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Immunopathogenesis of Hidradenitis Suppurativa

  • Authors: James G. Krueger, MD, PhD
  • CPD Released: 5/9/2022
  • Valid for credit through: 5/9/2023
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Target Audience and Goal Statement

This activity is intended for a global audience of dermatologists, surgeons, primary care physicians, obstetricians & gynecologists, and emergency medicine physicians.

The goal of this activity is to highlight our current understanding of the immunopathogenesis of hidradenitis suppurativa (HS), its multifactorial etiology, and the role of the interleukin (IL)-17 pathway in the inflammatory process.

Upon completion of this activity, participants will:

  • Have increased knowledge regarding the
    • Role of genetics in the development of hidradenitis suppurativa (HS)
    • Multifactorial etiology of HS
    • Key inflammatory pathways in HS pathogenesis


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  • James G. Krueger, MD, PhD

    D. Martin Carter Professor in Clinical Investigation
    Head of Laboratory for Investigative Dermatology
    Center for Clinical and Translational Science
    The Rockefeller University Hospital
    New York City, New York, United States


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    Medical Education Director, WebMD Global, LLC 


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  • Diana Lucifero, PhD

    Scientific Content Manager, WebMD Global, LLC 


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  • Leigh Schmidt, MSN, RN, CMSRN, CNE, CHCP

    Associate Director, Accreditation and Compliance, Medscape, LLC


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Immunopathogenesis of Hidradenitis Suppurativa

Authors: James G. Krueger, MD, PhDFaculty and Disclosures

CPD Released: 5/9/2022

Valid for credit through: 5/9/2023


Activity Transcript

James G. Krueger, MD, PhD: Hello, I'm Dr Jim Krueger, head of the laboratory for investigative dermatology at the Rockefeller University in New York. Welcome to this program, entitled "Immunopathogenesis of Hidradenitis Suppurativa."

So what is HS? Hidradenitis suppurativa is also known as acne inversa. It is an inflammatory disease that affects perhaps 1% of the population. The disease manifests in skin folds of mostly the axillary, the inguinal, the gluteal, and the perianal body areas. It starts in or around hair follicles with inflammation that evolves into painful nodules, abscesses, and pus-discharging tunnels, as well as potentially extensive scars.

Internal inflammation is also common and manifests as a series of comorbidities that I will be discussing a bit later. And due to the pain and purulent secretion, mobility may be limited not only by the presence of extensive pus discharge but also scarring that can restrict the motion of limbs. It's also a disease, as I will discuss, that is very impactful on the overall quality of life and is a burden on the medical system.

A new study has shown that if a patient is hospitalized with this disease, that the readmission rate is comparable to heart failure, such that at 180 days, nearly half of the patients that are hospitalized are readmitted usually for another complication of skin inflammation with HS.

So HS is a disease with global prevalence. We do not have good demographics on the disease because there's a lot of underdiagnosis of the disease. We do know that this disease is highly prevalent in skin of color, and thus is somewhat a disease of the underserved.

Now, the disease characteristics include the kind of pictures that I showed you for chronic inflammation that can be debilitating and can even impair function of the limbs.

The disease has onset typically after puberty in young individuals. Often, it's associated with smoking and obesity. And there is an important delay in diagnosis of this disease that can be as long as 7 to 10 years, because the disease is not normally seen by dermatologists early and it's misdiagnosed as an abscess or folliculitis, or furuncle assumed to be due to a bacterial infection. However, we do not believe this is a disease that is an infectious disease caused by bacteria. There are bacterial associations with the disease largely of anaerobic organisms.

So the evidence against bacteria is that bacteria aren't always present or can be cultured. HS is not known to be transmissible like many infectious diseases, and there's not a common pathogen. However, the arguments for bacterial involvement are that there are clinical signs such as redness, pain, fever, and pus that are clinical signs of infection.

The study of the microbial flora has identified several bacteria which can be pathogenic in certain contexts. There are species like Prevotella and others that are anaerobes that can be found in the tunnels. And that may be one of the difficulties in trying to establish cultures because anaerobes are difficult to culture frequently.

Then, of course, there are some clinical responses to antibiotics that are seen but with the problem that many of the antibiotics that are used also have anti-inflammatory properties. So the debate will go on.

So, before I go into more detail on the immunobiology of HS, I want to briefly discuss with you what we know about disease genetics. So, there is a genetic component in HS, but it has been defined in only a minority of patients where there is a family history reported. Within families, there have been mutations traced in a gamma secretase complex, but the exact relationship between this gamma secretase complex and the immune activation that's happening in this disease is not something that is very clear at the moment.

The gamma secretase mutations are present only in a very small number, 6%, of nonfamilial cases. We need a lot more work to try to understand what is the link between complex genetics across multiple different potential targets and the other underlying features, be they immunopathogenesis or the set of tissue structural changes that are happening in the disease.

It's also important to know that HS is a disease with high comorbidity rates: not only other inflammatory disorders, but it's associated with endocrine abnormalities, with cardiovascular mortality, with obesity and metabolic syndrome, and frequently, with depression. So this gives the view that HS is a disease of systemic inflammation.

And to reinforce that point, I'm showing you here a comparison of psoriasis, which we believe to be a systemic inflammatory disease, and HS for serum proteomic profiles. And the point I want to make from this is that while psoriasis is a broad inflammatory disease of the skin, the serum proteome for inflammation in HS is much larger than psoriasis, even though the amount of skin involved may be less.

And in particular, there's high expression, as you can see on the left, of lipocalin 2, TNF-1 beta, IL-6, and IL-8 that are much higher than they are in psoriasis.

So, what about the pathogenesis of early-stage disease? Well, here you can see a nodule with many hair follicles that are associated with it. A pathogenic model that was drawn 3 or 4 years ago for this disease suggests that it begins with follicular occlusion and dilation. It leads to swelling and rupture of hair follicles and then potentially to the bridging of hair follicles, forming sinus tracks.

Now, this model does not really include a major role for T cells and argues more for a role of innate inflammation and the inflammasome. However, the picture of pathogenesis really differs as one goes to later stages of disease during which dermal tunnels are present that can't be seen and they can be inferred from the ostia at the skin surface, which are the fusion of the tunnels with the epidermis.

So a little bit, looking for the pathogenesis of HS can be said to be looking under the light: where psoriasis we can see the disease very well at the skin surface; but HS there's a lot of subcutaneous pathology that I want to discuss. So even if we shine the streetlight on HS, we don't see a good part of the disease. And that's because with the advancement of disease, there's the formation of dermal tunnels which can be seen in histology here with the blue arrow, but also by ultrasound as these hyperechoic bands.

I make the point here that the epithelia that is associated with tunnels is that of a stratified squamous epithelia with some clear features that look like psoriasis. So there are really 2 parts to this skin disease. The first is there's a surface alteration, which gives us an appearance that looks like superficial psoriasiform epidermal hyperplasia. And then there are these epithelialized tunnels and tracks that are deep in the dermis with leukocyte infiltrates that are both superficial and deep in this.

Now, where is inflammation occurring in HS? Well, it's not so visible at the surface, except for the drainage of pus. If we applied Doppler ultrasound to measure where inflammation is occurring, it's actually occurring half a centimeter or a centimeter under the skin centered around the dermal tunnels that you see with the red and yellow color for a Doppler image of HS.

Now, we've made some point in trying to characterize the features of both the surface transition and the features of tunnels. And I want to just say here that the tunnels are an epithelial structure that is very much like the epidermis. There are even melanocytes, which are on the appropriate basal surface of these. And there are heavy infiltrates of both neutrophils, seen with elastase, and T cells, seen with CD3. You can appreciate that the cases with tunnels really have even more infiltrates than the cases without tunnels.

Now, there is a complex pathogenesis of this disease, which in some patients has a genetic basis -- gamma secretase mutations that are present -- but in the majority of patients, there's not a clear genetic link of this. There is a microbiome dysbiosis that goes to many gram-negative organisms.

Keratinocytes are involved, B cells are involved, and then innate and adaptive cells are involved, that includes B cells making antibodies, T cells, and dendritic cells that interact. And putting this whole picture together into a cohesive pathogenesis is difficult at present. So we tend to look at the individual elements.

Now, we've taken a systematic approach to trying to profile hidradenitis by standardizing the place that biopsies are done. So we look at lesional skin, perilesional skin, which is defined as 2 cm away, and non-lesional skin, which is defined as 10 cm away. We have done an RNA-Seq study that I'm showing you data for here, which compares the mRNA expression to a healthy control skin of the same regions.

What you can see even for non-lesional skin at the bottom left is there's an inflammatory signal that has neutrophil involvement in the CD177. As we progressed to perilesional and lesional skin, there are now thousands of genes that become dysregulated. The inflammatory picture in perilesional and lesional skin is very similar, and you start to see many S100 proteins as well as neutrophil activation products.

In the upper right is an analysis by pathways for ingenuity pathway analysis. And the top pathway that's picked up in this disease is neutrophil degranulation and neutrophil activation suggesting that the core of this disease is about neutrophilic inflammation.

Now, we've seen that inflammation in patients like this can be subdivided by the level of lipocalin expression. And we have cases which are high in expression of lipocalin and low. The low expression is inflammatory above background, but the lipocalin too high is a broad inflammatory signature that goes with S100 proteins and many neutrophil chemoattractants being very highly expressed. And you see a very similar picture in both lesional and perilesional skin.

If we take the lipocalin too high and look at the expression of neutrophil chemotaxis products, what you see is these are very high in both perilesional and lesional skin.

Now, if we think about pustular psoriasis, there is a pathway which is stimulated by IL-17, but involves the amplification of the signal through IL-36, IL-17C within epidermal keratinocytes. And because HS is a pustular disease, we wanted to look at expression of these elements in HS. So this is now the non-lesional, perilesional, and lesional profiling in comparison with psoriasis, which are the red bars at the bottom that shows high expression of chemokine CXCL8 that would cause neutrophils to appear. IL-17A, IL-17C, and IL-17F are all at levels that are higher in psoriasis, and there's high IL-36 expression.

So we think that the same pathway that's playing out for the pustular process in pustular psoriasis may take place within the epithelial tracks in particular in HS, where we have seen IL-36 and IL-17C expression and chemokine gradients for neutrophil-attracting chemokines that would bring neutrophils towards the lumen of this structure.

And if we look at activated neutrophils, as you can see at the right with staining, you can see not only are there many neutrophils in the lumen, but there are extracellular traps or nets that are being formed that indicate neutrophil activation.

So, if you see an ostia with pus at the surface, underneath this, there is a connection to the dermal tunnels. And we believe that these dermal tunnels through the actions of IL-17 and the amplification with IL-36 and IL-17C lead to the creation of a neutrophil pump, where the surface pus reflects the activity of the underlying epithelia in the tunnels.

Now, the treatment of HS is currently very challenging. In fact, there are a number of different therapeutic approaches that are taken. Some are medical and some are surgical. Because there is a dysbiosis, antibiotics are often chosen for this disease. But some of that is also the confusion with this potentially being an infectious disease, which I don't believe that it is. Then you can see a number of anti-inflammatory medications that are given, 1 biologic which is a TNF inhibitor is approved for the treatment of this disease, and then there's frequently incision and drainage, and other surgical approaches to try to diminish swelling and drainage from these lesions.

Now, there's a lot of unmet need here because even what may be the best treatment we have, which is a TNF antagonist that's FDA approved, leads to a lot of primary failure. Only about 50% of people respond well. And then there's secondary failure in the majority of people such that you can't control this disease predictably over a long period of time.

So if you ask, are patients satisfied with what is available to treat this disease now? About half of patients are dissatisfied with the current treatment approaches, and that's primarily because there's poor efficacy for virtually this entire range of things that we have, along with quite disabling surgery if one goes for surgical excision.

So, what are the pathogenic cytokines or candidates for pathogenic cytokines in HS? The cytokine milieu of HS is very complicated and even more than psoriasis or atopic dermatitis. And the evidence for the pathogenic contribution of different cytokines has to come from translational studies in which antagonists are actually tried in people with the disease.

And based upon clinical testing, I think one can pretty strongly implicate TNF, IL-1 alpha, and IL-17 isoforms IL-17A and IL-17F, with the potential amplification downstream of these signals through IL-17C and IL-36.

So the data that we have that implicate IL-1 are first, an early study from 2015, that was done with anakinra, which is an IL-1 receptor antagonist -- it blocks out IL-1 alpha and IL-1 beta. And in this study, which involved 10 patients in the placebo group and 10 patients in the drug treatment group, there were reductions in a disease activity score that you can see here in the blue line.

And the acquisition of a HiSCR, which is a 50% improvement in nodules, in about 60% to 70% of patients who were treated with anakinra, and with a statistical difference between the treatment group and the placebo group. So that puts IL-1 on the map as a potential cytokine.

The IL-1 antagonists became more specific when an IL-1 alpha antibody was tried in HS patients that were either failures on adalimumab or not eligible for adalimumab. What was seen in this 12-week study is that 60% of patients attained the HS clinical response (HiSCR), or 50% reduction in nodules. And you can see here over time, the decrease in the number of nodules that's happening, which is greater with IL-1 alpha antagonism compared with placebo control.

That was a study using quite high doses of an IV drug. The same drug is now called bermekimab, and this has been tried in an open-label study with smaller doses of subcutaneous antibody. And it was tried in patients who were both TNF naive and TNF failure patients. You can see here around 50% improvement in the inflammatory lesion count with both experienced and non-experienced patients. If one uses HiSCR as a measure of activity, one sees that there is a statistical significance for disease improvement over the baseline condition, but there was no placebo in this study.

Now, since I've made the case that there are similarities of this disease to pustular psoriasis and there's upregulation of IL-36 and IL-17C as one of those other IL-17s, there has been the question of whether IL-17 might be a driver of this process in HS.

So there are several antagonists that have been given to block different IL-17 isoforms. They go from secukinumab and ixekizumab that block IL-17AA and AF to brodalumab, which blocks the IL-17 receptor and hits all of the IL-17 isoforms including IL-17C, and bimekizumab which is an antibody that blocks IL-17AA, AF, and FF.

Now the data for what happens when patients are in a clinical trial and given an IL-17 antagonist is shown here for secukinumab. This was a small, open-label study in which 9 patients were treated with secukinumab at a standard psoriasis dose. And you can see that 7 of the 9 after 24 weeks have a disease improvement in the inflammatory lesion count, which is reflected in the HiSCR at week 24.

I want to say here we eagerly await phase 3 trials that are now going on with secukinumab to see whether these kinds of results will be repeated in randomized controlled trials in a large number of patients with this disease.

There has been a published phase 2 study with bimekizumab that used a reference adalimumab arm, but didn't perform statistical comparisons between these as there is a point of reference.

What you see at the end of 12 weeks of treatment, blocking IL-17A and F with bimekizumab gives a HiSCR or 50% improvement response that's more or less the same as adalimumab, which is the only approved drug. However, if we go to a higher amount of improvement and now demand 75% reduction in inflammatory nodules, then what you see is that blocking IL-17 seems to have a higher number of patients that respond compared with blocking TNF. Both of these are clearly better than the placebo that was given in the study. Here too, we eagerly await the results of phase 3 trials that are now going on that's exploring the activity in HS in a large number of patients.

We have conducted a small, open-label cohort trial with brodalumab, which is the broadest of all of the IL-17 blockers, because it binds IL-17RA and prevents signal transduction. What you can see across this 24-week study is that at some point, all of the patients achieved a 50% reduction in inflammatory nodules, but only about 50% to 60% achieved a complete elimination of the nodules that were present.

We reduced deep dermal inflammation by blocking IL-17 with this molecule. You can see here, the Doppler ultrasound before and after treatment where there's no discernible increase in blood flow around the tunnels. We've also seen a quite marked reduction in nodule counts. And here at the bottom, you can see a group of patients that have no nodules that are residual and the draining tunnel count in the IHS4 score which takes into account draining nodules shows very marked and significant reductions by blocking IL-17.

So to sum up, HS is potentially the most impactful dermatological disease with a large number of affected individuals, and treatment is very difficult at present. There is a complex pathogenesis by cellular and molecular profiling along with a complex number of environmental associations, as well as a genetic contribution.

We are just beginning to understand disease heterogeneity, which may go to the presence of different endotypes that I have suggested, such as lipocalin high vs lipocalin low.

And there is, I think, some clear potential for future therapeutic targeting by blocking specific cytokines that include TNF, IL-1, an IL-17. I just want to point out that there's an interaction between TNF and IL-1 and IL-17, and then that these 2 sets of cytokines synergized are linked to very, very high-level production of inflammatory products that regulate neutrophil trafficking and other features of inflammation in epithelial tissues.

Finally, I think our treatment goal for this disease has to be to stop progression from early-stage disease, at which there are only nodules, and prevent the formation of tunnels because tunnels are a neoplastic structure that likely persist indefinitely, but have the amount of inflammation that they control, which appears to be modulatable at least through IL-17 blockade.

Thank you for participating in this activity. Please continue on to answer the questions that follow and complete the evaluation.

This is a verbatim transcript and has not been copyedited.

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