Donna Culton, MD, PhD: The Evolving Understanding of Blistering Disease

One of the hallmarks of blistering disease is, of course, the blisters, but how do you identify the disease when that signature tell is absent? Donna Culton, MD, PhD, professor of dermatology at the University of North Carolina at Chapel Hill, focused on this and other aspects of blistering disease in her session at Maui Derm NP+PA Fall 2024, held September 15-18, 2024, in Nashville, Tennessee.

This transcript has been edited for clarity.

Dermatology Times: Tell us about your session on blistering disease presented at Maui Derm NP+PA Fall, and why is it important to provide this education to an audience of dermatology advanced practice providers?

Donna Culton, MD, PhD: This session is a session that's case-based, which I think, a lot of times, hits home a little more than just a straight didactic session because we all have these difficult cases that come into our clinic and struggle with what's the best way to diagnose them. First to recognize the disease, but then to make an accurate diagnosis and consider all the treatment options, which, up until the last 10 years, we didn't really have a lot of treatment options. We're having more and more treatments come out, and so the main point of this session is to really, through cases, highlight some of the new things that we're learning about blistering disorders in terms of their clinical presentation, the diagnosis, but also, most importantly, the management.

Advanced practice providers really are the first line for many of our patients, seeing some of these very challenging patients right out of the gates. And so the thought is that we all can learn to recognize the diseases better, and I think feel more confident about the diagnosis. Many of the treatments are high-risk, and so you really want an accurate diagnosis, and we all feel much better about starting treatments when we have a confirmed diagnosis for these patients.

DT: Your presentation focuses on the recognition of atypical clinical presentations of some diseases, such as pemphigus. Why did you feel this was important to include?

DC: These cases that I presented were my own cases and, so, very challenging cases. Even during my training, right? We think of blistering disorders as presenting with blisters, but we're learning more and more that that is not always the case. And so both with pemphigus, and with pemphigoid even moreso these days, many, many reports of atypical clinical presentations that may not present with the classic blisters.

I think we as practitioners of dermatology, when we see a blister, our mind is going through a lot of the differential diagnosis, but especially to blistering disorders, because that's how we're trained to recognize these rare disorders. But when they present without blisters, they can be really challenging. And so there's a lot of data out there now that patients with atypical clinical presentations have a delay in diagnosis and then therefore a delay in treatment. And as we're learning more with pemphigus and the use of rituximab, the earlier the treatment has started, the more effective it is in inducing a durable remission for these patients. So diagnosis is really key and, of course, you won't diagnosis it if you don’t think of it, so recognizing these atypical forms is critical. And so I show a lot of pictures of what these atypical forms might look like, but they're out there in the literature too, and again, just being increasingly described in the medical literature.

DT: What new insights can you share on the pathophysiology of some of these blistering diseases?

DC: When it comes to pemphigus, we're learning more. The old dogma pretty much still stands. It's an antibody-mediated autoimmune disorder where the antibodies themselves create the blisters in the skin. We used to think of it, and it still is, really a systemic disease where the autoreactive B cells are kind of the main player. So the idea that rituximab works pretty well for these patients, I think what we're learning about pemphigus, specifically, in terms of some new things about pathophysiology, is really that there may actually be autoreactive B cells in the lesional tissue, which I think we really had not understood for a long time, and that's some newer data, kind of on the basic science side, but taken from patient tissue, and then having some clinical implications.

We all have some of these patients with pemphigus who have recalcitrant, stubborn lesions in the exact same spot. Or when they get a flare-up, the lesions come in the exact same spot. And so I think it definitely fits with what we see clinically, and is changing how we use our treatment. So rituximab, obviously, FDA-approved for pemphigus vulgaris, and standardly given intravenous but there are some newer reports that intralesional rituximab can be helpful. This is not being done routinely at all, but … again for a disease that we thought we knew everything about, we're still learning more about the pathophysiology.

And then in bullous pemphigoid, we've known for a long time that even though it's antibody-mediated, there's a lot of inflammation in the tissue there, both on histology and again, clinically, we see the inflammation in the patient's skin, which is why topical steroids can be really helpful for patients with kind of localized forms of the disease, or patients who want to avoid systemic steroids. But we're learning more about different pathways, inflammatory pathways, that are upregulated in terms of type 2 inflammation, and really how that is opening the door to newer medications that are coming down the pipeline for these patients and safer medications, especially for our bullous pemphigoid patients, [who] are medically fragile, elderly patients most of the time.

DT: One of the cases highlighted immune checkpoint inhibitor-induced bullous pemphigoid. Can you talk about the difference between drug-induced and drug-triggered disease?

DC: We see a lot of patients that come in, of course, with bullous pemphigoid. They're elderly. Many times they're on a slew of medications. It's hard to know when they started these medicines, and so we're always taught, of course, with any skin reaction, to think about drugs. And for a long time, we thought about drug-induced forms of pemphigoid. But I would say, in the last 5 to 10 years, there's a clear understanding that there are 2 drug-associated forms of pemphigoid. The gliptins are 1 which I cover a little bit, and that's a treatment for diabetes. And there is a clear association with patients who are on the gliptins that they're at risk of pemphigoid.

The other one is the checkpoint inhibitors. And for the checkpoint inhibitors, these medications, of course, used to treat malignancy. And part of how they work is they kind of open the gates for autoreactive cells to be unleashed. And so it brings up the concept [of], we think of drug-induced forms of disease, that we can just stop the medication, and potentially the disease gets better. But what we're realizing, especially with checkpoint inhibitors, is that may not be true, and it may end up being a drug-induced form, or drug-triggered form, where the drug has let the autoreactive B cells out. And even if you stop the drug, the autoreactive B cells are out there running amok and there's no stopping that once it's already happened.

Drug-induced, meaning maybe if you stop the drug, it would get better. Drug-triggered is like now you just have pemphigoid, and you can stop the offending medication all day long, but it really doesn't change the fact, and I think we're just still really learning, to be honest, how these different diseases play out, the different drug-associated forms. But certainly for checkpoint inhibitors, most patients do end up having to stop their checkpoint inhibitor, which is really unfortunate, because of course, oftentimes those are lifesaving treatments for these patients with malignancies, and so we're looking for better ways to help patients treat through so we cover a little bit of that, of what's out there in terms of treating these patients that are, again, now even more medically fragile because they have malignancy, and we're trying to find treatments that don't further suppress the immune system, but also allow the checkpoint inhibitor continue to work.

DT: What emerging treatments are you most excited about in the blistering disease space?

DC: We're kind of having a moment in blistering disorders, which is really exciting. I think all during residency, there was nothing new coming and nothing being studied and now there [are] many clinical trials. In fact, I think it can be hard to enroll because there [are] not enough patients to be in all these studies, which is really exciting for our patients, right? Because any trials mean new medications coming to market, hopefully. I think 1 option, if we talk about both pemphigus and pemphigoid, they're antibody-mediated, so any medications that are really aimed at the antibodies themselves can have a high impact, and could be part of an armamentarium of different medications that we might use.

We're always looking for things that are lower-risk for our patients in terms of safety. And so the FcRn inhibitors have been out there for a while now being studied in pemphigus and pemphigoid. We're looking at a lot of how we design the trials to really show what these medications can do, but they seem to have a good safety profile and a pretty early onset of efficacy, which is pretty exciting.

In terms of pemphigoid, there [are] a lot of new treatments coming out that are really aimed at the inflammatory cascade, particularly the type 2 inflammation, and so really excited to see as dupilumab is finishing up its clinical trials in pemphigoid, and we should have the data — it should be out soon — and so that would be really exciting. It would be, if it works, a game changer for how we treat pemphigoid.

DT: Is there anything else you’d like to add?

The only other thing really to highlight is, we're trained to think about these autoimmune blistering disorders when we see blisters and the only other thing I sometimes see in my clinic is a patient who has blisters, who has had multiple direct immunofluorescence (DIF) biopsies … and it very clearly becomes apparent that the patient does not have an autoimmune blistering disorder. And so I would challenge everyone to think and remind themselves of other diseases that can lead to blisters in the skin. We do cover DIF-negative mimics of autoreactive blistering disorders, but I think that, at some point, if you've done multiple, multiple direct immunofluorescence biopsies, [and they are] negative, or ELISAs [are] negative, to really challenge yourself to think about what other things that we see all the time can have a blistering variant.

Reference:

Culton D. Blistering diseases: what’s the diagnosis?! Presented at: Maui Derm NP+PA Fall; September 15-18, 2024; Nashville, Tennessee.