CEBD Evidence Update

December 2016

Introduction

Season's greetings, and welcome to this month's CEBD Evidence Update, bringing you the latest evidence-based publications in dermatology, with an emphasis on clinical guidelines and systematic reviews. We are sending this edition out earlier than usual because of the Christmas and New Year Break.

CEBD Evidence Updates are compiled by the Centre of Evidence Based Dermatology at the University of Nottingham, with funding from Nottingham University Hospitals NHS Trust, as a service to the dermatology community. These updates are the first step in our aim of developing a CEBD Evidence Network, to bring together users of research evidence in dermatology. An archive of these updates is available on the list home page: CEBD-EVIDENCE-UPDATES.

The title of each item provides a link to the abstract in PubMed. If the paper is open-access or you have an institutional subscription to the journal concerned, you can access it by clicking on the full text link at the top right of the PubMed record. It is important to appraise the quality of systematic reviews before applying to your practice—we recommend the AMSTAR tool, which is very quick and easy to use. See also this open-access article: Research Techniques Made Simple: Assessing Risk of Bias in Systematic Reviews.

Do please forward this e-mail to other colleagues who might be interested and encourage them to sign up.

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We welcome all feedback and suggestions for improvement—please e-mail Douglas Grindlay, douglas.grindlay@nottingham.ac.uk.

Contents

GuidelinesSystematic reviews & evidence summaries

Eczema & dermatitisPsoriasis & psoriatic arthritisAcne & rosaceaSkin cancers & sun protectionInfections of the skinDrug & treatment reactions/safetyVitiligo & Pigmentary DisordersHair & nail disordersChronic wounds & ulcersOther disorders affecting the skinSkin conditions in generalSkin surgeryService delivery & management

Prescribing and safety alertsCEBD publications & newsOther key publications that have caught our eyeNotes

Guidelines

UK

Scottish Medicines Consortium decision on pembrolizumab (Keytruda)

After a resubmission assessed under the end of life and orphan process pembrolizumab is not recommended within NHS Scotland as monotherapy (after ipilimumab) for advanced (unresectable or metastatic) melanoma in adults. "The submitting company did not present a sufficiently robust economic analysis and in addition its justification of the treatment's cost in relation to its health benefits was not sufficient to gain acceptance by SMC."

Non-UK

Diagnosis and Treatment of Leishmaniasis: Clinical Practice Guidelines by the Infectious Diseases Society of America (IDSA) and the American Society of Tropical Medicine and Hygiene (ASTMH).

Aronson N, Herwaldt BL, Libman M, Pearson R, Lopez-Velez R, Weina P, Carvalho EM, Ephros M, Jeronimo S, Magill A.

Clin Infect Dis. 2016 Dec 15;63(12):1539-1557.

These guidelines for the clinical management of persons with leishmaniasis were prepared by a Panel of the Infectious Diseases Society of America and the American Society of Tropical Medicine and Hygiene. They describe approaches to the diagnosis and management of cases of cutaneous, mucosal, and visceral leishmaniasis, the three main clinical syndromes caused by infection with Leishmania parasites.

[Hereditary epidermolysis bullosa: French national guidelines (PNDS) for diagnosis and treatment].

Chiaverini C, Bourrat E, Mazereeuw-Hautier J, Hadj-Rabia S, Bodemer C, Lacour JP.

Ann Dermatol Venereol. 2016 Dec 5. pii: S0151-9638(16)31102-4. doi: 10.1016/j.annder.2016.07.016. [Epub ahead of print]

Note: In French, with English summary

The aim of these French recommendations (national diagnostic and treatment protocol [PNDS]) is to provide healthcare professionals with guidance on the course of hereditary epidermolysis bullosa and on optimal patient management.

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Systematic reviews & evidence summaries

Eczema & dermatitis

Vitamin D status and efficacy of vitamin D supplementation in atopic dermatitis: A systematic review and meta-analysis.

Kim MJ, Kim SN, Lee YW, Choe YB, Ahn KJ.

Nutrients. 2016 Dec 3;8(12). pii: E789.

"Observational studies and randomized controlled trials were included based on the available data on the serum 25-hydroxyvitamin D (25(OH)D) level and quantified data available for severity assessed using the Scoring Atopic Dermatitis (SCORAD) index or Eczema Area and Severity Index (EASI) score. Compared with healthy controls, the serum 25(OH)D level was lower in the AD [atopic dermatitis] patients of all ages (standardized mean difference = -2.03 ng/mL; 95% confidence interval (CI) = -2.52 to -0.78), and predominantly in the pediatric AD patients (standardized mean difference = -3.03 ng/mL; 95% CI = -4.76 to -1.29). In addition, the SCORAD index and EASI score decreased after vitamin D supplementation (standardized mean difference = -5.85; 95% CI = -7.66 to -4.05). This meta-analysis showed that serum vitamin D level was lower in the AD patients and vitamin D supplementation could be a new therapeutic option for AD."

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Psoriasis & psoriatic arthritis

Adherence, satisfaction and preferences for treatment in patients with psoriasis in the European Union: a systematic review of the literature.

Belinchón I, Rivera R, Blanch C, Comellas M, Lizán L.

Patient Prefer Adherence. 2016 Nov 17;10:2357-2367.

"Adherence rates are generally low in psoriasis patients regardless of the type of treatment, severity of disease or methods used to measure adherence. Biologic therapy is associated with greater clinical improvement. There is a direct association between physician recommendations, patient preferences and several domains of treatment satisfaction.

CONCLUSION: The results of this review support the conclusion that adherence rates in patients with psoriasis are suboptimal and highlight the need to improve patient compliance and satisfaction with treatment. Patients' preferences should be taken into account in the treatment decision-making process in order to improve patients' clinical outcomes by ensuring satisfaction and adherence."

Health-related quality of life in children and adolescents with psoriasis: A systematic review and meta-analysis.

Randa H, Todberg T, Skov L, Larsen LS, Zachariae R.

Acta Derm Venereol. 2016 Dec 16. doi: 10.2340/00015555-2600. [Epub ahead of print]

"Eligible studies were required to report HRQOL [health-related quality of life] data for children and/or adolescents with psoriasis (4-18 years) using validated HRQOL questionnaires. Seventeen eligible studies (total n=1,185) were identified. Moderation analyses revealed that study samples with a higher percentage of girls were associated with better HRQOL (β = 0.19), while a higher mean age of onset (β = 0.83) and study quality (β = 0.28) were associated with lower HRQOL (all p<0.05). Several papers did not provide the information necessary for exploring between-study differences, thus the moderation analysis results should be interpreted with caution. In conclusion, children and adolescents with psoriasis experience moderate impairment of HRQOL. Certain demographic characteristics (e.g. sex) and clinical characteristics (e.g. age at onset) appear to moderate this impact."

Protective effects of methotrexate against ischemic cardiovascular disorders in patients treated for rheumatoid arthritis or psoriasis: novel therapeutic insights coming from a meta-analysis of the literature data.

De Vecchis R, Baldi C, Palmisani L.

Anatol J Cardiol. 2016 Jan;16(1):2-9. doi: 10.5152/akd.2015.6136.

"RESULTS: Seven observational studies, mostly engaging patients with RA, were included in the meta-analysis. The pooled odds ratio (OR) was 0.73 (95% CI=0.70- 0.77 p<0.001). When stratified meta-analysis models were assessed, the pooled OR was 0.80 (95% CI=0.66-0.97; p=0.022) for studies adjusting for clinical severity of RA [rheumatoid arthritis]. Furthermore, the OR was even more significant after adjustment for concomitant use of other drugs specific for RA(OR=0.71, 95% CI=0.67-0.75, p<0.001).

CONCLUSION: Methotrexate at low doses, such those used for maintenance therapy of RA, predicted a decreased risk of CVE. Since methotrexate doesn't interfere with blood lipids, platelet aggregation or insulin resistance, the protective association may originate from mechanisms other than those exerted by antiplatelet drugs or statins."

Association between plasma interleukin-17 levels and risk of psoriasis: a meta-analysis.

Zhou XY, Bao J, Huang B, Jin Y.

Clin Exp Dermatol. 2016 Dec 7. doi: 10.1111/ced.13033. [Epub ahead of print]

"RESULTS: In total, eight cross-sectional study studies were included in the final analysis. The mean plasma levels of IL-17 were higher in patients with psoriasis than in healthy controls (SMD = 0.47, 95% CI = 0.07-0.86, P < 0.001).

CONCLUSIONS: Based on this literature review, there appears to be a positive association between IL-17 plasma levels and psoriasis."

Relative versus absolute risk of comorbidities in patients with psoriasis.

Saleem MD, Kesty C, Feldman SR.

J Am Acad Dermatol. 2016 Dec 13. pii: S0190-9622(16)31152-5. doi: 10.1016/j.jaad.2016.11.037. [Epub ahead of print]

"RESULTS: The comorbidities associated with psoriasis with the highest relative risk were nonmelanoma skin cancer, melanoma, and lymphoma, with relative risks of 7.5, 6.12, and 3.61, respectively; the attributable risk for these 3 conditions were 0.64, 0.05, and 0.17 per 1000 person-years, respectively. To attribute 1 event of these conditions to psoriasis would require seeing 1551; 20,135; and 5823 patients, respectively.

LIMITATIONS: Database studies might not fully account for confounders, resulting in overestimates of the risk impact of comorbidities.

CONCLUSIONS: Presenting attributable risk in the form of the number needed to harm provides a clearer picture of the magnitude of risk and a basis for wiser medical decision making and patient education."

Epigenetics of psoriatic disease: A systematic review and critical appraisal.

Pollock RA, Abji F, Gladman DD.

J Autoimmun. 2016 Dec 10. pii: S0896-8411(16)30363-8. doi: 10.1016/j.jaut.2016.12.002. [Epub ahead of print]

"Studies reflect a broad range of epigenetic sub-disciplines, the most common being DNA methylation, followed by the parent of origin effect or genomic imprinting, expression or activity of epigenetic modifying enzymes, and histone modifications. Epidemiological studies demonstrating excessive paternal transmission provided the earliest evidence of epigenetic deregulation in psoriatic disease, however few studies have examined its molecular mechanisms. Methylation studies evolved rapidly from low resolution global to targeted analyses of known psoriatic disease susceptibility loci such as HLA-C*0602. The recent explosion of epigenome-wide association studies has provided us with novel insights into psoriasis pathogenesis, and the mechanism of action of UVB, methotrexate, and anti-TNF therapies, as well as molecular signatures of psoriasis that may have clinical relevance. Finally, recent studies of pharmacological inhibitors of epigenetic modifier enzymes demonstrate their potential applicability as novel treatment modalities for psoriasis. Challenges of epigenetics research in psoriasis and PsA [psoriatic arthritis] were identified and future perspectives are discussed herein."

Mapping the effect of psoriatic arthritis using the international classification of functioning, disability and health.

Gudu T, Kiltz U, de Wit M, Kvien TK, Gossec L.

J Rheumatol. 2016 Dec 15. pii: jrheum.160180. [Epub ahead of print]

"RESULTS: Eleven studies (13 articles) were included in the analysis. Twenty-five domains of impact were cited, of which the ability to work/volunteer and social participation were the most cited (both by 10 studies). In total, 258 concepts were identified, of which 217 could be linked to 136 different ICF [International Classification of Functioning, Disability and Health] categories; 41 concepts, mostly personal factors, could not be precisely linked. The most represented ICF component was activities and participation (42.6%) rather than body structures (10.3%) or body functions (29.4%). Ten studies (90.9%) reported impairments in the ability to work/volunteer and social participation, and 7 (63.6%) reported leisure activities, family and intimacy, pain, skin problems, and body image.

CONCLUSION: PsA [psoriatic arthritis] widely affects all aspects of patients' lives, in particular aspects related to activities and participation. The ICF is a useful approach for the classification of disease effect."

Risk of herpes zoster in individuals on biologics, disease-modifying antirheumatic drugs, and/or corticosteroids for autoimmune diseases: A systematic review and meta-analysis.

Marra F, Lo E, Kalashnikov V, Richardson K.

Open Forum Infect Dis. 2016 Sep 28;3(4):ofw205.

"RESULTS: Data were pooled from 40 eligible RCTs (20136 patients) and 19 observational studies (810939 patients). Biologics were associated with a greater risk of HZ [herpes zoster] than control (RCTs: OR = 1.71, 95% CI = 1.11-2.64; observational studies: OR = 1.58, 95% CI = 1.39-1.81). In RCTs, the OR of non-tumor necrosis factor (TNF) blockers was 2.19 (95% CI 1.20-4.02), but that of TNF blockers was not significantly different from control. Increased risks of HZ with nbDMARDs [nonbiological disease-modifying antirheumatic drugs] (OR = 1.21; 95% CI = 1.15-1.28) and corticosteroids (OR = 1.73; 95% CI = 1.57-1.89) were observed in observational studies, but few RCTs examined these comparisons.

CONCLUSIONS: Immunocompromised patients receiving biologics were associated with an increased risk of HZ. The risk is also increased with corticosteroids and nbDMARDs. These findings raise the issue of prophylaxis with zoster vaccine in patients initiating immunosuppressive therapy for autoimmune diseases."

Risk of infections using anti-TNF agents in rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis: a systematic review and meta-analysis.

Minozzi S, Bonovas S, Lytras T, Pecoraro V, González-Lorenzo M, Bastiampillai AJ, Gabrielli EM, Lonati AC, Moja L, Cinquini M, Marino V, Matucci A, Milano GM, Tocci G, Scarpa R, Goletti D, Cantini F.

Expert Opin Drug Saf. 2016 Dec;15(sup1):11-34.

"Our study encompassed data from 71 randomized controlled trials involving 22,760 participants (range of follow-up: 1-36 months) and seven open label extension studies with 2,236 participants (range of follow-up: 6-48 months). Quantitative synthesis of the available data found statistically significant increases in the occurrence of any infections (20%), serious infections (40%), and tuberculosis (250%) associated with anti-TNF drug use, while the data for opportunistic infections were scarce. The quality of synthesized evidence was judged as moderate. Further evidence from registries and long-term epidemiological studies are needed to better define the relationship between anti-TNF agents and infection complications."

Risk of malignancies using anti-TNF agents in rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis: a systematic review and meta-analysis.

Bonovas S, Minozzi S, Lytras T, González-Lorenzo M, Pecoraro V, Colombo S, Polloni I, Moja L, Cinquini M, Marino V, Goletti D, Matucci A, Tocci G, Milano GM, Scarpa R, Cantini F.

Expert Opin Drug Saf. 2016 Dec;15(sup1):35-54.

"Fifty-five RCTs with 20,631 patients met the eligibility criteria. Of these, 32 trials with 15,539 patients reported at least one case of cancer, for a total of 112 malignancies. The degree of

variability between studies was consistent with what would be expected to occur by chance alone. There was no evidence of an association between anti-TNF agents and cancer risk (fixed-effects model (OR: 1.31, 95% CI: 0.89, 1.95); a random-effects model (OR: 1.16, 95% CI: 0.75, 1.81)). We found evidence of selective outcome reporting or publication bias suggesting that the pooled effect estimate for cancer may have been overestimated. The evidence is imprecise, and the risk of bias was high or unclear across primary studies."

Impact of body weight on the achievement of minimal disease activity in patients with rheumatic diseases: a systematic review and meta-analysis.

Lupoli R, Pizzicato P, Scalera A, Ambrosino P, Amato M, Peluso R, Di Minno MN.

Arthritis Res Ther. 2016 Dec 13;18(1):297.

"RESULTS: We included 17 studies (10 on RA [rheumatoid arthritis] and 7 on PsA [psoriatic arthritis]) comprising a total of 6693 patients (1562 with PsA and 5131 with RA) in the analysis. The MDA [minimal disease activity] achievement rate was significantly lower in obese patients than in normal-weight subjects (OR 0.447, 95% CI 0.346-0.577, p < 0.001, I 2 = 62.6%, p < 0.001). Similarly, overweight patients showed a significantly lower prevalence of MDA achievement than normal-weight subjects (OR 0.867, 95% CI 0.757-0.994, p = 0.041, I 2 = 64%, p = 0.007). Interestingly, the effect of obesity on MDA was confirmed when we separately analyzed data on patients with RA and patients with PsA. In contrast, when we evaluated the effect of overweight, our results were confirmed for PsA but not for RA. A meta-regression analysis showed that follow-up duration, age, male sex, and treatment duration are covariates significantly affecting the effect of obesity/overweight on MDA achievement.

CONCLUSIONS: The results of our meta-analysis suggest that obesity and overweight reduce the chances to achieve MDA in patients with rheumatic diseases receiving treatment with traditional or biologic disease-modifying antirheumatic drugs."

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Acne & rosacea

None found this month.

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Skin cancers & sun protection

Teledermatology for the diagnosis and management of skin cancer: A systematic review.

Finnane A, Dallest K, Janda M, Soyer HP.

JAMA Dermatol. 2016 Dec 7. doi: 10.1001/jamadermatol.2016.4361. [Epub ahead of print]

"FINDINGS: Twenty-one studies were reviewed. The diagnostic accuracy (defined as agreement with histopathology for excised lesions or clinical diagnosis for nonexcised lesions) of FTF dermatology consultation remains higher (67%-85% agreement with reference standard, Cohen κ, 0.90) when compared with teledermatology (51%-85% agreement with reference standard, κ, 0.41-0.63), for the diagnosis of skin cancer. However, some studies do report high accuracy of teledermatology diagnoses. Most studies of diagnostic accuracy and concordance had significant methodological limitations. Studies of health service outcomes found teledermatology reduced waiting times and could result in earlier assessment and treatment. Patients reported high satisfaction and were willing to pay out of pocket for access to such services.

CONCLUSIONS AND RELEVANCE: Robust implementation studies of teledermatology are needed, paying careful attention to reducing risk of bias when assessing diagnostic accuracy. Teledermatology services consistently reduced waiting times to assessment and diagnosis, and patient satisfaction was high."

Clinical response rates from interleukin-2 therapy for metastatic melanoma over 30 years' experience: A meta-analysis of 3312 patients.

Bright R, Coventry BJ, Eardley-Harris N, Briggs N.

J Immunother. 2017 Jan;40(1):21-30.

"In total, 34 studies met inclusion criteria, with 41 separate treatment arms. For all IL-2 [interleukin-2] treatment modalities collectively, the CR [clinical regression-complete responses] rate was 4.0% [95% confidence interval (CI), 2.8-5.3], PR [partial responses] 12.5% (95% CI, 10.1-15.0), and OR 19.7% (95% CI, 15.9-23.5). CR pre-1994 was 2.7% versus 6.1% post-1994. High and intermediate-IL-2 dosage showed no CR difference, while low-dose IL-2 showed a nonstatistical trend toward an increased CR rate. The highest CR rate resulted from IL-2 combined with vaccine at 5.0%. The meta-analysis showed that IL-2 immunotherapy for advanced metastatic melanoma delivered a CR rate of 4% (range, 0-23%) across nearly 30 years of clinical studies, with gradual improvement over time. The significance is that, contrary to popular belief, the data demonstrated that CR rates were similar for intermediate versus high-IL-2 dosing."

A systematic review on the role of imiquimod in lentigo maligna and lentigo maligna melanoma: need for standardization of treatment schedule and outcome measures.

Tio D, van der Woude J, Prinsen CA, Jansma EP, Hoekzema R, van Montfrans C.

J Eur Acad Dermatol Venereol. 2016 Dec 17. doi: 10.1111/jdv.14085. [Epub ahead of print]

"RESULTS: Twenty-six case reports, 11 retrospective studies, 3 prospective studies and 1 randomized controlled trial were included. One case report of poor quality was excluded. Complete clinical clearance was seen in 369 of 471 patients (78.3%). Histological clearance was present in 285 of 370 (77%) patients. LMM [lentigo maligna melanoma] was diagnosed in 9 (1.8%) patients 3.9 months (range 0-11 months) post treatment. Univariate multinominal

logistic regression showed that 6-7 applications/week had a 6.47 greater odds (p=0.017) of resulting in complete clinical clearance compared to 1-4 applications/week. An intensity of 6-7 applications/week showed a 8.85 greater odds (p=0.003) of resulting in histological clearance compared to 1-4 applications. Applying imiquimod >60 times during a treatment period of 12 weeks (range 4-36) showed a 7.75 greater odds (p=0.001) of resulting in histological clearance compared to <60 total applications.

CONCLUSIONS: A treatment schedule using imiquimod 6-7 applications per week, with at least 60 applications shows the greatest odds of complete clinical and histological clearance of LM [lentigo maligna]. Imiquimod is an option for patients unfit for not willing to undergo surgery or radiotherapy. Nine cases of LM progressed to LMM shortly after treatment. Our hypothesis is that these LMM may have been present before starting imiquimod."

Coffee consumption and risk of nonmelanoma skin cancer: a dose-response meta-analysis.

Vaseghi G, Haghjoo-Javanmard S, Naderi J, Eshraghi A, Mahdavi M, Mansourian M.

Eur J Cancer Prev. 2016 Nov 29. [Epub ahead of print]

"We separately estimated the relative risk of the three conditions, for exposure to different doses of coffee consumption, kind of study design, and analysis restricted to the basal cell carcinoma type. The summary relative risks for nonmelanoma skin cancer were 0.96 [95% confidence interval (CI): 0.92-0.99] for one cup of coffee, 0.92 (95% CI: 0.88-0.97) for one to two cups of coffee, 0.89 (95% CI: 0.86-0.93) for two to three cups of coffee, and 0.81 (95% CI: 0.77-0.85) for more than three cups of coffee per day, respectively. This meta-analysis suggested that caffeinated coffee might have chemopreventive effects against basal cell carcinoma dose dependently. However, other prospective studies are warranted to confirm these effects."

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Infections of the skin

Efficacy and safety of nucleoside antiviral drugs for treatment of recurrent herpes labialis: A systematic review and meta-analysis.

Chen F, Xu H, Liu J, Cui Y, Luo X, Zhou Y, Chen Q, Jiang L.

J Oral Pathol Med. 2016 Dec 9. doi: 10.1111/jop.12534. [Epub ahead of print]

"RESULTS: Our analysis included 16 publications reporting 25 randomized controlled trials (8453 patients). Nucleoside antiviral drugs decreased the time-to-healing of all lesions (mean difference: -0.74 days; 95% confidence interval: -0.86, -0.62), especially classic lesions (mean difference: -1.09 days; 95% confidence interval: -1.27, -0.92). They also reduced the time-to-resolution of pain (mean difference: -0.38 days; 95% confidence interval: -0.58, -0.18) and increased the percentage of aborted lesions (rate ratio: 1.15; 95% confidence interval: 1.07, 1.23). Valaciclovir more effectively reduced the time-to-healing of all lesions and the time-to-

resolution of pain than did aciclovir. Both nucleoside antiviral drugs increased the percentage of aborted lesions, whereas penciclovir and famciclovir did not.

CONCLUSIONS: Nucleoside antiviral drugs are safe and beneficial for the treatment of recurrent herpes labialis; both systemic and topical formulations are recommended. Valaciclovir is more effective than aciclovir, especially in reducing the time-to-healing of lesions."

[Use of intracutaneous or subcutaneous botulinum toxin for postherpetic neuralgia].

Halb L, Amann BJ, Bornemann-Cimenti H.

Nervenarzt. 2016 Dec 6. [Epub ahead of print] German.

"The results in the currently available literature show that BoNT [botulinum neurotoxin] is an effective therapeutic option for postherpetic neuralgia. In all studies, a significant effect on the pain and also on relevant patient-oriented secondary variables, such as the quality of life and especially the quality of sleep was shown. The only reported side effect was pain during administration."

The treatment of scabies.

Dressler C, Rosumeck S, Sunderkötter C, Werner RN, Nast A.

Dtsch Arztebl Int. 2016 Nov 14;113(45):757-762. doi: 10.3238/arztebl.2016.0757.

"RESULTS: A literature search yielded 596 initial hits; after screening in accordance with the defined inclusion and exclusion criteria, 16 studies were selected for this review. Among topical treatments for scabies, permethrin was equally effective or more effective than crotamiton or benzyl benzoate. In a comparison of topical versus systemic treatment, topical permethrin and systemic ivermectin did not differ substantially in efficacy (7 comparative studies revealed no difference; one revealed a difference in favor of permethrin). Comparative trials of topical benzyl benzoate versus systemic ivermectin yielded inconsistent findings. Single and double administrations of ivermectin were similarly effective. In trials involving entire populations with a high prevalence of scabies, systemic ivermectin was found to be superior to topical permethrin.

CONCLUSION: There are hardly any differences in efficacy between the available treatments for scabies. Single administrations of permethrin 5%, crotamiton 10%, and systemic ivermectin are all comparably effective. There are differences in the frequen[c]y and ease of application as well as when eradicating scabies in populations with a high prevalence."

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Drug & treatment reactions/safety

Topical interventions to prevent acute radiation dermatitis in head and neck cancer patients: a systematic review.

Ferreira EB, Vasques CI, Gadia R, Chan RJ, Guerra EN, Mezzomo LA, De Luca Canto G, Dos Reis PE.

Support Care Cancer. 2016 Dec 12. [Epub ahead of print]

"RESULTS: Thirteen randomized clinical trials were included in this review. The trials were published in Chinese, English, or French, from 1980 to 2015. Pharmacological interventions used in the trials were trolamine, aloe vera, allantoin, Lianbai liquid, sucralfate, Na-sucrose octasulfate, olive oil, hialuronic acid, and dexpanthenol. Non-pharmacological topical controls were usual care/institution routine, aqueous cream, mild soap, water thermal gel, placebo, and no intervention.

CONCLUSIONS: There was no strong evidence that indicates differences between topical pharmacological interventions or non-pharmacological topical controls in the prevention of acute radiation dermatitis among patients with head and neck cancer undergoing radiotherapy."

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Vitiligo & Pigmentary Disorders

Laser treatments for postinflammatory hyperpigmentation: A systematic review.

Agbai O, Hamzavi I, Jagdeo J.

JAMA Dermatol. 2016 Dec 14. doi: 10.1001/jamadermatol.2016.4399. [Epub ahead of print]

"FINDINGS: Of 1295 results, 20 unique studies with 224 patients met the inclusion criteria. These studies included 1 randomized clinical observer-blinded study (6 patients), 4 nonrandomized clinical trials (133 patients), 1 cohort study (34 patients), 7 case series (44 patients), and 7 case reports (7 patients). Multiple lasers were studied; however, most of the studies were not methodologically rigorous. Some studies showed no improvement or worsening of PIH [postinflammatory hyperpigmentation] after laser treatment. The most extensively studied device was the Q-switched Nd:YAG laser, which has shown promising results based on multiple outcome measures as listed above.

CONCLUSIONS AND RELEVANCE: Some lasers may be beneficial in the treatment of PIH. The evidence suggests that additional studies would be required to determine the benefit of laser treatment of PIH."

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Hair & nail disorders

None found this month.

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Chronic wounds & ulcers

Reconstructive surgery for treating pressure ulcers.

Wong JK, Amin K, Dumville JC.

Cochrane Database Syst Rev. 2016 Dec 6;12:CD012032. [Epub ahead of print]

"MAIN RESULTS: We did not identify any studies that met the review eligibility criteria nor any registered studies investigating the role of reconstructive surgery in the management of pressure ulcers.

AUTHORS' CONCLUSIONS: Currently there is no randomised evidence that supports or refutes the role of reconstructive surgery in pressure ulcer management. This is a priority area and there is a need to explore this intervention with more rigorous and robust research."

Protease-modulating matrix treatments for healing venous leg ulcers.

Westby MJ, Norman G, Dumville JC, Stubbs N, Cullum N.

Cochrane Database Syst Rev. 2016 Dec 15;12:CD011918. [Epub ahead of print]

"AUTHORS' CONCLUSIONS: The evidence is generally of low certainty, particularly because of risk of bias and imprecision of effects. Within these limitations, we are unclear whether PMM [protease-modulating matrix] dressing regimens influence venous ulcer healing relative to dressing regimens without PMM activity. It is also unclear whether there is a difference in rates of adverse events between PMM and non-PMM treatments. It is uncertain whether either resource use (products and staff time) or total costs associated with PMM dressing regimens are different from those for non-PMM dressing regimens. More research is needed to clarify the impact of PMM treatments on venous ulcer healing."

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Other disorders affecting the skin

Critical review of the role of intravenous immunoglobulins in idiopathic inflammatory myopathies.

Anh-Tu Hoa S, Hudson M.

Semin Arthritis Rheum. 2016 Jul 29. pii: S0049-0172(16)30145-7. doi:

10.1016/j.semarthrit.2016.07.014. [Epub ahead of print]

"RESULTS: The efficacy of IVIg [intravenous immunoglobulins] in IIM [idiopathic inflammatory myopathies] is supported by 3 randomized controlled trials, involving dermatomyositis and polymyositis subjects, in refractory, relapsed, or steroid-dependent disease, as well as part of first-line therapy in elderly dermatomyositis subjects. Other indications for IVIg are supported by uncontrolled evidence only. Limitations of studies include open, uncontrolled or retrospective study designs, small and selected samples, short-term follow-up and ad hoc outcome measures. Despite the limited evidence, there is strong biological plausibility for the role of IVIg in IIM.

CONCLUSION: Robust, controlled evidence to support the use of IVIg using validated outcome measures is urgently required to guide therapeutic decision-making and maximize outcomes in IIM."

The effect of intravenous immunoglobulin combined with corticosteroid on the progression of Stevens-Johnson syndrome and toxic epidermal necrolysis: A meta-analysis.

Ye LP, Zhang C, Zhu QX.

PLoS One. 2016 Nov 30;11(11):e0167120. doi: 10.1371/journal.pone.0167120.

"RESULTS: A total of 26 studies were selected from public available databases. The combination of IVIG [intravenous immunoglobulin] and corticosteroid markedly reduced the recovery time (by 1.63 days, 95% CI: 0.83-2.43, P < 0.001), compared with solo corticosteroid group. The favorable effects were greater in Asian (2.19, 95% CI: 1.41-2.97, P < 0.001), TEN (2.56, 95% CI: 0.35-4.77, P = 0.023) and high-dose IVIG treated individuals (1.78, 95% CI: 0.42-3.14, P = 0.010). The hospitalization length reduced by 3.19 days (95% CI: 0.08-6.30, P = 0.045), though the outcome was proven to be unstable. We found heterogeneities, which sources were probably regional factors. Besides, IVIG was inclined to decrease SJS/TEN [Stevens-Johnson syndrome/toxic epidermal necrolysis] mortality (SMR: 0.84, 95% CI: 0.66-1.08, P = 0.178). This impact was possibly more profound when patients were treated with high dose IVIG (SMR: 0.74, 95% CI: 0.50-1.08, P = 0.116), or when patients were diagnosed as TEN (SMR: 0.68, 95% CI: 0.45-1.01, P = 0.058).

CONCLUSIONS: Our current meta-analysis suggests that IVIG combined with corticosteroid could reduce recovery time for SJS and TEN. This effect is greater among Asian patients. Whereas, its impact on reducing mortality is not significant."

Treatment of primary hyperhidrosis with oral anticholinergic medications: a systematic review.

Cruddas L, Baker DM.

J Eur Acad Dermatol Venereol. 2016 Dec 15. doi: 10.1111/jdv.14081. [Epub ahead of print]

"RESULTS: Twenty-three articles relevant to the inclusion criteria were analysed. Oxybutynin

therapy improved symptoms in an average of 76.2% (range 60-97%) patients and improved QOL in 75.6% (range 57.6-100%) of patients. Methantheline bromide therapy was associated with a 41% reduction in axillary sweating, 16.4% reduction in palmar sweating, 25% decrease in HDSS score and 40.9% increase in DLQI score. Outcome measures of glycopyrrolate therapy were too variable to collate. Dry mouth was reported in 73.4% (range 43.3-100%) of participants taking oxybutynin 10 mg/d, 38.6% (range 27.8-63.2%) of patients taking glycopyrrolate and 68.8% of patients taking methantheline bromide. Nine studies reported that patients stopped therapy due to adverse events. In eight of these studies a mean of 10.9% of total participants ceased treatment due to dry mouth.

CONCLUSION: Evidence of oral anticholinergic therapy for hyperhidrosis is limited. However, its use is associated with improvement in quality of life and clinical symptoms but at the cost of considerable adverse events."

Efficacy of low level laser therapy in the treatment of burning mouth syndrome: A systematic review.

Al-Maweri SA, Javed F, Kalakonda B, AlAizari NA, Al-Soneidar W, Al-Akwa A.

Photodiagnosis Photodyn Ther. 2016 Dec 2. pii: S1572-1000(16)30253-8. doi: 10.1016/j.pdpdt.2016.11.017. [Epub ahead of print]

"RESULTS: Ten clinical studies fulfilled the eligibility criteria, five of which were randomized clinical trials. In these studies, the laser wavelengths, power output and duration of irradiation ranged between 630- 980nm, 20-300mW, 10 seconds-15minutes, respectively. Most of studies reported laser to be an effective therapy strategy for management of BMS [burning mouth syndrome].

CONCLUSION: Majority of the studies showed that laser therapy seemed to be effective in reducing pain in BMS patients. However, due to the varied methodologies and substantial variations in laser parameters among these studies, more clinical trials are required to ascertain the efficacy of laser for treating BMS."

Crohn's disease should be considered in children with inflammatory oral lesions.

Skrzat A, Olczak-Kowalczyk D, Szybka AT.

Acta Paediatr. 2016 Nov 29. doi: 10.1111/apa.13686. [Epub ahead of print]

"This systematic review presents the oral manifestations of paediatric Crohn's disease. Our review of 28 papers published from 2000 to 2015 showed that the prevalence of oral manifestations was 10 to 80%. Specific symptoms included mucosal tags, swelling of the lips, cheeks and gingiva and cobblestoning mucosa. Non-specific symptoms included aphthous-like ulcers, angular cheilitis, lip fissuring and gingivitis.

CONCLUSION: The oral manifestations of Crohn's disease might precede intestinal inflammation or coincide with it. Crohn's disease should be considered in children with

multiple oral manifestations and paediatric dentists and gastroenterologists should be involved in their co-ordinated evaluation and follow up."

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Skin conditions in general

Foot conditions among homeless persons: A systematic review.

To MJ, Brothers TD, Van Zoost C.

PLoS One. 2016 Dec 9;11(12):e0167463. doi: 10.1371/journal.pone.0167463.

"RESULTS: Of 333 articles screened, 17 articles met criteria and were included in the study. Prevalence of any foot problem ranged from 9% to 65% across study populations. Common foot-related concerns were corns and calluses, nail pathologies, and infections. Foot pathologies related to chronic diseases such as diabetes were identified. Compared to housed individuals across studies, homeless individuals were more likely to have foot problems including tinea pedis, foot pain, functional limitations with walking, and improperly-fitting shoes.

DISCUSSION: Foot conditions were highly prevalent among homeless individuals with up to two thirds reporting a foot health concern, approximately one quarter of individuals visiting a health professional, and one fifth of individuals requiring further follow-up due to the severity of their condition. Homeless individuals often had inadequate foot hygiene practices and improperly-fitting shoes. These findings have service provision and public health implications, highlighting the need for evidence-based interventions to improve foot health in this population. An effective interventional approach could include optimization of foot hygiene and footwear, provision of comprehensive medical treatment, and addressing social factors that lead to increased risk of foot problems. Targeted efforts to screen for and treat foot problems could result in improved health and social outcomes for homeless individuals."

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Skin surgery

Energy-based facial rejuvenation: Advances in diagnosis and treatment.

Britt CJ, Marcus B.

JAMA Facial Plast Surg. 2016 Dec 1. doi: 10.1001/jamafacial.2016.1435. [Epub ahead of print]

"FINDINGS: Three broad categories of technology are leading non-energy-based rejuvenation technology: lasers, light therapy, and non-laser-based thermal tightening devices. Laser light therapy has continued to diversify with the use of ablative and nonablative resurfacing technologies, fractionated lasers, and their combined use. Light therapy has developed for use in combination with other technologies or stand alone. Finally, thermally based nonlaser

skin-tightening devices, such as radiofrequency (RF) and intense focused ultrasonography (IFUS), are evolving technologies that have changed rapidly over the past 5 years.

CONCLUSIONS AND RELEVANCE: Improvements in safety and efficacy for energy-based treatment have expanded the patient base considering these therapies viable options. With a wide variety of options, the modern facial plastic surgeon can have a frank discussion with the patient regarding nonsurgical techniques that were never before available. Many of these patients can now derive benefit from treatments requiring significantly less downtime than before while the clinician can augment the treatment to maximize benefit to fit the patient's time schedule."

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Service delivery & management

Teledermatology for the diagnosis and management of skin cancer: A systematic review.

Finnane A, Dallest K, Janda M, Soyer HP.

JAMA Dermatol. 2016 Dec 7. doi: 10.1001/jamadermatol.2016.4361. [Epub ahead of print]

See above under Skin cancers & sun protection

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Prescribing and safety alerts

We acknowledge the NICE Medicines Awareness Service and MHRA Drug Safety Update as sources in compiling this section.

Otezla (apremilast): Advice regarding suicidal ideation and behaviour (PDF)

A letter to healthcare professionals from Celgene in agreement with the European Medicines Agency and the Medicines & Healthcare Products Regulatory Agency indicates the following:

         "Suicidal ideation and behaviour have been reported from clinical trials and postmarketing experience (with or without a history of depression) with a frequency of uncommon (≥1/1,000 to ≤1/100), while cases of completed suicide were reported postmarketing in patients taking apremilast.

         Carefully assess the balance of benefits and risks of treatment with apremilast for patients with a history of psychiatric symptoms or patients taking medicines which are likely to cause psychiatric symptoms.

         If patients suffer from new or worsening psychiatric symptoms, or if suicidal ideation or suicidal behavior is identified, it is recommended to discontinue treatment with apremilast.

         Instruct patients and caregivers to notify the prescriber of any changes in behaviour or mood or of any signs of suicidal ideation."

Revised SPC: Dovobet (calcipotriol and betamethasone) gel

The Summary of Product Characteristics (SPC) for Dovobet gel (calcipotriol and betamethasone) has had "hair colour changes" added as a potential adverse effect of treatment of unknown frequency.

Revised SPC: Mirvaso (brimonidine) 3mg/g gel

The Summary of Product Characteristics (SPC) for Mirvaso (brimonidine) 3mg/g Gel has been updated to include pallor at the application site as an adverse effect.

Revised SPC: Soolantra (ivermectin) 10mg/g Cream

The Summary of Product Characteristics (SPC) for Soolantra (ivermectin) 10mg/g Cream has had erythema added to the SPC as an adverse event with unknown frequency.

Revised SPC: Bosulif (bosutinib)

The Summary of Product Characteristics (SPC) for Bosulif (bosutinib as monohydrate) 100mg and 500mg tablets has been updated to include Steven-Johnson syndrome, toxic epidermal necrolysis and tumour lysis syndrome as undesirable effects associated with bosutinib.

"Bosulif is indicated for the treatment of adult patients with chronic phase (CP), accelerated phase (AP), and blast phase (BP) Philadelphia chromosome positive chronic myelogenous leukaemia (Ph+ CML) previously treated with one or more tyrosine kinase inhibitor(s) and for whom imatinib, nilotinib and dasatinib are not considered appropriate treatment options."

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CEBD publications & news

A programme of research to set priorities and reduce uncertainties for the prevention and treatment of skin disease.

Thomas KS, Batchelor JM, Bath-Hextall F, Chalmers JR, Clarke T, Crowe S, et al.

Programme Grants Appl Res 2016;4(18)

This is the full report of the NIHR-funded SPRUSD Programme Grant which addressed eczema, vitiligo, squamous cell skin cancer and pyoderma gangrenosum and aimed to set priorities and reduce uncertainties for the treatment and prevention of these diseases.

Surgery versus 5% imiquimod for nodular and superficial basal cell carcinoma: 5-year results of the SINS randomized controlled trial.

Williams HC, Bath-Hextall F, Ozolins M, Armstrong SJ, Colver GB, Perkins W, Miller PS; Surgery Versus Imiquimod for Nodular and Superficial Basal Cell Carcinoma (SINS) Study Group..

J Invest Dermatol. 2016 Nov 23. pii: S0022-202X(16)32538-6. doi: 10.1016/j.jid.2016.10.019. [Epub ahead of print]

"Five-year success was defined as 3-year success plus absence of recurrences identified through hospital, histopathology, and general practitioner records. Of 501 participants randomized, 401 contributed to the modified intention-to-treat analyses at year 3 (primary outcome), 383 (96%) of whom had data at year 5. Five-year success rates for imiquimod were 82.5% (170/206) compared with 97.7% (173/177) for surgery (relative risk of imiquimod success = 0.84, 95% confidence interval = 0.77-0.91, P < 0.001). These were comparable to year 3 success rates of 83.6% (178/213) and 98.4% (185/188) for imiquimod and surgery, respectively. Most imiquimod treatment failures occurred in year 1. Although surgery is clearly superior to imiquimod, this study shows sustained benefit for lesions that respond early to topical imiquimod."

Development of a critical appraisal tool to assess the quality of cross-sectional studies (AXIS).

Downes MJ, Brennan ML, Williams HC, Dean RS.

BMJ Open. 2016 Dec 8;6(12):e011458. doi: 10.1136/bmjopen-2016-011458.

"RESULTS: An initial list of 39 components was identified through examination of existing resources. An international Delphi panel of 18 medical and veterinary experts was established. After 3 rounds of the Delphi process, the Appraisal tool for Cross-Sectional Studies (AXIS tool) was developed by consensus and consisted of 20 components. A detailed explanatory document was also developed with the tool, giving expanded explanation of each question and providing simple interpretations and examples of the epidemiological concepts being examined in each question to aid non-expert users.

CONCLUSIONS: CA [critical appraisal] of the literature is a vital step in evidence synthesis and therefore evidence-based decision-making in a number of different disciplines. The AXIS tool is therefore unique and was developed in a way that it can be used across disciplines to aid the inclusion of CSSs [cross-sectional studies] in systematic reviews, guidelines and clinical decision-making."

Cellulitis Priority Setting Partnership Survey 2 – Do you treat or have had cellulitis?

Help set the research agenda for cellulitis in the UK and select your top ten research priorities in our second survey for the James Lind Alliance (JLA) Cellulitis Priority Setting Partnership (PSP).

Previously, we collected questions about the prevention and management of cellulitis from people with cellulitis, their families and the people who care for them and treat them. We then checked to ensure the questions submitted had not already been answered by research.

We are now asking you to help prioritise the questions by voting for your favourite topics.

Have your say by following the link here—it should only take 5 minutes:

https://www.surveymonkey.co.uk/r/Cellulitis_Survey2

Evidence Based Update Meeting - Eczema and Contact Dermatitis

Booking is now open for our 2017 Evidence Based Update meeting, which is on Eczema and Contact Dermatitis, and will be held on Wednesday 17 May 2017 at the East Midlands Conference Centre in Nottingham. More details and the programme can be found on the event webpage.

Please follow this link for the online booking form.

Opportunity as Editorial Trainee for the British Journal of Dermatology

Another exciting opportunity has arisen for a young dermatologist to join the British Journal of Dermatology (BJD) as an editorial trainee, now that the first trainee is nearing completion of their two year post. The role has been refined with feedback from the current trainees, to maximise its educational and career value. This is a joint initiative between the British Journal of Dermatology and the Centre of Evidence Based Dermatology. Please see here for more details.

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Other key publications that have caught our eye

Dermatological content of UK undergraduate curricula: where are we now?

Yaakub A, Cohen SN, Singh M, Goulding JM; Teachers of Undergraduate Dermatology sub-committee of the British Association of Dermatologists..

Br J Dermatol. 2016 Nov 26. doi: 10.1111/bjd.15206. [Epub ahead of print]

"Questionnaires were sent to dermatology undergraduate teaching leads, followed by periodic reminders to non-respondents. Responses were obtained from 30 out of 35 medical schools (86%). Dermatology teaching was mandatory for all students in 24 (75%). The duration of the dermatology clinical attachment ranged from 1 to 8 weeks (median 1 week). Longer attachments were integrated with other specialities. The minimum number of clinics that students were required to attend ranged from 0 to 10, (mean 3.5, median 3). There were some notable omissions in basic learning outcomes in some courses: for example, two failed to specify examination of the skin, five lacked acne in their learning outcomes and some failed to cover common types of skin cancer. Specific summative assessment of dermatology – usually by multiple choice questions or objective structured clinical examination – only occurred in 17 medical schools (57%), though skin-related cases reportedly could feature in

the final examination in 22 (73%).

Overall, the results were similar to those of 2009. Students at a quarter of medical schools are able to graduate with no exposure to clinical dermatology learning. Summative assessment of the subject was similarly deficient in a significant proportion of schools. This variation exists as UK medical schools set their own curriculum and methods of assessment. From 2022, all medical students will be required to pass the UK medical licensing assessment 4. Assuming that dermatological problems will be included, the delivery of consistent learning opportunities across medical schools will be an important consideration for students."

Dermatologists must take an active role in the diagnosis of cellulitis.

Imadojemu S, Rosenbach M.

JAMA Dermatol. 2016 Nov 2. doi: 10.1001/jamadermatol.2016.4230. [Epub ahead of print] No abstract available.

This editorial argues the case for the role of dermatologists in the diagnosis of cellulitis, given its high prevalence and frequent misdiagnosis. It states: "studies suggest that dermatology consultation for suspected cellulitis can improve the quality of care delivered, leading to lower health care costs, fewer delays in diagnosis and appropriate treatment, and decreased adverse reactions and public health concerns associated with inappropriate antibiotic use".

Treatment of moderate-to-severe atopic eczema in adults within the UK: results of a national survey of dermatologists.

Taylor K, Swan DJ, Affleck A, Flohr C, Reynolds NJ; collaboration with UK TREND and the UK DCTN.

Br J Dermatol. 2016 Dec 11. doi: 10.1111/bjd.15235. [Epub ahead of print]

Note: The CEBD supported this study by preparing and distributing the survey to the UK Dermatology Clinical Trials Network (UK DCTN).

"RESULTS: 61 respondents from at least 35 centres reported on management of moderate-to-severe atopic eczema in adults, outwith the context of an acute flare. Phototherapy/PUVA was the most common therapeutic modality chosen as first-line (46%), and this was usually narrowband UVB. Systemic therapy was chosen as a first-line approach by 36% of dermatologists, with most using azathioprine (46%), followed by oral corticosteroids (43%), ciclosporin (37%) and methotrexate (25%). Methotrexate was the most common second-line treatment, chosen by 49% of respondents. The key factors that influenced decision-making on the use of phototherapy and systemic agents were: respondent's clinical experience, results of baseline tests (systemic agents), and knowledge of both efficacy and acute and chronic side-effect profiles. The most important evidence gaps identified were: the relative effectiveness of treatments, the alternatives to current approaches and the safety of long-term maintenance treatment. With regard to future trials, respondents suggested that

priority should be given to studies involving methotrexate.

CONCLUSIONS: While survey study designs have limitations, including the possibility of selection and recall bias, we found that phototherapy, in particular narrow-band UVB, was respondents' preferred first-line treatment for adults with recalcitrant moderate-to-severe atopic eczema, perhaps reflecting access to, and clinical experience of, this approach. Azathioprine is widely used as a longer-term maintenance treatment."

Registration of Cutaneous T-Cell Lymphoma (CTCL) in England (PDF)

This Short Report from the National Cancer Registration and Analysis Services aims "to explore the CTCL [cutaneous T-cell lymphoma] data available from the National Cancer Registration and Analysis Service (NCRAS) in order to estimate the number of cases diagnosed and to consider the CTCL disease distribution across the strategic clinical networks (SCNs) in England from 2009 to 2013."

"Key messages:

    the average annual number of registered CTCL cases in England is 332

    men have higher incidence of CTCL than women

    percentage of completed stage was low but appears to be improving."

Advances in the medical management of skin and soft tissue infections.

McClain SL, Bohan JG, Stevens DL.

BMJ. 2016 Dec 14;355:i6004. doi: 10.1136/bmj.i6004

"Skin and soft tissue infections are some of the most common infectious disease diagnoses in both inpatient and outpatient settings. With bacterial resistance to antimicrobials growing, decision making on empiric antibiotics is becoming increasingly difficult. Additionally, the most recent guidance from a professional society on the treatment of skin and soft tissue infections was published in 2014 by the Infectious Diseases Society of America and is now two years old. New antimicrobial agents have been developed and approved for the treatment of skin and soft tissue infections since then, and more are in the pipeline. This review summarizes the evidence on treatments that are new or in development and the potential repurposing of old antimicrobials. The clinical utility of these treatments is also discussed."

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Notes

The provision of a link to an item in this e-mail shall not be taken as an endorsement of any kind. Whilst reasonable efforts have been made to ensure the accuracy of the information in

this newsletter, we cannot guarantee its correctness or completeness.

Many more useful resources can be found on the CEBD Website. Do take a look!