Prurigo nodularis and lichen simplex chronicus

ABSTRACT:  Emotional tensions in predisposed subjects may play a key role in inducing a pruritic sensation, leading to a scratching that, becoming a self-perpetuating pathomechanism, may represent the main feature of two distinct cutaneous clinical entities: prurigo nodularis and lichen simplex chronicus. Psychogenic factors play a relevant role in both conditions, and they are often associated with depression and dissociative experiences. Hence, the importance of the evaluation of these patients from the point of view of psychodermatology, which may analyze the relationship between skin disease and psychological factors. Patients with real or perceived imperfections in particular areas of the body (face, scalp, hands, and genital area) are more prone to psychologic distress, whereas cutaneous diseases may lead to experience a heightened level of distress. As psychosomatic factors have been estimated to be present in at least one-third of dermatologic patients, effective management of skin conditions involves consideration of the associated emotional factors.     

The role of neuropeptides in psoriasis

The pathogenesis of psoriasis is incompletely understood but cutaneous neurogenic inflammation is probably involved. This involvement is suggested by a number of clinical and histological observations. Reports about the distribution of cutaneous nerves and the quantification of nerve growth factor and neuropeptides, including calcitonin gene-related peptide and vasoactive intestinal peptide, in lesional and nonlesional psoriatic skin suggest that sensory neuropeptides contribute to the development of psoriasis. This review summarizes what is known about the role of neurogenic markers in psoriasis.     

Therapeutic Hotline: Treatment of prurigo nodularis and lichen simplex chronicus with gabapentin

Psychocutaneous conditions are frequently encountered in dermatology practice. Prurigo nodularis and lichen simplex chronicus are two frustrating conditions that are classified in this category. They are often refractory to classical treatment with topical corticosteroids and antihistamines. Severe, generalized exacerbations require systemic therapy. Phototherapy, erythromycine, retinoids, cyclosporine, azathiopurine, naltrexone, and psychopharmacologic agents (pimozide, selective serotonin reuptake inhibitor antidepressants) were tried with some success. Here five cases with lichen simplex chronicus and four cases with prurigo nodularis, who responded well to gabapentin, are presented.     

Neuropeptides and their receptors in psoriatic skin in relation to pruritus

BACKGROUND: Pruritus in patients with psoriasis has been reported to be more common than previously thought. OBJECTIVES: To determine the actual prevalence of pruritus in psoriasis according to severity of psoriasis and to verify the hypothesis of involvement of neuropeptides and their receptors in psoriatic pruritus. METHODS: We analysed questionnaire replies from 152 patients with chronic plaque-type psoriasis and we assayed the expression of neuropeptides and their receptors in lesional skin biopsies obtained from psoriatic patients with pruritus compared with those from psoriatic patients without pruritus, nonlesional skin of patients with pruritic psoriasis and normal controls by confocal laser scanning microscopy. RESULTS: Of the 152 patients with psoriasis, 112 (73.7%) had pruritus, and these patients had a higher mean Psoriasis Area and Severity Index (PASI) score than psoriatic patients without pruritus. There was positive correlation between the PASI score and the intensity of pruritus. Keratinocytes in the psoriatic plaques of patients with pruritus showed consistently increased expression of substance P receptor (SPR), high-affinity nerve growth factor receptor (TrkA) and calcitonin gene-related peptide receptor (CGRPR). CONCLUSIONS: Pruritus is a common feature in psoriasis. Considering the well-known roles of neuropeptides in pathogenesis of both psoriasis and pruritus, increased SPR, TrkA and CGRPR may be involved in the pathogenesis of pruritus in psoriasis and in the severity of psoriasis.     

Evidence for neurogenic inflammation in lichen planopilaris and frontal fibrosing alopecia pathogenic mechanism

Lichen planopilaris (LPP) and frontal fibrosing alopecia (FFA) are lymphocytic scarring alopecias affecting primarily the scalp. Although both diseases may share some clinical and histopathological features, in the last decade, FFA has become an “epidemic” particularly in Europe, North and South America with unique clinical manifestations compared to LPP, thus, raising the idea that this disease may have a different pathogenesis. Symptoms such as scalp burning, pruritus or pain are usually present in both diseases, suggesting a possible role for nerves and neuropeptides in the pathogenesis of both diseases. Based on some previous studies, neuropeptides, such as substance P (SP) and calcitonin gene-related peptide (CGRP), have been associated with lipid metabolism and many chronic inflammatory disorders. In this study, we asked if these neuropeptides are associated with LPP and FFA scalp lesions. Alteration in the expression of SP and CGRP in affected and unaffected scalp skin from patients with both diseases was found with examination of sections using immunohistochemical techniques and confocal microscopy. We then quantitatively assessed and compared SP and CGRP expression from control, LPP and FFA scalp biopsies. Although LPP and FFA share similar histopathologic findings, opposite results were found in affected and unaffected scalp in the ELISA tests, suggesting that these diseases may have different pathogenic mechanisms. We also found presence of histopathological inflammation irrespective of evident clinical lesions, which raises the possibility that both diseases may be more generalized processes affecting the scalp.     

Plasma concentration of selected neuropeptides in patients suffering from psoriasis

The aim of this study was to evaluate plasma levels of substance P (SP), calcitonin gene-related peptide (CGRP), vasoactive intestinal peptide (VIP) and neuropeptide Y (NPY) during psoriasis course. METHODS: Seventy-three patients with psoriasis and 32 healthy volunteers were included. Detailed demographic and disease anamnesis was obtained from every patient. The disease severity was assessed using the Psoriasis Area and Severity Index score. Plasma levels of SP, CGRP, VIP and NPY were measured radioimmunologically. RESULTS: Plasma levels of SP and NPY did not significantly differ between patients with psoriasis and controls (median SP: 52.8 and 57.9 pg/ml, respectively; P = 0.32; median NPY: 8.5 and 8.2 pg/ml, respectively; P = 0.67). CGRP plasma concentration was significantly elevated in psoriatic individuals both before (median 43.1 pg/ml) and after treatment (median 45.4 pg/ml), in comparison with healthy donors (median 13.5 pg/ml; P < 0.01 and P = 0.03, respectively). Treatment did not significantly influence plasma CGRP levels (P = 0.3). Median VIP plasma concentration in psoriatics before treatment was significantly higher compared with healthy controls (medians 66.9 and 60.1 pg/ml, respectively; P = 0.04), but the therapy resulted in significant decrease in VIP plasma level (median 19.0 pg/ml; P < 0.001). In psoriatic patients significant correlations were noted between NPY and VIP (R = 0.34; P < 0.01), and VIP and CGRP plasma levels, both before (R = 0.28; P = 0.03) and after the treatment (R = 0.44; P < 0.01). CONCLUSIONS: Based on our results and previous literature data it could be suggested that neuropeptides may be involved in the development of psoriatic lesions.     

Ontogeny of nerves and neuropeptides in skin of rat: An immunocytochemical study

Abstract The sequence of maturation of nerves and appearance of neuropeptides was investigated in skin from fetal and neonatal rats by immunocytochemistry using antisera to protein gene product 9.5, substance P, calcitonin gene-related peptide (CGRP), vasoactive intestinal polypeptide (VIP) and neuropeptide Y (NPY). Immunoreactivity for PGP 9.5 appeared on fetal day 16 in face and nose, somewhat later (fetal day 19) in paws and tail. The sensory neuropeptides, CGRP/substance P (fetal day 19 and postnatal day 1, respectively) appeared earlier than the autonomic peptides VIP and NPY (postnatal day 7). Thus, the study shows that neuropeptides do not appear simultaneously with nerves and that the development is rostrocaudal.     

Dialog between skin and its microbiota: Emergence of “Cutaneous Bacterial Endocrinology”

Microbial endocrinology is studying the response of microorganisms to hormones and neurohormones and the microbiota production of hormones-like molecules. Until now, it was mainly applied to the gut and revealed that the intestinal microbiota should be considered as a real organ in constant and bilateral interactions with the whole human body. The skin harbours the second most abundant microbiome and contains an abundance of nerve terminals and capillaries, which in addition to keratinocytes, fibroblasts, melanocytes, dendritic cells and endothelial cells, release a huge diversity of hormones and neurohormones. In the present review, we will examine recent experimental data showing that, in skin, molecules such as substance P, calcitonin gene-related peptide, natriuretic peptides and catecholamines can directly affect the physiology and virulence of common skin-associated bacteria. Conversely, bacteria are able to synthesize and release compounds including histamine, glutamate and γ-aminobutyric acid or peptides showing partial homology with neurohormones such as α-melanocyte-stimulating hormone (αMSH). The more surprising is that some viruses can also encode neurohormones mimicking proteins. Taken together, these elements demonstrate that there is also a cutaneous microbial endocrinology and this emerging concept will certainly have important consequences in dermatology.     

Dynamic changes in nerve growth factor and substance P in the murine hair cycle induced by depilation

Increasing evidence suggests that various neurotrophins and neuropeptides play an important role in the progression of hair follicle cycling. Among them, nerve growth factor (NGF) and substance P (SP) have attracted special interest recently. However, the interaction between these factors during hair cycling has not yet been systematically studied. We therefore investigated the mutual relationships between NGF and SP and the mechanism by which the anagen stage of the hair cycle is initiated. Fluctuations in numbers of SP-positive nerve fibers and variations in amounts of SP, NGF, and another neurotrophic factor, glial cell-derived neurotrophic factor, in skin in the C57BL/6 mouse depilation-induced hair cycle model, together with the spatiotemporal expression patterns of each of these factors, were followed simultaneously by enzyme-linked immunosorbent assay and immunohistochemistry. The main finding was that a surge in NGF expression and a rapid increase in NGF content in skin is an initial event within 1 day after depilation, followed by elevation of SP content and numbers of SP-containing fibers 2 days after the increase in NGF. Our findings suggest that a rapid and abundant increase in NGF plays a key role in the induction and progression of anagen hair cycling through keratinocyte growth promotion. NGF may also induce plastic changes such as sprouting and hyperplasia in dermal nerve fibers and enhance their SP production. Elevated levels of SP in skin may additionally contribute to the progression of consecutive anagen hair cycles.     

Nerve growth factor and substance P are useful plasma markers of disease activity in atopic dermatitis

BACKGROUND: Neurogenic components, such as neurotrophic factors and neuropeptides, are probably involved in the pathogenesis of atopic dermatitis (AD) via the neuroimmunocutaneous system. Numerous in vitro and in vivo studies have shown that nerve growth factor (NGF), the best-characterized member of the neurotrophin family, modulates the synthesis of the neuropeptide substance P (SP), both of which may be associated with the pathogenesis of human allergic diseases. OBJECTIVES: To evaluate the levels of NGF and SP in the plasma of patients with AD and to examine their possible correlation with disease activity. METHODS: We measured plasma levels of NGF by an immunoenzymatic assay and of SP by aradioimmunoassay in 52 patients with AD, and compared them with 35 normal non-atopic controls. The severity of the disease in AD patients was evaluated using validated clinical scoring systems. RESULTS: Patients with AD had significant increases in plasma levels of NGF and SP compared with controls (P < 0.0005 and P < 0.0001, respectively). A positive correlation between the plasma levels of NGF and SP was found in AD patients (correlation coefficient, Cc = 0.920, P < 0.0001). There was a significant correlation of plasma NGF and SP levels with disease activity evaluated using three different scoring systems: the grading system of Rajka and Langeland (P < 0.001 and P < 0.01, respectively), the objective Severity Scoring of AD (Cc = 0.656, P < 0.005 and Cc = 0.752, P < 0.0005, respectively) and the Eczema Area and Severity Index (Cc = 0.740, P < 0.001 and Cc = 0.765, P < 0.005, respectively). CONCLUSIONS: These data represent the first reported evidence of increased plasma levels of NGF and SP in an allergic human skin disease. They suggest that these neurogenic factors systemically modulate the allergic response in AD, probably through interactions with cells of the immune-inflammatory component. In addition, NGF and SP may be useful markers of disease activity in patients with AD.     

Time course effect and sequential morphological changes of subepidermal nerve fibers in guinea pig skin after application of histamine ointment: a laser scanning confocal fluorescence microscopic and electron microscopic study

This study was undertaken to elucidate the morphological effects of histamine on subepidermal nerve fibers. A 10% histamine ointment was topically applied to the back skin of 17 adult male Hartley guinea pigs. Biopsy specimens were obtained at times from 5 min to 24 h, and were examined by conventional immunofluorescence (IF), laser scanning confocal fluorescence microscopy (LSCM) and transmission electron microscopy. On IF and LSCM, marked diminutions in the immunoreactivity of protein gene product 9.5-immunoreactive (PGP 9.5-IR) fibers as well as of substance P-immunoreactive (SP-IR) and calcitonin gene-related peptide-immunoreactive (CGRP-IR) substances were observed 5 min after histamine application. By 30 min, immunoreactivity of PGP 9.5, SP and CGRP was completely lost. By 2 h, however, immunoreactivity of PGP 9.5-IR fibers and CGRP-IR substances started to show recovery. By 4 h, immunoreactivity of PGP 9.5, SP and CGRP had almost recovered, but the recovery time for each substance was slightly different (PGP 9.5 first, CGRP next, and SP last). By 6 h after histamine application, immunoreactivity of all these substances had fully recovered. Ultrastructurally, 5 min after histamine application, axonal and mitochondrial swelling and glycogen deposition were seen in the axons of subepidermal nerve fibers. By 30 min, severe axonal degeneration had occurred in some of the axons. It was only by 4 to 6 h that almost normal ultrastructural features were observed. Schwann cells and perineurial cells did not show any pathological changes. These findings demonstrate that 10% histamine ointment produced organic changes in the axons in the subepidermal nerve fibers of guinea pig skin, but these morphological changes were short-lived, reversible and transitory.     

Lichen sclerosus: a review and practical approach

ABSTRACT:  Lichen sclerosus (LS) is a chronic dermatitis predominantly found in the anogenital area. It can be found in patients of any age group, sex, or race, but is most commonly present in Caucasian peri- or postmenopausal women. Although the etiology of LS remains uncertain, an autoimmune process is believed to underlie this condition. With many cases going unreported, its incidence is still unknown. There is no cure for LS, but treatment offers control of the condition. They are three reasons for treating LS: relief of symptoms and discomfort; prevention of any or further anatomical changes; and a theoretical prevention of malignant transformation. Although many treatments have been suggested to treat LS over the years, only potent or ultra-potent corticosteroids remain as the treatment of choice. After initial therapy, some patients might only use corticosteroids as needed, while others may require a twice-weekly maintenance therapy. There is no place for surgery in uncomplicated LS. Surgery should be limited exclusively to patients with malignancy and to correct scarring secondary to the disease. Lichen sclerosus is associated with a 4–6% risk of squamous cell carcinoma, making long-term follow-up essential in these patients.     

Hair growth inhibition by psychoemotional stress: a mouse model for neural mechanisms in hair growth control

Stress has long been discussed controversially as a cause of hair loss. However, solid proof of stress-induced hair growth inhibition had long been missing. If psychoemotional stress can affect hair growth, this must be mediated via definable neurorendocrine and/or neuroimmunological signaling pathways. Revisiting and up-dating relevant background data on neural mechanisms of hair growth control, we sketch essentials of hair follicle (HF) neurobiology and discuss the modulation of murine hair growth by neuropeptides, neurotransmitters, neurotrophins, and mast cells. Exploiting an established mouse model for stress, we summarize recent evidence that sonic stress triggers a cascade of molecular events including plasticity of the peptidergic peri- and interfollicular innervation and neuroimmune crosstalk. Substance P (SP) and NGF (nerve growth factor) are recruited as key mediators of stress-induced hair growth-inhibitory effects. These effects include perifollicular neurogenic inflammation, HF keratinocyte apoptosis, inhibition of proliferation within the HF epithelium, and premature HF regression (catagen induction). Intriguingly, most of these effects can be abrogated by treatment of stressed mice with SP-receptor neurokinin-1 receptor (NK-1) antagonists or NGF-neutralizing antibodies - as well as, surprisingly, by topical minoxidil. Thus there is now solid in vivo-evidence for the existence of a defined brain- HF axis. This axis can be utilized by psychoemotional and other stressors to prematurely terminate hair growth. Stress-induced hair growth inhibition can therefore serve as a highly instructive model for exploring the brain-skin connection and provides a unique experimental model for dissecting general principles of skin neuroendocrinology and neuroimmunology well beyond the HF.     

Purinergic receptor expression in the regeneration epidermis in a rat model of normal and delayed wound healing

This study investigated changes in the protein expression of purinergic receptors in the regenerating rat epidermis during normal wound healing, in denervated wounds, and in denervated wounds treated with nerve growth factor (NGF), where wound healing rates are normalized. Excisional wounds were placed within denervated, pedicled, oblique, groin skin flaps, and in the contralateral abdomen to act as a control site. Six rats had NGF-treated wounds and six had untreated wounds. Tissue was harvested at day four after wounding. The re-epithelializing wound edges were analyzed immunohistochemically for P2X(5), P2X(7), P2Y(1) and P2Y(2) receptors, and immunostaining of keratinocytes was quantified using optical densitometry. In normal rat epidermis, P2Y(1) and P2Y(2) receptors were found in the basal layer where keratinocytes proliferate; P2X(5) receptors were associated with proliferating and differentiating epidermal keratinocytes in basal and suprabasal layers; P2X(7) receptors were associated with terminally differentiated keratinocytes in the stratum corneum. In the regenerating epidermis of denervated wounds, P2Y(1) receptor protein expression was significantly increased in keratinocytes (P<0.001) but P2Y(1) receptors (P<0.001) compared with untreated denervated wounds. In innervated wounds, NGF treatment enhanced expression in keratinocytes. P2X(5) (P>0.001) and P2Y(1) receptor protein (P<0.001) expression in keratinocytes. P2X(7) receptors were absent in all experimental wound healing preparations. P2X(5), P2X(7), P2Y(1) and P2Y(2) receptor protein expression in the regenerating epidermis was altered both during wound healing and also by NGF treatment. Possible roles for purinergic signalling and its relation to NGF in wound healing are discussed.