Identifying key components and therapeutic targets of the immune system in hidradenitis suppurativa with an emphasis on neutrophils.

Hidradenitis suppurativa (HS) is a chronic, inflammatory, recurrent and debilitating skin disease of the hair follicle unit that typically develops after puberty. The disorder is characterized by comedones, painful inflammatory nodules, abscesses, dermal tunnels and scarring, with a predilection for intertriginous areas of the body (axillae, inguinal and anogenital regions). Recruitment of neutrophils to HS lesion sites may play an essential role in the development of the painful inflammatory nodules and abscesses that characterize the disease. This is a review of the major mediators involved in the recruitment of neutrophils to sites of active inflammation, including bacterial components (endotoxins, exotoxins, capsule fragments, etc.), the complement pathway anaphylatoxins C3a and C5a, tumour necrosis factor-alpha, interleukin (IL)-17, IL-8 (CXCL8), IL-36, IL-1, lipocalin-2, leukotriene B4, platelet-activating factor, kallikreins, matrix metalloproteinases, and myeloperoxidase inhibitors. Pharmacological manipulation of the various pathways involved in the process of neutrophil recruitment and activation could allow for successful control and stabilization of HS lesions and the remission of active, severe flares.

Hidradenitis Suppurativa Area and Severity Index Revised (HASI-R): psychometric property assessment.

BACKGROUND: Validated, reliable, globally accepted outcome measurement instruments for hidradenitis suppurativa (HS) are needed. Current tools to measure the physical signs domain for HS rely on lesion counts, which are time-consuming and unreliable. OBJECTIVES: To assess the reliability and validity of the Hidradenitis suppurativa Area and Severity Index Revised (HASI-R) tool, a novel method for assessing HS severity, incorporating signs of inflammation and body surface area involved. METHODS: The measurement properties of the HASI-R tool were evaluated. The tool was created by combining the previously published HASI and Severity and Area Score for Hidradenitis instruments. Twenty raters evaluated 15 patients with HS in a hospital-based ambulatory dermatology clinic. The objectives of the study were to assess inter- and intra-rater reliability of the HASI-R and its components, as well as its construct and known-groups validity. Existing lesion count-based clinician-reported measures of HS and their components were also assessed. Raters were also asked their preferences regarding the various HS severity assessment tools. RESULTS: The HASI-R had moderate inter-rater reliability [intra-class correlation coefficients (ICC) 0·60]. This was better than all other HS physical sign outcome measures evaluated, which had poor inter-rater reliability (ICC < 0·5). HASI-R had the highest intra-rater reliability (ICC 0·91). The HASI-R had good construct validity and demonstrated known-groups validity. The HASI-R was also the most preferred tool by all raters. CONCLUSIONS: Results from the clinometric assessment of the HASI-R are encouraging, and support continued evaluation of this clinician-reported outcome measure.

Specimen Collection for Translational Studies in Hidradenitis Suppurativa.

Hidradenitis suppurativa (HS) is a chronic inflammatory disorder characterized by painful nodules, sinus tracts, and scars occurring predominantly in intertriginous regions. The prevalence of HS is currently 0.053-4%, with a predominance in African-American women and has been linked to low socioeconomic status. The majority of the reported literature is  retrospective, population based, epidemiologic studies. In this regard, there is a need to establish a repository of biospecimens, which represent appropriate gender and racial demographics amongst HS patients. These efforts will diminish knowledge gaps in understanding the disease pathophysiology. Hence, we sought to outline a step-by-step protocol detailing how we established our HS biobank to facilitate the formation of other HS tissue banks. Equipping researchers with carefully detailed processes for collection of HS specimens would accelerate the accumulation of well-organized human biological material. Over time, the scientific community will have access to a broad range of HS tissue biospecimens, ultimately leading to more rigorous basic and translational research. Moreover, an improved understanding of the pathophysiology is necessary for the discovery of novel therapies for this debilitating disease. We aim to provide high impact translational research methodology for cutaneous biology research and foster multidisciplinary collaboration and advancement of our understanding of cutaneous diseases.

Quality of life and sexual health in patients with hidradenitis suppurativa.

BACKGROUND: Hidradenitis suppurativa (HS) is a chronic, recurrent, debilitating follicular disease. The effect of HS on physical and psychological aspects of sexual function is not well understood. OBJECTIVE: The objective of this study is to investigate the contribution of sexual dysfunction to the quality of life (QoL) of patients with HS and to investigate the extent to which sexual health predicts the QoL in these patients. METHODS: This is an observational cross-sectional study of 50 patients with HS and 50 healthy volunteers who completed questionnaires to measure QoL and sexual functioning using four validated tools. RESULTS: Male patients experienced higher sexual dysfunction and a reduced quality of sexual life, while female patients reported higher sexual distress, compared with control groups. In male patients, sexual QoL and erectile dysfunction predicted a 72% decline in QoL. In female patients, sexual distress and sexual dysfunction predicted 46% variability in QoL index scores, beyond the effects of disease severity. CONCLUSION: Disruptions to sexual functioning greatly contribute to QoL impairments in patients with HS regardless of genital lesions. Health care professionals should inquire about and pay close attention to sexual health concerns in patients with HS.

Th17 cytokines interleukin (IL)-17 and IL-22 modulate distinct inflammatory and keratinocyte-response pathways.

BACKGROUND: Psoriasis vulgaris is an inflammatory skin disease mediated by Th1 and Th17 cytokines, yet the relative contribution of interferon (IFN)-gamma, interleukin (IL)-17 and IL-22 on disease pathogenesis is still unknown. OBJECTIVES: In this study, we sought to identify the cytokines produced by skin-resident T cells in normal skin, localize the receptors for these cytokines, and examine how these cytokines alter gene expression profiles of the cells bearing cognate receptors. METHODS: We used intracellular cytokine staining and flow cytometry to evaluate T cell cytokine production, and immunohistochemistry and double-label immunofluorescence to localize cytokine receptors in skin. Gene array analysis of cytokine-treated keratinocytes was performed using moderated paired t-test controlling for false discovery rate using the Benjamini-Hochberg procedure. RESULTS: We demonstrate that T-helper cells producing IL-17, IL-22 and/or IFN-gamma, as well as the cells bearing cognate cytokine receptors, are present in normal human skin. Keratinocytes stimulated with IL-17 expressed chemokines that were different from those induced by IFN-gamma, probably contributing to the influx of neutrophils, dendritic cells and memory T cells into the psoriatic lesion. In contrast, IL-22 downregulated genes associated with keratinocyte differentiation and caused epidermal alterations in an organotypic skin model. CONCLUSIONS: Our results suggest that the Th17 cytokines IL-17 and IL-22 mediate distinct downstream pathways that contribute to the psoriatic phenotype: IL-17 is more proinflammatory, while IL-22 retards keratinocyte differentiation.

Transient reactive papulotranslucent acrokeratoderma associated with cystic fibrosis.

A 20-year-old female with cystic fibrosis presented with a white marginal palmar eruption after exposure to water. There was no family history of keratoderma. A biopsy showed hyperkeratosis around dilated eccrine ostia. These features are similar to a recently described condition, transient reactive papulotranslucent acrokeratoderma. This is thought to be a variant of hereditary papulotranslucent acrokeratoderma, one of the punctate keratodermas. Association with cystic fibrosis has not been described previously.

Cytokine profiles in spontaneously regressing basal cell carcinomas.

BACKGROUND: Basal cell carcinomas (BCCs) can cause considerable morbidity due to their ability to enlarge progressively and to destroy underlying tissues. However, some BCCs may undergo spontaneous regression in the absence of therapy capable of inducing antineoplastic effects. Histological criteria for this process have been described, and previous studies have suggested that it may be mediated by infiltrating activated CD4-positive T cells. OBJECTIVES: The purpose of this study was to compare the expression of cytokines in actively regressing and non-regressing BCCs, to ascertain if active regression is associated with a particular cytokine profile. METHODS: Reverse transcriptase-polymerase chain reaction, a sensitive, quantitative technique allowing analysis of multiple cytokines from small tumour samples, was used. RESULTS: Interferon (IFN)-gamma was significantly elevated in actively regressing BCCs compared with non-regressing BCCs. Furthermore, interleukin (IL)-2, tumour necrosis factor (TNF)-beta and CD3 delta tended to be elevated in actively regressing tumours, although not to statistically significant levels. IFN-gamma, IL-2, IL-10, TNF-beta, granulocyte-macrophage colony-stimulating factor and Fas ligand showed strong positive correlations with CD3 delta, indicating an association between infiltrating T cells and these cytokines. CONCLUSIONS: These findings support a role for T-helper 1 type cytokines in mediating spontaneous regression of BCCs.

Benign melanocytic proliferative nodule within a congenital naevus.

A neonate presented with a deeply pigmented papule within a medium-sized congenital naevus. Histologically, this proved to be a benign proliferative nodule in a congenital naevus. This case is presented to highlight the occurrence of this lesion, the main differential of which is the rare entity of true congenital melanoma.

Keratoacanthomas have an immunosuppressive cytokine environment of increased IL-10 and decreased GM-CSF compared to squamous cell carcinomas.

To investigate the relationship between keratoacanthoma (KA) and squamous cell carcinoma (SCC), cytokine mRNA in 12 KA and eight SCC were compared. Normal skin was also studied. Reverse transcription polymerase chain reaction (RT-PCR) was used to quantitate mRNA in each sample utilizing DNA standards. Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) was used as an internal control, and CD3delta as an indication of the T-cell infiltrate. KAs showed a significant increase in interleukin (IL)-10, and a decrease in granulocyte macrophage colony-stimulating factor (GM-CSF) mRNA compared to SCCs. CD3delta mRNA was also increased in the KAs. There was no difference between KAs and SCCs in expression of lymphotoxin-alpha, IL-2, interferon-gamma (IFN-gamma), IL-13, transforming growth factor-beta (TGF-beta), or the pro-inflammatory cytokines IL-8 or tumour necrosis factor-alpha (TNF-alpha). These results indicate that KAs spontaneously resolve in an immunosuppressive environment. KAs grow rapidly over a period of weeks and then involute. It is possible that a suppressed immune response enables unimpeded growth and that the KA cells rapidly undergo the finite number of cell divisions of which they are capable, and then die without reaching immortality.

Regression of melanoma, but not keratoacanthoma, is associated with increased HLA-B22 and decreased HLA-B27 and HLA-DR1.

Sixty three Caucasian patients with either melanoma, keratoacanthoma or squamous cell carcinoma were human leucocyte antigen (HLA) typed. The regressing tumour groups were compared with their non-regressing counterparts, and the patient groups were compared with a control Caucasian population. Melanoma patients showing histological regression were more likely to be HLA-B22 positive, and HLA-B27 and -DR1 negative, than those without features of regression. When compared with a control population, the group of melanoma patients were more likely to be HLA-B22 positive. Comparison of the group of keratoacanthomas, a self-regressing tumour, and the group of squamous cell carcinomas, a non-regressing tumour, did not show any significant differences in HLA typing.

T helper 1 cytokine mRNA is increased in spontaneously regressing primary melanomas.

Spontaneous tumor regression, which is observed clinically and histologically in some primary melanomas, occurs in the absence of any effective therapy. It is probably immunologically mediated, because regressing melanomas are infiltrated with larger numbers of activated T cells, primarily CD4+, than nonregressing melanomas. To investigate the hypothesis that spontaneous regression of melanomas is caused by T-cell cytokine production, cytokine mRNA expression in 20 primary melanomas was examined using a noncompetitive, quantitative reverse-transcriptase polymerase chain reaction method. DNA standards were used to generate known numbers of molecules in each sample. Results were standardized to the internal control, glyceraldehyde-3-phosphate dehydrogenase. mRNA for CD35, lymphotoxin (TNF-beta), and IL-2 were significantly elevated in the ten regressing melanomas compared to the ten nonregressing melanomas. IFN-gamma mRNA was also elevated in regressing melanomas but failed to reach statistical significance. The Th2 cytokines IL-10 and IL-13 did not show differences in the regressing melanomas compared to nonregressing melanomas; neither did the pro-inflammatory cytokines IL-1alpha, IL-1beta, IL-6, IL-8, and TNF-alpha, nor the growth factors, bFGF and TGF-beta or GM-CSF. This study shows an association between Th1 cytokines and spontaneously regressing melanomas. Although we have not shown that these cytokines cause regression, these findings support our hypothesis that activated CD4+ T cells may mediate melanoma regression by secretion of Th1 cytokines.