Showing papers in "British Journal of Dermatology in 2015"

Cellular and molecular mechanisms of repair in acute and chronic wound healing

Abstract: A considerable understanding of the fundamental cellular and molecular mechanisms underpinning healthy acute wound healing has been gleaned from studying various animal models, and we are now unravelling the mechanisms that lead to chronic wounds and pathological healing including fibrosis. A small cut will normally heal in days through tight orchestration of cell migration and appropriate levels of inflammation, innervation and angiogenesis. Major surgeries may take several weeks to heal and leave behind a noticeable scar. At the extreme end, chronic wounds – defined as a barrier defect that has not healed in 3 months – have become a major therapeutic challenge throughout the Western world and will only increase as our populations advance in age, and with the increasing incidence of diabetes, obesity and vascular disorders. Here we describe the clinical problems and how, through better dialogue between basic researchers and clinicians, we may extend our current knowledge to enable the development of novel potential therapeutic treatments.

A global perspective on the epidemiology of acne.

Abstract: Summary Acne is estimated to affect 9·4% of the global population, making it the eighth most prevalent disease worldwide. Epidemiological studies have demonstrated that acne is most common in postpubescent teens, with boys most frequently affected, particularly with more severe forms of the disease. This paper aims to provide an update on the epidemiology of acne worldwide. Recent general and institutional studies from around the world have shown that the prevalence of acne is broadly consistent globally (with the exception of specific populations, which are discussed). However, this review highlights that there is a wide range of disparate outcome measures being applied in epidemiology studies, and we emphasize the need to develop a widely accepted, credible, standard assessment scale to address this in the future. In addition we discuss special populations, such as those devoid of acne, as well as the impact of potential determinants of acne on disease epidemiology.

Efficacy and safety of apremilast, an oral phosphodiesterase 4 inhibitor, in patients with moderate-to-severe plaque psoriasis over 52 weeks: a phase III, randomized controlled trial (ESTEEM 2).

Abstract: SummaryBackground Apremilast, an oral phosphodiesterase 4 inhibitor, regulates immune responses associated with psoriasis. Objectives ESTEEM 2 evaluated the efficacy and safety of apremilast 30 mg twice daily for moderate-to-severe plaque psoriasis. Methods This phase III, double-blind, placebo-controlled trial randomized adults to apremilast or placebo (2 : 1). At week 16, placebo patients switched to apremilast. At week 32, apremilast patients achieving ≥ 50% reduction in Psoriasis Area and Severity Index (PASI 50) were rerandomized (1 : 1) to continue apremilast or receive placebo. Upon loss of 50% of PASI improvement obtained at week 32, patients rerandomized to placebo resumed apremilast. Results The modified intention-to-treat population (full analysis set) included 137 placebo and 274 apremilast patients. At week 16, significantly more apremilast patients achieved PASI 75 (28·8%), PASI 50 (55·5%) and static Physician's Global Assessment score of 0 or 1 (20·4%) vs. placebo (5·8%, 19·7%, 4·4%, respectively; P < 0·001). Most patients rerandomized to apremilast at week 32 had a PASI 50 response at week 52 (80%). Patients treated with apremilast showed significant improvements in quality of life (as assessed by the Dermatology Life Quality Index) and pruritus at week 16 compared with placebo (P < 0·001). The exposure-adjusted incidence of adverse events did not increase with continued apremilast treatment for up to 52 weeks. The most common adverse events were nausea, diarrhoea, nasopharyngitis and upper respiratory tract infection. Conclusions Apremilast was effective in the treatment of moderate-to-severe plaque psoriasis over 52 weeks.

Secukinumab administration by pre-filled syringe: efficacy, safety and usability results from a randomized controlled trial in psoriasis (FEATURE).

Abstract: SummaryBackground Secukinumab, a fully human anti-interleukin-17A monoclonal antibody, demonstrated efficacy and safety in moderate-to-severe plaque psoriasis when administered via subcutaneous injection. Self-administration by pre-filled syringe (PFS) can offer patients clinical benefits of a drug, with increased convenience. Objectives To assess efficacy, safety and usability of secukinumab administration via PFS in subjects with moderate-to-severe plaque psoriasis. Materials and methods Subjects in this phase 3 trial were randomized 1 : 1 : 1 to secukinumab 300 or 150 mg or matching placebo. Results to week 12 are presented here. Each treatment was delivered using a PFS once weekly to week 4, and again at week 8. Co-primary endpoints were secukinumab superiority over placebo for week 12 PASI 75 (≥ 75% reduction in Psoriasis Area and Severity Index) and IGA mod 2011 (2011 modified Investigator's Global Assessment) 0/1 response rates. Secondary endpoints included PFS usability, determined by observer rating of successful, hazard-free self-injection and subject rating of acceptability by the Self-Injection Assessment Questionnaire (SIAQ). Results Co-primary endpoints were met, with demonstration of superiority for each secukinumab dose vs. placebo at week 12 (PASI 75: 75·9%, 69·5% and 0% for secukinumab 300 mg, 150 mg and placebo; IGA mod 2011 0/1: 69·0%, 52·5% and 0%, respectively; P < 0·0001 for all comparisons vs. placebo). PFS usability was high: 100% of subjects successfully self-administered treatment at week 1, and subjects reported high SIAQ-assessed acceptability of the PFS throughout the trial. No new/unexpected safety signals were observed. Conclusions Secukinumab administration by PFS was effective, with an acceptable safety profile and high usability. The PFS provides a reliable, convenient form of secukinumab administration in subjects with moderate-to-severe plaque psoriasis.

Diagnostic delay in hidradenitis suppurativa is a global problem.

Abstract: DEAR EDITOR, Hidradenitis suppurativa (HS) is clinically defined with recognized diagnostic criteria and recognizable physical characteristics. Untreated, the disease causes significant morbidity. The prevalence varies between 0 0003% and 4% depending on the study population. Estimates from insurance databases suggest a prevalence of < 0 1%. This variation strongly suggests a significant selection bias or misclassification, and it may be speculated that not all patients present for care. This is reinforced by clinical experience and published evidence indicating a significant delay in diagnosis. This study explores the delay in diagnosis for patients with HS on an international level. The study (survey) was conducted in 2013. Observational data were collected during routine visits or extracted from case records. Because of the simple and obvious symptomatology of recurrent painful lesions present in restricted welldefined areas of the body, patients’ self-reported history was considered valid regarding onset of symptoms. Consecutive patients with HS and psoriasis were included from each participating centre during a period of 4 months or less. The data were anonymized by removing any names, addresses and social security numbers, and included age, sex, age at disease onset, age at diagnosis, delay in diagnosis, time from onset of symptoms to first physician contact, age at first medical contact, number of physicians seen prior to the diagnosis, family history and disease severity. If the diagnosis was made by a primary care physician or by a specialist other than a dermatologist prior to seeing a dermatologist, this was recorded as the date of the diagnosis. Individual centres were responsible for and obtained any locally required permissions and signed informed consent forms, for example ethics committee approval, in accordance with national registry and data protection rules. Patients diagnosed with HS or psoriasis (and confirmed by the investigator) were included. The primary outcome was quantification of the delay in diagnosis. Additionally, documentation was made of both the delay in visiting a physician (and so gaining access to specialist treatment) and the relative delay in diagnosis of HS compared with psoriasis with/without a family history. The severity of HS was determined by Hurley’s staging criteria: stage I, mild; stage II, moderate and stage III, severe. In patients with psoriasis, severity was evaluated by the Psoriasis Area and Severity Index: score < 7, mild; 7–12, moderate and > 12, severe. The t-test, Wilcoxon rank sum test and v-test were used where appropriate. Univariate and multivariate logistic regression analyses were used to identify factors predictive of significant diagnostic delay. Diagnostic delay > 2 years was defined as significant. Diagnosis, sex, age of onset, family history and disease severity were selected as potentially important

Management of bullous pemphigoid: the European Dermatology Forum consensus in collaboration with the European Academy of Dermatology and Venereology

Abstract: Bullous pemphigoid is the most common autoimmune subepidermal blistering disease of the skin and mucous membranes. This disease typically affects the elderly and presents with itch and localized or generalized bullous lesions. In up to 20% of affected patients, bullae may be completely absent, and only excoriations, prurigo-like lesions, eczematous lesions, urticated lesions and/or infiltrated plaques are observed. The disease is significantly associated with neurological disorders. The morbidity of bullous pemphigoid and its impact on quality of life are significant. So far, a limited number of national treatment guidelines have been proposed, but no common European consensus has emerged. Our consensus for the treatment of bullous pemphigoid has been developed under the guidance of the European Dermatology Forum in collaboration with the European Academy of Dermatology and Venereology. It summarizes evidence-based and expert-based recommendations.

Tofacitinib, an oral Janus kinase inhibitor, for the treatment of chronic plaque psoriasis: Results from two randomized, placebo-controlled, phase III trials

Abstract: SummaryBackground Tofacitinib is an oral Janus kinase inhibitor being investigated for psoriasis. Objectives To determine the 16-week efficacy and safety of two oral tofacitinib doses vs. placebo in patients with moderate-to-severe chronic plaque psoriasis. Methods Patients in two similarly designed phase III studies (OPT Pivotal 1, NCT01276639, n = 901; OPT Pivotal 2, NCT01309737, n = 960) were initially randomized 2 : 2 : 1 to tofacitinib 10 or 5 mg or placebo, twice daily. Coprimary efficacy end points (week 16) included the proportion of patients achieving Physician's Global Assessment (PGA) of ‘clear’ or ‘almost clear’ (PGA response) and the proportion achieving ≥ 75% reduction in Psoriasis Area and Severity Index (PASI 75). Results Across OPT Pivotal 1 and OPT Pivotal 2, 745 patients received tofacitinib 5 mg, 741 received tofacitinib 10 mg and 373 received placebo. At week 16, a greater proportion of patients achieved PGA responses with tofacitinib 5 and 10 mg twice daily vs. placebo (OPT Pivotal 1, 41·9% and 59·2% vs. 9·0%; OPT Pivotal 2, 46·0% and 59·1% vs. 10·9%; all P < 0·001). Higher PASI 75 rates were observed with tofacitinib vs. placebo (OPT Pivotal 1, 39·9%, 59·2% and 6·2%, respectively, for tofacitinib 5 and 10 mg twice daily and placebo; OPT Pivotal 2, 46·0%, 59·6% and 11·4%; all P < 0·001 vs. placebo). Adverse event (AE) rates appeared generally similar across groups; rates of serious AEs, infections, malignancies and discontinuations due to AEs were low. Twelve patients reported herpes zoster across the tofacitinib treatment groups in both studies vs. none in the respective placebo groups. The most common AE across groups was nasopharyngitis. Conclusions Oral tofacitinib demonstrated significant efficacy vs. placebo during the initial 16 weeks of treatment in patients with moderate-to-severe psoriasis. Safety findings were consistent with prior studies.

Comparison of long‐term drug survival and safety of biologic agents in patients with psoriasis vulgaris

Abstract: SummaryBackground Drug survival (time to drug discontinuation) has recently emerged as an important parameter reflecting the long-term therapeutic performance in a real-life setting. Biologic drug survival in psoriasis is mainly limited by a gradual loss of efficacy over time. Previous studies have been limited by small patient population size and short observation times and yielded discrepant survival times for different biologics. Objectives To calculate the long-term drug survival for adalimumab, etanercept, infliximab and ustekinumab in a large cohort of real-life patients with psoriasis vulgaris and to analyse the factors that influence drug survival. Patients and methods Data were extracted from the prospective registry DERMBIO covering all patients with psoriasis vulgaris treated with biologic agents in the academic centres in Denmark. Drug survival was analysed using the Kaplan–Meier method. The influence of different covariates on drug survival was analysed by Cox regression. Results Included in the analysis were 1867 treatment series (adalimumab n = 774, etanercept n = 449, infliximab n = 253, ustekinumab n = 391) administered in 1277 patients for up to 10 years. Drug survival was significantly longer for ustekinumab than for anti-tumour necrosis factor (TNF)-α agents (P < 0·001). Etanercept had the shortest survival time [median survival 30 months, 95% confidence interval (CI) 25·1–34·9] whereas adalimumab and infliximab had comparable survival rates (59 months, 95% CI 45·6–72·4; 44 months, 95% CI 33–54·9, respectively). Survival was longer in men [odds ratio (OR) 1·51, 95% CI 1·31–1·74 vs. women] and in patients who had not previously received any biologic agent (OR 1·24, 95% CI 1·05–1·46). Loss of efficacy accounted for 67% of all drug discontinuations. Conclusions Ustekinumab has a significantly longer drug survival than the anti-TNF-α agents. Switching from one biologic to another is associated with an impairment of drug survival. Preventing loss of efficacy is a major area of medical need in the biologic therapy of psoriasis and the strategies that improve drug survival should be further investigated.

Tildrakizumab (MK‐3222), an anti‐interleukin‐23p19 monoclonal antibody, improves psoriasis in a phase IIb randomized placebo‐controlled trial

Abstract: SummaryBackground Tildrakizumab is a high-affinity, humanized, IgG1/κ, anti-interleukin (IL)-23p19 monoclonal antibody that does not bind human IL-12 or p40 is being developed for the treatment of chronic plaque psoriasis. Objectives To evaluate the safety and efficacy of subcutaneous tildrakizumab in patients with moderate-to-severe chronic plaque psoriasis. Methods A three-part, randomized, double-blind, phase IIb trial was conducted in 355 adults with chronic plaque psoriasis. Participants were randomized to receive subcutaneous tildrakizumab (5, 25, 100, 200 mg) or placebo at weeks 0 and 4 (part I) and every 12 weeks thereafter until week 52 (part II). Study drug was discontinued at week 52 and participants were followed through week 72 (part III). Primary efficacy end point was Psoriasis Area and Severity Index (PASI) 75 response at week 16. Adverse events (AEs) and vital signs were monitored throughout the study. Results At week 16, PASI 75 responses were 33·3% (n = 14), 64·4% (n = 58), 66·3% (n = 59), 74·4% (n = 64) and 4·4% (n = 2) in the 5-, 25-, 100- and 200-mg tildrakizumab and placebo groups, respectively (P ≤ 0·001 for each tildrakizumab dose vs. placebo). PASI 75 response was generally maintained through week 52; only eight of 222 participants who achieved PASI 75 response at week 52 and continued to part III relapsed following discontinuation up to week 72. Possible drug-related serious AEs included bacterial arthritis and lymphoedema (part I), and melanoma, stroke, epiglottitis and knee infection (part II). Conclusions Tildrakizumab had treatment effects that were superior to placebo, maintained for 52 weeks of treatment, and persisted for 20 weeks after cessation. Tildrakizumab was generally safe and well tolerated. These results suggest that IL-23p19 is a key target for suppressing psoriasis.

Dysregulated cytokine expression in lesional and nonlesional skin in hidradenitis suppurativa.

Abstract: SummaryBackground There is a dearth of information on the precise pathogenesis of hidradenitis suppurativa (HS), but immune dysregulation is implicated. Objectives To determine the nature of the immune response in HS. Methods Skin biopsies – lesional, perilesional (2 cm away) and uninvolved (10 cm away) – were obtained from patients with HS and healthy controls. The expression of various cytokines was determined by enzyme-linked immunosorbent assay, flow cytometry and real-time polymerase chain reaction. Results The expression of the inflammatory cytokines interleukin (IL)-17, IL-1β and tumour necrosis factor-α was enhanced in lesional skin of patients with HS. In addition, IL17A and IL1B mRNA were enhanced in clinically normal perilesional skin. CD4+ T cells produced IL-17 in HS, while CD11c+ CD1a− CD14+ cells were sources of IL-1β. Activated caspase-1 was detected in HS skin and was associated with enhanced expression of NLRP3 and IL18. Inhibition of caspase-1 decreased IL-1β and IL-18 production, suggesting that the caspase-1 pathway participates in IL-1β and IL-18 expression in HS. Abnormal cytokine expression was detected in perilesional and uninvolved skin, which may suggest that subclinical inflammation is present in HS skin prior to the formation of an active lesion. Conclusions This study demonstrates that CD4+ T cells produce IL-17 in HS and that the IL-17 pathway may be important in HS pathogenesis. CD11c+ CD1a− CD14+ cells are a source of IL-1β in HS, the production of which was shown to be mediated, in part, via a caspase-1-dependent pathway. These results suggest that IL-17 and the caspase-1-associated cytokines IL-1β and IL-18 may play a role in the pathogenesis of HS.

What the Eczema Area and Severity Index score tells us about the severity of atopic dermatitis: an interpretability study.

Abstract: SummaryBackground The Eczema Area and Severity Index (EASI) is an investigator-assessed instrument measuring the severity of clinical signs in atopic dermatitis (AD). The EASI was identified as one of the best-validated outcome measures for AD; however, no previous studies address how to interpret the EASI score for clinical use. Objectives To evaluate the interpretability and the ease of use of the EASI. Methods A retrospective analysis of paediatric and adult patients with AD was performed. Interpretability was evaluated by stratifying the EASI scores according to the Investigator's Global Assessment. The severity strata displaying the highest kappa coefficient of agreement were then selected as the recommended EASI band. The time to administer the EASI was recorded in a subgroup of patients. Results The suggested severity strata for the EASI are as follows: 0 = clear; 0·1–1·0 = almost clear; 1·1–7·0 = mild; 7·1–21·0 = moderate; 21·1–50·0 = severe; 50·1–72·0 = very severe (κ = 0·75). The EASI was also found to be acceptable in terms of ease of use, with assessments by trained investigators taking approximately 6 min. Conclusions Our study provides the first guide for interpreting the EASI score. It enables translation of the EASI numerical output into an AD global severity state that should be more meaningful to providers and patients. Along with a short administration time, the EASI demonstrates adequate feasibility, further supporting its use in clinical trials.

Approach to chronic wound infections

Abstract: Infection is the likeliest single cause of delayed healing in healing of chronic open wounds by secondary intention. If neglected it can progress from contamination to colonization and local infection through to systemic infection, sepsis and multiple organ dysfunction syndrome, and it can be life-threatening. Infection in chronic wounds is not as easy to define as in acute wounds, and is complicated by the presence of biofilms. There is, as yet, no diagnostic for biofilm presence, but it contributes to excessive inflammation - through excessive and prolonged stimulation of nitric oxide, inflammatory cytokines and free radicals - and activation of immune complexes and complement, leading to a delay in healing. Control of biofilm is a key part of chronic wound management. Maintenance debridement and use of topical antimicrobials (antiseptics) are more effective than antibiotics, which should be reserved for treating spreading local and systemic infection. The continuing rise of antimicrobial resistance to antibiotics should lead us to reserve their use for these indications, as no new effective antibiotics are in the research pipeline. Antiseptics are effective through many mechanisms of action, unlike antibiotics, which makes the development of resistance to them unlikely. There is little evidence to support the theoretical risk that antiseptics select resistant pathogens. However, the use of antiseptic dressings for preventing and managing biofilm and infection progression needs further research involving well-designed, randomized controlled trials.

Long-term efficacy and safety of ustekinumab, with and without dosing adjustment, in patients with moderate-to-severe psoriasis: results from the PHOENIX 2 study through 5 years of follow-up.

Abstract: Summary Background Evaluation of the dosing flexibility and long-term efficacy of biological agents is limited. Objectives To evaluate the long-term efficacy and safety of ustekinumab with and without dosing adjustment in the 5-year PHOENIX 2 study. Methods Patients were randomized to placebo or ustekinumab (45 or 90 mg) at weeks 0, 4, then every 12 weeks; patients receiving placebo crossed-over at week 12. Dosing adjustments were permitted at/beyond week 28 for early adjusters (weeks 28 or 40 per response); late adjusters (during long-term extension per investigator judgement); and nonadjusters (maintained randomized treatment throughout the study). Efficacy and safety were evaluated through weeks 244 and 264, respectively. Results In the overall population, 70% (849 of 1212) of ustekinumab-treated patients completed treatment through week 244, with high proportions of patients responding to the 45-mg and 90-mg doses, respectively: 75% improvement in Psoriasis Area and Severity Index (PASI 75) (76·5% and 78·6%) and PASI 90 (50·0% and 55·5%). Approximately 20% of patients were early adjusters, 30% were late adjusters and 50% were nonadjusters. Approximately half of the late adjusters initiated adjustments after already achieving PASI 75. Improved response was generally observed following dosing adjustments. Through week 264, safety event rates did not increase and event rates were generally comparable between dose groups and between patients with and without dosing adjustment. Conclusions Treatment with ustekinumab for up to 5 years was safe and effective. Improved response was generally demonstrated following dosing adjustments; further investigations are required to quantify actual incremental benefits. The results also suggest that some patients may desire treatment goals beyond PASI 75.

Superiority of ivermectin 1% cream over metronidazole 0·75% cream in treating inflammatory lesions of rosacea: a randomized, investigator-blinded trial.

Abstract: SummaryBackground Few therapeutic alternatives currently exist in the treatment of papulopustular rosacea (PPR) Objectives To demonstrate superiority of once-daily ivermectin 1% cream (IVM 1%) once daily vs twice-daily metronidazole (MTZ 0·75%) cream, regarding percentage reduction of inflammatory lesions in subjects with moderate to severe PPR Methods In this Phase 3, investigator-blinded, randomized, parallel-group study, subjects received IVM 1% once daily, or MTZ 0·75% twice daily over 16 weeks Efficacy assessments were inflammatory lesion counts and Investigator's Global Assessment (IGA) Safety assessments included incidence of adverse events (AEs) and local tolerance parameters Subjects evaluated their disease following a 5-grade scale and completed questionnaires Results A total of 962 subjects were randomized to receive IVM 1% (n = 478) or MTZ 0·75% (n = 484) At week 16, IVM 1% was significantly superior to MTZ 0·75% in terms of reduction from baseline in inflammatory lesions (83·0% vs 73·7%; P < 0001), observed as early as week 3 (Last Observation Carried Forward, LOCF) IGA results (subjects ‘clear’ or ‘almost clear’) also favoured IVM 1%: 84·9% vs 75·4%, respectively (P < 0001) Incidence of AEs was comparable between groups and local tolerability was better for IVM 1% More subjects receiving IVM rated their global improvement as ‘excellent’ or ‘good’ Conclusions Ivermectin 1% cream was significantly superior to MTZ 0·75% cream and achieved high patient satisfaction

The sensitivity and specificity of optical coherence tomography for the assisted diagnosis of nonpigmented basal cell carcinoma: an observational study

Abstract: SummaryBackground The diagnostic criteria for basal cell carcinoma (BCC) using optical coherence tomography (OCT) have been described previously, but the clinical value of these findings remains unknown. Objectives To investigate the diagnostic value of OCT for BCC in a typical clinical setting. The primary efficacy end point was a diagnosis of BCC for each lesion. Secondary end points were the diagnosis of other possible conditions. Methods This was an observational, prospective, multicentre study in which consecutive patients with nonpigmented pink lesions suspicious for BCC underwent clinical assessment, dermoscopy and OCT, with the diagnosis recorded at each stage. Once all diagnoses had been recorded, the histological results were disclosed. In total 164 patients with 256 lesions were recruited. Histology was missing for 21 lesions, leaving 235 lesions in 155 patients for analysis. Results Sixty per cent of lesions (141 of 235) were identified as BCC by histology. A slight increase of sensitivity was noted following OCT, which did not reach statistical significance. The specificity increased significantly from 28·6% by clinical assessment to 54·3% using dermoscopy and to 75·3% with the addition of OCT (P < 0·001). The positive predictive value for the diagnosis of BCC using OCT was 85·2% [95% confidence interval (CI) 78·6–90·4], and the negative predictive value was 92·1% (95% CI 83·6–97·0). The accuracy of diagnosis for all lesions increased from 65·8% with clinical evaluation to 76·2% following additional dermoscopy and to 87·4% with the addition of OCT. Conclusions OCT significantly improved the diagnostic specificity for BCC compared with clinical assessment and dermoscopy alone.

Hidradenitis suppurativa and metabolic syndrome: a comparative cross-sectional study of 3207 patients

Abstract: Summary Background Hidradenitis suppurativa (HS) is a chronic relapsing inflammatory skin disease. Objectives To evaluate the association between HS and metabolic syndrome and its component morbidities in a large, community-based cohort of patients with HS, using the database of Clalit Health Services, the largest public healthcare provider in Israel. Methods A cross-sectional study was performed. Metabolic syndrome was defined as the presence of at least three of the following conditions: diabetes, hyperlipidaemia, hypertension and obesity. The association between HS and metabolic syndrome was assessed by a multivariate logistic regression model, adjusting for age, sex, diabetes, hypertension, hyperlipidaemia, obesity and smoking status. Results The study included 3207 patients with HS (general frequency of 0·07%) diagnosed by a dermatologist in primary-care centres, and 6412 age- and sex-matched control patients without HS. HS was significantly associated with metabolic syndrome [odds ratio (OR) 1·61, 95% confidence interval (CI) 1·36–1·89], diabetes (OR 1·41, 95% CI 1·19–1·66), obesity (OR 1·71, 95% CI 1·53–1·91), hyperlipidaemia (OR 1·14, 95% CI 1·02–1·28) and hypertension (OR 1·19, 95% CI 1·03–1·38). Conclusions We found an association between HS and diabetes, hyperlipidaemia, obesity, hypertension and metabolic syndrome among a large community-based cohort of patients with HS. Clinicians should take into account that patients with HS may have one or more undiagnosed components of metabolic syndrome despite their young age. Thus, appropriate targeted screening is advised.

Smartphone applications for melanoma detection by community, patient and generalist clinician users: a review

Abstract: Summary Smartphone health applications (‘apps’) are widely available but experts remain cautious about their utility and safety. We reviewed currently available apps for the detection of melanoma (July 2014), aimed at general community, patient and generalist clinician users. A proforma was used to extract and assess each app that met the inclusion criteria, and we undertook content analysis to evaluate their content and the evidence applied in their development. Thirty-nine apps were identified with the majority available only for Apple users. Over half (n = 22) provided information or education about melanoma, ultraviolet radiation exposure prevention advice, and skin self-examination strategies, mainly using the ABCDE (A, Asymmetry; B, Border; C, Colour; D, Diameter; E, Evolving) method. Half (n = 19) helped users take and store images of their skin lesions either for review by a dermatologist or for self-monitoring to identify change, an important predictor of melanoma; a similar number (n = 18) used reminders to help users monitor their skin lesions. A few (n = 9) offered expert review of images. Four apps provided a risk assessment to patients about the probability that a lesion was malignant or benign, and one app calculated users’ future risk of melanoma. None of the apps appeared to have been validated for diagnostic accuracy or utility using established research methods. Smartphone apps for detecting melanoma by nonspecialist users have a range of functions including information, education, classification, risk assessment and monitoring change. Despite their potential usefulness, and while clinicians may choose to use apps that provide information to educate their patients, apps for melanoma detection require further validation of their utility and safety.

Paediatric mastocytosis: a systematic review of 1747 cases

Abstract: Paediatric mastocytosis was previously considered to be a benign and spontaneously regressing disease. However, this evolution is impossible to predict. To clarify the characteristics and course of paediatric mastocytosis, we performed a literature review of 1747 cases published between 1950 and April 2014. Lesions occurred before the age of 2 years in 90% of cases, and presented as urticaria pigmentosa (75% of cases), mastocytoma (20%) or diffuse cutaneous mastocytosis (5%). The male-to-female ratio was 1·4. KIT D816V mutation was detected in 34% of 215 tested patients. Clinical regression (complete or partial) occurred in 67% of cases and stabilization in 27%. However, the outcome was fatal in 2·9% of patients.

Cardiovascular disease risk factors in patients with hidradenitis suppurativa: a systematic review and meta-analysis of observational studies.

Abstract: Summary Hidradenitis suppurativa (HS) is a chronic, inflammatory, debilitating skin disease. The aim of the study was to systematically review the literature and critically answer the question: In patients with HS, do cardiovascular risk factors appear at a significantly higher rate compared with controls? The main search was conducted in Medline, Embase and the Cochrane Central Register. Studies eligible for inclusion were of case–control, cross-sectional and cohort design, and included comparison of any cardiovascular risk factor(s) in patients with HS with those of control groups. An I2 value > 50% was considered to show substantial heterogeneity. In this case, DerSimonian and Laird random-effect models were considered to compute pooled odds ratios (OR). Otherwise, a fixed-effects model was suitable. Nine studies, with 6174 patients with HS and 24 993 controls, were included. Significant association of HS with obesity [OR 3·45, 95% confidence interval (CI) 2·20–5·38, P < 0·001], central obesity (OR 2·97, 95% CI 1·41–6·25, P = 0·004), active smoking (OR 4·34, 95% CI 2·48–7·60, P < 0·001), history of smoking (OR 6·34, 95% CI 2·41–16·68, P < 0·001), hypertriglyceridemia (OR 1·67, 95% CI 1·14–2·47, P = 0·009), low high-density lipoprotein (HDL) (OR 2·48, 95% CI 1·49–4·16, P < 0·001), diabetes (OR 2·85, 95% CI 1·34–6·08, P = 0·007) and metabolic syndrome (OR 2·22, 95% CI 1·62–3·06, P < 0·001) was detected. Associations were significant both in population and hospital patients with HS, with hospital HS groups having uniformly higher ORs than the population HS groups. Causality could not be assessed. Heterogeneity was substantial in all analyses. This systematic review indicated that cardiovascular risk factors appear at a significantly higher rate in patients with HS compared with controls. The need for screening of patients with HS for modifiable cardiovascular risks is emphasized.

Clinical and immunological findings in 104 cases of paraneoplastic pemphigus.

Abstract: SummaryBackground Although there are many reports of sporadic patients with paraneoplastic pemphigus (PNP), only a few systematic studies on large cohorts of patients with PNP have been reported. Objectives To analyse the clinical and immunological findings in a large cohort of patients with PNP. Methods This retrospective study consisted of 104 patients with PNP. Clinical and histopathological manifestations, associated neoplasms, complicating diseases, prognosis and results of immunofluorescence, immunoblotting and enzyme-linked immunosorbent assays (ELISAs) were analysed. Results The clinical and histopathological findings in this study were generally similar to those in previous reports. The most common associated neoplasms included malignant lymphomas, malignant solid tumours and Castleman disease, in that order, while 12 patients had no detectable tumours. Novel ELISAs for desmocollins (Dscs) showed that 19 (18·6%), 42 (41·2%) and 62 (60·8%) of 102 patients with PNP showed antibodies to Dsc1, Dsc2 and Dsc3, respectively. Thirty-two (60%) of 53 patients had antibodies to alpha-2-macroglobulin-like protein 1 (A2ML1). We found statistically significant correlations between positive desmoglein 3 reactivity and genital lesions, and between positive desmoglein 3 reactivity and bronchiolitis obliterans. Conclusions We consider that antibodies to Dscs and A2ML1 are useful for the diagnosis of PNP.

Tofacitinib withdrawal and retreatment in moderate-to-severe chronic plaque psoriasis: a randomized controlled trial.

Abstract: SummaryBackground Tofacitinib is an oral Janus kinase inhibitor being investigated for the treatment of moderate-to-severe plaque psoriasis. Objectives To compare outcomes following tofacitinib withdrawal with outcomes of continuation. Methods In this phase 3 study (NCT01186744), patients received tofacitinib 5 mg (n = 331) or 10 mg (n = 335) twice daily for 24 weeks. The patients who achieved both ≥ 75% reduction in Psoriasis Area and Severity Index (PASI 75) score from baseline and Physician's Global Assessment (PGA) of ‘clear’ or ‘almost clear’ (PGA response) received a placebo (withdrawal) or the previous dose. At relapse (> 50% reduction in the PASI improvement during initial treatment) or week 40, the patients received the initial dose. Results Initial treatment: 33·5% and 55·2% achieved both PASI 75 and PGA responses with tofacitinib 5 and 10 mg twice daily, respectively, making them eligible for the treatment-withdrawal period. Withdrawal: 56·2%, 62·3%, 23·3% and 26·1% maintained PASI 75 responses with tofacitinib 5, 10 mg, placebo (5 mg) and placebo (10 mg) twice daily, respectively; 49·9%, 63·9%, 22·9% and 18·0% maintained PGA responses; and 92·3%, 93·0%, 32·8% and 42·9% did not relapse. Elevations in low-density lipoprotein–cholesterol levels following initial treatment (mean increase: 8·71 mg dL−1 with 5 mg twice daily, 10·26 mg dL−1 with 10 mg twice daily) were reversed upon withdrawal. Retreatment: 36·8% and 61·0% of patients who relapsed achieved PASI 75 responses with tofacitinib 5 or 10 mg after 16 weeks; 44·8% and 57·1% regained PGA responses. Conclusions Patients who received continuous treatment maintained a response more effectively when compared with placebo recipients. Safety profiles were comparable in both the continuous treatment group and retreatment group. Of those patients who relapsed, up to 60% recaptured a response with tofacitinib.

What's new in the physiopathology of acne?

Abstract: Summary There are four central factors that contribute to acne physiopathology: the inflammatory response, colonization with Propionibacterium acnes, increased sebum production and hypercornification of the pilosebaceous duct. In addition, research in the areas of diet and nutrition, genetics and oxidative stress is also yielding some interesting insights into the development of acne. In this paper we review some of the most recent research and novel concepts revealed in this work, which has been published by researchers from diverse academic disciplines including dermatology, immunology, microbiology and endocrinology. We discuss the implications of their findings (particularly in terms of opportunities to develop new therapies), highlight interrelationships between these novel factors that could contribute to the pathology of acne, and indicate where gaps in our understanding still exist.

Clinical practice guidelines for identification, screening and follow-up of individuals at high risk of primary cutaneous melanoma: a systematic review.

Abstract: Understanding how individuals at high-risk of primary cutaneous melanoma are best identified, screened and followed up will help optimize melanoma prevention strategies and clinical management We conducted a systematic review of international clinical practice guidelines and documented the quality of supporting evidence for recommendations for clinical management of individuals at high risk of melanoma Guidelines published between January 2000 and July 2014 were identified from a systematic search of Medline, Embase and four guideline databases; 34 guidelines from 20 countries were included High-risk characteristics that were consistently reported included many melanocytic naevi, dysplastic naevi, family history, large congenital naevi, and Fitzpatrick Type I and II skin types Most guidelines identify risk factors and recommend that individuals at high risk of cutaneous melanoma be monitored, but only half of the guidelines provide recommendations for screening based on level of risk There is disagreement in screening and follow-up recommendations for those with an increased risk of future melanoma High-level evidence supports long-term screening of individuals at high risk and monitoring using dermoscopy Evidence is low for defining screening intervals and duration of follow-up, and for skin self-examination, although education about skin self-examination is widely encouraged Clinical practice guidelines would benefit from a dedicated section for identification, screening and follow-up of individuals at high risk of melanoma Guidelines could be improved with clear definitions of multiple naevi, family history and frequency of follow-up Research examining the benefits and costs of alternative management strategies for groups at high risk will enhance the quality of recommendations

The use of propranolol in the treatment of infantile haemangiomas: an update on potential mechanisms of action

Abstract: Currently, propranolol is the preferred treatment for problematic proliferating infantile haemangiomas (IHs). The rapid action of propranolol has been shown to be especially dramatic in IHs involving dyspnoea, haemodynamic compromise, palpebral occlusion or ulceration. Another remarkable aspect of propranolol treatment revealed that the growth of the IHs was not only stabilized, but also that the improvement continued until complete involution was achieved, leading to a considerable shortening of the natural course of IH. However, the mechanisms underlying the effects of propranolol have not been fully elucidated. Recent studies have offered evidence of a variety of mechanisms. These include the promotion of pericyte-mediated vasoconstriction, the inhibition of vasculogenesis and catecholamine-induced angiogenesis, the disruption of haemodynamic force-induced cell survival, and the inactivation of the renin-angiotensin system. This review summarizes these mechanisms and the new concepts that are emerging in this area of research. Moreover, several molecular mechanisms by which propranolol may modify neovascularization in IH have also been proposed. The antihaemangioma effect of propranolol may not be attributable to a single mechanism, but rather to a combination of events that have not yet been elucidated or understood. Further studies are needed to evaluate and verify these mechanisms to gain a greater understanding of the effects of the intake of propranolol on haemangioma involution.

Combination of ablative fractional laser and daylight-mediated photodynamic therapy for actinic keratosis in organ transplant recipients - a randomized controlled trial.

Abstract: Summary Background Topical photodynamic therapy (PDT) for actinic keratoses (AK) is hampered by pain during illumination and inferior efficacy in organ-transplant recipients (OTR). Objectives We assessed ablative fractional laser (AFL)-assisted daylight photodynamic therapy (PDT) (AFL-dPDT) compared with daylight PDT (dPDT), conventional PDT (cPDT) and AFL alone (AFL) in field treatment of AK in OTR. Methods In each patient, four areas in the same region were randomized to one treatment with AFL-dPDT, dPDT, cPDT and AFL. AFL was delivered with a 2940-nm AFL at 2·3 mJ per pulse, 1·15 W, two stacks, 50-μs pulse-duration, 2·4% density. In dPDT and AFL-dPDT, methyl aminolaevulinate (MAL) was applied for 2·5 h without occlusion during daylight exposure. For cPDT, MAL was occluded for 3 h followed by red-light (630 nm) irradiation at 37 J cm−2. The primary end-point was complete response (CR) 3 months post-treatment. Results Sixteen patients with 542 AK (grades I–III) in field-cancerized skin of the scalp, chest and extremities were treated during August and September 2012. After 3 months, CR (AK I–III) rates were 74% after AFL-dPDT, 46% after dPDT, 50% after cPDT and 5% after AFL (P < 0·001). CR rates in AFL-dPDT, dPDT and cPDT were also significantly different (P = 0·004). Median maximal pain scores differed significantly during AFL-dPDT (0), dPDT (0), AFL (0) and cPDT (5) (P < 0·001). Erythema and crusting were more intense following AFL-dPDT than dPDT and cPDT, but only transient hypopigmentation was observed. Conclusions AFL-dPDT is a novel PDT modality that enhances CR with excellent tolerability compared with dPDT and cPDT in difficult-to-treat AK in OTR.

Histopathology of drug rash with eosinophilia and systemic symptoms syndrome: a morphological and phenotypical study.

Abstract: SummaryBackground The histopathological features of drug rash with eosinophilia and systemic symptoms (DRESS) syndrome remain poorly characterized. Objectives To better characterize the histopathological features of DRESS syndrome, and define the phenotype of the effector cells in the skin and compare it with maculopapular rash (MPR). Methods We conducted a retrospective study on 50 skin biopsies from patients with DRESS syndrome (n = 36). Histopathological and immunophenotypical features were studied and compared with a series of MPRs (n = 20). Results Foci of interface dermatitis, involving cutaneous adnexae, were frequently seen in cases of DRESS. Eosinophils were seen in only 20% of cases and neutrophils in 42%. Eczematous (40%), interface dermatitis (74%), acute generalized exanthematic pustulosis-like (20%) and erythema multiforme-like (24%) patterns were observed. The association of two or three of these patterns in a single biopsy was significantly more frequent in cases of DRESS than in a series of nondrug-induced dermatoses (P < 0·01), and appeared to be more marked in DRESS syndrome with severe cutaneous lesions (P = 0·01) than in less severe cases of DRESS and MPR. A higher proportion of CD8+ and granzyme B+ lymphocytes was observed in cases of DRESS with severe cutaneous eruptions (erythroderma and/or bullae). Atypical lymphocytes were found in 28% of biopsies, and expressed CD8 in most cases; a cutaneous T-cell clone was rarely found (6%). Conclusions The histopathology of DRESS syndrome highlights various associated inflammatory patterns in a single biopsy. Cutaneous effector lymphocytes comprise a high proportion of polyclonal CD8+ granzyme B+ T lymphocytes.

Socioeconomic and lifestyle factors and melanoma: a systematic review.

Abstract: Evidence of social determinants of disease and awareness of the impact of these factors on outcomes continues to increase. Social determinants include both socioeconomic and lifestyle factors. This review examines the interface between socioeconomic status (SES) and lifestyle and their effects on melanoma incidence and mortality. Lifestyle factors including occupation, occupational exposures, body mass index, marital status, smoking, recreational sun exposure and tanning were explored as they have a known relationship with melanoma. A remarkable association of SES with melanoma incidence and prognosis has been acknowledged worldwide. Melanoma incidence is increased in populations of higher SES, especially among the highly educated, while lower SES populations present with later-stage disease at time of diagnosis and display greater mortality. The aforementioned lifestyle factors are also related to SES, and have been shown internationally to affect melanoma incidence and mortality. This comprehensive systematic review suggests that lifestyle factors including occupation, occupational exposure, obesity, recreational sun exposure and tanning may explain the relationship between SES and melanoma.

Elevations in T-helper-2-initiating cytokines (interleukin-33, interleukin-25 and thymic stromal lymphopoietin) in lesional skin from chronic spontaneous (‘idiopathic’) urticaria

Abstract: Summary Background The mechanism of wealing in chronic spontaneous urticaria (CSU) is largely unknown. We previously demonstrated increased expression of T-helper 2 [interleukin (IL)-4 and IL-5] cytokines in skin biopsies from CSU. This suggested that Th2-initiating cytokines [IL-33, IL-25 and thymic stromal lymphopoietin (TSLP)], released through innate immune mechanisms, may play a role in pathogenesis. Objectives To identify Th2-initiating cytokines in lesional and nonlesional skin from patients with CSU and to compare the results with a control group. Methods Paired biopsies (one from a 4–8 h spontaneous weal and one from uninvolved skin) were taken from eight patients with CSU and nine control subjects, and studied by immunohistochemistry and confocal microscopy. Results There were increases in IL-4+ and IL-5+ cells in lesional skin vs. controls (P = 0·03 and P < 0·001, respectively) and marked elevations in the numbers of IL-33+, IL-25+ and TSLP+ cells in the dermis of lesional skin vs. both nonlesional skin (P = 0·002, P = 0·01 and P = 0·04, respectively) and controls (P = 0·001, P < 0·001 and P = 0·005, respectively). There was also a correlation between the numbers of IL-33+ and IL-25+ cells (r = 0·808, P = 0·015). IL-33 localized to CD31+ endothelial cells, CD90+ fibroblasts, CD68+ macrophages and tryptase+ mast cells, whereas IL-25 was expressed by epithelial cells, mast cells and major basic protein-positive eosinophils. IL-33 and IL-25 were constitutively expressed in the epidermis of both controls and patients with CSU. Conclusions Increased expression of Th2-initiating cytokines in lesional skin in CSU suggests that innate pathways might play a role in the mechanism of wealing. As Th2-initiating cytokines play a role in mast cell activation, inflammation and vascular leakage in CSU, these findings may also have therapeutic implications.

Assessment of atopic dermatitis using self-report and caregiver report: a multicentre validation study.

Abstract: SummaryBackground The epidemiology of atopic dermatitis (AD) in the U.S.A. has been described largely via US population-based questionnaire studies. However, the validity of the questions used for self- and caregiver-reported eczema has not been previously demonstrated. Objectives To validate the assessment of self- and caregiver-reported eczema. Methods We performed a prospective multicentre dermatology-practice-based study (three sites) to determine the validity of caregiver- and self-reported ever having eczema and 1-year history of eczema. Questionnaires were administered to unselected patients prior to their encounter. Patients (n = 782) were then evaluated by expert dermatologists trained in utilizing the Hanifin and Rajka criteria for AD. Sensitivity, specificity, positive predictive value (PPV) and negative predictive value were determined. Results Caregiver-reported 1-year history of childhood eczema was found to have a sensitivity (95% confidence interval) of 0·70 (0·59–0·80), specificity of 0·96 (0·93–0·99) and PPV of 0·87 (0·78–0·96) when compared with a physician's diagnosis of AD at that visit. Similarly, self-reported 1-year history of adult eczema was found to have a sensitivity of 0·70 (0·59–0·80), specificity of 0·95 (0·93–0·97) and PPV of 0·76 (0·64–0·85). The specificities and PPVs of a history of ever having caregiver- (0·89, 0·82–0·96 and 0·81, 0·70–0·93) and self-reported eczema (0·97, 0·95–0·99 and 0·91, 0·85–0·97) were high, with a high sensitivity in children (0·83, 0·72–0·95) but not in adults (0·43, 0·37–0·51). Conclusions Self- and caregiver-reported diagnosis of eczema ever or in the past year based on a single question demonstrates sufficient validity for the epidemiological study of AD.

Compression for leg wounds

Abstract: The main points in this scholarly review on the use of compression therapy in leg ulcers are the different modes of action of this treatment and the tools that are available including their practical applicability and use for self management. Due to its effect of counteracting gravity, compression is also suggested for ulcers with aetiologies that are not usually thought to require compression. The clinical evidence reported in ulcer-healing studies are discussed and some considerations are made relating to the cost-effectiveness of this management. In general, the failures of compression therapy are not caused by poor compression material but due to poor knowledge and application techniques of the care providers. Future studies comparing different compression devices should also report details concerning the compression material used and the pressure exerted.