Hidradenitis Suppurativa: From Pathogenesis to Diagnosis and Treatment
Synposis of Research:
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.
Version 1. F1000Res. 2017; 6: 1272.
Published online 2017 Jul 28. doi: 10.12688/f1000research.11337.1
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
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.