Graft-versus-Host Disease: How it Affects Skin, Nails and Hair

  Download Speaker Slides  

Graft-versus-Host Disease: How it Affects Skin, Nails and Hair

Presenter:  Silvina Pugliese, MD, Clinical Associate Professor of Dermatology, Stanford Cancer Institute

May 2, 2024

Presentation is 41 minutes, followed by 19 minutes of Q&A

Many thank to Incyte and Sanofi whose support helped make this presentation possible.

Summary: Graft-versus-host disease (GVHD) often affects the skin, nails, hair, mouth and/or genitals. This presentation will discuss potential treatments for various forms of acute and chronic skin GVHD, dry skin care, sun protection and how to monitor your skin for skin wounds and skin cancer.

Highlights:

• 60 to 80% of patients who have chronic graft-versus-host disease will have some degree of skin involvement.
• Chronic GVHD can cause a skin rash, hair loss, itching, scaly bumps on the skin, scarring, tightness or rippled skin, mouth sores, dry lips,  genital sores and/or decreased range of motion.
• Chronic GVHD increases the risk of developing skin cancer. Good dry skin care and sun protection can help prevent flares of GVHD as well as skin cancer.

Key Points:

(14:15): The skin consists of several three layers. Symptoms of chronic skin GVHD differ depending on which layer of skin it is affecting.

(14:59): When chronic GVHD affects the top layer of skin – the epidermis – it looks like pink-purple bumps joined together in a large area, or like blood vessel on the skin. Topical steroids, topical calcineurin inhibitors, JAK inhibitors, and narrowband UVB  light therapy are treatment options.

(19:12): When chronic GVHD affects the middle layer of the skin – the dermis – it looks like skin scarring and tightening. When it affects deepest layer of the skin – the subcutaneous tissue – it can look like cellulitis and cause grooves in the skin.

(22:46): Chronic GVHD can affect a person’s range of motion, making it difficult to fully extend hands, arms and feet, or raise arms over the head.

(23:49): Sometimes a skin biopsy is needed to diagnose skin GVHD to rule out other diseases that can look like GVHD.

(26:27): GVHD can affect the mouth and lips causing dryness and mouth sores. Topical steroids are the usual treatment.

(27:56): Chronic GVHD can affect genital skin causing pain in the vagina or on the penis, a burning sensation when urinating, painful sex and other changes. Topical steroids and calcineurin inhibitors are the usual treatment.

(29:15): Chronic GVHD can cause hair loss. Treatment for hair loss caused by GVHD may include topical or injected steroid or minoxidil.

(31:57): Graft-versus-host disease can cause lifting of the nails, lines running through the nails, or complete loss of nails. This is typically treated with topical steroids.

(37:17): Chronic GVHD increases the risk for skin cancers.  Limiting sun exposure for long time periods of time, especially at peak UV-index times, using sunscreen with SPF-30 or higher, and wearing protective clothing can reduce the risk skin cancer.

Transcript of the presentation:

(00:00): [Marla O’Keefe] Welcome to the workshop Graft-versus-Host Disease: How it Affects Skin, Nails and Hair. My name is Marla O’Keefe, and I will be your moderator for this workshop.

(00:10): Before we begin, I'd like to thank Incyte and Sanofi whose support helped make this workshop possible.

(00:18): Introduction of Speaker. It is my pleasure to introduce today's speaker, Dr. Silvina Pugliese. Dr. Pugliese is a Clinical Associate Professor of Dermatology and Attending Physician at Stanford Hospitals and Clinics and the Stanford Cancer Institute. She specializes in the management of skin complications associated with chemotherapy, radiation therapy, and bone marrow transplantation with an emphasis on graft-versus-host disease and survivorship.  Please join me in welcoming Dr. Pugliese.

(00:56): [Dr. Silvina Pugliese]: Thank you so much for that kind introduction and thank everyone for being here today. I'm looking forward to discussing graft-versus-host disease with you all today and I'll be focusing on my field of dermatology, specifically how GVHD affects the skin, nails, and hair.

(01:18): Learning objectives for presentation. My learning objectives today. First, I will review the skin symptoms of acute graft-versus-host disease and review some skin-directed treatment options. Then we'll move on to chronic graft-versus-host disease of the skin and discuss how it might manifest in the mouth, genital skin, hair, and nails. We'll then move on to talk about some skin-directed treatment options for the various forms of chronic skin GVHD. And we'll wrap up at the end by talking about some basic tenets of dry skin care and sun avoidance and protection, both of which are very important in patients with chronic skin GVHD. And then we'll discuss how to monitor your skin for skin wounds and how to evaluate for skin cancers.

(02:02): Graft-versus-host disease (GVHD) occurs when the donor stem cells, or the graft, view the recipient cells, or the host, as foreign and attack them. What is graft-versus-host disease (GVHD)? I know that a few days into this conference, you have already learned a lot about graft-versus-host disease. In summary, graft-versus-host disease is what occurs when the donor stem cells or the graft view the recipient cells or the host as being foreign and they attack those cells, and that's when we get the changes that we see on the skin that we call skin graft-versus-host disease.

(02:31): I'll be focusing on the skin. This encompasses the mouth, genital skin, hair and nails, and then I'll be reviewing both acute skin GVHD and chronic skin GVHD.

(02:45): GVHD is diagnosed as acute or chronic GVHD based on the symptoms, not when it occurs after transplant. One thing I'd like to introduce in this beginning portion is that in the past, we would classify acute skin GVHD and compare it to chronic skin GVHD based on the timeline - how many days past transplant the patient was when we saw these skin findings. But now we know that we can see acute skin GVHD much later than we expected in the past, and we can also see some chronic graft-versus-host disease arising earlier on. All this to say that we diagnose a type of graft-versus-host disease based on the skin findings that we see and not so much the timeline.

(03:27): Up to 50% of patients who are transplanted with donor cells develop acute GVHD. When we talk about acute GVHD, it is hard to kind of pin down an incidence rate because it really all depends on how acute GVHD is measured and documented and which organ system is checked. So, it can be hard to find exact numbers. The number I'm using here is up to 50% risk, and I know that there are some studies that show as high as 70%. But for the purpose of this talk today, I'm going to mention up to 50% incidence rate.

(03:57): Now again, we classically view acute GVHD as occurring during the first 100 days post-transplant, but now we know that if the clinical features are there, it can occur beyond 100 days.

(04:09): Acute GVHD affects the skin but it can also affect the gut, the GI tract and the liver. Skin involvement can often occur at the same time as gut or GI involvement. And this might show up with a symptom such as diarrhea. And lab tests may show some signs of liver injury as well. But when dermatology is involved, it's usually because there is a change on the skin.

(04:35): Acute skin GVHD typically looks like pink, red or purple bumps, similar to measles. What does it look like? Generally, it's going to be pink, red or purple bumps. We call it a measles-like rash, meaning that it's sort of red and widespread. It can be on the trunk, meaning the chest, the back, the belly. It can be on the arms and the legs. It can even be on the face. And it very commonly will affect the hands and the feet. In some cases, it can be itchy and, in some cases, patients might have rash everywhere but have no symptoms associated with it.

(05:06): Here are some representative photographs of acute skin graft-versus-host disease. You can see that the hands have a lot of involvement on the palms in this photo, a lot of small red bumps. They’re sort of all joining together to be a big red area of involvement.

(05:24): The photo of the back shows that some of the skin is sloughing off. That is a sign of a little bit more serious acute skin GVHD, when we get the skin peeling or what we call desquamation.

(05:39): You can see that in some skin types, the red color appears a bit more purple, it might be more subtle on exam. And we see in the photograph on the top right-hand corner that the areas involved are the chest, the arms, essentially seeing this very sun-distributed type of appearance in that one photograph.

(06:02): Treatment for acute skin GVHD may be topical steroids, calcineurin inhibitors, or Janus kinase inhibitors in cream or ointment form.  When we see skin GVHD in the acute phase presenting on the skin, some of the treatments that we can utilize, the skin-directed treatments, are going to be topical steroids, topical calcineurin inhibitors, topical Janus kinase inhibitors. And when I say topical, I mean usually creams and ointments. And we'll talk a little bit about each of these categories as we proceed with this talk.

(06:26): Narrowband ultraviolet B is another potential treatment for acute skin GVHD. Another treatment we can utilize is Narrowband ultraviolet B. This is a treatment that we do in clinics. And then in cases where we do have skin peeling and more of a wound, we will start kind of more intensive wound care.

(06:39):If the skin is itchy, which it can be in some types, then we might start topical anti-itch medications. So that could be things like camphor menthol, pramoxine, or we might start oral medications including antihistamines, or we might start a medication like Gabapentin or Pregabalin. It just depends on how extensive the itch is, how much it's impairing someone's ability to go along with their daily activities, to sleep at night, et cetera. And of course, whether some of the topical things that we're using, if they're helping or not.

(07:16): Steroids are effective in treating skin GVHD and the risk of side effects is low. We really do love topical steroids in dermatology. They're very effective, and if they're used correctly, the risk of side effects is low. And as long as we're kind of monitoring how long they're used for, we can feel safe and comfortable having patients use these.

(07:33): They come in several different, what we call vehicles, meaning the mechanism by which they're dispensed. So commonly they'll come as a cream. That's the white tube you see at the bottom. Or an ointment. An ointment's going to be more like a petroleum jelly type of consistency. They can come as solutions or liquids, which are self-explanatory, but they're more liquid form. They can come as oils or sprays.

(08:02): In general, ointments are going to absorb best into the skin. You put them on your skin. They're very occlusive. They absorb very well into the skin. The main reason that we sometimes will move on to a cream is because some patients don't love the way the ointments feel on their body, or they get them on their clothes. So of course we modify depending on patient preference.

(08:26): If it's an area of the body that has a lot of hair, then generally we'll use a solution or an oil because you can imagine it's very challenging to get an ointment or a cream through someone's scalp when they have a lot of hair or chest or back when they have a lot of hair in those areas.

(08:41): One important thing to remember is that the strength of a steroid really depends on the chemical structure, not so much the percentage. For example, hydrocortisone 2.5% cream, which seems very high, is one of our weaker steroids, whereas clobidazole 0.5%, which would seem to be much lower, based on the percentage, is actually one of our strongest ones.

(09:05): If you find yourself with a lot of steroids at home that you've accumulated through a couple months of rashes, it's always totally fine of course to ask your doctor or to ask the dermatologist, which one should you be putting where? And the reason that is important is because topical steroids do have some side effects, and we know that the side effects are increased the longer that we're using topical steroids and if we're using topical steroids that are too strong for the area that we're putting them on.

(09:34): Side effects of topical steroids for skin GVHD include thinning skin, stretch marks, bruising, acne and an allergic reaction on the skin. Some areas of the body like the face, the folds of the body, the genital skin can be thinner and can be more prone to steroid side effects. Some of the things that we can see are skin thinning, stretch marks, bruising, acne, and a type of rash that we call a contact allergy, which is basically an allergic reaction on the skin from putting a cream in that area. It's not usually a systemic reaction, but it's a reaction localized to one area of skin.

(10:12): Thinning skin.  If you start noticing signs of skin thinning, which for some people you might notice that the skin is a little bit redder like on the palms of the hands or you're seeing your blood vessels a little bit more or you're noticing more bruising, then generally stopping the topical steroids is the best thing to do.

(10:34): If stretch marks do develop, of course, we similarly stop topical steroids, and we might consider certain creams. Now none of these are 100% effective at treating stretch marks, which can be quite challenging. But tretinoin, glycolic acid, and L-ascorbic acid have all shown some efficacy in treating stretch marks. And in some cases when we have red stretch marks, laser modalities can be helpful.

(11:03): When we notice bruising on the skin, again, we'll stop topical steroids. And then the best way to try to protect the skin from bruising is by moisturizing to make sure that epidermal skin barrier is as intact as possible. And then physically protect. Wearing long-sleeve shirts, et cetera. And there are sometimes some topical medications like arnica, which can be helpful in fading bruises, but again, bruising can be really challenging to treat.

(11:32): Now we know also that steroids can cause acne. So not uncommonly, we might be using a steroid to treat the face, chest or the back and develop acne in those areas. Now there are many other reasons for acne. We want to make sure we're not missing another cause, but if we think it's related to the steroids, we'll stop the steroids and then recommend some common acne washes like benzoyl peroxide, salicylic acid, glycolic acid. And in many cases, we might use topical or oral antibiotics.

(12:00): For the contact allergy rash that I mentioned, we do know that if we switch to a different steroid class that does not react with the one steroid that caused the allergy, we often can get both improvement in the rash and then no further contact allergy. And then in some cases we'll consider some non-steroidal topicals and we'll talk about these in a little bit as well.

(12:24): All this to say for the contact allergy you're putting on a steroid and it's causing your rash to get worse, we do want to think about contact allergy, although often it can be that there might be another reason for the rash, another treatment that might work better.

(12:42): 30 to 70% of transplant patients who are transplanted with donor cells develop chronic GVHD. Now that we've gone through some of the characteristics of acute GVHD, I'm going to transition to talking about chronic GVHD. So again, it can be tough to know the exact incidence, but has been reported in a wide range of 30 to 70% of transplant patients who receive donor cells.

(13:00): Now the reason dermatology is so important to the care of these patients is that 60 to 80% of patients who have chronic graft-versus-host disease will have some degree of skin involvement. And the nice thing about skin is that we can see it, which makes it easy for us sometimes to diagnose or to do some testing on the skin that can help us diagnose chronic graft-versus-host disease. And by that same token, we can also see how our treatment is going, if the treatment is helping, by seeing whether there are positive changes on the skin.

(13:35): Again, the timeline is not so important, so we're really going to be looking for the features of chronic graft-versus-host disease, which we'll review in detail today.

(13:44): And the other important thing about chronic graft-versus-host disease, as you know well and has been emphasized during the symposium, is that it can affect multiple organ systems. So of course, beyond just the skin, and we talked about the mouth, we can also have eye involvement, we can have joint involvement, liver, lung and gut involvement. Because of that reason, this is often something that's managed by multiple doctors working together.

(14:15): The skin consists of several layers. Symptoms of chronic skin GVHD differ depending which  layer of skin it is affecting. Chronic graft-versus-host disease is what we call polymorphous, meaning that it occurs in many different forms. And how it looks on the skin partially depends on which area, which layer of the skin is affected.

The very top layer of the skin we call our epidermis, and then deeper in the skin is our dermis. And then at the bottom we have the subcutaneous tissue. And when graft-versus-host disease affects each layer, it'll look a bit different, and we'll look at some photos today to kind of see what that difference might look like on the skin.

(14:49): And then usually this is going to look quite different from acute graft-versus-host disease, and it can sometimes mimic some other skin conditions, and we'll go into that in detail.

(14:59): When chronic GVHD affects the top layer of skin, it looks like pink-purple bumps joined together in a large area, or life blood vessel on the skin. When chronic graft-versus-host disease affects the outermost skin layer, we see changes that generally take place in the very top layer of the skin. These are forms of chronic graft-versus-host disease that we call, for example, lichen planus-like or poikilodermatous. This is either kind of scaly, pink-purple bumps on the skin joining together to form a larger area of involvement, or it could be sometimes like blood vessels on the skin, similar to some of the changes we get from UV exposure.

(15:36): Treatment for chronic GVHD on the top layer of skin. When we have epidermal chronic graft-versus-host disease, the skin-directed treatments are very similar to acute graft-versus-host disease. When we can reach things that are in the top layer of the skin, it's similar to the treatment that we do for acute. So that means, again, topical steroids, which we just went over, topical calcineurin inhibitors, the JAK inhibitors, Narrowband UVB, and pulling in our tenants of wound care and itch care for when those symptoms are present.

(16:11): Topical calcineurin inhibitors, such a tacrolimus, are sometimes used instead of steroids to reduce the risks associated with long-term steroid use. I want to talk a little bit about topical calcineurin inhibitors. The medication names are tacrolimus, which you might recognize and pimecrolimus. These are nonsteroidal medications that can help with inflammation on the skin, and we often will incorporate these into a treatment regimen for both acute and epidermal chronic graft-versus-host disease to use something other than topical steroids to try to mitigate the risk factors of chronic long-term topical therapies.

(16:42): One caveat is that these can sometimes produce a bit of a burning sensation when they're applied on the skin. Generally, we'll have patients test a small area before putting it in all the affected areas. And also sometimes we'll mix it with either petroleum jelly or a cream-based moisturizer to dilute it a bit. This is a very nice option to have because it's very safe to put in sensitive areas, around the eyes, for example.

(17:14): Janus kinase inhibitors can be useful to treat chronic GVHD that affects a small area of the skin. And then the topical Janus kinase inhibitors like ruxolitinib, these are newer. Obviously, they're not actually approved for dermatologic use for this indication, but as you can already see, we use a lot of off-label medications for skin-directed treatments. And this is a nice option for limited involvement. So, patients that might have some GVHD of the face, for example, and we can use it in a small area. There's some risk with using it all over very inflamed skin, in which case patients might be at risk for some more systemic side effects of the JAK inhibitors.

(17:55): One unique treatment modality that we have in dermatology is called Narrowband UVB. This is a very thin sliver of ultra UV radiation that we can use. It's 211, 212 nanometers. It's a little box that has this UV light and patients generally will be treated with this three times a week in clinic.

The sessions are quite short. They start off being a few seconds long and they progress to a few minutes in length, and increase each time you come in. We don't ever want to jump from a short time to a long time because that could lead to skin burning. The treatment course is usually a few months. There are certain centers that do this treatment a lot more for both acute GVHD and for the epidermal variants of chronic GVHD.

(18:47): There is a website through our American Academy of Dermatology organization where you can search for dermatologists who have phototherapy. This can also be used for things like psoriasis and other skin conditions. It is a common treatment that we do in dermatology and can sometimes transfer to the graft-versus-host disease patient population.

(19:12): When chronic GVHD affects the middle layer of the skin – the dermis – it looks like skin scarring and tightening. Now, when chronic graft-versus-host disease affects the middle layer of the skin, the more dermal variants, this is going to look a little bit different on the skin. We can have skin that looks a bit more scar-like. We can have skin tightening, so what we call sclerosis.

(19:31): When chronic GVHD affects the deepest layer of the skin it can look like cellulitis and cause grooves in the skin. When it affects the deepest layer of the skin, some of the changes that we can see almost look a little bit like in some cases almost like cellulitis or you can have little grooves in the skin. And these are all signs that the rippling of the skin, et cetera, all signs that chronic GVHD could be affecting those deepest layers of the skin.

(19:57): Treatment options for GVHD that affects the deepest layer of ski include topical steroids under occlusion, injected steroids and ultraviolet A light. Now, this does make it a little bit harder to treat patients with the skin-directed methods that we often use in dermatology, primarily because we just can't get the medications to where they need to be.

(20:08) In some cases, we can try some topical medications like steroids under what we call occlusion. For example, we might have, if there was involvement of the leg, we could do clobetasol. Let's think about the ankle – we put clobetasol on the ankle, wrap it with saran wrap and hopefully there'll be enough penetration into the skin to help to kind of soften that skin.

(20:32): Another treatment that can be a little bit more effective is we can actually inject a steroid into the skin. It's not like getting an injection into the muscle. If you've ever had a steroid injection like in the buttocks and it's supposed to go in the muscle, and that's supposed to be kind of a systemic dose of the steroid. This is more than just trying to target. Usually, we'll use it for kind of thicker sclerotic areas of skin in very focal locations to help a little bit with the discomfort, with the pain and hopefully with some mobility in the area.

(21:04): For patients that have deeper chronic graft-versus-host disease we'll usually, if we're going to use any kind of UV, ultraviolet-based treatment, it'll be ultraviolet A, and I'll talk about that on the next slide.

(21:20): Ultraviolet A has just deeper penetration into the skin. You can see based on the longer wavelength, it's going to penetrate deeper into the skin and reach into the dermis.

Now there aren't tons of ultraviolet A machines available for treatments. It's a specialized treatment. And because we now have more systemic treatment options for chronic graft-versus-host disease, it's probably not utilized as much as it used to be, but it is a treatment that can be used for chronic graft-versus-host disease that's deeper in certain situations.

(21:56): Chronic GVHD can develop where there is pressure on the skin, or in areas where the skin has been injured. One thing to know about chronic graft-versus-host disease is that certain variants can develop in areas of pressure. It's not uncommon to have these skin changes under the bra or along the waistline, the waistband of jeans, for example, underwear. These can be areas that are also very tender.

(22:16): By that same token, they can also develop in areas of skin injury. In skin that was affected by an infection like shingles for example, where there was a line in the skin, where there was a blood draw. Any kind of puncture to the skin or injury, including prior radiation, we can sometimes see graft-versus-host disease gravitating to those areas of prior injury or new injury.

(22:46): Chronic GVHD can affect a person’s range of motion. And one important part of the evaluation for chronic graft-versus-host disease is to see whether it is at all impacting motion. So as part of the evaluation, we'll have patients raise their hands, their arms above their head, bend their arm at the elbow, make a prayer sign, and then point and flex their foot to see whether they are noticing any restrictions in the movement there.

(23:22): So how do we diagnose chronic graft-versus-host disease of the skin? Well, there are some diagnostic skin findings. Nothing that I think is important for you to have to memorize, but when we see certain things on the skin like that more kind of purple scaly lichen planus look or the red poikiloderma or the thickening sclerotic look, then we can feel confident that a patient likely has chronic graft-versus-host disease.

(23:49): Sometimes a skin biopsy is needed to diagnose skin GVHD to rule out other diseases that can look like GVHD. In some cases, because there are so many different variants of chronic graft-versus-host disease, and because there's so many mimickers of chronic graft-versus-host disease, we will go ahead and do a skin biopsy. And just to note, some of the skin conditions that can sometimes mimic chronic graft-versus-host disease are conditions that you might've heard about. So eczema, psoriasis, sometimes certain drug rashes can mimic graft-versus-host disease, lichen planus of the skin, vitiligo, keratosis pilaris, even sometimes nutritional deficiencies. And to complicate matters, we can often have graft-versus-host disease along with something else. All that to say that it's very important to look closely at these rashes.

(24:33): A skin biopsy is an easy procedure. But if we need to do a skin biopsy, rest assured that it is a very easy outpatient procedure, meaning it just happens at the office usually at the same time as your visit to dermatology. We call this type of biopsy a punch biopsy. I'm not sure who named it, but it doesn't feel like a punch. We generally will numb the skin first. That is a small injection into the skin. We usually inject lidocaine and epinephrine and of course if there's any allergies, we modify that. We use this little instrument. It's like a small little cookie cutter. You can think of it that way. And we take a small little piece of skin and then we put in one to three stitches. Generally, they'll just come out. Some of the stiches will dissolve or we'll have put some in that we cut out in two weeks or so.

(25:23): The main side effects are that wherever we take the biopsy, there will be a small scar left behind. It'll bleed, and then that's usually stopped when you're in the clinic. And there's a small risk of infection anytime we cut into the skin. But the skin biopsy can be helpful in providing some hints as to whether someone's rash could be graft-versus-host disease versus something else.

(25:47): Changes in immunosuppression, sunburn or UV exposure, infections and drug rashes can trigger skin GVHD. There are some hints that patients sometimes tell us that could be a sign that this is more likely to be graft-versus-host disease because these are all things that can trigger graft-versus-host disease. For example, any change in immunosuppression. That happens quite frequently. If there's any history of a donor lymphocyte infusion recently, CAR T-cell therapy.

(26:09): Another trigger that we see is sunburn or UV exposure, that's more than usual. Infections are quite common. And then of course, any new medications causing a drug rash, that could sort of be a trigger for graft-versus-host disease as well.

(26:27): GVHD can also affect the mouth and lips. Now in the same way that we have GVHD affecting the skin, we can also have primarily oral changes or oral changes along with skin changes. The symptoms are quite varied. It can show up as dry mouth, dry lips, and/or sores in the mouth.

(26:43): Sometimes we see these white little lines or streaks in the mouth. The gums could be puffy. There could be pain in the mouth. Sometimes pain with eating. Trouble eating, reduction in appetite just because it hurts so much to eat or swallow. And some patients will note some sensitivity to certain foods like spicy foods. And some of the changes that you see here, you can tell there's a lot of these white little lines over the lips, on the tongue and on the sides of the mouth here.

(27:15): Topical steroids are typically used to treat GVHD in the mouth. When we have chronic graft-versus-host disease of the mouth, then usually we'll use topical steroids, but it's a different formulation than the usual creams and vitamins on the body. We tend to do a lot of liquids, some swish and spit formulations, sometimes some gels or dental paste that stays in place, all with topical steroids in them.

(27:33): We'll sometimes use topical calcineurin inhibitors. We'll mix a capsule content with water and do a swish and spit with that, or get other types compounded. And then, if there is a lot of pain with eating, topical lidocaine can be really helpful in reducing that pain temporarily so that patients are able to eat without feeling so much discomfort.

(27:56): Chronic GVHD can affect genital skin causing pain in the vagina or on the penis, a burning sensation when urinating, painful sex or other changes. Another place that we can have graft-versus-host disease is genital skin. And it's completely understandable that some patients might feel uncomfortable talking about genital symptoms, but just know that this is a common thing that we see in dermatology. Genital skin is part of the evaluation from skin checks and rash checks and things of that sort. And it is important to identify because it can significantly impact quality of life.

(28:22): Some symptoms that patients might notice are they're having pain in the vagina or the penis, pain with sexual intercourse, pain or burning sensation with urinating, or they might see skin changes on the penis or vulva as well.

(28:38): And our treatment is going to involve, again, a combination of topical steroids, sometimes topical calcineurin inhibitors. We might, depending on the area of involvement and the symptoms and whether we think anything else could be going on along with the GVHD, refer to gynecology or urology.

(28:56): Pelvic floor physical therapy can be helpful for genital GVHD. And we do have some centers that have dermatologists who actually specialize in genital skin or what we call gynecologic dermatology. So that obviously is also an incredibly valuable asset to have.

(29:15): Chronic GVHD can cause hair loss. Another area that can be really impactful is the hair. There can be a lot of hair changes that happen during the time of transplant and post-transplant and really with any sort of chronic medical condition. But speaking about graft-versus-host disease specifically, chronic GVHD can show up as both a scarring type of hair loss or a non-scarring type of hair loss.

(29:37): A scarring hair loss is going to manifest as redness of the skin, flaking, scale of the skin. Those are some symptoms that patients might notice. Sometimes itchiness is associated with that or even pain or soreness. And usually we'll see a loss of hair follicles.

(29:55): A non-scarring hair loss generally does not have those symptoms and we might see the hair loss more diffusely throughout the scalp. In some cases it can be localized. And remember that we're talking about all the hair, so of course this is the scalp hair, but also eyebrows, eyelashes, anywhere on the body can also be affected.

(30:14): Treatment for hair loss caused by GVHD may include topical or injected steroid or minoxidil. For treatment of hair loss if we think it's more of this kind of scarring inflammatory hair loss, we can use certain topicals like topical steroids and there are others to treat the symptoms specifically. We sometimes will also do injections of steroids in the same way we talked about injecting the steroids into firmer sclerotic areas of skin. We can do injections into the scalp for certain variants of scarring hair loss.

(30:39): In many cases we'll use topical minoxidil, which comes with foam or solution. The brand name is Rogaine. You might've heard of that. It's very common. That does have some side effects of skin irritation, sometimes growing some hair on the face, which I know my female patients really don't appreciate. And sometimes we get a little bit of hair shedding with it. But it can be a helpful treatment to try to prevent further hair shedding.

(31:04): And then we also use a lot of oral minoxidil. Same medication but taken by mouth. Traditionally a blood pressure medication, it's used very commonly now for hair loss. And we generally use a lower dose in blood pressure dosing.

(31:18): Of course, because some of these treatments can take a long time, hair does not grow very quickly. We need to stop inflammation when it's there. We need to wait for the hair cycle, for the hair recovery. There are some treatments that can be done right away to try to get some improvement.

(31:33): We now have a variety of powders and lotions and sprays that can be utilized to mask thinning hair. And in some cases we will work with insurance companies, and try to get the hair or cranial prostheses covered. And then of course some patients, depending on the type of hair loss, may also be candidates for a hair transplant.

(31:57): Graft-versus-host disease can cause lifting of the nails, lines running through the nails, or complete loss of nails. The other area related to skin that we treat are nails. Now, nails sometimes are easy to ignore. They're very small on our body but having any kind of condition that affects the nail, including chronic graft-versus-host disease can be very disabling. We don't recognize how much we need our nails until we have any disease that affects them or if we lose them for any reason.

(32:26): The changes that we see, sometimes lifting of the nails, lines running through the nails or the most serious one is the complete loss of nails. That can be very painful and significantly impact just the things that patients need to do day-to-day, just normal routine activities.

(32:44): When we have chronic graft-versus-host disease of the nails, we'll use topical steroids. We can do injections of steroids into the nail. In certain cases, we might start topical antifungals to prevent fungal infections if the nail plate is impaired. Patients can be at increased risk for that.

(33:03): We often might recommend biotin at 2,500 micrograms to make the nails stronger. Just my caveat: biotin can interfere with certain lab tests. So, we don't want to just use it as a blanket supplement. We want to make sure that if you are using it, you're letting your doctors know when they're ordering labs.

(33:25): Steps that GVHD patients can take to protect the skin are dry skin care and sun protection. We do a lot of good dry skin care. Avoid washing your hands with hot water, avoid very strong soaps on your hands, use gloves when you're doing any kind of wet work so you're not constantly having that irritant that is water coming in contact with your nails. And then often apply cream-based moisturizers and then petroleum jelly around the nail folds can be helpful as well.

(33:49): Generally, the two main tenets of skin care that I like to emphasize for patients who have chronic graft-versus-host disease are dry skin care and sun protection.

(33:59): Dry skin care is an excellent habit to get into because it can help to prevent and treat itch, rashes, bruising and open skin. Good sun protection can help to prevent and treat some of the things that speak a little more to our vanity like sun freckles and skin discoloration and skin aging. But then of course also can help to prevent more serious things like skin cancer, flares of chronic GVHD, and I'll mention also the skin discoloration related to those flares of chronic GVHD.

(34:30): Habits that improve dry skin are showering and washing hands with lukewarm water, wearing gloves when doing wet work, avoiding harsh soaps and fragrances, and moisturizing on a daily basis. Some habits that we have to improve dry skin are showering or washing our hands like I mentioned with lukewarm water. So not too hot, not too cold. Trying to keep those showers and baths short, wearing gloves when washing dishes or doing any kind of wet work, avoiding harsh soaps and avoiding fragrances. Some people can be very sensitive to fragrances and perfumes.

Moisturizing on a daily basis, primarily for very dry skin with cream-based moisturizers and then using ointment moisturizer at night with white cotton gloves over them. That helps with that occlusive aspect that we talked about to try to get the cream-based moisturizers or the ointment to penetrate more into the skin and hydrate the hands better.

(35:18): Protect skin against the sun by limiting sun exposure for a long time, especially at peak UV-index times, using sunscreen and wearing protective clothing. On the topic of sun avoidance and protection, I usually think about this as being just a very comprehensive approach. Part of it is the sun avoidance piece. If you know you're going to be outdoors for a long period of time, avoid peak UV-index times. And then wearing protection -UPF clothing to protect you if you're going to be out for a long time.

(35:42): Use sunscreen with a SPF-30 or higher. For sunscreen, we look for SPF-30 and above. I usually have you go a little bit above only because it is hard to perfectly apply sunscreen. If you get that sort of SPF-30 to 50, 50 to 60, you're most likely to get at least SPF-30 on your skin.

(35:58): The two main families of sunscreens are going to be our chemical blockers and our physical blockers. Everyone always asks, "Is there one? Do you have a favorite sunscreen? What's the best one?" I don't think there's one best one, but you really must do a little trial and error which is the sunscreen that you are going to wear because if the best one sits on your bathroom counter, it's not going to be effective protecting you against the sun.

(36:22): And then I do mention that you want to find something water resistant depending on your activities that you'll be doing outdoors.

(36:32): It's very important to monitor your skin for wounds. Some of the factors that contribute to wound development can also contribute to delayed wound healing such as GVHD, nutritional status, risk of injury, circulation, underlying circulation issues. And then in some cases, infection can get in the way of wound healing.

(36:52): When we evaluate a wound, we're going to be wanting to take all of these different potential causes into effect and also potential things that are delaying the wound healing. And I always say that wounds that do not heal as expected should be evaluated for skin cancer. We expect that wounds might take a long time to heal, but if they're not going in the right direction, we might need a little skin biopsy there.

(37:17): Chronic GVHD increases the risk for skin cancers.  Symptoms include pink, red or purple shiny or scaly bumps; spots that bleed or are painful; wounds that don’t heal or scars that open up.  And just to end with how to identify skin cancers. There was a little more talked about this on my Saturday talk on just general skin care, but we do know that patients who have undergone a bone marrow transplant have an increased risk of developing skin cancers. And we know that chronic GVHD increases the risk of skin cancer development.

(37:37): On the skin we're going to look for pink, red, purple, shiny or scaly bumps. I look for spots that bleed or are painful, wounds that don't heal or any scars that open up.

(37:52): In addition, of course, we don't want to ignore melanoma, which is a common skin cancer, and those might show up more as brown or black spots. We think about the ABCDEs of melanoma, asymmetry, border, the color being more than one, diameter larger than the head of a pencil eraser and if they're evolving, although some melanomas can also be pink and red.

(38:16): In summary, don't feel like you have to check everything on your skin by yourself. We're always happy to help in dermatology. Primary care is very helpful as well with the skin exams and anything that looks kind of funny should be evaluated given the increased risk after bone marrow transplant and chronic GVHD.

(38:34): You can check the BMT InfoNet Directory of GVHD Clinics and Specialists if you're looking for a dermatologist familiar with GVHD. And also know that many dermatologists have training to identify all different types of rashes on the skin.

(38:52): Well, thank you so much for allowing me today to run through acute skin GVHD, chronic GVHD, and then some of the basic tenets of skin care, sun protection and how to evaluate for wounds and skin cancers. And I'm happy to take any questions at this time.

Question and Answer Session

(39:11): [Marla O’Keefe]: Thank you Dr. Pugliese for this excellent presentation. We will now begin the question-and-answer session. Is minoxidil only effective as long as you take it? Does the condition return once you stop it?

(39:39): [Dr. Silvina Pugliese]: That's a good question and this is one that we get all the time. So minoxidil is only effective as long as you take it. The question as to whether it comes back after you stop it, really depends on the type of hair loss.

Let's say we're using it for something like just normal female and male pattern hair loss. We know that this is a progressive type of hair loss that just sort of worsens with time. If we have that condition, we take minoxidil, it will improve for the patients who it helps; it'll improve the hair loss while they're on it and then if they stop, that hair condition is still ongoing and therefore the hair shedding will start again.

(40:23): Now we do sometimes use minoxidil with certain hair conditions where there might be also something else going on, like we talked about a little bit of an inflammatory component. If we use minoxidil to try to retain some of the hair during that time and then also at the same time we are treating the inflammatory component to reduce that and prevent future hair shedding, then in those cases we might be able to stop the minoxidil without the hair falling out again.

(40:52): If we use minoxidil temporarily in cases of stress-related hair loss where we think there might also be a very minor component of female pattern hair loss, then we can again use the minoxidil temporarily and then taper it off. But all this is to say that in many cases of hair loss, we have to continue on the minoxidil to get that improvement, that continued improvement and in some cases we're able to stop it.

(42:42): [Marla O’Keefe]: Thank you. Next question is, any suggestions for a Revlimid rash?

(42:51): [Dr. Silvina Pugliese]:  Yeah, thanks so much. That's a great question. There are a number of different rashes that have been reported with the use of Revlimid. It does depend a little bit on exactly the kind of rash that it is. Some of them might be just kind of our more standard red rashes that can affect the whole body. Sometimes we can have some rashes where you have more accentuation of the follicles, so kind of an acne or folliculitis type of rash. Sometimes we get swelling of the skin, some of you get just itching without really any rash other than the secondary change from the itch. The treatment would depend on what the rash looks like.

(43:35): Some of the things that we do might be topical steroid medications, repairing the dry skin if there's a lot of itchiness using some topical or oral medications for itch.

(43:50): [Marla O’Keefe]: Thank you. Okay, next question. I live in Arizona and since transplant I've become heat intolerant. So when wearing lotion, especially cream-based, it traps the heat in my body and I become much hotter. Do you have any suggestions on what to use to allow my skin to breathe while it's hydrating?

(44:13): [Dr. Silvina Pugliese]: That's a great question. I definitely run into this problem in California as well and it can occur in any climate where it can be quite hot.

I always say creams are great moisturizers and so are ointments, and some people just really can't tolerate them. So of course there might be other reasons. I'm not sure if the person asking the question has, for example, chronic GVHD that affects the sweat glands, in which case that could lead to there being more heat production. But if it's just the feel of the cream on the skin, I always think it's very reasonable to try lotion-based moisturizers. They can be quite good. I mean, I have patients that use them, I use them myself often, and as long as you're using them and your skin isn't dry, there's really not a problem. So in the same way I think about sunscreen, you want to find the one that works for you and use it.

(45:04): We might have our textbook idea of what we think is going to work best, but it really does depend on what you're able to tolerate. So the first thing I would do would be to try one of the pumps, like a lotion-based moisturizer and see if you're able to tolerate that in the heat.

(45:20): And the other thing would be if it's really hard to tolerate having something on your skin during the day, think about moisturizing during the time that you're home. So let's say if you in the evenings you moisturize and you sleep with it overnight, for many people that's going to be a good amount of moisturizer to have.

(45:39): [Marla O’Keefe]: Thank you. Next question. Does Jakafi help with skin GVHD?

(45:50): [Dr. Silvina Pugliese]: Yes. Thank you so much for asking that question. It does help with skin GVHD and it's very exciting because it's one of our FDA-approved treatments for skin GVHD and it can be used for both acute GVHD and also for chronic GVHD. It is a medication that was not around when I first started seeing cases of GVHD and now is proof of treatment. So that's a great option to have.

(46:22): [Marla O’Keefe]: Thank you. Thoughts on hyperbaric oxygen therapy for skin GVHD?

(46:33): [Dr. Silvina Pugliese]: Oh, thanks for that question. So, it's not our treatment that we do in dermatology, but we have had patients here be seen in our wound care center for treatment sometimes with wounds in the setting of chronic skin GVHD with the oxygen therapy. That's the time that I've seen it utilized.

(47:00): [Marla O’Keefe]: Very good. What kind of moisturizer for fingernails that are splitting is best at night when wearing gloves?

(47:11): [Dr. Silvina Pugliese]: Generally, when we think specifically about moisturizers, I usually will recommend petroleum jelly. I think it is really nice and occlusive and fits on the nails and can absorb really well.

And for folks that don't love that, there are several cream-based moisturizers available. There's CeraVe, Cetaphil…Neutrogena has a nice hand cream and Vanicream has a great product. I mean there are so many. I could probably spend the rest of this Q&A session talking about them. But I think that petroleum jelly is a great place to start.

(47:47): [Marla O’Keefe]: Okay. And along the same lines, someone wants to know what they can do to make their nails grow back to normal.

(47:54): [Dr. Silvina Pugliese]: So, whether the nails came back to normal can depend on a lot of different things. One, let's say we're just staying true to this talk. If it's graft-versus-host disease affecting the nail, then we'll want to see what degree of activity there is in the nail and target that. So that would be using topical steroids, injections of steroids into the nail .for example, to try to get some improvement if there is any GVHD activity.

(48:27): Now we know that there are a lot of different reasons why the nails can be affected. Nails can be affected by chemotherapy. They can be affected by environmental factors that we've talked about, a lot of the dryness, et cetera. They can be affected by medications. If you're on a medication that continues to affect the nails, that might be a time that the nails will be a little bit less normal to go along with the thread of the question.

(48:50): And then there can be other things. We can get fungal infections of the nail. So it's really important to try to figure out exactly why the nail is not growing up.

(49:03): If we're able to identify specific causes that we can mitigate or change in some way, and that's not possible in many cases with medications, for example. It is possible with some of the modifiable habits that we have. And if we can identify, for example, okay, there is a fungus in this nail or, oh, the nail actually does look really weak and we see the cuticles are kind of affected and maybe the dryness is a big factor here, so we'll modify what we're able to modify and we look at the nail.

One of those things is sometimes nutritional deficiencies. We know that certain nutritional deficiencies can contribute to the nail being a little bit weaker. So that's something that we can check through laboratory work and supplement as needed.

(49:49): There's not just one thing that we do to get the nail back to normal, but it's trying to figure out why is the nail looking the way that it is and of those reasons that we think why it's happening, what can we treat and what can we improve upon.

(50:05): [Marla O’Keefe]: Thank you. I have small goose bump-like bumps on my skin in the arms and top of my head. Could that be GVHD?

(50:18): [Dr. Silvina Pugliese]: That's a great question. When we think sometimes about little goose bumps-like spots on the skin, we think of a condition called keratosis pilaris, which some people call chicken skin because you might've heard that in terms of marketing for different topical medications that can help with it, like over-the-counter or sort of beauty products.

(50:42): This condition tends to be small little bumps. They look almost like accentuations of the hair follicle. Really common places for it are the upper arms, the upper thighs. And patients can also get it on their abdomen, their belly, the back and it can be more widespread. So it could just be keratosis pilaris, which is common. We see it all the time in patients without cancer, without chemotherapy, without transplant, without GVHD. And it can start in childhood and just continue through life. And we can sometimes have people develop it in adulthood.

(51:19): But we also know that sometimes graft-versus-host disease can show up having this keratosis pilaris look. And one of the things that we look for with graft-versus-host disease is whether the follicles are accentuated on the exam. So it's hard to say for sure. Again, it could be multiple things, but it would be good to just get your skin checked out and see whether your doctor thinks there might be concern for any skin GVHD when they look at your skin.

(51:50): [Marla O’Keefe]: Thank you. You use the term nail folds in your presentation. What does that mean?

(51:59): [Dr. Silvina Pugliese]:  Yeah, thanks. If you're looking at your nail right now, you see that you have the hard nail plate, what we call the nail, and then around it you have a little U-shaped skin, and that's what I call the nail fold. So you have the sides, the lateral nail fold, and you have the nail fold at the bottom is where the cuticle is. So that's the nail fold, it's just the skin directly surrounding the nail.

(52:29): [Marla O’Keefe]: Thank you. I didn't know that either. Okay, the next question. My skin bruises easily. If I just put one hand on top of the other very, it gets kind of like a burning blue bruise. Is there anything I can do for that?

(52:47): [Dr. Silvina Pugliese]: So, this is a really, really common symptom and it's very frustrating. It's like any little type of contact sometimes can cause a large bruise. So there's a couple of things to consider.

(53:05): One, we know there are some things that definitely predispose people to skin bruising. Over time, our skin definitely gets thinner. So little kids tend to need a lot of injury to get a bruise on their arm. And then as we get older, we just need a little bump, like you mentioned, to get a bruise.

(53:25): UV exposure. So having chronic UV exposure, exposure to the sun, just not even just kind of being out and about outdoors, living in a nice climate, wearing short sleeves, et cetera, doing an outdoor sport, occupation, et cetera, can make you more prone to having these changes on the skin caused by UV light that thin out the skin and predispose patients to bruising of the skin.

(53:49): Sometimes there can be medications, so medications commonly like steroids by mouth or oral steroids, prednisone, et cetera, or topical steroids can thin out the skin and cause more bruising. And there can be other medications as well in that family, not in that family, but other medications taken by mouth that can cause bruising.

(54:08): Now sometimes there can be some conditions of the blood, like platelet conditions, et cetera, that can contribute to bruising. I think it's reasonable always to ask your doctor, see if you have any other symptoms that could point to something more serious. But as long as that is not the case, and again, we can't just stop any medication because it has a side effect when it's an important one that we need to be using. The things that we can do to try to help the skin are, well one, if the bruises develop, sometimes certain topical medications like Arnica, which is available over-the-counter or a prescription medication like Tretinoin have been reported to help in some cases with bruising of the skin. And there are others. But again, the evidence isn't that strong, but it's something I think that is helpful to try and see if there's improvement.

(54:58): And then again, we love moisturizing in dermatology. So moisturizing, sun protection and physical protection with clothing to try to prevent the bruising as much as possible.

(55:09): [Marla O’Keefe]: Thank you. Since transplant, I have extremely dry skin on my toes. Can this tough dry skin cause ingrown toenails and how can I avoid that?

(55:24): Dr. Silvina Pugliese]: Okay, there can be a lot of dryness on the skin. Generally we'll see that on the soles of the feet. Sometimes it could be along the toes, maybe on the areas that are rubbing against shoes and things like that. There can be sometimes a little bit of a frictional component.

(55:47): The things that usually are going to cause the ingrown nails are whether we have, if the nail itself is cut in a way that it grows into the nail fold, the side where the skin is next to the nail, those are the times we're going to see some more ingrown nails. Or if we cut the nail super very short and then it kind of grows into that. Or if we're doing repetitive injury to that side of the foot where you're getting the ingrown nail. Those are probably the more common things as opposed to just the thickness of the skin there.

(56:29): [Marla O’Keefe]: Okay, thank you. This will have to be our last question. This person is three years post-allo transplant and they're off immunosuppressants for six months and they want to be outside. She says she's usually covered head to toe and she loves being in the sun. Will she ever be able to go to the beach or the pool again?

(56:52): [Dr. Silvina Pugliese]:  I know. I think it can be a big change from not having to think about being in the sun. I mean, as dermatologists, we want everybody to think about being in the sun. But certainly when there's a medical reason, a medication that makes you more prone to sun burning or puts you at increases for skin cancer, it can be a big change from the normal life that a patient might be used to living. So I'll say yes, you absolutely can be. We're not anti-outdoor activity in dermatology. You can be in the sun at the pool, just making sure that you have some degree of protection..

(57:31): The UPF clothing are helpful in reducing worry you have with the the sunscreen. And then sunscreen on the exposed areas with re-application. I mean even to somebody that hadn't had a transplant, I still wouldn't recommend just tanning at the beach or the pool. So that's going to be my recommendation as well to my transplant patients.

(57:51): But our goal is to have patients live full lives and do the things they want to do with maybe some additional layer of precautions. But we certainly don't expect that people will just stay indoors all day and do nothing that they enjoy because that's definitely not our goal. So my answer would be yes, you can go ahead in the pool and at the beach and just have some layer of precautions.

(58:16): [Marla O’Keefe]:   That is a good answer. Perfect end. On behalf of BMT InfoNet and our partners, I'd like to thank Dr. Pugliese for a very helpful presentation. And thank you, the audience, for your excellent questions. Please contact BMT InfoNet if we can help you in any way.