Chronic Graft-vs-Host Disease of Skin and Connective Tissues

Graft-vs-host disease (GVHD) often affects skin after a stem cell transplant. Learn the symptoms and treatment options.

Presenter: Catherine Lee MD, Utah Blood and Marrow Transplant Program, Huntsman Cancer Institute, University of Utah


Chronic graft-versus-host disease (GVHD) of the skin is common following a transplant using cells from a donor (allogeneic transplant). It can affect different layers of the skin as well as the mouth, genitals, hair and sweat glands. This presentation discusses the symptoms of skin GVHD and current treatment options.

42 minute presentation followed by 18 minutes of Q&A


•    80% of people who develop chronic GVHD will have some skin involvement
•    First-line treatment for chronic GVHD of the skin is topical steroids
•    If topical steroids don’t work, systemic steroids (prednisone) will help 50% of patients
•    Patients with chronic skin GVHD have an increased risk of developing skin cancer; protecting skin against exposure to the sun is important

Key Points:

02:25  Risk factors for developing chronic GVHD of the skin  
03:44  Chronic GVHD can affect each layer of skin, as well as nails and hair 
08:40  Chronic GVHD can affect skin around lungs and chest, causing breathing problems
10:00  Chronic GVHD can cause lichenoid-like bumps on the skin’s surface, changes in skin color and deep tissue scarring and tightening  
20:04  Topical steroids are the first line of treatment for chronic GVHD of the skin 
24:13  Systemic steroids, that affect the whole body, may be needed if topical steroids fail
24:29  If systemic steroids fail, other therapies such as sirolimus, mycophenolate mofetil, rituximab and imatinib, PUVA and extracorporeal photopheresis (ECP) may help
26:31  Two new drugs show promise in treating chronic GVHD of the skin:  ibrutinib (Imbruvica®) and ruxolitinib (Jakafi®)
34:14  Gentle stretching and physical therapy can help patients with chronic GVHD of the skin
35:47  How to avoid skin cancer and GVHD flare ups 

This recording was made possible, in part, by a grant from Pharmacyclics and Janssen, Incyte Corp. and the Meredith A. Cowden Foundation. 

Transcript of Presentation

00:00  Introduction of Speaker: Thanks for all being here. This is my second day of talking. I already recognize some faces from yesterday. Today I'll be focusing on giving a talk on chronic graft-versus-host disease of the skin and hopefully won't be any technical issues today.  Hopefully the knowledge that I give you today will help you understand what chronic graft-versus-host disease of the skin is and what are the symptoms.

00:22  Overview of Talk:  Talk about the overview a little bit. What are the symptoms of chronic graft-versus-host disease of the skin. Some of the treatment principles and treatment options that are available. Other necessary supportive care in order to optimally manage chronic graft-versus-host disease of the skin. Some issues that you should know of how to prevent any graft-versus-host disease flares, and how to prevent some late effects of having this syndrome such as secondary skin cancers, which can happen down the road. Then, lastly just to summarize the oral presentation and to give some last pointers of how to empower yourselves with having this knowledge and taking ownership of your health.

01:16  80% of survivors with chronic GVHD have skin involvement:  Chronic graft-versus-host disease of the skin can be a common long-term complication of having a donor transplant. It's usually an early sign of the systemic or the multi-organ form of chronic graft-versus-host disease. As you all are aware graft-versus-host disease is where the donor cells, in addition to attacking and eradicating any cancer cells or any other abnormal blood cells. Sometimes these donor cells will recognize healthy tissue in the patient and as well attack them and causes overwhelming inflammatory disorder. Usually the skin is involved in up to 80% of survivors with chronic graft-versus-host disease and the damage that's done to the skin or other organs that might be involved is usually due to inflammation, scarring in a fibrotic process. That's what differentiates chronic graft-versus-host disease from the acute form. Chronic graft-versus-host disease is a syndrome of fibrosis forming scar tissue.

02:25  Risk factors for developing skin GVHD):  Risk factors for chronic graft-versus-host disease include having a mismatched donor or using an unrelated donor. However, these days we're actually getting better, overcoming this risk factor, by improving graft-versus-host disease prevention regimens as well as treating the donor cells with certain modifications before we infuse them into the patient. Hopefully, this risk factor will be taken off the list in the future because we're getting better.  

Older age, either the patient or the donor is a risk factor for chronic graft-versus-host disease. Having a female donor cells put into a male patient is a risk factor. 

Use of peripheral blood stem cell source versus a bone marrow source has been actually studied in a clinical trial and has been shown to be a risk factor for graft-versus-host disease, but again we're coming up with better regimens for prevention of graft-versus-host disease so hopefully we can overcome this risk factor. Definitely having a prior history of having acute graft-versus-host disease is a risk factor for having chronic form.

03:44  The different layers of skin and their function:  Just to understand what gets affected in chronic graft-versus-host disease of the skin. First it's  important to understand how your skin is made up. We have different layers of the skin. The topmost layer of the skin, which is the area of the skin that we see every day is called the epidermis. The epidermis, what's important [about] the epidermis is it basically protects you from all the outside elements. It protects you from infections. It gives you the color of your skin. 

The next layer below that, the dermis, is where we find our sweat glands or our hair follicles as well this is where some of our fine nerve endings that can be involved in sensory or very small blood vessels begin. 

Then, the subcutaneous, the deepest layer is the area of the skin that provides insulation for warmth and helps regulate hot and cold. As well, the subcutaneous fatty tissue is important for attaching the dermis part of your skin to the underlying tissue overlying your muscle and bone. 

This understanding helps you understand how chronic graft-versus-host disease develops, how it's effecting you and your skin. 

04:55  How chronic GVHD affects the top layer of skin (epidermis):  Some of the symptoms that you might be experiencing; for example, [if] the chronic graft-versus-host disease just effects the topmost layer, the epidermis, usually patients will see a change in the color of their skin. They may see some hyperpigmentation, some redness or some purplish color plaques or they may develop a rash, a reddish rash. 

05:52  How chronic GVHD affects the middle layer of skin (dermis): If the chronic graft-versus-host disease involves the dermis layer, again, this is where this is the physiology of this is scar tissue fibrosis. This area is where the nerves sit, the sweat glands, the hair follicles. This is where sometimes patients will have some nerve damage, some burning sensation, or some numbness. As well, they may have trouble producing sweat.

06:13  How chronic GVHD affects the deep layers of skin (subcutaneous): As the chronic graft-versus-host disease involves deeper layers and the scar tissue forms this is the time period where we start seeing the sclerotic form, the very tightening, thick form of chronic graft-versus-host disease of the skin. This is because the fibrosis is  pulling down the skin and making it attach very tightly to the bone and the underlying muscles. 

06:41  How chronic GVHD can affect nails and hair:  Other epidermal tissue organs that can be effected include the nails and some of you may have experienced some nail breakage, or the nail bed lifting off, some ridging. Sometimes it's due to chemotherapy, but then, when there are definitely other signs of chronic graft-versus-host disease, usually it's those donor cells that are causing some of the symptoms that you're having or some of the changes that you're seeing in your nails. Then, as well, graft-versus-host disease can effect hair growth. The donor cells will like to attack the hair follicle. So some men and women will have areas of hair loss or what we call alopecia.

07:28  Symptoms of chronic GVHD of the skin:  What are the symptoms? Sure some of you have experienced some of this. Itching is very common. Thickness and tightness of the skin. As it progresses some patients can have some joint stiffness. Sometimes muscle cramps and that's again because the fascia and the tissue is very tight around the muscles. Sometimes tingling or burning or pain lancing across the skin. Again, these are because the nerves are effected. As chronic graft-versus-host disease progresses sometimes the skin will get very thin, and usually because patients are also taking steroids, [they are] already also contributing to thin skin and sometimes tearing of the skin. 

08:19  Sores caused by chronic GVHD of the skin:  Sores can develop and it takes a while for them to heal because graft-versus-host disease is, the whole basis of it is this immune dysregulation. So, it's very hard for the body to heal wounds in a very rapid way and, as well, if you're on steroids or on immune suppression these medications also delay wound healing. 

08:40  How chronic GVHD can affect skin around lungs and chest:  For patients who have skin involvement around the lungs, the thorax, the chest and sometimes with deep involvement with chronic graft-versus-host disease, it restricts how well the lungs can expand. Some patients will experience shortness of breath, difficulty breathing, feel like they can't get a good breath in. Sometimes fluid will accumulate in the lung and this is because the underlying fascia has formed scar tissue. It's very difficult for it to be flexible and to expand appropriately.  

09:17  Chronic GVHD can affect regulation of skin temperature:  Again, regulation of skin temperature can be problematic here. That's because the top layers [are] often exfoliating for patients who have diffuse erythematous graft-versus-host disease.

09:35  Effect of chronic GVHD)on genitals: For some patients, men and women, they'll complain that there is some genital burning or dryness or sometimes difficulty urinating. When complaints like that occur, definitely these are symptoms and signs that you should report to your doctor and sometimes a specialist, like a urologist or a gynecologist, consultation is necessary. 

10:00  Most common forms of skin GVHD):  What are the most common forms of the disease? The way this is laid out is from, again, superficial to deep. Along the epidermal surface I've listed some medical terms that you might hear coming out of your transplant doctor's mouth. Many times, when only the superficial layer is involved, we say that patients have a lichen planus-like or lichenoid features of chronic graft-versus-host disease. Sometimes you'll hear the word poikiloderma. What that means is just differences in the skin color; either hyperpigmentation where the skin is very red or purplish looking, or hypopigmentation where there isn't much skin color. Sometimes in those areas of skin changes you can see small little capillaries breaking. If the deeper levels are involved, it becomes, you'll hear the words sclerosis more frequently. This refers to the underlying fibrosis and scar tissues that's forming.

11:10  Photos of lichenoid-like chronic GVHD of the skin:  I'll show you some pictures of these. For example, here we have a patient who has a diagnosis of lichenoid chronic graft-versus-host disease. He has these red and sometimes a little bit purplish looking plaques or papules. That's what we describe as these raised lesions, little swellings above the skin. If you were to run your hand flat you would feel some raised bumps. Sometimes these lesions can be very localized, just to one extremity, one arm or one part of the body, or sometimes they can be very diffuse like this. They can involve the skin around the face and particularly around the eyes, the orbits. 

11:55  How chronic GVHD can affect the mouth:  GVHD can affect the mucous membranes so every time you've gone for a follow up visit with your transplant doctor they always want to look inside your mouth. Our mucous membranes, which line our mouth through our GI tract all the way to our rectum and anus is epidermal skin. It can be involved in graft-versus-host disease. This is an example of the inflammation going on the lips. These little fine white lines are called Wickham's Striae. This is something that we can commonly see. I won't say commonly, but sometimes see in the clinic.  As we look inside the mouth these fine white lacy patterns are often seen on the buccal mucosa or on the hard palate on the top of the mouth. This gives us an indication that this process is occurring. Sometimes when these develop the patients will be reporting to us at the same time that they're having increased sensitivities to foods, irritation, dryness, difficulty swallowing foods, if some of the upper GI tract starts becoming involved.

13:13  Chronic GVHD can cause loss of pigment in skin:  As I said before, in our epidermal layer that's where our melanin or our skin color pigmentation cells are and if those cells are being attacked and they're not working correctly some patients can get some dis-pigmented skin or Vitiligo. This is what happens when patients develop Vitiligo; They lose their melanin in that area of the skin and they have very light patches compared to the rest of their body. This is not very common, but it can occur.

13:48  Chronic GVHD can cause skin sclerosis and fibrosis:  As we continue, as chronic graft-versus-host disease continues to involve the deeper layers of the skin; this is examples of fibrosis occurring or sclerosis occurring along the tendons. Scar tissue, or fibrosis,  gives this grooving sign along the major tendons of the muscles. Sometimes you can get an appearance of cellulite without any over lining skin rash, but seeing this rippling pattern especially along the inner arms, the inner thighs, the torso and the abdomen, this is a sign of deeper involvement of chronic graft-versus-host diseases.

Lastly, this is one of the more extreme forms. The very sclerotic form, what we call bone hide or pipe stem. You can see these legs are very rigid looking, they look like piping and that's because the fibrosis is really holding the dermis down to the bone. The tissue covering the bone. In situations like this it's very hard to reverse what we see here and oftentimes wounds will develop and open sores because this skin isn't getting good blood flow or oxygenation and nutrients to the skin. We have to monitor for broken skin and infections in these patients. 

For those patients who do have the deep sclerosis every time they come to our chronic GVHD clinic we often test their flexibility or their range of movement. Some of you may have undergone this evaluation. We ask patients to do the prayer sign or the Buddhist sign. We can measure how much movement, or range of movement, that they have and we'll either do the prayer sign or ask them to elevate their arms at their shoulders or look at how well they can flex or extend their ankles. Once we start treatment this is a way to assess if they're responding to treatment.

16:09  Photos of how chronic GVHD)affects nails and skin:  As I mentioned before the nails can be effected and this is just an example of some of the nail changes in this patient he actually lost his nail bed. Then, example of the hair follicles being involved by graft-versus-host disease; Alopecia, hair thinning, hair loss. 

16:27  Deciding on the right treatment for skin GVHD):  When we think about treatment there are several principles that transplant doctors like to go by. The first thing is we want to control the current symptoms that you or other patients are experiencing. We want to prevent additional organ damage, minimize treatment toxicity, and if we can avoid systemic steroids, which we all hate, we'll do so. Avoid other late treatment effects. Then, at the same time we want to make sure we're treating you with medications that don't put you at risk for your original blood disorder to come back.

When we think about how we're going to treat it, the first thing that we will look at is how much is the skin involved, how much of the skin, how much of the body surface area. Then what do we think how deep the chronic GVHD is affecting? Do we think it's affecting the really deep underlying tissues or is it just really affecting the very superficial layer? 

Then we look to see if there's other organ involvement. How are your eyes doing? How's your mouth doing? Your GI tract? Do your liver numbers look okay?  In general, if only these superficial, the epidermal portion of the skin is involved it's generally very treatable. But, if we're dealing with a multi-organ, three or more organs being involved or the sclerotic form of chronic graft-versus-host disease we have to start using more aggressive treatments, systemic treatments.

18:07  The role of moisturizers, anti-itch medication, antibiotics and wound dressings to treat skin GVHD: One of the most important interventions to start as, actually as soon as you come out of transplant, is to begin regular use of moisturizers on the skin. I'm talking about medical emollients. Not the emollients that are perfumy or have all these promises of antiaging properties, but medicinal, medical grade emollients, which are like thick creams. For those who suffer from really bad itch, your doctor can prescribe anti-itch medications, either ointments, or sometimes pills. For those who have developed skin tears or ulcers we want to prevent infection so oftentimes we'll use antibiotics applied to the skin. Usually, I get a wound care consult service evaluation. Sometimes patients need specialized wound dressings or need debridement if there's lots of tissue that's getting involved. Oftentimes, like with that patient I showed you who had the pipe stem legs, sometimes patients will develop a fluid accumulation in their lower extremities. We need to control the edema either through wraps or through medication.

19:31  Range of therapies available to treat chronic GVHD of the skin:  Treatment options. General treatment options include topical treatments. What I mean by topical, again, is applying it directly to the area of the tissue that's effected. Systemic treatments, which are usually either given through a pill that you ingest or through intravenous route. There's something called phototherapy or light therapy. Then, of course, supportive measures such as physical therapy, massage. All these ancillary support services are also very important. 

20:04  Topical steroids to treat (GVHD of the skin:  Topical therapies: The first line that we go to are steroids. There are different strengths [that] are available. Hydrocortisone is available over the counter. It's considered a low potency steroid and it comes as a cream or an ointment. Your moderate strength is triamcinolone and the more potent strength is clobetasol.  In my practice it depends on how angry the rash looks or how diffuse. If the rash looks very fine and very minimal I'll start off with a moderate strength. I'll try that for about two to four weeks. If I don't see any improvement on a moderate strength steroid I'll move up to a very potent like steroid such as clobetasol. Some patients only need to start off on hydrocortisone. 

It's also important for your doctor to tell you which areas shouldn't be exposed to a moderate or a strong strength such as the face. The face should never be exposed to a very strong potency steroid such as clobetasol, the same as the genital area. We tend to use either a low or a moderate strength for those areas.  

As I said before the steroids can come in different formulations, lotions, creams, ointments. We tend to use ointments because of the viscosity it tends to allow the steroid, the active medication, to get into the skin better. Most patients don't like ointments because it feels very greasy and it's very viscous, but in terms of efficacy we feel that ointments are probably the best way to go.  

21:52  Applying emollients after steroids:  Use of emollients after steroids may increase potency, but that being said, when you use emollients after steroids you shouldn't apply it directly after the steroid use. You should wait at least about 30 minutes after the steroid cream or ointment has been applied; wait 30 minutes and then put on your emollient. If your doctor's prescribing you topical Prograf® or tacrolimus you want to wait at least two hours before you apply an emollient moisturizer after that.  

22:25  Applying wet wraps on top of steroids:  For some people and I've actually seen very good benefit with this, use of wet wraps on top of the steroid or the topical treatment will help the absorption of that medication and sometimes I see a much more dramatic response to that topical treatment. 

22:46  Avoid using topical steroids for too long:  With the steroids you want to be careful of being exposed to it for too long. Usually you don't want to be exposed to it for more than six weeks. Some transplant doctors will use it longer than that, but generally after six weeks your skin will start to get very thin and fragile.  Again, I just already mentioned Tacrolimus ointment, the brand name is Protopic® or there's another called pimecrolimus or and the other name for that is Elidel®.

23:15  Treatment for chronic GVHD in the mouth (oral GVHD):  For those who have involvement of the mouth, the buccal mucosa. options include a dexamethasone swish and spit, which is the most preferred, but there are other potent levels of steroid solutions. Using a steroid gel or a steroid paste directly to the lesion can help. Then, something called intralesional steroid injections for really refractory cases of ulcers can also be very beneficial. 

23:52  Treatment for chronic GVHD in genital area:  For those who have involvement of the skin in the genital area; water based lubricants and topical estrogen along the vulva or vagina can be helpful and this is where it's really important to see a gynecologist who's very familiar with treating graft-versus-host disease of the genital area.

24:13  Steroids are the first line of systemic therapy to treat chronic graft-versus-host disease (GVHD) of the skin:  Moving on to systemic therapies. Again, [they] either it comes in oral form or intravenous. The first line agents that we use these days are steroids, still. It's proven to be the most effective. Approximately 50% of patients will respond to steroids. 

If the patient does not respond to steroids, other systemic agents consider:  The other 50% who don't respond, we have this whole other list of agents that are totally up for game.  Most of patients might still be on their calcineurin inhibitor. They're either their tacro[limus] or their cyclosporine. If these agents have already come off, your transplant doctor may put them back on to help give an extra boost with the steroids. The whole goal of all these agents is really to get you off the steroids as quickly as possible because we all know that long-term steroids doesn't make you feel good and it has long-term late effects. If we can add on other agents so that we can decrease the steroids as rapidly as possible, that's what we're trying to do.   

Sirolimus is another type of immune suppressive drug that we use to treat chronic graft-versus-host disease. Mycophenolate mofetil or the other name is or the other name is Cellcept®. 

Rituximab, this is an anti CD20 antibody that we typically use for in lymphoma's. Patient who have lymphoma's, but we know that it targets the B cells and in chronic graft-versus-host disease we know that it's both the B cells and the T cells that are involved in causing this whole issue. That's why rituximab might be brought up as an option to help basically kill off those really active B cells that are producing the antibodies that are causing the graft-versus-host disease.  

Imatinib is another type of pill. It's one of the TKIs or tyrosine kinase inhibitors. It's been tested for sclerodermatitis chronic graft-versus-host disease. I'll say that probably in general all of these in terms of efficacy are pretty similar between each other. 

The two newest agents that we're using in the clinics these days are ibrutinib and ruxolitinib. 

26:31  Ibrutinib (Imbruvica®) to treat chronic GVHD) of the skin:  Ibrutinib is the first and only FDA approved agent for treatment of chronic graft-versus-host disease for those who failed steroids. It was just approved last year. This is another medication that's typically used for lymphoma for patients who have CLL or mantle cell lymphoma because similar to rituximab, it targets the B-cells, the B-cells that are producing their antibodies. We actually have seen that it can also affect the T-cells so it hits both of those bad players. 

The one issue that I've seen with ibrutinib in the clinic is that half of the patients can't really tolerate it very well at the dose that it's recommended at because it can cause some muscle cramps. It can cause the platelets to go down, and so sometimes we have to keep dose reducing or sometimes some patients just have to come off of it just because of those annoying side effects. 

27:34:  Ruxolitinib (Jakafi®) to treat chronic GVHD of the skin:  Lastly, ruxolitinib, or the other name is Jakafi®, has been a very promising agent. There was this big study that came out from Europe last year, actually it’s probably been about two years now, where they surveyed a bunch of German physicians based on their experience of just using this. It wasn't in a clinical trial. It was just based on prescribing it and see what happens to their patient. As a whole, these physicians saw a marked improvement in chronic graft-versus-host disease of the skin, the GI tract and a little bit in the liver, but mainly skin and GI tract, with this agent.  It’s actually being tested right now in a randomized phase three trial in the United States. Patients are randomly being allocated to either a ruxolitinib with steroids or just steroids without ruxolitinib. Steroids and a placebo. It'll probably take a couple of years to get that data, maybe over more than two years, but hopefully we'll see that this has very high efficacy.  

28:45  Vismodegib (Erivedge®) to treat chronic graft-versus-host disease of the skin:  The other thing is coming from University of Utah, we also have a couple clinical trials coming out or available. Right now we are actually testing a hedgehog inhibitor for those who have sclerodermatitis, the really fibrotic form of the graft versus host disease. We're testing this new agent to see if it can help prevent any progression or reverse some of the fibrosis. The drug is called vismodegib. What we've seen so far - again, there are side effects, muscle cramping, altered taste change - but, for half of the patients who are on it, they've actually felt improvement in some of the restriction that they had previously. One of our patients, female patient who is very active in yoga and stretching, actually feels that she can even do more now with her exercise. Another patient who was having very severe muscle cramps because of the GVHD is reporting improvement in the muscle cramps. This affects quality of life; it improves quality of life.  We actually have that at the Huntsman Cancer Institute and then soon we'll be opening up a trial where we're testing something called photopheresis, which I'm going to talk about, with a Jak1 inhibitor and not use steroids at all for first line treatment of chronic graft-versus-host disease. That's in the works right now. That's the way that I think we're going to have to go in treatment of chronic graft-versus-host disease. We know that long-term steroids are bad and so now we're trying to test agents where we don't have to use steroids or use steroids for long periods of time.  

30:23  PUVA to treat chronic graft-versus-host disease (GVHD) of the skin:  Moving on to phototherapy or light therapy. Some of you might have utilized PUVA. The P stands for Psoralen and then it's ultraviolet A rays, like what I wrote there. It's only used for skin involvement and it can be effective especially if there's no deep sclerotic GVHD that's present. I know physicians who do try it for sclerotic GVHD, but the efficacy is probably not optimal. It's not recommended to use in patients who have a prior history of skin cancer, and it can also be a risk factor for skin cancer. In this process, what happens is the patients will ingest or have applied to their skin a chemical called Psoralen, and then these UV ultraviolet rays will be shown on the skin and will activate the Psoralen. And what happens is that this basically immunosuppresses. It quenches the immune reaction that's going on. It makes the T cells and the B-cells quiet so that it makes the whole GVHD process quiescent. Other phototherapies that have been used in the past is also using UVA-1, UVB, narrow-band UVB.

31:47  Extracorporeal photopheresis (ECP) to treat chronic graft-versus-host disease (GVHD) of the skin:  We typically don't use PUVA where I am at right now at the University of Utah. We rely on something called extracorporeal photopheresis, or ECP, as our next line of therapy if the patients don't respond to steroids. Have any of you every received photopheresis?  Actually quite a bit. I would say almost half the room. 

It's a similar concept [to PUVA] except that this time the patient sits at the machine. It looks like a hemodialysis machine, actually a little bit, and they usually have a central line placed and the machines draws the blood out of them it separates the red blood cells and takes all the white blood cells. Separates, filters out and then the white blood cells are exposed to that chemical Psoralen, then it's  zapped by the ultraviolet light. Then it's reintroduced into the body. The patient doesn't have to take any pill or have any chemical applied to their skin. Their white blood cells are actually taken out of their body exposed to the chemical, the light and then put back into them. Then, again, how it works is basically  suppresses the whole GVHD reaction.  

We've seen really great benefit from the use of ECP in both the acute and the chronic graft-versus-host disease. In the absence of no clinical trial this is our standard therapy at the University of Utah. We use it for patients who don't respond to steroids if they have skin GVHD, GI GVHD, liver GVHD, lung GVHD and we actually see really good response. I've actually put a couple of my patients who have a sclerotic form of GVHD [on it] and although there's no cosmetic change, at least in the first eight to twelve weeks there's actually, with physical therapy, there can be a functional change. I have one patient who has lung GVHD and then came down with an infection and I was able to get his GVHD back under control and get him back on his home oxygen requirement with the use of ECP. Again, with other patients with physical therapy and sometimes a little bit of steroids we can actually see skin softening and improved function.

34:14  Gentle stretching and physical therapy can help some patients with graft-versus-host disease (GVHD) of the skin:  As I have stressed before this really can't be just done by itself. There are additional services that should be looked into that you should all participate in if you're being treated for a graft-versus-host disease of the skin, particularly the sclerotic form. Gentle stretching every day can be very beneficial.   Physical therapy, I don't know how many of you just came out of the fatigue and function workshop where the physical therapist were doing some exercises. Ryan actually works with me in the clinic. The way we have our clinic set up is I have all my chronic graft-versus-host disease patients and actually all my post-transplant patients get at least 30 minutes to 45 minutes of physical therapy with Ryan, and he works with them on specific areas where there's a lot of stiffness or lack of movement and sends them home with exercises, and follows them up every time they come in for their ECP treatment. This combination makes a difference. I didn't realize how important it was. Where I was before we didn't have physical therapy integrated into our clinics, but being at Utah for the past three years and seeing this combination, I'm really impressed by the changes that some of my patients have; they're much more functional, they can move better, and improve their quality of life and they're just happier. I can't stress enough the importance of physical therapy. For some people who have the financial resources to do deep massages, [that] can help loosen up the scar tissue, the fibrosis.

35:47  Use sunscreen to avoid flare ups of chronic graft-versus-host disease and skin cancer:  Just as importantly as treatment is prevention. We want to prevent any flare of GVHD. We want to prevent any onset of graft-versus-host disease and we want to reduce the risk of any skin cancer that can develop down the years for patients who do have graft-versus-host disease. I think all of you've been educated on this from your transplant doctor, but you definitely want to avoid excessive sun exposure or intense sun exposure. This occurs typically between 10:00 AM and 4:00 PM throughout the day. If you are going out you want to use a sunscreen. The National Institutes of Health recommend using a sunscreen SPF level of greater than 20. I actually tell my patients to use an SPF minimum of 30 with broad spectrum UVA and UVB protection. You want to have protective clothing; long-sleeved shirts and pants, hats. Avoid any photosensitizing agents, any skin lighteners. Actually, a couple of my patients, and they have some boxes out there, they've been adding this special detergent that you can add into your clothes wash that has that protective chemical for sun protection. 

37:02  Risk of skin cancer following graft-versus-host disease (GVHD) of the skin:  One thing that you should all know about is that patients with chronic graft-versus-host disease are at risk for developing skin cancer down the road. The three skin cancers that we monitor for [are] squamous cell cancer, basal cell cancer, and melanoma. As you can see here, through research, we have found that the risk of squamous cell cancer is anywhere from three to eleven times higher in patients who have skin involvement. The average time of diagnosis is between two to seven years.  For basal cell the risk is anywhere between, it's around two times more than the general population and can occur about seven to nine years after the diagnosis. Then malignant melanoma, even though I wasn't able to find how much the risk is increased, it can occur. It's not as often as squamous or basal, but it can occur, and it usually will occur one to four years after.

37:59  Pictures showing how to assess yourself for signs of skin cancer:  While we advocate for all of our patients to see a dermatologist and have a skin check at least once a year, I'm putting these pictures up here so that you are aware, and that you're able to do your own self-assessment every few months and be able to know what you're looking for. 

This is an example of basal cell cancer. These lesions can look very pearly or waxy. Usually they form in sun exposed areas. Sometimes they are called fleshy looking. They can be any color. They can be clear, they can be pink, red, I even seen a light blue tinge. They're usually translucent. That's why they're called pearly. Sometimes you can see little tiny blood vessels or capillaries in them. Sometimes they are scaly with raised edges and they rarely spread.   

Squamous cell cancer on the other hand usually are firm, red nodules. Sometimes they have a crusty overlaying crust and sometimes they could be bleeding. Sometimes you might think of it as a new sore that just popped out of nowhere. That can be a little bit alarming. That's something that you should have a doctor look at. Again, a new sore or coming out of an old area scarring.  

Example of melanoma. Usually, unlike these two guys, melanoma is very irregular appearing. It's usually flat. There's border irregularity. The color can change over time. It can become progressively darker usually is what I've seen. Then the diameter is usually greater than a pencil eraser. Then melanoma it changes over time, so that's why if you start to see, you first see something unusual, look at it again a month later or three months later. If you start seeing changes in the way it looks that's concerning. You should tell your doctor or see a skin doctor. Melanoma, once it spreads, if it's not caught early enough and not treated early enough, can be very difficult to treat, and it likes to spread.  Melanoma's a very aggressive skin cancer. It can go to the liver. It can go to the brain. It can go to the lung. This is one that you definitely want to treat as early as possible. Melanoma just doesn't have to be on the face or the arms or sun exposed areas. Sometimes patients will actually have an abnormal brown lesion along the nail bed. You should always look at your nails as well and your toenails.

40:49  Procedures to avoid if you have active graft-versus-host disease of the skin:  Procedures to avoid if you have active skin GVHD: try not to undergo any cosmetic procedures or surgery; no skin lightening products or tanning products or vigorous outdoor activities if you're going to be exposed to intense sunlight.

More precautions or supportive treatments if you are on steroids or on immunosuppression:  Your doctor should have you on preventative antibiotics, especially antifungal, antibacterial. Acyclovir to prevent any shingles outbreak. People who are on steroids. Patients who are steroids, bone strengthening agents are necessary, vitamin D supplementation with calcium to keep your bones strong because steroids can weaken bones over a long period of time. Then, those patients on steroids should also make sure they get a bone densitometry scan at least once a year, if not every six months.

 It's important to take ownership of your health. Report your symptoms, don't be shy, don't blow it off, tell your doctor. Protect your skin; moisturize regularly even if you don't have graft-versus-host disease. Do a skin self-check. Do yourself a favor and prevent another cancer from happening down the road.

42:06  Summary of talk:  Summary; I won't have to go through this, but essentially it highlights everything I just talked about. Incorporate stretching, physical therapy and massage. I think that's super important. Treating chronic GVHD can be a long process but don't lose hope; we are coming out with new medications. We're testing them. We're trying to avoid steroids so hopefully in the future we'll find that magic pill. Thank you.

42:36  Question about clinical trials using ruxolitinib (Jakafi®) and trials using vismodegib to treat chronic graft-versus-host disease (GVHD) of the skin

Audience member:  You mentioned a trial that's being done at Huntsman and you also mentioned a Jakafi® combination drug that's being tested. Could you repeat those?

Dr. Lee:  Ruxolitinib, it’s called ruxolitinib or otherwise, Jak1 and 2, is being tested in a phase three trial. Some of the centers involved in that are Vanderbilt, Washington University. I believe Moffitt [is] involved in that. I'm going to try to bring that to the Huntsman. I'm going to see if we can open it up at the University of Utah. I'm not sure if Colorado is involved in it yet, but that's testing that medication that the Germans reported doing very well with steroids, versus steroids and a placebo or a non-Rux. The one that we're working on at the University is a hedgehog inhibitor or the name is vismodegib. That's for patients who had that sclerotic form of graft versus host disease.   

44:05 has information about clinical trials for graft-versus-host disease (GVHD):  For anyone who’s interested in clinical trials the best site to go to, the website is One word. If you type in a search word GVHD or graft versus host disease you will see a whole panel of clinical trials that are going on across the nation.  

There are a few handouts in the back if you guys want to pick those up. 

44:30 Question about normal progression of graft-versus-host (GVHD) of the skin.

Audience member: Is there any rhyme or reason how these things progress? I started with a rash and then I started having the sclerotic. Now there's nerve involvement and is there any like order to this? One begets the next symptom?

Dr. Lee:  Usually with patients it does start off with a rash; the superficial part of the skin is involved.  Even with treatment, [for] patients who are treated effectively for the rash, there is no rhyme or reason. These patients can still have involvement of the underlying dermis layer or the subcutaneous layer. We do our best. We at least hope that intervening early will prevent progression and it does sometimes, but then there are other patients, too, who we treat effectively [for] the rash, but then still a few months later it'll come back again and then deeper layers can be involved as well. So, no clear-cut path.

45:37  Question about whether Kenalog® injections help to treat flare ups of chronic graft-versus-host disease (GVHD) of the skin and joints: 

Audience member:  How do you feel about using Kenalog® injections when you have flare ups on the legs and the feet, mainly joints?      

Dr. Lee:  I have not personally used steroid injections in actual localized areas of GVHD. I actually haven't heard too many transplant doctors doing that. I have colleagues who have used Botox for areas of very rigid muscle or people who are having muscle cramps and it has actually helped for these people, just injections of Botox, but I've never used steroids. 

[inaudible exchange between Dr. Lee and Dr. Treister of Harvard, who ways he does sometimes use steroid injections for oral GVHD]

46:42  Question about difference between scarring from athletes feet and scleroderma from chronic graft-versus-host disease (GVHD):  

Audience member:  We took my husband to the dermatologist and I did have him look at his feet. In the beginning we wondered if maybe if was athletes foot or if it was GVHD between the toes. I have still been treating. I put creams and stuff on but not the like the Tacrolimus creams or anything like that. He does have a little bit of thickening between his toes and I don't know if that was scarring from possibly having athletes foot between his toes or if it's actually sclerodermas.

Dr. Lee:  So GVHD can happen, we call [it] acral GVHD [of] the skin, and it can happen along the skin between toes and fingers. Have you tried steroids, just to see if they've helped or ...

Audience member:  A couple of weeks ago, I did, and it didn't seem to help. I don't know if maybe I was using the wrong one?

Dr. Lee:  It depends on how long you use it and if you're using it twice a day consistently. Has it been biopsied at all? Has it been suggested to biopsy it? 

Audience member:  No. He goes back to the dermatologist this week so I'll bring it up again.

Dr. Lee: There are a couple of ways, I mean you could try a more potent dose of steroid cream or ointment and apply it twice a day and see if there's any changes. You need to give it at least probably a couple of weeks.

Audience member:  Will the thickening go away?

Dr. Lee:  It can. It can if it's GVHD. Yup. You could also try experimentally some Protopic, the topical tacrolimus and see if that helps, but probably the most definitive way and the fastest way of knowing is just to do a skin biopsy and see whether it's athletes foot versus some inflammatory condition.

Attendee:  It seems to respond better to the antifungal creams. 

Dr. Lee answer:   Well. So, yeah.

Attendee:  But now I've got the scarring, so?

Dr. Lee answer:  It's got the scarring. Yeah, biopsy may; I would ask the dermatologist what he thinks about a biopsy. 

48:45  Audience question about negative effects of using sunscreens: 

Audience member:  I have seen in recent years a lot more studies coming out describing the negative effects of sunscreen like oxybenzone and things like that, that are endocrine disruptors or actually can cause genetic mutations in cells. Is there a point where using sunscreen becomes counter-productive? Is there a certain sunscreen that you recommend to your patients that doesn't contain a lot of those potential chemicals?

Dr. Lee:  No, actually I would have to read the data to see how they came out with those results and how they tested that and what sunscreens they tested. As of right now without knowing the data we are just going by the benefits of sunscreen in preventing flares of GVHD. We continue to recommend it. We don't recommend any particular brand of sunblock. But that's an interesting issue that you bring up.

Audience member:  Do you think that the mineral sunscreens like the zinc oxide and stuff are enough? Do they block enough of the UV spectrum?

Dr. Lee:  Zinc? Yes, zinc oxide should, yup. But I would have to go back ... I would want to look at that data myself. 

Attendee: Thank you.

Dr. Lee:  Any other questions?  I'll be up here if anyone wants to ask me questions privately.  Thank you. 

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