Molecular diagnostics of psoriasis, atopic dermatitis, allergic contact dermatitis and irritant contact dermatitis.

BACKGROUND: Microarray studies on the epidermal transcriptome in psoriasis and atopic dermatitis (AD) have revealed genes with disease-specific expression in keratinocytes of lesional epidermis. These genes are possible candidates for disease-specific pathogenetic changes, but could also provide a tool for molecular diagnostics of inflammatory skin conditions in general. OBJECTIVES: To analyse if gene expression signatures as found in purified epidermal cells from AD are also present in other eczematous conditions such as allergic and irritant contact dermatitis. METHODS: We used real-time quantitative polymerase chain reaction, immunohistochemistry and bioinformatics to investigate gene expression in different forms of eczema. Normal epidermis and psoriatic epidermis were analysed for comparison. RESULTS: Carbonic anhydrase II was highly induced in epidermis from all forms of eczema but not in psoriasis. Remarkably, the presumed neuron-specific Nel-like protein 2 showed a strong induction only in AD epidermis. Interleukin-1F9, elafin, beta-defensin-2 and vanin-3 were strongly induced in psoriasis, but not in any type of eczema. High levels of the chemokines CCL17 and CXCL10 were predominantly found in epidermis of allergic contact dermatitis. The chemokine CXCL8 was highly expressed in psoriasis, AD and allergic contact dermatitis, but not in irritant contact dermatitis. Cluster analysis or multinomial logistic regression indicated that expression levels of a set of seven genes are a strong predictor of the type of inflammatory response. CONCLUSIONS: These observations contribute to molecular diagnostic criteria for inflammatory skin conditions.

Pain-relieving properties of topically applied morphine on arterial leg ulcers: a pilot study.

OBJECTIVE: To assess whether topical morphine is pharmacologically effective in relieving pain from ulcers caused by arterial insufficiency and identify whether this effect is centrally or peripherally mediated. METHOD: The analgesic effect of a topically applied hydrogel containing 0.5% of morphine was evaluated in a double-blind, placebo-controlled, three-way crossover pilot study involving nine patients with painful arterial leg ulcers. All patients had a baseline pain intensity of at least 5 on a 10-point numeric rating scale. They received the following three treatments in random order: morphine hydrogel plus a subcutaneous (SC) placebo infusion; placebo gel plus a SC infusion of 5mg morphine over six hours and a placebo gel plus a SC placebo infusion. Each treatment lasted one day. Pain was assessed during the first 24 hours after application of the hydrogel and the start of the subcutaneous infusion. RESULTS: There was a statistically significant difference between average baseline pain scores and those reported during treatment, but this difference was not clinically relevant. The three treatments did not differ in terms of the pain relief provided. CONCLUSION: Topical morphine does not have a clinically relevant analgesic effect in patients with painful arterial leg ulcers. Further research should focus on ulcers of other aetiology.

Skin irritancy of surfactants as assessed by water vapor loss measurements.

A method to assess the irritancy of chemicals on human skin that is based on measurements of skin (water) vapor loss (SVL) is presented. The SVL measurements were performed with the Servo Med Evaporimeter in a group of 27 healthy volunteers. Four surfactants, distilled water, and NaCl 0.9% in distilled water were assayed. For the exposures a chamber technique was used. Sodium lauryl sulfate and cocobetaine most markedly influenced the loss of water through the skin. Polysorbate-60 and sodium laurate had less effect on SVL. The mean difference between the test substances were found statistically significant, except for the mean difference between sodium laurate and polysorbate-60 (p greater than 0.1) and between polysorbate-60 and distilled water (p greater than 0.05). The reactions of the tested subjects to the surfactants suggest that each individual has his own pattern of susceptibility to these substances. The mean values of the SVL measurements were compared with the macroscopically perceptible morphologic changes of the exposed test sites. The results of the SVL measurements. The correlation coefficient between the mean values of both methods was found to be high (r = 0.98).

Differential effects of detergents on keratinocyte gene expression.

We have studied the effect of various detergents on keratinocyte gene expression in vitro, using an anionic detergent (sodium dodecyl sulfate), a cationic detergent cetyltrimethylammoniumbromide (CTAB), and two nonionic detergents, Nonidet P-40 and Tween-20. We measured the effect of these detergents on direct cellular toxicity (lactate dehydrogenase release), on the expression of markers for normal differentiation (cytokeratin 1 and involucrin expression), and on disturbed keratinocyte differentiation (SKALP) by northern blot analysis. As reported in other studies, large differences were noted in direct cellular toxicity. In a culture model that mimics normal epidermal differentiation we found that low concentrations of sodium dodecyl sulfate could induce the expression of SKALP, a proteinase inhibitor that is not normally expressed in human epidermis but is found in hyperproliferative skin. Sodium dodecyl sulfate caused upregulation of involucrin and downregulation of cytokeratin 1 expression, which is associated with the hyperproliferative/inflammatory epidermal phenotype found in psoriasis, wound healing, and skin irritation. These changes were not induced after treatment of cultures with CTAB, Triton X-100, and Nonidet-P40. This effect appeared to be specific for the class of anionic detergents because sodium dodecyl benzene sulfonate and sodium laurate also induced SKALP expression. These in vitro findings showed only a partial correlation with the potential of different detergents to induce clinical, biophysical, and cell biologic changes in vivo in human skin. Both sodium dodecyl sulfate and CTAB were found to cause induction and upregulation of SKALP and involucrin at low doses following a 24 h patch test, whereas high concentrations of Triton X-100 did not. Sodium dodecyl sulfate induced higher rates of transepidermal water loss, whereas CTAB treated skin showed more signs of cellular toxicity. We conclude that the action of anionic detergents on epidermal keratinocytes is qualitatively different from the other detergents tested, which might have implications for in vitro toxicology studies that use cell biologic parameters as a read-out. We would hypothesize that detergents cause skin injury by several mechanisms that include direct cellular toxicity, disruption of barrier function, and detergent specific effects on cellular differentiation, as demonstrated here for sodium dodecyl sulfate, sodium dodecyl benzene sulfonate, and sodium laurate.

Sjögren's syndrome with specific cutaneous manifestations and multifocal clonal T-cell populations progressing to a cutaneous pleomorphic T-cell lymphoma.

A case is presented of primary Sjögren's syndrome of the parotid gland with specific skin manifestations, consisting of diffuse lymphoid infiltrates with proliferative and metaplastic changes of sweat glands, a histologic picture similar to that seen in the parotid gland. Material of the parotid gland, a submandibular lymph node showing expanded T-cell areas, and several skin biopsies were studied immunohistologically for the presence of clonal B-cell populations. Because of a polyclonal kappa/lambda pattern of the B-lymphocytes, the possibility of a B-cell non-Hodgkin's lymphoma (NHL) was excluded. The initially morphologically benign lymphocytic skin infiltrates (1985) changed into a pleomorphic T-cell lymphoma (1987). Southern blot analysis of the atypical skin infiltrates and of the original material of the parotid gland and submandibular lymph node revealed identical clonal rearrangements of the T-cell receptor B-chain. Rearrangement of Ig genes was not found.

Follicular non-Hodgkin's lymphoma with refractory paraneoplastic pemphigus: case report with review of novel treatment modalities.

In this paper a patient with a non-Hodgkin's lymphoma (NHL) and paraneoplastic pemphigus (PNP) is described. PNP is a very rare, painful mucocutaneous intraepithelial blistering disease associated with occult or confirmed malignancy. Patients with PNP show severe, progressive mucocutaneous disease with a high mortality rate, because of drug-induced infectious complications. The patients sometimes benefit from high doses of oral corticosteroids. However, pulse therapy with high doses of prednisolone (or dexamethasone) in combination with other immunosuppressants induces variable and inconstant results. Intravenous immunoglobulin (IVIg) has been applied in different cases of PNP with encouraging results. Plasmapheresis or plasma exchange (PE) in combination with corticosteroids and/or cyclophosphamide or azathioprine showed similar rapid and beneficial results in association with decreasing auto-antibody levels in this group of refractory pemphigus. Another interesting therapeutic option is rituximab, a chimeric monoclonal antibody directed against the CD20 antigen, which is found on the surface of normal and malignant B-lymphocytes. Administration of rituximab for patients with PNP in combination with follicular NHL is not always successful regarding oral lesions as we report in this case. PE leading to prompt depletion of autoreactive antibodies combined with immunosuppressants or synchronisation of PE with IVIg seems the best treatment modality for this refractory group, but the therapeutic value and appropriate timing of rituximab obviously deserve further evaluation in patients with low grade NHL and PNP.

Treatment with UV-B for psoriasis and nonmelanoma skin cancer: a systematic review of the literature.

BACKGROUND: In a cost-effectiveness study currently being conducted of short-contact anthralin treatment for psoriasis in an outpatient setting as compared with the standard treatment with UV-B radiation, the excess incidence (IDD) of skin cancer due to exposure to UV-B could not be ascertained because the study did not last long enough. A meta-analysis of published data was deemed appropriate. OBJECTIVE: To quantify the IDD of nonmelanoma skin cancer as a function of the total dose of UV-B and specific for time since first exposure, age at first treatment, and other treatments received. METHODS: Systematic review of the literature with meta-analysis of all available evidence published in English, French, German, or Dutch between 1980 and 1996. RESULTS: Four articles contained information that enabled us to calculate an overall IDD of nonmelanoma skin cancer. The estimates varied between -0.6 and 2 extra skin cancers per 100 patients with psoriasis treated with UV-B phototherapy per year. However, these estimates were calculated under several assumptions, and do not allow for the construction of a dose-response model specific for time since exposure or age at first treatment. A model based on animal data suggests that a total of 5 excess skin cancers can be expected per 100 treated in the 60 years after the start of treatment with 500 minimum effective doses of UV-B per year from age 25 years. CONCLUSIONS: The available evidence is insufficient for quantifying the IDD of nonmelanoma skin cancer in patients with psoriasis treated with UV-B radiation. However, it seems unlikely that the excess risk exceeds 2% per year. As yet, it is not possible to assess at what level of exposure this IDD occurs, or how long after exposure excess risk is present.

Changes in keratinocyte differentiation following mild irritation by sodium dodecyl sulphate.

Although the induction of acute irritant dermatitis by detergents has been studied extensively in recent years, our understanding of the cell biological events in the repair phase, and its relevance for the development of chronic irritant dermatitis is limited. Here we studied the reaction pattern of human skin to short-term application of sodium dodecyl sulphate (SDS) in a model that induced a minimal acute inflammatory reaction (absence of polymorphonuclear leucocytes, PMN) and did not have cytopathic effects on the epidermal keratinocytes as determined by histological investigation. All parameters were measured up to 14 days after exposure to SDS. Application of SDS caused disturbances of barrier function as measured by transepidermal water loss and had vascular effects as judged by erythema. Several cell biological markers for epidermal growth and differentiation were examined by immunohistochemistry. A rapid and strong induction of the cornified envelope precursor protein involucrin was seen in the stratum spinosum, with a peak at 24 h. Within 24 h a strong upregulation of epidermal fatty acid binding protein (E-FABP) was noted, with a peak at 7 days after injury. Cellular proliferation in the basal layer was increased fivefold as assessed by nuclear staining for the Ki-67 antigen, showing a peak at 48 h. Surprisingly, no significant induction of cytokeratin 16 and SKALP/elafin expression, two markers associated with epidermal hyper-proliferation and inflammation, was seen. These findings suggest that the cellular changes following exposure to detergent are distinct from those seen in other forms of skin injury. We would speculate that the epidermal response to detergent exposure is primarily directed at restoration of barrier function.

The effect of the PDE-4 inhibitor (cipamfylline) in two human models of irritant contact dermatitis.

BACKGROUND: New therapeutic approaches have to be considered in the treatment of irritant contact dermatitis (ICD). Recently, phosphodiesterase 4 (PDE-4) inhibitors have been introduced as nonsteroidal, antiinflammatory agents. These agents inhibit the secretion of the cytokines thought to be involved in the pathogenesis of ICD. We investigated the effect of a new selective PDE-4 inhibitor (cipamfylline) in human models using single and repeated exposures to an irritant in a blind, randomized pilot study with healthy volunteers. We compared the effect of cipamfylline ointment with a strong corticosteroid (betamethasone-17-valerate) and with a placebo ointment. METHODS: Ten volunteers were patch tested at four investigation sites with sodium dodecyl sulphate (1%) for 24 h. In a model that simulates chronic damage, 11 volunteers were patch tested with sodium dodecyl sulphate (0.2%) for 4 h daily for four consecutive days. The investigation sites were treated once a day with the above-mentioned agents. One site was left untreated. We used erythema scoring, measurements of transepidermal water loss (TEWL) and several immunohistochemical markers for epidermal proliferation and differentiation. RESULTS: Repeated application revealed that betamethasone-17-valerate caused a statistically significant reduction in erythema and TEWL compared to cipamfylline and placebo. We also observed a significant suppression of proliferating cells and cytokeratin 16 expression at sites treated with betamethasone compared to the other sites. In the model for acute ICD, no significant differences were seen between the investigated sites. CONCLUSIONS: Our results show that betamethasone-17-valerate may modulate the response in ICD. In this human model of ICD we could not confirm the efficacy of cipamfylline. Clinical studies are needed before the effect of PDE-4 inhibitors in ICD can be refuted with certainty.

The impact of the frequency of short contact dithranol treatment.

Dithranol short contact treatment is usually applied once a day. For some patients this does not fit their possibilities or needs. Therefore we investigated the efficacy of two other treatment strategies in two small groups of patients. In the attempt to shorten the treatment time, one group of patients was treated twice daily. In order to not withhold short contact dithranol treatment from patients who are unable to perform the treatment daily or at home, a thrice-weekly treatment regimen was studied. 8 patients were treated twice daily and all achieved at least a 90% reduction of the area of involved skin (clearance) within 12.3 (+/- 1.6) weeks. In the thrice weekly group six out of eight patients achieved a clearance of their psoriasis within 13.1 (+/- 4.2) weeks. The aim of shortening the treatment period was not achieved by twice daily treatment in a day-care centre. However, the thrice-weekly treatment regimen certainly appeared to be an effective one. Further studies are needed on larger populations of patients to find out the optimal regimen for intermittent dithranol short contact treatment.

Effectiveness and side effects of UVB-phototherapy, dithranol inpatient therapy and a care instruction programme of short contact dithranol in moderate to severe psoriasis.

The efficacy of UVB-phototherapy (UVB) and dithranol treatment for psoriasis is well established. However, well-conducted clinical trials on the efficacy of dithranol are not available, making comparison between these time-honoured treatments with currently available therapies impossible. We studied the effectiveness of dithranol in a care instruction programme using short time exposures (short contact treatment), UVB-phototherapy and dithranol treatment in an inpatient setting. In an open randomised study we included 250 patients with moderate to severe psoriasis. The intention to treat group existed of 238 patients. 100 patients were treated with short contact dithranol, 78 Patients were treated with UVB and 60 patients underwent inpatient dithranol treatment. We found UVB and dithranol treatment to be effective and safe in moderate to severe psoriasis. The efficacy of short contact dithranol treatment equals the efficacy of UVB-phototherapy. Dithranol treatment at the inpatient department showed superior efficacy in clinical response rate and treatment duration as compared to UVB and short contact treatment. The median number of days in remission was significantly longer after short contact treatment as compared to inpatient treatment. Although the use of dithranol is hampered by skin irritation and staining, the present study shows that dithranol treatment has an outstanding efficacy and safety profile. Comparison between different antipsoriatic treatments should, besides clearing capacity, reconcile duration of remission, safety, patient acceptability and costs.

[Allergic contact eczema due to 'tea tree' oil]. / Allergisch contacteczeem voor 'tea tree'-olie.

In four patients, three women aged 45, 29 and 52 years and a man aged 45 years, allergic contact dermatitis due to 'tea tree' oil was diagnosed. The case of the man was published before. 'Tea tree' oils are essential oils distilled from the leaves of myrtaceous trees and shrubs occurring in Australia and South-East Asia. The 'tea tree' oil available in the Netherlands is distilled from the Melaleuca alternifolia and mainly contains eucalyptol. Eucalyptol is probably the most important allergen.

DNA adducts in skin biopsies and 1-hydroxypyrene in urine of psoriasis patients and healthy volunteers following treatment with coal tar.

Coal tar ointments (CTO) are frequently used in the treatment of psoriasis and eczema, but CTO contain carcinogenic polycyclic aromatic hydrocarbons (PAH). PAH are absorbed and metabolized in the skin. In psoriasis, the skin barrier is altered and therefore, absorption and metabolism of PAH may differ from healthy skin. In this study, levels of urinary 1-hydroxypyrene and PAH-DNA adducts in the skin were studied in psoriatic patients and healthy volunteers. Three punch biopsies were taken from the lower back of 10 male volunteers and from a psoriatic plaque in 10 male patients. A surface of 6.25 cm(2) was treated with CTO. After 96 h CTO was removed and another three skin biopsies were collected from the treated area. DNA was isolated from skin biopsies and urine was collected during and after the exposure period. After 24h, a twofold lower 1-hydroxypyrene urinary excretion was observed in patients compared to healthy volunteers and after 48 h, this difference reached statistical significance (p<0.05). Over 96 h the median level of the sum of PAH-DNA adducts, analyzed by (32)P-post-labeling, increased from 3.5 before CTO administration to 21.1 adducts per 10(8) nucleotides in volunteers, and from 1.0 to 3.6 adducts per 10(8) nucleotides in patients. At 96 h, PAH-DNA levels were higher in healthy volunteers than in patients (p<0.05). Biomarkers for uptake, bioavailability and bioactivation of PAH were lower in patients compared to volunteers. These data suggest a lower risk of carcinogenic effects of CTO in psoriatic skin compared to healthy skin.

The Impact of Chronic Skin Disease on Daily Life (ISDL): a generic and dermatology-specific health instrument.

BACKGROUND: In dermatological research and clinical practice, there is a need for comprehensive self-report instruments that assess a broad spectrum of health implications of chronic skin diseases, including generic and skin-specific aspects of disease-related quality of life. The advantages of dermatology-specific, multidimensional instruments over generic instruments or single-dimensional quality-of-life measures are in the detailed and specific information they provide about health areas that are affected by the skin condition and that may change through therapeutic intervention. OBJECTIVES: The development of a multidimensional health status inventory for chronic skin diseases (Impact of Chronic Skin Disease on Daily Life, ISDL) is described. The dermatology-specific part of the inventory assesses dimensions of physical functioning, more specifically skin status, physical symptoms of itch, pain and fatigue and scratching responses as well as disease-related stressors like stigmatization. The generic part gauges dimensions of psychological functioning, disease-related impact, illness cognitions and social support by means of existing scales validated for other chronic diseases. METHODS: Reliability and validity of the questionnaire were studied in various samples of patients with psoriasis and atopic dermatitis. RESULTS: The ISDL showed high reliability and test-retest reliability in both patient groups. Convergent validity was indicated by moderate to strong correlations with other validated questionnaires. The scales proved sensitive to change both for dermatological ultraviolet B radiation therapy and cognitive behavioural treatment for itching. CONCLUSION: With its convincing results for reliability and validity the present evaluation supports the usefulness and applicability of the instrument for different chronic skin diseases.

A comparison of twice-daily calcipotriol ointment with once-daily short-contact dithranol cream therapy: quality-of-life outcomes of a randomized controlled trial of supervised treatment of psoriasis in a day-care setting.

BACKGROUND: Calcipotriol ointment and short-contact dithranol cream therapy are well-established topical treatments for psoriasis. Quality of life, i.e. the physical, psychological, and social functioning and well-being of the patient, has become an essential outcome measure in chronic skin disease. OBJECTIVES: To compare the quality-of-life outcomes of calcipotriol ointment with that of short-contact dithranol cream in a supervised treatment regimen, and to determine the degree of improvement in quality of life these topical treatments can accomplish. METHODS: In a multicentre randomized controlled trial in six centres in the Netherlands, 106 patients with chronic plaque psoriasis were included, 54 receiving calcipotriol ointment twice daily and 52 dithranol cream once daily in a 12-week intensive treatment programme. Patients were treated at the day-care centre, using the care instruction principle of daily visits during the first week and twice-weekly visits subsequently for up to 12 weeks. Quality of life was assessed with the Skindex-29 and the Medical Outcomes Study 36-item Short-Form General Health Survey (SF-36). RESULTS: At the end of treatment, no statistically significant differences were found between the calcipotriol and the dithranol group in any of the quality-of-life domains or scales of the Skindex-29 and the SF-36. Over time, a significant improvement of quality of life was found on all three scales of the dermatology-specific Skindex-29, predominantly of a moderate magnitude. In the calcipotriol group, a significant change of a small magnitude was found in the Physical Component Summary of the SF-36. No significant changes were found in the Mental Component Summary (or on any of the eight scales composing the questionnaire) of the SF-36. CONCLUSIONS: The hypothesis was confirmed, that no statistically significant differences in improvement of quality of life could be found between calcipotriol ointment and dithranol short-contact cream in a day-care setting. Given this result, both calcipotriol and dithranol can be welcome alternatives for the patient. Calcipotriol, being more practical and patient friendly, can be considered as a first-line approach in clinical practice. However, in patients recalcitrant to calcipotriol and/or other topical treatments, preference should be given to the dithranol regimen. Topical treatment in combination with interventions explicitly focusing on improvement of coping behaviour and psychosocial functioning may further increase the degree of improvement in the psychosocial domains of quality of life. The results of this study are likely to give further evidence to the notion that the generic SF-36 is little or not responsive to small to moderate changes in quality of life in mild to moderate psoriasis.

Psychosocial well-being of patients with skin diseases in general practice.

BACKGROUND: Skin diseases are a substantial part of the problems dealt with by general practitioners. Although the psychosocial consequences of skin diseases in secondary care has been extensively studied, little is known about the psychosocial well-being of patients with skin diseases in primary care. OBJECTIVE: To investigate the psychosocial well-being of patients with skin diseases in primary care. PATIENTS/METHODS: Questionnaires about the psychosocial consequences of skin diseases were sent to patients with a skin disease who were registered within a research network (continuous morbidity registration) of general practices that continuously have recorded morbidity data since 1971. Questionnaires completed by 532 patients were eventually suitable for analyses. RESULTS: Compared with the general population, patients with skin diseases reported significantly lower scores for psychosocial well-being. Furthermore, a lower psychosocial wellbeing was significantly related with higher levels of disease-severity, lower disease-related quality of life, longer disease duration, more comorbidity and more physical symptoms of itch, pain and fatigue. After demographic variables and comorbidity were controlled for, sequential regression analyses showed that disease duration, disease severity and physical symptoms (itch, pain and fatigue) were significant predictors of psychosocial well-being. CONCLUSION: The psychosocial well-being of patients with skin diseases in primary care is lower than that of the general population. Special attention has to be directed to those patients with lowered psychosocial well-being who might be at risk of developing severe psychosocial impairments such as clinical depression.

Prevalence of physical symptoms of itch, pain and fatigue in patients with skin diseases in general practice.

BACKGROUND: Physical symptoms of skin diseases have been shown to negatively affect patients' wellbeing. Although insight into physical symptoms accompanying skin diseases is relevant for the management and treatment of skin diseases, the prevalence of physical symptoms among patients with skin diseases is a rather unexplored territory. OBJECTIVES: The goal of the present study was to examine the prevalence of physical symptoms of itch, pain and fatigue in patients with skin diseases. METHODS: On the basis of a systematic morbidity registration system in primary care, questionnaires were sent to 826 patients with skin diseases. Eventually, questionnaires from 492 patients were suitable for our analyses. RESULTS: Results indicated that patients with skin diseases particularly experience symptoms of itch and fatigue. Approximately 50% of all patients report experiencing these symptoms and about 25% experience these symptoms as relatively severe. Pain was relatively less frequently reported by 23% of all patients, and was on average somewhat less intense. The physical symptoms showed relatively strong correlations with disease-related quality of life and self-reported disease severity. In contrast, only moderate correlations were found with comorbidity and demographic variables, which suggests that the physical symptoms of itch, pain and fatigue are consequences of the skin diseases. CONCLUSIONS: Itch and fatigue and, to a somewhat lesser extent, pain have a high prevalence among patients with skin diseases. Clinicians should be encouraged to carefully assess itch, pain and fatigue in patients with skin diseases, and where appropriate focus treatment to these symptoms.