Chronic Graft-versus-Host Disease of Skin and Connective Tissues
July 17, 2020 Part of the Virtual Celebrating a Second Chance at Life Survivorship Symposium 2020
Presenter: Milan Anadkat MD, Professor of Dermatology and Director of Clinical Trials, Washington University School of Medicine in St. Louis
Presentation is 36 minutes with 23 minutes of Q&A. Download Speaker Slides
Summary: Chronic graft-versus-host disease (GVHD) can affect the skin and underlying tissue. It can also affect the mouth and genitals. Therapies vary depending on the type of skin GVHD a patient is experiencing. People with skin GVHD need to be cautious in the sun and monitor themselves closely for signs of skin cancer.
- Skin is the most common organ affected by graft-versus-host disease (GVHD)
- The risk of skin cancer is approximately 30 times higher for a patient with GVHD than for the general population.
- You can reduce your skin cancer risk by doing regular skin checks at home and with a dermatologist as well as protecting your skin from the sun with hats, clothing and sun block.
07:38 There are two types of GVHD that affect the skin: acute and chronic GVHD.
08:56 Acute GVHD can cause a scaly red rash on the skin that looks like measles. Unlike other similar looking rashes, it can also appear on the hands and feet as well as the head, neck, face and scalp.
10:35 Chronic GVHD can cause a purple-colored skin rash, called lichenoid, that can discolor the skin for months after the rash is gone.
12:37 Chronic GVHD can also affect mucous membranes in the mouth and genitals of both men and women.
13:01 Chronic GVHD can cause tightening of the skin which, in some cases, impedes movement and causes the skin to breakdown and become susceptible to infection.
16:53 The most common treatment of skin GVHD is with steroid and non-steroid creams and ointments applied on the skin.
19:05 Overuse of steroid creams or ointments long-term can cause the skin to thin.
20:19 Acetretin (vitamin A) can be used to treat the lichenoid form of skin GVHD and does not affect the immune system.
21:12 Phototherapy delivered to the skin or to your blood (extracorporeal photopheresis) can decrease inflammation on the skin.
24:36 Stretching and deep tissue massage can help patients with tight skin.
26:58 Patients with GVHD have an increased risk of developing skin cancer and need to have a full body check for signs of skin cancer by a physician at least once a year after age 40.
31:47 There is no such thing as a safe tan. Clothing is the best protection against excessive sun exposure.
00:00 [Moderator] Welcome to the Chronic Graft-versus-Host Disease of the Skin and Connective tissue workshop. My name is Sue Stewart and I'll be your moderator today. It's my pleasure to introduce to you Doctor Milan Anadkat.
Dr. Anadkat is Professor of Dermatology, and the Director of Clinical Trials at Washington University School of Medicine in St. Louis and a dermatologist at the Siteman Cancer Center at Barnes-Jewish Hospital. His clinical and research interests include chemotherapy-associated skin toxicity, graft-versus-host disease and complex medical dermatology. Dr. Anadkat has served on working groups and tasks forces of the American Academy of Dermatology, National Cancer Institute, and the National Comprehensive Cancer Care Network. Please join me in welcoming Doctor Anadkat.
00:58 [Dr. Anadkat] Thank you for the introduction. Sue, that was great and good morning or good afternoon to everyone depending on what time zone you are in. Today we're going to speak about chronic graft-versus-host disease as it affects both the skin and connective tissue. This is something that's been a long-term interest of mine. I'm showing you first on the title slide here, just some images of where I work. This is the Siteman Cancer Center, which is part of Barnes-Jewish Hospital, and the site of Washington University School of Medicine in St. Louis. And so, this is a wonderful place to work. Lots of brilliant people to work alongside, along with just very great patients that are both appreciative and challenging at the same time with what they bring. And so, it's really just an honor to work there and to speak to you this morning.
I do have a number of disclosures. They're not necessarily relevant towards the lecture I'm about to give, but I think through my years of working in clinical trials and trying to help patients with better therapies really put me in contact with many companies along the way. Although most of the time I'm working on ways to help deal with side effects from a lot of these agents rather than prescribing them myself.
Objectives or Presentation
The objectives for the lecture today will specifically focus on explanation of risk factors that can lead to the development of skin graft-versus-host disease; to describe the various manifestations that we see in the skin with GVHD; to discuss potential therapies that are available to manage skin graft-versus-host disease; and then, lastly, to present best practices to help minimize the risk for developing skin cancer for all patients who have had graft-versus-host disease of the skin.
What Is Graft-Versus-Host Disease?
03:05 So we'll start by discussing what is graft-versus-host disease. And I know that this is probably covered in some other sessions so we'll keep it brief, but in my own words or at least the way I approach this and discuss it with my patients, is to understand that the graft, which is the donor, has immune cells and those cells are attacking the host, which is the recipient of that bone marrow or stem cell donation.
And when the graft attacks the host, we get disease. And so, this new immune system is attacking tissues in its new home. And because the new home appears unfamiliar, unlike the original home or body that it came from, the immune system is accurately attacking things that appear foreign.
Most commonly, when graft-versus-host disease develops, the sites that are affected are the skin, which is why people like myself have such an active role in caring for many patients. Other organs that are affected include the liver and the intestines which is why diarrhea is such a common symptom. And then later on in chronic forms of graft-versus-host disease, additional organ sites of both the lungs and the eyes are also potentially frequently involved, but the skin is actually the number one organ that is affected.
Risk Factors for Developing Skin Graft-Versus-Host Disease after Stem Cell Transplant
04:30 In terms of risk factors for developing skin graft-versus-host disease, the more unfamiliar the new home is, the more likely graft-versus-host disease will develop. And so, the greater degree of mismatch between the donor and the recipient on a genetic and immune level, the more likely graft-versus-host disease will develop.
Some other risk factors that can lead to this is increasing age of the donor; female donors, in particular after pregnancy, because of alterations in the immune system; and then if stem cells are collected from the bloodstream instead of being collected from the bone marrow directly or from an umbilical cord donation. So, these are all things that lead to an increased likelihood of graft-versus-host disease developing.
As I alluded to earlier, of the organs that are affected in graft-versus-host disease, the skin is the most common organ system followed by the mouth which is also often times the domain of a dermatologist to manage, followed by the liver. And then the other organ sites listed here, the eyes, genitals, the GI tract or the intestines, the lungs, the joints, the muscles and the nervous system also can be affected, but less frequently than those listed above.
Symptoms of Skin GVHD
06:01 So if we focus on the skin, which is the focus of this lecture, manifestations of skin graft-versus-host disease can be multifold. Most commonly patients are likely to experience a rash and I will show you some images of what that rash can look like in various skin types and in various stages of skin graft-versus-host disease.
Other things that can develop include sores within the mouth or on the genitals. Symptoms of itching can develop with or without the presence of a rash. Changes in skin color [can occur] and then lastly, damage to the sweat glands within the skin, which results in patients having both chronically dry skin or difficulties handling extremes of temperature, especially extremes of heat due to sweat gland damage.
Tightening of the skin can occur in certain forms of skin graft-versus-host disease, and this can lead to restriction in movement, such as opening of the mouth, limitations in movement of a joint. Oftentimes, because of tightening in deep the layers of the skin, the appearance of cellulite, what's technically termed pseudo cellulite. it's not really cellulite, in atypical areas can develop. And then also if tight enough on the skin, your ability to expand your chest when you take a deep breath can be limited.
Acute and chronic GVHD affect the skin differently
07:38 There are two main categories of rash that can develop from involvement with graft-versus-host disease. The first is what we termed acute graft-versus-host disease of the skin, and typically this occurs, shortly after a transplant in the first one to three months, and patients will present with a red scaly rash in a somewhat generalized manner. Then there is a chronic form of skin graft-versus-host disease that typically does not appear until many months after the transplant. In general, it's usually three or four months or later.
Oftentimes patients will present one or two years after their transplant with the first signs of chronic skin graft-versus-host disease, including purple spots on the skin, which we term lichenoid graft-versus-host disease, tightening of the skin or shiny patches on the surface of the skin, the latter two being emblematic of scleradermoid type graft-versus-host disease. So, let's take a look at some images.
Type of rash caused by acute GVHD
08:56 This is an example here of acute skin graft-versus-host disease. And as you can see redness and some fine scaling in a very generalized manner. So oftentimes many people will look at this and think of the rash from measles. And measles, has a very similar appearance, which is why rashes that look like this are termed, morbilliform or measles like. And so that similarity is there. This is also sometimes what an allergic rash after taking a medicine can look like. So, there are other things that can mimic the appearance of acute skin graft-versus-host disease.
One of the very unique things, however, that we see with acute skin graft-versus-host disease as opposed to some of these other rashes, is the appearance of this rash on the hands and the feet, along with the head and neck especially the face and the scalp. Those are a unique location to develop a rash that you typically do not see in either measles, or drug reactions, which oftentimes helps physician distinguish between them. Acute skin graft-versus-host disease can present on its own, or in association with internal organ involvement. And again, acute skin graft-versus-host disease typically appears within a few months after the transplant, usually three months or less.
10:35 We're going to contrast this with lichenoid type chronic skin graft-versus-host disease, and the lichenoid subtype looks purple. The term lichenoid is a descriptive term that describes the pattern of inflammation that we see under the microscope where there is a band of inflammation under the top layer of the skin. And it's that location of the inflammation that gives a very distinct purple appearance as you see for the image on the right. Because of its location it is unfortunate that it is very good at leaving a discoloration or stain that can persist for months after the acute inflammatory rash has resolved.
So, with lichenoid eruption, it can appear anywhere on the body. Again unique with graft-versus-host disease is the ability to appear on the face, as we're showing for the image on the left, and unfortunate with chronic skin graft-versus-host disease of this subtype, is the discoloration that can be left behind once the rash resolves. It is not a permanent scar, but it is a discoloration that can persist for months. The darker your skin is, the darker the stain will be, and the longer it will take for the discoloration to resolve.
Acute GVHD can affect fingernails
12:05 The other major category, or actually let's focus one more time, I'm sorry, on the lichenoid nail changes that we're seeing here. So not only can you get a purple rash, but you can get effects on other sites, including the nails which we're seeing here where you get scar like formation. And potentially destruction of the nail plate, where you can see the skin from the cuticle is essentially growing over and destroying itself.
Acute GVHD can affect mucous membranes in the mouth and genitals.
12:37 And then you can also get lichenoid involvement. within mucous membranes. So, you can see this both inside the mouth, as we're seeing here, on the lips or on the inside of the cheek, which is the most common two areas that we see mouth involvement. You can also see mucosal involvement within the genitals for both men and women.
Chronic GVHD can cause tightening of the skin
13:01 The other major subtype of chronic graft-versus-host disease is the sclerodermoid subtype where you see tightening of the skin. And that can be in focal areas, as you're seeing with these tiny circles that appear white for the picture on the left on the back of this gentleman's neck. Symptomatically, sometimes they can itch., but otherwise with that minimal involvement, has very little true quality of life impairment on this gentleman, as opposed to tightening of the skin over a broader area or overlying a joint as we see for the picture on the right, where you can see a much bigger impact on quality of life because of restriction of movement in addition to symptomatic itching.
The other issue with tightening of the skin is when we lose elasticity. Not only can we not move as much but the skin also runs the risk of breaking down easier, and then being very slow to heal after skin breakdown occurs. So, ulceration either from trauma or from other mechanisms in an area of sclerodermoid skin graft-versus-host disease heals very slowly, which then increases likelihood for infection.
Other forms of tightening of the skin, especially when it affects fascia layers or the layer that surrounds the muscles, so it's affecting deeper tissue under the skin where the subcutaneous fat is or where it approaches the muscle, can lead to this pseudo cellulite appearance. And again, the feeling of tightness in this area. Again, we call it pseudo cellulite. This is not true cellulite.
But you can see typically we think of cellulite on the back of the thighs or in the buttock, but for pseudo cellulite of chronic sclerodermatous graft-versus-host disease we see the atypical areas. The sides of the abdomen or the flank are a very common area. To see this form of graft-versus-host disease, along with the lower back in the inner portion of the upper arm, where you can see that there's retraction of the deeper tissues in that area. Again, sometimes itchy, sometimes painful, and oftentimes restricting your ability to move freely as you've lost elasticity in these tissues.
Diagnosing skin GVHD
15:33 So again, some rules that are overarching when it comes to diagnosing graft-versus-host disease in the skin. The distinction between acute graft-versus-host disease or chronic graft-versus-host disease is solely based on how it looks. There is a tendency for one to appear earlier after transplant and a tendency for one to appear later. But sometimes you can get either morphology at any time point. Oftentimes, patients are reintroduced to donor cells with subsequent blood transfusions or subsequent transplant.
And so, the appearance of acute or chronic can appear at any time point and can also occur at the same time point. What's very unique to skin graft-versus-host disease, as opposed to other skin rashes in general, is the appearance on the face and the scalp, along with appearance on the palms and the soles. And then most importantly, while a biopsy of the skin can be done, it's not necessary to establish a diagnosis. It is completely possible to make a diagnosis of skin graft-versus-host disease, either acute or chronic on looks alone.
Treatment for Skin GVHD: Steroid and non-steroid topical ointments and creams
16:53 So at this point we'll transition into focusing on some therapies for skin graft-versus-host disease. One of the most common symptoms that patients encounter is itching., along with decreased range of motion, and wound development, all of which we discussed earlier. And so, there are needs to treat specific symptoms of skin graft-versus-host disease. And there are skin specific therapies. Dermatologists will always keep in mind that they are part of the overall team. And so, we're going to discuss some specific therapies that dermatologists can employ while maintaining allegiance with the rest of the oncology team and not affecting therapies that you may be getting from other practitioners.
So far and away the most commonly used dermatologic therapy includes creams and ointments. And there are many, many, many topical anti-inflammatory medicines, but they essentially fall under two main categories. One is topical steroids. And then secondly are topical non steroid anti-inflammatory, most commonly tacrolimus and pimecrolimus.
So, steroids have been around for decades. They are relatively inexpensive. They vary in potency from very mild to very strong. They also vary in terms of vehicles in which they come in. So greasy ointments are helpful if the skin is dry. Greasy ointments also lack preservatives. So, for those that have especially sensitive skin, they are more likely to tolerate ointment. Creams are easier to rub in and dry faster. Gels dry very quickly and so have use for mucosal surfaces including inside the mouth. Lotions or solutions are very helpful for hairy skin such as if you had inflammation on the scalp.
Overuse of steroid ointments and cream can cause skin to thin
19:05 And so, keeping in mind these various properties, there's a lot of flexibility in how to use these agents. Non steroids tend to be more expensive, but they have a big advantage over steroids in that the major side effect of overuse of topical steroids is the potential for atrophy, which is a term that means thinning of the skin. And so, with overuse of topical steroids, it is possible to thin the skin. And so, in especially sensitive areas such as the face, we oftentimes will use the non-steroid if we know long term therapy is necessary. Very difficult to thin the skin with short term use, but with months of overuse it is possible.
Acitretin (vitamin A) can be used to treat some forms of skin GVHD
19:52 We'll then discuss here in just a minute some other skins specific therapies including phototherapy, photopheresis and Acitretin which is a vitamin A pill. Before we get into the two phototherapies and photopheresis, briefly Acitretin is an anti-inflammatory pill that helps the skin turn over properly.
So, with some of these diseases, the maturation of the skin is affected. So, by giving Acitretin, that maturation is then corrected for the skin. So, it's especially useful for that lichenoid or purple appearing rash and form of chronic skin graft-versus-host disease, along with lichenoid inflammation within the mouth or on the genitals. Acitretin is typically used to treat psoriasis, but it does have utility for this form. Most importantly Acitretin as a pill does not affect the immune system. It does not suppress the immune system. So, all of these agents, including this pill Acitretin, is a very easy addition to an existing therapeutic regimen that a bone marrow transplant survivor may already be on.
Phototherapy Treatment for Skin GVHD
21:12 Specifically we'll talk about phototherapy here in this slide, which can be delivered with either ultraviolet A or ultraviolet B light. Phototherapy is an effective dermatologic therapy because it is able to decrease inflammation within the skin and it's quick. It takes minutes and it's very safe. The risk is simply ultraviolet light. So, if you are taking medication that increase your ability to sunburn, the dosage of light therapy needs to be adjusted.
If you have fair skin, as opposed to dark skin, the dosage of light therapy would need to be adjusted and the dosage is essentially dictated by the time within a light booth. So, there is a cartoon image here on the right of what a typical phototherapy booth looks like. You would enter into a physician's office, enter into that room, get undressed, walk into the booth, close the door and then there's a bell or something to signal for the light therapy nurse to come in. They will come in, put in the numbers, and you will be dosed. Typically, it's on the order of one to four minutes. So, then you exit the booth, you get dressed and you leave. So, it's a very quick, safe, effective anti-inflammatory therapy, again, that adds additional anti-inflammatory therapy to the skin. With phototherapy, you completely avoid any internal therapy, which can be useful when the only manifestation you have is in the skin.
Extracorporeal photopheresis to treat skin GVHD
22:54 Another form of phototherapy is called extracorporeal photopheresis. Oftentimes simply called photopheresis. And this is similar in that you're delivering ultraviolet A light, but instead of delivering it to the skin, you're delivering it to the blood. And so another cartoon here on the right where blood is drawn from a patient into a machine, and in that machine, the blood is made into a very thin layer and across that thin layer ultraviolet light is being directed to the blood. After it has been exposed to ultraviolet light, the blood is then reintroduced to the patient.
So, the only purpose of this machine is to pull out the blood, expose it to ultraviolet light, and then redirect it back to the patient. And just like ultraviolet light is anti-inflammatory to inflammatory cells in the skin, it is anti-inflammatory to the blood as well. And the thought with photophoresis is that the ultraviolet light anti-inflammatory effects leads to a shift in the body's immune response to a more anti-inflammatory state, thereby decreasing inflammation internally. Photophoresis is typically administered over consecutive days. So, day one and day two, let's say a Monday and then a Tuesday for a few hours each day. The regimen can be as often as weekly, or as infrequent as monthly when patients are started on therapy. Again, it's very safe. It is invasive in that an IV is being inserted for that period of time, but it is very safe and again, easy to add on to other existing therapies when needed.
Stretching and deep tissue massage for tight skin caused by GVHD
24:36 Other things that are specifically useful for managing the sclerodermoid type of graft-versus-host disease or tightening of the skin, especially when it's affecting deeper layers of tissues, or over a joint is the value of stretching, myofascial release, and deep tissue massage and obviously there are experts in these fields that patients can be directed to help with any of these symptoms.
Oral steroids and immunosuppression for skin GVHD
25:06 And then of course there is an entire toolbox of options that the oncology team has in graft-versus-host disease or when graft-versus-host disease is involving the skin, along with other organs. The main treatment is steroids and definitely has the best evidence of working. But just as topical steroids have potential side effects, internal steroids also have a host of potential side effects, especially when used for longer durations of times which is why the subsequent list of non-steroid options that are widely used, both old immune suppressant, and emerging immune modulating therapies listed below, have been studied and have a potential role to our patient.
Skin cancer risk for patients with skin GVHD
26:07 The last thing I want to highlight is the issue of skin cancer and having skin graft-versus-host disease does increase the risk for skin cancer. This is for multiple reasons. Number one, many times at the time of transplantation, patients are exposed to whole body radiation as part of their conditioning regimen. Secondly, and importantly, many times patients with skin graft-versus-host disease or other forms of graft-versus-host disease are on immune suppressing therapies as we just alluded to on the prior slide. And when the immune system is suppressed for any duration of time, that increases the risk for skin cancers to develop. This is something we've seen for many decades with solid organ transplants.
But we also see it with bone marrow transplant. And so, the estimated risk of skin cancer is 30 times higher in a patient with graft-versus-host disease as opposed to a patient who never had a bone marrow transplant. And for this reason it is recommended that patients check their skin every one to two months at home, and then to get undressed for a doctor, at minimum, once a year, more often if you've had a skin cancer recently, or if you're deemed higher risk. But at minimum get undressed by and be evaluated by a doctor, at least once a year.
How to do a skin cancer check at home
27:37 In terms of checking your own skin we'd recommend you get in front of a mirror. Look at your back, your buttock the back of your legs, areas that you don't typically look [at]. The frequency of one to two months is so that you can actually have a chance to appreciate change. As you know, if you were staring at a freckle every five minutes it would be very hard to appreciate change or even every day. But the periodic overview allows you a chance to appreciate if any change has occurred.
Symptoms of basal cell skin cancer
28:06 There's three main types of skin cancer that I'm going to discuss today. Basal cell skin cancers are the most common skin cancer in the world. Squamous cell skin cancers are second, and melanoma are third most common.
So basal cell skin cancers are the most common, but they're also the least dangerous, and they typically appear with this shiny pink bump. And you can see how exaggerated the blood vessels are. We call them, arbor rising or tree branch like blood vessels within. The term curly or shiny is oftentimes used to describe a basal cell, but when they persist long enough, basal cell cancers can break down and ulcerate as we see on the picture on the right. Basal cell skin cancers are essentially driven by sunshine. So, they are most commonly seen on areas that have had long term chronic exposure to sunlight, including the nose and the ear, being the two most common areas.
Symptoms of squamous cell skin cancer
29:12 Squamous cell skin cancers are also driven by sunlight, but they are also seen more often in patients who have a suppressed immune system. So, while basal cell skin cancers are the most common in the world, squamous cell skin cancers are the most commonly seen in patients on immune suppressing medication. And you can see they look a little different, they tend to be more crusty, oftentimes warty is an appearance that's used. They oftentimes are noticed by patients because they're painful. These do have the potential to grow deeper into the skin and rarely have the potential to spread throughout the body. And so, they're definitely deemed a much more aggressive type of skin cancer.
Symptoms of melanoma
29:59 And the third skin cancer worth discussing this morning is melanoma, which is the most common of the deadly skin cancers. As you can see, sometimes they can appear quite innocuous and discolored where the color pattern is very irregular. They can either be flapped or bumpy and melanomas are known to have the ability to spread throughout the body. And so, catching these early would be important.
It's important to remember that skin cancer can develop anywhere you have skin. And so, when you evaluate yourself, you want to look under your feet at the soles of your feet. You'd want to look within your scalp in your hair, around your nails, and even your genitals as all are possible areas where one can develop skin cancer. Anywhere you have skin., you have the potential to grow a skin cancer.
Steps you can take to reduce the risk of skin cancer
30:49 So steps that you can take to reduce your risk of skin cancer is again to be looked at by a physician, have a total skin check where you are comfortable getting undressed at least once a year after the age of 40. We would recommend you specifically see a dermatologist if you had a history of skin cancer, or if you are high risk, meaning you're taking medications that suppress your immune system as many patients with graft-versus-host disease do. In those instances, you may even need more frequent monitoring. And then, when in doubt, if something new appears that looks funny - we oftentimes use the word, ugly duckling - when there is an ugly duckling spot that appears, it doesn't look like anything else, it doesn't act like anything else, that's worth consultation with your physician. It may be benign, but since you don't know and it's so odd and out of place on your skin, it's worth evaluating.
Clothing is the best protection against excessive sun
31:47 The other thing is prevention. So, there is no such thing as a safe tan. When you tan, it is your body's attempt to heal and to increase a barrier because it receives so much ultraviolet damage, it's trying to avoid doing that again so it's trying to increase melanin or the skin color in your skin. But most importantly when you tan, it's a sign that you were already damaged. So, remember that there's no such thing as a safe tan.
And so how to protect yourself. My favorite recommendation is clothing. So wide brim hats, long sleeves, clothing is most important. And it's most effective at preventing ultraviolet light from getting to and damaging your skin.
So again, I never tell patients that they have to live in the basement and never leave their house, but there are times of the day that you're an increased risk. A middle of the day, usually between ten in the morning and three in the afternoon, those are your peak ultraviolet hours. So, minimizing exposure to your skin during those hours -so if you like to jog or go for a walk, earlier in the morning or later in the evening would be better times. If you are out in the middle of the day, while sunscreen can help you, clothing is a much more effective strategy and clothing does not require re-application. Once you have a hat on, your hat stays on.
Most effective way to use sunscreen lotions and creams protest against skin cancer?
33:07 Now obviously, there are some areas that will be exposed on the skin and this is where sunscreens have value. I will say that most of the data, when we determine how effective sunscreens are, are done, assuming that you put two grams per centimeter squared, which is a lot of sunscreen, So I would say two to three times as thick as most people put on makeup which, as you know, most people probably are not completely compliant and putting on that much sunscreen.
The other thing is when you look for a sunscreen you want to look for something that lists itself as being broad spectrum. It blocks both UVA and UVB. The SPF listed on a sunscreen is only indicative of how well it blocks ultraviolet B.
We all know that there are varying numbers and I will tell you that SPF 30 is sufficient for most people. The difference in how much ultraviolet filtration occurs between an SPF 30 and an SPF 55 or 60, is very small. That difference is a matter of fine hairs. And so, SPF 30 is really the benchmark. Anything 30 or above is sufficient.
And then re-application needs to be done every two hours. You need to sun protect every day, whether it's raining, or the sun is shining. On a cloudy day, ultraviolet light is still able to get through clouds. Visible light does not. So again, visible light does not penetrate clouds, ultraviolet light does.
When you're in the car, the front and rear windshield has ultraviolet filtration. The side windows do not. So, if you are outside and you can see the sun, the sun can probably see you. Reapply every 90 minutes to two hours. If you get wet, you'll need to reapply. There is no such thing as a waterproof sunscreen. There are water resistant sunscreens that last about 20 minutes, and then they're no longer effective.
And remember, if you tanned or you burned, that is indicative that you did not put on enough.
So, at this point I'll stop. You know I think going through this journey from my angle as a physician has been very rewarding. Obviously, my family has made big sacrifices to allow me to do this and I thank them for that. My father had leukemia and did have a bone marrow transplant and did suffer from graft-versus-host disease and so I saw that also from the family side. Unfortunately, my dad passed away a few years ago but this is something that I was already heavily involved into this field but even more appreciative of what bone marrow transplant survivors go through having seen it firsthand. So, with this I'll stop, and I'll say thank you to everybody.
Question and Answer Session
36:02 [Moderator] Thank you very much Doctor Anadkat. That was a great presentation. I know I certainly learned a lot about what I need to do to protect myself against the sun and what have you. So now we'll take questions from the audience. Again, if you have a question, type it into the chat box on the left, and we're going to try to get to as many as possible. We have quite a few so bear with us.
First question, does phototherapy treatment increase the risk of skin cancer and do you use sunscreen before going in?
36:37 [Dr. Anadkat] That's a terrific question. So, there are two types of phototherapy, ultraviolet A and ultraviolet B. The ultraviolet A therapy is not effective as ultraviolet A alone. It's typically given with a photosensitizing pill called psoralen and psoralen is spelled with a P. So, it's P plus UVA, we call it PUVA. And the PUVA therapy, which is a much older form of phototherapy does increase your risk for skin cancer.
For the last 25 years, ultraviolet B therapy is more often given for inflammation of the skin and it does not require a pill so it's just ultraviolet B. And ultraviolet B therapy alone, when given in phototherapy doses, does not increase the risk for skin cancer. We do not put sunscreen on patients when they go into the booth. Typically, patients will rub their skin with mineral oil or something to deflect away the small scales on the skin just to allow the light to penetrate better. We cover eyes always and we cover genitals always.
A typical ultraviolet B treatment course is coming in three times a week for about eight weeks to get clear. So about 25 treatments. It's been shown that patients who have received up to 250 lifetime treatments of narrowband ultraviolet B therapy do not have an increased risk for skin cancer.
38:16 [Moderator] All right. Sandra would like to know whether over-the-counter vitamin A serum is effective in treating GBHD skin discoloration.
38:26 [Dr. Anadkat] Right so vitamin A therapy can be given as both pills, which I only recommend to be done by a physician, not to take over-the-counter vitamin A because it doesn't work exactly the same. And then topically. And so topical vitamin A therapies you'll commonly see as Retinol or Retin-A. And that can be done prescription or over the counter. That is effective at treating acne. That is effective at slowing down some very small aging related changes.
It's not super effective at helping with discoloration and the reason being is that discoloration from graft-versus-host disease is essentially a stain. And the way I try and describe this to understand is the top layer of the skin is where the color is, but when you have inflammation of that layer, the color essentially drops below. So, it drops under the skin. That stain or discoloration is actually a sign of that color that's been deposited under the skin. So topical creams are not able to reach under the skin, so they don't necessarily harm the skin, but they don't help the skin when you have discoloration. The only thing that really helps is time and giving your body time for its circulation to come by and clear up that discoloration.
39:51 [Moderator] All right. Dorothy wants to know whether, when GVHD affects the fascia under the skin, whether that restricts or causes muscles to atrophy or become weaker and whether massage is a good therapy to loosen the fascia and stop the progression of the restricting GVHD.
40:19 [Dr. Anadkat] Okay so that's a terrific question. I think there's a few layers to this question. I think the course of fascial graft-versus-host disease is variable. So, for some it is progressive, and you get progressive tightening and for some it gets to a certain stage and then essentially burns out. And to alter the course of that, this is where therapies that suppress the inflammation cascade are useful. So sometimes phototherapy is able to penetrate deep enough in the skin to help with that. Otherwise internal therapies like steroids or steroid-sparing internal drugs are necessary.
Now in terms of the symptoms of tightening and discomfort, you'll absolutely notice benefit with massage and stretching to help cope, and to kind of help manage and sometimes even reverse some of the tightening that has resulted as a result of some of the scarring. But I'm not sure that you'll reverse the active inflammatory disease with myofascial massage, but you will be able to relieve some of the damage that's happened.
Now in terms of the muscle atrophying, muscles atrophy when they're not used. So, the disease itself does not cause atrophy of the muscles directly, but it would happen indirectly. So if you had tightening of the skin and the fascia overlying the joints, and as a result you don't move that arm as much because it's tightening, because you're not moving that arm as much, the muscles will atrophy.
So, it's really because you're not moving that arm as much as the muscles will atrophy. So it's really an impetus to patients that I know it's tight, but you need to keep moving and you need to keep using, because if you don't use it, you'll lose it. So, it's an indirect atrophy that occurs, but that can be overcome by simply doing your best, obviously easier said than done, to maintain movement and range of motion.
42:21 [Moderator] Rose has a question. She wants to know; she says I read a study that was done using ablative CO2 laser therapy for sclerodermoid GVHD that was effective. Have you ever heard of this treatment?
42:36 [Dr. Anadkat] Yeah. So, this was a discussion that I was in this morning with someone. And so, there are studies and there are certain centers where people are attempting to use a laser. And this is what we would call an ablative laser. There are a few different types. CO2 is one type of an ablative laser and ablative means that it's trying to destroy the skin. And the idea is being studied. I have heard of it. It is by no means mainstream or widely used because we... Some people worry that by destroying the skin with an ablative laser, it can heal with scarring and you could potentially make it worse, but other people feel like, well the top layer right now is scarred from the graft-versus-host disease so if we were to destroy that and allow new, fresh skin to grow, you would loosen that area of tightening. So, it is an active area of study. It does have some logic to it, but it's not mainstreams yet.
43:44 [Moderator] All right Ellie has a question. She said in reference to your comment about limited joint movement, my husband gets a bear hug type of feeling around the midsection and ribs and a stretching sensation from neck to waist, causing terrible pain. We haven't been able to get to the root of it. Do you have any sense of what might be causing this?
44:04 [Dr. Anadkat] Yeah and so I think first and foremost, I'm sorry that your husband is feeling those symptoms. And I think there are potential explanations. One could be myofascial sclerodermoid graft-versus-host disease where he just has tightening of the deeper tissue layers. Again, in which case I think some of the things we've discussed earlier in terms of myofascial massage, in terms of systemic therapy or even phototherapy could potentially be helpful but I think the other thing is understanding that graft-versus-host disease can affect many organs.
And so one of the other organs that can sometimes be affected is the nervous system so the nerves within the skin or in the deeper layers that transmit our sensation of itch, or pain or burning, can also be affected. And so essentially a neuropathy, or a disease of the nerves, could be giving a false signal of tightening or stretching or some other symptom. Anti-inflammatory therapies that target internal graft-versus-host disease may have value. So I think without seeing tissue or knowing if tissue has tightening, which can sometimes be done with MRIs, or sometimes be done with ultrasound or CT imaging if they're too deep to actually do a tissue biopsy, could help guide that. But I think that's the two most likely explanations would be either a neuropathy, or there's nerve disease or myofascial sclerodermoid graft-versus-host disease.
45:41 [Moderator] All right, excuse me. Ed has been out 15 years since his transplant, and he says he has blisters on the lower part of his leg from GVHD. How do you treat the blisters, and do they go away? The leg is red with blisters.
45:58 [Dr. Anadkat] So congratulations on being 15 years out, that's terrific. So, Ed I think when we see redness on the skin, I think first and foremost I would see a dermatologist. I think a dermatologist could help here, but when you have inflammation of the skin, topical anti-inflammatories are very helpful. Sometimes when you have extra inflammation of the skin you can get blistering in that area.
Now, other potential causes of redness on the lower legs could be due to vascular congestion. In other words, blood sort of filling up in the legs. So swollen leg oftentimes will become red also, red and swollen, and if it's swelling quickly or has been swollen long enough you can get blisters because of chronic swelling, and that may or may not be related to graft-versus-host disease.
So, I think there's a few different components that could be targeted. Again, even a dermatologist who's not necessarily knowledgeable in graft-versus-host disease would probably still be capable of helping someone with red blisters on their leg, because the list of possibilities, while there are a few, they're not very long. But there are some simple therapies depending on what the source of that redness is.
47:24 [Moderator] All right Dina had her transplant two years ago. She had acute promyelocytic leukemia, and she says after her transplant she developed rosacea which she never had before. Could this be related to the transplant or GVHD?
47:40 [Dr. Anadkat] Yeah so, it's interesting, I would say the short answer is maybe, but not definitely. I think rosacea is a condition where you get redness and sometimes easy flushing and occasionally pimples on the face. It's what I term adult acne. And so, to get rosacea, teenagers don't have rosacea and younger children don't have rosacea. Rosacea is something that develops in adulthood. It could be as early as your 20s and it could be as late as your 50s and 60s. So, I think one thing that's changed pre- and post-transplant is that you're older, and so it is possible that you got rosacea because this was simply your age to get rosacea. Rosacea is not considered to be a transplant associated skin alteration, rather it is something that is felt to occur independent of that. That being said, there's so much that we know but so much we don't know that, yes, it's possible, but it's also very possible that someone who never had a transplant would develop presentation at that age and so it's much harder to connect those two.
48:49 [Moderator] All right, Susan has a question. She says her skin is very thin and it's hard to get sunscreen off it so she wants to know whether to protect your skin from the sun, do you need to wear clothing that has SPF protection or will regular clothing suffice? And if you do need SPF protection in clothing what should it be up to? 50 or what?
49:14 [Dr. Anadkat] Yeah, great question. I said this before, I think clothing is much more reliable than topical application of sunscreen. You're just going to cover all the spots; you're not going to miss a spot. You know, unless you're wearing sleeves with holes in it, you're just going to cover. Clothing in general works better than sunscreen. Sun protective clothing works a little bit better than regular clothing and the difference with sun protective clothing is that the weave of the clothing is a little tighter so there's less gaps for sun to get through. And oftentimes they're embedded with a chemical, though not always, that is sun protective as well. The labeling in sun protective clothing is UPF, so a universal protective factor. Anything again over 30 is great, although most, some protective clothing starts at a UPF 50. The other benefits of sun protective clothing is a lot of times they're more breathable, or lightweight. And so, I think comfort can be increased a little bit and you can find sun protective clothing at very inexpensive prices. They're primarily seen in sporting good type sections of stores or sporting goods stores. But I always comment to people that if you go to the warmest places in the world, the locals are wearing sleeves or pants and the only people wearing tank tops and shorts are the tourists. And so, I think if you are in a sunny climate for a prolonged period of time, sunscreens are just nearly not as effective as sun protective clothing.
50:51 [Moderator] All right. Laura Lee has not had any skin GVHD for five years and she wonders is it okay for her to go out in the sun for five to ten minutes so she can get some vitamin D?
51:05 [Dr. Anadkat] Yeah so, I think whether you have graft-versus-host disease or not, the risk for skin cancer is increased more so if you're on medicine that suppresses your immune system. I think everyone was born to get a little bit of sunlight so I'm not encouraging that anyone, again, live in the basement or stay without any color or light for the duration of life.
To make vitamin D, sunlight is very effective. It takes 15 minutes of ultraviolet B exposure three times a week and that is sufficient for your body to make vitamin D. So, 15 minutes, three times a week. So, what you have to ask yourself, is going out for five or ten minutes is completely okay and then coming back in? But do you get five to ten minutes without even realizing it? So how long is your commute or are you in the car? Are you outside doing other things and are we counting those minutes as well?
And most people are outside maybe a little bit less now, during the coronavirus era, because you're not commuting to work as much but that's what you need is 15 minutes, three times a week. So, five to ten minutes a day is completely reasonable to get your vitamin D. I will say if you get more than that, you don't get more vitamin D. And so, if you were out an hour a day you don't make more vitamin D than if you just had 15 minutes, three times a week. And if you get excessive amounts of sunshine, you can actually break down some of the vitamin D that you were producing, so this is definitely one of those things where a little bit as good, a little bit more is probably okay. Too much actually takes away some of what you were going for.
52:47 [Moderator] All right we have another question from a listener. I had level four GVHD, and third degree burns after my transplant. And I had photophoresis for almost two years. I'm now on low dose tacrolimus. Should I be concerned about my skin reacting this way again? And would ultraviolet light help me now as a maintenance therapy?
53:11 [Dr. Anadkat] I think that is a tougher course of graft-versus-host disease. Typically what you're describing in terms of grade three, grade four, that sort of blistering or burn-like reaction is seen with acute graft-versus-host disease, so less likely to rebound now, this many months or years after the time of your transplant. That's much more often seen in the acute or short-term period after the transplant.
In terms of whether or not you should do phototherapy, I would make that decision based on if there is currently active skin graft-versus-host disease as a treatment option, but to treat not to prevent. And so, I would do phototherapy or consider it if you have active skin graft-versus-host disease, but I wouldn't consider it as a strategy to prevent future skin graft-versus-host disease.
54:03 [Moderator] We have two questions here from Dorothy and Elle that I think are similar. Can skin GVHD cause nerves in the skin to be extra sensitive, causing temporary prickly shooting pain when touched or manipulated in things like massage or physical therapy? And can joints be affected in the same way? And Ellie has mentioned that she has pins and needles after a shower that causes itching and is that part of GVHD?
54:35 [Dr. Anadkat] It can be. So, graft-versus-host disease can affect the nerves. And so, some of those symptoms do include, for those that are affected, sometimes quickly, sometimes pins and needles. sometimes numbness, sometimes itching and sometimes burning. And it can also affect joints, where it can mimic other inflammatory joint diseases. So, both of those things are possible to be directly related to the graft-versus-host disease. They're also both possible to be independent because diseases like that occur in patients who have never had a bone marrow transplant, but they're definitely possible to all be related to graft-versus-host disease.
55:15 [Moderator] Melissa has a question. She said, I have severe hyper pigmentation of the skin especially on the face. It looks like a third-degree burn. I've tried face steroids, topicals, et cetera. What else can I use on the face and neck and will the skin eventually get back to normal?
55:34 [Dr. Anadkat] The skin will get back to normal. Again, discoloration from graft-versus-host disease, the darker your skin is initially, the longer it's going to take to fade, but it does fade. The problem is that that discoloration is deeper in the skin and so creams or other bleaching agents typically are not effective at lightening it, it just takes time. You get that discoloration after there was inflammation there, so as long as there's no current inflammation there's no need to currently treat it with creams or anything, but if you get a new rash you would want to treat that rash sooner rather than later so it doesn't leave a new stain. So topicals are only effective at calming down current inflammation, but the stain that is left, honestly, the only real effective therapy is time. But it is not permanent. It will come back to normal.
56:30 [Moderator] Stacy would like to know what your opinion is regarding the use of sirolimus for skin GVHD.
56:37 [Dr. Anadkat] I think it is one of many potentially useful options and I have seen it be effective for patients with skin graft-versus-host disease, and I have seen it not work for others with it. So, I think it is part of the reasonable options that are in the toolbox, which is kind of where I would leave that.
56:57 [Moderator] All right. And then Dorothy wants to know whether the scarring damage of the subcutaneous skin GVHD is reversible and are there new drugs to reverse the scarring process of GVHD?
57:10 [Dr. Anadkat] So scars eventually will soften. They don't always soften back to normal, and that's essentially what we see with scarring graft-versus-host disease or sclerodermoid graft-versus-host disease. I think once the inflammation is gone, the scars can soften, but that can take years to do and it's not always fully complete. There are countless studies and research being done to target sclerodermoid graft-versus-host disease but there is not a perfect cure at the moment. But yes, scars can soften and go back to normal.
57:50 [Moderator] All right, then our last question which I think you answered earlier but I'll ask it anyways is from Susan. She says she's Caucasian, has medium skin tone. Her arms particularly darkened quite a bit. And she's now four years out and the skin and her arms and lower legs look crepe-like and tear easily. The skin has tightened some but still dark. Will the discoloration in the thin skin ever be gone? She just took her last budesonide and will be off Flovid in a week only leaving Jakafi.
58:24 [Dr. Anadkat] Yeah so, I think there's probably many reasons as to why the skin is dark and is crepe-like and tears easily. One big potential reason is the budesonide or internal steroids can make you bruise easier, which can leave a lot of discoloration and can also thin out the skin. So being off of the steroids is probably the biggest factor in helping those changes improve. Discoloration in general, it's a stain it's not a scar, so just discolorations do fade, but they also can be replaced by new discoloration. And I think while you're on budesonide, you kept bruising in those areas perpetuating that discoloration. So being off of that is going to be most helpful.
59:04 [Moderator] And with that we need to close the session. I want to thank Dr. Anadkat for an excellent presentation and helpful question and answer period. And I also want to take this moment to thank you the listeners, the participants for your excellent questions.
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