Background: Hidradenitis suppurativa (HS) is a chronic, inflammatory, debilitating disorder of the pilosebaceous unit. Dermal tunnels, sinus tracts, or fistulas are unique features of HS. One may hypothesize that HS tunnels remain active and may contribute to inflammation and disease severity. Summary: Increased inflammatory infiltrate with an increased number and densities of immune cells was reported in HS tunnels. Moreover, significantly higher levels of IL-36, Il-17A, IL-17C, IL-17F, and CXCL8 mRNA compared to non-tunnel HS skin were found. Furthermore, in the lumen, a proliferative gelatinous mass consisting of inflammatory cells with similar cytokine levels as inflammatory HS lesions was found. It was also proven that HS sinus tracts are often colonized by Porphyromonas spp. and Prevotella spp. with a tendency to biofilm creation. The genetic profile of HS tunnels varies from non-tunnel HS skin, with upregulation of pro-inflammatory and downregulation of anti-inflammatory genes. Lastly, treatment with newly developed drugs targeting different subunits of IL-17 seems promising in decreasing dermal tunnel drainage and in the resolution of sinus tracts. Moreover, a higher percentage of patients treated with these drugs achieved HiSCR75 and HiSCR90.

Hidradenitis suppurativa (HS) is a chronic, inflammatory, debilitating disorder of the pilosebaceous unit [1]. Its prevalence varies depending on different data collection methods and ethnic variations [2, 4]. Nevertheless, authors estimate that HS may affect around 1% of the global population [1]. The disease usually starts in early adulthood, commonly after puberty; however, cases of pediatric HS have also been reported [1, 5]. The multifactorial nature of HS pathogenesis is not fully elucidated. It has been proven that inflammation is an essential element of HS development; however, genetic predisposition, smoking, obesity, microbiome, and hormonal disturbances may also play an important role [1, 6, 8]. HS primarily affects intertriginous zones, including axillae, ingles, anogenital, and submammary areas. It is characterized by the formation of multiple, painful inflammatory nodules, abscesses, and purulent tunnels, which subsequently progress into extensive scarring [1, 7]. The HS treatment is complex and frequently unsatisfactory [9]. It consists of a combination of topical therapy, systemic antibiotics, retinoids, biologics, and surgery [7].

In the last 20 years, more than two thousand articles regarding HS have been published. The vast majority concentrated on the pathophysiology and pathomechanisms in order to find a possible treatment target. The authors primarily focused on “active lesions,” including inflammatory nodules, abscesses, and draining tunnels. Traditionally, it was believed that static lesions, including scarring tissue and non-draining tunnels, do not take part in the further deterioration of skin lesions and were treated as end-stage fibrotic products of dermal inflammation [10, 11]. Nevertheless, in the light of new discoveries and recently published papers, one may hypothesize that HS tunnels remain active and may potentially contribute to inflammation and disease severity. In order to verify that hypothesis, we performed a review of the available literature on tunnels in HS, concentrating on their molecular and genetic involvement in HS pathogenesis, as well as possible therapeutic implications.

Dermal tunnels, sinus tracts, or fistulas are unique features of HS. Such a lesion was never identified in any other inflammatory skin disease; however, similar ones were observed in Crohn’s disease [12]. The presence of multiple interconnected tunnels is associated with a worse response to biologic therapy, severe pain, greater quality of life impairment, as well as higher disease activity and a more aggressive course of the disease [1, 7, 13]. From the histological point of view, an HS tunnel is an elongated cavity in the epidermis, dermis, or subcutis of various thicknesses lined with squamous epithelium. Moreover, hair shaft residues and deposition of keratin flakes are often reported as white gelatinous material in the lumen [12]. In ultrasonography, four types of fistulas (A–D) were described depending on the depth, complexity, and response to treatment by Martorell et al. in 2019 [14]. Tunnels A and B are dermal and dermoepidermal fistulas that respond well to adalimumab therapy in the majority of cases. In contrast, types B and C (complex or subcutaneous tunnels) do not respond to systemic treatment and require a surgical approach [14].

Although traditionally, tunnels were assessed as static lesions, recent studies on the immunological disturbances in fistulas have shown possible implications in HS pathogenesis. It was proposed that fibroblast-related pathways are activated in the lesional skin. Extensive tunnel formation, matrix remodeling, and subsequent epithelialization may be explained by the presence of PDFGRA+/− fibroblasts activated by inflammatory cytokines commonly elevated in HS (IL-1β, IL-6, IL-8) [10]. Moreover, an inflammatory active infiltrative proliferative gelatinous mass (IPGM) was found in the lumen of stratified squamous tunnel epithelium [15]. IPGM, which consists of inflammatory cells, neutrophils, macrophages, and Th cells, presents similar inflammatory characteristics to dermal HS lesions, with increased levels of interleukin (IL)-8, IL-1α, and IL-1β [15].

Nevertheless, due to slight changes in the immunological composition, IPGM itself should be treated as a distinct inflammatory entity, which may be responsible for further activation of fibroblasts and subsequent tissue damage [10, 11, 15]. It seems that a hypothetical IL-1β pathway proposed by Witte-Händel et al. [16] might be an important contributor to skin infiltration and destruction. According to the authors, large amounts of IL-1β, produced primarily by keratinocytes and macrophages, activate immune cells and fibroblasts, causing a potent production of chemokines, massive infiltration of immune cell, and subsequent skin structure destruction [16].

Immunological features of dermal tunnels were studied by Navrazhina et al. [11]. The authors observed that although the tunnel epithelium may resemble histologically overlying epidermis, it presents increased inflammatory infiltrate with an increased number and densities of T cell, dendritic cell, and neutrophil infiltration [11]. Moreover, the authors detected significantly higher levels of IL-36α, Il-17A, IL-17C, IL-17F, and CXCL8 mRNA in dermal tunnels in comparison to non-tunnel HS skin and healthy controls [11]. Interestingly, the authors described the possible source and mechanism of IPGM production. CXCL2 and CXCL8 transepithelial gradients in tunnels enhance neutrophil migration into the lumen, occurring with or without coexisting luminal biofilm [11].

The role of bacteria propagation in the development and exacerbation of HS is unclear. Although previously, it was believed that Staphylococcus aureus might play an important role in the inflammatory process [17], it was not confirmed in recent studies [18, 19]. Nevertheless, changes in the local microbiome were reported in healthy skin of HS patients. Therefore, one may believe that those alterations may contribute to the development of lesions rather than local bacterial propagation [20]. It is essential to underline that patients with HS tend to develop biofilms in chronic skin lesions [21]. It was confirmed that the majority of biofilms associated with inflammation were found inside the sinus tracts [21]. Only one study was performed on the tunnels’ microbiome in HS [22]. The authors found a potential link between anaerobic bacteria, including Porphyromonas spp. and Prevotella spp., within HS tunnels [22].

Interestingly, biofilm formation is an established virulence factor for Porphyromonas spp. [23]; this may explain antibiotic resistance in severe HS stages with tunnel formation and a possible beneficial effect of anti-biofilm therapy [24]. Furthermore, it has been speculated that the biofilm presence may lead to prolonged inflammation and subsequent exacerbation of the disease [21].

Genetic predispositions seem to be essential features of the development of HS, with 30–40% of patients reporting a family history of the disease [1]. It was observed that patients with HS present mutation in NCSTN, PSEN1, and PSENEN genes, which are essential for the maturation of hair follicles and the functioning of the immune system [25]. Very little is known about the differences in gene expression between tunnel and non-tunnel HS skin. In the sole study by Navrazhina et al. [11], a statistically significant gene upregulation in tunnel samples of pro-inflammatory cytokines (IL-1β, IL-6, and IL-36), keratinocyte-derived factors (S100A7, S100A8, S100A9, and LCN2), antimicrobial factors (DEFB4 and IL26), cytokines and chemokines promoting neutrophil chemotaxis (CXCL1 and CXCL8), neutrophil-associated factors (NCF1C), and B-cell-associated cytokines and chemokines (CD79A, TNFRSF13B, and IL20) were observed [11]. Moreover, downregulation of anti-inflammatory factors (IL-37 and macrophage migration inhibitory factor) indicates an upregulation of pro-inflammatory genes and downregulation of anti-inflammatory ones [11].

Treatment of HS remains a significant challenge for both patients and clinicians. The use of antimicrobials and anti-inflammatory drugs as the first line of HS management often fails to control the disease and further development of skin lesions [1]. The inclusion of multiple immunological pathways in the pathogenesis of HS has been proven [7]. Although adalimumab has already been FDA and EMA approved, the therapeutic role of different biologics in HS management is being studied. Several ongoing clinical trials investigate the efficacy of antibodies targeting IL-17, IL-23, IL-1, and complement inhibitors, [26]. Tunnels and scar tissue management is primarily carried out with deroofing, incisions, and wide tissue excisions [7]. Interestingly, newly developed drugs targeting different subunits of IL-17, which is highly expressed in tunnels, may be beneficial for treating HS static lesions. The results of the phase 2 clinical trial of bimekizumab [27] show that even though a similar percentage of patients treated with adalimumab reached HiSCR50, there was a statistically significant difference in achieving HiSCR75 and HiSCR90 in the bimekizumab group [27]. Similar results were reported for patients treated with brodalumab [28]. Moreover, the authors observed that besides reducing cutaneous nodules and abscesses, the treatment would lead to a reduction in dermal tunnel drainage [28]. This was later confirmed in the ultrasonographic study by Navrazhina et al. [11] on a group of 22 patients treated with brodalumab. The authors reported a statistically significant reduction in the lumen diameter and tunnel inflammation, assessed with Doppler ultrasonography, between the baseline visit and week 12 [11]. These data confirm the necessity to target HS static lesions to achieve higher therapeutic goals.

There is still very little known about the genetic, epigenetic, and cytokine profiles of HS tunnels. All the data mentioned above support the hypothesis that dermal tunnels are an active, inflammatory entity leading to further exacerbation of the disease. Moreover, based on available reports, one may believe that targeting tunnels is a crucial feature of achieving almost complete lesion clearance. Possible implications of tunnels in HS pathogenesis are summarized in Figure 1. Nevertheless, future studies are necessary to assess the differences between nodules, abscesses, and tunnels adequately, as well as investigate the impact of therapies on those lesions.

Fig. 1.

Molecular, microbiological, and genetic implications of tunnels in pathogenesis and exacerbations of HS. IL-interleukin, TNF α, tumor necrosis factor alfa; spp., species; Th, T-helper cell; MMPs, matrix metalloproteinases; IPGM, infiltrative proliferative gelatinous mass; IFN-γ, interferon gamma.

Fig. 1.

Molecular, microbiological, and genetic implications of tunnels in pathogenesis and exacerbations of HS. IL-interleukin, TNF α, tumor necrosis factor alfa; spp., species; Th, T-helper cell; MMPs, matrix metalloproteinases; IPGM, infiltrative proliferative gelatinous mass; IFN-γ, interferon gamma.

Close modal

All these data support the hypothesis that dermal tunnels are active, inflammatory entities with different molecular and genetic profiles.

Figure was adapted from “Basophil-Mediated skin inflammation,” by BioRender.com (2022) and retrieved from https://app.biorender.com/biorender-templates.

Prof. Szepietowski has served as advisory board member/consultant for AbbVie, Leo Pharma, Novartis, Sandoz, Sanofi-Genzyme, Trevi, and Viofor; as a speaker for AbbVie, Janssen-Cilag, Eli-Lilly, Leo Pharma, and Sanofi-Genzyme; and as an investigator in clinical trials for AbbVie, Amgen, BMS, Galderma, Galapagos, Incyte, InfraRX, Janssen-Cilag, Menlo Therapeutics, Merck, Novartis, Pfizer, Regeneron, UCB, and Trevi. Dr. Martorell Calatayud has served as a consultant for and received speaker fees from AbbVie, Celgene, Janssen, Novartis, MSD, UCB, Lilly, Leo Pharma, Isdin, and Pfizer. MD. Krajewski has served as an investigator in clinical trials for Celltrion, InfraRX, Janssen-Cilag, BMS, UCB.

This research was funded by Wroclaw Medical University research grant number SUBK.C260.22.075 and SUBZ. C260.22.056.

Conceptualization, investigation, writing – original draft preparation, and writing – review and editing: Piotr K Krajewski, Jacek C. Szepietowski, and Antonio Martorell; methodology and supervision: Jacek C. Szepietowski and Antonio Martorell; data curation and visualization: Piotr K Krajewski; funding acquisition, Piotr K Krajewski and Jacek C. Szepietowski.

1.
Sabat
R
,
Jemec
GBE
,
Matusiak
Ł
,
Kimball
AB
,
Prens
E
,
Wolk
K
.
Hidradenitis suppurativa
.
Nat Rev Dis Primers
.
2020
;
6
(
1
):
18
.
2.
Calao
M
,
Wilson
JL
,
Spelman
L
,
Billot
L
,
Rubel
D
,
Watts
AD
.
Hidradenitis Suppurativa (HS) prevalence, demographics and management pathways in Australia: a population-based cross-sectional study
.
PLoS One
.
2018
;
13
(
7
):
e0200683
.
3.
Jemec
GB
,
Kimball
AB
.
Hidradenitis suppurativa: epidemiology and scope of the problem
.
J Am Acad Dermatol
.
2015
73
5 Suppl 1
S4
7
.
4.
Kurokawa
I
,
Hayashi
N
Japan Acne Research Society
.
Questionnaire surveillance of hidradenitis suppurativa in Japan
.
J Dermatol
.
2015
;
42
(
7
):
747
9
.
5.
Choi
E
,
Ooi
XT
,
Chandran
NS
.
Hidradenitis suppurativa in pediatric patients
.
J Am Acad Dermatol
.
2022
;
86
(
1
):
140
7
.
6.
Wolk
K
,
Warszawska
K
,
Hoeflich
C
,
Witte
E
,
Schneider-Burrus
S
,
Witte
K
.
Deficiency of IL-22 contributes to a chronic inflammatory disease: pathogenetic mechanisms in acne inversa
.
J Immunol
.
2011
;
186
(
2
):
1228
39
.
7.
Zouboulis
CC
,
Desai
N
,
Emtestam
L
,
Hunger
RE
,
Ioannides
D
,
Juhász
I
.
European S1 guideline for the treatment of hidradenitis suppurativa/acne inversa
.
J Eur Acad Dermatol Venereol
.
2015
;
29
(
4
):
619
44
.
8.
Yu
W
,
Barrett
J
,
Liu
P
,
Parameswaran
A
,
Chiu
ES
,
Lu
CP
.
Novel evidence of androgen receptor immunoreactivity in skin tunnels of hidradenitis suppurativa: assessment of sex and individual variability
.
Br J Dermatol
.
2021
;
185
(
4
):
855
8
.
9.
Vellaichamy
G
,
Braunberger
TL
,
Jones
JL
,
Peacock
A
,
Nahhas
AF
,
Hamzavi
IH
.
Patient-reported outcomes in hidradenitis suppurativa
.
G Ital Dermatol Venereol
.
2019
;
154
(
2
):
137
47
.
10.
Frew
JW
,
Navrazhina
K
,
Marohn
M
,
Lu
PC
,
Krueger
JG
.
Contribution of fibroblasts to tunnel formation and inflammation in hidradenitis suppurativa/acne inversa
.
Exp Dermatol
.
2019
;
28
(
8
):
886
91
.
11.
Navrazhina
K
,
Frew
JW
,
Gilleaudeau
P
,
Sullivan-Whalen
M
,
Garcet
S
,
Krueger
JG
.
Epithelialized tunnels are a source of inflammation in hidradenitis suppurativa
.
J Allergy Clin Immunol
.
2021
;
147
(
6
):
2213
24
.
12.
Jørgensen
AR
,
Thomsen
SF
,
Karmisholt
KE
,
Ring
HC
.
Clinical, microbiological, immunological and imaging characteristics of tunnels and fistulas in hidradenitis suppurativa and Crohn's disease
.
Exp Dermatol
.
2020
;
29
(
2
):
118
23
.
13.
Vanlaerhoven
AMJD
,
Ardon
CB
,
van Straalen
KR
,
Vossen
ARJV
,
Prens
EP
,
van der Zee
HH
.
Hurley III hidradenitis suppurativa has an aggressive disease course
.
Dermatology
.
2018
234
5–6
232
3
.
14.
Martorell
A
,
Giovanardi
G
,
Gomez-Palencia
P
,
Sanz-Motilva
V
.
Defining fistular patterns in hidradenitis suppurativa: impact on the management
.
Dermatol Surg
.
2019
;
45
(
10
):
1237
44
.
15.
Kidacki
M
,
Cong
Z
,
Flamm
A
,
Helm
K
,
Danby
FW
,
Nelson
AM
.
Invasive proliferative gelatinous mass’ of hidradenitis suppurativa contains distinct inflammatory components
.
Br J Dermatol
.
2019
;
181
(
1
):
192
3
.
16.
Witte-Händel
E
,
Wolk
K
,
Tsaousi
A
,
Irmer
ML
,
Mößner
R
,
Shomroni
O
.
The IL-1 pathway is hyperactive in hidradenitis suppurativa and contributes to skin infiltration and destruction
.
J Invest Dermatol
.
2019
;
139
(
6
):
1294
305
.
17.
Jemec
GB
,
Faber
M
,
Gutschik
E
,
Wendelboe
P
.
The bacteriology of hidradenitis suppurativa
.
Dermatology
.
1996
;
193
(
3
):
203
6
.
18.
Katoulis
A
,
Koumaki
V
,
Efthymiou
O
,
Koumaki
D
,
Dimitroulia
E
,
Voudouri
M
.
Staphylococcus aureus carriage status in patients with hidradenitis suppurativa: an observational cohort study in a tertiary referral hospital in athens, Greece
.
Dermatology
.
2020
;
236
(
1
):
31
6
.
19.
Dinh
KM
,
Erikstrup
LT
,
Andersen
RK
,
Andersen
PS
,
Mikkelsen
S
,
Kjerulff
BD
.
Cross-sectional study identifies lower risk of Staphylococcus aureus nasal colonization in Danish blood donors with hidradenitis suppurativa symptoms
.
Br J Dermatol
.
2020
;
183
(
2
):
387
9
.
20.
Wark
KJL
,
Cains
GD
.
The microbiome in hidradenitis suppurativa: a review
.
Dermatol Ther
.
2021
;
11
(
1
):
39
52
.
21.
Ring
HC
,
Bay
L
,
Nilsson
M
,
Kallenbach
K
,
Miller
IM
,
Saunte
DM
.
Bacterial biofilm in chronic lesions of hidradenitis suppurativa
.
Br J Dermatol
.
2017
;
176
(
4
):
993
1000
.
22.
Ring
HC
,
Sigsgaard
V
,
Thorsen
J
,
Fuursted
K
,
Fabricius
S
,
Saunte
DM
.
The microbiome of tunnels in hidradenitis suppurativa patients
.
J Eur Acad Dermatol Venereol
.
2019
;
33
(
9
):
1775
80
.
23.
Mysak
J
,
Podzimek
S
,
Sommerova
P
,
Lyuya-Mi
Y
,
Bartova
J
,
Janatova
T
.
Porphyromonas gingivalis: major periodontopathic pathogen overview
.
J Immunol Res
.
2014
;
2014
:
476068
.
24.
Weigelt
MA
,
Lev-Tov
H
.
Intralesional anti-biofilm therapy for tunnels in patients with hidradenitis suppurativa
.
Ital J Dermatol Venerol
.
2021
;
156
(
5
):
618
9
.
25.
Goldburg
SR
,
Strober
BE
,
Payette
MJ
.
Hidradenitis suppurativa: epidemiology, clinical presentation, and pathogenesis
.
J Am Acad Dermatol
.
2020
;
82
(
5
):
1045
58
.
26.
Goldburg
SR
,
Strober
BE
,
Payette
MJ
.
Hidradenitis suppurativa: current and emerging treatments
.
J Am Acad Dermatol
.
2020
;
82
(
5
):
1061
82
.
27.
Glatt
S
,
Jemec
GBE
,
Forman
S
,
Sayed
C
,
Schmieder
G
,
Weisman
J
.
Efficacy and safety of bimekizumab in moderate to severe hidradenitis suppurativa: a phase 2, double-blind, placebo-controlled randomized clinical trial
.
JAMA Dermatol
.
2021
;
157
(
11
):
1279
88
.
28.
Frew
JW
,
Navrazhina
K
,
Grand
D
,
Sullivan-Whalen
M
,
Gilleaudeau
P
,
Garcet
S
.
The effect of subcutaneous brodalumab on clinical disease activity in hidradenitis suppurativa: an open-label cohort study
.
J Am Acad Dermatol
.
2020
;
83
(
5
):
1341
8
.