Increased levels of enkephalin following natural sunlight (combined with salt water bathing at the Dead Sea) and ultraviolet A irradiation

The opioid peptides enkephalins have been shown to modulate inflammatory responses and keratinocyte proliferation and differentiation. Furthermore, increased levels of enkephalin are present in psoriatic lesions. The purpose of the present study was to determine the effect of natural sunlight combined with salt water bathing in the Dead Sea on the methionine-enkephalin (e.n.k.) level in psoriatic skin. Ten patients were treated at the Dead Sea for 4 weeks, and keratotome biopsies were obtained before and after treatment. The amount of enkephalin extracted from the biopsies was measured by radioimmunoassay. Treatment at the Dead Sea resulted in a complete clinical clearance of psoriasis, and immunohistochemical stainings of lesional skin showed that the treatment decreased both epidermal thickness/parakeratosis and the dermal infiltration of CD3- and CD68-positive cells, although the number of CD3- and CD68-positive cells became normal in only two of the 10 cases. However, there was only a slight decrease in the mean enk levels (21%). Furthermore, the level of enk was high in non-lesional psoriatic skin after treatment at the Dead Sea, and immunostaining showed that, in some patients, the treatment induced a mild epidermal hyperplasia and a dermal infiltration of CD3- and CD68-positive cells. Enkephalin-like immunoreactivity was detected in the cytoplasm of both epidermal keratinocytes and dermal infiltrating cells. To determine whether the relatively high skin enk levels after treatment at the Dead Sea was caused by ultraviolet (UV) radiation, normal volunteers were exposed to a single dose of UVA and UVB (2 minimal erythema doses). UVA, but not UVB, irradiation stimulated the mean enk level in the irradiated skin by about sixfold. Furthermore, multiple whole-body UVA irradiations not only resulted in increased skin levels of enk, but also in increased plasma levels. In conclusion, natural sunlight combined with salt water bathing cleared psoriasis without causing a significant decrease in lesional enk levels. Furthermore, non-lesional enk levels were increased. These findings may be the result of a direct stimulatory effect of UVA irradiation on enk formation in the skin. It is possible that the increased circulating levels of enk after UV exposure may contribute to the beneficial effects of UVA irradiation.     

Demographic evaluation of successful antipsoriatic climatotherapy at the Dead Sea (Israel) DMZ Clinic

Background Natural balneologic properties, thermomineral springs and unequivocal success in improving psoriasis, attract an ever-growing number of psoriatlcs to the DMZ Clinic on the shores of the Dead Sea in Israel. Methods This paper analyses the rate of success of this balneotherapy in 740 psoriatics who flew in from Germany specifically for this treatment, during 1995, as a function of sex, family history of the disease, number of previous treatments at the Dead Sea, skin type, skin involvement, joint involvement, duration of treatment, sun-exposure schedule, remission length, and psychologic supervision. Results After 4 weeks, 70% of the patients were completely cleared, this improvement being about the same across both sexes. Family history of the disease, skin type, and psychologic support did not affect the rate of success. On the other hand, previous treatments at the Dead Sea, moderate to severe skin surface involvement, and participation of arthritis, improved the chance of better clearing of the psoriatic condition. Similar improvement was obtained by a longer sun-exposure schedule and a complete 4-week treatment. Conclusion These results indicate that the medical improvement in the psoriatic condition after a 4-week stay at the Dead Sea can be better enhanced and its remission prolonged if additional demographic and anamnestic factors are carefully taken into account.     

The mitogen-activated protein kinases p38 and ERK1/2 are increased in lesional psoriatic skin

BACKGROUND: Alterations in specific signal transduction pathways may explain the hyperproliferation and abnormal differentiation of the keratinocytes as well as the increased expression of inflammatory cytokines seen in psoriasis. Major signalling pathways used by eukaryotic cells to transduce extracellular signals into cellular responses impinge on the mitogen-activated protein kinases (MAPKs). OBJECTIVES: To investigate the expression of the MAPK p38, extracellular signal-regulated kinase (ERK) and c-Jun NH2-terminal kinase (JNK) in psoriatic skin. METHODS: Keratome biopsies were taken from patients with plaque-type psoriasis. Western blot analysis was used to determine p38, ERK and JNK activity and protein levels, whereas kinase assays were used to examine the kinase activity of p38. RESULTS: We demonstrated increased levels of the phosphorylated forms of p38 and ERK1/2 in lesional psoriatic skin compared with nonlesional psoriatic skin. No abnormality was found in the activation and expression of JNK1/2. Ex vivo kinase assays confirmed the increased activation of p38, and furthermore demonstrated increased kinase activity of the p38 isoforms p38alpha, p38beta and p38delta in lesional compared with nonlesional psoriatic skin. p38gamma was not detected in the psoriatic skin. Clearance of the psoriatic lesions, induced by climatotherapy at the Dead Sea for 4 weeks, led to a normalization in the activity of both p38 and ERK1/2. CONCLUSIONS: Taken together, our results demonstrate that the activity of the MAPKs p38alpha, p38beta and p38delta and ERK1/2 are increased in lesional psoriatic skin compared with nonlesional psoriatic skin, and that clearance of psoriasis normalizes the p38 and ERK1/2 activity. Thus, p38 and ERK1/2 might be potential targets in the treatment of psoriasis.     

Bathing in a magnesium-rich Dead Sea salt solution improves skin barrier function, enhances skin hydration, and reduces inflammation in atopic dry skin

Magnesium salts, the prevalent minerals in Dead Sea water, are known to exhibit favorable effects in inflammatory diseases. We examined the efficacy of bathing atopic subjects in a salt rich in magnesium chloride from deep layers of the Dead Sea (Mavena(R) Dermaline Mg(46) Dead Sea salt, Mavena AG, Belp, Switzerland). Volunteers with atopic dry skin submerged one forearm for 15 min in a bath solution containing 5% Dead Sea salt. The second arm was submerged in tap water as control. Before the study and at weeks 1-6, transepidermal water loss (TEWL), skin hydration, skin roughness, and skin redness were determined. We found one subgroup with a normal and one subgroup with an elevated TEWL before the study. Bathing in the Dead Sea salt solution significantly improved skin barrier function compared with the tap water-treated control forearm in the subgroup with elevated basal TEWL. Skin hydration was enhanced on the forearm treated with the Dead Sea salt in each group, which means the treatment moisturized the skin. Skin roughness and redness of the skin as a marker for inflammation were significantly reduced after bathing in the salt solution. This demonstrates that bathing in the salt solution was well tolerated, improved skin barrier function, enhanced stratum corneum hydration, and reduced skin roughness and inflammation. We suggest that the favorable effects of bathing in the Dead Sea salt solution are most likely related to the high magnesium content. Magnesium salts are known to bind water, influence epidermal proliferation and differentiation, and enhance permeability barrier repair.     

TREATMENT OF PSORIASIS AT A DEAD SEA DERMATOLOGY CLINIC

Background. The Dead Sea, with its unique optical, chemical, and atmospheric properties, provides an effective alternative treatment for psoriasis. Methods. The records of 1448 consecutive psoriasis patients treated at a Dead Sea psoriasis clinic were retrospectively evaluated concerning their treatment response and demographic characteristics. Results. Clearing of 80–100% was observed in 88% of the patients treated, including almost 58%, who had complete clearing. The demographic data studied that included gender, previous treatment at the Dead Sea, prior history of hospitalization for psoriasis, prior PUVA treatment, or a history of arthritis did not reveal any significant relationships, although overseas patients responded considerably better than Israelis. Conclusions. The overall response in a large cohort of psoriasis patients treated at the Dead Sea was excellent. Further prospective studies and basic investigations ate essential to understand the mechanism(s) involved and the relationships between other demographic data and the treatment response.     

Clearing of psoriatic erythroderma following heliotherapy in the Dead Sea area

We report herein a patient suffering from psoriatic erythroderma and psoriatic arthritis treated successfully in the Dead Sea area. Sun exposure (heliotherapy) and emollients, without any additional topical or systemic treatments, resulted in clearing of the erythroderma within 4 weeks of treatment. Additional regimens of climatotherapy and balneotherapy, given for another 2 weeks, led to marked alleviation of his arthritic complaints. The remission of skin disease persisted for 5 months without further therapy.     

In psoriasis lesional skin the type I interferon signaling pathway is activated, whereas interferon-alpha sensitivity is unaltered

The epidermal phenotype as observed in psoriatic skin results from inflammation and abnormal proliferation and terminal differentiation of keratinocytes. Mice deficient for interferon regulatory factor-2, a repressor of interferon signaling, display psoriasis-like skin inflammation. The development of this phenotype is strictly dependent on type I interferon (interferon-alpha/beta) signaling. The aim of this study was to assess the involvement of interferon-alpha/beta in the pathogenesis of human psoriasis. In psoriatic skin, we measured an increased expression of components that play central and crucial roles in interferon-alpha/beta signal transduction. Culturing keratinocytes or healthy skin biopsies with recombinant interferon-alpha stimulated this signaling pathway; however, this did not induce the expression of markers that are generally used to define the psoriasis phenotype. Furthermore, skin from psoriasis patients responded identically to interferon-alpha stimulation, demonstrating that psoriatic skin does not have an aberrant sensitivity to type I interferon. We conclude that in psoriatic lesional skin the type I interferon signaling pathway is activated, despite an unaltered interferon-alpha sensitivity. Our data furthermore show that type I interferon, in contrast to interferon-gamma, does not act directly on keratinocytes to induce a psoriatic phenotype. Thus, if the observed activated type I interferon signaling is indeed functionally involved in the pathogenesis of psoriasis, its contribution might be indirect, putatively involving other cell types besides keratinocytes.     

Sitagliptin, a dipeptidyl peptidase-IV inhibitor, improves psoriasis

A patient with a 17-year history of plaque psoriasis accompanied by type 2 diabetes mellitus discontinued cyclosporine and steroid ointment given for treatment of psoriasis because she was dissatisfied with the effects of the drugs. After sitagliptin, a dipeptidyl peptidase-IV (DPP-IV) inhibitor, was administered for control of blood glucose, psoriatic skin lesions were gradually diminished, although HbA1c did not improve. Three months after the administration of sitagliptin, infiltration, scales and erythema on all psoriatic plaques disappeared, leaving pigmentation on flat skin. DPP-IV in serum degrades the incretin hormones which stimulate β-cell insulin secretion. DPP-IV inhibitors, as incretin enhancers, cause an increase in glucose-dependent insulin secretion, and are applied for the treatment of diabetes mellitus. DPP-IV is also expressed on T cells as CD26, a surface antigen which plays an important role in activating T cells. As helper T cells are involved in the pathogenesis of psoriasis, it is possible that DPP-IV inhibitors improve psoriatic skin lesions by inhibiting T cell activation, independently of glycemic control. DPP-IV inhibitors could be an alternative for the treatment of psoriasis.     

Are patients with psoriasis susceptible to the classic risk factors for actinic keratoses?

BACKGROUND: An increased prevalence of benign solar damage (eg, facial wrinkles) but not neoplastic lesions was observed among patients with psoriasis who were exposed to Dead Sea climatotherapy compared with controls. OBJECTIVES: To compare the prevalence of actinic keratosis in psoriatic patients and controls and to assess whether known risk factors behave similarly in both groups. DESIGN: Multicenter cross-sectional study. SETTING: Dermatology clinics in 4 participating Israeli hospitals and at a Dead Sea clinic. PARTICIPANTS: Adult subjects (n = 460) with plaque-type psoriasis were recruited from the Israel Psoriasis Association (volunteer sample) and from dermatology clinics (convenience sample). The control group (n = 738) consisted of nonimmunosuppressed patients attending these clinics for benign conditions unrelated to sun exposure, such as atopic or contact dermatitis. MAIN OUTCOME MEASURES: Prevalence and distribution of actinic keratoses and odds ratios associated with skin, hair, and eye color and propensity or history of sunburn adjusted for age, ethnicity, and sun exposure. RESULTS: Actinic keratoses were observed in 200 controls (27%) and 51 subjects (11%) (P<.001). This increased prevalence occurred in both sexes, participants aged 35 years or older, all ethnic groups, smokers, and nonsmokers. The anatomical distribution of lesions did not substantially differ between subjects and controls. In multivariate analysis, psoriasis conferred a protective effect (odds ratio, <1), as did dark skin, dark eyes, and a history of severe sunburn in childhood. However, significant interactions were observed between psoriasis and hair color as well as psoriasis and propensity to sunburn, whereby a linear association was observed for controls but not for patients with psoriasis. CONCLUSIONS: Psoriasis confers protection against actinic keratosis. Hair color and propensity to sunburn exert differential effects among psoriatic patients and controls.     

Magnesium ions inhibit the antigen-presenting function of human epidermal Langerhans cells in vivo and in vitro. Involvement of ATPase, HLA-DR, B7 molecules, and cytokines

The combination of seawater baths and solar radiation at the Dead Sea is known as an effective treatment for patients with psoriasis and atopic dermatitis. Dead Sea water is particularly rich in magnesium ions. In this study we wished to determine the effects of magnesium ions on the capacity of human epidermal Langerhans cells to stimulate the proliferation of alloreactive T cells. Twelve subjects were exposed on four subsequent days on the volar aspects of their forearms to 5% MgCl2, 5% NaCl, ultraviolet B (1 minimal erythemal dose), MgCl2 + ultraviolet B, and NaCl + ultraviolet B. Epidermal sheets were prepared from punch biopsies and were stained for ATPase and HLA-DR. Compared with untreated skin, the number of ATPase+/HLA-DR+ Langerhans cells was significantly reduced after treatment with MgCl2 (p = 0.0063) or ultraviolet B (p = 0.0005), but not after NaCl (p = 0.7744). We next questioned whether this reduced expression of ATPase and HLA-DR on Langerhans cells bears a functional relevance. Six subjects were treated on four subsequent days with 5% MgCl2, ultraviolet B (1 minimal erythemal dose), and MgCl2 + ultraviolet B. Epidermal cell suspensions from treated and untreated skin were assessed for their antigen-presenting capacity in a mixed epidermal lymphocyte reaction with allogeneic naive resting T cells as responder cells. Treatment with MgCl2, similarly to ultraviolet B, significantly reduced the capacity of epidermal cells to activate allogeneic T cells (p = 0.0356). Magnesium ions also suppressed Langerhans cells function when added to epidermal cell suspensions in vitro. The reduced antigen-presenting capacity of Langerhans cells after treatment with MgCl2 was associated with a reduced expression by Langerhans cells of HLA-DR and costimulatory B7 molecules, and with a suppression of the constitutive tumor necrosis factor-alpha production by epidermal cells in vitro. These findings demonstrate that magnesium ions specifically inhibit the antigen-presenting capacity of Langerhans cells and may thus contribute to the efficacy of Dead Sea water in the treatment of inflammatory skin diseases.     

Malignant tumours and psoriasis: climatotherapy at the Dead Sea

In this retrospective, nation-wide cohort study, the risk of cancer was assessed for 1738 Danish patients with psoriasis subjected to climatotherapy at the Dead Sea during 1972-93, by linkage to the Danish Cancer Registry. The overall risk of cancer in patients treated at the Dead Sea (standardized incidence ratio, SIR = 1.59) was higher than that expected in the general population, owing to an excess risk of non-melanoma skin cancer (NMSC) [SIR = 4.2 for basal cell carcinoma (BCC) and 10.7 for squamous cell carcinoma (SCC)]. In addition, the distribution of NMSC among body sites, age groups and sexes was unusual in those treated at the Dead Sea, favouring NMSC in young individuals and at multiple sites (SIR = 10.7 for BCC and 57.2 for SCC), multiple BCCs being particularly common among young women. Thus, people subjected to climatotherapy at the Dead Sea for psoriasis constitute a high-risk group for NMSC, SCC in particular, but not for malignant diseases in general. The study design precludes conclusions on whether climatotherapy plays a specific part in skin carcinogenesis which is different from other sources of ultraviolet (UV) radiation, as climatotherapy is inevitably confounded by excess UV exposure.     

Climatotherapy at the Dead Sea for Pediatric-Onset Psoriasis Vulgaris

Abstract:   Climatotherapy at the Dead Sea is highly effective and safe for the treatment of psoriasis vulgaris in adults. We examine the efficacy and safety of climatotherapy at the Dead Sea in children with psoriasis vulgaris. More than 75% improvement in the Psoriasis Area and Severity Index was noted in 35.3% of the patients. None of the patients had side effects.     

K16 expression in uninvolved psoriatic skin: a possible marker of pre-clinical psoriasis

BACKGROUND: K16, a type I keratin, is upregulated in hyperproliferative states including psoriasis. It has been used as a marker of psoriasis and its expression is upregulated in relapsing psoriasis and downregulating in resolving. We evaluated non-lesional psoriatic skin for K16 expression. METHODS: Sixty-seven non-lesional and lesional skin samples from patients with psoriasis and normal skin from 19 non-psoriatic patients were studied by immunohistochemistry on frozen sections with K16. RESULTS: Seventeen of 19 normal skin samples showed staining of basal cells in the deeper part of the rete ridges. Sixty-two non-lesional psoriatic skin samples showed intense basal staining of K16. Of the remaining five non-lesional samples, diffuse intense suprabasal staining in one, pan-epidermal staining in two, and no staining was seen in two samples. Suprabasal (37), diffuse (14), sandwich (12), and basal (3) pattern staining were seen in psoriatic skin. One psoriatic skin sample did not show any expression. CONCLUSION: Our results demonstrate that K16 expression is also observed in non-lesional psoriatic skin and may serve as a marker of preclinical psoriasis.     

The effect of Tomesa therapy on epidermal Langerhans cells in experimental animals

In the last years a new therapy of psoriasis was developed, which consists in a treatment with salt solutions, resembling the water of the Dead Sea, and ultraviolet light (Tomesa-therapy). We studied the influence of the used salt on ATPase positive epidermal Langerhans cells in murine ear skin. An irreversible partial reduction of the Langerhans cell ATPase was found after salt treatment of separated epidermis or of full skin preparations. These results may have implications for the optimization and broader application of this therapy.     

Interleukin-20 plays a critical role in maintenance and development of psoriasis in the human xenograft transplantation model

Background  Interleukin (IL)-20 is a recently discovered cytokine displaying increased levels in psoriatic lesions. Interestingly, IL-20 levels decrease with antipsoriatic treatment, correlating with clinical improvement. However, the role of IL-20 in the aetiology of psoriasis is unknown.
Objectives  In this study, we investigate the effects both of blocking IL-20 signalling in psoriatic plaques and of adding IL-20 to nonlesional psoriasis skin.
Methods  We employed the human skin xenograft transplantation model in which psoriatic plaques and nonlesional keratome skin biopsies obtained from donors with moderate to severe plaque psoriasis were transplanted on to immuno-deficient mice. The transplanted mice were treated with anti-IL-20 antibodies or recombinant human IL-20.
Results  We demonstrate that blocking IL-20 signalling with anti-IL-20 antibodies induces psoriasis resolution and inhibits psoriasis induction. We also demonstrate that continuous IL-20 infusion, together with injection of additional nonactivated leucocytes, promotes induction of psoriasis in nonlesional skin from patients with psoriasis.
Conclusions  The results suggest that IL-20 plays a critical role in the induction and maintenance of psoriasis, and IL-20 is suggested as a new possible specific target in psoriasis treatment.     

Genital psoriasis: a questionnaire‐based survey on a concealed skin disease in the Netherlands

Background Psoriatic lesions may involve nearly all sites of the body. Involvement of the genital skin is frequently classified as part of intertriginous psoriasis without special awareness and treatment for this presentation of the disease. Gaining knowledge about the frequency of the involvement of genital skin in these patients will improve the overall care for patients with psoriasis. Objectives We studied the prevalence of genital psoriasis in the Netherlands and epidemiological characteristics of this specific presentation of the disease. Furthermore, we studied the relation between flexural and genital psoriasis. Patients/Methods A self‐administered questionnaire was sent to all 5300 members of the Dutch Psoriasis Society. Sociodemographic patient characteristics and disease‐related data (such as localization of psoriatic lesions, involvement of the genitalia, age at onset of genital psoriasis and severity of genital psoriatic lesions) were collected and analysed. Results A response rate of 37% was achieved. Almost 46% of the responding patients with psoriasis, that is 16.5% of all potential responders (n = 5300), report genital involvement at some time during the course of their disease. The genitalia can become affected at any age. Many patients with current genital involvement (38%) do not have the flexural skin affected. Conclusions A large part of patients with psoriasis suffer from genital psoriasis, which was not associated with flexural involvement in at least one third of them. More attention to the genital region is required in the current standard treatment of both male and female psoriatic patients at any age.     

RNA, DNA, and cell surface characteristics of lesional and nonlesional psoriatic skin

We have measured the RNA and DNA content and examined cell surface characteristics of human epidermal cells derived from normal skin, and lesional and nonlesional areas of psoriatic skin prior to and following treatment on a modified Goeckerman protocol. Our results show that cells from active psoriatic lesions contain greater numbers of basal keratinocytes when compared with either nonlesional skin from the same patients or skin from healthy volunteers and individuals with other inflammatory skin lesions. Follow-up measurements 2-3 weeks after the initiation of therapy showed that the numbers of basal keratinocytes in resolving psoriatic lesions had decreased and approached normal levels. Multiparameter RNA/DNA flow cytometric analysis on parallel samples from the same psoriasis patients revealed an increased growth fraction and proportion of cycling cells in both the nonlesional and lesional skin compared with controls. Furthermore, the cellular RNA content was elevated in lesional psoriatic skin when compared with either nonlesional or normal skin. Flow cytometric examination of nonlesional and lesional epidermal cells obtained 2-3 weeks after the commencement of therapy revealed that the growth fraction and mean RNA content of the keratinocytes from resolving psoriatic plaques decreased in response to therapy. In contrast, the proportion of keratinocytes within the S + G2 + M phases of the cell cycle remained elevated. These data indicate that "uninvolved" psoriatic skin exhibits characteristics more closely resembling lesional psoriatic skin than normal skin. The results further suggest that quantitation of cellular RNA content and basal cell number might be sensitive indicators of early treatment response in psoriasis.     

Quality of Life and Treatment Satisfaction among Patients with Psoriasis and Psoriatic Arthritis and Patients with Psoriasis Only

Introduction: Five to forty percent of patients with cutaneous psoriasis develop an inflammatory, oligoarticular spondyloarthropathy known as psoriatic arthritis. Objective: To compare health-related quality of life (QOL) between cutaneous psoriatic patients with and without psoriatic arthritis. Method: Secondary cross-sectional analysis of data obtained from the 2005 Spring US National Psoriasis Foundation Quality of Life Telephone/Internet Survey. 426 patients with psoriasis and/or psoriatic arthritis were included in the 2005 survey. Among these respondents, the self-reported disease histories of 140 patients with cutaneous psoriasis and psoriatic arthritis were compared with those of 278 patients with cutaneous psoriasis only. Both groups were compared with respect to demographics, skin disease severity, treatment history and satisfaction, and QOL using previously validated assessment scales. Results: Compared with those with skin psoriasis only, respondents with cutaneous psoriasis and psoriatic arthritis were slightly older, more likely to be female and members of the National Psoriasis Foundation, and more likely to report a younger age of disease onset. They were also more likely to be unemployed, to report their job was affected by their condition, and to report a higher mean estimate of lost annual wages. On both univariate and multivariate analysis, however, no significant differences between groups were detected in skin disease severity, overall QOL, and satisfaction with current treatment options. At the same time, individuals with skin psoriasis and psoriatic arthritis were more likely to be taking systemic agents. They also reported higher mean scores for pain, while those with cutaneous psoriasis reported higher mean scores for self-consciousness only. Conclusion: In contrast to previous reports that did not control for skin disease severity, this study demonstrates that patients with cutaneous psoriasis and psoriatic arthritis do not report significantly worse health-related QOL compared with patients with cutaneous psoriasis only. Nor do they report significantly greater dissatisfaction with current treatment options. These findings may reflect the intrinsic inadequacy of the QOL instruments used in this study for capturing the additional burden of joint disease. Alternatively, these findings may reflect the existence of a threshold of joint disease in patients with skin psoriasis and psoriatic arthritis below which joint symptoms are perceived as negligible relative to cutaneous disease.