Position Statement: Linear prurigo is a subtype of chronic prurigo.

BACKGROUND: Chronic prurigo (CPG) is a distinct disease characterized by chronic pruritus, history and/or signs of prolonged scratching and multiple pruriginous lesions. It may present with various clinical manifestations, including papules, nodules, plaques or umbilicated lesions. Some patients with chronic pruritus show pruriginous linear and scaring scratch lesions (LSSL) and it is unclear whether these lesions belong to the spectrum of CPG. OBJECTIVE: To achieve a consensus on the classification of pruriginous LSSL and establish criteria to differentiate them from similar appearing conditions of different nature. METHODS: Members of the Task Force Pruritus (TFP) of the European Academy of Dermatology and Venereology participated in the consensus conference, discussing representative clinical cases. Using the Delphi method, consensus was reached when ≥75% of members agreed on a statement. RESULTS: Twenty-one members of the TFP with voting rights participated in the meeting. It was consented that LSSL occurs due to chronic pruritus and prolonged scratching, and share common pathophysiological mechanisms with CPG. LSSL were thus considered as belonging to the spectrum of CPG and the term 'linear prurigo' was chosen to describe this manifestation. CONCLUSION: Considering linear prurigo as belonging to the spectrum of CPG has important clinical implications, since both the diagnostic and therapeutic approach of these patients should be performed as recommended for CPG. Importantly, linear prurigo should be differentiated from self-inflicted skin lesions as factitious disorders or skin picking syndromes. In the latter, artificial manipulation rather than pruritus itself leads to the development of cutaneous lesions, which can show clinical similarities to linear prurigo.

Intellectual disability and cognitive ability in Darier disease: Swedish nation-wide study.

BACKGROUND: Darier disease is an autosomal dominant skin disorder caused by mutations in the ATP2A2 gene. Anecdotal reports suggest a relationship between Darier disease and intellectual disabilities, but these reports are based on small clinical samples and limited by absence of control populations. OBJECTIVES: To examine the risk of intellectual disability and subclinical impairments in cognitive ability in Darier disease. METHODS: We conducted a matched cohort study based on Swedish Population-, Patient- and Conscript Registers. The risk of being diagnosed with intellectual disability was estimated in 770 individuals with Darier disease, compared with matched comparison individuals without Darier disease. Associations were examined with risk ratios from conditional logistic regressions. In addition, we analysed test-based cognitive ability data (i.e. IQ data) from the Swedish conscript examination, for a subset of patients without diagnosed intellectual disability. RESULTS: Individuals with Darier disease had a sixfold increased risk of being diagnosed with intellectual disability (risk ratio 6.2, 95% confidence interval 3.1-12.4). For conscripted individuals with Darier disease but no diagnosed intellectual disability, mean cognitive ability scores were about half a standard deviation lower than for comparison subjects. CONCLUSIONS: Darier disease is associated with intellectual disability and subclinical impairments in cognitive ability. The Darier-causing mutations merit further attention in molecular genetic research on intellectual disability and cognitive ability.

Use of serotonin reuptake inhibitors in patients with psoriasis is associated with a decreased need for systemic psoriasis treatment: a population-based cohort study.

OBJECTIVE: To investigate whether psoriasis is affected by the use of serotonin reuptake inhibitors (SSRIs). DESIGN: A population-based cohort study. SETTING: The general adult population with plaque psoriasis in Sweden between 1997 and 2006. SUBJECTS: A total of 69 830 patients with plaque psoriasis were identified in the National Patient Register. Whether study subjects were exposed to SSRIs was identified through the Swedish Prescribed Drug Register. The SSRI-exposed subjects (n = 1282) had a prescription for SSRIs dispensed twice during 6 months at a Swedish pharmacy between 1 July 2006 and 1 April 2008, with a wash-out period of 1 year or longer. The reference subjects (n = 1282), who were not exposed to SSRIs, were matched for age, county of residence, sex, psoriasis severity and seasonal variation. MAIN OUTCOME MEASURE: Change in psoriasis severity defined by switching between nonsystemic and systemic psoriasis treatments 6 months after exposure to SSRIs. RESULTS: The risk of switching from nonsystemic to systemic psoriasis treatments was significantly decreased in the SSRI-exposed group (odds ratio 0.44, 95% confidence interval 0.28-0.68). CONCLUSION: SSRI use in patients with psoriasis is associated with a decreased need for systemic psoriasis treatment.

Substance P alterations in skin and brain of chronically stressed atopic-like mice.

BACKGROUND: Stress is known to worsen the symptoms of atopic eczema (AE). Substance P is likely to play an important role in the development and pathogenesis of AE. OBJECTIVE: To examine a possible connection between chronic mild stress and changes in the expression of substance P and its receptor (R) neurokinin (NK) 1 in the skin and stress-related brain regions in NC/Nga atopic-like mice. METHODS: The mice were divided into three groups (eight animals per group): SE (stressed eczematous), NSE (non-stressed eczematous) and SC (stressed control). Ears and brains of the mice were investigated using immunohistochemistry and RT-PCR. RESULTS: In the skin, there was a decrease in the number of substance P immunoreactive nerve fibres in SE compared with SC group. RT-PCR showed a strong tendency to an increase in mRNA for NK1R in the skin of SE compared with NSE mice. There was an increase in the number of mast cells and the degree of their degranulation in the SE compared with both other groups. A decrease in substance P immunoreactivity in medial hippocampus was found in SE compared with NSE animals. In prefrontal cortex and central amygdala, there were no significant differences in substance P immunoreactivity between the three groups. CONCLUSION: Exposure to chronic mild stress in NC/Nga atopic-like mice may result in altered expression patterns of substance P in the skin and hippocampus.

Expression of tachykinins and their receptors in plaque psoriasis with pruritus.

UNLABELLED: BACKGROUND Various mediators of pruritus have been suggested that might be responsible for the mechanism of pruritus in psoriasis. OBJECTIVES: To study the expression levels of members of the tachykinin family, substance P and neurokinin (NK) A and their receptors, NK-1 and NK-2, in psoriasis and to correlate their expression with the intensity of pruritus. A possible correlation with chronic stress and depression was also evaluated. METHODS: Biopsies were obtained from 28 patients with chronic plaque psoriasis; the majority had pruritus. The samples were taken from lesional and nonlesional areas on the back and also from 10 healthy controls, for immunohistochemistry staining, and from lesional skin for radioimmunoassay. Prior to biopsy, the clinical severity of the psoriasis of each patient was assessed by the Psoriasis Area and Severity Index (PASI) and the intensity of pruritus was measured by using a visual analogue scale (VAS). Levels of depression and stress were measured using Beck's Depression Inventory (BDI) and the salivary cortisol test, respectively. RESULTS: Substance P-, NKA- and NK-2 receptor-immunoreactive nerves, and non-neuronal inflammatory cells positive for substance P and NKA and their respective receptors, NK-1 and NK-2, were numerous in psoriasis compared with healthy controls. The numbers of substance P-positive nerves and NK-2 receptor-positive cells in lesional skin were significantly correlated to pruritus intensity. The cortisol ratio was inversely correlated with the number of NK-1 receptor-immunoreactive inflammatory cells in lesional and nonlesional psoriasis skin. There was also a positive correlation between the BDI score and the number of substance P-positive cells in nonlesional skin and with NK-1 receptor-positive cells in lesional and nonlesional skin. CONCLUSIONS: Tachykinins may play a role in psoriasis per se, in addition to pruritus in this disease. Targeting the combined NK-1 and NK-2 receptors might be a possible treatment.

Responses to intradermal injections of substance P in psoriasis patients with pruritus.

BACKGROUND: Various mediators have been suggested for the pathogenesis of pruritus in psoriasis. METHODS: To investigate cutaneous responses of substance P in pruritic lesional and nonlesional areas of psoriasis patients and in healthy controls, substance P, saline and histamine were injected intradermally. After each injection, pruritus, flare and wheal were recorded. RESULTS: There was no statistical difference in the latency period, duration, area under the curve and maximum intensity of pruritus evoked by substance P (10(-5) and 10(-6) mol/l) between psoriasis and healthy control skin. Substance P (10(-5) mol/l) induced a tendency to a greater intensity of pruritus in lesional compared to nonlesional psoriatic skin (p = 0.08). Histamine produced a shorter itch latency period (p < 0.05) and a lower maximum intensity of pruritus (p = 0.05) in lesional psoriasis skin than in healthy control skin. No significant difference in flare area was observed between the psoriasis patients and healthy controls. The histamine-induced wheal was smaller in psoriasis patients than in healthy individuals (p < 0.05). CONCLUSION: Intradermally injected substance P induced pruritus, flare and wheal in psoriasis patients. However, these responses did not differ significantly from those of the healthy controls.

Neuronal changes in psoriasis exacerbation.

BACKGROUND: The nervous system contributes to inflammatory skin diseases. Objective The aim of this investigation was to study the neuronal contribution to psoriasis at the remission and exacerbation phases. METHODS: We examined the expression of the neuronal markers protein gene product 9.5 (PGP 9.5), growth-associated protein-43 (GAP-43) and substance P, in addition to its receptor (R), neurokinin-1R (NK-1R) in psoriatic skin from seven female patients at remission and exacerbation, using immunohistochemistry. RESULTS: The number of epidermal PGP 9.5 immunoreactive nerve fibres in the involved skin during exacerbation was decreased (P < 0.01) compared to involved skin at remission and non-involved skin at the exacerbation phase. GAP-43-positive nerve fibres were decreased (P < 0.05) in the involved skin in contrast to non-involved skin, during exacerbation. Substance P expression was seen on both immunoreactive nerve fibres and cells with a down-regulation (P < 0.01) in the number of positive nerve fibres in the involved skin compared to non-involved skin, at the exacerbation phase. The number of substance P-positive cells was slightly lower in the involved skin at exacerbation than at remission. The number of NK-1R immunoreactive cells was increased (P < 0.01) in the involved skin in contrast to non-involved skin, at the exacerbation phase. CONCLUSION: Our findings suggest a crosstalk between the nervous system and inflammation during psoriasis exacerbation in the form of an altered expression of nerve fibres, substance P and its NK-1R.

Patients' perspective of pruritus in chronic plaque psoriasis: a questionnaire-based study.

BACKGROUND: Pruritus in psoriasis patients has not been regarded as a major symptom. Objective To study the pattern of pruritus in chronic plaque psoriasis. METHODS: A questionnaire was sent out to 109 patients with a diagnosis of chronic plaque psoriasis, who attended our outpatient departments during the period of January 2006 to January 2007. RESULTS: Out of 109 patients, 80 patients (74%) answered the questionnaire. Pruritus was found in 80% of the patients, with an intensity of 5.2 +/- 2.6 (+/-SD) using a visual analogue scale (0-10). The frequency and intensity of pruritus were higher in women. Lower leg and scalp were reported to be the most commonly affected sites. Major aggravating factors for pruritus were stress and dryness of skin. Sun, sleep and vacation could relieve pruritus. The most common antipruritic treatments used by the patients were topical steroids, topical vitamin D, emollients and ultraviolet light therapy, whereas antihistamines were used by a small number of patients. Mood, concentration and sleep were negatively affected by pruritus. CONCLUSION: Pruritus is a common symptom in patients with chronic plaque psoriasis.

Psoriasis and stress: a prospective study.

BACKGROUND: Psoriasis is generally thought to be worsened by stress. This presumption has been supported primarily by retrospective studies using questionnaires. No controlled prospective study on this issue has been performed. METHODS: Nine women with moderate plaque psoriasis were enrolled in the study. They all believed that their psoriasis was worsened by stress. They filled in a daily diary with estimations of actual stress levels and grades of psoriasis. The study of each patient started when her skin disease was in a stable phase and was concluded when her psoriasis was worsened by at least 25% from the starting level. Psoriasis area severity index scores were recorded at the start, as soon as possible after exacerbation and 2 weeks later. Stress-related blood samples were taken at the same visits. The study was analysed as a nine-case study. RESULTS: No clear pattern was found between stress levels and worsening of psoriasis in our nine patients. One patient had elevated stress levels 13 days before exacerbation of psoriasis, but for at least seven patients, there were no identifiable time relationships between stress and psoriasis appearance. For two patients, there were clear elevations of stress levels after psoriasis outbreak. CONCLUSION: This limited study does not support the assumption that stress is a worsening factor in psoriasis.

Neuroimmune mechanisms in patients with atopic dermatitis during chronic stress.

OBJECTIVE: To identify pathoaetiological neuroimmune mechanisms in patients with atopic dermatitis (AD) and chronic stress, focusing at nerve density, sensory neuropeptides, and the serotonergic system. METHODS: Eleven patients with AD with histories of stress worsening were included. Biopsies from involved and non-involved skin were processed for immunohistochemistry. Salivary cortisol test was done as a marker for chronic stress. RESULTS: There were more acanthosis and fewer nerve fibres in epidermis and papillary dermis of involved compared with non-involved skin. Whereas there was no significant change in the number of substance P and calcitonin gene-related peptide-positive nerve fibres between the involved and non-involved skin, there was an increase in the epidermal fraction of 5-hydroxtrytamine 1A (5-HT1A) receptor and serotonin transporter protein (SERT) immunoreactivity in the involved skin. The number of 5-HT2AR, CD3-positive cells, and SERT-positive cells, most of them being CD3 positive, was increased in involved skin. There was an increase in mast cells in the involved skin, and these cells were often located close to the basement membrane. There was a strong tendency to a correlation between 5-HT2AR positive cells in the papillary dermis of involved skin and low cortisol ratios, being an indicator of chronic stress. CONCLUSION: A changed innervation and modulation of the serotonergic system are indicated in chronic atopic eczema also during chronic stress.

A serotonin-like immunoreactivity is present in human cutaneous melanocytes.

Immunohistochemistry was applied in the investigation of the possible existence of serotonin in human skin. It was found that epidermal melanocytes express a serotonin-like immunoreactivity. The immunoreactivity was associated with both the cytoplasm and the cellular membrane, though the latter was only found in certain cells. The serotonin anti-serum labeled the same cells as NKI-beteb, which is known as a reliable marker of melanocytes. Blocking experiments showed that both serotonin and NKI-beteb have different epitopes in the melanocytes. In in vitro studies, serotonin-like immunoreactivity appeared in approximately 90% of cultured human melanocytes, and was found both in the cytoplasm and also in the nuclei. Thus, we believe the melanocytes to be the origin of serotonin (or a serotonin-like molecule) in the skin.

Increased expression of keratinocyte interleukin-8 in human contact eczematous reactions to heavy metals.

Heavy metal-induced contact eczematous human skin reactions to cobalt chloride and mercuric chloride were investigated for immunoreactivity to interleukin-8 (IL-8), by using an indirect immunoperoxidase staining technique. There was suprabasal epidermal staining for IL-8, with a decrease in the vicinity of areas with parakeratotic epithelium. However, in the immediate vicinity of a vesicular formation, intense staining of some apically situated keratinocytes was found. In addition, increased immunoreactivity over the acrosyringial area compared with the surrounding epidermis was obtained. These findings indicate an increased synthesis of keratinocyte IL-8 in contact eczematous skin.

Vasoactive intestinal polypeptide inhibits the established allergic contact dermatitis in humans.

There is increasing evidence indicating that the nervous system influences the immune response. In the present study the potential immunomodulatory role of vasoactive intestinal polypeptide (VIP) in established allergic contact dermatitis in humans was investigated. Positive patch-test reactions were elicited by application of nickel sulphate for 48 h. VIP was applied under patch-test conditions after another 24-h period. The test areas were measured before and 24 h after application of VIP and biopsy specimens were taken for immunohistochemistry. After application of VIP at 10(-5) mol/L, there was a significant reduction in the diameter of the test reaction. In addition, there was a reduction in the number of Leu 3a+ cells. The influence of VIP on the proliferative response of peripheral blood mononuclear cells from nickel-allergic subjects to nickel sulphate was also tested. The cells were cultured for 6 days and VIP was added after 3 days. There was no effect on the proliferative response. However, when VIP was added at 10(-6) and 10(-5) mol/L, a higher level of interferon gamma was found in the nickel-treated cell cultures compared to the controls. In conclusion, VIP may have an inhibitory effect on established allergic contact dermatitis. This inhibitory effect is possibly mediated through an increased production of interferon gamma by peripheral blood mononuclear cells.

Neuropeptide Y concentrations in experimental Leishmania major cutaneous leishmaniasis.

Neuropeptide Y (NPY) concentrations were investigated by radioimmunoassay and immunohistochemistry in a murine model of cutaneous leishmaniasis, using a susceptible (BALB/c) and a resistant (C57BL/6) mouse strain. The analyses were performed on the skin, secondary lymphoid organs and dorsal root ganglia (DRG) at 1, 3, 6 and 9 weeks postinfection. An overall reduction in the NPY concentrations in the studied organs was observed in both mouse strains; the reduction in the skin and draining lymph nodes was more evident and progressive in the susceptible strain. Using immunohistochemistry there seemed to be a reduction in NPY immunoreactivity in all inflamed tissues analysed compared to the controls. These observations might indicate a possible pathophysiological role for NPY in murine cutaneous leishmaniasis.

Expression of interleukin-6 in human dorsal root ganglion cells.

The expression of Interleukin-6 (IL-6) was studied in normal dorsal root ganglia (DRG) of juvenile and foetal humans, using immunohistochemistry and in situ hybridization techniques. There was an expression of IL-6-like immunoreactivity in more than 75% out of neuronal cells in the juvenile ganglia with a peripheral localization, and also an expression in the foetal ganglion cells. There was a co-localization of IL-6 with substance P (SP) and calcitonin gene-related peptide (CGRP) in more than 60% of the DRG cells, respectively. By in situ hybridization 0.9% of the cells in the juvenile ganglia and 1.1% of the cells in the foetal ganglia showed a positive signal for IL-6. In addition, expression of IL-6 was found in juvenile medulla spinalis, preferentially in the white matter.

Decreased concentrations of CGRP in Leishmania major murine cutaneous leishmaniasis.

The expression of the sensory neuropeptide calcitonin gene-related peptide (CGRP) in the skin, secondary lymphoid organs and dorsal root ganglia (L4-L6) in Leishmania major-induced inflammation was evaluated by radioimmunoassay. The investigation was conducted on two mouse strains, the susceptible BALB/c and the resistant C57BL/6. The CGRP concentration in the inflamed skin of both mouse strains was decreased as early as 1 week postinfection, compared to controls. A further reduction was observed in both mouse strains throughout the 9-week study period, but was more evident in the susceptible strain. The CGRP concentration was increased in the ipsilateral dorsal root ganglia (L4-L6) of mice of the resistant strain 1 week postinfection, while no change was observed in the susceptible strain. In the remaining part of the study period there was a reduction in CGRP in the ipsilateral dorsal root ganglia of both mouse strains. In the spleen, a reduction was noted in the infected BALB/c at all measurement times (significant at 6 and 9 weeks), while no change was observed in C57BL/6 strain. These findings may indicate a regulatory function of CGRP in the pathophysiology of murine cutaneous leishmaniasis and hence in the disease outcome. The reduction in CGRP might also explain the defective nociception observed in patients with cutaneous leishmaniasis.

Gamma/delta T cells and human skin reactivity to heavy metals.

Gamma/delta T cells may act as a first line of defence and respond to stress signals from the surrounding tissue. In the present investigation the occurrence of gamma/delta T cells was studied in the human skin after application of heavy metal salts by a routine epicutaneous patch-testing procedure. Gamma/delta cells were not found in normal skin. They were observed in all 14 allergic or irritant patch-test reactions to gold chloride and in 6/8 such reactions to mercuric chloride, where they comprised 16 +/- 6% and 15 +/- 6%, respectively, of the CD3+ cells in the dermis. They were also epidermotropic. Very few of these cells were found in reactions to salts of nickel and silver, except that they were increased in hair follicle epithelium in a reaction to silver nitrate. The gamma/delta cells expressed the V delta 2 and the V gamma 2 gene segments and were CD4-8-, indicating that they had the same phenotype as gamma/delta lymphocytes in the peripheral blood. Moreover, they were 'memory' T cells. These results indicate that gamma/delta lymphocytes play a role in the skin defence against highly reactive heavy metals.

Vasoactive intestinal polypeptide in allergic contact dermatitis: an immunohistochemical and radioimmunoassay study.

Vasoactive intestinal polypeptide (VIP) is a neuropeptide with immunomodulatory properties. To elucidate the possible role of VIP in the pathophysiology of cutaneous contact hypersensitivity, we compared involved with uninvolved skin of allergic contact dermatitis (ACD) from nickel-allergic patients. Assays included quantification of VIP-immunoreactive (VIP-IR) nerve fibres and cells bearing immunoreactivity for VIP1 and VIP2 receptors in skin biopsy specimens, and of the concentration of VIP-like immunoreactivity (VIP-LI) in extracts of biopsy specimens. VIP-IR nerve fibres were found in the deeper part of the dermis close to sweat glands and hair follicles. No difference in the presence of VIP-IR nerve fibres was found between involved and uninvolved skin of ACD. VIP1 and VIP2 receptor immunoreactivity was seen on keratinocytes in the basal layer of the epidermis, with no difference between involved and uninvolved skin. Staining was also seen on vessel walls and mononuclear cells in the dermis. The highest staining intensity in the mononuclear cells was noted with the antibodies against the VIP2 receptor. While most of the mononuclear cells were stained in uninvolved skin, a minority of the cells showed a positive signal in involved skin. The concentration of VIP-LI in uninvolved skin was 1.53+/-0.790 pmol/g and in involved skin 1.41+/-0.735 pmol/g. It is concluded that there is no significant difference in either the distribution of VIP-IR fibres or the concentration of VIP-LI between involved and uninvolved skin of ACD. However, the number of dermal mononuclear cells showing VIP2 receptor immunoreactivity in skin of ACD was reduced.

Skin nerve fibres and their contacts with mast cells in patients with palmoplantar pustulosis.

Patients with palmoplantar pustulosis (PPP) frequently report that stress worsens their condition. A study was therefore made of the distribution and number of nerve fibres positive for protein gene product (PGP) 9.5 (a general nerve marker) and nerve fibres with substance P- and calcitonin gene-related peptide-like immunoreactivity in involved skin from patients with PPP and in skin from healthy controls. The number of mast cells in the papillary dermis was larger (P = 0.0003) in lesional palmar PPP skin than in control skin, and the number of contacts between mast cells and nerve fibres was significantly larger (P = 0.02) in PPP skin than in control skin. Image analysis of the nerve fibres around the sweat glands showed that the positively stained area as a percentage of the total area of the sweat gland (coil + surrounding nerves) was significantly lower in PPP skin (P = 0.0006). Furthermore, the nerves seemed to be fragmented. Neutrophils within and below the pustules and in the papillary dermis showed positive substance P staining. The increased number of contacts between nerves and mast cells in PPP skin and the intense substance P-like immunoreactivity of the neutrophils indicate that neuromediation may influence the inflammation in PPP, whereas the destruction of the nerve fibres around the sweat glands might be a result of the inflammation.

Immunohistochemical localization of interleukin-6-like immunoreactivity to peripheral nerve-like structures in normal and inflamed human skin.

Interleukin-6-like (IL-6-like) immunoreactivity was sought in inflamed and normal human skin using the same immunohistochemical technique as for detection of neuropeptides. Such immunoreactivity was found in dermal and in a few intraepidermal nerve-like fibres in biopsy specimens from inflamed skin from patients with positive epicutaneous patch-test reactions to nickel sulphate, and in skin specimens from patients with atopic dermatitis and prurigo nodularis. However, IL-6-like immunoreactivity was also found in nerve-like fibres in specimens from nonlesional skin. In skin from patients with positive epicutaneous patch-test reactions there was a statistically significantly (P < 0.01) higher number of IL-6-positive nerve fibres in the epidermis than in normal skin, in contrast to the papillary dermis, in which no difference was found. Moreover, there were clusters of nerve-like fibres with IL-6-like immunoreactivity in the dermis of prurigo nodularis lesions. In these nerve-like fibres, the colocalization of the immunoreactivities for IL-6 and calcitonin gene-related peptide was indicated. Localization of immunoreactivity to nerve-like structures surrounding the eccrine sweat glands indicates that IL-6 is present in autonomic as well as in sensory nerve fibres.