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Chronic spontaneous urticaria (CSU) is a debilitating skin disease characterized by intensely itchy wheals, angioedema, or both. Symptoms recur spontaneously, on a near-daily basis, over >6 weeks; many patients experience flare-ups over several years and, consequently, reduced quality of life. Differences between the inflammatory profiles of the skin of CSU patients (wheals and nonlesional sites) and healthy controls indicate that key drivers such as mast cells, eosinophils, and basophils interact, release vasoactive mediators, and prime the skin, leaving patients predisposed to symptoms. Many cytokines and chemokines involved in these inflammatory networks and their corresponding intracellular signaling cascades have been identified. These insights informed the development of therapies such as omalizumab, dupilumab, and Bruton's tyrosine kinase (BTK) inhibitors, marking a renewed focus on pathogenesis in CSU clinical research. Despite progress, current therapies provide symptomatic control but do not appear to redress the inflammatory balance in the skin permanently. A deeper understanding of CSU pathogenesis will permit a more targeted approach to developing novel treatments with curative intent. Here, we review what is known about the pathogenesis of CSU and consider how this can be used to identify rational targets to improve patient care further.

BACKGROUND Treatments for alopecia areata (AA) patients with extensive scalp hair loss are limited, and recent evidence supports a role for type 2 T-cell (Th2)-immune response in AA. Dupilumab, a monoclonal antibody inhibiting Th2 signaling, approved for type 2 diseases including atopic dermatitis, was evaluated in AA patients. METHODS Alopecia areata patients with and without concomitant atopic dermatitis were randomized 2:1 to receive weekly subcutaneous dupilumab (300 mg) or placebo for 24 weeks, followed by another 24-week dupilumab open-label phase. The primary outcome was change from baseline in the Severity of Alopecia Tool (SALT) score at week 24; secondary outcomes included a range of measures of hair regrowth. RESULTS Forty and 20 patients were assigned to the dupilumab and placebo arms, respectively. At week 24, disease worsening was documented in the placebo arm, with a least-squares mean change in the SALT score of -6.5 (95% confidence-interval [CI], -10.4 to -2.6), versus a change of 2.2 (95% CI, -0.6 to 4.94) in the dupilumab arm (p

Background Treating to absolute treatment targets rather than relative measures such as Psoriasis Area and Severity Index (PASI)-75 is emerging as an important clinical concept included in psoriasis guidelines and clinical practice. Achieving treatment targets is associated with achievement of long-term outcomes. Objective To evaluate the relationship between psoriasis severity, disease characteristics, and achievement of PASI ≤2 with apremilast in a pooled analysis of the phase 3 ESTEEM 1 and 2 (NCT01194219 and NCT01232283), phase 3b LIBERATE (NCT01690299), and phase 4 UNVEIL (NCT02425826) clinical trials. Methods Pooled data from patients with moderate to severe plaque psoriasis randomized to apremilast 30 mg BID were analyzed by baseline PASI quartiles (Q1: 2.4-13.1, Q2: 13.2-15.9, Q3: 16.0-20.0, Q4: 20.1-57.8). Assessments included PASI, Dermatology Life Quality Index (DLQI), Scalp Physician's Global Assessment (ScPGA, ScPGA ≥1), and target (worst) Nail Psoriasis Severity Index (NAPSI, NAPSI ≥1). Results Of 1,062 patients, 963 had ScPGA ≥1 and 643 had NAPSI ≥1, 771 patients with baseline and Week 32 PASI assessments were included in analyses of Week 32 PASI target achievement. Rates of PASI ≤2 at Week 32 were greater in lower PASI quartiles (Q1: 43.5%, Q2: 31.2%, Q3: 26.8%, Q4: 18.4%). Most patients achieving PASI ≤2 target (83.6%) achieved DLQI ≤5 at Week 32, 59.3% of patients who did not achieve PASI ≤2 target achieved DLQI ≤5. At Week 32, mean improvements in ScPGA and NAPSI were similar with more moderate versus more severe disease (ScPGA, range: 1.1-1.4, NAPSI, range: 1.6-2.5). In a subgroup analysis, achievement of PASI ≤2 target was higher in the lowest PASI quartile and with disease duration Conclusions Greater achievement of PASI ≤2 was observed in patients with more moderate versus more severe skin disease. Apremilast may be particularly beneficial in more moderate disease early in the treatment paradigm.

Background Itch is common in psoriasis, adversely affecting health-related quality of life (HRQoL) and sleep. Objective We evaluated the efficacy of topical fixed-dose combination calcipotriol 50 μg/g plus betamethasone dipropionate 0.5 mg/g cutaneous foam (Cal/BD foam) on itch, itch-related sleep loss and HRQoL vs. foam vehicle. Methods We pooled data from three Phase II/III trials (NCT01536886/NCT01866163/NCT02132936) of Cal/BD foam vs. foam vehicle in adults with mild-severe psoriasis. For itch-related analyses, patients with baseline itch visual analogue scale (VAS) >40 (range 0-100) were analysed. Outcomes included the following: itch VAS reduction >40, ≥70% improvement in itch (Itch70) or itch-related sleep loss, 75% improvement in modified Psoriasis Area and Severity Index (excluding head; mPASI75) and Dermatology Life Quality Index (DLQI) scores 0/1 through 4 weeks. Results Of 837 patients, 800 had baseline itch VAS >0 (Cal/BD foam, n = 610; foam vehicle, n = 190); 484 had baseline itch VAS >40. There was no correlation between itch VAS score and mPASI at baseline (R2 = 0.021). In patients with baseline itch VAS >40, more patients achieved itch VAS reduction >40 in the active vs. vehicle group from Day 5 onwards (Day 5: 57.5% vs. 40.2% [P 40 and sleep loss >20, improvements in itch-related sleep loss occurred at Week 1 and continued through 4 weeks. Itch-related improvements occurred before improvements in mPASI75. There were significant differences in the proportion of Cal/BD-foam- vs. foam-vehicle-treated patients with baseline DLQI >10 (n = 172 vs. n = 50) achieving DLQI ≤1 (25.0% vs. 4.0%; P = 0.001) and DLQI 0 (17.4% vs. 2.0%; P = 0.006) at Week 4. Conclusion Compared with foam vehicle, Cal/BD foam offers more rapid and effective itch relief, with associated significant improvements in sleep and DLQI.

Psoriasis is a chronic inflammatory disease which affects nearly 3% of the adult US population. Due to the chronic nature of the disease and need for long-term treatment, psoriasis is associated with substantial disease burden and negative impact on patients' quality of life. In the past, systemic agents such as methotrexate, cyclosporine, and acitretin have been the mainstay treatment for moderate to severe psoriasis. Multiple new molecular targets have been recently identified, and novel biologic therapies directed at these targets have been approved leading to a paradigm shift in psoriasis management. However, despite the availability of several treatment options and continued introduction of highly efficacious biologics, undertreatment of psoriasis patients remains a huge problem. This can be largely attributed to several causes including high cost of biologics, lack of experience, and reluctance of practitioners to initiate or switch to systemic treatment regimens in moderate to severe psoriasis patients. In this article, we aim to provide a concise review of mechanism, safety, and efficacy of the approved systemic treatments for psoriasis.

Item does not contain fulltext BACKGROUND: Psoriasis symptoms may decrease quality of life for patients. Skin-related personal relationship difficulties in psoriasis patients are common, under-reported and poorly understood. OBJECTIVE: To assess the effect of ixekizumab (IXE) treatment on skin-related personal relationship difficulties in patients with moderate-to-severe psoriasis. METHODS: Pooled data (N = 2570) on skin-related relationship problems were obtained from two large phase 3 trials (UNCOVER-2 and UNCOVER-3) in patients with moderate-to-severe plaque psoriasis randomized to subcutaneous placebo (PBO, N = 361), etanercept (ETN; 50 mg twice weekly, N = 740), or 80 mg IXE as one injection every 4 (IXEQ4W, N = 733) or 2 weeks (IXEQ2W, N = 736) for 12 weeks, following a 160-mg initial dose. The Dermatology Life Quality Index (DLQI) Personal Relationships Domain (PRD) (Items 8 and 9) was used to assess how much the skin caused any personal relationship difficulties at weeks 0, 2, 4 and 12. Improvement was compared for IXE vs PBO and ETN using logistic models. Factors associated with improvement were assessed using multiple linear regressions. DLQI Item 9, assessing sexual difficulties, was also analysed separately. RESULTS: PRD scores (mean +/- standard deviation) at baseline were similar across all treatment groups (PBO: 1.8 +/- 1.9; ETN: 1.7 +/- 1.8; IXEQ4W: 1.6 +/- 1.8; IXEQ2W: 1.7 +/- 1.8). Treatment with IXE rapidly and significantly improved the mean PRD score compared to PBO and ETN (P < 0.001 at all time points). Baseline PRD score was the strongest negative predictor of improvement. IXE enabled significantly more patients with moderate-to-severe plaque psoriasis to reduce their skin-related sexual difficulties at Week 12 compared to PBO (P < 0.001) or ETN (P < 0.001). CONCLUSION: Ixekizumab improves patient-reported skin-related PRD difficulties in patients with moderate-to-severe psoriasis.

Atopic dermatitis (AD) and psoriasis are inflammatory skin diseases that negatively affect patients' quality of life. Although distinctions exist between these diseases, both are characterized by erythematous, thickened epidermal lesions that vary in intensity and affected body surface area. Early models of aetiology attributed symptoms of both diseases to cutaneous inflammation at lesion sites, but recent studies have established that activated immune mediators in the circulation drive disease severity. Activation of T helper 2 (Th2) and Th22 cells in the circulation appears to be the principal initiator of acute AD pathology, with the emergence of Th1 and Th17/interleukin (IL)-23 pathway activation marking the transition to a chronic state. The Th17/IL-23 pathway also has an important role in psoriasis. The role of systemic inflammation in AD and psoriasis is supported by the occurrence of non-cutaneous comorbidities that affect patients, most of which intensify morbidity and disability associated with lesional skin. Atopic dermatitis is associated with allergic disorders consisting of the "atopic march," whereas psoriasis is frequently accompanied by psoriatic arthritis. Patients with both disorders are at significantly higher risk of obesity, metabolic disorders, and cardiovascular diseases, all of which feature inflammatory components in their pathology models. These insights have led to novel therapeutics aimed at addressing psoriasis by targeting tumor necrosis factor- and Th17-related cytokine pathways. The success of these agents in psoriasis management is driving new therapeutic approaches for moderate-to-severe AD, including agents targeting the Th2 and Th17/Th22 cytokine pathways.

Background Facial cysts can become large (1-5 cm) or giant (>5 cm) on the face. Objective To describe the medical course of large and giant facial cysts in adolescents. Methods A case series of 11 patients with large or giant facial cysts seen in an outpatient pediatric dermatology practice. Results Seven patients underwent incision and drainage with culture of cyst contents growing Cutibacterium acnes in six, while the seventh grew Cutibacterium acnes from a frequently worn hat. All patients were treated with traditional therapeutics for cystic acne including intralesional triamcinolone (n = 9), oral antibiotics (n = 10), and isotretinoin (n = 1). Three patients who did not undergo cyst drainage had persistent symptomatology requiring cyst excision, whereas the seven patients whose cysts were drained (3 on initial management and 4 after recurrence) eventually had complete healing without need for surgery. Conclusion Incision and drainage (I & D) and culture of cyst contents can identify cases of cysts related to Cutibacterium acnes. For some cases of large facial cysts related to Cutibacterium acne, I&D combined with conservative acne management (using standard acne guidelines) can prevent the need for surgical excision in some patients. Prospective studies are needed to determine whether this combination of therapy leads to best outcomes clinically and cosmetically.

Secukinumab is a human interleukin-17A antagonist indicated for the treatment of moderate to severe plaque psoriasis in adults who are candidates for systemic therapy or phototherapy. The objective of this analysis was to measure the treatment response on psoriasis-related itching, pain, and scaling via the Psoriasis Symptom Diary (PSD)(©).ERASURE (n = 738) and FIXTURE (n = 1306) were double-blind, multicenter phase 3 studies in adults randomized to secukinumab (300, 150 mg, n = 1144) or placebo (n = 574) (administered at Weeks 0, 1, 2, 3, and 4, followed by dosing every 4 weeks) or a biologic active control (FIXTURE only). Patient-reported itching, pain, and scaling were assessed during the first 12 weeks of treatment using the PSD. The results reported here are limited to subjects in the secukinumab and placebo treatment groups who completed the PSD. The proportions of subjects achieving prespecified responses (improvement:reduction of at least 2.2 points for itching, 2.2 points for pain, or 2.3 points for scaling) were compared for secukinumab versus placebo.Overall, 39% of subjects completed the PSD at baseline and Week 12 (n = 453 secukinumab; 225 placebo). Subjects treated with secukinumab achieved significantly greater improvements in itching, pain, and scaling at Week 12 versus placebo (all P0.0001) and had significantly greater proportions of itching, pain, and scaling responders at Week 12 versus placebo (all P0.05).Secukinumab significantly improves patient-reported itching, pain, and scaling in adults with moderate to severe psoriasis compared with placebo.

Corticosteroids are the mainstay of topical therapies for the treatment of mild to moderate psoriasis. Selection of vehicle, concentrations of corticosteroid and coadministered medications, and frequency of administration are critical factors that enhance bioavailability of topical corticosteroids. Topical corticosteroids are commonly used as polytherapy and combination therapy with other agents, such as salicylic acid, vitamin D analogues and tazarotene. Combinations are selected for the ability to enhance efficacy while minimizing corticosteroid-related side-effects, such as cutaneous atrophy. New, innovative products such as sprays, foams and nail lacquers provide opportunities to tailor treatment for individuals, which promotes patient adherence to medications. This review covers features of topical corticosteroid formulations that affect bioavailability, efficacy and safety when used as monotherapy and in combination with other agents for the treatment of mild to moderate psoriasis.

Experts in psoriasis, hepatology, pharmacokinetics and pharmacogenetics convened to discuss the safety and monitoring of methotrexate with respect to hepatotoxicity when used in the treatment of psoriasis. Methotrexate is an efficacious and cost-effective treatment for psoriasis, but is associated with significant safety issues, particularly relating to hepatotoxicity. Current British, Dutch, German, EU and US guidelines for baseline evaluations, monitoring and prevention of hepatotoxicity in patients with psoriasis receiving methotrexate were evaluated. Liver safety monitoring is currently reliant upon multiple methods, including biopsy, serological tests for biomarkers such as type III procollagen amino terminal propeptide (PIIINP), and liver function tests based on liver enzymes. Monitoring of patients receiving long-term therapy is expected to be improved by the utilization of serum biomarkers currently in development such as the Enhanced Liver Fibrosis (ELF) panel and other non-invasive tests of hepatic architecture, such as fibroelastography, microbubbles and magnetic resonance imaging. Appropriate studies to determine optimal dosing to maximize efficacy and minimize toxicity, potentially utilizing pharmacogenetic principles, are clearly needed. Key questions for future research are identified including needs for optimal screening and monitoring, identification of appropriate biomarkers, assessment of relationships between dosing and safety, utility of liver biopsy, optimal dosing regimens (including route of administration), methods to measure methotrexate levels in blood, and use of methotrexate as a standardized active comparator in trials of experimental drugs used to treat psoriasis.

Udgivelsesdato: 2010-Feb-1 Abstract Corticosteroids are a mainstay of topical therapy for psoriasis. While efficacious and relatively safe when used carefully, the potential for side effects, notably skin atrophy and adrenal suppression, have been associated with excesses in potency, prolonged or widespread use. The International Psoriasis Council Working Group on Topical Therapy has reviewed the efficacy and safety of topical corticosteroids and recommends strategies for safe, long-term use of these agents.

We compared the frequency and spectra of p53 mutations in skin tumors from UVB-irradiated and benzo(a)pyrene-UVA-treated SKH-1 mice. Analysis of p53 mutations using a combination of polymerase chain reaction, denaturing high-performance liquid chromatography, and sequencing shows that the frequency and spectrum of p53 mutations in BaP-UVA-induced tumors are quite different from those in UVB-induced tumors. SKH-1 mice were treated with BaP-UVA or UVB for 30 weeks after which skin tumors were collected for analysis of p53 mutations. Among the 11 BaP-UVA-induced tumors with diameters of 5-10 mm, two displayed mutations in exon 8 yielding a mutation frequency of 18.2%. In contrast, the mutation frequency among BaP-UVA-induced tumors was 10.5%. In UVB-induced tumors, the mutation frequency in exon 8 was highly correlated with tumor size. A total of 77.8% of tumors with diameters larger than 10 mm contained p53 mutations. The overall mutation frequency among UVB-induced tumors was 17.9% in exon 8 and only 3.8% in exon 5. Hotspots for p53 mutation in UVB-induced tumors were found at codons 128 and 149 (exon 5), and at codons 268, 270, 271 and 273-276 (exon 8). In addition to widely recognized C → T missense mutations, there were also tandem CC → AG changes coupled with either an insertion of T, a C → G substitution or G → C/T mutations. All of the mutations were found at tri- or tetra-pyrimidine sites. Thirty-nine per cent of all p53 mutations occurred at codons 274 and 275; 53% occurred at codons 268-271. Two multiple mutation clusters were located at codons 268-271 and 274-276. Both BaP-UVA and UVB caused C → T transitions at codon 275 in exon 8. A C → T mutation at codon 294 was induced only by BaP-UVA treatment. In contrast to UVB treatment, BaP-UVA treatment did not induce any mutations in exon 5. We show that individually subcarcinogenic levels of BaP and UVA synergistically induce a novel p53-mutation fingerprint. This fingerprint could serve as a prognostic indicator for the development of BaP-UVA-induced skin tumors.

Collectively, new developments in the field of medical dermatology will ultimately lead to improved patient care. We review several new findings in the dermatologic literature including the following: new questions regarding the malignant potential of anti-tumor necrosis factor agents, which are widely used for the treatment of moderate to severe psoriasis as well as psoriatic arthritis; anti-interleulin-12, a promising anticytokine for the treatment of psoriasis; diagnostic advances in the detection of latent Mycobacterium tuberculosis; advances in the primary prevention of human papillomavirus and herpes zoster; and new therapeutic options with existing medications for neuropathic pain and pruritus.

Item does not contain fulltext BACKGROUND: Available literature on psoriasis and psoriatic arthritis (PsA) demonstrates a tremendous burden of disease and suggests underdiagnosis and undertreatment. OBJECTIVE: To obtain real-world physician perspectives on the impact of psoriasis and PsA and its treatment on patients' daily lives, including perceptions of, and satisfaction with, current therapies. METHODS: The Multinational Assessment of Psoriasis and Psoriatic Arthritis (MAPP) surveyed dermatologists (n = 391) and rheumatologists (n = 390) in North America (Canada and the United States) and Europe (France, Germany, Italy, Spain and United Kingdom). RESULTS: Dermatologists classified 20.3% and 25.7% of their patients as having severe psoriasis and severe PsA respectively; rheumatologists indicated that 48.4% of their PsA patients had active disease. Of the psoriasis patients complaining of joint pain, only 33.0% had a diagnosis of PsA. An impact on daily activities or social/emotional well-being was recognized by 57.2% to 79.3% of physicians. In patients with moderate-to-severe psoriasis, dermatologists reported 74.9% were receiving topical therapy, 19.5% conventional oral therapy and 19.6% biologics. Dermatologists and rheumatologists reported similar rates of topical ( approximately 45%) and biologic ( approximately 30%) therapy utilization for their PsA patients; conventional oral therapy was more often prescribed by rheumatologists (63.4%) vs. dermatologists (35.2%). Reasons for not initiating or maintaining systemic therapies were related to concerns about long-term safety, tolerability, efficacy and costs (biologics). CONCLUSION: Physicians in North America and Europe caring for patients with psoriasis and PsA acknowledge unmet treatment needs, largely concerning long-term safety/tolerability and efficacy of currently available therapies; evidence suggests underdiagnosis of PsA and undertreatment of psoriasis among dermatologists.

Far from being a "benign" arthropathy, as it was initially characterized, psoriatic arthritis (PsA) affects approximately 0.2% of the US population and can be associated with considerable joint damage, symptomatology, and quality of life impairment. PsA shares many characteristics with rheumatoid arthritis (RA), and new, rationally designed drugs that are effective in RA also are proving active in PsA. Two such drugs, etanercept and infliximab, target tumor necrosis factor (TNF), a key component of the inflammatory response. This review discusses the rationale for and experience with the use of these agents in PsA. Etanercept is a dimeric fusion protein that binds specifically to TNF, blocking its interaction with cell surface TNF receptors. Infliximab is a chimeric (murine/human) monoclonal antibody that binds to TNF and inhibits its binding to its receptor. A randomized placebo-controlled trial of etanercept in PsA found statistically significant benefits for this agent in measures of arthritic activity and psoriatic severity. There have been anecdotal reports of the efficacy of infliximab in PsA, but results from controlled clinical trials of this agent in PsA have not been reported. TNF inhibitors represent new therapeutic options for patients with PsA. The potential advantages of treatment with etanercept and infliximab early in the disease course are discussed.

Background The treatment options for facial and intertriginous skin are limited because these sites are more susceptible to corticosteroid-induced atrophy. The long-term management of these corticosteroid-sensitive sites requires the use of dosing regimens that are effective, but also safe. Methods The affected areas in 21 patients with atopic dermatitis were treated twice daily for 2 weeks, and then once daily for two consecutive days each week for eight more weeks. Results After 2 weeks, treatment success occurred in 95% of facial and intertriginous lesions and also in 95% of nonfacial, nonintertriginous lesions. During long-term therapy, treatment success was maintained in > 76% of facial and intertriginous lesions, and > 76% of other lesions. Recurrence rates were low, and skin atrophy and telangiectasia did not occur. Conclusions Patients with atopic dermatitis of facial and intertriginous areas were successfully treated with a limited application of fluticasone propionate ointment, 0.005%. The treatment resulted in rapid healing and provided efficacy with a low rate of recurrence and no evidence of skin atrophy or telangiectasia over 8 weeks.

Background Topical medications are often the first line therapy utilized by dermatologists for a variety of conditions. However, a common side effect of topical medications is application site irritation. The aim of this study was to evaluate and compare the sensory irritation caused by hydrocortisone butyrate lipocream 0.1% using a non-invasive and inexpensive technique. Methods Twenty participants with corticosteroid-responsive dermatoses were enrolled. Three target areas of unaffected skin were abraded. A negative control (petrolatum ointment), a positive control (an over-the-counter [OTC] anti-itch preparation containing benzyl alcohol), and a test product (hydrocortisone butyrate lipocream 0.1%) were each applied to separate target areas on the legs. Participants rated the irritation of each target area using a 10-point scale (1 [no symptoms] to 10 [intolerable burning/ stinging requiring removal of the medication]). Results The mean irritation scores for petrolatum ointment, the OTC anti-itch preparation, and hydrocortisone butyrate lipocream 0.1% were 1.30, 5.70, and 1.95, respectively. The difference in irritation between the OTC anti-itch preparation and hydrocortisone butyrate lipocream 0.1% was highly significant (P

Sun exposure histories were obtained from a series of patients age 35 or younger following diagnosis and removal of a basal cell carcinoma (BCC). The DNA was extracted from tumor biopsy samples derived from BCC of 10 patients who reported that they did not use sunscreens during youth (age 18 or younger) and 10 patients who routinely employed sunscreens during this age period. Exons 5-9 of the p53 gene were then amplified in three fragments from these samples using a nested polymerase chain reaction (PCR) approach and screened for mutations using an RNA heteroduplex assay. All PCR products displaying evidence of a mutation were sequenced. It was found that 6 of the 10 patients who were not routine sunscreen users displayed mutations in these p53 exons. All of the mutations were located at dipyrimidine sites, five of the six were C-->T transitions and one mutation was a tandem double mutation, consistent with a role for solar UVB in BCC formation. In contrast, only one p53 mutation was detected in the group of 10 patients who routinely employed sunscreens during childhood and adolescence. Hence, a significantly (P = 0.029) lower level of p53 mutations was detected in the BCC obtained from sunscreen users compared with tumors derived from nonusers. These findings suggest that the mechanisms involved in the etiology of skin carcinogenesis differ in sunscreen users compared with people who did not routinely employ sunscreens. These data are also indicative of a protective effect associated with sunscreen use against the formation of p53 mutations. It is possible that the patients who were diagnosed with BCC despite their use of sunscreens possessed a genetic susceptibility for skin cancer formation and developed BCC through a p53-independent pathway. Alternatively, solar UVA wavelengths, that were generally not blocked by the suncare products employed by the sunscreen users, may have played a significant role in BCC development through induction of a mutation(s) in an oncogene and/or a tumor suppressor gene, other than p53, for these patients.

Acanthosis nigricans (AN) and scleredema are two skin conditions that have been reported in association with diabetes mellitus. Few cases associating scleredema and AN have been reported. A literature search did not reveal any reports of diabetic patients developing AN on top of a scleredema plaque. Here we report a patient with diabetes mellitus who developed AN within the same indurated scleredema plaque.

The major histological characteristic of sun-damaged skin is the accumulation of an elastotic material that appears to replace collagen. This elastotic material consists primarily of elastin and histological studies suggest a large loss of collagen in the dermis of chronically sun-damaged skin. In this study, we examine the content and distribution of collagen and procollagen in sun-damaged human skin. The total collagen content of sun-damaged skin was 20% less than nonsolar-exposed skin (524 micrograms collagen per mg total protein in sun-damaged skin and 667 micrograms collagen per mg total protein in nonsolar-exposed skin). In addition, there was a 40% decrease in the content of intact amino propeptide moiety of type III procollagen in sun-damaged skin (0.68 U per 50 mg wet weight) as compared to nonsolar-exposed skin (1.12 U per 50 mg wet weight). The data suggest that this change in collagen content is due to increased degradation. The distribution of collagen in sun-damaged skin was examined by indirect immunofluorescence. Mild digestion of sun-damaged skin with elastase removed the elastin and revealed the presence of collagen in the elastotic material. Therefore, the elastin appears to mask the presence of collagen fibers in the dermis of sun-damaged skin.

Fifty patients were enrolled in a double-blind, randomized, parallel-group study designed to determine whether tazarotene may have a role in maintenance therapy for psoriasis. The patients had stable moderate-to-severe plaque psoriasis on up to 15% of their body surface area, on sites other than the face and scalp. Their mean age was 55 years and the majority had had psoriasis for more than 10 years. Washout periods were: 2 weeks for topical drugs, 4 weeks for UVB or PUVA treatment, and 8 weeks for systemic drugs that might alter the course of psoriasis. For the initial open-label treatment phase, patients applied tazarotene 0.1% gel plus clobetasol propionate 0.05% ointment for 6 weeks. The frequency of application of both medications was initially once daily and then was tapered to ensure gradual weaning. Thus, during weeks 1 and 2, patients applied tazarotene each morning and clobetasol propionate each evening. During weeks 3 and 4, patients applied tazarotene each morning and clobetasol propionate each Tuesday, Thursday, and Saturday evening. Finally, during weeks 5 and 6, patients applied tazarotene each Monday, Wednesday, and Friday morning, and clobetasol propionate each Tuesday and Thursday evening. For the subsequent double-blind maintenance phase, patients were randomized to receive one of three maintenance regimens for 20 weeks – tazarotene/clobetasol (tazarotene 0.1% gel on Monday, Wednesday, and Friday mornings, plus clobetasol propionate 0.05% ointment on Tuesday and Thursday evenings), tazarotene/vehicle (tazarotene 0.1% gel on Monday, Wednesday, and Friday mornings, plus white petrolatum on Tuesday and Thursday evenings), and vehicle (tazarotene gel vehicle on Monday, Wednesday, and Friday mornings plus white petrolatum on Tuesday and Thursday evenings). Patients were instructed to apply a thin film of medication to their psoriatic plaques. Emollient use was permitted, but other topical formulations and excessive exposure to ultraviolet light were not. Efficacy was evaluated – at baseline, every 2 weeks during the initial treatment phase, and every 4 weeks during the maintenance phase – in terms of overall disease severity, plaque elevation, scaling, erythema, pruritus, and global response to treatment. The first four of these were rated by the physician as 0 = none, 2 = mild, 4 = moderate, 6 = severe, and 8 = very severe. Pruritus was rated as 0 = none, 1 = trace, 2 = mild, 3 = moderate, 4 = marked, and 5 = severe. Global response was rated as 0 = cleared, 1 = almost cleared (∼90% improvement), 2 = marked (∼75%) improvement, 3 = moderate (∼50%) improvement, 4 = slight (∼25%) improvement, 5 = unchanged, and 6 = worse. Analysis of variance and the Student's t-test were used to compare maintenance regimens (P ≤ 0.05). In the maintenance phase, the last recorded score for each patient was carried forward to all subsequent visits.

Two hundred and nineteen patients completed this multicenter, randomized, evaluator-blind, parallel-group study evaluating the efficacy and safety of once-daily application of mometasone furoate 0.1% cream compared with twice-daily hydrocortisone valerate 0.2% cream in children with moderate to severe atopic dermatitis. Enrolled patients were between 2 and 12 years of age and had failed to respond to at least 7 consecutive days of treatment with a topical hydrocortisone preparation, with the last application of hydrocortisone occurring within a week before enrolling in the current study. Patients were randomized to treatment from 10 centers in the USA with either mometasone furoate 0.1% cream (n = 109) or hydrocortisone valerate 0.2% cream (n = 110) for up to 3 weeks. At enrollment, a target area of dermatitis (not the face or forehead) of at least 20 cm2 was selected by the investigator for specific evaluation of the effects of treatment on disease signs and symptoms. Additionally, patients had to present with at least 15% total body surface involvement, excluding the face and forehead, with the current exacerbation of atopic dermatitis. The severity of erythema, induration/lichenification, scaling/crusting, exudation, excoriation, and pruritus was graded on the following scale: 0 = none; 1 = mild; 2 = moderate; 3 = severe. A total sign/symptom severity score (sum of six individual sign/symptom severity scores) of ≥ 8 was required in the target area (maximum = 18), with a severity score of ≥ 2 required for erythema and for one other sign. Patients were examined on return visits on days 4, 8, 15, and 22 of treatment and the severity of the signs and symptoms present in the target area was rated by the investigator at each visit. Areas outside the target area were also treated with the study medications and evaluated by the investigator in the global response to treatment. The criteria for global clinical response compared to baseline were as follows: cleared (100% improvement); excellent (75–99% improvement); good (50–74% improvement); fair (25–49% improvement); poor (

Background Several instruments are available for assessing impairment and disability associated with psoriasis. The first true psoriasis-specific quality of life (QoL) questionnaire suitable for use in clinical trials, the Psoriasis Index of Quality of Life (PSORIQoL), has recently been developed in the UK. The aim of the current study was to produce and validate a conceptually equivalent US version of the PSORIQoL with equally good psychometric properties. Methods A lay translation panel was employed to ensure that the wording of the questionnaire was appropriate for a US population. Semi-structured interviews conducted with 37 patients tested the instrument's ease of completion, relevance and comprehensiveness. Finally, a test-retest validation mail survey was conducted with 72 patients to determine reliability, internal consistency and construct validity. Results Few changes were necessary to the wording of the questionnaire. Interviewees found the questionnaire easy to complete (requiring an average of 4 min) and the content relevant and comprehensive. The adapted measure had comparable psychometric properties to the original, with a test-retest reliability coefficient of 0.90, indicating excellent reproducibility. Internal consistency and initial indications of construct validity were also good, with scores on the measure related as expected to perceived general health and severity of psoriasis and the presence of visible lesions. Conclusions The US PSORIQoL is a practical, reliable and valid instrument for measuring the impact of psoriasis and its treatment on QoL in clinical trials and in routine practice. It remains necessary to establish the instrument's responsiveness to changes in QoL associated with effective interventions.

Proliferating cell nuclear antigen (PCNA) is an active nuclear protein involved in DNA replication, recombination and repair. PCNA is found throughout the basal layer in normal skin and in all layers of the epidermis in malignancy. This study evaluates PCNA's expression after acute and chronic UV-B irradiation. Skh-1 hairless mice exposed to 1.5 and 4.5 kJ/m2 of UV-B were sacrificed at 6, 12, 24, 48, 72 and 168 h. Immunohistochemical analysis revealed PCNA expression throughout the basal layer of untreated skin, with diminished expression at 6 h, indicative of immediate UV damage, and evidenced by the observable upregulation in pyrimidine dimer formation early on. Subsequently, PCNA immunoreactivity progressively increased, demonstrating an aberrant upward epidermal migratory pattern in association with chronic exposure. The 4.5 kJ/m2 group exhibited prolonged recovery in staining and also demonstrated this altered migratory pattern with chronic exposure. Progressive reactivation of PCNA expression occurs with repair. PCNA migration to upper layers of the epidermis indicates proliferation and possibly a subsequent increased malignant potential. We conclude that PCNA can serve as a marker of DNA repair and indirectly as an indicator of UV-B-induced damage, expression being time dependent and dose related. Specific immunoreactivity patterns and the observable atypia in keratinocytes are relevant in elucidating malignant potentiation.

Polycyclic aromatic hydrocarbons, including benzo[a]pyrene (BaP), are ubiquitous environmental carcinogens. BaP is metabolized in vivo to reactive intermediates that become covalently bound to DNA and form BaP-DNA adducts, an initial event in carcinogenesis. Ultraviolet A (UVA) synergizes with BaP to significantly enhance genetic damage and accelerate carcinogenic processes. This study was initiated to investigate in vivo cellular changes related to carcinogenesis induced by repeated exposures to BaP plus UVA. Simulated chronic exposure to an environmental carcinogen and sunlight was conducted through biweekly topical application of BaP followed 2 h later by UVA exposure over a 10 week period. BaP diol epoxide (BPDE)-DNA adducts were measured in vivo by immunohistochemistry using an anti-BPDE-DNA monoclonal antibody. Oxidative DNA damage was measured by the detection of 8-hydroxy-2'-deoxyguanosine (8-OHdG) formation using high-performance liquid chromatography. Alterations in the cell cycle that were relevant to carcinogenesis were revealed by changes in p53, as identified in vivo using a polyclonal anti-p53 antibody. We found that cells containing BPDE-DNA adducts and nuclear p53 expression significantly increased between 2 and 10 weeks of BaP-UVA treatment, whereas neither BPDE-DNA adducts nor significant changes in p53 were observed in untreated skin. Using regression analysis, oxidative 8-OHdG damage also showed a parallel increase over 2-10 weeks (r = 0.80). These results indicate that genetic damage caused by exposures to BaP plus UVA accumulates with time and increases the potential for inductive events leading to carcinogenesis and tumor formation.