Host: Welcome to the podcast series from the specialists at Penn Medicine. I'm Melanie Cole. And we have a panel for you today with two Penn Medicine specialists to highlight graft versus host disease. Joining me is Dr. Pashna Munshi. She's an associate professor of Clinical Medicine in Hematology Oncology at Penn Medicine. And Dr. Emily Baumrin, she's an assistant professor of Dermatology and the director of the GVHD Subspecialty Clinic in the Department of Dermatology at Penn Medicine.

Doctors, thank you so much for joining us today. And Dr. Munshi, I'd like to start with you. Could you please describe the physiology of graft versus host disease and its link to allogenic stem cell and bone marrow transplantation?

Dr. Pashna Munshi: Hi. Thank you. Sure. So graft-versus-host disease is essentially part and parcel and a complication of allogeneic stem cell transplant, and it's an immune-mediated complication where the donor cells recognize recipient tissue as foreign, and part of the donor cells release inflammatory and cytokines, and then it eventually damages the host tissue.

Essentially, it can happen very early on in an acute setting where the regimens that we give to our patients have radiation, and they have certain forms of chemotherapy that are highly toxic and damaging to the endothelium and epithelium, and it causes all this injury in the mucosa and lining of the gut and skin, things like that.

And once that initial damage happens and the donor T-cells go in, they recognize that this host is damaged. They release certain effector cells, and the cytotoxic inflammatory markers end up causing skin rashes and diarrhea, nausea and vomiting, and eventually even liver injury. It can be quite severe.

And then later on, in the course of the trajectory of transplant, sometimes the immune system remains dysregulated. And then there is a form of graft-versus-host disease called chronic graft-versus-host disease and that's mediated by antibodies from the donor cells that remain in the recipient and continue to damage the host and people can end up having different forms of skin changes.

Dr. Baumrin can speak a little bit to that later on how the skin can react to that. It can lose its turgor, it becomes sclerotic, it can become stiff. People can have joint aches, joint changes, dry eyes, dry mouth and a whole different form of complications later on.

Host: Well, thank you for that. So, Dr. Baumrin, what should dermatologists be looking for with regard to GVHD in the months following allogeneic transplantation? What are some of the first signs?

Dr. Emily Baumrin: Hi. Thank you. So, as Dr. Munshi mentioned, in the months following allogeneic transplantation, we're really looking for signs of acute GVHD or that kind of early onset form. And this typically presents as something called a morbilliform eruption. The term morbilliform is used to describe a measles-like eruption or red macules and papules coalescing into kind of confluent red patches and plaques on the body.

And in the acute GVHD skin rash, we characteristically see this involve the face and the scalp and hands and feet, and sometimes showing what we call follicular accentuation or redness around the hair follicles. In mild forms of acute GVHD, sometimes this just looks like redness of the face and upper chest, and it can be hard to distinguish from other rashes.

But in the severe form, patients can develop red skin all over their body called erythroderma, and it can become so severe that the skin can blister and cause open wounds almost like a burn patient or a patient suffering from a severe drug eruption.

Patients also have symptoms associated with this, so they can have extreme itching and also skin burning feeling like a sunburn.

And sometimes these symptoms can actually be out of proportion of what we see in terms of the rash. And then the last thing I'll mention is in patients with darker skin tones, you have to have a high index of suspicion to be looking out for these rashes because the redness that we see in white patients can sometimes be more subtle. Patients with darker skin tones can have a slightly different presentation with kind of hyperpigmented or brown skin, or sometimes the redness can be subtle. 

Host: That's so interesting. Dr. Baumrin, as we're talking about this, one thing I find really interesting is the post-transplant mimics. So what helps dermatologists distinguish between GVHD and those post-transplant mimics such as drug hypersensitivity eruptions, conditioning regimen, phototoxicity? There's so many things in Graft-vs-Host syndrome.

Tell us a little bit about how you differentiate.

Dr. Emily Baumrin: I don't have the perfect answer for this because this is what we struggle with as inpatient consult dermatologists seeing these sick patients in the hospital after transplantation, kind of wrestling with these different causes. But as you mentioned, you know, that morbilliform eruption that I described is not specific to acute GVHD.

And we can see it in some of these other causes like a drug hypersensitivity reaction, a viral exanthem, engraftment syndrome as you mentioned. And the skin can look quite similar even though sometimes we look for clues like that head and neck predominance or the follicular accentuation. It doesn't necessarily perfectly distinguish.

And similarly to the clinical presentation, a skin biopsy or the histopathology often does not distinguish between these causes either. And so because the skin looks similar on exam, histopathologically, we see an interface dermatitis for many of these causes of skin rash, such as viral exanthem, drug reaction, and acute GVHD.

So we do look for clues on the skin biopsy that can help us, such as follicular involvement of the interface dermatitis, but it's not a perfect test to distinguish between the acute GVHD mimics. And so we really hang our hat on the clinical presentation. So for acute GVHD, for example, we look for liver involvement and nausea, vomiting, diarrhea, as Dr. Munshi mentioned, alongside the morbilliform eruption. For engraftment syndrome, we typically would expect this to occur much earlier after transplant when the host is engrafting and be associated typically with other manifestations that would be atypical for GVHD, like fever or pulmonary infiltrates or edema.

And then for drug eruptions, we look for culprit medications that were started in the weeks prior to the rash. And if we're thinking about a severe drug eruption, like drug eruption with eosinophilia and systemic symptoms or DRESS, we also look for kind of liver and kidney involvement and eosinophilia.

So, we have to use our history and physical exam and predominantly make a clinical diagnosis to distinguish acute GVHD from mimics, but we can sometimes use histopathology to help us with some clues.

Host: Dr. Munshi, as we're talking about imitations, it's really a great mystery. So, when we think of years after the transplant, do we understand why some of these things crop up then? The telling signs when we're looking a few years down the lines in the guise of scleroderma or rheumatoid arthritis and other conditions.

Do we know anything about those? What do we know now?

Dr. Pashna Munshi: Yeah, I think for transplant, it doesn't just end where the donor cells go, and in fact, that's when the transplant journey starts. And oftentimes I tell my patients that you're going to be be our patient for the rest of your life, which means that we're following these patients in their survivorship phases of transplant well into years after transplant if they have the fortune to survive their disease.

And so in the survivorship phase, because they've had such toxic chemotherapy, sometimes high-dose radiation, these are damaging over the course of years to even organs. And aside from graft versus host disease, we have to look for other problems like coronary artery disease or cerebrovascular accidents or new skin cancers, and that's why they have to go to people like Dr. Baumrin once a year to, make sure they're not having squamous cell carcinomas, things like that. And it's possible that sometimes they may develop some kind of arthritic problems. But oftentimes these arthritic problems really trick us. As Dr. Baumrin mentioned, it's really challenging to discern what's happening because it's a new disease that the patient's suffering through, or it's a manifestation of graft versus host disease, which again can be really subtle.

So we're trying our best to  use patient-reported outcomes or  use some kind of symptom scores for patients to track and tell us if new changes happen, if they have joint pains and aches, and are they subtle? Do they get worse? Is there swelling associated with it through the course of their survivorship phase?

And of course, if it's elusive, we do send them to rheumatology. Oftentimes we have to send them to endocrinologists because sometimes they end up having thyroid complications or changes in diabetes, things like that. Scleroderma, really, if it happens, most likely this is graft versus host disease in the setting of transplant.

It would be quite unusual to see a new rheumatologic sclerodermatic change after transplant in somebody who's never had a history of it or family history of it, or the donor may have had it. But I think over time, it's really important to follow these patients, and that's why we also focus on communicating with referring physicians, local primary care providers, making sure that we're there as a support.

But most of the time the patients travel to us at Penn and they live very far away. And so, we really engage with our community partners to also guide these treatments and symptoms.

Dr. Emily Baumrin: And I'll just add to that, Dr. Munshi, thatI tell my residents and my trainees that chronic GVHD can fool anybody because it just presents so heterogeneously and can have all these atypical manifestations. And so, it's good to evaluate, of course, for other causes, but to remain on alert that, for example, in the skin, chronic GVHD can look like eczema. It can look like lichen planus, psoriasis vitiligo. It can really mimic a lot of our dermatologic conditions. And so, we have to have a high index of suspicion as patients even years out of transplant come see us.

Host: Dr. Baumrin, you represent two specialties working together to treat graft versus host disease. Tell us about your combined clinic and the multidisciplinary approach. What are you finding are the largest benefits?

Dr. Emily Baumrin: So this has been an extremely rewarding part of my job. And we established the formal GVHD subspecialty clinic about five years ago. And it's housed within the Department of Dermatology. And so, as a director and the clinician seeing these patients, the patients are seen only by a dermatologist in the Department of Dermatology—but where the multidisciplinary, interdisciplinary connection comes in is that decisions made after evaluation are always made in conjunction with the transplant clinicians and advanced practice providers who the patients are often seeing same day, if not the same week, as in the dermatology clinic.

There's always open communication between the two specialties, making joint decisions. And we in the dermatology clinic bring the expertise of  being able to look, define, diagnose, and grade the severity of skin disease and then make collective decisions on how we can move forward with skin-directed therapy in place of systemic therapy or a combination of the two with the transplant team.

And we enhance this collaboration also by attending joint patient care meetings and then with the dermatologists and the transplant clinicians, and we even have some ongoing clinical studies as well to strengthen this collaboration. So, it's been a great clinic, and I hope Dr. Munshi can speak to how she has experienced it on her side.

Dr. Pashna Munshi: Yeah, I will chime in. It's just a blessing to work with Dr. Baumrin and just have her around in her expertise for our patients, right? Because at any given time, I'm struggling with these terrible rashes, and patients respond to the, you know, initial treatments of topical steroids. And you try and get them off the steroids, and the rash comes back again, or they continue to remain red, and you just don't know what's going on.

And so it's so helpful that we have dermatology right there and the expertise where they can immediately either do a skin biopsy or trial and error of maybe stopping a drug that could be aggravating the skin rash and cause something like phototoxicity. So there is a lot of communication that I think is warranted around this time.

And I think it's humble for me always because it's always a learning experience when I'm looking at somebody and experiencing rashes with them because to me, everything looks like graft versus host disease because obviously that's me as a transplant physician. But I have to be humble enough to understand that maybe it isn't, and I need expert eyes to do a second look and try and figure out what else it could be.

And we just shared a patient, Dr. Baumrin and I, who has some form of folliculitis related to skin mites. And she's undergoing significant treatment and her GVHD got resolved after treating that skin condition. So I think there's a lot of partnership that's needed around this time.

Host: Well, that's so important. And Dr. Munshi, what prophylactic therapies are available to prevent the progression and worsening of GVHD in either of its manifestations?

Dr. Pashna Munshi: Yeah, I mean, this is a really evolving topic. I mean, it's so many drugs that have come into the limelight for treatment of graft versus host disease, acute and chronic, and some of these drugs are now being used in the upfront setting to prevent graft versus host disease in the form of clinical trials.

So in the last decade, we've had an explosion of all these treatment options, which is amazing to see, which we don't really see for graft versus host disease in the years prior to this. And so, traditionally we use drugs like calcineurin inhibitors, which is tacrolimus and cyclosporine as prevention, and it's built into the regimen that patients get in the hospital when they're getting their transplant.

 And these drugs have essentially been used in solid organ transplant recipients, and so patients stay on these drugs for a period of three to six months before they get tapered off. There are anti-proliferative agents like methotrexate which used to be the traditional drug of choice with tacrolimus before post-transplant cyclophosphamide was introduced.

And so methotrexate, along with mycophenolate mofetil, this is an oral drug, so patients stay on this as well for about a month after transplant. And then, by and large, most of our transplants now utilize a form of chemotherapy given on the third and fourth day after the stem cell transplant goes in.

And this chemotherapy is an old drug. It's an alkylator. It's called cyclophosphamide, and it helps to sort of remodel the early alloreactive immune response of the donor T cells. And it's a very strong, powerful mechanism to prevent acute graft versus host disease and also some degree of chronic graft versus host disease.

And so there's a whole bunch of drugs, and now we've got more recently a drug called abatacept. It blocks the costimulatory signaling from the T cells and it's been shown in clinical trials to help prevent graft versus host disease. There's some gut trafficking inhibition drugs like vedolizumab, which have been seen more in the treatment form and, we don't really use it very often, but there have been clinical trials showing that it can be effective.

And then there are older drugs like that really cause in vivo T cell depletion, like Campath and ATG, and they reduce alloreactive T cell burden, but it certainly comes with the cost of higher infections. And then I would be remiss if I didn't mention the JAK inhibitor drugs, specifically ruxolitinib, which now really has become our bread and butter treatment drug for patients who have graft versus host disease that are becoming insensitive to steroids or are dependent on steroids.

And so ruxolitinib is now also being used in clinical trials upfront to see if it can prevent GvHD. So, there's a whole bunch of drugs that we are getting used to and learning and trying to understand the right combinations.

Host: Thank you both, and I'd love to give you each a final thought. And Dr. Baumrin, histopathological confirmation is a vital tool in the diagnosis of GVHD. What distinguishes the cutaneous pathology services at Penn Medicine, and what would you like the key takeaways from today's discussion to be?

Dr. Emily Baumrin: So as I mentioned before, you know, we have to work really closely with the dermatopathologist to make these diagnoses, to discuss subtleties in what they're seeing and how to connect it with the clinical presentation that we're seeing with the patient. And what's really unique about the cutaneous pathology services at Penn is that they are housed within the Department of Dermatology instead of within the Department of Pathology.

And this facilitates easy access and collaboration between the treating clinicians and the dermatopathologists. We attend the same case conferences. We can pop by and discuss a case very informally, and this really enhances clinical pathologic correlation and patient care. The other thing to note is the cutaneous pathology service is comprised of board-certified dermatopathologists, so they have expertise in cutaneous conditions beyond GVHD and they are able to offer a real breadth of testing beyond routine histology, including immunofluorescence, immunohistochemistry, and this allows us to really hone in on diagnosis for our patients.

And I think the main takeaway is that you may not see GVHD or some of its mimics every day for the dermatologists out in the community, primary care providers, or even at academic centers, but expertise is out there, and we remain a good resource if you need to contact us.

And just knowing the basics can get you the first step of the way to getting to these patients to the correct care.

Host: Thank you for that. And Dr. Munshi, last word to you. How would a physician contact you with questions about GVHD or refer a patient? And what would you like the key takeaways to be?

Dr Pashna Munshi: I'll start off with your last question. The key takeaways I think really is that this is a team effort. I think we need to have experts talking with one another. Dr. Baumrin and I are part of a larger chronic graft versus host disease group. And in fact, we meet once a month on Fridays, and we discuss cases and review challenging treatments through the National Institutes of Health, and other physicians participate.

So I think the main takeaway is that it's okay to not know what is happening, but reach out for help, and we will connect you with all our experts. And the best way to get in touch with me would be via email, and I'm happy to help anybody who has questions about graft versus host disease.

Host: Thank you both so much for joining us today and sharing your expertise for other providers. And to refer your patient, please call our 24/7 provider-only line at 877-937-PENN, or you can submit your referral via our secure online referral form by visiting our website at pennmedicine.org/refer. That concludes this episode from the specialists at Penn Medicine. I'm Melanie Cole.