Complete blood collection-based systemic inflammation biomarkers for patients with hidradenitis suppurativa.

BACKGROUND: Hidradenitis suppurativa (HS) is a relatively common chronic inflammatory condition of intertriginous skin. In recent years, the neutrophil/lymphocyte ratio (NLR), platelet/lymphocyte ratio (PLR), monocyte/lymphocyte ratio (MLR) and platelet/neutrophil ratio (PLR) have been shown to be indicators of systemic inflammation correlating with severity of inflammatory conditions. OBJECTIVES: We aimed to analyse for the first time the systemic inflammation biomarkers also including the pan-immune-inflammation value (PIV) and the systemic immune-inflammation index (SII) in HS patients and controls. METHODS: This study retrospectively investigated clinical and laboratory data of 142 patients with HS. Moreover, a sex-age-matched healthy control group was included. The severity of HS was routinely assessed by the Hurley staging, the mHSS and the SAHS score. All inflammation-based biomarkers were calculated from absolute values of complete blood counts. Receiver-operating characteristics analyses, including the Youden index, were performed in order to determine optimal cut-off values and test performance. RESULTS: Whereas PIV and SII were significantly higher in HS patients, PLR, MLR and PNR were significantly lower in HS patients when compared to controls. Almost all inflammation-based biomarkers significantly correlated with disease severity. However, PIV was the only test that was significantly associated with HS severity as indicated by a Youden index of 0.56 (associated criterion: 756.4; AUC: 0.79, P < 0.0001). CONCLUSIONS: Although all systemic inflammation-based biomarkers investigated are more or less associated with HS severity, the PIV appears to have the best performance in this regard. It may be employed in adjunction with the clinical scores for treatment decision making or clinical trial assessments.

Prompt response of advanced cutaneous squamous cell carcinoma to cemiplimab in a kidney transplant patient receiving treatment with everolimus.

The safety and efficacy of immune checkpoint inhibitors in solid organ transplant recipients (SOTR) are unclear, as SOTR are usually excluded from clinical investigations due to their high risk for irreversible allograft rejection. We observed a kidney transplant patient with metastatic cutaneous squamous cell carcinoma who experienced complete response under anti-tumour therapy using cemiplimab and prevention of transplant rejection by fixed dose everolimus.

NOD2 signalling in hidradenitis suppurativa.

BACKGROUND: Hidradenitis suppurativa (HS) is associated with dysregulated immune responses including altered expression of cytokines, chemokines, and antimicrobial peptides and proteins (AMPs). AIMS: To evaluate the expression of nucleotide-binding oligomerization domain-containing (NOD)2 and related factors in HS skin samples and keratinocyte cultures. METHODS: We performed real-time PCR for NOD2, receptor-interacting serine/threonine-protein kinase (RIP)2, cyclic amine resistance locus (CARL), skin-derived antileukoproteinase (SKALP)/elafin, human ß-defensin (hBD)2, LL37, psoriasin and RNAse7 in lesional and nonlesional skin of 19 patients with HS and in keratinocyte cultures [unstimulated, muramyl dipeptide (MDP)-stimulated or Pam2CSK4 (Pam2)-stimulated] from and nonlesional skin. RESULTS: We observed significantly elevated mRNA expression for NOD2 (P < 0.01), hBD2 (P = 0.02), RNase7 (P < 0.001), psoriasin (P < 0.01) and SKALP/elafin (P = 0.02) in lesional compared with nonlesional skin. We found a significant correlation between NOD2 mRNA and hBD2 (r = 46; P = 0.04), psoriasin (r = 0.67; P < 0.01) and SKALP/elafin (r = 0.65; P < 0.01). In unstimulated, Pam2-stimulated and MDP-stimulated normal keratinocytes, NOD2, RIP2, CARL and SKALP/elafin expression significantly (P < 0.05) increased from 6 to 48 h, whereas in unstimulated, Pam2-stimulated and MDP-stimulated HS keratinocytes, RIP2, CARL and SKALP/elafin expression significantly (P < 0.05) declined from 6 to 48 h. mRNA expression of NOD2 (unstimulated, Pam2-stimulated, MDP-stimulated), CARL (unstimulated, Pam2-stimulated, MDP-stimulated) and SKALP/elafin (unstimulated, Pam2-stimulated) at 6 h was significantly increased in HS compared with normal keratinocytes. CONCLUSION: We have shown for the first time that NOD2 signalling is activated in HS and might contribute to the pathogenesis via induction of AMPs and activation of other pathways such as nuclear factor κB signalling.

Increased expression profile of NCSTN, Notch and PI3K/AKT3 in hidradenitis suppurativa.

BACKGROUND: In a small number of kindreds with familial hidradenitis suppurativa (HS) different mutations of NCSTN (nicastrin) have been identified. Blocking of NCSTN leads to impairment of the Notch and PI3K/AKT signalling pathway, which is assumed to play a pathogenic role in HS. However, very limited data are available concerning expression levels of these pathway components in HS skin. OBJECTIVES: To analyse the mRNA and protein expression of NCSTN, Notch1-3, PIK3R3 and AKT3 in HS. METHODS: Skin samples from healthy controls, lesional and perilesional skin of HS patients with and without a positive family history were analysed by quantitative real-time RT-PCR and immunohistochemistry. Univariate statistical analyses were conducted regarding association between expression levels and patient's characteristics. RESULTS: Expression levels of all investigated genes showed significantly higher levels in lesional HS skin compared with healthy controls. Univariate analysis showed no association between a positive family history and mRNA expression levels. Perilesional HS skin of patients with mild disease severity (Hurley I) showed significant higher mRNA expression levels of the investigated pathway components compared to moderate (Hurley II) and severe disease (Hurley III). CONCLUSION: We found no evidence for diminished expression levels of the Notch signalling. In contrast, the NCSTN, Notch and PI3K/AKT signalling components are overexpressed in HS. Future research is needed to investigate a possible pathogenetic role or to reveal a coactivation of these overexpressed components during inflammatory response in HS.

[Hidradenitis suppurativa/acne inversa in the genitoanal region]. / Hidradenitis suppurativa/Acne inversa in der Genitoanalregion.

Hidradenitis suppurativa/acne inversa (HS/AI) is a chronic inflammatory skin disease. Several studies showed that perianal, perineal and gluteal involvement is more common in men. Axillary, submammary and inguinal localizations seem to be more prevalent in women. Involvement of the genitoanal region is associated with a higher reduced quality of live and sexual health compared to other locations. Moreover HS/AI in the genitoanal region can lead to serious complications. The knowledge of perianal fistula formation, pubogenital lymphedema and squamous cell carcinoma, which are three of the most severe complications, is critical for adequate treatment.

Frequency of circulating subpopulations of T-regulatory cells in patients with hidradenitis suppurativa.

BACKGROUND: Decreased number of T-regulatory cells (Tregs) and/or their loss of function potentially lead to uncontrolled immune-mediated inflammatory responses. There are only few data available on Tregs in hidradenitis suppurativa (HS) - a disease in which it has been suggested that host immune factors and an overactive immune system of the follicular epithelium play a pathogenetic role. OBJECTIVES: To analyse frequencies of Tregs subpopulations in blood of HS patients in comparison with a healthy control group. MATERIALS & METHODS: Blood samples obtained from HS patients and healthy controls were evaluated by flow cytometry and enzyme-linked immunosorbent assay. RESULTS: The frequency of natural Tregs among CD4+ T lymphocytes were significantly reduced in the HS group compared to the healthy controls. The proportion of activated Tregs, non-suppressive Tregs and proliferating Tregs showed no significant difference when compared to controls. Regarding Tregs frequencies, there was no significant difference between the three Hurley stages. Serum concentrations of IL-10, TGF-ß1 and IL-17A did not show significant differences between the HS and control group. CONCLUSION: The reduction of natural Tregs observed in blood of HS patients could be the result of Tregs homing to sites of inflammatory hot spots in HS skin. Further studies are justified evaluating the role of circulating Tregs during the evolution of HS lesions and as a biomarker for treatment response.

Altered epigenetic pathways and cell cycle dysregulation in healthy appearing skin of patients with koebnerized squamous cell carcinomas following skin surgery.

BACKGROUND: Koebnerized non-melanoma skin cancer following skin trauma represents a rare and obscure event. OBJECTIVES: To study molecular pathological parameters in koebnerized squamous cell carcinomas (K-SCCs) occurring after complete tumour removal. METHODS: We assessed two patients with multiple sclerosis who were on treatment with dimethylfumarate (DMF) preceded by long-term azathioprine therapy. Both patients rapidly developed several K-SCCs following histopathologically proven complete excision of cutaneous SCCs. We performed immunohistochemistry for p53, p16, Ki-67, TET-2, IDH-2, 5-hmc and 5-mc. PCR was carried out for the detection of human papilloma viruses. Mutation analysis was performed for BRAF, K-RAS and EGFR. RESULTS: All lesions investigated were negative for HPV DNA. Mutations were not detected. Healthy appearing skin of both patients showed relatively high Ki-67, p16 and p53 expression which was comparable to the expression observed in primary SCCs as well as K-SCCs. Protein expression of Ki-67, p16 and mutant p53 was barely detected in the specimens of the healthy controls. A decreased protein expression of TET-2 enzyme was seen in all tumours and healthy appearing skin when compared to the skin of healthy controls. CONCLUSIONS: We observed two patients with K-SCCs developing under DMF treatment. In healthy appearing skin of patients with K-SCCs, wound healing processes, including induction of proliferation and growth factor release, might promote the growth of preneoplastic keratinocytes and cancer formation on the basis of pre-existing altered epigenetic pathways and cell cycle dysregulation. Although fumarates can reduce TET-2 expression, the role of DMF intake in the development of K-SCCs remains unclear.

[Surgical treatment options for hidradenitis suppurativa/acne inversa]. / Operative Behandlungsoptionen bei Hidradenitis suppurativa/Acne inversa.

Hidradenitis suppurativa/acne inversa (HS/AI) is a chronic inflammatory skin disease. Therapy consists of conservative and surgical treatment options. In Hurley stages II and III, surgical intervention is regarded as the method of choice for areas with irreversible tissue destruction. Resection techniques with different grades of invasiveness are described in the literature. Nevertheless, there is no generally accepted concept regarding resection and reconstruction techniques or specific postoperative care. Due to lack of definitions of recurrence after surgery and poor study quality, recurrence rates are difficult to determine.

Histological findings after argon plasma coagulation: an ex-vivo study revealing a possible role in superficial ablative treatment of the skin.

Argon plasma coagulation (APC) is an electrosurgical technique which can be used to ablate skin lesions with limited invasion depth into dermal tissue. Hence, APC might be well suited for the removal of epithelial tumours. However, there are no data on the effects of APC on human skin tissue. Thus, the aim of this study was to determine the extent of epidermal and dermal damage after APC of human skin. We performed APC ex-vivo on 91 freshly resected human skin samples, which were obtained after reconstructive surgical closures in actinically damaged areas. Tissue effects were evaluated histologically and compared across different power settings. Using 15, 30, and 45 W, median (interquartile range; IQR) coagulation depths were 110.0 µm (91.7-130.0), 113.3 µm (85.8-135.0), and 130.0 µm (100.0-153.3.0), respectively. Median (IQR) thickness of necrosis zone was 30.0 µm (23.3-40.0) at 15 W, 26.7 µm (20.0-41.6) at 30 W, and 43.3 µm (30.8-57.5) at 45 W. The Kruskal-Wallis test showed significant differences between 15 and 30 W versus 45 W for coagulation depth (P = 0.0414), necrosis zone (P = 0.0017), and necrosis according to overlaying epidermal thickness (P = 0.0467). In summary, APC is a simple and controllable electrosurgical technique to remove epidermal tissue with limited penetration to the dermis. Thus, APC is particularly suited for the ablation of epithelial skin lesions and, therefore, may serve as possible treatment approach for intraepithelial neoplasms such as actinic keratosis.

Interleukin-36 in hidradenitis suppurativa: evidence for a distinctive proinflammatory role and a key factor in the development of an inflammatory loop.

BACKGROUND: Possible regulatory involvement of the interleukin (IL)-36 family in inflammatory diseases has been suggested. OBJECTIVES: To analyse the expression of IL-36α, IL-36ß, IL-36γ and the antagonistic cytokines IL-36 receptor agonist (IL-36Ra), IL-37 and IL-38 in the skin of patients with hidradenitis suppurativa (HS). METHODS: Skin samples from lesional and corresponding perilesional HS skin, and from healthy controls were included in this study and analysed by quantitative real-time reverse-transcriptase polymerase chain reaction (PCR). To evaluate the PCR results of IL-36α, IL-36ß and IL-36γ, a subset of skin samples was studied by immunohistochemistry. RESULTS: Expression levels of IL-36α, IL-36ß, IL-36γ and IL-36Ra were all significantly higher in lesional HS skin than in healthy controls. IL-37 and IL-38 levels were significantly higher in perilesional HS skin than in healthy controls and were decreased in lesional HS skin. Limitations of the study are its descriptive nature and the small sample size. CONCLUSIONS: Our results showed a possible involvement of IL-36 cytokines in the inflammatory network of HS and a dysbalance between the agonistic and antagonistic cytokines in HS skin.

T regulatory cells and other lymphocyte subsets in patients with bullous pemphigoid.

BACKGROUND: Bullous pemphigoid (BP) is the most common autoimmune blistering disease, and is associated with autoantibodies to the hemidesmosomal BP autoantigens BPAG1 and BPAG2. AIM: We aimed to investigate the significance of T regulatory cells and other lymphocyte subsets in patients with BP. METHODS: In total, 31 inpatients with BP were treated with systemic prednisolone in a tapered dose regimen, while 28 healthy individuals matched for age and sex served as the healthy control (HC) group., Blood samples were taken at baseline and after treatment, and levels of inducer/helper and suppressor/cytotoxic T lymphocytes, B lymphocytes, natural killer cells, CD4+CD25++CD127- cells were assessed by flow cytometry, while CD4, CD8, and FOXP3 positivity were assessed by immunohistochemistry, and FOXP3 mRNA was assessed by reverse transcription (RT)-PCR. RESULTS: Flow cytometry showed that numbers of CD8+ and CD4+CD25++CD127- cells were significantly increased, while the number of CD4+ cells and the CD4/CD8 ratio were significantly decreased at baseline and after therapy in patients with BP compared with HCs. Immunohistology revealed that CD4+, CD8+ and FOXP3+ cells were significantly increased at baseline and post-treatment in patients with BP compared with HCs. FOXP3 mRNA levels were significantly increased in the blood of patients with BP compared with HCs. CONCLUSION: These results indicate that increased numbers of CD8+, CD4+CD25++CD127- cells and FOXP3+ cells may play a pathogenetic role during the course of BP.

The microRNA effector RNA-induced silencing complex in hidradenitis suppurativa: a significant dysregulation within active inflammatory lesions.

Recently, we could show that the expression levels of the key regulators of the microRNA (miRNA) maturation and transport were dysregulated in inflamed hidradenitis suppurativa (HS) tissue (Heyam et al. in Wiley Interdiscip Rev RNA 6:271-289, 2015). The RNA-induced silencing complex (RISC) is the central element of the miRNA pathway and regulates miRNA formation and function. We investigated the expression of the RISC components, namely transactivation-responsive RNA-binding protein-1 (TRBP1), TRBP2, protein activator (PACT) of the interferon-induced protein kinase R, Argonaute RISC Catalytic Component-1 (AGO1) and Component-2 (AGO2), metadherin, and staphylococcal nuclease and Tudor domain-containing-1 (SND1) in inflamed HS tissue compared to healthy and psoriatic controls by real-time reverse transcription polymerase chain reaction. Expression levels of all investigated components were significantly lower in lesional HS skin (n = 18) compared to healthy controls (n = 10). TRBP1, PACT, AGO1, AGO2, and SND1 expression levels were significantly down-regulated in lesional HS skin compared to healthy-appearing perilesional skin (n = 7). TRBP2 and SND1 expression levels were significantly lower in healthy-appearing perilesional skin compared to healthy controls. In lesional HS skin, expression levels of PACT, AGO1, and AGO2 were significantly lower compared to psoriatic skin (n = 10). In summary, our data showed that all investigated components of RISC are dysregulated in the skin of HS patients, providing support for the hypothesis that miRNAs may have a pathological role in the inflammatory pathogenesis of HS.

Expression of miRNA-155, miRNA-223, miRNA-31, miRNA-21, miRNA-125b, and miRNA-146a in the Inflammatory Pathway of Hidradenitis Suppurativa.

Hidradenitis suppurativa (HS) has been associated with marked inflammatory perturbation. The mechanisms regulating the inflammatory network remain elusive. microRNAs (miRNAs) have been described as gene regulators of inflammation. We evaluated the messenger RNA (mRNA) expression levels of six selected inflammation-related miRNAs in lesional and perilesional skin samples of HS patients and in healthy controls. Samples of 15 HS patients and 10 healthy controls were included in this prospective study. Expression levels of the miRNAs miRNA-155-5p, miRNA-223-5p, miRNA-31-5p, miRNA-21-5p, miRNA-125b-5p, and miRNA-146a-5p were studied by quantitative real-time reverse transcription polymerase chain reaction. We observed a significant overexpression of miRNA-155-5p, miRNA-223-5p, miRNA-31-5p, miRNA-21-5p, and miRNA-146a-5p in lesional HS skin compared to healthy controls. Expression of these miRNAs was also significantly increased in lesional HS skin when compared to perilesional skin. Only miRNA-155-5p showed an increased expression in perilesional skin compared to healthy controls. In contrast, miRNA-125b-5p had a significantly lower expression in lesional HS skin compared to perilesional skin. We found that the studied inflammation-related miRNAs were significantly dysregulated in lesional HS skin and may have regulatory roles in the inflammatory process of HS. Given their predicted targets and functions, our findings point to these miRNAs as potential disease biomarkers, and manipulation might be used therapeutically to target the inflammatory pathway in HS.

Stress-coping styles of 459 emergency care physicians in Germany : A pilot study.

AIM: In addition to assessing stress-coping strategies in patients, equal attention should be paid to health-care professionals. The literature on the stress-coping strategies of emergency physicians - health-care professionals who are frequently subject to stress in a fast-paced clinical setting - is scant. Therefore, we aimed to investigate the stress-coping strategies of emergency-care physicians (ECPs) in Germany. METHODS: We conducted a cross-sectional study by approaching German Associations of Emergency Medicine Physicians and the two largest ECP recruitment agencies in Germany to invite their members to participate. We used the German Stress Coping Strategies Inventory ("Stressverarbeitungsfragebogen" SVF-78) to generate stress-coping scores that would cover both positive and negative strategies. Differences according to sex were also examined. Analyses including chi-square test, t test, and multinomial logistic regression modeling were performed. RESULTS: A total of 459 German ECPs were included in the study. Compared with men, women tended to have negative coping strategies (beta = 1.77, p < 0.001). Specifically, women tended to use social support (beta = 1.55, p = 0.002), avoidance (beta = 2.59, p < 0.001), escape (beta = 1.39, p = 0.004), rumination (beta = 1.58, p < 0.001), and resignation (beta = 2.09, p < 0.001), while being less likely than men to rely on minimization and denial of guilt. CONCLUSION: ECPs experience stress in the same manner as patients and other professionals, and they must address and cope with stress appropriately. For future research, studies with a longitudinal approach to monitor the underlying mechanisms are suggested. For clinical practice and policy-making, structural changes in work patterns and psychological support should be considered, which may be of particular benefit for female ECPs.

Next-generation sequencing of the basal cell carcinoma miRNome and a description of novel microRNA candidates under neoadjuvant vismodegib therapy: an integrative molecular and surgical case study.

BACKGROUND: MicroRNAs (miRNAs) have been identified as key players in posttranscriptional gene regulation and have a significant impact on basal cell carcinoma (BCC) development. The Sonic hedgehog pathway inhibitor vismodegib has been approved for oral therapy of metastatic or advanced BCC. Here, a high-throughput miRNA sequencing analysis was carried out to identify differentially expressed miRNAs and possible novel miRNA candidates in vismodegib-treated BCC tissue. Additionally, we described our surgical experience with neoadjuvant oral vismodegib therapy. PATIENTS AND METHODS: A punch biopsy (4 mm) from a patient with an extensive cranial BCC under oral vismodegib therapy and a corresponding nonlesional epithelial skin biopsy were harvested. Total RNA was isolated, after which a sequencing cDNA library was prepared, and cluster generation was carried out, which was followed by an ultra-high-throughput miRNA sequencing analysis to indicate the read number of miRNA expression based on miRBase 21. In addition to the identification of differentially expressed miRNAs from RNA sequencing data, additional novel miRNA candidates were determined with a tool for identifying new miRNA sequences (miRDeep2). RESULTS: We identified 33 up-regulated miRNAs (fold change ≥2) and 39 potentially new miRNA candidates (miRDeep scores 0-43.6). A manual sequence analysis of the miRNA candidates on the genomic locus of chromosome 1 with provisional IDs of chr1_1913 and chr1_421 was further carried out and rated as promising (chr1_1913) and borderline (chr1_421). Histopathology revealed skip lesions in clinically healthy appearing skin at the tumor margins, which were the cause of seven re-excisions by micrographic controlled surgery to achieve tumor-free margins. CONCLUSION: miRNA sequencing revealed novel miRNA candidates that need to be further confirmed in functional Dicer knockout studies. Clinically, on the basis of our surgical experience described here, neoadjuvant vismodegib therapy in BCC appears to impede histopathologic evaluations with effects on surgical therapy. Thus, larger studies are necessary, but are not preferable at this time if other options are available.

[Hidradenitis suppurativa/acne inversa: An update]. / Hidradenitis suppurativa/Acne inversa : Ein Update.

Hidradenitis suppurativa/acne inversa (HS/AI) is a chronic inflammatory disease characterized by painful nodules, abscesses, fistulas, sinus tracts and scarring, which may lead to severe functional and psychological impairment. Patients often suffer for many years before the right diagnosis is finally made. HS/AI is still a therapeutic challenge. Conservative therapies play a role in mild stages of the disease; however they do not result in healing. Therapy of choice associated with the lowest recurrence rate is a radical wide excision of involved skin.

Comparison of lipidocolloid and chlorhexidine-impregnated tulle gras dressings following microscopically controlled surgery.

OBJECTIVE: Modified microscopically controlled surgery (MCS) is a staged and margin-controlled excision; after MCS, the selection of an appropriate initial wound dressing plays an important role in wound healing. A wide range of dressings is available for temporary wound coverage; however, data comparing different types of wound dressings after MCS are lacking. The aim of this study was to compare two commonly used and commercially available types of wound dressings. METHOD: We assessed pain levels, wound adherence, bleeding upon dressing removal and signs of infection, with chlorhexidine-impregnated tulle gras and a lipidocolloid dressing used for primary wound dressing following MCS. RESULTS: A total of 42 patients were included. Adherence of the dressing to the wound (p<0.001) and bleeding after removal (p=0.001) were significantly higher in the chlorhexidine-impregnated tulle gras dressing group. Pain during removal of wound dressing had a higher visual analogue scale score (1.9 ± 2.2) in the chlorhexidine-impregnated tulle gras dressing group compared to 0.7 ± 1.0 in the lipidocolloid dressing group (p=0.022). CONCLUSION: The results indicate that the lipidocolloid dressing, when compared with the chlorhexidine-impregnated tulle gras dressing, offers a significant benefit during removal in terms of less pain, less wound adherence and less wound bleeding. DECLARATION OF INTEREST: The authors have no conflict of interest to declare.