Expression of calcitonin gene-related peptide in atopic dermatitis and correlation with distress.

BACKGROUND: Atopic dermatitis (AD) is a chronic, inflammatory, often severely itching skin disorder. It may worsen due to stress, depression, or anxiety. Calcitonin gene-related peptide (CGRP) may be involved in inflammation signaling. CGRP has also been suggested in relation to stress, depression, and anxiety. This study aimed to investigate the expression of CGRP in the skin of patients with AD. METHODS: Twenty-seven adult patients with AD, characterized with clinical and psychodemographic parameters, were investigated regarding CGRP expression in skin biopsies, using an immunohistochemical technique. RESULTS: The total number of CGRP-positive nerve-like fibers was found to be higher in lesional skin than in non-lesional skin. Moreover, more inflammatory cells of dendritic shape intruded into the epidermis in lesional skin compared to non-lesional skin. Keratinocytes showing expression of CGRP were also found in lesional skin. Interestingly, the number of CGRP-positive nerve-like fibers in lesional skin correlated with depressive and anxiety scores. Correlation with depressive score was also found for round CGRP-positive inflammatory cells in the epidermis. CONCLUSIONS: CGRP may have a role in both the inflammatory process and distress, in AD.

Psychological Stress and Atopic Dermatitis: A Focus Group Study.

BACKGROUND: Atopic dermatitis (AD) is a chronic inflammatory skin disorder. It is often reported to be worsened by psychological stress. OBJECTIVE: To explore the role of psychological stress and related triggers in AD, and its connection to worsening of this disease, focusing on patients' perspectives. METHODS: In total, 28 patients with AD were included in focus groups. Topics regarding psychological stress and psychological triggers were discussed. RESULTS: The hypothesis that psychological stress may have impact on eczema and its pruritus was supported by all of the patients. Distinguishing the worsening effect of psychological stress from effects of physiological triggers, such as infection, climate and allergic factors, was claimed to be difficult by many patients. Most of the patients thought that chronic stress affected the AD more when compared to acute stress. Family problems, financial problems, work overload, school exam periods, lack of structure at work, and unforeseen events were identified as important psychological triggers. Conventional treatment/therapy with topical corticosteroids and emollients, UV light treatment, were suggested as possible treatments, as well as psychological intervention and physical exercise. CONCLUSION: Psychological stress is an important factor to consider in the management of patients with AD. In particular, chronic stress tends to worsen AD. The type of stress can possibly also affect the quality of the pruritus experienced by the patients. Unforeseen events and decision making were frequently mentioned as important triggers. Furthermore, physical exercise was reported to provide beneficial effects.

Psoriasis and alcohol.

Psoriasis is a chronic inflammatory skin disease that may be triggered or worsened by several factors, including alcohol. A higher than average alcohol consumption is common among individuals with psoriasis. Neurobiological signaling affected by alcohol intake includes a range of neurotransmitters, such as the dopaminergic, serotonergic, and tachykinergic systems, involved in reward and drug-seeking. These neurotransmitters may also have an impact on the inflammatory processes per se in psoriasis. Future therapy may, therefore, be targeted at neurotransmitter networks involved with both alcohol intake and the inflammatory processes.

Tachykinin upregulation in atopic dermatitis.

Context: Atopic dermatitis (AD) is a chronic, inflammatory, itching skin disorder, which may worsen due to stress, depression and anxiety. Tachykinins may be involved in inflammation signaling as well as they may have a role in stress, depression and anxiety. Objective: This study aimed to measure the expression of tachykinin markers, in the skin of patients with AD, and the correlation of these tachykinins with clinical and psychodemographic parameters. Materials and methods: Twenty-eight adult patients with AD were investigated regarding tachykinin expression in skin biopsies, using an immunohistochemical technique. The patients were characterized with clinical and psychodemographic parameters. Results: The number of substance P and neurokinin (NK)A positive nerve fibers, as well as NKA positive mononuclear dermal cells, was increased in lesional compared to non-lesional skin. Interestingly, the depression score and the number of dermal NK-1 receptor (R) positive cells in lesional as well as in non-lesional skin showed a correlation. Conclusion: These findings indicate an upregulation of the tachykinergic system in the inflamed skin of AD.

Substance P Antagonist Aprepitant Shows no Additive Effect Compared with Standardized Topical Treatment Alone in Patients with Atopic Dermatitis.

Atopic dermatitis (AD) is a chronic, itchy, inflammatory skin disorder that may worsen due to stress and anxiety. Tachykinins have been suggested to be involved in the inflammation in AD, as well as pruritus. Aprepitant is a NK-1 receptor antagonist. This open randomized trial evaluated the effect of aprepitant added to topical treatment in adult patients with moderate-severe AD. The treatment group (n = 19) received 80 mg/day aprepitant for 7 days as a supplement to standardized topical treatment with a moderately strong steroid and a moisturizer. The control group (n = 20) received topical treatment alone. Patients were monitored for the extent of the disease (using SCORing of Atopic Dermatitis; SCORAD), pruritus, and scratching movements. In both the aprepitant-treated and the control groups there was a decrease in SCORAD, pruritus and scratching movements. However, there was no significant additional improvement in any of these parameters in the aprepitant-treated group compared with the control group.

[In case of pruritus, always consider scabies!]. / Vid klåda, tänk alltid på skabb!

In case of pruritus, always consider scabies! Scabies is an itching skin disease caused by the mite Sarcoptes scabiei which affects more than 100 million people worldwide. Regarded as a neglected tropical disease by the WHO, it is a major public health burden in endemic areas. As direct skin-to-skin contact is the main route of transmission family members and sexual partners are often affected. Typical presentation includes a severely pruritic rash with predilection for the extremities and the trunk. Definitive diagnosis relies on microscopic identification of the mites. Future, more efficient, diagnostic methods may include serological testing or PCR for S. scabiei DNA. A benzyl benzoate and disulfiram based lotion, Tenutex, is the treatment of choice in Sweden with topical permethrin or oral ivermectin being used in certain cases. Scabies is an important diagnosis to consider in all patients presenting with pruritus.

Dermatophytosis: fluorostaining enhances speed and sensitivity in direct microscopy of skin, nail and hair specimens from dermatology outpatients.

Direct microscopy of keratinised specimens is a standard screening procedure that assists clinicians to differentiate true superficial mycoses from non-fungal disorders of the skin, nail and hair. Most clinical dermatologists use bright-field microscopy when searching for dermatophyte fungi in clinical samples while laboratory-based mycologists increasingly favour fluorescence microscopy in order to optimise visualisation of fungal elements. This study compared the validity and speediness of fluorescence microscopy vs. conventional light microscopy when screening for fungi in 206 dermatological samples from dermatology outpatients. Both senior dermatologist and a less experienced investigator (medical student) attained high and comparable levels of specificity (91.7-93.8%), positive predictive value (77.1-81.4%) and negative predictive value (83.7-89.9%) using either method. Fluorostaining with Blankophor prior to fluorescence microscopy increased the sensitivity by 22 ± 1% as compared to light microscopy of unstained samples. For both investigators, the time required to identify fungal elements by the fluorescence-based technique was reduced by at least 50%, thus improving the performance of direct microscopy in the clinical setting.

Serotonergic Markers in Atopic Dermatitis.

Stress and anxiety may worsen atopic dermatitis (AD) through the serotonin system. Serotonergic expression was measured in 28 patients with AD in relation to extent of the disease (SCORing of Atopic Dermatitis; SCORAD), pruritus intensity (visual analogue scale; VAS), anxiety traits (Swedish Universities Scales of Personality; SSP) and depression (Montgomery-Åsberg Depression Rating Scale-Self assessment; MADRS-S). Biopsies were taken from lesional and non-lesional AD skin, and investigated for expression of serotonin, its receptors 5-HT1A and 5-HT2, and serotonin transporter protein (SERT), using immunohistochemistry. 5-HT1AR-immunoreactivity (ir) was higher in lesional skin in apical epidermis and in mast cell-like cells in dermis, and 5-HT2AR-ir in apical epidermis and on blood vessels. In contrast, a basement membrane 5-HT2AR-ir signal was higher in non-lesional skin. The distribution of SERT-ir in the basal epidermal layer was higher in lesional skin. Positive and negative correlations were found between serotonergic markers and SCORAD, inflammation, pruritus intensity, anxiety traits, and depression score, indicating that serotonergic mechanisms are involved in AD.

Alcohol intake measured by phosphatidylethanol in blood and the lifetime drinking history interview are correlated with the extent of psoriasis.

BACKGROUND: Psoriasis has been reported to be associated with alcohol consumption. OBJECTIVE: To investigate the level of alcohol intake in individuals with psoriasis and correlate intake with the extent of disease and pruritus. METHODS: Twenty-nine outpatients (15 females and 14 males) with stable chronic plaque psoriasis of moderate severity were recruited. The Psoriasis Area and Severity Index (PASI) and the degree of pruritus (visual analogue scale) were compared with measures of drinking habits as determined by the Lifetime Drinking History (LDH), the Alcohol Use Disorders Identification Test and whole-blood phosphatidylethanol (PEth), an alcohol-specific biomarker. RESULTS: The majority of patients were social drinkers with moderate alcohol consumption as determined by PEth and LDH. Alcohol consumption correlated significantly with the PASI score. There was no correlation between alcohol use and pruritus. CONCLUSION: The level of alcohol consumption is correlated with the extent of psoriasis.

The association between Darier disease, bipolar disorder, and schizophrenia revisited: a population-based family study.

OBJECTIVES: Darier disease is an autosomal dominant skin disorder caused by mutations in the ATPase, Ca++ transporting, cardiac muscle, slow twitch 2 (ATP2A2) gene and previously reported to cosegregate with bipolar disorder and schizophrenia in occasional pedigrees. It is, however, unknown whether these associations exist also in the general population, and the objective of this study was to examine this question. METHODS: We compared a national sample of individuals with Darier disease and their first-degree relatives with matched unexposed individuals from the general population and their first-degree relatives, respectively. To examine risks for bipolar disorder and schizophrenia, risk ratios and 95% confidence intervals (CIs) were estimated using conditional logistic regressions. RESULTS: Individuals with Darier disease had a 4.3 times higher risk of being diagnosed with bipolar disorder (95% CI: 2.6-7.3) and a 2.3 times higher risk of being diagnosed with schizophrenia (95% CI: 1.1-5.2) than matched individuals from the general population. Relatives of individuals with Darier disease had a 1.6 times higher risk of having bipolar disorder (95% CI: 1.1-2.5) than relatives of matched individuals from the general population, but no increased risk of schizophrenia (risk ratio = 0.8, 95% CI: 0.4-1.8). CONCLUSIONS: The association between Darier disease and bipolar disorder is manifest also in the population, and our data suggest that genetic variability within the ATP2A2 gene that causes Darier disease also confers susceptibility for bipolar disorder. The Darier-causing mutations merit additional attention in molecular genetic research on bipolar disorder.

Pirfenidone in idiopathic pulmonary fibrosis: expert panel discussion on the management of drug-related adverse events.

Pirfenidone is currently the only approved therapy for idiopathic pulmonary fibrosis, following studies demonstrating that treatment reduces the decline in lung function and improves progression-free survival. Although generally well tolerated, a minority of patients discontinue therapy due to gastrointestinal and skin-related adverse events (AEs). This review summarizes recommendations based on existing guidelines, research evidence, and consensus opinions of expert authors, with the aim of providing practicing physicians with the specific clinical information needed to educate the patient and better manage pirfenidone-related AEs with continued pirfenidone treatment. The main recommendations to help prevent and/or mitigate gastrointestinal and skin-related AEs include taking pirfenidone during (or after) a meal, avoiding sun exposure, wearing protective clothing, and applying a broad-spectrum sunscreen with high ultraviolet (UV) A and UVB protection. These measures can help optimize AE management, which is key to maintaining patients on an optimal treatment dose.

Adult atopic dermatitis patients and physical exercise: a Swedish questionnaire study.

Physical activity promotes health and prevents disease. When patients with atopic dermatitis (AD) undertake exercise, the itch often gets worse due to sweating, and this may reduce their engagement in physical exercise. The aim of this study was to determine the level of physical exercise in patients with AD compared with a control group from a normal population. Our hypothesis was that patients with AD have a lower level of physical exercise due to their skin disease. A total of 110 patients with AD and 196 subjects from a normal population, age range 20-34 years, answered a questionnaire. Eleven patients with AD underwent an in-depth interview. The patients with AD had the same level of physical exercise and attitude to physical exercise as the normal population. Therefore, our hypothesis could not be confirmed. In conclusion, the skin symptoms of AD do not appear to be an obstacle to moderate physical exercise.

Serotonin transporter protein overexpression and association to Th17 and T regulatory cells in lupoid leishmaniasis.

The immunopathogenesis of chronic non-healing Old World cutaneous leishmaniasis is challenging. There is a bidirectional communication between the nervous and immune systems, serotonin being an important mediator in this respect. Our aim was to study the role of the serotonin transporter protein (SERT) and its relation to T cell-related immune responses in lupoid leishmaniasis. Paraffin-embedded skin biopsies of 12 cases of lupoid and 12 cases of usual types of cutaneous leishmaniasis were investigated using immunohistochemistry regarding expression of SERT, Th1, Th2, Th17 and T regulatory cell (Treg) markers. SERT as well as Tregs and interleukin (IL)-17 positive cells were more prevalent while IL-5 (Th2) and interferon (IFN)-γ (Th1) expressing cells were less numerous in the lupoid tissue compared to those from the usual type of leishmaniasis. The majority of the SERT(+) cells were also tryptase(+) (mast cells). There was a positive correlation between a higher number of SERT(+) and IL-17(+) cells in the lupoid type, while lower numbers of SERT(+) cells were significantly related to lower percentages of CD25(+) cells in the usual type of leishmaniasis. These results might indicate a role for SERT, Th17 and Tregs in the pathogenesis of lupoid leishmaniasis.

Interleukin-2 expression in lupoid and usual types of old world cutaneous leishmaniasis.

BACKGROUND: Interleukin (IL)-2 plays a central role in T cell-dependent immune responses. OBJECTIVES: We conducted this study to determine and compare IL-2 expression in lupoid and usual types of Old World Cutaneous Leishmaniasis (OWCL), using immunohistochemistry. PATIENTS AND METHODS: Thirteen paraffin-embedded specimens of lupoid and 12 specimens of usual types of OWCL were used. A mouse monoclonal anti IL-2 antibody was used for staining by the envision technique. RESULTS: There were strongly stained discrete foci of staining through inflammatory infiltrates of dermis and also in basal layers of epidermis and adnexal structures, with a distinctive pattern of hot spot activity foci (mean of 9.31 ± 6.4 versus 8.17 ± 6.9 foci per HPF for lupoid and usual types, respectively). The expression of IL-2 had no correlation with the pattern of granulomatous inflammation (tuberculoid, sarcoidal or mixed suppurative). CONCLUSIONS: Interleukin-2 takes part in the immunological response of the granulomatous reaction of OWCL and is not statistically different between lupoid and usual types (P = 0.674).

Chronic mild stress modulates 5-HT1A and 5-HT2A receptor expression in the cerebellar cortex of NC/Nga atopic-like mice.

Atopic eczema symptoms may worsen due to stress. In the present study, the cerebellar cortex of the atopic-like mouse NC/Nga was studied regarding the effect of chronic mild stress on expression of two well-characterized serotonergic receptors (R), 5-HT1A and 5-HT2A. In total 24 mice were used. Sixteen of these mice were subjected to unpredictable stressors for 12 weeks, and 8 mice were used as controls. In order to evoke an eczema, a mite antigen was applied to 16 mice from week 9 of the experiment. Thus, three groups of mice, stressed eczematous (SE), non-stressed eczematous (NSE) and stressed control (SC), respectively, were obtained. The expression of the 5-HT1AR was analyzed using quantitative immunohistochemistry. For evaluation of 5-HT2AR a semi-quantitative technique was used, the cell density and signal intensity being measured. The highest average value for 5-HT1AR expression, in the Purkinje cells, was recorded in the NSE group, while the lowest average was in the SC group. 5-HT1AR expression differed significantly between the groups. The highest average value for density of 5-HT2AR positive Purkinje cells was evident in the SE group, while the lowest was in the SC group, this difference between groups also being statistically significant. In addition, the signal intensity was highest in the SE group, with a difference compared to the other groups. In conclusion, chronic mild stress modulates serotonergic receptor expressions in the cerebellar cortex of atopic-like mice.

Pruritic and vascular responses induced by serotonin in patients with atopic dermatitis and in healthy controls.

Atopic dermatitis (AD) is a chronic inflammatory skin disease with often severe itch. The aim of this study was to determine the pruritogenic and vascular effect of serotonin (5-hydroxytryptamine; 5-HT) in patients with AD and in healthy controls. A 50 µg dose of 5-HT was injected intradermally into non-lesional skin of 25 patients with AD and 25 healthy control individuals, and the effect compared with 0.2 µg histamine as a positive control, and buffer as a negative control. Pruritus was recorded by the subjects, using a computerized visual analogue scale, while flare and wheal were recorded by the investigator. There was no qualitative or quantitative difference in 5-HT-induced itch between patients and control subjects, or between males and females. However, reduced flare and wheal were found in the patient group for 5-HT. There were no correlations between clinical findings (i.e. eczema severity, clinical pruritus) and recorded experimental itch, or flare or wheal responses for 5-HT, in the patients with AD. In both groups a shorter itch latency was found for 5-HT compared with histamine. Through the use of intradermal injections, making it possible to calculate the dose of substance delivered, a lower vascular response to 5-HT was shown in patients with AD compared with healthy controls. In addition to confirming a pruritogenic role of 5-HT in both patients with AD and healthy controls, we found a shorter itch latency for 5-HT compared with histamine in both groups. The short itch latency time may indicate a direct effect of 5-HT on itch receptors.

The expression of serotonin transporter protein correlates with the severity of psoriasis and chronic stress.

Psoriasis may be worsened by stress and mood disorders. There is an increased expression of the serotonin transporter protein (SERT) in involved psoriatic skin as compared to non-involved psoriatic skin and normal skin. The aim of this study was to investigate if the increased expression of SERT in psoriasis correlates with the severity of disease, chronic stress, and depression. Biopsies from involved and non-involved skin from the back of 20 patients with chronic plaque psoriasis were immunohistochemically analysed, using a monoclonal antibody to SERT. The severity of psoriasis was assessed for each patient using the Psoriasis area and severity index (PASI). Levels of depression and chronic stress were measured using Beck's Depression Inventory (BDI) and the salivary cortisol test, respectively. A positive correlation (r = 0.53; p < 0.05) between PASI and the numbers of SERT-positive dendritic cells in the epidermis of involved psoriatic skin was determined. We also observed a negative correlation (r = -0.46; p < 0.05) between salivary cortisol ratio levels and the numbers of SERT-positive cells in the epidermis of involved psoriatic skin, indicating a correlation between SERT expression and chronic stress. The serotonergic system may be involved in the chronic inflammation evident in psoriatic skin. Through modulating the levels of SERT, there might be a therapeutic possibility for reducing chronic inflammation in psoriasis.

Serotonin and its 5-HT1 receptor in human mastocytosis.

CONTEXT: Human mastocytosis is a rare disease, in which the serotonergic system may be involved. OBJECTIVE: The objective of the present study was to examine the possible presence of serotonin (5-HT) and its 5-HT1A receptor (R) in the skin of patients with mastocytosis. In addition, the effect of the 5-HT1AR was tested on human mastocytosis cells, cultured in vitro. MATERIALS AND METHODS: The expression of 5-HT and 5-HT1AR in patients with urticaria pigmentosa and mastocytoma was studied using immunohistochemistry. The effects of 8-OH-DPAT, an agonist of 5-HT1AR, on the proliferation (cell number), viability, apoptosis, spontaneous release of histamine, as well as a possible 5-HT metabolism, in the human HMC-1 mast cell line, were investigated. RESULTS: Both 5-HT and 5-HT1AR were expressed in the mast cells in biopsies of mastocytoma and urticaria pigmentosa, as well as in HMC-1 cells. However, no metabolism of 5-HT by the cell line could be detected by the methodology used. The 5-HT1AR agonist had no significant effect on the viability and number of HMC-1 cells, and was without effect on the apoptosis. At concentrations of 10⁻6 mol/L and 10⁻8-10⁻¹° mol/L (i.e. also at physiological concentrations), the agonist inhibited histamine release by these cells by as much as 30%. CONCLUSION: These findings indicate that 5-HT and its 5-HT1AR are expressed in human mastocytosis and that an agonist of the 5-HT1AR might be of value in the treatment of these patients.

Polymorphisms in the serotonin transporter gene of patients with atopic dermatitis-association with personality traits related to high level of anxiety.

CONTEXT: The symptoms of atopic dermatitis (AD) are often aggravated by anxiety, and the serotonin transporter (5-HTT) has been shown to be of importance in this context. Three polymorphisms affecting transcription of this gene are known: a repetitive element, in the promoter region (5HTTLPR), a variable number tandem repeats (VNTR) within intron 2 referred to as STin2, and a single-nucleotide (A/G) polymorphism (SNP) located within the 5-HTTLPR. OBJECTIVE: To examine for possible relationships between these polymorphisms and aggravation of AD by stress. MATERIALS AND METHODS: Thirty-three patients with a history of such aggravation, together with 33 age- and gendermatched healthy control subjects, were recruited. The Karolinska Scales of Personality questionnaire was employed to evaluate anxiety-related personality traits and genomic DNA was extracted from blood samples and analyzed using the polymerase chain reaction. RESULTS: Although the prevalence of the short and long alleles of 5-HTTLPR did not differ between the patients and healthy controls, there was a tendency towards high prevalence of the short (10-copy) variant of STin2 among the patients. When the study population was further analysed by subdivision into subgroups all AD patients with high- anxiety traits carried the short variant of STin2. In the corresponding healthy control group, the prevalences of the 10-and 12-copy variants were 62% and 38%, respectively (P < 0.01). CONCLUSION: These findings indicate a possible association between the 10-copy variant of STin2 and aggravation of AD by anxiety.

Effect of chronic mild stress on serotonergic markers in the skin and brain of the NC/Nga atopic-like mouse strain.

Atopic eczema is often worsened by stress. While acute stress is associated with increased turnover of serotonin (5-hydroxytryptamine; 5-HT), chronic stress causes a decrease. In chronic stress, there is a decrease of the 5-HT1A receptor (R)- and an increase in the 5-HT2AR-responsiveness to 5-HT. In the present study, the impact of chronic mild stress on the expression of 5-HT1A and 5-HT2A receptors and serotonin transporter protein (SERT) was investigated in eczematous skin and brain of atopic-like NC/Nga mice. Twenty-four NC/Nga mice were subjected to chronic mild stress for 12 weeks, and eczema was induced by applying a mite antigen (Dermatophagoides pteronyssinus) on the ears for the last 4 weeks. The mice were divided into three groups, eight per group, stressed eczematous (SE), non-stressed eczematous (NSE) and stressed control (SC). The biopsies were analysed by immunohistochemistry, using a streptavidin-biotin technique. There was an increased number of 5-HT containing dermal mast cell-like mononuclear cells in the skin of mice with eczema (SE and NSE, respectively) compared with the SC, and a tendency to more 5-HT-positive cells in the SE compared with the NSE group. Increased 5-HT1AR immunoreactivity (IR) in the skin and hippocampus of the eczematous groups compared to the control group was seen, but no difference between the SE and NSE groups. The epidermal immunoreactivity for 5-HT2AR was highest in the SE and NSE compared to the SC group, and was also higher in the SE compared to NSE. 5-HT2AR expression was also seen on nerve bundles, the number and intensity of such bundles being decreased in the SE compared to the NSE group. In the CA1 area of the hippocampus, there was an increase in the quantity of cells immunoreactive for 5-HT2AR in the SE versus the NSE group and also in the SE versus the SC group. SERT-IR was found also on nerve bundles with a decreased number in the SE compared to the NSE and SC group. There is a modulation of the expression of serotonergic markers in the eczematous skin and brain of the atopic-like mouse during chronic mild stress.