Acne Inversa Patients Research Articles

Discovery and Potential Functional Characterization of Long Noncoding RNAs Associated with Familial Acne Inversa with NCSTN Mutation

Background: Long noncoding RNAs (lncRNAs) are associated with many dermatologic diseases. However, little is known about the regulatory function of lncRNAs in familial acne inversa (AI) patients with nicastrin (NCSTN) mutation. Objectives: The aim of this study was to explore the regulatory function of lncRNAs in familial AI patients with NCSTN mutation. Methods: The expression profiles of lncRNAs and mRNAs in skin tissues from familial AI patients with NCSTN mutation and healthy individuals were analysed in this study via RNA sequencing (RNA-seq). Results: In total, 359 lncRNAs and 1,863 mRNAs were differentially expressed between the two groups. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses revealed that the dysregulated mRNAs targeted by lncRNAs were mainly associated with the immune regulation, Staphylococcus aureus infection and B cell receptor signalling pathways. The lncRNA-miRNA-mRNA coexpression network contained 265 network pairs comprising 55 dysregulated lncRNAs, 11 miRNAs, and 74 mRNAs. Conservation analysis of the differentially expressed lncRNAs between familial AI patients with NCSTN mutation and Ncstn keratinocyte-specific knockout (Ncstn^ΔKC) mice identified 6 lncRNAs with sequence conservation; these lncRNAs may participate in apoptosis, proliferation, and skin barrier function. Conclusions: These findings provide a direction for exploring the regulatory mechanisms underlying the progression of familial AI patients with NCSTN mutation.

γ-Secretase mutations in acne inversa

Acne inversa is a chronic inflammatory skin disease of the folliculo-sebaceous-apocrine unit. Currently, genetic and immunological factors are hot topics in the study of its pathogenesis. Genetic factors are mainly related to γ-secretase mutations, and abnormal expression of the γ-secretase-Notch axis leads to increased keratinization of hair follicles and inflammation in some patients with haploinsufficiency of the γ-secretase gene. Mutations in the γ-secretase gene are not necessary for acne inversa, and the risk of Alzheimer′s disease in familial acne inversa patients still remains unclear. Some progress has been made in researches on the association of genotype with phenotype in acne inversa patients, but further studies with large sample size are needed for verification. Key words: Hidradenitis suppurativa; γ-Secretase; Mutation; Receptors, Notch; Pathogenesis

Nicastrin/miR-30a-3p/RAB31 Axis Regulates Keratinocyte Differentiation by Impairing EGFR Signaling in Familial Acne Inversa

Nicastrin (NCSTN) mutations are associated with familial acne inversa (AI), and emerging evidence suggests that microRNAs (miRNAs) are involved in various skin diseases. However, whether NCSTN mutations affect miRNA levels and their subsequent signaling pathways in familial AI patients has not been studied. We aimed to elucidate the relationship between NCSTN mutations and familial AI pathogenesis by investigating differential miRNA expression and their related pathways. Combined with miRNA microarray data from familial AI patients, Ncstn keratinocyte-specific-knockout (NcstnΔKC) mice and bioinformatics predictions showed that NCSTN mutations led to decreased miR-30a-3p levels, which negatively regulated RAB31 expression. Moreover, enhanced RAB31 levels accelerated degradation of activated EGFR, leading to abnormal differentiation in keratinocytes. The impaired EGFR signaling and its effects on epidermal differentiation were also observed in familial AI patients and NcstnΔKC mice. Thus, our study showed that miR-30a-3p/RAB31/EGFR signaling pathway may play a key role in the pathogenesis of familial AI with NCSTN mutations.

Acne inversa/hidradenitis suppurativa: An update

Acne inversa (AI)/hidradenitis suppurativa is achronic, recurrent, immune-mediated dermatosis characterized by deep inflammatory nodules, abscesses, fistulas, and undermined scars in skin areas bearing apocrine glands. In addition to the cutaneous manifestation, numerous AI patients show metabolic changes, spondyloarthritis, and depression. AI leads to astrong reduction in the quality of life and an impairment of the sexual life of affected individuals and often culminates in social withdrawal, stigmatization, unemployment, and suicidal thoughts. In this overview, we summarized the most important facts about AI and propose asimple algorithm for therapy.

439 Mechanisms underlying the different susceptibility to cutaneous viral infections in atopic dermatitis versus psoriasis

436 Lipocalin-2 as a novel biomarker in Acne inversa K Wolk, E Witte, A Tsaousi, K Witte, H Volk, W Sterry, J Wenzel, S Schneider-Burrus and R Sabat 1 Interdisciplinary Group of Molecular Immunopathology, Dermatology/Medical Immunology, University Hospital Charite, Berlin, Germany, 2 Berlin-Brandenburg Center for Regenerative Therapies, University Hospital Charite, Berlin, Germany, 3 Department of Dermatology and Allergy, University Hospital Charite, Berlin, Germany and 4 Department of Dermatology and Allergy, University of Bonn, Bonn, Germany Acne inversa (AI) patients present with painful and disabling cutaneous nodules, abscesses, fistulae and extensive scarring, typically situated within the large humid skin folds of the axillary, inguinal, perianal and/or submammary areas. In addition, AI patients frequently suffer from metabolic, endocrinological, and psychological morbidities. The high burden of patients contrasts with the fragmentary understanding of underlying pathogenetic processes and the lack of biomarkers reflecting the inflammatory state. To illuminate this issue we individually quantified the levels of 40 parameters in the blood of AI patients including proteins and microRNAs. These analyses revealed lipocalin-2 (LCN2) to be most significantly upregulated. Regarding the cellular sources, we demonstrated that neutrophilic granulocytes, abundant in AI lesions, secreted LCN2 especially after TNFa stimulation. Furthermore, LCN2 production was evident for keratinocytes in response to TNFa with amplifying contribution of IL-17A, but not for fibroblasts or endothelial cells. Accordingly, LCN2 levels positively correlated with systemic TNFa levels in AI. LCN2 blood levels also positively correlated with the disease severity. In-depth analyses revealed a link between LCN2 blood levels and the number of regions with inflammatory nodes and fistulas, but not with the number of scars. Functionally, we found evidences for a role of LCN2 in cardiovascular alterations as deduced from the correlation between LCN2 and both resistin and chemerin blood levels. In summary, we demonstrate elevated LCN2 levels in skin lesions and blood of AI patients, shed light on their cellular sources, suggest their role in metabolic comorbidities, and recommend LCN2 as blood biomarker for AI disease activity. 437 Integrated molecular and morphological characterization of psoriasis skin provides insights into disease mechanisms U Wehkamp, F Degenhardt, E Rodriguez, H Baurecht, N Volks, F Thielking, A Franke and S Weidinger 1 Department of Dermatology, University Hospital Schleswig-Holstein, Kiel, Germany and 2 Institute of Clinical Molecular Biology, Christian-Albrechts-University, Kiel, Germany Skin global gene expression profiling has indicated the presence of distinct gene expression signatures in patients with inflammatory skin diseases such as atopic dermatitis and psoriasis. However, many studies suffer from small sample sizes, imperfect patient and biopsy matching, and limitations related to the use of microarray technologies. We here assessed the cutaneous transcriptomal architecture in 28 patients and 39 healthy controls matched for age, sex and site of biopsy using next generation sequencing generating w26 million (median) paired-end reads per sample. We performed a differential gene expression (DEG) analysis using DESeq2 adjusting for age, gender and experimental conditions. Functional annotation was performed using the R-package goseq and the Gene Ontology database. DEGs were defined by absolute log2 fold-change (FC) of above 1 and a Benjamini-Hochberg corrected pvalue of below 0.05. The absolute number of detected genes ranged between 23.000 and 29.000. Digital image analysis was performed including total cell count, CD3, CD8 and neutrophil elastase expression in relation to epidermal and dermal area. First analyses identified 11 and 5554 transcripts differentially expressed in non-lesional psoriasis (PN) versus healthy skin (NN) and lesional psoriasis (PL) versus NN (11/2104 upand 0/3450 downregulated), respectively. In non-lesional psoriatic skin, upregulated genes were related to epidermal differentiation and neutrophil aggregation. These genes were further strongly upregulated in PL with an approx. 5 fold log2FC. Compared to PN, in PL also an upregulation of multiple genes associated with Th17 inflammation and neutrophil chemotaxis and aggregation was observed. Currently pathway and gene co-expression network analysis as well as correlation analysis with tissue composition based on computer-aided quantitative analysis of digital images is being performed.

436 Lipocalin-2 as a novel biomarker in Acne inversa

436 Lipocalin-2 as a novel biomarker in Acne inversa K Wolk, E Witte, A Tsaousi, K Witte, H Volk, W Sterry, J Wenzel, S Schneider-Burrus and R Sabat 1 Interdisciplinary Group of Molecular Immunopathology, Dermatology/Medical Immunology, University Hospital Charite, Berlin, Germany, 2 Berlin-Brandenburg Center for Regenerative Therapies, University Hospital Charite, Berlin, Germany, 3 Department of Dermatology and Allergy, University Hospital Charite, Berlin, Germany and 4 Department of Dermatology and Allergy, University of Bonn, Bonn, Germany Acne inversa (AI) patients present with painful and disabling cutaneous nodules, abscesses, fistulae and extensive scarring, typically situated within the large humid skin folds of the axillary, inguinal, perianal and/or submammary areas. In addition, AI patients frequently suffer from metabolic, endocrinological, and psychological morbidities. The high burden of patients contrasts with the fragmentary understanding of underlying pathogenetic processes and the lack of biomarkers reflecting the inflammatory state. To illuminate this issue we individually quantified the levels of 40 parameters in the blood of AI patients including proteins and microRNAs. These analyses revealed lipocalin-2 (LCN2) to be most significantly upregulated. Regarding the cellular sources, we demonstrated that neutrophilic granulocytes, abundant in AI lesions, secreted LCN2 especially after TNFa stimulation. Furthermore, LCN2 production was evident for keratinocytes in response to TNFa with amplifying contribution of IL-17A, but not for fibroblasts or endothelial cells. Accordingly, LCN2 levels positively correlated with systemic TNFa levels in AI. LCN2 blood levels also positively correlated with the disease severity. In-depth analyses revealed a link between LCN2 blood levels and the number of regions with inflammatory nodes and fistulas, but not with the number of scars. Functionally, we found evidences for a role of LCN2 in cardiovascular alterations as deduced from the correlation between LCN2 and both resistin and chemerin blood levels. In summary, we demonstrate elevated LCN2 levels in skin lesions and blood of AI patients, shed light on their cellular sources, suggest their role in metabolic comorbidities, and recommend LCN2 as blood biomarker for AI disease activity. 437 Integrated molecular and morphological characterization of psoriasis skin provides insights into disease mechanisms U Wehkamp, F Degenhardt, E Rodriguez, H Baurecht, N Volks, F Thielking, A Franke and S Weidinger 1 Department of Dermatology, University Hospital Schleswig-Holstein, Kiel, Germany and 2 Institute of Clinical Molecular Biology, Christian-Albrechts-University, Kiel, Germany Skin global gene expression profiling has indicated the presence of distinct gene expression signatures in patients with inflammatory skin diseases such as atopic dermatitis and psoriasis. However, many studies suffer from small sample sizes, imperfect patient and biopsy matching, and limitations related to the use of microarray technologies. We here assessed the cutaneous transcriptomal architecture in 28 patients and 39 healthy controls matched for age, sex and site of biopsy using next generation sequencing generating w26 million (median) paired-end reads per sample. We performed a differential gene expression (DEG) analysis using DESeq2 adjusting for age, gender and experimental conditions. Functional annotation was performed using the R-package goseq and the Gene Ontology database. DEGs were defined by absolute log2 fold-change (FC) of above 1 and a Benjamini-Hochberg corrected pvalue of below 0.05. The absolute number of detected genes ranged between 23.000 and 29.000. Digital image analysis was performed including total cell count, CD3, CD8 and neutrophil elastase expression in relation to epidermal and dermal area. First analyses identified 11 and 5554 transcripts differentially expressed in non-lesional psoriasis (PN) versus healthy skin (NN) and lesional psoriasis (PL) versus NN (11/2104 upand 0/3450 downregulated), respectively. In non-lesional psoriatic skin, upregulated genes were related to epidermal differentiation and neutrophil aggregation. These genes were further strongly upregulated in PL with an approx. 5 fold log2FC. Compared to PN, in PL also an upregulation of multiple genes associated with Th17 inflammation and neutrophil chemotaxis and aggregation was observed. Currently pathway and gene co-expression network analysis as well as correlation analysis with tissue composition based on computer-aided quantitative analysis of digital images is being performed.

MMP8 Is Increased in Lesions and Blood of Acne Inversa Patients: A Potential Link to Skin Destruction and Metabolic Alterations

Acne inversa (AI; also designated as hidradenitis suppurativa) is a chronic inflammatory disease with still unknown pathogenesis that affects the intertriginous skin of perianal, inguinal, and axillary sites. It leads to painful nodules, abscesses, and fistulas with malodorous secretion and is frequently associated with metabolic alterations. Here, we demonstrate that one of the most highly upregulated molecules in AI lesions is matrix metalloproteinase 8 (MMP8), an enzyme specialized in the degradation of extracellular matrix components and the HDL component apolipoprotein A-I. Granulocytes, which were present in AI lesions, secreted high amounts of MMP8 especially after TNF-α stimulation. Furthermore, activated fibroblasts but not keratinocytes were found to express MMP8. The high lesional MMP8 levels were accompanied by elevated blood levels that positively correlated with TNF-α blood levels and disease severity assessed by Sartorius score, especially with the number of regions with inflammatory nodules/abscesses and fistulas. Additionally, we found a negative correlation between blood MMP8 and HDL-cholesterol levels, suggesting a contributory role of MMP8 in metabolic alterations in AI. In summary, we demonstrate elevated MMP8 levels in AI lesions, suggest their role in skin destruction and metabolic alterations, and recommend the use of MMP8 as blood biomarker for AI disease activity assessment.

γ-Secretase Mutation and Consequently Immune Reaction Involved in Pathogenesis of Acne Inversa.

Acne inversa (AI) is a chronic recurrent inflammatory skin condition, and gamma secretase gene mutation was found related to familial AI. However, other scholars found that only a few familial AI patients had pathogenic gamma secretase mutation. Here, we collected another seven Chinese AI families including 32 patients and 48 normal individuals, and detected gene mutations of gamma secretase. Clinical features of patients with mutations of nicastrin or presenilin enhancer were summarized, and serum levels of different cytokines including IL-2, IL-4, IL-5, IL-10, IL-17A, TNF-a, and IFN-g were investigated. We revealed seven novo mutations of gamma secretase in these families. Young male patients were found more frequently affected and posterior neck was the most easily affected area in patients with nicastrin or presenilin enhancer mutation. Comparing with normal controls, we also discovered that TNF-a and IL-10 levels were elevated in AI patients with nicastrin or presenilin enhancer mutation. It was concluded that gamma secretase mutation had a close relationship with Chinese familial AI, and Chinese AI patients had specific clinical characteristics. In patients with both nicastrin and presenilin enhancer mutation, TNF-a and IL-10 may play important roles in AI pathogenesis. MEETING REPORT

Depression is a frequent co‐morbidity in patients with acne inversa

Acne inversa (AI) is a common chronic inflammatory disease that has a profound impact on the patientsí quality of life. We hypothesized a higher level of depression in AI patients compared to controls. We studied depression in patients with AI and control subjects. Additionally, we evaluated whether the severity of the disease, anxiety, sexual distress and acute inflammation may have an influence on depression. The Hospital Anxiety and Depression Scale (HADS) was given to 90 voluntary study participants to assess depression in AI patients and in age-, gender-, and BMI-matched controls. Moreover, the correlation between depression and conjectural influencing factors was evaluated. This study demonstrated that AI patients have a higher depression score than matched controls. Importantly, 38.6% of AI patients are affected by depression compared to 2.4% of the control subjects. In contrast to the duration of the disease and the AI patientsí age, anxiety and sexual distress showed a strong correlation with the degree of depression. Patients with AI have a higher risk of developing depression. Physicians should be alert to the possible development of depression when treating patients with this disorder.

Acne inversa (Hidradenitis suppurativa): A review with a focus on pathogenesis and treatment

Acne inversa (AI) is a disabilitating chronic inflammatory disease with major negative impact on quality of life and significant co-morbidities. This is an important link to insights into immune dysfunction, which stimulated therapeutic approaches like tumor necrosis-α inhibitor therapy. This new off-label drug treatment is particularly beneficial when used in combination with wide excision of inflamed skin and subcutaneous tissue. Retinoids have been reported to be helpful in secondary prevention. The standard of therapy in advanced cases is surgery with wide excisions and healing by secondary intention. This treatment results in significant reduction of complaints and achieves satisfactory body contouring.

Pulsed dye laser-mediated photodynamic therapy for acne inversa is not successful: A pilot study on four cases

The relapses and the chronicity of acne inversa cause a significant impact on the quality of life of the affected patients and urge for a search of more effective treatments. We report the treatment of four consecutive acne inversa patients with pulse dye laser-mediated photodynamic therapy (PDL-PDT). Three months after the end of the treatment there was no improvement in comparison with opposite control sites. Intense pain during treatment was reported by all the patients. These cases do not support the use of PDL-PDT for treating acne inversa.

Chirurgische Behandlung der Acne inversa an der Universität Heidelberg

Acne inversa is a chronic, recurrent, fistula- and abscess-forming disease formerly called hidradenitis suppurativa, pyodermia fistulans sinifica or acne tetrade. Like in acne vulgaris, the main pathogenetic mechanism consists of follicular occlusion with subsequent inflammation of the pilosebaceous unit. The aim of this study was to determine the outcome of the surgical procedure and wound management applied in our clinic, to indentify pathogenetic factors contributing to the course of the disease and to evaluate acne inversa patients with special respect to clinical manifestations, histology and bacterial colonisation. We evaluated 66 patients with acne inversa, treated in our clinic between 1987 and 1999. Radical excision combined with open wound healing was performed in all patients. We found both sexes equally frequent, mean age at disease onset was 22.5 years, mean age at the presentation was 34.7 years, mean duration of disease was 11 years. 55% of patients also had a family history of acne inversa. 80% of patients were smokers. 80% of males suffered also from pilonidal sinus compared to 57% of females, while only 45% of males had inguinal or perianal lesions compared to 90% of females. There was no correlation of disease activity or prevalence with other diseases, especially not with atopic dermatitis, Crohn's disease or colitis ulcerosa. Histologically most patients showed follicular occlusion, fibrosing granulomatous dermatitis and formation of sinus tracts lined by pathologicall differentiated epithelia. Staphylococcus aureus was frequently found pre-operatively. Minor recurrent disease on operated sites was noted in 23% of patients, but only 5.75% of patients required further surgical intervention. Over 90% of patients were satisfied with functional and esthetical result. Since the inflammatory process clearly emerges from the pilosebaceous unit, the aim of surgical treatment has to be the elimination of hair follicle bearing skin from the affected intertriginous areas. Radical excision combined with subsequent open wound healing has proven to be a reliable treatment resulting in minimal recurrent disease and satisfactory cosmetic result.