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Issue 51 - 2018Making Education Easy

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Welcome to issue 51 of Dermatology Research Review.Research reporting lentigo maligna recurrence following neoadjuvant topical 5% imiquimod cream before conservatively staged excision begins this issue, followed by an analysis of RCT data to evaluate if aspirin or folate is associated with BCC risk. There is also interesting research looking at the relationship between premature greying of hair and metabolic syndrome. Other topics covered in this issue include atopic dermatitis, pyoderma gangrenosum, hidradenitis suppurativa, burning mouth syndrome and the efficacy of a natural sunscreen.

I hope you enjoy reading this issue, and I look forward to your questions and comments.

Kind Regards,

Clinical Associate Professor Saxon Smithsaxon.smith@researchreview.com.au

Rate of recurrence of lentigo maligna treated with off-label neoadjuvant topical imiquimod, 5%, cream prior to conservatively staged excisionAuthors: Donigan JM et al.

Summary: With the aim of investigating recurrence rates, these researchers retrospectively reviewed the medical records of 334 patients with 345 biopsy-confirmed lentigo maligna tumours who received topical 5% imiquimod cream 5 nights per week for 2–3 months prior to staged excision beginning with a 2mm margin; patients with an inadequate inflammatory response also received 0.1% tazarotene gel twice weekly. Over mean follow-up of 5.5 years, the recurrence rate was 3.9%, with recurrences occurring in a mean of 4.3 years.

Comment: Australia still has one of the highest rates of invasive melanoma in the world (currently second to New Zealand). There is early evidence suggesting that the rate of invasive melanoma might be stabilising (mainly in women) or perhaps starting to decline (in those under 40 years of age). However, there is corresponding evidence that the rate of melanoma in situ may be increasing at a greater rate. Lentigo maligna seems to peter out at the edges, blending into the background of overall sun damage and atypical melanocytic proliferation. Therefore, strategies around managing lentigo maligna are challenging. There have been trials in the use of 5% imiquimod cream as curative treatment. This is the first to see it used as neoadjuvant therapy. Both of these uses of 5% imiquimod cream are off-label. However, it is clear it could be advantageous in the right patient population.

Reference: JAMA Dermatol 2018;154:885–9Abstract

In this issue: > Lentigo maligna recurrence after topical imiquimod prior to staged excision

> BCC risk with aspirin/folic acid for preventing colorectal adenomata

> Associations of disease control with patient-reported atopic dermatitis burden

> Associations of atopic dermatitis with depression, anxiety and suicidal ideation

> Systemic treatments for pyoderma gangrenosum

> Surgical treatment of hidradenitis suppurativa

> Management of reticular oral lichen planus with burning mouth syndrome-like symptoms

> Associations of premature hair greying with metabolic risk factors

> C. myrrha oil vs. sunscreen for UV protection

BCC = basal cell carcinoma; QOL = quality of life;RCT = randomised controlled trial; SPF = sun protection factor;UV = ultraviolet.

Abbreviations used in this issue:

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Risk of basal cell carcinoma in a randomized clinical trial of aspirin and folic acid for the prevention of colorectal adenomasAuthors: Passarelli MN et al.

Summary: Patients with a previous adenoma (n=1121) received aspirin 81 or 325 mg/day for ~3 years and/or folic acid 1 mg/day for ~6 years for the prevention of colorectal adenomata in a randomised placebo-controlled clinical trial, and the incidence of BCC was investigated in this analysis. Among non-Hispanic white participants (n=958), 104 were diagnosed with a BCC over median follow-up of 13.5 years. The respective cumulative incidences of BCC associated with aspirin 81mg, aspirin 325mg and placebo use were 16%, 15% and 12%, with no statistically significant difference between aspirin and placebo use. There was a significantly higher risk of BCC risk associated with aspirin use in participants without prior skin cancer, but a lower risk among those with prior skin cancer (p≤0.03 for interactions). There was no evidence of an association between folic acid supplementation and BCC incidence.

Comment: Aspirin is an incredibly common medication used in a range of patients, but especially common in those over the age of 50 years. Furthermore, the incidence rate of nonmelanoma skin cancer increases in Australians over the age of 50 years. Therefore, understanding or dispelling any possible increased risk of BCC is important. This sizeable population study gives us reassurance that there is no association between aspirin use and increased risk of BCC. Furthermore, in dermatology, folate supplementation is common, especially when prescribing methotrexate. Therefore, it is reassuring that there appears to be no increase in BCC risk in this population as well.

Reference: Br J Dermatol 2018;179:337–44Abstract

Association of inadequately controlled disease and disease severity with patient-reported disease burden in adults with atopic dermatitisAuthors: Simpson EL et al.

Summary: The burden of atopic dermatitis according to patient reports was described for 1519 US adults with the condition in this cross-sectional study. Compared with mild atopic dermatitis (n=689), moderate or severe disease (n=830) was associated with more patient reported severe itching and pain, greater adverse effects on sleep, a greater prevalence of anxiety or depression (50.2% vs. 27.3%) and greater health-related QOL impairment. Within the moderate/severe atopic dermatitis group, inadequate versus adequate disease control was associated with more days per week with itchy skin (5.7 vs. 2.7), a higher proportion with itch lasting longer than half a day (22.8% vs. 2.9%), greater trouble sleeping, longer sleep latency (38.8 vs. 21.6 minutes), more frequent sleep disturbances (2.6 vs. 0.4 nights in the prior week) and a greater proportion using over-the-counter sleep medications (39% vs. 21%).

Comment: There is a new wave of research and interest in atopic dermatitis, which is likely due to the upsurge in research for potential pharmaceutical treatment options. As with many chronic diseases, it is not surprising to see that more severe disease is associated with poorer disease control. In this particular patient population it is critical to recognise the biopsychosocial impact that this will have. More severe itch and pain will directly lead to poorer quality of sleep. This in turn leads to wider impacts on all aspects of QOL, work/academic performance and image of self. It helps to show that there is an obvious need for more therapeutic options for this patient population.

Reference: JAMA Dermatol 2018;154:903–12Abstract

Association of atopic dermatitis with depression, anxiety, and suicidal ideation in children and adultsAuthors: Rønnstad ATM et al.Summary: This systematic review and meta-analysis included data on associations between atopic dermatitis and depression, anxiety and suicidal behaviour. Atopic dermatitis was found to be significantly associated with depression (pooled odds ratio 2.19 [95% CI 1.87–2.57]) and anxiety (2.19 [1.75–2.73]) in adults, depression in children (1.27 [1.12–1.45]), and suicidal ideation in adults and adolescents (4.32 [1.93–9.66]). The association of atopic dermatitis with completed suicide was assessed in only a few studies, but most showed a positive association.

Comment: As seen in the previous Simpson et al. article, there is significant impact on the QOL in patients who suffer moderate-to-severe atopic dermatitis. It is understandable that this will lead to higher rates of depression, anxiety and even suicide. This article by Rønnstad et al. illustrates this exact issue well. Therefore, it is key for physicians who treat adults with moderate-to-severe atopic dermatitis to have this front of mind when having a holistic approach to the management of these patients. The other important take-home message from this article is that there are also increased risks of depression and anxiety in children, and also an increased risk of suicidal ideation in adolescents. This highlights that effective management of children and adolescents is critical to help their mental health at their developing age of life.

Reference: J Am Acad Dermatol 2018;79:448–56Abstract

Effectiveness of systemic treatments for pyoderma gangrenosumAuthors: Partridge ACR et al.Summary: This was a systematic review of 26 retrospective cohort studies, three prospective cohort studies, seven case series, one case-control study, two open-label trials and two RCTs (n=704) evaluating systemic therapies for pyoderma gangrenosum; 32 studies investigated systemic corticosteroids, 21 cyclosporin, 16 biologic agents and 11 oral dapsone. One RCT reported prednisolone and cyclosporin were similar with complete healing rates of 15–20% at 6 weeks and 47% at 6 months. Another RCT reported that infliximab was associated with a higher 2-week response rate than placebo (46% vs. 6%), and a 6-week complete healing rate of 21%. Two uncontrolled trials showed that canakinumab and infliximab were associated with 4-month healing rates of 60% and 37%, respectively. The remaining studies, which were of poor quality and had small sample sizes, supported corticosteroid, cyclosporin and biologic agent use.

Comment: Pyoderma gangrenosum remains a curious disease process without a clear understanding of its pathophysiology. The pain and rapid evolution of this inflammatory ulcerating condition makes it an important condition to recognise and treat. However, as is often the case, when there is still a somewhat ‘black box’ in our understanding as why the condition occurs, there are a range of treatment options that can be used, but a typical no single answer for all patients. Furthermore, there have been concerns around expected treatment outcomes and potential side effects. Therefore, having a systemic review helps to give some clarity on the best options. Systemic corticosteroids and cyclosporin appear to be the first-line choices, with potential for compassionate supply for infliximab needing to be considered for these patients.

Reference: Br J Dermatol 2018;179:290–5Abstract

Selection of papers and comments are provided by Clinical Associate Professor Saxon Smith, who is the principal dermatologist at The Dermatology and Skin Cancer Centre in Gosford and St Leonards, NSW; a staff specialist at Royal North Shore Hospital, St Leonards, NSW; and a clinical associate professor at the University of Sydney, Australia. His current research areas include psoriasis, atopic dermatitis, hidradenitis suppurativa, skin cancer, medical education, and the medico-legal interface in dermatology. Associate Professor Smith has been a keynote speaker and invited speaker at many national and international conferences. He has over 40 peer-reviewed journal publications and over 45 published abstracts. Associate Professor Smith is a past President of the Australian Medical Association (NSW).

See approved Product Information before prescribing. Approved product information is available here.Abbreviations: PASI: Psoriasis Area and Severity Index. References: 1. Novartis Data on File. 2. Bissonnette R et al. J Eur Acad Dermatol Venereol 2018 Feb 14. doi: 10.1111/jdv.14878. Cosentyx is a registered trade mark of Novartis AG. Novartis Pharmaceuticals Australia Pty Limited. ABN 18 004 244 160. 54 Waterloo Road, Macquarie Park NSW 2113. Ph (02) 9805 3555. AU-6293. July 2018. NODE14051W/DRR.

PBS Information: Section 85 Authority Required for the treatment of severe chronic plaque psoriasis, active ankylosing spondylitis and severe psoriatic arthritis. Refer to PBS Schedule for full Authority information.

‘ I am so much more than my psoriasis’1

Cosentyx patient

Cosentyx improved psoriasis on average by 90% through 5 years. Mean improvement in mean absolute PASI from baseline to Year 5 was 90.1%.2

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Research Reviews are prepared with an independent commentary from relevant specialists. To become a reviewer please email geoff@researchreview.com.au.Research Review Australia Pty Ltd is an independent Australian publisher. Research Review receives funding from a variety of sources including Government depts., health product companies, insurers and other organisations with an interest in health. Journal content is created independently of sponsor companies with assistance from leading local specialists. Privacy Policy: Research Review will record your email details on a secure database and will not release them to anyone without your prior approval. Research Review and you have the right to inspect, update or delete your details at any time. Disclaimer: This publication is not intended as a replacement for regular medical education but to assist in the process. The reviews are a summarised interpretation of the published study and reflect the opinion of the writer rather than those of the research group or scientific journal. It is suggested readers review the full trial data before forming a final conclusion on its merits. Research Review publications are intended for Australian health professionals.

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Surgical treatment of hidradenitis suppurativaAuthors: Kofler L et al.

Summary: Survey responses regarding postoperative outcomes, cosmetic results and QOL were reported for 255 patients who had undergone wide local excision for hidradenitis suppurativa. Disease-specific restrictions on everyday life were reported by 95% of respondents. While 75% reported no postoperative adverse events, 38% did report postoperative pain requiring analgesia. Four out of every five respondents reported they were satisfied or very satisfied after surgery, and 85% would recommend surgery to others.

Comment: Hidradenitis suppurativa is an uncommon but also under-reported inflammatory condition. We are still evolving our understanding of the pathophysiology of hidradenitis suppurativa. Therefore, when we lack clarity on pathophysiology, it impairs our ability to best manage this painful, suppurating and odorous condition. There are some treatment guidelines in Europe, but these are under revision again. Similarly, there are treatment guidelines in evolution in America. However, all of them still include a role of surgery. The type and extent of possible surgery needs to be considered with the potential outcomes. Incision and drainage may provide immediate pressure relief, but the lesions frequently recur. Local excision or deroofing may provide a temporary solution for individual lesions. Wide excision is both more difficult to perform and has significant healing time afterwards as large flap repairs are required. However, it is critical to consider this in the context of the individual patient. This study helps to reassure physicians that patients tolerate surgery well and would recommend it to others affected with hidradenitis suppurativa.

Reference: J Eur Acad Dermatol Venereol 2018;32:1570–4Abstract

Management of reticular oral lichen planus patients with burning mouth syndrome-like oral symptomsAuthors: Adamo D et al.

Summary: Twenty-eight patients with symptomatic reticular oral lichen planus were treated with topical clonazepam for 2 months and benzodiazepine and antidepressant drugs for 6 months in this pilot study. After benzodiazepine and antidepressant drug treatment, significant decreases in median scores from baseline were seen for numerical rating scale (from 9.0 to 2.0 [p<0.001]), Total Pain Rating Index (from 10.5 to 3.0 [p<0.001]), and Hamilton rating scales for depression (from 15.0 to 6.0 [p<0.001]) and anxiety (from 13.0 to 5.5 [p<0.001]).

Comment: Oral lichen planus can be a condition that is both a challenge to manage and causes patients significant pain due to the burning pain it causes. It is an autoimmune inflammatory condition that when it affects the oral mucosa typically lasts for years. Therefore, effective management is key for these patients. However, there is a cohort of patients who do not respond well to standard therapies, including dexamethasone mouthwash and oral therapies. In this situation a shift in therapeutic focus to symptomatic control is important. This article provides an evidence-based therapeutic that may provide this symptomatic control.

Reference: J Dermatolog Treat 2018;29:623–9Abstract

Association between premature hair greying and metabolic risk factorsAuthors: Paik SH et al.Summary: This cross-sectional study of 1929 young healthy subjects explored associations between premature hair greying and metabolic risk factors; 704 of the participants were categorised as having premature hair greying. Participants with versus without premature hair greying had greater mean waist circumference (76.3 vs. 74.3cm [p<0.001]), mean systolic and diastolic blood pressure (111.7 vs. 109.2mm Hg [p<0.001] and 66.2 vs. 65.0mm Hg [p=0.003], respectively) and mean fasting blood glucose level (91.6 vs. 90.8 mg/dL [p=0.013]) and a lower mean serum high-density lipoprotein cholesterol level (65.4 vs. 68.1 mg/dL [p<0.001]). A multivariate logistic regression analysis revealed a significant association between ≥2 metabolic risk factors and premature hair greying (odds ratio 1.725 [p=0.036]).

Comment: Metabolic syndrome remains a key public health issue around the world with its association with obesity and cardiovascular disease. It was with interest I came across this article exploring the potential association with premature hair greying. There is evidence linking premature hair greying with obesity and heart disease. Therefore, it becomes less surprising to see this article’s results suggesting a direct relationship between premature hair greying and metabolic syndrome. Perhaps the premature greying reflects microvascular disease placing the follicle under stress or the physiological stress of metabolic syndrome leading to a premature aging effect for which the hair follicles might be the early calling card. Regardless of which is the chicken or the egg, it is interesting to consider this in patients who present with premature hair greying.

Reference: Acta Derm Venereol 2018;98:748–52Abstract

UV protection by natural products: C. myrrha oil versus sunscreenAuthors: Chakravarty N et al.Summary: These researchers grew UV-sensitive strains of Saccharomyces cerevisiae in petri dishes, and covered one half with aluminium foil and the other half with clear polyethylene food wrap. The halves covered with polyethylene wrap were then treated with either SPF-15 or SPF-30 sunscreen, Commiphora myrrha oil or a combination of C. myrrha oil and either sunscreen, and were exposed to sunlight. Colony death was then estimated visually. C. myrrha oil on its own was a less effective UV blocker than the synthetic sunscreens, but the combination of C. myrrha oil and SPF-15 sunblock was significantly more effective than SPF-15 sunblock alone.

Comment: Since the 1980s, public health campaigns have targeted the ‘slip, slop, slap’ messaging. In recent years the messaging has evolved to ‘slip, slop, slap, seek and slide’. However, sunscreen remains a key component to this Australian sun protection mantra. Worryingly with the advent of ‘social influencers’ with hundreds and thousands of followers, there is a new battleground on the erosion of this messaging with these populists providing nonevidence-based alternatives to traditional sunscreens. There are ‘home-made’ remedy alternatives and social blogs suggesting ‘potential’ negative impacts when using traditional sunscreens that are readily searchable on the internet. If we set aside the critical quality assurance issues of reliability, reproducibility and lack of adherence to Australian Standards for home-made sunscreens, there is a general lack of evidence of some of the ingredients used that these blogs recommend. This article does indicate that this particular natural ingredient may provide some additive SPF benefit when combined with a standard sunscreen product.

Reference: J Drugs Dermatol 2018;17:905–7Abstract