Updates in HS: Dr Rosenblum on Pathophysiology

In this podcast, Michael Rosenblum, MD, reviews the pathophysiology of hidradenitis suppurativa and a possible immune activation signature that could potentially identify patients who may respond to TNF therapies.

Dr Rosenblum is an associate professor with the department of dermatology at the University of California San Francisco.

Visit JCI Insights to read the study

Transcript

Melissa: Hello, everyone. Today, I’ll be speaking with Dr Michael Rosenblum about the pathophysiology of hidradenitis suppurativa. Dr Rosenblum is an associate professor with the department of dermatology at the University of California San Francisco.

He recently published the paper “Immunopathogenesis of hidradenitis suppurativa and response to anti-TNF-α therapy” with his colleagues at UCSF in JCI Insight. In this study, they compared lesional and nonlesional skin of patients with HS to controls as well as patients with psoriasis to identify immune pathways in the disease and biomarkers for treatment response.

Thank you so much for joining us today, Dr Rosenblum. What is known about the pathophysiology of hidradenitis suppurativa?

Dr Michael Rosenblum: The pathophysiology of HS has been somewhat controversial over the past several decades, and it’s not fully fleshed out, I would say, at this point. But my understanding and my thinking of this disease is that it is a disease of hair follicular occlusion.

I think that hair follicles in certain areas of the body, the intertriginous areas of the body, in HS patients, the hair shafts are predisposed to not be able to exit the follicles properly. This may be from increased proliferation of epithelium at the upper portion of the follicle. That creates, basically, a cyst, a hair follicle cyst, and that cyst then ruptures.

Many people have these ingrown follicles, and we resolve them. However, HS patients, the second hit in the pathophysiology is they’re unable to resolve the inflammatory response that is incited after one of these follicles occlude, and that’s because there’s a defect in regulation, immune regulation around the follicle.

Then that inflammatory response then becomes amplified as it’s unable to resolve, and the inflammatory cascade just cycles out of control, eventually ending up in fibrosis.

The two main hits are inability of hair shafts to properly exit the follicles in intertriginous regions and a defect in immune regulation once these follicles rupture. That is the basic pathophysiology of HS, as I believe it.

Melissa: Why has it been so hard to characterize the disease and identify targets for treatment?

Dr Rosenblum: That’s a really interesting question. I think it’s quite a prevalent disease. It’s a very morbid disease. For quite some time, there has not been a huge focus of both research dollars and commercial dollars spent by pharma companies to try to understand and treat this disease.

I think that’s a multifactorial rationale as to why that’s occurred. Part of it is because HS is a very deep process. Unlike psoriasis, which affects the very superficial skin–it’s a little easier to study because it’s a little easier to access–these inflammatory abscesses and sinus tracts that you see in HS patients are quite deep, and they’re quite painful.

Really, accessing them is a little more difficult, and understanding the biology is a little more difficult based on how deep this disease is.

I also think that the technology has not been...Only till recently have we really had the technologies where we...When we do get skin from HS patients really have the technology to understand the cellular and molecular pathways that are active in this disease have only recently become available.

Again, it’s multifactorial, but I think it’s the nature of this disease and where it happens, where it affects people, the depth of this disease, as well as limitations in technology previously haven’t really enabled us to do a deep dive into understanding how this disease happens.

Melissa: The study on immunopathogenesis of HS, you did try to highlight some of that. Could you elaborate on those findings that you were able to identify with the immune cells in both lesional and nonlesional skin?

Dr Rosenblum: What we now know is the immune system is constantly being regulated. We used to think that the immune system was really in a standstill. Then when you wanted to mount an immune response, the analogy is, put the gas on the accelerator, and that would generate an immune response. That’s what we try to do in the context of vaccinations.

When you get an infection and try to fight off infection, the old way of thinking about this was that the car is basically parked and then you put the gas on to try to generate an immune response to fight an infection.

We now know that the immune system is always on. The car is always moving. It’s just being regulated constantly by the brake. The analogy is that you’re driving the car. Car is always moving slowly. But sometimes the gas goes on. You go faster. Sometimes you push the brake and go slower, but the car is always moving. The brake is always on.

That’s to say that in normal, healthy individuals, the immune system is being constantly regulated, and if you take off that regulation, people’s immune systems really are active and start attacking cells.

What we found in HS patients is that this component of the immune system, the regulatory component, the component that’s always regulating inflammation, is defective, and we found that, actually, in nonlesional skin.

When we look in nonlesional skin – this is clinically appearing normal skin in HS patients – and we ask whether these regulatory cells are acting properly, we found they’re not, that they’re defective in various ways.

There’s multiple populations of these cells that are defective, such that when a hair follicle occludes and you develop these follicular occlusion cysts that rupture, the ability to regulate that and suppress that is completely altered. We think that in nonlesional skin and probably skin throughout the body in these patients, there’s really a defect in the regulation.

In this paper, we identified two major cell types that are responsible for regulating inflammation in the skin and that those cells are not working properly in nonlesional HS skin really suggests that why these patients are predisposed to have this uncontrolled inflammatory response.

Melissa: Could you talk a little bit about identifying that immune activation signature and what that means for future developments of HS therapies?

Dr Rosenblum: One of the key differences between HS and psoriasis is that there’s a really big B cell infiltrate into HS, and you don’t normally see B cells and plasma cells in psoriatic skin. This is one of the many things that differentiate these diseases.

One of the most surprising findings in our study was that when patients went on adalimumab, we saw a suppression in this B cell response. It was pretty selective. We’re not fully understanding how blocking TNF-alpha in this disease actually suppresses B cells, but it actually has been shown in other translational studies as well.

I don’t think we really understand the mechanism behind that. Suffice to say we found that treatment with a TNF-alpha blockade actually suppresses really the B cell component and the plasma cell component in HS lesions. Not everyone, obviously, responds to that agent. It’s probably about 30 to 40% effective.

What was interesting is the people that did respond had the most mild B cell infiltrate to begin with. The way that I think about it is that if, in HS skin, TNF-alpha blockade is primarily suppressing the B cell response and your B cell response is not too high to begin with, those are the patients that really do respond to anti-TNF-alpha therapy.

It’s like this is the rock that it pushes. If the rock is really small, it’s able to push it pretty effectively, but if the rock is too large, then it doesn’t really have an effect. I think that was one of the most surprising and major findings in our study, and I think it opens up a lot of questions.

One of the biggest is “Is targeting B cells through more effective or more B-cell-directed therapies going to be efficacious in HS?” We do have directed B cell therapies out there right now. We have B-cell-depleting agents, and we have agents that specifically target B cell signaling.

One of the big questions that has come out of our work is “Are any of these agents potentially going to be effective to treat HS given that anti-TNF-alpha seems to be blocking this response and some patients do respond and the patients who respond have this B cell signature, albeit a lessened B cell signature?”

Melissa: Was that B cell signature based on disease severity?

Dr Rosenblum: Yeah. Clinical disease correlating with the B cell signature, it was. It was the patients that had pronounced B cell signature but were clinically let’s severe. Let’s say their clinical score were less severe. Those are the patients that responded well, so it did correlate. That B cell signature, at least in the patients that responded, did correlate with clinical severity.

Melissa: Why did you compare HS immune dysregulation to psoriasis?

Dr Rosenblum: I think that, honestly, that’s the main reason why we want, they’re very different diseases, as I just outlined, and we’ve known for quite some time that they’re very different diseases.

However, a lot of pharmaceuticals that have been shown to be efficacious in psoriasis, there’s a large attempt to just pivot those medications over into HS. I understand that because there’s a lot of development, the clinical and drug development, that has to happen to develop a new drug for HS.

One of the easier roads is to just pivot a drug and just say, “We’ve already developed this for psoriasis. It seems to work in psoriasis. Let’s see if it’ll work in HS.”

Because there’s that movement out there by many pharmaceutical companies that have drugs in psoriasis to move to HS, we really wanted to understand whether any of the drugs that are currently available to treat psoriasis might work. There might be a good rationale to treat HS.

That’s one of the main reasons why we compared HS and psoriasis in this study to inform all of the individuals out there that are thinking about taking psoriasis drugs or drugs developed for psoriasis and seeing if they’ll work in HS.

Melissa: Will this form of molecular profiling become a part of personalized medicine for patients with HS?

Dr Rosenblum: It’s a goal. I mean, that really is the goal. I think this is the first of hopefully many studies that will try to get at this question, and I think we’ve just opened a bunch of doors but clearly don’t understand this in its entirety.

I think HS is a very heterogeneous disease. It’s heterogeneous with respect to clinical severity. It’s heterogeneous with respect to infiltrating cell types.

It’s very heterogeneous, and I think trying to identify different types of patients or subtypes of patients that will respond to different therapies is going to be the Holy Grail. This is personalized medicine, so you’re not basically taking risk and wasting precious time by treating patients with therapies that aren’t going to be effective for their specific disease.

I do think this type of work and the type of doors we open might be able to pre-stratify patients. For example, we identify a signature in the skin that predicts response, to some degree, of patients that will respond to a TNF-alpha blockade.

I think a larger study needs to be performed, taking patients with the signature and then stratifying them to get the drug or not and then see whether patients with this signature prospectively have a better response rate to TNF-alpha blockade. I think that’s the next study that I think should be undertaken based on the results that we just published.

Melissa: In your opinion, what other research is needed to expand the understanding of HS pathogenesis and therapeutic targets?

Dr Rosenblum: I think two things. It’d be really nice to have a better animal model of this disease. We’re working hard to do that, and we have funding from the US government to do that, actually. I think that’s a key step.

One thing that catapulted the translational efforts and drug development in psoriasis was mouse models of psoriasis that don’t recapitulate every aspect of disease but recapitulate many aspects of the disease. That allowed an accelerated drug development timeline because many of these things could be tested in animals and pathways could be worked out.

Then you just have to make sure those pathways are active in the psoriatic patient, and then you have your scientific rationale, your proof-of-concepts, or your reason to believe that this drug could work. HS doesn’t have that yet. We don’t have a really good animal. We don’t have an animal model, and that’s a problem.

There, you’re basically reliant entirely on clinical specimens and clinical tissue to do the translational work, and that’s difficult because this is a very painful disease where patients don’t love having biopsies of their axilla and groin when they’re highly inflamed and very painful. I think establishing a really robust mouse model of HS is a huge priority in terms of advancing the science.

I also think there’s just got to be more clinical work done. There just has to be more funding by both pharmaceutical companies and the government or private agencies to just enroll patients to get clinical samples so we can just continue to do this type of work.

That will allow us to develop all kinds of assays with human tissues that can better understand the disease pathogenesis but also help test novel therapies.

Melissa: What key takeaways would you like to leave our audience with?

Dr Rosenblum: I think that most dermatologists understand that HS can be a very debilitating and severe disease and that we need better treatments for these patients. I think we’ve started to understand the molecular underpinnings of this disease and that the more we study this disease and better try to understand this disease, I think the quicker we will have better therapies for these patients.

I do know now that a lot of drug companies are interested in HS. I think there will be more available options out there. I just think we have to be very smart about which medications we’re going to attempt in this disease and to treat patients with this disease in these clinical trials.

That’s going to take some more translational research like the study that we just published. More work in this area is needed, but I think it’s exciting times.

Melissa: Thank you so much for taking the time to do this today.

Dr Rosenblum: Yeah. Thanks, Melissa.

Melissa: If you have any questions or comments for Dr Rosenblum, please submit them in the feedback box below. Thank you.