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