Inflammatory, Auto-inflammatory, Systemic and Follicle Research
Is Mechanical Stress an Important Pathogenic Factor in Hidradenitis Suppurativa?
Synopsis:
In summary, we present a patient with inflammatory lesions, resembling HS, at an ectopic location free of apocrine sweat glands and probably induced by a leg prosthesis. We argue that predilection sites of HS are not characterized by the presence of apocrine sweat glands but instead by mechanical friction and a warm humid, occlusive microclimate favorable to bacteria.
Hidradenitis suppurativa (HS) is a chronic of recurrent, inflammatory, follicular disease that usually presents after puberty with painful deep-seated, inflamed lesions in the inverse skin areas of the body. It has been hypothesized that mechanical pressure or friction is a risk factor for HS. We describe the case of a man with a lower leg amputation who presented HS-like lesions on his leg stump after wearing a leg prosthesis. Although pilonidal sinus-like disease could not be excluded, we diagnosed him with HS-like lesions, induced by prosthesis-related friction. We argue that this case supports the concept that mechanical friction and a warm humid microclimate by occlusion contribute to HS development.
Research Synopsis:
https://pubmed.ncbi.nlm.nih.gov/22379963/
Full Research Circulation:
https://onlinelibrary.wiley.com/doi/full/10.1111/j.1600-0625.2012.01443.x
Intrinsic Defect in Keratinocyte Function Leads to Inflammation in Hidradenitis
Synopsis:
In this study, we observed an increased frequency of functional CD4+ T cells secreting IL-17 or IL-22 in the blood of patients with HS compared with healthy donors (HD). However, we did not observe an increased frequency of infiltrating CD4+ T cells secreting IL-22 in HS skin lesions, but we found an increased frequency of infiltrating CD4+ T cells secreting both IL-17 and IFN-γ compared with healthy skin. Transcriptome analysis performed on whole lesional skin confirmed these results. We showed that keratinocytes isolated from HFs of patients with HS presented a distinctive pattern of AMP expression. They constitutively exhibit an inflammatory profile. After pattern recognition receptor stimulation, these cells produced higher amount of IL-1β leading to an increased production of proinflammatory cytokines. This profile severely contrasts with keratinocytes from HD. Globally, these results point out a primary dysfunction of keratinocytes from patients with HS characterized by a defect in enhancing a tissue protective response, but rather a chronic inflammatory response, to microbial products leading to a perpetual inflammation at sites of infection in skin lesions.
Full study:
https://www.jidonline.org/article/S0022-202X(16)31247-7/fulltext
Neutrophil extracellular traps, B cells, and type I interferons contribute to immune dysregulation in hidradenitis suppurativa
Synopsis:
Implicating the immune system in hidradenitis suppurativa
The cause of the painful skin condition hidradenitis suppurativa (acne inversa) is unknown. To better understand pathogenesis of this debilitating disease, Byrd et al. examined blood and lesional skin of patients and healthy controls. They observed prominent neutrophil extracellular traps (NETs), plasma cells, autoantibodies, and a type I IFN signature in patient samples. Inflammation and netting neutrophils may promote B cell activation and autoantibody secretion, and all of these mechanisms may contribute to tissue damage. These results suggest that multiple arms of the immune system are dysregulated in hidradenitis suppurativa and could be potentially targeted in new therapies.
Abstract
Hidradenitis suppurativa (HS), also known as acne inversa, is an incapacitating skin disorder of unknown etiology manifested as abscess-like nodules and boils resulting in fistulas and tissue scarring as it progresses. Given that neutrophils are the predominant leukocyte infiltrate in HS lesions, the role of neutrophil extracellular traps (NETs) in the induction of local and systemic immune dysregulation in this disease was examined. Immunofluorescence microscopy was performed in HS lesions and detected the prominent presence of NETs. NET complexes correlated with disease severity, as measured by Hurley staging. Neutrophils from the peripheral blood of patients with HS peripheral also displayed enhanced spontaneous NET formation when compared to healthy control neutrophils. Sera from patients recognized antigens present in NETs and harbored increased antibodies reactive to citrullinated peptides. B cell dysregulation, as evidenced by elevated plasma cells and IgG, was observed in the circulation and skin from patients with HS. Peptidylarginine deiminases (PADs) 1 to 4, enzymes involved in citrullination, were differentially expressed in HS skin, when compared to controls, in association with enhanced tissue citrullination. NETs in HS skin coexisted with plasmacytoid dendritic cells, in association with a type I interferon (IFN) gene signature. Enhanced NET formation and immune responses to neutrophil and NET-related antigens may promote immune dysregulation and contribute to inflammation. This, along with evidence of up-regulation of the type I IFN pathway in HS skin, suggests that the innate immune system may play important pathogenic roles in this disease.
Research circulation link:
Hidradenitis Suppurativa: From Pathogenesis to Diagnosis and Treatment
Synopsis of Research:
Etiology Auto-inflammatory
Many previously accepted models of HS pathogenesis are being challenged. It is now believed that HS is a systemic inflammatory disease of multifactorial basis, possibly due to auto-inflammation 53.
It was formerly hypothesized that the disease originated in apocrine-bearing locations of the body, such as the groin and anogenital and axillary regions. However, the inframammary region, neck, trunk, and thighs are frequently involved as well 7. These areas experience recurrent friction, perhaps supporting the role of mechanical stress in the development of disease. Additionally, it was previously theorized that the first step in HS disease progression was the occlusion of the follicular infundibulum due to hyperkeratosis of adjacent epithelium. This hyperkeratosis was thought to act as a nidus for secondary infection, which caused the subsequent massive local inflammation associated with classic HS lesions 48, 54. Although follicular occlusion is paramount in the manifestations of HS, the instigating mechanism of occlusion is controversial. It has been hypothesized that these inflammatory events are instead secondary to an underlying aberrant inflammatory state in patients with HS instead of the primary cause of the disease 55.
Although the driving force behind the development of HS lesions is unknown, recent studies have proposed various theories to describe the instigating pathology. One study observed the basement membrane of lesional and clinically uninvolved skin and found abnormal epithelial support and basement membrane surrounding the follicular junction in lesional tissue based on periodic acid-Schiff (PAS) histologic staining. These findings suggested that individuals with HS may have an underlying anatomic defect in the basement membrane predisposing to secondary infections 56. Blok et al. similarly evaluated perilesional biopsies in patients with HS compared to healthy controls. Contrary to the previous findings, this study found neither a significant difference in PAS staining nor a difference in many other basement membrane constituents between patients and controls. However, this study observed significant upregulation of integrins α6 and β4 (signaling molecules with adhesive properties) within the sebaceous gland of HS patients compared to controls. The role of these integrins in HS is unclear at this time 57.
Additionally, it is known that keratinocytes and neutrophils play a role in the secretion of pro-inflammatory molecules in HS 58. Hotz et al. proposed that abnormal keratinocyte function plays a role in HS development. Compared to controls, keratinocytes in HS lesions showed a diminished inflammatory response to muramyl dipeptide, a pathogen-associated molecular pattern (PAMP) inflammatory antigen 59. Keratinocyte malfunction further suggests structural and molecular abnormalities allowing for follicular occlusion and disease progression. Although the precise cause of the follicular occlusion remains debated, cellular markers and other immunologic sources of inflammation are important topics of discussion in the ongoing search to determine the etiology of HS.
In summary, overarching themes of inflammation and abnormal cellular activity appear to provide the appropriate environment for the progression to HS clinical features. It is probable that many factors allow for altered cellular barrier mechanisms and anomalous secretion of pro-inflammatory cytokines in the progression to classic HS symptoms 48.
Inflammation in hidradenitis suppurativa
HS is a systemic inflammatory disease, and auto-inflammation is suggested to play a role in disease pathogenesis. This theory was bolstered by the association of comorbid autoimmune and inflammatory diseases, abnormal biochemical findings, and an infiltration of innate and adaptive immune cells within both lesional and perilesional skin before clinical manifestations of the disease arise 60. In particular, auto-inflammatory diseases (AIDs), are unprovoked systemic inflammatory diseases that classically occur in the absence of infection or autoantibodies. These disorders are thought to be due to altered regulation and signaling patterns in the innate immune system. As described above, HS has been associated with many AIDs 53, 61, 62.
The exact cytokine profile of HS has yet to be determined, although abnormal levels of several inflammatory cytokines have been observed in HS, with notable elevations in IL-1β, IL-10, IL-11, IL-17A, and CXCL9 (monokine induced interferon [IFN]-γ). Additionally, mRNA and protein quantities of TNF-α, IL-1β, and IL-10 were reportedly elevated in HS 63– 65. Interleukins are a part of the body’s natural response to stressors, secreted by innate immune cells, each with its own specific role in immunomodulation. It is important to note that individual cytokine profiles differ between patients 66. While an in-depth discussion of the abnormal cytokine profile in HS is beyond the scope of this review, notable findings and common cytokine trends associated with HS will be expanded upon.
Increased activity of the pro-inflammatory IL-23/Th17 pathway has been implicated in many chronic inflammatory diseases, recently including HS. Studies have supported that IL-12 and IL-23 were expressed in large quantities by macrophages in HS lesional skin, along with the infiltration of IL-17-producing helper-T and CD4 + T cells 65, 67, 68. IL-17-producing cells were similarly found in lesional and perilesional skin in HS patients. The knowledge of IL-17 as an activator of keratinocytes and source of inflammatory modulators in HS has provided important insights into the disease process as well as potential management options 25, 58, 69. These findings have important implications in the management of HS as ustekinumab, a monoclonal antibody against IL-23 and IL-12, has demonstrated some efficacy for HS management 70.
IL-1β is another pro-inflammatory cytokine elevated in lesional HS tissue 63. This cytokine is well known as a pyrogen and leukocyte-activating factor, among numerous other functions. A controlled clinical trial by Tzanetakou et al. determined that HS disease activity and exacerbations were attenuated with anakinra therapy. Anakinra is an antagonist of the IL-1 receptor, making the IL-1 pathway a reasonable target to pursue for disease management. Additionally, during the course of treatment with anakinra, the treatment group also exhibited decreased levels of other pro-inflammatory markers such as IL-6, TNF, and IFN-γ compared to controls, further supporting the role of the IL-1 pathway in HS pathogenesis 71
.
IL-6 is another pro-inflammatory molecule of interest. This cytokine is elevated in inflammatory diseases such as rheumatoid arthritis, CD, and HS. Levels of IL-6 were significantly elevated in lesional HS tissue compared to controls in a recent study by Xu et al. 72. Interestingly, increased levels of IL-6 and C-reactive protein (CRP) were found to confer a poor response to infliximab treatment, making these markers reasonable adjunctive assessments in determining appropriate management 73. Further studies are needed to fully elucidate the role of IL-6 and methods to appropriately manage patients using this biochemical pathway.
Increased levels of chemotactic agents such as B-lymphocyte chemoattractant (BLC), CCL3, CCL5, and IL-16 have also been observed with HS 63, 74. These cytokines similarly play a role in inflammation, particularly the acute-phase reaction 60. Interestingly, markers such as IL-2, IL-4, IL-5, and IFN-γ were found to be extremely low in perilesional HS skin 63.
TNF-α is secreted by both innate and adaptive immune cells and has been implicated in the disease process of many other inflammatory conditions, such as psoriasis and inflammatory bowel disease. These findings have been instrumental in the development of biologic medications and led to the first approved biologic medication for HS, adalimumab 75. TNF-α has been shown to be elevated in HS through numerous studies, indicating important involvement in the disease pathogenesis, and as an effective target for management 64, 74.
Of note was the finding that levels of IL-1β, TNF-α, and IL-10 correlated with increased severity of HS, further supporting these markers as suitable targets for therapy 63, 65, 74. Following this work, Hotz et al. observed increased levels of CD4 + T cells in patients with HS and increased levels of IL-17 and IFN-γ from the aforementioned T cells 59. Another study observed cytokine concentrations in purulent drainage obtained from HS lesions and found that, overall, pro-inflammatory cytokines such as TNF-α, IL-1β, IL-1α, and IL-17 were increased in addition to elevations in anti-inflammatory cytokines IL-10 and IL-1ra, although each patient exhibited a unique cytokine profile. This multifaceted study also provided evidence that peripheral blood monocytes in HS patients produced fewer cytokines and were less active in responding to stimulation than were controls, indicating systemic involvement in the disease 66.
Antimicrobial peptides (AMPs), such as β-defensin (BD) 1, BD2, BD3, and other S100 proteins, such as psoriasin and calgranulins A and B, are believed to play a role in the pathogenesis of HS. AMPs are natural defense molecules constitutively expressed by keratinocytes, although irritants and other inflammatory stimulators can modify their expression. Tissue samples from six HS patients exhibited overexpression of AMPs compared to skin from healthy controls 76. Interestingly, a similar study of seven patients evaluated AMPs and cytokines within HS lesions and found a relative decrease in all analyzed AMPs. It was thought that the decrease in AMPs contributed to the susceptibility to secondary infections. This study also provided evidence that a deficiency of IL-22 and IL-20 may be responsible for decreased AMP levels, although further studies are needed on this topic 77.
From a different molecular perspective, microRNAs (miRNAs) are short, non-coding nucleotide chains involved in gene regulation. miRNAs are thought to regulate inflammatory markers in many chronic inflammatory diseases, such as psoriasis. In 2016, Hessam et al. observed that the miRNA modulators Drosha and DGRC8 were significantly downregulated in perilesional HS tissue, although no change was observed in these markers in lesional tissue 78. Following this work, Hessam et al. evaluated levels of specific miRNA molecules. Interestingly, significant overexpression of several miRNAs was observed in lesional compared to healthy control skin, including miRNA-31 and miRNA-125b. Of note, miRNA-31 is thought to be involved in regulating skin inflammation, and miRNA-125b is proposed as an important regulator of keratinocyte proliferation and TNF-α production 79. Although further studies are needed to fully assess the dysregulation of miRNA in HS, these findings contributed to the understanding of the HS disease process at the molecular level.
This information, which will surely be supplemented by future studies, has provided the basis of knowledge for understanding HS as an inflammatory disease and supported the use of biologics in its management.
Article information
Version 1. F1000Res. 2017; 6: 1272.
Published online 2017 Jul 28. doi: 10.12688/f1000research.11337.1
PMCID: PMC5538037
PMID: 28794864
Mallory K Smith,1 Cynthia L Nicholson,2 Angela Parks-Miller,2 and Iltefat H Hamzavia,2
1Wayne State University School of Medicine, Detroit, MI, USA
2Henry Ford Hospital Department of Dermatology, Detroit, MI, USA
aEmail: gro.shfh@1vazmahi
The referees who approved this article are:
Geoffrey David Cains, Department of Dermatology, University of New South Wales, Sydney, Australia
No competing interests were disclosed.
Christopher Sayed, Department of Dermatology, The University of North Carolina at Chapel Hill, Chapel Hill, NC, USA; UNC Dermatology and Skin Cancer Center, Chapel Hill, NC, USA
Competing interests: Christopher Sayed has held roles with Abbvie Inc. as a speaker, Advisory Board Member and co-investigator.
Robert Micheletti, Department of Dermatology and Department of Medicine, University of Pennsylvania, Philadelphia, USA
No competing interests were disclosed.
Link to full study: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5402905/#idm140150744356048title
32 Studies Supporting HS as an Auto-Inflammatory Illness
A total of 32 eligible publications were identified by the systematic search; these were supplemented with three additional publications. The extracted data indicated that four key themes underlie the pathogenesis of HS . Based on recent data, an integrative viewpoint is presented on the pathogenesis of HS.
Current evidence highlights a complex multifactorial pathogenesis (5). A key triggering factor is the occlusion of the hair follicle, caused by keratosis and hyperplasia of the follicular epithelium leading to cyst development (6, 7). Subsequently, the cyst will rupture, causing a fierce immune response and inflammation that, depending on the severity, may progress to abscess and sinus tract development and scarring (6, 7). The name of the disease implies that sweating and bacterial infection are a fundamental part of the disease process. This is misleading and now considered a misnomer: no evidence has been found showing that HS is triggered by events in the apocrine or eccrine glands. (8). In addition, HS can occur with several co-morbid immune-mediated inflammatory diseases (IMIDs), notably inflammatory bowel disease (IBD) (9).
Clear evidence suggests the involvement of pro-inflammatory cytokines in immune dysregulation in HS, with elevated levels of tumor necrosis factor (TNF)-α, interleukin (IL)-1ß, IL-17 and interferon (IFN)-γ observed in HS lesions (5, 10, 11). Data also indicate the involvement of T helper (Th) cells, which accumulate in HS lesions, in the pathogenesis of HS (11, 12). In addition, studies have shown that antimicrobial peptides (AMPs) like cathelicidin (LL-37) and human β-defensin are increased in HS lesions compared with normal skin of HS patients (13). The use of TNF-α inhibitors such as adalimumab and infliximab have been associated with improvements in immune dysregulation in HS and support the importance of local molecular drivers in the pathogenesis of HS (1, 14, 15).
Furthermore, mutations in γ-secretase genes, whose gene products act on many substrates including Notch (16), suggest that Notch or other substrates of γ-secretase may play a role in the pathogenesis of HS. Interestingly, γ-secretase knock-out mice are characterized by a phenotype of multiple cutaneous cysts, a key feature of HS (17). To date it remains unclear whether the effects of Notch on follicle development or its immune role play a significant role in HS pathogenesis.
Rapidly evolving understanding in the auto-inflammatory arena is needed to improve awareness of HS, disease management, and ultimately improve patient outcomes.
https://www.frontiersin.org/articles/10.3389/fimmu.2018.02965/full
Synopsis:
In this review, we collected all the information concerning the OMICs studies performed on HS patients aimed at unraveling the mechanisms at the basis of the disease or associated to clinical severity and/or the successful response to pharmacological treatment (including biological drugs).
The general picture of the OMICs contribution in the context of HS is not so clear and/or rich of clinical useful information, since most of the studies focused only on one aspect (genome, transcriptome, or proteome) of the disease, enrolling small numbers of patients (this is quite limiting for the genetic studies) from different geographical areas, looking just a few aspects of HS pathogenesis without any integration of the findings obtained or a comparison within studies.
In this sense just two articles [(97, 100): described above] constructively compared the transcriptomic and proteomic profiles of skin and serum from HS patients with previous data present in biological repositories. We do think that this is the right path to be followed to disclose the fine mechanisms at the basis of HS and its clinical course.
An integrated approach using OMICs tools is strongly required to study the full genome, the skin transcriptome and proteome (from lesional, perilesional, and non-lesional biopsies as well as serum) of HS patients stratified based on the severity of the diseases, type of treatment and response to drugs; the number of enrolled patients, with the same ethnic background, is a key issue, especially for the genetic studies, in this sense we do recommend the constitution of consortia to better address this key-point. A comparison and integration with the findings present in the OMICs repositories is mandatory, so in a theoretic pipeline the Skin-OMICs profile obtained from each HS patient should be compared and integrated with repositories and literature data by using appropriate InterOMICs approach (i.e., see the interesting work performed on 16 types of cancer integrating pathways and biological network data by Cava et al. (102). Figure 2 shows the possible integrated strategy to be adopted for tailored diagnosis and treatment of HS patients.
Full Research:
https://www.frontiersin.org/articles/10.3389/fimmu.2019.00892/full
Hidradenitis Suppurativa: The Role of Deficient Cutaneous Innate Immunity
Synopsis:
A rather long, yet interesting Oxford Article link is below which explains auto-inflammatory disorders and the innate immune.
Hidradenitis suppurativa (HS) has long been considered an anatomical disorder of apocrine sweat glands or an immunodeficiency. More recently it has become clear that it behaves as an auto-inflammatory disorder.
The auto-inflammatory syndromes represent an expanding spectrum of intriguing disorders. Many of them are relatively rare, however, the growing insights into the pathophysiology of these incapacitating disorders not only provide new directions for their treatment, but also teach us about the mechanisms of more common inflammatory diseases. So far, IL-1 has been the major player in many of the auto-inflammatory disorders, allowing for therapy targeted towards this cytokine. Other inflammatory mediators and mechanisms (e.g. the proteasome subunits) have been found to be deranged in distinct auto-inflammatory disorders [52], while in others the basic defects are still unknown. A major challenge is to find targeted therapies for these disorders.
Full circulation link to research
https://jamanetwork.com/journals/jamadermatology/fullarticle/1105221
Full circulation link to research PDF
https://drive.google.com/file/d/1PmGvW38uTZCvvYTi9XzSTDSbSyeFoHsM/view?usp=drivesdk
Complement activation in hidradenitis suppurativa:
A New Pathway of Pathogenesis
Synopsis:
Background: Despite the heavy purulence observed in hidradenitis suppurativa (HS), the kinetics of complement anaphylatoxins acting to prime chemotaxis of neutrophils has not been studied.
Objectives: To explore complement activation in HS.
Methods: Circulating concentrations of complement factor C5a, as well as of membrane attack complex C5b-9, were determined in the plasma of 54 treatment-naïve patients and of 14 healthy controls, as well as in the pus of seven patients. Results were correlated with Hurley stage and International Hidradenitis Suppurativa Severity Score. Peripheral blood mononuclear cells (PBMCs) were isolated from seven patients with Hurley stage III HS and seven healthy volunteers and stimulated in the presence of 25% of plasma for the production of tumour necrosis factor-α (TNF-α).
Results: Circulating C5a and C5b-9 were significantly greater in patient than in control plasma; however, concentrations in pus were very low. Circulating C5a levels exceeding 28 ng mL-1 were associated with a specificity > 90% with the occurrence of HS. Circulating levels of C5a and C5b-9 were greater in patients with more severe HS. PBMCs of patients produced high concentrations of TNF-α only when growth medium was enriched with patient plasma; this was reversed with the addition of the C5a blocker IFX-1.
Conclusions: Systemic complement activation occurs in HS and may be used as a surrogate biomarker of HS. C5a stimulates overproduction of TNF-α and may be a future therapeutic target.
Full study:
https://www.ncbi.nlm.nih.gov/pubmed/29405257
Link to full research circulation PDF:
https://drive.google.com/file/d/1TxhfMrq7LJ2rMAEq9d5mXLuokPo1L_tA/view?usp=drivesdk
Intrinsic Defect in Keratinocyte Function Leads to Inflammation in Hidradenitis
https://www.jidonline.org/article/S0022-202X(16)31247-7/fulltext
HS as an Auto-Inflammatory Disease Study
Hidradenitis suppurativa is an auto‐inflammatory disease: results of an ex vivo study
Synopsis:
Immune dysregulation, carrying a strong IL‐1 signature, is implicated in the pathogenesis of hidradenitis suppurativa (HS). Interleukin 1 production is based on activation of auto‐inflammatory pathways including the inflammasome, and consequential induction of various cytokines and chemokines. The objective of this study was to determine whether the lesional HS cytokine protein and gene expression profiles could be mimicked/induced by stimulation of perilesional HS skin with IL‐1α and IL‐1ß.
Skin punch biopsies from normal appearing perilesional HS skin (HSP) were obtained from 10 HS patients and compared with five skin samples from healthy controls (NN) . All samples were cultured for 24 h in a transwell system using a culture media and media containing either IL‐1α 10 ng/mL or IL‐1ß 10 ng/mL. Subsequently pro‐inflammatory cytokine protein levels in the culture media using a customised 16‐Plex Assay (Luminex) and mRNA expression of four pro‐inflammatory markers in the skin biopsies using real‐time quantitative PCR were analysed. First, the Mann‐Whitney U test was used to compare protein concentrations in the culture media of HSP with NN skin. Second, the Wilcoxon signed rank test was used to pairwise compare stimulated conditions to a condition without stimulation, i.e. culture media (fold change = 1.00).
Overall 62.5% (10/16) of the inflammatory proteins were significantly elevated in HSP skin compared with NN skin. After stimulation with IL‐1α or IL‐1ß respectively 40.0% (6/15) and 78.6% (11/14) of the inflammatory proteins were significantly elevated in NN skin compared with 7.1% (1/14) and 38.5% (5/13) in HSP skin. Similar results were found for mRNA expression levels in stimulated HSP and NN skin. Altogether, cytokine levels in HSP skin are already upregulated and almost not further inducible by IL‐1.
This study reveals the auto‐inflammatory nature of HS, characterized by the spontaneous increased production of a broad range of pro‐ and anti‐inflammatory cytokines. Our results show that IL‐1ß is a more potent stimulus compared with IL‐1α in both NN and HSP skin.
IMMUNOLOGY
008 OS02‐01 ‐ oral session
A. R. J. V. Vossen, K. R. van Straalen, E. Florencia, E. P. Prens
Erasmus University Medical Center, Department of Dermatology, Rotterdam, The Netherlands
Auto-inflammatory and Hair Follicle Involvement in HS
Second International HS Research Symposium Abstracts
The term “hidradenitis suppurativa” is firmly entrenched in the dermatological literature although it refers to a false pathogenetic concept. The term was historically coined based merely on the characteristic distribution of the apocrine glands and the anatomical coincidence with the disease process. The herein reported histopathological analysis of specimens of “hidradenitis suppurativa” from patients found at the center stage of the disease not a suppurative inflammation of the apocrine sweat glands but an occlusion of the hair follicles, comparable to acne vulgaris. The disease process starts with follicular hyperkeratosis and dilatation of the follicular infundibula evolving into comedones, comparable to the ones observed in acne vulgaris.
At this time, the apocrine glands are not involved. Eventually the dilated follicular infundibulum ruptures and the content spills into the surrounding dermis, evoking an acute inflammatory response in the immediate vicinity of the rupture site. Again, the apocrine glands do not show any signs of involvement nor an indication that they are the anatomical starting point of the sequence of events. If the inflammation remains confined to the immediate vicinity of the hair follicle, over time the initially neutrophilic infiltrate subsides and is gradually replaced by a granulomatous one, often with the addition of multinucleated foreign body giant cells. If, however, the acute inflammatory response following rupture is more florid, a large abscess develops which may extend into the subcutaneous tissue. Apocrine glands near the abscess but not involved by it, are unremarkable. Only by extension of the inflammatory process, apocrinitis evolves and apocrine glands are destroyed. Apocrine glands located further away from the extending abscess are morphologically unremarkable. When extensive tissue destruction has ensued, naked hair shafts, surrounded by an inflammatory infiltrate, are often the only indication that the process started from the hair follicle. In an attempt of the tissue to confine the inflammatory reaction and to prevent further spread, remnants of the hair follicle epithelium proliferate and sinus tracts form, often surrounded by fibrosis. The sinus tracts communicate with the surface. Upon bacterial superinfection, they rupture and the process becomes self maintaining and enters into a vicious cycle. Sinus tract formation is the main reason for the chronicity of the disease and why radical surgery is the only therapeutic option capable of achieving long lasting cure.
Thus, “hidradenitis suppurativa” is a disorder that shares histopathological and clinical aspects with acne vulgaris modified under the special circumstances of anatomical regions rich in apocrine glands. It is acne inversa because in contrast to acne vulgaris the disease involves intertriginous localizations and not the regions classically affected by acne.
Auto-inflammatory Mechanisms in the Pathogenesis of HS
Evangelos J. GiamarellosBourboulis, MD, PhD 4th Department of Internal Medicine, University of Athens, Medical School, Greece.
There is accumulating body of evidence suggesting that patients with HS have severe derangements of their innate immune system. This evidence is based on monocyte stimulation assays and on the favorable clinical responses with biological therapies. Blood monocytes were isolated from patients and stimulated with lipopolysacchraride (LPS) of Escherichia coli O144:H4 (1). Defective monocyte responses characterized by reduced production of tumor necrosis factoralpha (TNF_) and interleukin6 (IL6) were found. In the same study, it was shown that NK cells of patients were increased. These findings pointing towards serious derangements of the innate immune responses in the event of HS, led to a prospective, openlabel, one arm clinical trial of the administration of etanercept in patients with HS. Etanercept was administered at a dose of 50 mg sc once weekly for 12 weeks. Efficacy of treatment was evaluated by the Sartorius score and by the disease activity index. A more than 50% decrease of both scores compared with baseline was found in seven patients. All patients reported decreased pain by week 4 whereas the number of fistulas was significantly decreased. Treatment was well tolerated. Relapse was noted within 48 weeks after cessation of therapy.
The above findings implicate derangements of the innate immune system as part of the mechanism of pathogenesis of HS.
References
1. GiamarellosBourboulis EJ, Antonopoulou A, Petropoulou C, et al. Altered innate immune response in patients with hidradenitis suppurativea. Br J Dermatol: 2007; 156: 5156. 2. GiamarellosBourboulis EJ, Pelekanou E, Antonopoulou A, et al. An open label phase II study of the safety and efficacy of etanercept for the therapy of hidradenitis suppurativa. Br J Dermatol 2008; 158: 567572.
An Update on Connecting the Tracts: HS as an Auto-inflammatory Condition
Synopsis:
HS is now believed to be a systemic inflammatory condition, contrary to previous hypotheses classifying HS as a purely cutaneous disorder. Many previously accepted models of HS pathogenesis are being challenged. It is now believed that HS is a systemic inflammatory disease of multifactorial basis due to auto-inflammation 53.
It was formerly hypothesized that the disease originated in apocrine-bearing locations of the body, such as the groin and anogenital and axillary regions. However, the inframammary region, neck, trunk, back, and thighs are frequently involved as well. Additionally, it is theorized that the first step in HS disease progression is the occlusion of the follicular infundibulum due to hyperkeratosis of adjacent epithelium. Follicular occlusion is paramount in the manifestations of HS, the instigating mechanism of occlusion.
Additionally, it is known that keratinocytes and neutrophils play a role in the secretion of pro-inflammatory molecules in HS 58. Hotz et al. proposed that abnormal keratinocyte function plays a role in HS development. Compared to controls, keratinocytes in HS lesions showed a diminished inflammatory response to muramyl dipeptide, a pathogen-associated molecular pattern (PAMP) inflammatory antigen59. Keratinocyte malfunction further suggests structural and molecular abnormalities allowing for follicular occlusion and disease progression. Although the precise cause of the follicular occlusion remains debated, cellular markers and other immunologic sources of inflammation are important topics of discussion in the ongoing search to determine the etiology of HS. In summary, overarching themes of inflammation and abnormal cellular activity appear to provide the appropriate environment for the progression to HS clinical features. It is probable that many factors allow for altered cellular barrier mechanisms and anomalous secretion of pro-inflammatory cytokines in the progression to classic HS symptoms 48.
Inflammation in hidradenitis suppurativa is a systemic inflammatory disease and auto-inflammation is suggested to play a role in disease pathogenesis. This theory was bolstered by the association of comorbid autoimmune and inflammatory diseases, abnormal biochemical findings, and an infiltration of innate immune cells within both lesional and perilesional skin before clinical manifestations of the disease arise 60. In particular, auto-inflammatory diseases (AIDs) unprovoked systemic inflammatory diseases that classically occur in the absence of infection or autoantibodies. These disorders are thought to be due to altered regulation and signaling patterns in the innate immune system. As described above, HS has been associated with many AIDs 53, 61, 62.
The exact cytokine profile of HS has yet to be determined, although abnormal levels of several inflammatory cytokines have been observed in HS, with notable elevations in IL-1β, IL-10, IL-11, IL-17A, and CXCL9 (monokine induced interferon [IFN]-γ). Additionally, mRNA and protein quantities of TNF-α, IL-1β, and IL-10 were reportedly elevated in HS 63– 65. Interleukins are a part of the body’s natural response to stressors, secreted by innate and adaptive immune cells, each with its own specific role in immunomodulation. It is important to note that individual cytokine profiles differ between patients 66. While an in-depth discussion of the abnormal cytokine profile in HS is beyond the scope of this review, notable findings and common cytokine trends associated with HS will be expanded upon.
Increased activity of the pro-inflammatory IL-23/Th17 pathway has been implicated in many chronic inflammatory diseases, recently including HS. Studies have supported that IL-12 and IL-23 were expressed in large quantities by macrophages in HS lesional skin, along with the infiltration of IL-17-producing helper-T and CD4 + T cells 65, 67, 68. IL-17-producing cells were similarly found in lesional and perilesional skin in HS patients. The knowledge of IL-17 as an activator of keratinocytes and source of inflammatory modulators in HS has provided important insights into the disease process as well as potential management options 25, 58, 69. These findings have important implications in the management of HS as ustekinumab, a monoclonal antibody against IL-23 and IL-12, has demonstrated some efficacy for HS management 70.
IL-1β is another pro-inflammatory cytokine elevated in lesional HS tissue 63. This cytokine is well known as a pyrogen and leukocyte-activating factor, among numerous other functions. A controlled clinical trial by Tzanetakou et al. determined that HS disease activity and exacerbations were attenuated with anakinra therapy. Anakinra is an antagonist of the IL-1 receptor, making the IL-1 pathway a reasonable target to pursue for disease management. Additionally, during the course of treatment with anakinra, the treatment group also exhibited decreased levels of other pro-inflammatory markers such as IL-6, TNF, and IFN-γ compared to controls, further supporting the role of the IL-1 pathway in HS pathogenesis 71.
IL-6 is another pro-inflammatory molecule of interest. This cytokine is elevated in inflammatory diseases such as rheumatoid arthritis, CD, and HS. Levels of IL-6 were significantly elevated in lesional HS tissue compared to controls in a recent study by Xu et al. 72. Interestingly, increased levels of IL-6 and C-reactive protein (CRP) responding to infliximab treatment, making these markers reasonable adjunctive assessments in determining appropriate management 73. Further studies are needed to fully elucidate the role of IL-6 and methods to appropriately manage patients using this biochemical pathway
Increased levels of chemotactic agents such as B-lymphocyte chemoattractant (BLC), CCL3, CCL5, and IL-16 have also been observed with HS 63, 74. These cytokines similarly play a role in inflammation, particularly the acute-phase reaction 60. Interestingly, markers such as IL-2, IL-4, IL-5, and IFN-γ were found to be extremely low in perilesional HS skin 63. TNF-α is secreted by innate immune cells and has been implicated in the disease process of many other inflammatory conditions, such as psoriasis and inflammatory bowel disease. These findings have been instrumental in the development of biologic medications and led to the first approved biologic medication for HS, adalimumab 75. TNF-α has been shown to be elevated in HS through numerous studies, indicating important involvement in the disease pathogenesis, and as an effective target for management 64 and 74.
Of note was the finding that levels of IL-1β, TNF-α, and IL-10 correlated with increased severity of HS, further supporting these markers as suitable targets for therapy 63,65, 74. Following this work, Hotzet al. observed increased levels of CD4 + T cells in patients with HS and increased levels of IL-17 and IFN-γ from the aforementioned T cells 59. Another study observed cytokine concentrations in purulent drainage obtained from HS lesions and found that, overall, pro-inflammatory cytokines such as TNF-α, IL-1β, IL-1α, and IL-17 were increased in addition to elevations in anti-inflammatory cytokines IL-10 and IL-1ra, although each patient exhibited a unique cytokine profile. This multifaceted study also provided evidence that peripheral blood monocytes in HS patients produced fewer cytokines and were less active in responding to stimulation than were controls, indicating systemic involvement in the disease 66.
Full study can be found here: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5538037/
This information, which will surely be supplemented by future studies, has provided the basis of knowledge for understanding HS as an autoinflammatory disease and supported the use of biologics in its management.
Geoffrey David Cains, Department of Dermatology, University of New South Wales, Sydney, Australia
Christopher Sayed, Department of Dermatology, The University of North Carolina at Chapel Hill, Chapel Hill, NC, USA; UNC Dermatology and Skin Cancer Center, Chapel Hill, NC, USA
Robert Micheletti, Department of Dermatology and Department of Medicine, University of Pennsylvania, Philadelphia, USA
Greater Systemic Inflammatory Load
Synopsis:
Hidradenitis is a chronic inflammatory skin disease with recurrent nodules, tunnels, scarring and suppuration of intertriginous areas. Hospital-treated HS patients have an increased risk of metabolic syndrome and a wide array of co-morbidities that possibly are related to systemic inflammation. Neutrophile to lymphocyte ratio has been suggested as a marker of systemic inflammation. Studies of psoriasis patients have found their neutrophile to lymphocyte ratio to be increased. In this study, routine blood samples collected during control visits from 50 HS patients are examined, and compared to routine blood samples from 250 age- and sex-matched dermatological outpatients. The neutrophile to lymphocyte ratio does not appear to be increased in HS patients as seen in psoriasis patients, but CRP was found to be higher in HS patients, indicating systemic inflammation. However, N/L ratio was positively correlated to Hurley stage (p < 0.006). The inflammatory biochemical markers for HS patients appear to differ from psoriasis patients and other non-HS dermatological patients; however, a larger study with healthy controls is warranted to further explore the characteristics of inflammatory markers in HS.
Link to research:
Pathophysiology of Hidradenitis Suppurativa
Abstract
The pathophysiology of hidradenitis suppurativa (HS) is not well understood. Some of our knowledge comes from clinical and epidemiological observations, along with studies of the histopathology and immunohistochemistry of affected skin. More recently, cutaneous molecular studies and transcriptomic analyses have provided additional information regarding inflammatory processes. The chronic cutaneous inflammation, systemic symptoms, and associated comorbidities suggest that HS should be classified as an immune-mediated disease, rather than a primary infectious disease. As such, a proposed integrated disease pathway is presented. At a fundamental level, there appears to be a primary abnormality in the pilosebaceous-apocrine unit, which leads to follicular occlusion, perifollicular cyst development that traps commensal microbes, and rupture into the dermis. This can trigger an exaggerated response of the cutaneous innate immune system. Initially this is an acute event, but ongoing intermittent disease activity can lead to recurrent inflammatory nodules and dermal tunnels. Once underway, the cutaneous inflammation is very difficult to turn off, leading to suppurative inflammation in whole anatomic regions. As the disease progresses, we propose that there is recruitment of the systemic immune system perpetuating the chronic cutaneous inflammatory process. There remains much to be done to understand the pathogenesis and immune signature of this challenging disease
Conclusion
As we are in the early stages of defining the pathophysiology of HS using modern molecular approaches, this review has focused on clinical observations and studies on lesional skin and the immune system to synthesize what they reveal about the causes of HS. It is clear that HS is a complicated disease, which results in great morbidity and impairment of quality of life. We do not yet have a complete understanding of the pathophysiology, and it is essential that we address this unmet need urgently. As we go forward, we can leverage our knowledge about other chronic immune-mediated diseases to guide future studies to help our suffering patients.
Full Research:
https://pubmed.ncbi.nlm.nih.gov/28538743/?from_term=Hidradenitis+innate+immune&from_pos=10
Keratinocytes and neutrophils are important sources
of proinflammatory molecules in hidradenitis suppurativa
Synopsis:
Background
The pathogenesis of the chronic inflammatory skin disease hidradenitis suppurativa (HS, also known as acne inversa) involves epidermal alterations such as psoriasiform epidermal hyperplasia and keratin plugging. Keratinocytes are an important source of proinflammatory molecules in inflammatory skin diseases and can be stimulated by interleukin (IL)-17+ cells.
Objectives
To explore the possible role of the epithelium in the pathogenesis of HS
Methods
We performed immunohistochemical stainings and Western blot experiments to investigate the localization and expression of inflammation-associated molecules, including the cytokine IL-17, components of the inflammasome including caspase-1, and the endogenous danger-associated molecular pattern molecules S100A8 and S100A9 (calprotectin). To examine a possible effect of upregulated proinflammatory cytokines on the inflammatory infiltrate, differences in the cellular composition of perifollicular and deep dermal infiltrates were analysed.
Results
The number of IL-17+ cells is increased in lesional and perilesional HS skin. The epidermis produces proinflammatory molecules and shows an upregulated expression of components of the NLRP3 inflammasome, activated caspase-1 and expression of S100A8/S100A9. Additionally, the course of the inflammatory process in HS involves influx of innate immune cells, particularly IL-17-expressing neutrophils.
Conclusions
IL-17-producing cells are present in lesional and perilesional HS skin and may contribute to the initiation of inflammatory processes. Furthermore, the epidermis is a source of proinflammatory cytokines, shows inflammasome activation and expresses S100A8/S100A9, thereby possibly contributing to the propagation of inflammation. A massive influx of IL-17-expressing neutrophils is observed in the deep infiltrate.
Full Research:
https://onlinelibrary.wiley.com/doi/abs/10.1111/bjd.14214
Dysregulation of the Th17:Treg Cell Axis
HS may be considered an autoinflammatory disease
Synopsis:
Hidradenitis suppurativa (HS) is a chronic, inflammatory, and debilitating disease of hair follicles with 1–4% prevalence and high morbidity. There is a dearth of information on the pathogenesis and immune dysregulation underlying HS; therefore, we carried out a detailed analysis of skin-infiltrating T cells. Cells isolated from skin biopsy samples and blood from HS patients and healthy control subjects were analyzed by 16-parameter flow cytometry to provide detailed profiles of CD4 T-cell subsets. We observed substantial infiltration of inflammatory T cells with a striking T helper (Th) type 17-skewed cytokine profile in HS skin; these cells expressed the Th17 lineage marker CD161 and IL-17, as well as proinflammatory cytokines GM-CSF, IL-22, IFN-γ, and tumor necrosis factor. Regulatory T cells were also enriched in HS lesional skin; however, the ratio of Th17 to regulatory T cells was nonetheless highly dysregulated in favor of Th17 cells. In contrast, lesional skin from anti-tumor necrosis factor–treated HS patients who showed substantial clinical improvement exhibited a significant reduction in the frequency of Th17 cells and normalization of the Th17 to regulatory T cell ratio. These data suggest that inhibition of pathogenic IL-17 via tumor necrosis factor blockade is associated with improvement in immune dysregulation in HS and may provide a rationale for targeting IL-17 in the disease.
Full Research:
https://www.jidonline.org/article/S0022-202X(17)31666-4/fulltext
Defining Hidradenitis Suppurativa Phenotypes
Based on the Elementary Lesion Pattern: Results of a Prospective Study
Synopsis:
Background: It has been proposed that two main phenotypes of hidradenitis suppurativa (HS) exist. This proposal is based upon different elementary structures detected in the skin, namely follicular subtypes and inflammatory subtypes. Having an accurate definition of these two variants could help us to better identify patients who may require an early intervention with currently approved targeted immunomodulatory therapies.
Objective: To define and distinguish between the epidemiological, clinical and analytic characteristics of these two HS phenotypes.
Methods: An observational, descriptive, non-randomized and prospective study was conducted. Patients diagnosed with HS between May 2012 and April 2017 by a specialized unit were included. Ultrasound evaluation was performed in all cases.
Results: About 197 patients were included, 100 women and 97 men, aged between 25 and 47 years. The mean age of onset was significantly different between phenotypes, ranging between 26.69 ± 9.05 in the inflammatory subtype and 17.62 ± 6.42 in the follicular subtype. Follicular subtype patients exhibited a significantly higher number of nodules combined with the presence of multiple commedons (5.65 ± 3.38 versus 0.89 ± 2.72). This contrasted with the higher count of abscesses and fistulas detected in the inflammatory subtype (respectively, 4 ± 2.74 and 3.11 ± 2.56 versus 0.56 ± 1.02 and 0.26 ± 0.56). IgA levels were significantly higher in the inflammatory subtype (497.71 ± 262.26 versus 232.38 ± 84.06). Mean IHS4 score evaluation was higher in the inflammatory subtype (21.04 ± 11.9) compared with the follicular phenotype (7.54 ± 4.66). The inflammatory subtype was found to be an independent risk factor for disease aggressiveness in the multivariate analysis (OR 0.034 [95% CI 0.015-0.072]).
Limitations: Small sample size.
Conclusion: Preliminary data suggest the existence of an inflammatory HS phenotype that is associated with higher aggressiveness and major risk of progression during natural history of the disease.
Full Study:
https://www.ncbi.nlm.nih.gov/m/pubmed/31919904/?i=1&from=hidradenitis%20suppurativa
Matrix remodelling and MMP expression/activation are associated
with hidradenitis suppurativa skin inflammation
Synopsis:
Hidradenitis suppurativa/acne inversa (HS) is a chronic, inflammatory, recurrent, debilitating skin disease of the hair follicle, associated with considerable tissue remodelling. Although abnormal cytokine expression was detected both in perilesional and in uninvolved skin, up to now there is no model allowing a better understanding of the implicit inflammatory mechanisms in HS. The aim of this study was to investigate the inflammatory response in HS skin by mean of an ex vivo model culture. To that purpose, nine skin biopsy specimens from patients suffering from HS and controls were cultured up to 4 days. Microscopy imaging investigations showed variations of collagen I and III organization, and an increase in elastin fibres fragmentation in HS skin after 4 days of culture. The HS matrix structure remodelling was associated with high level of MMP-2 and MMP-9 in HS lesional skin. After 4 days of culture, the MMP expression in HS perilesional skin reached the level observed in HS lesional skin. Concomitantly, an increase in IL-1β concentration was observed in all skin samples after 4 days of culture, although IL-1β concentrations remained significantly higher in HS lesional skin as compared with control skin. Meanwhile, neither IL-17 concentrations nor the inflammasome components NLRP3 and caspase-1 varied. Thus, our HS skin model culture showed that MMP-induced matrix alteration could participate in HS inflammation by releasing biological active peptides and inflammatory factors from the extracellular matrix (ECM), and open new opportunities to investigate the regulation of the inflammatory mechanism associated with HS.
Full Research Circulation:
https://www.ncbi.nlm.nih.gov/m/pubmed/30903721/?i=7&from=hidradenitis%20follicle
The role of interleukin-17 in the pathogenesis of hidradenitis suppurativa
Hidradenitis suppurativa is a chronic inflammatory skin condition affecting primarily the axillary, perianal, and inguinal areas. Patients with hidradenitis suppurativa present with occlusion and subsequent rupture of follicular ducts, profound abscesses, fistulae, odorous discharge, fibrosis, and scar formation, causing significant morbidity. Knowledge of the pathogenesis of hidradenitis suppurativa is limited and treatment with antimicrobial drugs, immunosuppressants, and surgical procedures have shown varying results. The pathogenic role of the interleukin-17 cytokine family in chronic inflammatory skin conditions has been described. Interleukin-17A and interleukin-17F have similar properties and induce the production of cytokines, chemokines, antimicrobial peptides, and metalloproteinases, all of which take part in the inflammatory response. The efficacy of anti-interleukin-17A therapy in psoriasis has also been proven and anti- interleukin-17A drugs are already in use for this condition. There is currently no consensus on the role of interleukin-17 in the pathogenesis of hidradenitis suppurativa. Studies have demonstrated increased interleukin-17 mRNA expression in lesional hidradenitis suppurativa skin, whereas the protein concentrations of interleukin-17 were found to be normal compared to healthy control skin in one other study. A phase II clinical trial on anti- interleukin-17 therapy in hidradenitis suppurativa is ongoing.
Conclusion and future perspectives
As suggested by the studies presented herein, interleukin-17 plays a role in several chronic
inflammatory skin conditions including hidradenitis suppurativa. The background knowledge on the
proinflammatory properties of interleukin-17 combined with the studies revealing enhanced
interleukin-17 gene expression in hidradenitis suppurativa patients provides a reason for the
therapeutic value of targeting interleukin-17 and its receptors in the treatment of hidradenitis suppurativa.
Currently, a phase II anti-interleukin-17 clinical trial in hidradenitis suppurativa is ongoing (ClinicalTrials.
gov - identifier: NCT02421172). As the remaining functions of interleukin-17, along with the missing
links in the pathogenesis of hidradenitis suppurativa are unveiled, the future looks promising for anti-
interleukin-17 therapy in hidradenitis suppurativa. Nonetheless, further research is needed to clarify
the role of interleukin-17 in the pathogenesis of Hidradenitis suppurativa.
Full Research:
https://www.ncbi.nlm.nih.gov/m/pubmed/29469692/?i=21&from=hidradenitis%20occlusion
Seventy-MHz Ultrasound Detection of Early Signs Linked to the Severity, Patterns of Keratin Fragmentation, and Mechanisms of Generation of Collections and Tunnels in Hidradenitis Suppurativa
Synopsis:
Ultrasound can detect early HS signs that are significantly linked to severity and 2 types of fragmentation of the keratin, which could support the generation and perpetuation of the fluid collections and tunnels. These ultrasound signs can help prompt diagnosis and management, the development and testing of medications, and the measure of treatment outcomes in HS.
Full Research:
https://www.ncbi.nlm.nih.gov/m/pubmed/31705709/?i=1&from=hidradenitis%20follicle
Preliminary findings suggest hidradenitis suppurativa may be due to defective follicular support
Synopsis:
The BMZ PAS positivity of clinically uninvolved FPSUs of patients with HS appears to be wispy or not present at all. It is speculated that this may explain the apparent fragility of the sebofollicular junction. There is an increased concentration of inflammatory cells adjacent to these areas, while inflammatory cells are scarce in areas where the PAS-positive material is intact. It is hypothesized that the PAS gap identifies (i) areas susceptible to leakage, trauma and rupture, leading to release of materials that trigger inflammatory mediators, and (ii) the seeding of the dermis with free-living stem cells generating benign but invasive epithelialized sinuses, spreading horizontally in and below the dermis.
Full study:
The Danish Blood Donor Staphylococcus aureus Carriage Study
Full study link: