(33:53) There may be solid tumors like oral cancer as a late complication five or 10 years following transplant, and the risk factors are summarized as your previous treatments, total body radiation, GVHD and its therapy, tobacco and alcohol use and possibly HPV. That's the viral infection that I was mentioning earlier.

(34:13) Dentists have limited experience with oral medicine and cancer. Ask your transplant center or a local hospital for a referral to a dentist with oral medicine experience. Okay. We're getting close to the end of what I wanted to present. The question that we will follow up with these slides just in a minute is seeking oral and dental care after transplant, where do you go? We know that there are some limitations in the general dental community. Most general dentists have limited oral medicine experience, but also limited oncology experience.

(34:41) The cancer center where you were treated could provide... if they have a dental team, that may support your needs, or other community resources may be known by the transplant center for access, but there's still a limitation of experience and knowledge in oral GVHD, and this can be challenging.

(35:00) In the community, one of the things that I think people can do is look for a dentist who's had either has an ongoing hospital appointment because. At least, they're more integrated and interactive with the medical community and also, those who've had hospital training, meaning residencies. Dentists with oral medicine typically have both hospital training and experience.

(35:19) Again, they still may not be as focused on oncology, and you can look for contacts through GVHD support groups, because there may be suggestions they can provide.

(35:31) Summary or presentation.  In summary, and then we'll just do a quick survey and open for questions, oral care is an important support for individuals following transplant. Patient management is much more complex in many cases in relation to both dental disease, but also all these other oral and systemic complications. Dental involvement should be present before, during, and after transplant and actually after hepatic radiation therapy. The therapy can affect oral health in treating the cancer, but oral health also affects the quality of life and systemic health.

(36:05): I want to just go back to the final slide, which shows one happy mouth in Mexico, good looking teeth, and good oral opening. My last slide just as a fill-in is you remember the skull with the gum disease and the dental disease, and we want people looking and feeling more like this photo. Again, I'd like to thank you for your attention, and we should go to questions now.

Question & Answer Session

(36:43) [Mark Spina]    Thank you Dr. Epstein. That was an excellent presentation. We've got a couple questions here on dexamethasone. I'll ask them both and ask you to just try to hit as much as you can, but the first is, "Is it okay to use dexamethasone mouth rinse two to four times daily long term, more than six months?" Then the second similar is just that... I'm sorry go ahead and answer that...

(37:13) [Joel Epstein]  Well, give me the second one too because they may relate.

(37:16) [Mark Spina]  "I was given dexamethasone swish for five minutes two to three times a day. Halfway through the bottle, my teeth or nerve endings hurt very much. I never used it again. My oral GVHD is mild, but bothersome. Why did dexamethasone hurt so much after a few weeks of use?"

(37:37) [Joel Epstein]   Great, okay. Dexamethasone is the only liquid steroid commercially available, and it's really a liquid. It was designed for people to swallow for systemic absorption when it was difficult to swallow pills. It really wasn't for topical oral use, so couple issues. Dexamethasone is actually pretty highly absorbed. If you're trying to avoid systemic dosing because either you don't need it because the other sites are not involved with GVHD and it isn't active there, then it's a bit of a challenge.

(38:13) Now, it is also a low strength low potency steroid, and the other thing is, and this is where the tooth sensitivity and actually most sensitivity can come in, is it's a commercial product that has some preservatives, but also alcohol and flavoring in it. Those two components, the alcohol and the flavoring can increase sensitivity both with initial use on really sore tissues, but also on the teeth. That's likely the reason why there was those dental issues.

(38:46) Management of GVHD does depend on a couple things, and it's also how active is the mucosal condition, how symptomatic is it. We still like to keep it under control as best as possible. That's why I didn't actually list dexamethasone rinse. It's the only commercial one, and then you're getting into compounding. One of the problems with compounding is insurance costs and reimbursement. Having said that, if you need a stronger topical therapy and there's widespread mucosal or oral involvement by GVHD, then a rinse is the most applicable format.

(39:24) Then if the dexamethasone which is commercially available and isn't adequately effective, we can increase the strength by compounding. Then if you're going to do that, you really should consider in my view budesonide because of the limited absorption, and also because you can increase the strength of the product. It's a more potent topical steroid.

(39:48) [Mark Spina]      Okay, thank you and the next question is actually related as well and that is, how long does it take for the GVHD in the mouth to respond to that topical steroid rinse?

(40:02) [Joel Epstein]      Yeah, that's a tough one. It depends how active the GVHD is and whether it's accelerating or declining, but having said that, typically for most of these conditions, we would probably suggest a one-month follow-up, so four weeks of therapy. If you're not having benefits by then, it's really unlikely. For highly active therapies, you can often get an impression of say reduced pain or reduced redness of the lesion much sooner than that, but after a month's use, I think then that means you needed your other additional therapies, or a change in the therapy to improve the management. I think a month follow-up is pretty standard and probably appropriate.

(40:49) [Mark Spina]      Thank you doctor. The next question is in regard to Xylitol. Is it beneficial in toothpaste or mint form, and use the brand Squiggle and Spry?

(41:01) [Joel Epstein]      Well, we're not going to support brands per se, but I will support Xylitol in general. Xylitol is an interesting sugar substitute. It is not used by bacteria. It can be taken up in the cavity producing and gum disease producing bacteria. In fact, in some cases actually is bactericidal. In other words, it's better than the other sugars in that this will actually not feed the bacteria, so they're more active, it will actually have a negative effect. So it's antibacterial. One of the problems with Xylitol is excessive or increased use for some people leads to some esophageal or upper GI irritation, and that's the main limit.

(41:52) Some of the products if you wanted to use a Xylitol lozenge or Xylitol candy or a Xylitol gum, some people if they're doing a lot of it will get upper GI irritation, but if you don't, there's no limit, as often as you want to use it. Putting that into toothpaste is an appropriate sweetener. Mint is an interesting product for flavoring and because it has some anti-inflammatory effects. But for some people, it is irritating, especially if there's ulcers on the oral tissues. Flavoring is a challenge for everybody because in some cases, it may cause problems. In some cases, it may be beneficial. Most of the mouth wetting products that are available as rinses, sprays, gels and in other formats, it's how it feels, it's how it tastes to the individual.

(42:53) You have to try until you find one. On the toothpaste issue, fluoride is important to suppress bacteria as well, and also to maintain the crystal structure of the tooth as I mentioned. Some products have limited or no fluoride, and so you need to be aware of that.

(43:18) For a lot of people with sore mouths, over-the-counter kids toothpaste is less flavoring and less intensely flavored, but it has a low amount of fluoride, but you can use that more easily than the adult over-the-counter paste which has the same amount of fluoride, because the taste is less sensitizing. That gets you into some of the prescription... well toothpaste which have high potency fluoride, usually limited flavoring and usually limited abrasivity.

(43:52) The abrasiveness of toothpaste is potentially an issue, especially if you're dealing with a demineralized structure like I showed in some of those pictures, where the surface is softened. If you abrade away some of the physical anatomy or of the enamel structure, then you have to replace it down the road with again filling materials, which are designed to replace structure that's lost. Abrasiveness of toothpaste can be an issue, especially in a demineralized environment of teeth. These prescription products have low abrasivity as well, and that's something that probably is pretty important to be aware of.

(44:36) [Mark Spina] Thank you doctor. Next question, "What kind of specialist should evaluate GVHD and/or infection in the mouth in cases when a dentist is not capable?"

(44:49) [Joel Epstein] Oh, that's the hard part. Again, in communities and I think this is the best way to approach it is I would contact the transplant center that you were transplanted at, see if they have people in the community that they know have more experience. You can also find them though by looking for people again with active hospital appointments, whether it be in a general hospital or especially in a cancer center, because they're in more frequent contact and should have more background. The really challenging cases...

(45:23) [Cindy Kessler]      Dr. Epstein...

(45:23) [Joel Epstein]      Yes?

(45:25) [Cindy Kessler]  I wanted to add that BMT InfoNet is in the process of developing a GVHD directory with different specialists, and oral GVHD will be included in this directory.

(45:38) [Joel Epstein]  Yeah, and I think I mentioned at the beginning support networks also to be contacted, but having said that, those are the kind of resources. But even what I was moving to is some of the conditions are very challenging to manage. Then you might need to look at this model of highest level of expertise at the biggest transplant centers, and most of the big transplant centers have active oral support care teams. Some of the smaller ones don't, but the big ones typically do. Some of these need to go back probably to one of these higher level centers when the conditions are very complicated, or not responding to therapy, but in the meantime, I think in the community, there's so many ongoing dental issues that you need to access dentists that have had a little more experience and are interested in.

(46:42) Some of the ways to find them is people with hospital programs. In fact, they're the ones that are going to be at these hospital centers as well, and see if they have a list and look at the support groups that was just mentioned as an access for resources to people that are just more informed I guess and more willing to treat. In fact, in some cases, if say you're a dentist in the community and you don't know much about GVHD, there are many dentists that will say, "Well, I just don't know what to do to treat you." In many cases, you would rather have that admission than people just go ahead and maybe do something that isn't going to help the situation and maybe complicate care.

(47:29) As an educator too, we have the responsibility to inform the community, but again, in some cases, even in that setting, some of these conditions are very complicated and really need a higher level of integrated care that may involve the big transplant centers.

(47:51) [Mark Spina]   Okay. We have a number of great questions still to go, but only a few minutes, so hopefully we can get to a few as quickly as possible. The next one, "If you don't have oral GVHD now, can you get it later? Is dry mouth an indicator of potential oral GVHD?"

(48:11) [Joel Epstein]   Yeah, GVHD often develops while there's an acute form, which is an extension of the treatment itself, but is pretty much defined as after six months. It can arise six months, 12 months, 24 months even without much in the way of symptoms. Probably in those cases, many are triggered by another infection which up regulates or stimulates those immune system cells that are not quite integrated yet, and then they develop a GVHD.

(48:45) Yeah, are there preliminary symptoms? Salivary dysfunction can have multiple causes. Multiple medications caused it, total body radiation, local radiation. Diabetics have dry mouth more commonly. Antidepressant medicines and pain relievers also can all affect this. Dry mouth per se may not be a predictor.

(49:10) Dry mouth associated with increasing GVHD is, but dry mouth needs management in its own right regardless of the cause. Yeah, we look at GVHD as one, there's evidence that acute GVHD may potentially predict the high risk people for chronic, but not necessarily, and it can develop on its own later, and typically within the couple years of transplant.