Effectiveness of systemic treatments for pyoderma gangrenosum: a systematic review of observational studies and clinical trials.

BACKGROUND: Pyoderma gangrenosum (PG) is a neutrophilic dermatosis with substantial morbidity. There is no consensus on gold-standard treatments. OBJECTIVES: To review the effectiveness of systemic therapy for PG. METHODS: We searched six databases for 24 systemic therapies for PG. Primary outcomes were complete healing and clinical improvement; secondary outcomes were time to healing and adverse effects. RESULTS: We found 3326 citations and 375 articles underwent full-text review; 41 studies met the inclusion criteria. There were 704 participants in 26 retrospective cohort studies, three prospective cohort studies, seven case series, one case-control study, two open-label trials and two randomized controlled trials (RCTs). Systemic corticosteroids were the most studied (32 studies), followed by ciclosporin (21 studies), biologics (16 studies) and oral dapsone (11 studies). One RCT (STOP-GAP, n = 121) showed that prednisolone and ciclosporin were similar: 15-20% of patients showed complete healing at 6 weeks and 47% at 6 months. Another RCT (n = 30) found that infliximab was superior to placebo at 2 weeks (46% vs. 6% response), with a 21% complete healing rate at 6 weeks. Two uncontrolled trials showed 60% and 37% healing within 4 months for canakinumab and infliximab, respectively; other data suggest that patients with concurrent inflammatory bowel disease may benefit from biologics. The remaining studies were poor quality and had small sample sizes but supported the use of corticosteroids, ciclosporin and biologics. CONCLUSIONS: Systemic corticosteroids, ciclosporin, infliximab and canakinumab had the most evidence in treating PG. However, current literature is limited to small and lower-quality studies with substantial heterogeneity.

Towards global consensus on core outcomes for hidradenitis suppurativa research: an update from the HISTORIC consensus meetings I and II.

BACKGROUND: A core outcomes set (COS) is an agreed minimum set of outcomes that should be measured and reported in all clinical trials for a specific condition. Hidradenitis suppurativa (HS) has no agreed-upon COS. A central aspect in the COS development process is to identify a set of candidate outcome domains from a long list of items. Our long list had been developed from patient interviews, a systematic review of the literature and a healthcare professional survey, and initial votes had been cast in two e-Delphi surveys. In this manuscript, we describe two in-person consensus meetings of Delphi participants designed to ensure an inclusive approach to generation of domains from related items. OBJECTIVES: To consider which items from a long list of candidate items to exclude and which to cluster into outcome domains. METHODS: The study used an international and multistakeholder approach, involving patients, dermatologists, surgeons, the pharmaceutical industry and medical regulators. The study format was a combination of formal presentations, small group work based on nominal group theory and a subsequent online confirmation survey. RESULTS: Forty-one individuals from 13 countries and four continents participated. Nine items were excluded and there was consensus to propose seven domains: disease course, physical signs, HS-specific quality of life, satisfaction, symptoms, pain and global assessments. CONCLUSIONS: The HISTORIC consensus meetings I and II will be followed by further e-Delphi rounds to finalize the core domain set, building on the work of the in-person consensus meetings.

Tanning among Ontario adolescents pre-legislation: Prevalence and beliefs.

To establish adolescent tanning beliefs and behaviors, prevalence and location of UV tanning device (beds/lamps) use, awareness of risk and restriction signage, and frequency of tanning service refusal, noting differences by grade and sex, prior to a ban on UV tanning device use among those under 18 in Ontario, Canada. Data were collected May 5 to 20 of 2014. Children in grades 7 to 12, and under age 18 completed an on-line questionnaire that asked their age, sex, grade, methods used to tan, frequency, length and location of UV tanning device use, if services were refused and why, awareness and content of signs/warning labels, tanning beliefs and knowledge, and use of eye protection. Of 1561 participants (10% response rate), 49% were male, 51% female. There were significant differences between the sexes regarding tanning behaviors (e.g. not tanning, tanning outside). Seven percent (108) had 'ever' used UV tanning devices, females more than males (p=0.0026). Over half (57%) of the 104 using UV tanning devices in the past 12months noticed warning signs/labels, of which most noticed that UV tanning devices can cause cancer (65%), and that UV exposure can contribute to premature aging (67%). While most (66%) tanned at tanning salons/studios and beauty salons/studios, gyms/fitness clubs (35%) and home use were common (25%). A relatively low proportion of adolescents used UV tanning devices prior to the ban, with use more common among females and those in higher grades.

An Ontario Health (Cancer Care Ontario) Clinical Practice Guideline: Surveillance Strategies in Patients with Stage I, II, III or Resectable IV Melanoma Who Were Treated with Curative Intent.

AIMS: To make recommendations on managing the surveillance of patients with stage I, II, III or resectable IV melanoma who are clinically free of disease following treatment with curative intent. MATERIALS AND METHODS: This guideline was developed by Ontario Health's (Cancer Care Ontario's) Program in Evidence-Based Care and the Melanoma Disease Site Group (including seven medical oncologists, four surgical oncologists, three dermatologists, one radiation oncologist and one patient representative). The MEDLINE, EMBASE, Cochrane Library, PROSPERO databases and the main relevant guideline websites were searched. Internal and external reviews were conducted, with final approval by the Program in Evidence-Based Care and the Melanoma Disease Site Group. The Grading of Recommendations, Assessment, Development and Evaluation approach was followed, and the Modified Delphi method was used. RESULTS: Based on the current evidence (eight eligible original study papers and four relevant guidelines) and the clinical opinions of the authors of this guideline, the initial recommendations were made. To reach 75% agreement for each recommendation, the Melanoma Disease Site Group (16 members) voted twice and one recommendation was voted on three times. After a comprehensive internal and external review process (including national and international reviewers), 12 recommendations, three weak recommendations and six qualified statements were ultimately made. CONCLUSIONS: After a systematic review, a comprehensive internal and external review process and a consensus process, the current guideline has been created. The guideline authors believe that this guideline will help clinicians, patients and policymakers make well-informed healthcare decisions that will guide them in clinical melanoma surveillance and ultimately assist in improving patient outcomes.

Glucagon-like peptide-1 (GLP-1) receptor agonists, obesity and psoriasis: diabetes meets dermatology.

Type 2 diabetes mellitus is characterised by beta cell failure, which frequently develops in the setting of insulin resistance. Inflammation contributes to the pathophysiology of type 2 diabetes by impairing insulin action in peripheral tissues and via reduction of beta cell function. Inflammation may also play an important role in the development of complications that arise in patients with type 2 diabetes. Hence, the anti-inflammatory actions of commonly used glucose-lowering drugs may contribute, indirectly, to their mechanisms of action and therapeutic benefit. Herein we highlight the anti-inflammatory actions of glucagon-like peptide-1 (GLP-1), which exerts direct and indirect actions on immune function. The observations that GLP-1 receptor agonists exert anti-inflammatory actions in preclinical studies, taken together with case reports linking improvements in psoriasis with GLP-1 receptor agonist therapy, illustrates the emerging clinical implications of non-classical anti-inflammatory actions of incretin-based therapeutics.

Ultraviolet radiation induction of ornithine decarboxylase in rat keratinocytes.

UV radiation plays an important role in the induction of cutaneous malignancy, including basal cell and squamous cell carcinomas and malignant melanoma. In addition to its effects on DNA damage and repair mechanisms, UV radiation has been shown to modulate the expression of specific genes, altering the levels of their mRNAs and the synthesis of their corresponding proteins. In order to gain further information about the molecular effects of UV radiation, we have studied the regulation of ornithine decarboxylase (ODC) gene expression in response to UVB radiation. ODC is the rate-limiting enzyme in polyamine biosynthesis, is involved in growth and differentiation, and has been implicated in carcinogenesis. Keratinocytes grown in culture were either sham-irradiated or exposed to increasing doses of UVB (1-5 mJ/cm2). Northern blot analysis of keratinocyte RNA under basal conditions demonstrated the presence of two ODC mRNA transcripts. Increasing exposure to UVB resulted in a dose-dependent increase in the levels of both ODC mRNA transcripts. The induction of ODC gene expression following UVB was noted 2 h after UVB exposure, and ODC mRNA levels continued to increase up to 24 h after UVB exposure. The UVB-induced increase in ODC gene expression was not serum dependent, despite the ability of serum alone to induce ODC gene expression. The mRNA transcripts for actin and hexosaminidase A were not induced after UVB exposure. These studies show that the UVB-induced increase in ODC activity is due, at least in part, to an increase in ODC gene expression and they provide a useful model for the analysis of the molecular effects of UVB radiation.

UVB radiation induces p21Cip1/WAF1 and mediates G1 and S phase checkpoints.

In a search for effectors and targets of UVB signaling in mammalian cells, we screened a keratinocyte cDNA library with differentially subtracted UVB-enriched cDNA probes. One of the UVB induced cDNA clones proved to be the rat p21Cip1/WAF1 homologue. UVB irradiation caused a rise in p53 protein levels, in association with induction of p21Cip1/WAF1 and cyclin G expression. The effects of UVB irradiation induced p21Cip1/WAF1 on the cell cycle were examined. In contrast to gamma irradiation, which caused G2 arrest, UVB treatment of asynchronous neonatal rat keratinocytes (NK) led to a marked inhibition of replicative DNA synthesis and prolonged G1 and S phase arrests, persisting to 18-24 h, with recovery of cycling by 36 h post-UVB. G1 arrest was accompanied by inhibition of cyclin D-, E- and A-associated kinases. Kinase inhibition was not due to reduction in cyclin or cdk proteins. While the association of cyclin E with Cdk2 was moderately reduced, cyclin D1/Cdk4 and cyclin A/Cdk2 complexes were not disrupted. The activating threonine 160 phosphorylation of Cdk2 in cyclin complexes was not inhibited. An incremental binding of p21 with Cdk4 paralleled the inhibition of cyclin D1/Cdk4 kinase and a similar rise in Cdk2 binding to p21 was associated with inhibition of cyclin E and cyclin A dependent kinases. Furthermore, a rise in measurable p21Cip1/WAF1-Cdk2 inhibitory activity paralleled the loss of G1 cyclin-dependent kinase activity, supporting a role for p21Cip1/WAF1 in the UVB-induced checkpoints.

A comparison of the melanocyte response to narrow band UVA and UVB exposure in vivo.

The visible cutaneous pigmentary response to ultraviolet-A (UVA) is immediate and, following sufficient exposure, may persist, whereas ultraviolet-B (UVB)-induced pigmentation appears after a delay of several days. We compared the in vivo response of melanocytes to single and multiple exposures of narrow band UVA and UVB irradiation which produced visibly equal increases in pigmentation. Using a xenon-mercury source matched to a monochromator, human volunteers were exposed to 304 (+/- 5) and 365 (+/- 10) nm radiation. Biopsies were performed 1, 7, and 14 days after irradiation. For each biopsy, the number of melanocytes per square millimeter of epidermis was determined using L-3,4-dihydroxyphenylalanine (dopa)- and tyrosine-incubated split epidermal preparations. Vertical sections were also examined. At days 7 and 14, after both 304 and 365 nm radiation, melanocytes were more intensely dopa-positive than in unirradiated controls, and demonstrated enlarged perikarya and a greater number of enlarged dendrites. Following both 304 and 365 nm radiation the number of dopa-positive melanocytes was increased at days 7 and 14 by 44% and 58%, respectively. Tyrosine positivity, an indicator of enhanced tyrosinase activity and increased melanin formation, was absent in controls and at day 1, and became positive in all but one sample at day 7 and day 14. Therefore, one day after UVA exposure, visible pigmentation but not tyrosinase activity was increased. At day 7, the number of tyrosine-positive melanocytes approximately equaled the number of dopa-positive melanocytes. Although UVA and UVB induce different pigmentary responses, their effects on melanocyte number and function were indistinguishable.

UVB and gamma-radiation induce the expression of mRNAs encoding the ribosomal subunit L13A in rat keratinocytes.

Ultraviolet B radiation produces an array of cellular perturbations in the skin. We isolated a keratinocyte cDNA encoding the rat 60S ribosomal subunit protein L13a following differential cDNA library screening with UVB-enriched probes. In contrast to the reported structure of liver L13a, the keratinocyte L13a cDNA contains a longer 3'-untranslated region. Northern blot analysis detected two L13a mRNA transcripts, approximately 800 bp and approximately 1.2 kb, in keratinocytes and a variety of rat tissues. Both L13a mRNA transcripts were induced by UVB irradiation, forskolin and gamma-irradiation. In contrast, no induction of L13a mRNA transcript levels was observed following exposure of keratinocytes to 12-O-tetradecanoylphorbol-13-acetate, serum and the DNA damage-inducing agents methyl methanesulfonate or 4-nitroquinoline-N-oxide. These observations suggest that increased expression of ribosomal subunit genes may be a molecular component of the keratinocyte response to UVB in particular and not part of a nonspecific response to DNA damage.

Immediate pigment darkening: visual and reflectance spectrophotometric analysis of action spectrum.

Immediate pigment darkening (IPD) occurs in human skin upon exposure to ultraviolet-A and visible radiation. The spectral changes that occur during IPD were measured with a rapid scanning reflectance spectrophotometer (RS) which employs optical fiber bundles for delivery and detection of light between 400 and 750 nm. The radiation dose dependence and wavelength dependence (334-549 nm irradiation) of IPD were studied by both the classical visual grading method and by spectrophotometric scoring using the RS system. The spectral changes that occur at long wavelengths with IPD mimic the natural absorption spectrum of melanin. Therefore, the IPD was scored in terms of the apparent change in melanin optical density, using the method Kollias and Baqer [Photochem. Photobiol. 43, 49-54 (1986)], based on reflectance in the 620-720 nm range. The nonlinearity of the visual grading method is demonstrated. The degree of IPD is first-order with respect to delivered dose and saturates after high doses. The maximum amount of IPD attained at saturation is greater for shorter wavelengths. Extrapolation of the reflectance data suggests the longest wavelength capable of eliciting IPD is about 470 nm.

Photoprotection.

Protection from solar ultraviolet radiation is discussed. Methods of protection include avoiding outdoor activities during times of greatest ultraviolet radiation insolation, seeking shade while outdoors, and wearing appropriate clothing. Sunscreens are reviewed, including newer compounds that may also offer photoprotection.

UVB radiation-activated genes induced by transcriptional and posttranscriptional mechanisms in rat keratinocytes.

The mechanisms utilized by ultraviolet B (UVB) radiation in the regulation of gene expression, as well as the genetic targets for transmission of the UVB signal, remain incompletely understood. To elucidate the mechanisms and targets for UVB activation in mammalian cells, we screened a keratinocyte cDNA library with differentially subtracted UVB-enriched cDNA probes. Twenty-three UVB-induced cDNA clones were isolated, including cDNAs for keratin, elongation factor-1 alpha, ferritin heavy chain, thioltransferase, cyclin G, cornifin, cellubrevin, poly(A) binding protein, and the surfeit locus. The temporal kinetics of maximal RNA induction following UVB exposure were heterogeneous, varying from 1 to 24 h post-UVB radiation. Analysis of the regulation of gene expression demonstrated that the levels of most UVB-induced mRNAs were also independently induced by serum and cycloheximide, features previously described for genes induced by DNA damage and members of the immediate early gene family. In contrast to results from studies of immediate early genes, treatment of keratinocytes with both serum and cycloheximide resulted in superinduction of only one mRNA transcript. Nuclear run-on assays demonstrated that UVB radiation increased the transcription rate in 8 of 23 genes, suggesting that UVB radiation utilizes both transcriptional and posttranscriptional mechanisms for the modulation of keratinocyte gene expression. The identification of a group of UVB-inducible keratinocyte genes should prove useful for the characterization of the genomic response to UVB radiation and the analysis of the molecular mechanisms underlying the UVB regulation of gene expression.

Interaction of TPA and ultraviolet B radiation in regulation of ODC gene expression in rat keratinocytes.

Ultraviolet B radiation (UVB) and phorbol esters are known to promote tumor formation in skin; however, the interaction between UVB and phorbol esters in the regulation of gene expression remains incompletely understood. To define the interaction of UVB and phorbol esters in the control of keratinocyte gene expression, we have studied the effects of the phorbol ester 12-O-tetradecanoylphorbol-13-acetate (TPA) and UVB on the regulation of ornithine decarboxylase (ODC) gene expression in a rat keratinocyte cell line. Both UVB and TPA alone increased ODC activity and induced the expression of the ODC gene. The combination of UVB and TPA produced a further increment in ODC gene expression at 12 h, but UVB markedly attenuated the TPA induction of ODC mRNA transcripts at 3 h. Protein synthesis inhibition with cycloheximide also induced ODC mRNA transcripts, but did not eliminate the further induction of ODC gene expression by UVB or TPA. No changes in actin gene expression following exposure to TPA/UVB were detected in the same experiments. UVB and TPA alone or in combination had no effect on the transcriptional activity of an ODC-chloramphenicol acetyltransferase fusion gene in transfected rat keratinocytes. The results of these studies suggest a complex posttranscriptional interaction of phorbol esters and UVB in the control of keratinocyte gene expression.

Ultraviolet B radiation induction of ornithine decarboxylase gene expression in mouse epidermis.

The cellular effects of u.v. radiation have been studied by using a hairless-mouse model in vivo. U.v. B radiation (u.v.B) induced the activity of the enzyme ornithine decarboxylase (ODC) in mouse epidermis. Maximal induction was noted after radiation with 90 mJ/cm2, and increased ODC activity was first detected 2 h after u.v.B exposure. U.v.B. also induced the expression of the ODC gene in a time- and dose-dependent manner, but did not induce the levels of actin mRNA transcripts. Cycloheximide treatment did not alter basal levels of ODC mRNA transcripts and had no effect on the u.v.B induction of ODC-gene expression. The results of these experiments demonstrate that u.v.B radiation induces both the expression of the ODC gene and the activity of the enzyme, and provides a useful 'in vivo' paradigm for the analysis of the molecular effects of u.v.B radiation.

Identification and characterization of a novel sucrose-non-fermenting protein kinase/AMP-activated protein kinase-related protein kinase, SNARK.

Subtraction hybridization after the exposure of keratinocytes to ultraviolet radiation identified a differentially expressed cDNA that encodes a protein of 630 amino acid residues possessing significant similarity to the catalytic domain of the sucrose-non-fermenting protein kinase (SNF1)/AMP-activated protein kinase (AMPK) family of serine/threonine protein kinases. Northern blotting and reverse-transcriptase-mediated PCR demonstrated that mRNA transcripts for the SNF1/AMPK-related kinase (SNARK) were widely expressed in rodent tissues. The SNARK gene was localized to human chromosome 1q32 by fluorescent in situ hybridization. SNARK was translated in vitro to yield a single protein band of approx. 76 kDa; Western analysis of transfected baby hamster kidney (BHK) cells detected two SNARK-immunoreactive bands of approx. 76-80 kDa. SNARK was capable of autophosphorylation in vitro; immunoprecipitated SNARK exhibited phosphotransferase activity with the synthetic peptide substrate HMRSAMSGLHLVKRR (SAMS) as a kinase substrate. SNARK activity was significantly increased by AMP and 5-amino-4-imidazolecarboxamide riboside (AICAriboside) in rat keratinocyte cells, implying that SNARK might be activated by an AMPK kinase-dependent pathway. Furthermore, glucose deprivation increased SNARK activity 3-fold in BHK fibroblasts. These findings identify SNARK as a glucose- and AICAriboside-regulated member of the AMPK-related gene family that represents a new candidate mediator of the cellular response to metabolic stress.

Are topical corticosteroids useful in phototherapy for psoriasis?

A prospective, randomized, double-blind, placebo-controlled trial was performed to assess the effect of a potent topical corticosteroid cream used in conjunction with ultraviolet B (UVB) phototherapy on psoriasis with respect to time to clearing and duration of remission after clearing. Of the 53 outpatients who received suberythemogenic UVB phototherapy three times per week, 24 applied the topical corticosteroid and 29 applied the placebo cream twice daily until clearing was achieved. Nine patients in each group failed to comply with the protocol. Although there was a trend toward a slightly more rapid response in the topical corticosteroid-treated group, there was no significant difference in patients' early response to therapy, number of treatments, and UVB dose required to achieve clearing. Patients in the topical corticosteroid-treated group remained in remission longer than did patients in the control group (183 vs 116 days). Life-table analysis predicts that 62% of emollient-treated patients flare within 6 months of clearing compared with only 42% of topical corticosteroid-treated patients (p less than 0.1). For most patients with psoriasis who receive UVB therapy in an outpatient setting, the use of potent topical corticosteroids appears to produce, at most, a modest beneficial effect.