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Hidradenitis Suppurativa and Related Disorders

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (15 February 2023) | Viewed by 24984

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Special Issue Editors

Dr. Kerstin Wolk

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Guest Editor

1. Psoriasis Research and Treatment Center, Department of Dermatology and Allergy, Institute of Medical Immunology, University Medicine Charité, Charitéplatz 1, 10117 Berlin, Germany
2. Berlin-Brandenburg Center of Regenerative Therapies, University Medicine Charité, Augustenburger Platz 1, 13353 Berlin, Germany
Interests: chronic inflammatory skin diseases; epithelia-targeting cytokines; cytokine networks; epidermal immune defense; skin barrier; epigenetic memory of the inflamed skin

Dr. Robert Sabat

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Guest Editor

Interdisciplinary Group of Molecular Immunopathology, Dermatology/Medical Immunology, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, 10117 Berlin, Germany
Interests: chronic inflammatory skin diseases; link between local inflammation and systemic comorbidity; novel cytokines; T cell subpopulations; transplantation immunology; innovative treatments for chronic inflammation; biomarkers; biologics

Prof. Dr. Johann Gudjonsson

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Guest Editor

Department of Dermatology, University of Michigan, Ann Arbor, MI 48109, USA
Interests: chronic inflammatory skin diseases; autoimmunity; sex bias; stromal-immune interactions; keratinocytes; fibroblasts; bioinformatics; single-cell and spatial-seq technologies

Special Issue Information

Dear Colleagues,

Hidradenitis suppurativa (HS) is a chronic inflammatory skin disease affecting ~1% of the Western population. HS manifests with painful, deep-seated inflamed nodules, abscesses and pus-draining epithelialized tunnels that develop primarily in axillary, inguinal, gluteal and perianal body areas (1). In addition, patients often suffer from systemic comorbidities, such as metabolic syndrome, arteriosclerosis and spondyloarthritis. HS not only profoundly impairs affected individuals’ private and professional lives but also reduces their life expectancy. The pathomechanisms underlying the skin inflammation in HS are only partially understood. Skin lesions are known to harbor highly activated immune cells, including neutrophils, macrophages, T cells and B cells. As the disease progresses, these cells provoke pus formation and local destruction of the physiological skin architecture. IL-1, TNF-α, IL-17 and G-CSF apper to play important roles in these processes. Interestingly, some similar molecular pathomechanisms have been found in other chronic skin diseases, such as folliculitis decalvans (FD), pyoderma gangrenosum (PG), acne conglobate (AC), palmoplantar pustulosis (PPP) and pityriasis rubra pilaris (PRP).

The paucity of knowledge about the pathogenesis of HS, FD, PG, AC, PPP or PRP is largely responsible for the currently very limited treatment options for these diseases. This Special Issue aims to provide a platform for dedicated scientists to publish recent discoveries on the pathogenesis of HS and related skin disorders, thereby advancing our understanding of the molecular mechanisms of these diseases and stimulating the development of innovative, targeted therapeutics.

Topics of interest for this Special Issue include, but are not limited to:

Molecular mechanisms through which lifestyle factors drive the onset of the diseases;
Molecular and immunological pathomechanisms underling skin inflammation;
Role of innate immune receptors (PRPs);
Crosstalk between tissue and immune cells in the inflamed skin;
Mediators of the dysfunction of keratinocytes, fibroblasts, or endothelial cells;
Molecular markers of immune cell heterogeneity;
Elements linking cutaneous inflammation to systemic commodities;
Potential novel therapeutic targets for the treatment of the diseases;
Molecular or immunological biomarkers for the severity or progressive course of the diseases.

(1) Hidradenitis suppurativa. Sabat R, Jemec GBE, Matusiak Ł, Kimball AB, Prens E, Wolk K. Nat Rev Dis Primers. 2020 Mar 12;6(1):18.

Dr. Kerstin Wolk
Dr. Robert Sabat
Prof. Dr. Johann Gudjonsson
Guest Editors

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Keywords

hidradenitis suppurativa
acne inversa
palmoplantar pustulosis
pyoderma gangrenosum
inflammation
cytokines
IL-1
IL-17
TNF
G-CSF
inflammasome
intercellular communication
T cells
B cells
plasma cells
neutrophilic granulocytes
omics
therapeutic targets

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Published Papers (8 papers)

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Research

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16 pages, 2551 KiB

Open AccessArticle

Blood T Helper Memory Cells: A Tool for Studying Skin Inflammation in HS?

by Katrin Witte, Sylke Schneider-Burrus, Gabriela Salinas, Rotraut Mössner, Kamran Ghoreschi, Kerstin Wolk and Robert Sabat

Int. J. Mol. Sci. 2023, 24(10), 8854; https://doi.org/10.3390/ijms24108854 - 16 May 2023

Cited by 3 | Viewed by 1826

Abstract

Hidradenitis suppurativa (HS) is an inflammatory skin disease characterized by painful lesions on intertriginous body areas such as the axillary, inguinal, and perianal sites. Given the limited treatment options for HS, expanding our knowledge of its pathogenetic mechanisms is a prerequisite for novel therapeutic developments. T cells are assumed to play a crucial role in HS pathogenesis. However, it is currently unknown whether blood T cells show specific molecular alterations in HS. To address this, we studied the molecular profile of CD4⁺ memory T (Th_mem) cells purified from the blood of patients with HS and matched healthy participants. About 2.0% and 1.9% of protein-coding transcripts were found to be up- and down-regulated in blood HS Th_mem cells, respectively. These differentially expressed transcripts (DETs) are known to be involved in nucleoside triphosphate/nucleotide metabolic processes, mitochondrion organization, and oxidative phosphorylation. The detected down-regulation of transcripts involved in oxidative phosphorylation suggest a metabolic shift of HS Th_mem cells towards glycolysis. The inclusion of transcriptome data from skin from HS patients and healthy participants in the analyses revealed that in HS skin lesions, the expression pattern of transcripts identified as DETs in blood HS Th_mem cells was very similar to the expression pattern of the totality of protein-coding transcripts. Furthermore, there was no significant association between the extent of the expressional changes in the DETs of blood HS Th_mem cells and the extent of the expressional changes in these transcripts in HS skin lesions compared to healthy donor skin. Additionally, a gene ontology enrichment analysis did not demonstrate any association of the DETs of blood HS Th_mem cells with skin disorders. Instead, there were associations with different neurological diseases, non-alcoholic fatty liver disease, and thermogenesis. The levels of most DETs linked to neurological diseases showed a positive correlation to each other, suggesting common regulatory mechanisms. In summary, the transcriptomic changes in blood Th_mem cells observed in patients with manifest cutaneous HS lesions do not appear to be characteristic of the molecular changes in the skin. Instead, they could be useful for studying comorbidities and identifying corresponding blood biomarkers in these patients. Full article

(This article belongs to the Special Issue Hidradenitis Suppurativa and Related Disorders)

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13 pages, 5462 KiB

Open AccessArticle

Modulation of Disease-Associated Pathways in Hidradenitis Suppurativa by the Janus Kinase 1 Inhibitor Povorcitinib: Transcriptomic and Proteomic Analyses of Two Phase 2 Studies

by Huiqing Liu, Leandro L. Santos and Susan H. Smith

Int. J. Mol. Sci. 2023, 24(8), 7185; https://doi.org/10.3390/ijms24087185 - 13 Apr 2023

Cited by 8 | Viewed by 2704

Abstract

Janus kinase (JAK)/signal transducer and activator of transcription signaling (STAT) has been implicated in the pathophysiology of hidradenitis suppurativa (HS). This study evaluated treatment-related transcriptomic and proteomic changes in patients with moderate-to-severe HS treated with the investigational oral JAK1-selective inhibitor povorcitinib (INCB054707) in two phase 2 trials. Lesional skin punch biopsies (baseline and Week 8) were taken from active HS lesions of patients receiving povorcitinib (15 or 30 mg) once daily (QD) or a placebo. RNA-seq and gene set enrichment analyses were used to evaluate the effects of povorcitinib on differential gene expression among previously reported gene signatures from HS and wounded skin. The number of differentially expressed genes was the greatest in the 30 mg povorcitinib QD dose group, consistent with the published efficacy results. Notably, the genes impacted reflected JAK/STAT signaling transcripts downstream of TNF-α signaling, or those regulated by TGF-β. Proteomic analyses were conducted on blood samples obtained at baseline and Weeks 4 and 8 from patients receiving povorcitinib (15, 30, 60, or 90 mg) QD or placebo. Povorcitinib was associated with transcriptomic downregulation of multiple HS and inflammatory signaling markers as well as the reversal of gene expression previously associated with HS lesional and wounded skin. Povorcitinib also demonstrated dose-dependent modulation of several proteins implicated in HS pathophysiology, with changes observed by Week 4. The reversal of HS lesional gene signatures and rapid, dose-dependent protein regulation highlight the potential of JAK1 inhibition to modulate underlying disease pathology in HS. Full article

(This article belongs to the Special Issue Hidradenitis Suppurativa and Related Disorders)

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19 pages, 1637 KiB

Open AccessArticle

Metformin Treatment of Hidradenitis Suppurativa: Effect on Metabolic Parameters, Inflammation, Cardiovascular Risk Biomarkers, and Immune Mediators

by Roisin Hambly, Niamh Kearney, Rosalind Hughes, Jean M. Fletcher and Brian Kirby

Int. J. Mol. Sci. 2023, 24(8), 6969; https://doi.org/10.3390/ijms24086969 - 9 Apr 2023

Cited by 4 | Viewed by 4728

Abstract

Hidradenitis suppurativa (HS) is a common cutaneous and systemic inflammatory disease with a significant impact on mental health and quality of life. It is associated with obesity, insulin resistance, metabolic syndrome, cardiovascular (CV) disease, and increased all-cause mortality. Metformin is used frequently in HS treatment and is effective for some patients. The mechanism of action of metformin in HS is unknown. A case-control study of 40 patients with HS (20 on metformin and 20 controls) was conducted to assess differences in metabolic markers, inflammation (C-reactive protein [CRP], serum adipokines, and CV risk biomarkers), and serum immune mediators. Body mass index (BMI), insulin resistance (77%), and metabolic syndrome (44%) were high overall, but not significantly different between the groups. This highlights the need for co-morbidity screening and management. A significant reduction in fasting insulin and a trend towards a reduction in insulin resistance were identified in the metformin group compared with pre-treatment levels. CV risk biomarkers were significantly favourable in the metformin group (lymphocytes, monocyte–lymphocyte ratio, neutrophil–lymphocyte ratio, and platelet–lymphocyte ratio). CRP was lower in the metformin group but was not statistically significant. Adipokines were dysregulated overall but were not different between the two groups. Serum IFN-γ, IL-8, TNF-α, and CXCL1 trended lower in the metformin group but did not reach significance. These results suggest that metformin improves CV risk biomarkers and insulin resistance in patients with HS. When the results of this study are considered alongside other studies in HS and related conditions, it is likely that metformin also has beneficial effects on metabolic markers and systemic inflammation in HS (CRP, serum adipokines, and immune mediators), warranting further research. Full article

(This article belongs to the Special Issue Hidradenitis Suppurativa and Related Disorders)

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11 pages, 445 KiB

Open AccessArticle

Screening for Diabetes Mellitus in Patients with Hidradenitis Suppurativa—A Monocentric Study in Germany

by Nessr Abu Rached, Thilo Gambichler, Lennart Ocker, Johannes W. Dietrich, Daniel R. Quast, Christina Sieger, Caroline Seifert, Christina Scheel and Falk G. Bechara

Int. J. Mol. Sci. 2023, 24(7), 6596; https://doi.org/10.3390/ijms24076596 - 1 Apr 2023

Cited by 12 | Viewed by 2764

Abstract

Hidradenitis suppurativa (HS) is a chronic skin disease that is often associated with metabolic disorders. Diabetes mellitus (DM) is a frequent comorbidity in HS. There is currently no established screening for DM in HS patients. The aim of our study was to identify high-risk groups of HS patients that develop DM and to assess the frequency of different types of DM present in HS patients. To do so, we conducted a monocentric study in 99 patients with HS. All patients underwent detailed clinical and laboratory assessments, including the determination of glycated hemoglobin. Among the 20.2% of patients that presented with DM, type 2 was by far the most prevalent (19 out of 20 patients). Moreover, male gender, age, BMI, Hurley stage, modified Hidradenitis Suppurativa Score (mHSS), DLQI and hypertension all correlated with the glycated hemoglobin levels in the HS patients. In the multivariable analysis, Hurley stage III, older age, and higher BMI were significantly associated with DM. Specifically, patients at Hurley stage III were at a 5.3-fold increased risk of having DM type II compared to patients at earlier Hurley stages. Since many of the HS patients had not been diagnosed, our study reveals shortcomings in the screening for DM and suggest that this should be routinely performed in HS patients at high risk to avoid secondary complications. Full article

(This article belongs to the Special Issue Hidradenitis Suppurativa and Related Disorders)

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12 pages, 3710 KiB

Open AccessArticle

Interleukin-19 Levels Are Increased in Palmoplantar Pustulosis and Reduced following Apremilast Treatment

by Kerstin Wolk, Dagmar Wilsmann-Theis, Katrin Witte, Theresa-Charlotte Brembach, Christian Kromer, Sascha Gerdes, Kamran Ghoreschi, Kristian Reich, Rotraut Mössner and Robert Sabat

Int. J. Mol. Sci. 2023, 24(2), 1276; https://doi.org/10.3390/ijms24021276 - 9 Jan 2023

Cited by 5 | Viewed by 2297

Abstract

Palmoplantar pustulosis (PPP) is a chronic inflammatory skin disease characterised by neutrophilic granulocyte (neutrophil)-filled pustules on the palms and soles. The pathogenesis of PPP is poorly understood. This study conducted an identification of the immune mediators associated with PPP and an exploration of apremilast treatment effects on them. We screened for immune mediators elevated in blood taken from 68 patients with PPP versus control participants and included the most promising parameters in the protocol of phase the 2, multicentre study of apremilast (PDE4 inhibitor) in 21 patients with moderate-to-severe PPP (APLANTUS; EudraCT 2016-005122-11) for respective analysis of blood and skin samples of study patients. We investigated stimulated neutrophils and three-dimensional reconstituted epidermis cultures. Interleukin (IL)-19 was found to be the most upregulated immune mediator in the blood of PPP patients. IL-19 serum levels were independent of patients’ age, gender, and BMI but were associated with strongly upregulated cutaneous IL-19 expression and correlated with the number of palmoplantar pustules. In patients participating in the APLANTUS study, apremilast reduced pustules more effectively than erythema and scaling. Moreover, this treatment significantly reduced IL-19 blood and skin levels. The reduction in IL-19 blood levels at week 4 correlated with the reduction in pustule counts at week 20 (end of treatment). IL-19 was expressed by neutrophils activated in vitro and induced CXCL6, a neutrophil-attracting chemokine, in epidermis models. This work demonstrates elevated IL-19 levels in the blood and skin of PPP patients and suggests a relevant role of this cytokine in the appearance of pustules in this disorder. It also suggests the suitability of IL-19 blood levels as a predictive biomarker for the treatment response of PPP patients, which should be validated in further studies. Full article

(This article belongs to the Special Issue Hidradenitis Suppurativa and Related Disorders)

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13 pages, 1818 KiB

Open AccessArticle

Serum Immunoglobulin G Is a Marker of Hidradenitis Suppurativa Disease Severity

by Dillon Mintoff, Isabella Borg and Nikolai P. Pace

Int. J. Mol. Sci. 2022, 23(22), 13800; https://doi.org/10.3390/ijms232213800 - 9 Nov 2022

Cited by 5 | Viewed by 1960

Abstract

Hidradenitis suppurativa (HS) is a chronic inflammatory condition of the skin that is brought about by autoinflammation and hyperkeratosis at the pilosebaceous unit. The clinical severity of HS can be measured using static (Hurley Severity Scoring (HSS)) and/or dynamic (International HS Severity Scoring System (IHS4)) severity scoring instruments. However, few clinically available serological parameters have been found to correlate with disease severity. In this study, we sought to investigate the role of serum immunoglobulin (Ig) G, M and A levels as biomarkers of disease severity and to compare them with other, more conventional inflammatory indices, such as the erythrocyte sedimentation rate, C-reactive protein, the neutrophil–lymphocyte ratio, the platelet–lymphocyte ratio and the systemic immune-inflammation index. In this cross-sectional study, patients were recruited from the only dermatology referral centre in Malta, Europe, and subjected to clinical examination and the assessment of inflammatory and immunologic parameters. Serum IgG, M and A levels were assessed using the Atellica^® NEPH 630 System (SIEMENS-Healthineers AF, Erlangen, Germany) nephelometric analyser. Serum IgG, M and A levels correlate with both dynamic and static HS severity scoring systems. Serum IgG behaves as a marker of severe HS disease as categorised by HSS and the IHS4. Our findings suggest that the serum IgG level can be used in the clinical setting as a biomarker of disease severity and, therefore, as an adjunct to clinical severity scoring. Full article

(This article belongs to the Special Issue Hidradenitis Suppurativa and Related Disorders)

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Review

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22 pages, 895 KiB

Open AccessReview

The Role of Hormones in Hidradenitis Suppurativa: A Systematic Review

by Nessr Abu Rached, Thilo Gambichler, Johannes W. Dietrich, Lennart Ocker, Caroline Seifert, Eggert Stockfleth and Falk G. Bechara

Int. J. Mol. Sci. 2022, 23(23), 15250; https://doi.org/10.3390/ijms232315250 - 3 Dec 2022

Cited by 25 | Viewed by 4542

Abstract

Hidradenitis suppurativa (HS) is a chronic inflammatory disease manifesting in inverse body regions. In a systematic review, the role of hormones in HS will be presented to better understand the pathomechanisms of HS. The review is based on the PRISMA criteria. Systematic research was carried out using keywords. Subsequently, the data were analyzed based on the clinical response and other relevant information. The main focus of our systematic review was on HS manifestation, exacerbation, sex hormones, antiandrogen therapy, thyroid function, polycystic ovary syndrome, insulin resistance, and adipokines. In HS, there appears to be a dysregulated adipokine release that is shifted towards pro-inflammatory adipokines. Insulin resistance is significantly more common in HS than in healthy patients regardless of BMI, age, and gender. Insulin resistance in HS patients leads to further cardiovascular disease. The mechanism of insulin resistance and role of adipokines should be investigated in future studies to better provide the pathomechanisms of HS. The role of androgens seems to be important in a certain subgroup of female patients. Anti-androgenic therapy can be useful and helpful in some patients. However, further studies are needed to better understand the hormonal relationship in HS. Full article

(This article belongs to the Special Issue Hidradenitis Suppurativa and Related Disorders)

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16 pages, 1787 KiB

Open AccessReview

Phytotherapeuthics Affecting the IL-1/IL-17/G-CSF Axis: A Complementary Treatment Option for Hidradenitis Suppurativa?

by Katrin Witte, Robert Sabat, Ellen Witte-Händel, Kamran Ghoreschi and Kerstin Wolk

Int. J. Mol. Sci. 2022, 23(16), 9057; https://doi.org/10.3390/ijms23169057 - 13 Aug 2022

Cited by 4 | Viewed by 2821

Abstract

Hidradenitis suppurativa (HS; also designated as acne inversa) is a chronic inflammatory disease characterized by painful skin lesions that occur in the axillary, inguinal, gluteal and perianal areas of the body. These lesions contain recurring deep-seated, inflamed nodules and pus-discharging abscesses and fistulas. Affecting about 1% of the population, this common disease has gained appropriate clinical attention in the last years. Associated with numerous comorbidities including metabolic syndrome, HS is considered a systemic disease that severely impairs the quality of life and shortens life expectancy. Therapeutic options for HS are limited, comprising long-term antibiotic treatment, the surgical removal of affected skin areas, and neutralization of TNF-α, the only approved systemic treatment. Novel treatment options are needed to close the therapeutic gap. HS pathogenesis is increasingly better understood. In fact, neutrophilic granulocytes (neutrophils) seem to be decisive for the development of the purulent destructive skin inflammation in HS. Recent findings suggest a key role of the immune mediators IL-1β, IL-17A and G-CSF in the migration into and activation of neutrophils in the skin. Although phytomedical drugs display potent immunoregulatory properties and have been suggested as complementary therapy in several chronic disorders, their application in HS has not been considered so far. In this review, we describe the IL-1/IL-17/G-CSF axis and evaluate it as potential target for an integrated phytomedical treatment of HS. Full article

(This article belongs to the Special Issue Hidradenitis Suppurativa and Related Disorders)

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