Publications by authors named "Christos C Zouboulis"

365 Publications

Case Report: PsAPSASH syndrome: an alternative phenotype of syndromic hidradenitis suppurativa treated with the IL-17A inhibitor secukinumab.

F1000Res 2021 13;10:381. Epub 2021 May 13.

Departments of Dermatology, Venereology, Allergology and Immunology, Dessau Medical Center, Brandenburg Medical School Theodor Fontane and Faculty of Health Sciences Brandenburg, Dessau, 06847, Germany.

Syndromic hidradenitis suppurativa (HS) is a form of symptom constellations, which differs from the familial and genetic form and comprises predominantly osteoarticular manifestations. Many forms include pyoderma gangrenosum and acne (PASH), pyogenic arthritis (PAPASH), spondyloarthritis (PASS) and psoriatic arthritis (PsAPASH) and are categorized in the autoinflammatory syndromes. Anti-TNF-α and anti-IL-1a blockade are between the therapeutic approaches that improve skin symptoms and prevent permanent osteoarticular damage. This case report refers to the successful treatment of a mixed phenotype of the aforementioned symptoms using the IL-17A inhibitor secukinumab after initial treatment with adalimumab. The therapy improved both cutaneous and reported osteoarticular symptoms. Different approaches for these recalcitrant HS syndromes are essential in order to achieve long-term remission for those patients.
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http://dx.doi.org/10.12688/f1000research.52100.2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8424462PMC
May 2021

Interleukins 4 and 13 drive lipid abnormalities in skin cells through regulation of sex steroid hormone synthesis.

Proc Natl Acad Sci U S A 2021 Sep;118(38)

Department of Dermatology, University of Texas Southwestern Medical Center, Dallas, TX 75390;

Atopic dermatitis (AD) is a chronic inflammatory skin disease characterized by skin dryness, inflammation, and itch. A major hallmark of AD is an elevation of the immune cytokines IL-4 and IL-13. These cytokines lead to skin barrier disruption and lipid abnormalities in AD, yet the underlying mechanisms are unclear. Sebaceous glands are specialized sebum-producing epithelial cells that promote skin barrier function by releasing lipids and antimicrobial proteins to the skin surface. Here, we show that in AD, IL-4 and IL-13 stimulate the expression of 3β-hydroxysteroid dehydrogenase 1 (HSD3B1), a key rate-limiting enzyme in sex steroid hormone synthesis, predominantly expressed by sebaceous glands in human skin. HSD3B1 enhances androgen production in sebocytes, and IL-4 and IL-13 drive lipid abnormalities in human sebocytes and keratinocytes through HSD3B1. Consistent with our findings in cells, HSD3B1 expression is elevated in the skin of AD patients and can be restored by treatment with the IL-4Rα monoclonal antibody, Dupilumab. Androgens are also elevated in a mouse model of AD, though the mechanism in mice remains unclear. Our findings illuminate a connection between type 2 immunity and sex steroid hormone synthesis in the skin and suggest that abnormalities in sex steroid hormone synthesis may underlie the disrupted skin barrier in AD. Furthermore, targeting sex steroid hormone synthesis pathways may be a therapeutic avenue to restoring normal skin barrier function in AD patients.
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http://dx.doi.org/10.1073/pnas.2100749118DOI Listing
September 2021

[Cutaneous leishmaniasis in Germany-still a travel-related disease].

Hautarzt 2021 Aug 30. Epub 2021 Aug 30.

Hochschulklinik für Dermatologie, Venerologie und Allergologie, Immunologisches Zentrum, Städtisches Klinikum Dessau, Medizinische Hochschule Brandenburg Theodor Fontane und Fakultät für Gesundheitswissenschaften Brandenburg, Auenweg 38, 06847, Dessau, Deutschland.

Cutaneous leishmaniasis is an infectious disease caused by several Leishmania species. It is transmitted to humans by the bite of the infected female phlebotomus sandfly. Today, more than 1 billion people in leishmaniasis endemic areas are at risk of infection. More than 1.5 million new cases of cutaneous leishmaniasis occur every year. On the basis of two cases, we show that cutaneous leishmaniasis is still an imported tropical disease in Germany. However, due to the increasing intercontinental travel, cases may increase. Therefore, cutaneous leishmaniasis should be considered in the differential diagnosis in patients with nonhealing wounds, ulcers, papules or nodules and the corresponding travel history.
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http://dx.doi.org/10.1007/s00105-021-04890-6DOI Listing
August 2021

Efficacy and Safety of Bimekizumab in Moderate to Severe Hidradenitis Suppurativa: A Phase 2, Double-blind, Placebo-Controlled Randomized Clinical Trial.

JAMA Dermatol 2021 Aug 18. Epub 2021 Aug 18.

UCB Pharma, Slough, United Kingdom.

Importance: Hidradenitis suppurativa (HS) is a chronic inflammatory disease with a high burden for patients and limited existing therapeutic options.

Objective: To evaluate the efficacy and safety of bimekizumab, a monoclonal IgG1 antibody that selectively inhibits interleukin 17A and 17F in individuals with moderate to severe HS.

Design, Setting, And Participants: This phase 2, double-blind, placebo-controlled randomized clinical trial with an active reference arm was performed from September 22, 2017, to February 21, 2019. The study included a 2- to 4-week screening period, a 12-week treatment period, and a 20-week safety follow-up. Of 167 participants screened at multiple centers, 90 were enrolled. Eligible participants were 18 to 70 years of age with a diagnosis of moderate to severe HS 12 months or more before baseline.

Interventions: Participants with HS were randomized 2:1:1 to receive bimekizumab (640 mg at week 0, 320 mg every 2 weeks), placebo, or reference arm adalimumab (160 mg at week 0, 80 mg at week 2, and 40 mg every week for weeks 4-10).

Main Outcomes And Measures: The prespecified primary efficacy variable was the proportion of participants with a 50% or greater reduction from baseline in the total abscess and inflammatory nodule count with no increase in abscess or draining fistula count (Hidradenitis Suppurativa Clinical Response [HiSCR] at week 12. Exploratory variables included proportion achieving a modified HiSCR with 75% reduction of HiSCR criteria (HiSCR75) or a modified HiSCR with 90% reduction of HiSCR criteria (HiSCR90), change in Patient's Global Assessment of Pain, and Dermatology Life Quality Index total scores.

Results: Eighty-eight participants received at least 1 dose of study medication (61 [69%] female; median age, 36 years; range, 18-69 years). Seventy-nine participants completed the study, including safety follow-up. Bimekizumab demonstrated a higher HiSCR rate vs placebo at week 12 (57.3% vs 26.1%; posterior probability of superiority equaled 0.998, calculated using bayesian analysis). Bimekizumab demonstrated greater clinical improvements compared with placebo. Improvements in the International Hidradenitis Suppurativa Severity Score (IHS4) were seen at week 12 with bimekizumab (mean [SD] IHS4, 16.0 [18.0]) compared with placebo (mean [SD] IHS4, 40.2 [32.6]). More bimekizumab-treated participants achieved positive results on stringent outcome measures compared with placebo. At week 12, 46% of bimekizumab-treated participants achieved HiSCR75 and 32% achieved HiSCR90, whereas 10% of placebo-treated participants achieved HiSCR75 and none achieved HiSCR90; in adalimumab-treated participants, 35% achieved HiSCR75 and 15% achieved HiSCR90. One participant withdrew because of adverse events. Serious adverse events occurred in 2 of 46 bimekizumab-treated participants (4%), 2 of 21 placebo-treated participants (10%), and 1 of 21 adalimumab-treated participants (5%).

Conclusions And Relevance: In this phase 2 randomized clinical trial, bimekizumab demonstrated clinically meaningful improvements across all outcome measures, including stringent outcomes. Bimekizumab's safety profile was consistent with studies of other indications, supporting further evaluation in participants with HS.

Trial Registration: ClinicalTrials.gov Identifier: NCT03248531.
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http://dx.doi.org/10.1001/jamadermatol.2021.2905DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8374742PMC
August 2021

Efficacy and Safety of Adalimumab in Conjunction With Surgery in Moderate to Severe Hidradenitis Suppurativa: The SHARPS Randomized Clinical Trial.

JAMA Surg 2021 Aug 18. Epub 2021 Aug 18.

Department of Dermatology, Dessau Medical Center, Brandenburg Medical School Theodor Fontane, Dessau, Germany.

Importance: Surgery is a mainstay in the management of hidradenitis suppurativa (HS). Adalimumab is the first drug approved for HS.

Objective: To investigate the efficacy and safety of adalimumab in combination with wide-excision surgery followed by secondary intention healing.

Design, Setting, And Participants: The Safety and Efficacy of Adalimumab for Hidradenitis Suppurativa Peri-Surgically (SHARPS) trial was a phase 4, randomized, double-blind, placebo-controlled study of adalimumab in conjunction with surgery. Patients were enrolled in 45 sites across 20 countries from July 18, 2016, to February 2, 2019, with the last patient visit on October 16, 2019. Eligible patients (aged 18-65 years) had moderate to severe HS that required radical surgery in an axillary or inguinal region and had 2 other anatomical regions affected, with 1 or more regions at Hurley stage II or III. Analysis was conducted in November 2019.

Interventions: Patients were randomized 1:1 to receive continuous adalimumab, 40 mg, or placebo during presurgery (12 weeks), perioperative (2 weeks), and postoperative (10 weeks) periods.

Main Outcomes And Measures: The primary end point was the proportion of patients achieving HS clinical response across all body regions at week 12.

Results: Overall, 103 patients were randomized to adalimumab and 103 to matching placebo. Among all patients, 51% (n = 106) were women, 94% (n = 193) were White, and the mean (SD) age was 37.6 (11.3) years. At week 12, significantly more patients receiving adalimumab (49 of 103 [48%]) vs placebo (35 of 103 [34%]; P = .049) achieved HS clinical response across all body regions (treatment difference, 14% [95% CI, 0%-27%]). Treatment-emergent adverse events were reported in 74 of 103 patients (72%) and 69 of 103 patients (67%) in the adalimumab and placebo groups, respectively. No increased risk of postoperative wound infection, complication, or hemorrhage was observed with adalimumab vs placebo. Two deaths occurred in the adalimumab group; neither was considered as having a reasonable possibility of relationship to study drug.

Conclusions And Relevance: Adalimumab was efficacious in conjunction with wide-excision surgery followed by secondary intention healing, with no need to interrupt treatment prior to surgery. These data support further investigation of adalimumab as an adjuvant therapy to surgery in patients with moderate to severe HS.

Trial Registration: ClinicalTrials.gov Identifier: NCT02808975.
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http://dx.doi.org/10.1001/jamasurg.2021.3655DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8374740PMC
August 2021

Resveratrol ameliorates lipid accumulation and inflammation in human SZ95 sebocytes via the AMPK signaling pathways in vitro.

J Dermatol Sci 2021 Jul 24. Epub 2021 Jul 24.

Department of Dermatology, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, PR China. Electronic address:

Background: Acne vulgaris is a prevalent skin disease lacking effective and well-tolerated treatment. An earlier study indicated that resveratrol (RVT) has therapeutic effects in acne patients through unknown mechanisms.

Objectives: To evaluate the effects of RVT on linoleic acid (LA)-induced lipogenesis and peptidoglycan (PGN)-induced inflammation in cultured SZ95 sebocytes in vitro, and to investigate the underlying mechanisms.

Methods: RNA-sequencing was used to analyze the whole transcriptome. Nile red staining was used to detect intracellular neutral lipids, whereas lipidomics was used to investigate changes in the lipid profile in sebocytes. Interleukin (IL)-1β and IL-6 mRNA and protein levels were assessed through quantitative real-time PCR and Enzyme-linked immunosorbent assay, respectively. Western blot was used to evaluate the expression of lipogenesis-related proteins, the inflammatory signaling pathway, and the AMP-activated protein kinase (AMPK) pathway. Further, specific small interfering RNA (siRNA) was used to knockdown sirtuin-1 (SIRT1) expression.

Results: RVT inhibited the lipogenesis-related pathway and nuclear factor-kappa B (NF-κB) signaling pathway in SZ95 sebocytes. It also downregulated LA-induced lipogenesis, the expression of lipid-related proteins, and the contents of unsaturated fatty acids. Besides, RVT promoted SIRT1 expression and deacetylation of the NF-κB p65 subunit, thereby lowering IL-1β and IL-6 secretion under PGN induction. Furthermore, pretreatment with AMPK inhibitor Compound C abolished RVT-mediated sebosuppressive and anti-inflammation effects. Meanwhile,SIRT1 silencing abrogated the anti-inflammatory potential of RVT.

Conclusion: In human SZ95 sebocytes, RVT exhibits sebosuppressive and anti-inflammatory effects partially through the AMPK pathway, which may justify the role of RVT treatment in acne vulgaris.
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http://dx.doi.org/10.1016/j.jdermsci.2021.07.010DOI Listing
July 2021

[Hidradenitis suppurativa/acne inversa: From "orphan disease" to a curable inflammatory skin disorder].

Hautarzt 2021 Aug 29;72(8):647-650. Epub 2021 Jul 29.

Klinik und Poliklinik für Dermatologie und Venerologie, Uniklinik Köln, Köln, Deutschland.

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http://dx.doi.org/10.1007/s00105-021-04863-9DOI Listing
August 2021

Anti-Inflammatory and Pro-Differentiating Properties of the Aryl Hydrocarbon Receptor Ligands NPD-0614-13 and NPD-0614-24: Potential Therapeutic Benefits in Psoriasis.

Int J Mol Sci 2021 Jul 13;22(14). Epub 2021 Jul 13.

Laboratory of Cutaneous Physiopathology and Integrated Center of Metabolomics Research, San Gallicano Dermatological Institute, IRCCS, 00144 Rome, Italy.

The aryl hydrocarbon receptor (AhR), a ligand-activated transcription factor expressed in all skin cell types, plays a key role in physiological and pathological processes. Several studies have shown that this receptor is involved in the prevention of inflammatory skin diseases, e.g., psoriasis, atopic dermatitis, representing a potential therapeutic target. We tested the safety profile and the biological activity of NPD-0614-13 and NPD-0614-24, two new synthetic AhR ligands structurally related to the natural agonist FICZ, known to be effective in psoriasis. NPD-0614-13 and NPD-0614-24 did not alter per se the physiological functions of the different skin cell populations involved in the pathogenesis of inflammatory skin diseases. In human primary keratinocytes stimulated with tumor necrosis factor-α or lipopolysaccharide the compounds were able to counteract the altered proliferation and to dampen inflammatory signaling by reducing the activation of p38MAPK, c-Jun, NF-kBp65, and the release of cytokines. Furthermore, the molecules were tested for their beneficial effects in human epidermal and full-thickness reconstituted skin models of psoriasis. NPD-0614-13 and NPD-0614-24 recovered the psoriasis skin phenotype exerting pro-differentiating activity and reducing the expression of pro-inflammatory cytokines and antimicrobial peptides. These data provide a rationale for considering NPD-0614-13 and NPD-0614-24 in the management of psoriasis.
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http://dx.doi.org/10.3390/ijms22147501DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8304622PMC
July 2021

Metabolic Disorders/Obesity Is a Primary Risk Factor in Hidradenitis Suppurativa: An Immunohistochemical Real-World Approach.

Dermatology 2021 Jul 22:1-9. Epub 2021 Jul 22.

Departments of Dermatology, Venereology, Allergology and Immunology, Dessau Medical Center, Brandenburg Medical School Theodor Fontane and Faculty of Health Sciences Brandenburg, Dessau, Germany.

Background: Hidradenitis suppurativa (HS) is an inflammatory, potentially scarring disease of the hair follicle, affecting the apocrine gland-bearing skin areas. The major comorbid disorders associated with the occurrence or the aggravation of the disease are obesity and smoking. Numerous efforts to dissociate these factors led to controversial results.

Objectives: To assess the importance of metabolic disorders/obesity, smoking/environmental toxins, and inflammation in HS by utilizing the differential expression of major relevant protein markers in lesional skin of obese/smoking versus non-obese/non-smoking HS patients.

Methods: Lesional skin specimens deriving from two groups of HS patients (BMI >30 and smokers, n = 12 vs. BMI <30 and non-smokers, n = 10) were stained with antibodies raised against irisin, PPARγ, and IGF-1R, which correlate with metabolic disorders/obesity, EGFR and AhR, associated with smoking, and IL-17, IL-17R, and S100A8, as markers of inflammation.

Results: Metabolic disorders/obesity-related markers exhibited marked differential expression between the two groups, while smoking-associated markers a limited one. IL-17R expression was stronger in obese/smokers, and S100A8 staining exhibited intense strong immunoreactivity in both groups without significant difference.

Conclusions: The notion that obesity plays a role in HS development appears to be supported by the prominent regulation of the associated lesional biomarkers. Tobacco smoking might contribute less to HS than previously suspected.
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http://dx.doi.org/10.1159/000517017DOI Listing
July 2021

Quality of Life in Hidradenitis Suppurativa: An Update.

Int J Environ Res Public Health 2021 06 6;18(11). Epub 2021 Jun 6.

European Hidradenitis Suppurativa Foundation e.V., 06847 Dessau, Germany.

Knowledge on hidradenitis suppurativa/acne inversa (HS) is rapidly increasing. HS has a profound impact on patients and their family life. Several factors, such as comorbidities, unemployment and HS severity, make this impact even more severe. The most widely used instrument to measure this impact is the dermatology-specific DLQI. We also identified six HS-specific health-related quality of life (HRQoL) instruments. Of them, HIDRAdisk, HSIA, HiSQOL and HSQoL-24 are better validated but there is still lack of experience of its use. Several treatment methods showed positive effect on patients' HRQoL. Surgery remains a method with a substantial positive effect on HRQoL. Several studies confirming a positive effect of adalimumab on the HRQoL of patients with HS were published during the last three years. Data on the influence of several other biologics on HRQoL of HS patients are controversial or based on studies with a small number of patients.
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http://dx.doi.org/10.3390/ijerph18116131DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8201351PMC
June 2021

Porphyrins produced by acneic strains activate the inflammasome by inducing K leakage.

iScience 2021 Jun 21;24(6):102575. Epub 2021 May 21.

Laboratory of Pharmaceutical Microbiology, Faculty of Pharmaceutical Sciences, Ghent University, 9000 Ghent, Belgium.

Some subgroups dominate on healthy skin, whereas others are frequently acne associated. Here we provide mechanistic insights into this difference, using an anaerobic keratinocyte-sebocyte- co-culture model. An acneic strain as well as its porphyrins activates NRLP3 inflammasome assembly, whereas this was not observed with a non-acneic strain. Low levels of intracellular K in keratinocytes stimulated with extracted porphyrins or infected with the acneic strain were observed, identifying porphyrin-induced K leakage as trigger for inflammasome activation. Using a panel of strains, we found that porphyrin production and IL-1β release are correlated and are higher in acneic strains. This demonstrates that the latter produce more porphyrins, which interact with the keratinocyte cell membrane, leading to K leakage, NLRP3 inflammasome activation, and IL-1β release and provides an explanation for the observation that some strains are associated with healthy skin, whereas others dominate in acneic skin.
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http://dx.doi.org/10.1016/j.isci.2021.102575DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8188554PMC
June 2021

Ferredoxin reductase regulates proliferation, differentiation, cell cycle and lipogenesis but not apoptosis in SZ95 sebocytes.

Exp Cell Res 2021 08 4;405(2):112680. Epub 2021 Jun 4.

Department of Dermatology, Affiliated Hospital of Guangdong Medical University, Zhanjiang, Guangdong, China; Medical Cosmetic and Plastic Surgery Center, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China. Electronic address:

Ferredoxin reductase (FDXR), a mitochondrial membrane-associated flavoprotein, is essential for electron transfer and modulates p53-dependent apoptosis in cancer cells.FDXR may be implicated in epidermal and sebocytic differentiation, but its explicit function in sebocytes remains to be elucidated. In the present study, immunohistochemistry revealed that FDXR expression was increased in sebaceous cells of acne lesions. FDXR, PPARγ, LXRα/β, SREBP1 and Sox9 expression was incremental during sebocyte differentiation. FDXR overexpression induced by Ad-GFP-FDXR infection enhanced differentiation, reactive oxygen species (ROS), lipogenesis and PPARγ expression, and consequnently inhibited proliferation in SZ95 sebocytes. Flow cytometry showed that FDXR overexpression induced significant blockade of G2/M phase but had no effect on sub-G1 (apoptotic) sebocytes. Insulin-like growth factor-1 (IGF-1)-induced FDXR and PPARγ expression and lipogenesis were abolished by pretreatment with PI3K inhibitor LY294002. These results suggest that FDXR overexpression might promote differentiation and lipogenesis via ROS production and suppress proliferation via G2/S blockade in SZ95 sebocytes. IGF-1 could facilitate differentiation and lipogenesis through PI3K/Akt/FDXR pathway. FDXR could serve as a potential marker of advanced sebaceous differentiation, and its overexpression may be involved in the development of acne lesions.
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http://dx.doi.org/10.1016/j.yexcr.2021.112680DOI Listing
August 2021

Hidradenitis suppurativa in skin of colour.

Exp Dermatol 2021 Jun;30 Suppl 1:27-30

Department of Dermatology, Howard University College of Medicine, Washington DC, USA.

Hidradenitis suppurativa/acne inversa (HS) more prevalent and disproportionally affects African American females. Although there are limited studies in HS skin of colour populations in the USA, there is more scarcity of HS skin of colour studies in other countries, which limits the overall understanding of the disease among these patients. Herein, our overview of the 10th European Hidradenitis Suppurativa Foundation (EHSF) e.V. Conference provided a crude example of the limited number of skin of colour physicians, physician scientists and inclusion of skin of colour patients highlighting the need to increase awareness of this important issue. We summarized the epidemiology, pathogenesis, clinical picture and focused on treatment options from southeast Asia and Africa. Our outlined general recommendations for diagnosis will render better clinical care and outcomes for diverse patient populations.
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http://dx.doi.org/10.1111/exd.14341DOI Listing
June 2021

Anti-COVID-19 measurements for hidradenitis suppurativa patients.

Exp Dermatol 2021 06;30 Suppl 1:18-22

European Hidradenitis Suppurativa Foundation e.V., Dessau, Germany.

The reported incidence of COVID-19 among cohorts of patients with inflammatory bowel and skin diseases under treatment with biologicals is low. Treatment may further modify disease severity as some biological modifiers, such as anakinra, are also proposed for the management of COVID-19 patients potentially providing HS patients with an advantage. The above preliminary evidence suggests that hidradenitis suppurativa (HS) does probably not provide an increased susceptibility for COVID-19 and that any susceptibility is unlikely to be modified negatively by treatment with biologicals. On the occasion of its 10th International Conference, experts of the European Hidradenitis Suppurativa Foundation e.V. have prepared a consensus statement regarding anti-COVID-19 measurements for HS patients. Based on the available knowledge, patients with HS may be vaccinated against SARS-CoV2 and patients affected by metabolic syndrome constitute a high-risk group for COVID-19 and should be vaccinated at the earliest convenient point in time. HS patients on treatment with adalimumab can be vaccinated with non-living virus anti-SARS-CoV2 vaccines. A possible suboptimal effect of the vaccine may be suspected but might not be expected universally. The management of the biological treatment in HS patients is at the discretion of the dermatologist / responsible physician.
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http://dx.doi.org/10.1111/exd.14339DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8207032PMC
June 2021

Target molecules for future hidradenitis suppurativa treatment.

Exp Dermatol 2021 Jun;30 Suppl 1:8-17

European Hidradenitis Suppurativa Foundation e.V., Dessau, Germany.

The registration of the tumour necrosis factor-α inhibitor adalimumab in 2015 was a major step forward in the treatment of hidradenitis suppurativa/acne inversa (HS). However, it soon became evident that the effectiveness of adalimumab in daily practice was highly variable. A significant unmet medical need of HS patients remained, and the search for novel therapeutic targets was intensified. During the 10th European Hidradenitis Suppurativa Foundation (EHSF) e.V. Conference, reknown international HS investigators virtually presented and discussed the published data on these potential target molecules for future HS treatment. This article addresses the most promising molecules currently under investigation from a pathophysiological and clinical point of view. With phase III trials ongoing, the anti- interleukin (IL)-17 biologics bimekizumab and secukinumab are in the most advanced stage of clinical development showing promising results. In addition, targeting IL-1α with bermekimab has shown encouraging results in two clinical trials. Directing treatment at neutrophil recruitment and activation by targeting IL-36 with spesolimab fits well in the pathogenic concept of HS and clinical phase II trial results are pending. In contrast to in situ evidence, Complement 5a (C5a) and C5a receptor blockade have only shown greater clinical benefit in patients with severe HS. Inhibition of Janus kinase (JAK) 1 signalling in HS showed clinical efficacy only in the highest dosage, highlighting that careful surveillance of the balance between safety and efficacy of JAK inhibition is warranted. Overall, clinical efficacies of all novel treatments reported so far are modest. To guide drug development, more and better-defined translational data on the pathogenesis of this severe and enigmatic inflammatory skin disease are required.
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http://dx.doi.org/10.1111/exd.14338DOI Listing
June 2021

3D-SeboSkin Model for Human ex vivo Studies of Hidradenitis Suppurativa/Acne Inversa.

Dermatology 2021 Jun 2:1-8. Epub 2021 Jun 2.

Departments of Dermatology, Venereology, Allergology, and Immunology, Dessau Medical Center, Brandenburg Medical School Theodor Fontane and Faculty of Health Sciences Brandenburg, Dessau, Germany.

Background: Hidradenitis suppurativa/acne inversa (HS) is a chronic, recurrent inflammatory skin disease. Its pivotal pathogenetic event is believed to be the occlusion of the hair follicle generating a perifollicular lympho-histiocytic inflammation. However, knowledge of the exact HS pathogenesis requires further research.

Objective: To develop a human HS model applicable in preclinical research which could help to understand the pathophysiology of HS and to determine the action of therapeutic candidates.

Methods: The 3D-SeboSkin technology was applied to maintain explants of involved and uninvolved skin of HS patients ex vivo for 3 days. Detection of differential expression of previously detected HS biomarkers was performed by immunohistochemistry in a group of female patients (n = 9, mean age 37.2 ± 8.4 years).

Results: The application of the 3D-SeboSkin model preserved the structural integrity of lesional and perilesional HS skin ex vivo, as previously described for healthy skin. Moreover, the HS 3D-SeboSkin setting maintained the differential expression and pattern of several HS biomarkers (S100A9, KRT16, SERPINB3) in epidermal and dermal tissue and the appendages.

Conclusion: We have validated HS 3D-SeboSkin as a reproducible, human model, which is appropriate for preclinical lesional and perilesional HS skin studies ex vivo.
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http://dx.doi.org/10.1159/000515955DOI Listing
June 2021

Prevalence of Hidradenitis Suppurativa: A Systematic Review and Meta-regression Analysis.

JAMA Dermatol 2021 Aug;157(8):924-931

Departments of Dermatology, Venereology, Allergology and Immunology, Dessau Medical Center, Brandenburg Medical School Theodor Fontane and Faculty of Health Sciences Brandenburg, Dessau, Germany.

Importance: Hidradenitis suppurativa/acne inversa (HS) is a chronic inflammatory skin disease characterized by occlusion of hair follicles as a primary pathogenic factor. There are scarce data regarding the prevalence of HS.

Objective: To estimate overall HS prevalence.

Data Sources: This review and meta-regression analysis was conducted using the Meta-analysis of Observational Studies in Epidemiology (MOOSE) reporting guideline. The academic search included PubMed, Cochrane registry, ClinicalTrials.gov, and evidence by NHS UK and Trip databases from inception through May 2020. To analyze HS prevalence, only cross-sectional studies or baseline assessments of longitudinal cohorts using census-based surveys or probabilistic and nonprobabilistic epidemiologic methods were considered. The search terms were (prevalence OR incidence OR epidemiology) AND (hidradenitis suppurativa OR acne inversa OR Verneuil's disease). No language restriction was applied.

Study Selection: Original investigations that reported HS prevalence were included. After exclusion criteria were applied, 17 studies qualified for qualitative analysis, but only 16 studies were quantitatively assessed.

Data Extraction And Measures: Two reviewers extracted data by age, diagnostic criteria, presence of any comorbidity, sample sizes, continent/location, sex, and other characteristics. Assessment of bias risk used the Joanna Briggs Institute Critical Appraisal Instrument for Studies Reporting Prevalence Data using random-effects models to synthesize available evidence.

Main Outcomes And Measures: Hidradenitis suppurativa prevalence (with 95% CI) among the overall population and among subgroups. Between-study heterogeneity was assessed (Cochran Q statistic) and quantified (I2 statistic).

Results: In 16 quantitatively assessed studies included, prevalence estimates were reported only from Western European and Scandinavian countries, the US, and Australia. Meta-analysis with random effects, after adjusting for publication bias in the prevalence estimates, revealed a 0.40% prevalence (95% CI, 0.26%-0.63%) for HS. Studies based on clinical samples revealed a higher pooled prevalence of HS (1.7%) than population-based studies (0.3%).

Conclusions And Relevance: The findings of this systematic review and meta-regression analysis may help facilitate policy formulation, channeling funding and guiding principles for better disease diagnosis using universal valid tools and management.
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http://dx.doi.org/10.1001/jamadermatol.2021.1677DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8156162PMC
August 2021

Epidermal Growth Factor Modulates Palmitic Acid-Induced Inflammatory and Lipid Signaling Pathways in SZ95 Sebocytes.

Front Immunol 2021 6;12:600017. Epub 2021 May 6.

Department of Dermatology, Faculty of Medicine, University of Debrecen, Debrecen, Hungary.

Epidermal growth factor (EGF) acts as a paracrine and autocrine mediator of cell proliferation and differentiation in various types of epithelial cells, such as sebocytes, which produce the lipid-rich sebum to moisturize the skin. However, sebum lipids direct contact and by penetrating through the epidermis may have regulatory roles on epidermal and dermal cells as well. As EGF receptor (EGFR) is expressed throughout the proliferating and the lipid-producing layers of sebaceous glands (SGs) in healthy and acne-involved skin, we investigated the effect of EGF on SZ95 sebocytes and how it may alter the changes induced by palmitic acid (PA), a major sebum component with bioactive roles. We found that EGF is not only a potent stimulator of sebocyte proliferation, but also induces the secretion of interleukin (IL)6 and down-regulates the expression of genes involved in steroid and retinoid metabolism. Importantly, when applied in combination with PA, the PA-induced lipid accumulation was decreased and the cells secreted increased IL6 levels. Functional clustering of the differentially regulated genes in SZ95 sebocytes treated with EGF, PA or co-treated with EGF+PA further confirmed that EGF may be a potent inducer of hyperproliferative/inflammatory pathways (IL1 signaling), an effect being more pronounced in the presence of PA. However, while a group of inflammatory genes was up-regulated significantly in EGF+PA co-treated sebocytes, PA treatment in the absence of EGF, regulated genes only related to cell homeostasis. Meta-analysis of the gene expression profiles of whole acne tissue samples and EGF- and EGF+PA -treated SZ95 sebocytes showed that the EGF+PA co-activation of sebocytes may also have implications in disease. Altogether, our results reveal that PA-induced lipid accumulation and inflammation can be modulated by EGF in sebocytes, which also highlights the need for system biological approaches to better understand sebaceous (immuno)biology.
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http://dx.doi.org/10.3389/fimmu.2021.600017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8134683PMC
June 2021

Histone Deacetylase 1 Reduces Lipogenesis by Suppressing SREBP1 Transcription in Human Sebocyte Cell Line SZ95.

Int J Mol Sci 2021 Apr 25;22(9). Epub 2021 Apr 25.

Department of Dermatology, Seoul National University College of Medicine, Seoul 03080, Korea.

Proper regulation of sebum production is important for maintaining skin homeostasis in humans. However, little is known about the role of epigenetic regulation in sebocyte lipogenesis. We investigated histone acetylation changes and their role in key lipogenic gene regulation during sebocyte lipogenesis using the human sebaceous gland cell line SZ95. Sebocyte lipogenesis is associated with a significant increase in histone acetylation. Treatment with anacardic acid (AA), a p300 histone acetyltransferase inhibitor, significantly decreased the lipid droplet number and the expression of key lipogenic genes, including sterol regulatory-binding protein 1 (SREBP1), fatty acid synthase (FAS), and acetyl-CoA carboxylase (ACC). In contrast, treatment with trichostatin A (TSA), a histone deacetylase (HDAC) inhibitor, increased the expression of these genes. Global HDAC enzyme activity was decreased, and HDAC1 and HDAC2 expression was downregulated during sebaceous lipogenesis. Interestingly, HDAC1 knockdown increased lipogenesis through SREBP1 induction, whereas HDAC1 overexpression decreased lipogenesis and significantly suppressed promoter activity. HDAC1 and SREBP1 levels were inversely correlated in human skin sebaceous glands as demonstrated in immunofluorescence images. In conclusion, HDAC1 plays a critical role in reducing SREBP1 transcription, leading to decreased sebaceous lipogenesis. Therefore, HDAC1 activation could be an effective therapeutic strategy for skin diseases related to excessive sebum production.
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http://dx.doi.org/10.3390/ijms22094477DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8123291PMC
April 2021

Lokale anticholinerge Therapie multipler ekkriner Hidrozystome: Bericht über zwei Fälle und Literaturübersicht.

J Dtsch Dermatol Ges 2021 Apr;19(4):605-607

Hochschulklinik für Dermatologie, Venerologie und Allergologie, Immunologisches Zentrum, Städtisches Klinikum Dessau, Medizinische Hochschule Brandenburg Theodor Fontane und Fakultät für Gesundheitswissenschaften Brandenburg, Dessau.

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http://dx.doi.org/10.1111/ddg.14398_gDOI Listing
April 2021

Different Types of Auricular Keloids and Treatment by Intralesional Cryosurgery: Best Practice for Obtaining Long-Lasting Clinical Results.

Dermatology 2021 Apr 7:1-10. Epub 2021 Apr 7.

Departments of Dermatology, Venereology, Allergology and Immunology, Dessau Medical Center, Brandenburg Medical School Theodor Fontane and Faculty of Health Sciences Brandenburg, Dessau, Germany.

Background: Auricular keloids belong to the most perplexing medical conditions, which have significant psychosocial impact on the patient's body image and quality of life.

Summary: The article is purposed to provide dermatologists and plastic surgeons with the best proven practice using intralesional cryosurgery for the treatment of the different auricular keloid types in order to obtain superior clinical results by minimizing the probability of recurrence. In the past 20 years, the authors have developed novel procedures in order to increase the effectiveness of intralesional cryosurgery on auricular keloids, including hydrodissection, warm gauze technique, and excision of dangling skin. Long-lasting clinical results with a low recurrence rate and a satisfactory aesthetic outcome are achieved with no deformation of the ear framework.
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http://dx.doi.org/10.1159/000514954DOI Listing
April 2021

Formalin-killed Propionibacterium acnes activates the aryl hydrocarbon receptor and modifies differentiation of SZ95 sebocytes in vitro.

Eur J Dermatol 2021 Feb;31(1):32-40

Department of Dermatology, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, PR China.

Background: Acne vulgaris is a common pilosebaceous disease associated with Propionibacterium acnes (P. acnes). Resolution of comedones may occur in association with shrunken sebaceous glands (SGs) containing de-differentiated cells, however the role of P. acnes is unclear.

Objectives: To investigate the effects of P. acnes on aryl hydrocarbon receptor (AhR) activation, lipogenesis and differentiation in cultured immortalized human SZ95 sebocytes.

Materials & Methods: Cultured sebocytes were incubated with formalin-killed (f-) P. acnes (f-P. acnes) at different ratios of multiplicity of infection. The mRNA levels of the AhR downstream cytochrome P450 (CYP) genes were measured by quantitative RT-PCR, nuclear translocation of AhR by western blot and immunofluorescence, lipogenesis and keratinization by gene set enrichment analysis (GSEA), lipid related analysis by Oil red O staining and Nile red staining, and sebaceous differentiation-related gene expression by western blot.

Results: f-P. acnes upregulated CYPs mRNA levels and induced translocation of AhR protein from the cytoplasm into the nucleus. GSEA revealed downregulation of lipogenesis and upregulation of keratinization. f-P. acnes inhibited linoleic acid-induced neutral lipid synthesis and expression of sebocyte markers, keratin 7 and mucin1/EMA, but increased expression of keratinocyte markers, keratin 10 and involucrin, which were abolished by AhR gene silencing. Inhibition of lipogenesis-related genes, such as sterol response element-binding protein, was also observed.

Conclusion: f-P. acnes inhibits lipogenesis and induces terminal differentiation of sebocytes, into keratinocyte-like cells, via activation of the AhR pathway in vitro, suggesting that follicular P. acnes is not only acnegenic but also promotes acne remission through feedback regulation of sebum production.
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http://dx.doi.org/10.1684/ejd.2021.3964DOI Listing
February 2021

Involvement of Pattern Recognition Receptors in the Direct Influence of Bacterial Components and Standard Antiacne Compounds on Human Sebaceous Gland Cells.

Skin Pharmacol Physiol 2021 18;34(1):19-29. Epub 2021 Feb 18.

Department of Internal Medicine III, University Hospital Carl Gustav Carus, University of Dresden, Dresden, Germany.

Introduction: Pattern recognition receptors are involved in innate and adaptive immunity by detecting microbial components. Bacteria have been accused to play a role in inflammatory acne. We investigated the potential involvement of Toll-like receptor (TLR)2, TLR4, TLR6, and CD14 in the direct influence of bacterial components and standard antiacne compounds on human sebocytes.

Methods: mRNA and protein expression of TLR2, TLR4, TLR6, and CD14 in SZ95 sebocytes was evaluated by real-time qRT-PCR and immunocytochemistry. The effects of lipopolysaccharides (LPS) and lipoteichoic acid on TLR2, TLR4, and CD14 expression and of cytokine/chemokine secretion by 13-cis-retinoic acid, all-trans-retinoic acid, retinol, and hydrocortisone at the mRNA and protein levels were assessed by real-time qRT-PCR and ELISA and verified by cocultivation with neutralizing antibodies.

Results: The constitutive expression of TLR2, TLR4, and CD14 in SZ95 sebocytes was augmented by exposure to LPS. Hydrocortisone induced TLR2, but markedly reduced TLR4 expression. 13-cis-retinoic acid and all-trans-retinoic acid regulated IL-6 release. LPS enhanced and hydrocortisone reduced cytokine and chemokine release. Anti-TLR4 and anti-CD14 mAb blocked LPS-induced IL-8 and IL-6 release.

Conclusions: Microbial components use pattern recognition receptors to directly activate sebocytes to express a wide range of proinflammatory molecules and especially IL-8 and IL-6 in a TLR4- and CD14-specific manner. Retinoids, but mostly corticosteroids, also use this pathway to exhibit anti-inflammatory effects.
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http://dx.doi.org/10.1159/000513259DOI Listing
February 2021

[Low-dose, long-term fumaric acid esters in recalcitrant cutaneous sarcoidosis : Report of two cases].

Hautarzt 2021 Oct 17;72(10):909-912. Epub 2021 Feb 17.

Hochschulklinik für Dermatologie, Venerologie und Allergologie, Immunologisches Zentrum, Städtisches Klinikum Dessau, Medizinische Hochschule Brandenburg Theodor Fontane und Fakultät für Gesundheitswissenschaften Brandenburg, Auenweg 38, 06847, Dessau, Deutschland.

Fumaric acid esters lead to reduction of cell fusion and inhibition of giant cell formation in vitro, which is considered to be a reason for their therapeutic effect on cutaneous granulomatous diseases. We have reported that successful treatment of the skin lesions of a patient with recalcitrant systemic sarcoidosis with Fumaderm® (Biogen, Munich, Germany; 360-720 mg/day dimethyl fumarate) had to be discontinued due to the development of lymphocytopenia. Therefore, we treated two further patients with the low-dose Fumaderm® Initial (90 mg/day dimethyl fumarate) and observed a partial remission of the skin lesions over a minimum 18 month follow-up without signs of lymphocytopenia.
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http://dx.doi.org/10.1007/s00105-021-04766-9DOI Listing
October 2021

Local anticholinergic treatment for multiple eccrine hidrocystomas: report of two cases and literature review.

J Dtsch Dermatol Ges 2021 04 14;19(4):605-607. Epub 2021 Jan 14.

Departments of Dermatology, Venereology, Allergology and Immunology, Dessau Medical Center, Brandenburg Medical School Theodor Fontane and Faculty of Health Sciences Brandenburg, Dessau, Germany.

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http://dx.doi.org/10.1111/ddg.14398DOI Listing
April 2021

Phylotype I and II Strains Interact Differently With Human Skin Cells.

Front Cell Infect Microbiol 2020 16;10:575164. Epub 2020 Nov 16.

Laboratory of Pharmaceutical Microbiology, Ghent University, Ghent, Belgium.

Acne vulgaris is one of the most common skin disorders and affects the pilosebaceous units. Although the exact pathogenesis of acne is still unknown, (formerly known as ) is considered one of the key contributing factors. In fact, a significant association exists between strains belonging to phylotype I and acne. However, there is still heavy debate on the exact role of in acne and its behavior in the pilosebaceous unit, and more specifically its interactions with the human skin cells. In this study, key elements of the host-pathogen interaction were studied for a collection of strains, belonging to phylotype I and II, including association with HaCaT keratinocytes and SZ95 sebocytes, the effect of on keratinocyte tight junctions in a HaCaT monoculture and in an additional keratinocyte-sebocyte co-culture model, and invasion through the keratinocyte cell layer. Our data showed association of all strains to both skin cell lines, with a significantly higher association of type I strains compared to type II strains. Microscopic imaging and western blot analysis of the tight junction protein ZO-1, together with transepithelial electrical resistance (TEER) measurements revealed an initial induction of keratinocyte tight junctions after 24 h infection but a degradation after 48 h, demonstrating a decline in cell lining integrity during infection. Subsequently, was able to invade after 48 h of infection, although invasion frequency was significantly higher for type II strains compared to type I strains.
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http://dx.doi.org/10.3389/fcimb.2020.575164DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7717938PMC
June 2021

Cryosurgery as a Single Agent and in Combination with Intralesional Corticosteroids Is Effective on Young, Small Keloids and Induces Characteristic Histological and Immunohistological Changes: A Prospective Randomized Trial.

Dermatology 2021 4;237(3):396-406. Epub 2020 Dec 4.

Department of Dermatology, Andreas Sygros Hospital, National and Kapodistrian University of Athens, Athens, Greece.

Background: As the pathogenesis of keloids is poorly understood, there is no sound biological basis of keloid management. Few controlled therapeutic studies have been published, and recurrences are a major reason for treatment failure.

Objective: To detect efficacy and safety of cryosurgery regimens on keloids and the occurring biological changes caused by the treatment.

Methods: This prospective randomized study compared efficacy and tolerability as well as histological/immunohistochemical effects of liquid nitrogen contact cryosurgery as a single regimen (group A) and combined with intralesional corticosteroids (group B) on young (<2 years old), small (≤10 cm2) keloids in 40 patients (2-sided effect, α-error 1%, power 95%).

Results: Marked flattening of the lesions was achieved by both regimens. Median lesional volumes decreased from 106 to 7 mm3 in group A (p = 0.001) and from 138 to 6 mm3 in group B (p < 0.0001; ns, between groups). Good to excellent responses were registered in 83.3 and 90% of patients in groups A and B, respectively, by evaluating the lesional volume, in 80 and 95% of patients by the physician's evaluation and in 95% of patients in either group by the patient's assessment. Follow-up of 6-36 months revealed no further significant changes. Cryosurgery was generally well tolerated, with minor pain during treatment not requiring (27.5%) or requiring local anaesthesia (5%) - but not analgesics -, and hypopigmentation (25%). Histological examination showed increased vessel number and lumen dilatation after treatment in group B and reduction of rete ridge length in both groups with more prominent changes in group A. Tenascin C staining demarcated keloids from normal skin before therapy, while after therapy the entire treated tissue was labelled. Interferon-γ expression was significantly decreased after therapy both regarding positively stained cells and intensity in both groups.

Conclusion: Cryosurgery without and with intralesional corticosteroids is effective and safe on young, small keloids not only as a destructive physical procedure, but also by inducing biochemical and immunological scar rejuvenation.
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http://dx.doi.org/10.1159/000511624DOI Listing
December 2020

[Persistent, unilateral eczema of the nipple in a man].

Hautarzt 2021 Jul;72(7):615-618

Hochschulklinik für Dermatologie, Venerologie und Allergologie, Immunologisches Zentrum, Städtisches Klinikum Dessau, Medizinische Hochschule Brandenburg Theodor Fontane und Fakultät für Gesundheitswissenschaften Brandenburg, Auenweg 38, 06847, Dessau, Deutschland.

A 69-year-old man presented with a 12-month history of unilateral eczematous changes of the left nipple and areola without any signs of systemic inflammation. His main complaints were mild, intermittent itching, and occasionally local pain or burning. An external initial treatment with topical corticosteroids combined with disinfectants/antibiotics did not lead to an improvement. Triggering factors or any other conditions that could affect the diagnosis could not be detected. Histopathological examination of a biopsy from the left nipple performed at admission confirmed the suspected diagnosis of Paget disease. Radical left breast mastectomy was performed and the patient is under regular follow-up.
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http://dx.doi.org/10.1007/s00105-020-04724-xDOI Listing
July 2021

The Pro-Differentiation Effect of Doxycycline on Human SZ95 Sebocytes.

Dermatology 2021 22;237(5):792-796. Epub 2020 Oct 22.

The UCD Charles Institute of Dermatology, University College Dublin, Dublin, Ireland.

Background: Despite their widespread clinical use in both acne vulgaris and rosacea, the effects of tetracyclines on sebocytes have not been investigated until now. Sebaceous glands are central to the pathogenesis of acne and may be important in the development of rosacea.

Objective: The aim of this study was to assess the effects of doxycycline on the immortalized SZ95 sebaceous gland cell line as a model for understanding possible effectiveness on the sebaceous glands in vivo.

Methods: The effects of doxycycline on SZ95 sebocyte numbers, viability, and lipid content as well as its effects on the mRNA levels of peroxisome proliferator-activated receptors α and γ, in comparison to the peroxisome proliferator-activated receptor γ agonist troglitazone, were investigated.

Results: Doxycycline reduced the cell number and increased the lipid content of SZ95 sebocytes in vitro after 2 days of treatment. These doxycycline effects may be explained by an upregulation of peroxisome proliferator-activated receptor γ mRNA levels at 12 and 24 h, whereas troglitazone already upregulated peroxisome proliferator-activated receptor γ levels after 6 h. Both compounds did not influence peroxisome proliferator-activated receptor α mRNA levels.

Conclusion: These new findings illustrate a previously unknown effect of doxycycline on sebocytes, which may be relevant to their modulation of disorders of the pilosebaceous unit, such as acne vulgaris and rosacea.
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http://dx.doi.org/10.1159/000510885DOI Listing
October 2020

What causes hidradenitis suppurativa ?-15 years after.

Exp Dermatol 2020 12;29(12):1154-1170

European Hidradenitis Suppurativa Foundation e.V., Dessau, Germany.

The 14 authors of the first review article on hidradenitis suppurativa (HS) pathogenesis published 2008 in EXPERIMENTAL DERMATOLOGY cumulating from the 1st International Hidradenitis Suppurativa Research Symposium held March 30-April 2, 2006 in Dessau, Germany with 33 participants were prophetic when they wrote "Hopefully, this heralds a welcome new tradition: to get to the molecular heart of HS pathogenesis, which can only be achieved by a renaissance of solid basic HS research, as the key to developing more effective HS therapy." (Kurzen et al. What causes hidradenitis suppurativa? Exp Dermatol 2008;17:455). Fifteen years later, there is no doubt that the desired renaissance of solid basic HS research is progressing with rapid steps and that HS has developed deep roots among inflammatory diseases in Dermatology and beyond, recognized as "the only inflammatory skin disease than can be healed". This anniversary article of 43 research-performing authors from all around the globe in the official journal of the European Hidradenitis Suppurativa Foundation e.V. (EHSF e.V.) and the Hidradenitis Suppurativa Foundation, Inc (HSF USA) summarizes the evidence of the intense HS clinical and experimental research during the last 15 years in all aspects of the disease and provides information of the developments to come in the near future.
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http://dx.doi.org/10.1111/exd.14214DOI Listing
December 2020
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