Chronic Graft-versus-Host Disease of the Skin and Connective Tissue

  Download Speaker Slides  

Chronic Graft-versus-Host Disease of the Skin and Connective Tissue

Tuesday, May 3, 2022.

Presenter: Sharon Hymes MD, The University of Texas MD Anderson Cancer Center

Presentation is 36 minutes long with 22 minutes of Q & A.

Summary:  The skin is the most common target of graft-versus-host disease (GVHD), a frequent complication that occurs after a transplant using donor cells. Although most skin changes after transplant are mild or moderate, more severe skin problems are possible.

Highlights:

• The skin consists of multiple layers, each of which is affected differently by GVHD.
• Topical therapies are effective when GVHD affects only the top layers of skin. Systemic therapy is needed to treat GVHD that affects deeper layers of skin.
• People who are immunosuppressed or have graft-versus-host disease have a higher risk of developing skin tumors, skin infections and hard-to-heal wounds

Key Points:

(08:47): When GVHD affects the top layer of the skin (epidermis) it can cause itching, burning and/or a fish scale-like appearance on the skin.

(09:41): GVHD can affect the skin’s pigment and cause a change in skin color.

(10:27): A common form of skin GVHD, called lichen-planus, causes lesions on both the top and middle layers of skin.

(12:20): GVHD can cause poikiloderma evidenced by thin skin, pigment change, and blood vessels showing through the surface of the skin.

(13:17): GVHD can cause permanent hair loss.

(14:26): Changes in fingernails occur in over 50% of GVHD patients.

(16:20): GVHD can cause scarring in several layers of the skin. This is called sclerotic or fibrotic GVHD.

(20:14): GVHD can cause fasciitis, which is inflammation of the deep skin layer that overlays muscles and tendons.

(24:30): The two major topical therapies used to treat skin GVHD are corticosteroids and calcineurin inhibitors.

(26:35): Phototherapy is a potential treatment if GVHD is only affecting the top layers of skin.

Transcript of Presentation:

(00:00): [Becky Dame] Introduction. Welcome to the workshop, Chronic Graft-versus-Host Disease of the Skin and Connective Tissues. I would like to thank Kadmon, a Sanofi Company, whose support help make this workshop possible.

(00:13): It is my pleasure to introduce to you, Dr. Sharon Hymes. Dr. Hymes is nationally recognized expert on skin problems after transplant and a clinical consultant at the University of Texas MD Anderson Cancer Center in Houston, Texas. Recently retired, she spent much of her career at the MD Anderson Cancer Center serving as the associate medical director of the Melanoma & Skin Center. In addition, Dr. Hymes has been an integral member of the MD Anderson Chronic GVHD Clinic. Dr. Hymes work has focused on skin GVHD as well as all skin problems that occur in the setting of a stem cell transplant. Please join me in welcoming Dr. Hymes.

(01:02): [Dr. Sharon Hymes] Overview of Talk. Thank you very much. This is Dr. Sharon Hymes, and it's my absolute pleasure to contribute to this symposium. I'm going to be talking today about chronic graft-versus-host disease of the skin and connective tissues. I have no disclosures for this discussion.

(01:20): So, my learning objectives today are to define graft-versus-host disease as it relates to skin; to recognize the skin changes of chronic graft-versus-host disease; and to explain how the diagnosis is made by the clinicians. I want to review skin-directed management of chronic graft-versus-host disease. I'm not going to talk about systemic therapy, but more skin-directed therapy. And I also want to bring to the fore some of the other skin problems that we see post-transplant. I'm happy to report that on Thursday, I will be back again and I'll talk a little bit in more detail about some of those skin problems after transplant.

(02:07): The skin is the most common target of graft-versus-host disease; it often affects other organs at the same time. So, let's go right to the meat of the discussion. What is graft-versus-host disease? I know most of you have been listening over the past few days and some of this may reiterate what you've already heard. Most of all, it's a multi-organ disorder. The skin is most prominently involved, often, in this disease, but it often involves multiple organs. It happens when immunocompetent donor T cells or the graft are given to the immunocompromised host, and it remains a major cause of morbidity or problems and mortality after transplant.

(02:46): Most skin changes after transplant are mild or moderate. Skin changes are very common. In this presentation, I'm going to show you some severe skin changes, but let me reassure you that many of the skin changes post-transplant are mild or moderate in severity. But in order to teach about them, I may show you some that are a little bit more severe. The skin changes often resemble the changes that we see in autoimmune disorders or connective tissue disorders, and these particular skin changes, although they can be seen outside the setting of stem cell transplant, when they're seen after transplant, may be a representative of graft-versus-host disease.

(03:33): Skin GVHD can resemble other inflammatory diseases as well as disease that cause skin scarring. So, what is skin graft-versus-host disease? The traditional definition of skin graft-versus-host disease refers to skin findings that look inflammatory. And by inflammatory, I'm referring to the process by which immune cells interact with the skin and create skin lesions or create redness, or they can be fibrotic or scar-like. So, inflammatory skin changes may look like skin changes we see outside the setting of transplant. And one of the diagnostic findings we can see, and I'm going to show you pictures of this, is something called lichen planus, which refers to purplish bumps or papules on the skin. And some of the fibrotic and scar-like changes can look very much like the changes of scleroderma, which is a type of connective tissue disease.

(04:31): Skin GVHD can occur early or late after transplant.  It used to be thought that this only occurred a hundred or more days post-transplant. Our current definition of skin GVHD is that it's a long-term complication of stem cell transplantation characterized by inflammatory or fibrotic skin problems. But we no longer define it by a hundred days after transplant. You can get chronic skin GVH before a hundred days. Most of these changes can be diagnosed just by clinical examination. There may be no preceding acute GVHD prior to the onset of chronic GVHD.

(05:13): The National Institutes of Health (NIH) has developed criteria to diagnose and grade skin GVHD. So, what does chronic GVHD of the skin look like? And how do we grade and document these changes? For this, we refer to the National Institute of Health Consensus Criteria. And what those criteria were, were an attempt to categorize the features of chronic GVHD for clinical trials. So, everybody was talking about the same skin changes when they were deciding on how to start clinical trials for skin GVHD.

(05:47): There are diagnostic features, those are features that we see that are sufficient to establish the diagnosis of graft-versus-host disease. There are distinctive features, and those are features that are suggestive of graft-versus-host disease, but insufficient alone to establish the diagnosis. And then there's a variety of other features that may be seen in the setting of graft-versus-host disease. And I think this will be clearer as we go along.

(06:18): When your clinician looks at you to determine if you have graft-versus-host disease in the skin, they're looking at three main factors. One is the morphology. And what that means is what exactly do these skin lesions look like? Are they raised? Are they flat? Are they scaly? Are they firm?

(06:39): They're looking at the body surface area that's involved. Some graft-versus-host diseases of the skin involves a very small area, some involves a larger area. And we actually document by the percent of the skin involved.

(06:56): We always especially look for the fibrosis, sclerosis, scleroderma, and I don't care which term you use for that, because that may indicate more severe skin graft-versus-host disease. Then of course we document other skin, nail or hair findings.

(07:17): The skin consists of multiple layers, each of which can be affected by GVHD differently. I think it's important to understand what the skin looks like structurally to understand what GVHD of the skin looks like clinically. On the left side, you're seeing a little cartoon depiction of the skin. The very top layer is called the stratum corneum, that's the scaly area you sometimes see on your skin. Underneath that, there's a beige area, that is the epidermis. It's separated by a basement membrane from the dermis, and in the dermis are a lot of the skin structures like hair follicles or sweat glands, nerves, and blood vessels. And underneath that, depicted by the yellow area, is fat. And even thin people have fat underneath their dermis. And underneath that is going to be bone and muscle and tendon.

 (08:16): The picture on the right is actually a pathologic cross-section of the same thing I'm showing you, with the scaly area on top, which is the stratum corneum, the area underneath, which is dark pink, which is the epidermis, the area underneath that, which is the dermis. And you'll see a hair follicle. And I think that's important, because graft-versus-host disease of the skin can look very different depending on which area of the skin is involved.

(08:47): When GVHD affects the top layer of the skin (epidermis) it can cause itching, burning and/or a fish scale-like appearance on the skin. So, what happens when we see chronic graft-versus-host disease at the epidermis? And I'm just showing you my little cartoon skin diagram where that is. Well, you can see several things. Sometimes we don't see anything at all. Patients will come in and say, "Oh, I'm itching," or "My skin is burning," or, "It feels uncomfortable." And we don't really see anything at all. Early on, we can start to see this fish scale-like change. It has a name, it's called ichthyosis. Ichthyosis can be seen outside the setting of stem cell transplant and some people are even born with ichthyosis. But when we see a patient that did not have this, then had an allogeneic stem cell transplant, and then develops this ichthyosis-like picture, we're a little concerned that that might represent early graft-versus-host disease.

(09:41): GVHD can affect the skin’s pigment and cause a change in skin color. If you remember the skin diagram I showed you, I showed you at the basement membrane is the area that separates the epidermis from the dermis. That's where the melanocytes or our pigment cells live. Anytime graft-versus-host disease interrupts those melanocytes at the basement membrane zone, we can get color change in the skin. That color change can be hypopigmented, which means less pigment. It can be hyperpigmented, that means more pigment. Or you can entirely lose the pigment. So, if you get chronic graft-versus-host disease of that area of the skin, we often see those pigment changes.

(10:27): A common form of skin GVHD, called lichen-planus, causes lesions on both top and middle layers of skin. Well, what happens if we get graft-versus-host disease of the epidermis and the dermis? Well, a diagnostic form of chronic graft-versus-host disease is lichen planus. And that affects both the dermis and the epidermis. And the picture that I'm showing you here are purplish polygonals, it has lots of angles, papules, because they're raised, and this is a diagnostic feature of chronic graft-versus-host disease. When we see this in the setting of allogeneic stem cell transplant, we are concerned for chronic graft-versus-host disease.

(11:09): A skin biopsy is often required to confirm the diagnosis of skin GVHD. And it can involve a very small area. This patient on the left just had a few little papules on his foot. Or it can be very widespread, and this patient on the right had very widespread lichen planus of the skin. You can also see other forms of chronic graft-versus-host disease in the skin that are less diagnostic and may require pathology or a biopsy to diagnose them. You can start to see scaly thick plaques and papules, plaques are just areas over about a centimeter in the skin or papules. And the picture on the top left shows what that looks like. These can all join together or become confluent like the palms of the hands that I'm showing you on the top right. On the bottom left, you see some papules and plaques. And it can even involve just the scalp, and you see some scaling in the scalp. So, when patients come in with this picture after transplant, it sometimes means we have to biopsy it to determine if this is indeed graft-versus-host disease.

(12:20): GVHD can cause poikiloderma evidenced by thin skin, pigment change, and blood vessels showing through the surface of the skin. Other problems that we can see with graft-versus-host disease is something called poikiloderma. Poikiloderma is a big name, and it's really shorthand for saying the three attributes below that I list. You can get thinning of the skin, called atrophy. You can get pigment change, either too much pigment or too little pigment. And you can start to see little blood vessels showing through the surface of the skin, and that's called telangiectasia. When that happens, we sometimes get a lot of fragility to the skin. So, any trauma can actually shear off the epidermis. And I know some of these slides are a little concerning when you see them. And I have to reiterate, again, that most of the graft-versus-host disease we see is mild or moderate, but this is a type of graft-versus-host disease of the skin I wanted you to be aware of.

(13:17): GVHD can cause permanent hair loss. And graft-versus-host disease can also just involve the hair follicles. You remember my diagram over there, in the dermis sits those hair follicles, and sometimes you can get graft-versus-host disease just at the outer lining of the hair follicles. It produces these scaly little papules everywhere a hair would appear. Now, this can be a normal finding outside the setting of stem cell transplant. It's only when we see this appear suddenly, or it's a new finding after allogeneic stem cell transplant, that we're concerned this could represent graft-versus-host disease.

(13:56): Why we are we concerned about this cosmetically? We are, because when you get enough inflammation around the hair follicles, you sometimes can produce scarring. So, the patient on the left has lichen planus-like graft-versus-host disease. It's starting to involve the hair follicles. And you can actually lose the hairs permanently in those areas. So, we like to intervene early if we see this occurring.

(14:26): Changes in fingernails occur in over 50% of GVHD patients. I'd be remiss if I didn't talk about changes in the nail, since over 50% of patients with chronic graft-versus-host disease can develop nail changes. So, when we say dystrophy, we're referring to any abnormal formation of the nail. At the half moon at the bottom, which we call the lunula, that's where your nail development starts and where your nail grows from. If you get graft-versus-host disease of the nail, of the lunula, you can start getting abnormal-looking nails. And the nails at the top of the picture are showing ridging, it's showing an abnormal wedge formation, it's showing dystrophy, abnormal nail formation. If we don't intervene, we sometimes can actually get complete nail destruction, called pterygium, which is scarring at the nail bed.

(15:30): The picture on the bottom shows somebody who has lost their nails. Once that happens, that's a scar, and we can't always get the nails back again. So, early on, if we see changes in the nails, we'll sometimes suggest that we intervene with treatment. Sometimes if the patient's getting systemic therapy for other forms of graft-versus-host disease, these nails will spontaneously improve. Sometimes we'll take a little bit of corticosteroid treatment, and we'll inject it at the base of the nail, into that growing area at the base of the nail, to try to decrease the amount of inflammation and decrease the possibility that there'll be dystrophy of the nails.

(16:20): GVHD can cause scarring in several layers of the skin. This is called sclerotic or fibrotic GVHD. I'm going to move on to sclerotic or scar-like changes that are associated with chronic graft-versus-host disease. So, these can occur in several areas. Usually it occurs in the dermis, and you see my arrow pointing to where that is. It can also occur in the fibrous septae that are in the fat, that's that yellow layer at the bottom. And it can even occur on top of the tendons and on top of the muscles. But I'm going to talk first about sclerotic changes that occur in the dermis.

(17:01): These sclerotic, and some people say scar-like, and some people say fibrotic, and some people say scleroderma-like changes, like I said, usually occur in the dermis, but can extend deeper. If these changes are superficial in the dermis, the areas are pinchable. You can pinch that area; you can move it around the overlying subcutaneous tissues. It's localized. My pictures here are showing that, so the patient on the left has a superficial sclerosis where the waistband was. The second patient has a superficial sclerosis where they had a line. The third patient over shows superficial sclerosis, you can move that skin over the overlying tissue and an area of trauma. The last patient on the right is showing little areas of white and that's superficial sclerosis that has occurred in multiple areas. So, that's scleroderma-like graft-versus-host disease. This is superficial. Some people use the word morphia for this, for the superficial localized disease.

(18:23): Sclerosis can go deeper in the skin causing hidebound skin. Now, this sclerosis can actually go deeper. When it goes deeper, you no longer can take the skin and move it. It's fixed down to the underlying structure. We call that hidebound skin. When you have this hidebound skin, the sclerosis can extend all throughout the dermis to the deeper layers, and you sometimes get overlying epidermal changes, and those changes may be pigment changes. And if you look at the legs at the bottom, the skin is shiny, the skin is dark, that's overlying epidermal changes, overlying at deeper sclerosis. You also can get some thinning of the epidermis. And if you look at my picture on the top, you're showing very thin firm legs with hidebound skin. The epidermis is very fragile and easy to get cuts and bruises and scrapes and erosions. And there are multiple erosions on those legs. It's prone to injury.

(19:35): GVHD can cause scarring in the fat layer of the skin and looks like cellulite. Sometimes you can get deep sclerosis way down in the fat without changes to the top layer of skin, without those pigment changes, or the shiny skin, or the thin skin. And that's deep sclerosis in the fat sometimes called cellulite, or if you like cellulite-like changes. You find those fibrous septae, and it almost looks like you've got cellulite. So, this is actually chronic graft-versus-host disease of the fatty layer, not involving the dermis and the epidermis quite as much.

(20:14): GVHD can cause fasciitis, which is inflammation of the deep skin layer that overlays muscles and tendons. Another type of graft-versus-host disease occurs even deeper, and here's my little cartoon diagram, underneath the adipose layer, and it's called fasciitis. That refers to inflammation of the layer of skin overlying the muscles and tendon. Well, what does fasciitis look like clinically? Can look a variety of ways. So, my picture on the left shows a leg that's painful and red, but the skin doesn't really look that abnormal. What's happened here is there's inflammation over the tendons in the muscle producing that redness and there's lots of swelling or edemas, that's one form of fasciitis.

(21:02): Fasciitis makes it difficult to fully extend fingers and the wrist. The picture in the center shows someone trying to make what we call a prayer sign, just like you were praying, put your fingers together, put your palms together and try to extend your wrist. But she's unable to do that because she's got inflammation over the fascia. And she doesn't have any skin problems on the surface, but she's unable to put her hands together. Occasionally, you can get fasciitis and have scleroderma hidebound skin. And that's what you're seeing in my picture on the far right side. You see the hyperpigmentation, the hidebound skin, but you also see a linear area in the bottom of the arm, which is fasciitis, it's inflammation over the insertion of the tendon. So, it can look a variety of ways.

(21:54): A skin punch, done with local anesthesia, may be required to diagnose skin GVHD.  Well, let's talk a little bit of how we diagnose skin chronic graft-versus-host disease. Well, I told you that there are some features that are diagnostic. I can look at them and say in the setting of transplant of an allogeneic stem cell transplant, this is chronic graft-versus-host disease. There are some findings I showed you that I need to do a skin biopsy to help diagnosis. I need our pathologist help. What I'm showing in this picture here is a punch biopsy. A punch biopsy's done right at the bedside with a little bit of anesthesia, local anesthesia. We take a little core of skin out and we either let that area heal, or we put a stitch in it and we send that little core of skin to the pathologist to help us make the diagnosis histologically of graft-versus-host disease.

(22:47): Once we diagnose it, I showed you the diagrams earlier, we characterize the morphology. I say what I see, is it scleroderma? Is it lichen planus? Is it papulosquamous? I use the words to describe it. And I describe the extent of involvement. Then I look to see, what else is involved? Are the nails involved? Is the mouth involved? Are the eyes involved? Are the lungs involved? What other organs are involved? And once I know I have graft-versus-host disease, I try to identify secondary skin problems. And I'm going to talk about that a little bit today and more about that on Thursday.

(23:30): It takes a team of specialists to diagnose and treat patients with skin GVHD. So, the message I want you to take is chronic skin GVHD, it takes a village of people to take care of this problem. The dermatologist is helpful, nursing, helpful, occupational therapy, wound care, we all work together once we identify graft-versus-host disease to diagnose and treat the patient.

(23:54): Topical treatments can be effective if GVHD affects only the top layer of skin. Well, I'm going to talk a little bit about treatment. I'm not going to talk about systemic treatment of this. I'm going to talk about topical treatment today. When we see graft-versus-host disease that affects the top layers of skin, the epidermis, and the superficial dermis, that may be amenable to topical therapy. When we have graft-versus-host disease that affects the fascia or the fat, or the deep dermis, you can't get those creams in there. So, it's not so amenable to using topical therapy or creams.

(24:30): The two major topical therapies used to treat skin GVHD are corticosteroids and calcineurin inhibitors. So, the two major topical therapies that we use are topical corticosteroids, and I'll talk a little bit about that, and topical calcineurin inhibitors. And those are things like the tacrolimus that you'll sometimes take systemically. They make it in a cream, and there's a close relative of it called pimecrolimus. That's sometimes used, and that can be useful for short-time treatment of localized disease. I'm not going to talk about topical ruxolitinib. There are the new JAK inhibitors that have come out for atopic dermatitis that are also being studied now in chronic graft-versus-host disease. And I'm going to say a word about phototherapy in addition.

(25:17): Topical steroids differ in potency; higher dosages can be more effective but can also cause thinning of the skin. So, when we talk about topical therapies, we're talking about topical steroids, and there are many, many different forms of topical steroids, depending on the country you live in, depending on what your insurance will cover. Basically, we break them down into the measure of potency or how strong they are. And we know how strong they are, because the stronger they are, the more anti-inflammatory properties they have, the more they take the red color out of the skin, and that's called vasoconstriction, and the more they can thin the skin. Which is why sometimes a doctor will start you on a very strong topical, or a very potent topical steroid and reduce the potency down, so we see fewer side effects.

(26:05): Calcineurin inhibitors are used on skin areas that are at high risk of thinning. The calcineurin inhibitors we use in areas that are at high risk to thin. So, often we'll use those more on faces or in the axilla or in the groin. They tend to burn if you have erosions or cuts or scrapes on your skin, so we don't use them there. And there is a possibility of systemic absorption, especially in children. So, we watch how much we give very carefully.

(26:35): Phototherapy is a potential treatment if GVHD is only affecting the top layers of skin. I wanted to say a word about phototherapy. This is something your dermatologist or your stem cell team may offer you. So, phototherapy, is sort of like a tanning box, but it's done in very controlled circumstances using specific wavelengths of light. It almost seems counterintuitive to some people that we use phototherapy, because I suspect that your oncology and your stem cell team have told you to stay out of the sun. And we think that sun can actually flare types of graft-versus-host disease. However, once you have graft-versus-host disease, phototherapy, in some instances, can be helpful.

(27:26): When is phototherapy helpful? Well, phototherapy doesn't penetrate very deeply. So, therefore it is not helpful for types of graft-versus-host disease that are in the deep dermis or in the subcutaneous tissue or in the fascia. But for some of the more superficial types of chronic graft-versus-host disease that I showed you, we'll sometimes initiate phototherapy with either UVB, which is ultraviolet B or ultraviolet A. Ultraviolet A penetrates a little deeper, ultraviolet B a little less.

(28:08): PUVA or ultraviolet A therapy is one form of phototherapy. You may hear the term PUVA. PUVA refers to ultraviolet A therapy combined with an oral drug called psoralen. Psoralen has a silent P, so that's why it has P in front of the UVA. And we call it PUVA for short. And that's used for graft-versus-host disease.

(28:31): The most common form of phototherapy used is called narrow band UVB.  Most commonly we use narrow band UVB. What we try to do is minimize the side effects of ultraviolet light by using a specific wavelength. I've just put it down for your interest, 311 to 313 nanometers. We'll occasionally use long wavelength UVA light to treat deeper in the dermis. So, those are the three types of most commonly used ultraviolet therapy for chronic GVHD.

 (29:04): How does it work? It modifies the inflammatory response, it modifies the cells in the epidermis, which help regulate the immune system. There's a lot of blood vessels in the skin, so to some degree, it modifies the circulating cells. So, the way we tend to use it here is we tend to use it only in epidermal and superficial dermal graft-versus-host disease. This was a patient who was on systemic steroids, and every time the systemic steroids were tapered, they flared the graft-versus-host disease in their skin. And we used narrow band UVB in him, and after 10 treatments, we cleared his skin, and we were able to taper this systemic steroid.

(29:55): Topical therapies do not work for fasciitis. These patients require systemic therapy. Does it work for fasciitis? No, it doesn't get down deep enough. Topical therapy is not effective for fasciitis. I'm showing a picture of someone trying to make a fist, but they're unable to do so, because they've got inflammation in the fascia. These people, these patients need systemic therapy.

(30:13): Occupational and physical therapy can help people with fasciitis maintain and improve mobility of the joints. And I need to also tout the benefits of physical and occupational therapy. Carly Cappozzo is going to talk about this on Thursday. These are actually from her slides talking about how it's very important to combine physical therapy and occupational therapy when you have fasciitis to maintain the mobility of your joints.

(30:41): People who are immunosuppressed or have graft-versus-host disease have a higher risk of developing skin tumors, skin infections and hard-to-heal wounds. Well, let me move on and say, what other skin problems can you see after transplant? Now, I will be talking more about this on Thursday, but I'll kind of introduce it now. People who are immunosuppressed or people who have graft-versus-host disease may have an increased incidence of certain tumors of the skin. And these may be benign, something like warts, which are caused by a virus, but they also may be malignant. They're also more prone to skin infections. And patients with graft-versus-host disease, especially scleroderma-like or fibrotic are more prone to hard-to-heal wounds.

(31:28): So, the picture I have on the left is a patient who has graft-versus-host disease of their leg. And in that stable graft-versus-host disease, they developed two hard spots, and they're labeled A and C in that. And these were both squamous cell skin cancers of the skin that we needed to address.

(31:48): The patient on the right has scleroderma-like graft-versus-host disease. And they've developed a lot of skin erosions or breakdown, and these can form very hard-to-heal wounds that we need to address.

(32:06): Skin cancers can develop from long-term immunosuppression, chemotherapy, persistent inflammation or radiation therapy. I want to say one more word about malignant tumors of the skin. I also not only deal with graft-versus-host disease, but I deal with skin malignancies. Skin malignancies may be related to long-term immunosuppression or chemotherapy, persistent inflammation, preceding damage, or when I say ionizing radiation, I mean people who have received radiation therapy. And that can lead to increased risk of squamous cell carcinoma of the skin, basal cells carcinoma in the skin, and even melanoma. The patient that you see on the right had chronic graft-versus-host disease of the leg and developed some scaly areas. On biopsy, these were squamous cell carcinomas, all of them. If we catch this early, this is curable and treatable.

(33:05): Early detection of skin cancer is important. Transplant recipients should visit a dermatologist for a full body skin scan at least once a year. So, what we need to do is you need to be very diligent about protecting your skin. Early recognition is important. One thing I really promote is when you go to see your doctor get undressed for a complete skin exam. You can't see your back, sometimes these early findings of chronic graft-versus-host disease can be quite subtle. Get undressed, show your skin to a health professional. You can also consider seeing a dermatologist at least on a yearly basis. Verbalize any skin concerns, even if you don't see a rash.

(33:50): At home, check your range of motion. I showed you pictures of people who had fasciitis, had no skin changes, but couldn't bend their wrists well, sometimes can't bend their ankles well. So, check your range of motion.

(34:05): Protect your skin from trauma and sun exposure. Protect your skin from trauma, especially if you have scleroderma graft-versus-host disease. Maybe this isn't the time to go out and prune your rose bushes and scrape your arms and your legs. So, protect your skin from trauma. If you do get skin trauma or skin cuts and scrape, make sure they don't get infected, make sure that you pay attention to them early. If there's any concern that you have, show them to your doctor. Use photo protection or protective clothing to protect you, or sunscreen.

 (34:44): Summary of talk. And now, just I'm going to summarize what I've said and then be open to whatever questions we have. Our objectives were to define graft-versus-host disease as it relates to the skin. It's a long-term complication of allogeneic stem cell transplantation characterized by inflammatory or fibrotic skin problems. I want you to be able to recognize the skin changes of chronic graft-versus-host disease, be they epidermal, dermal, subcutaneous or in the fascia. And to recognize if there are fibrotic or scleroderma-like skin changes. I wanted you to understand how the diagnosis is made, sometimes just clinically, sometimes we need a biopsy, and we always try to correlate with other organ systems.

(35:34): I reviewed with you some of the skin directed management of graft-versus-host disease, which includes topical therapy and sometimes, under special circumstances, ultraviolet radiation. I've talked a little bit about some of the other skin problems post-transplant, which includes things like infections, hard-to-heal wounds and skin cancers. I thank you very much for your attention. I think I have time for some questions.

Question and Answer Period

(36:10): [Becky Dame] Thank you, Dr. Hymes. This is an excellent presentation. We will now take questions. Our first question is from an eight year post-allogeneic transplant, unrelated donor. They mentioned they have two nail beds, two thumbnails that continue to be dry, rigid, and split. What can they do to promote a better nail for their thumbs in hopes that the GVHD will settle down?

(36:47): [Dr. Sharon Hymes] So, the question I would have to this questioner is do they have known GVHD? So, there are other things that can affect nails that are not graft-versus-host disease. If this is related to graft-versus-host disease and that's the only thing they have, I would say, see your dermatologist. We sometimes can inject those nails and see if we can abort further changes in those nails. However, I would see the dermatologist, because sometimes it isn't graft-versus-host disease at all. And a dermatologist should be able to tell you, is it infection? Is it eczema around the nail bed? They should be able to tell you what it is.

(37:39): [Becky Dame] Thank you very much. We have another patient from donor-related transplant in 2002, noting that they have had chronic GVHD of their eyes. And for the last four to five years, the skin is continually problematic on the torso, back, with itchy and sensitive skin. And they're wondering at a 20 year survivorship should she be worried that the skin problems are related to GVHD or not? And also wanted to note that heat also is a positive factor for problems.

(38:32): [Dr. Sharon Hymes] So, 20 years after transplant with no other signs of GVHD, I would not expect this to be skin GVHD. However, if they had skin GVHD after their transplant, sometimes you can damage some of those structures that I showed you in the skin. So, some people will complain, "I don't sweat as much as I used to." Or "My skin feels more fragile than it used to." So, I wouldn't expect, with no other GVHD, 20 years later to have skin GVHD. But I wonder if, A, they could have another problem going on or, B, if they had earlier GVHD of the skin, if they affected some of those structures, that could be a permanent change. Also, some people say, "My skin's just not the same. It's drier than it used to be. It's more fragile than it used to be." But that's not GVHD, it might be a sequela of GVHD, it might be a sequela of all they've gone through before.

(39:40): [Becky Dame] Thank you. Another question here is that they've mentioned that they washed behind their ear and developed something that looks like shearing of the skin. It's now open. They've talked to their medical team and are doing wound care. Could that be a manifestation of skin GVHD?

(40:03): [Dr. Sharon Hymes] So, skin GVHD can be very localized. However, I'm assuming this person does not have skin GVHD elsewhere. Any time you develop shearing of the skin, it doesn't have to be GVHD., Sometimes you could have had an infection like an impetigo or something else behind the skin and you've rubbed it and you've sheared off the very top layer of skin. So, it would be unusual to have such a localized area just behind the ears.

(40:39): [Becky Dame] Okay. Thank you. Another patient is saying that they have very thin skin on the perineum. Does that fall under skin GVHD? And do you recommend steroid cream to that area?

(41:00): [Dr. Sharon Hymes] On their perineum. Okay. Interesting. So, you can get vaginal GVHD, I'm sorry. I don't know if this is a male or a female. I'm assuming it's a female. You can get GVHD of the perineum, but this is another one that needs to be looked at. Because there are other things that can cause irritation in that area, either topical things, infections, there are other things that can do it.  We do use steroids on the perineum, we tend to use weak, not very potent steroids, because we atrophy that area.  But that's another one I think should be seen by the physician, because although GVHD can occur in that area and has some very characteristic features, you can get a lot of other things that can cause irritation.

(42:03): [Becky Dame] Okay. I believe you covered this, but just to reiterate, how does the UV light therapy improve skin health?

(42:22): [Dr. Sharon Hymes] Okay. UV light therapy does not improve skin health. UV light therapy comes with potential problems, including future skin cancers. In patients that have graft-versus-host disease, superficial forms of graft-versus-host disease, it may improve that. We're always weighing. It's always a balance. What can we do with the least side effects to help the patients? And in some patients, to get them off some of the systemic therapies, UV light therapy may help the ability to taper the systemic therapies, but it's not "healthy" for your skin. It's trying to get rid of the graft-versus-host disease.

(43:14): [Becky Dame] Okay. Thank you so much. Another patient on the same kind of line. They are 14 months post allogeneic transplant and have scleroderma, redness, tenderness, hardness, can't make the prayer sign, in both forearms and legs. And they're currently on systemic therapy along with prednisone, well, including prednisone. I know there are other effective drugs, but with their Medicare program, it's cost prohibitive, their question is, could undergoing ECP treatment be an effective treatment and be cost saving?

(43:53): [Dr. Sharon Hymes] Absolutely. So, I specifically didn't go into systemic therapies because corticosteroids are the first-line therapy. And then if we see resistant or refractive graft-versus-host disease, there are a lot of alternative therapies and certainly ECP, which is extracorporeal photopheresis is one of those therapies that is often added into first-line steroid therapy to treat scleroderma-like GVHD.

(44:25): [Becky Dame] Thank you very much. Another question is, is taking collagen a good idea? They have GVHD of the skin.

(44:41): [Dr. Sharon Hymes] There's no evidence that taking collagen has any effect on graft-versus-host disease of the skin.

(44:54): [Becky Dame] And another question, do laundry products or skincare products such as lotions ever cause increases for GVHD of the skin, such as like the softeners, could it not cause an allergy?

5:09): [Dr. Sharon Hymes] Okay. So, I think the question there is the over-the-counter creams, lotions, et cetera, are they ever used to treat GVHD of the skin? And can they cause an allergy? I'm going to address that actually a little bit more on Thursday when I talk. But we tend to use more creams and ointments than lotions. So, it all has to do with the amount of water in the product. Lotions are very easy to use, but they have a lot of water. Ointments are very hard to use, they're greasier, they have less water. And people who get the dry skin, remember the ichthyosis I showed you in the picture, we absolutely use those products.

(45:54): We try to use non-perfumed, hypoallergenic products, and we tend to go more with the creams or the ointments than we do the lotions. So, will it treat graft-versus-host disease? It treats the dryness of graft-versus-host disease in patients that have a good deal of breakdown in their skin. Like I showed you some of those legs with all the breakdown of the skin, it can aid in the healing of that. So, in that sense, yes, it can be used to treat graft-versus-host disease.

(46:28): [Becky Dame] Okay. This may be our last question, but can you have different types of GVHD in different parts of your body? They are eight years post-transplant. And I think they may have mentioned... I'm going to iterate that, maybe they meant different types of skin GVHD in different areas.

(46:52): [Dr. Sharon Hymes] Yes. The answer is yes, you can. So, you can have lichen planus-like GVHD and have scleroderma-like GVHD in another area. You can have fasciitis and have epidermal-like GVHD in another area. So, the morphology is not always the same in one person. That's why, when I showed you the diagram at the beginning, I showed you that we make sure to characterize the morphology, so we know exactly what the skin lesions look like in the different body areas.

(47:28): [Becky Dame] All right, thank you. And I was wrong, we have a time for a few more questions. So, let me find something here for you. We have a patient that is noting they're so itchy, it increases in the afternoon and at nighttime, any practical interventions for the itching?

(47:49): [Dr. Sharon Hymes] So, it depends if are they itching because they have dry skin? Are they itching because they have eczema? Are they itching because they have graft-versus-host disease? So, it becomes very important to determine what the diagnosis is to be able to tell you how best to take care of it. Itching is almost always worse in the evening and at night. I don't know if it's because we're just not as active and we're not as tuned into it, but I think it's important to determine the etiology, the reason you're itching, and then address it that way.

(48:25): [Becky Dame] Thank you. Have you seen amelioration of fasciitis with stretching and massage? Does the fasciitis usually plateau or get worse?

(48:39): [Dr. Sharon Hymes] So, I think, and I'd urge you also to listen to Carly Cappozzo's talk about this. Absolutely stretching is beneficial to the fasciitis. This is a very important part of the treatment. So, we do treat usually with systemic agents, but stretching becomes very important.

(49:05): [Becky Dame] Thank you. So, a patient also sent same line of thinking. Can myofascial release be a helpful therapy for hidebound skin on the side of the torso and for fascia in the legs in general? They have chronic GVHD affecting both... Can it affect both conditions?

(49:29): [Dr. Sharon Hymes] So, I'm going to have you address that to Carly Cappozzo, but I can tell you that it may be symptomatically very beneficial, but whether it will change the long-term process is questionable.

(49:54): [Becky Dame] I'm sure I'm not going to say this correctly, but they were diagnosed with Dupuytren's contracture one year post transplant by their primary care. Could there be a GVHD connection? They have the praying hands issue quite significantly.

(50:14): [Dr. Sharon Hymes] That's a very good question. So, Dupuytren's contracture is, for those who don't know, is affects the tendons of the hand and it kind of draws the hands in. So, it makes it much harder to extend the fingers. I think what I would want to do is identify, is it truly Dupuytren's contracture that you have? Or is this GVHD? And I think probably your oncologist would be the one to address that.

(50:46): [Becky Dame] Okay, thank you so much. And this participant, she gets hive-like lumps wherever she has pressure from clothes, like the waistband and bra line. These hives come in the evening and itch, and they go away. Can that be a manifestation of skin GVHD?

(51:06): [Dr. Sharon Hymes] That's a very good question. It is not a classic manifestation of GVHD, it sounds like you're getting pressure urticaria. So, in everywhere you have a pressure, like a bra or a waistline, you're getting hives. That's not a classic finding that we see with GVHD at all.

(51:27): [Becky Dame] All right. Anytime I get too warm, I get generalized itching and prickling of my skin all over my body. I already have GVHD in the eyes and soft tissues. Could this be related to GVHD in the skin? There's no rash.

(51:51): [Dr. Sharon Hymes] So, itching can be related to GVHD of the skin without a rash. I'm wondering if this individual had skin GVHD of the skin and maybe affected their sweat glands. Remember, I showed you the picture where the sweat glands live in the skin. But generalized itching alone can be a manifestation of GVHD. But again can be a manifestation of something else, like dry skin, et cetera.

(52:21): [Becky Dame] All right. You mentioned hard-to-heal wound. Is that because of a deficiency of a certain cell line like neutrophils, macrophages or lymphocytes? Can the risk be determined to some extent by looking at peripheral blood count?

(52:43): [Dr. Sharon Hymes] So, another excellent question. Certainly, if you have a deficiency in your immune system, wounds are much harder to heal, but in the pictures that I showed you, we actually had skin damage. And when you have lost the integrity of your skin, the epidermis and the dermis, it does not heal as well. So, therefore, in the setting of chronic graft-versus-host disease and loss of skin integrity, it is sometimes harder to heal wounds.

(53:17): [Becky Dame] Thank you.  Let's see here, someone's hair has never grown back after transplant. Would this be GVHD or could be caused by something else?

(53:35): [Dr. Sharon Hymes] So, these are excellent questions. Hair loss is for many reasons. I'm also going to talk about that on Thursday. It could be a scarring hair loss, or a non-scarring hair loss. Sometimes people are prone to hair loss. Their mothers, their fathers, their brothers have all lost hair, and it gets accelerated along with all that you go to post transplant. And even though chemotherapy should not be causing scarring, we know some people after transplant do not grow their hair back well at all. And we don't know exactly why. That being said, if you have GVH with the hair follicles, it may be difficult to grow your hair back. So, unfortunately, there's not a simple answer to that. Hair loss post-transplant really can be multifactorial.

(54:37): [Becky Dame] Thank you so much. We have another question. They stopped sweating after their transplant and couldn't tolerate heat. Could this be a sign of GVHD of the skin?

(54:48): [Dr. Sharon Hymes] It is not necessarily a sign of GVHD of the skin, but sometimes there is damage to the sweat glands after preconditioning, after chemotherapy. So we hear this complaint sometimes with people who have had chemotherapy and with GVHD. So, if you impact your sweat glands for any reason, you may have some trouble sweating after transplant.

(55:16): [Becky Dame] Okay. Thank you. And I believe this will probably be our last question, do people who have a transplant using their own stem cells ever get GVHD?

(55:33): [Dr. Sharon Hymes] So, that's a very interesting question and a matter of some debate. So, the simple answer would be unlikely because they're using their own stem cells. There are some that believe that GVH is a form of immune dysregulation, meaning that the cells that you receive are creating an immune imbalance in your body. So, if it does exist, it's probably less severe than after allogeneic stem cell transplant. And some people say, no, you don't get it with your own stem cells.

(56:16): [Becky Dame] Okay. Actually, so for time, we have three more minutes. So, I will throw in one last question here. Can chronic skin GVHD manifest itself at any time after the allogeneic transplant? And if so, are there common triggers?

(56:43): [Dr. Sharon Hymes] Usually when you are far out from the transplant and you've been stable for a long time, you're not going to get chronic GVHD. It is not defined by time though. It's defined by clinical features. What are the common triggers? Well, some of the common triggers... I'm not sure if they're asking why people get chronic GVHD - it's more common after peripheral blood stem cell transplants. I think they're asking me is there anything environmentally that causes it? So, some things that can trigger GVHD are infection. Sometimes sunlight can trigger chronic GVHD. Reduction or tapering of immunosuppression can trigger GVHD. In patients that have relapse, that need donor lymphocyte infusions, that can trigger GVHD. I think that's what they're asking me.

(57:46): [Becky Dame] Closing. Okay, perfect. Well, on behalf of BMT InfoNet and our partners, I'd like to thank you, Dr. Hymes, for your very helpful remarks and thank you to the audience for your excellent questions. Let BMT InfoNet know if we can assist you in any way, please enjoy the rest of your symposium.