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Issue 56 - 2019Making Education Easy

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Welcome to issue 56 of Dermatology Research Review.This month’s issue begins with an economic evaluation comparing talimogene laherparepvec plus ipilimumab versus ipilimumab monotherapy for advanced unresectable melanoma, finding that the costs associated with the combination are likely to be in excess of what we are willing to pay for the benefit provided. I have also included a cost-effectiveness analysis of treatments for stage IA mycosis fungoides – the most cost-effective option was local radiation, followed by the phototherapies NV-UVB and PUVA, with the various topical treatments ranked lower. There is also an interesting systematic literature review reporting on the strategies trial authors may use to distort interpretation of their findings. This issue concludes with a Danish nationwide case-control study reporting increased risks of Merkel cell carcinoma and malignant adnexal skin tumours associated with hydrochlorothiazide use.

I hope the selected studies in this issue are relevant to your clinical practice and academically interesting. As always, you are invited to send any feedback you may have.

Kind Regards,

Dr Warren Weightman

warren.weightman@researchreview.com.au

Economic evaluation of talimogene laherparepvec plus ipilimumab combination therapy vs ipilimumab monotherapy in patients with advanced unresectable melanomaAuthors: Almutairi AR et al.

Summary: This group from the US conducted progression-free survival analyses in patients with advanced unresectable melanoma, and found that the cost of talimogene laherparepvec plus ipilimumab was $US494,983 compared with $US132,950 for ipilimumab monotherapy. They concluded that the cost associated with one additional progression-free quality-adjusted life-year, one additional progression-free life-year or for one additional patient to attain an objective response would be ~$US1.6 million.

Comment: Economic analyses of high-cost drugs to treat metastatic cancer are likely to be studied further after this trial. Talimogene laherparepvec is a genetically modified herpes simplex virus 1, and is an oncolytic immunotherapy for melanoma. It is used for intralesional treatment of cutaneous, subcutaneous and nodal lesions that cannot be surgically removed. When combined with ipilimumab the extra cost was prohibitive for a gain of only one additional progression-free year of life. The use of surrogate endpoints such as objective response rate is unwarranted when metastatic cancers including melanoma have a short median survival of 12–18 months, and the endpoint should be the effect on overall survival. In this trial, there was no difference in progression-free survival. There is a finite amount of money that can be used to treat metastatic melanoma, which should go towards drugs that increase long-term survival.

Reference: JAMA Dermatol 2019;155:22–8Abstract

Genetic, clinical, and environmental factors associated with persistent atopic dermatitis in childhoodAuthors: Thorsteinsdottir S et al.

Summary: This 13-year follow-up of the Copenhagen Prospective Study on Asthma in Childhood 2000 birth cohort investigated factors associated with persistent atopic dermatitis in childhood. In the study, 411 children born to mothers with asthma were followed until the age of 13 years. Atopic dermatitis was diagnosed using Hanifin and Rajka major and minor criteria, and severity was determined by the Scoring Atopic Dermatitis index. Atopic dermatitis was diagnosed in 186 of the children before 13 years of age. Of these, 24.1% had persistent atopic dermatitis at the age of 13 years, and 76.0% were in remission. Factors associated with persistent atopic dermatitis included known genetic atopic dermatitis risk variants, paternal asthma and atopic dermatitis, high social circumstances, diagnostic minor criteria (e.g. white dermographism, intolerance to wool, itching when sweating, tendency to skin infection, food intolerance or allergy) and atopic dermatitis severity at onset.

Comment: It is helpful to be able to predict which atopic dermatitis patients will have persistent disease. The strongest determinant was the genetic risk, which included the presence of filaggrin mutations, which aren’t measured routinely in Australia, so paternal asthma and atopic dermatitis were the most important genetic factors to assess. The main clinical factors were the presence of minor diagnostic features, which included Dennie-Morgan folds, anterior neck fold, white dermographism, intolerance to wool, itching when sweating, tendency to skin infection, food intolerance and food allergy. In a neonate it may be difficult to assess some of these minor features, so the family history may be a more important criterion.

Reference: JAMA Dermatol 2019;155:50–7Abstract

In this issue: > Economics of ipilimumab ±talimogene laherparepvec for advanced melanoma

> Factors associated with persistent paediatric atopic dermatitis

> Topical resiquimod dosing regimens for actinic keratoses

> Relative efficacies of systemic atopic dermatitis treatments

> Radiation and phototherapies are cost-effective for stage IA mycosis fungoides

> Generalised severe EBS induces T helper 17 response, and responds to apremilast

> Spin in reporting of studies of topical treatments of photoaged skin

> Dupilumab for generalised prurigo nodularis

> Laser treatments for congenital melanocytic naevi

> Hydrochlorothiazide increases Merkel cell carcinoma/malignant adnexal skin tumour risk

EBS = epidermolysis bullosa simplex; NB-UVB = narrow-band ultraviolet B;PUVA = psoralen plus ultraviolet A.

Abbreviations used in this issue:

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Topical resiquimod dosing regimens in patients with multiple actinic keratosesAuthors: Stockfleth E et al.Summary: Patients with actinic keratosis lesions were randomised to receive topical 0.03% resiquimod gel once daily three times per week for 4 weeks, seven times within 2 weeks or five times for 1 week followed by no treatment for 8 weeks and then one repetition of the treatment cycle. In two additional arms, patients applied either 0.01% or 0.03% resiquimod gel three times per week until the biological endpoint of skin erosion or for a maximum of 8 weeks. A total of 217 participants were randomised. Complete clinical clearance rates of 56–85% were seen across the trial arms, with the highest rate in participants treated with 0.03% resiquimod once daily seven times within 2 weeks. The 0.03% strength was more effective than 0.01%. For the first three arms, comparing 0.03% resiquimod gel once daily at different dosing frequencies, the clearance rates were comparable and superior to placebo. The overall incidence of treatment-related adverse reactions was 59%.

Comment: This trial was designed to determine the optimum concentration and dosing schedule of resiquimod gel to achieve complete clearance of actinic keratoses with an acceptable safety profile. Previous trials with concentrations ranging from 0.01% to 0.1% achieved complete clearance rates from 77.1% to 90.3%. These clearance rates are at least as good or better than achieved with other field treatments. In the fourth and fifth arms of this trial, patients continued three times a week up until the biological end point of erosions. The mean number of applications in these arms was 22.2 or just over 7 weeks. Arm 5, which used the 0.03% concentration, achieved the highest clinical and histological clearance of 74% of all the arms. Although this study confirms that resiquimod is an effective field treatment, the most interesting finding is that treating to a biologic endpoint gave the best result, rather than a defined number of weeks. This may be able to be applied to other field treatments, particularly topical 5-fluorouracil, and supports the clinical impression that the greater the response with field treatments, the greater the benefit. This reinforces the need to review patients during their treatments and to stop when erosions begin to occur.

Reference: Br J Dermatol 2019;180:297–305Abstract

Relative efficacy of systemic treatments for atopic dermatitisAuthors: Seger EW et al.Summary: This systematic literature review included 41 randomised controlled trials investigating systemic treatments for atopic dermatitis in adults and children. Both dupilumab and cyclosporin were found to confer consistent improvements in Eczema Area and Severity Index and Scoring Atopic Dermatitis scores. Phase 2 clinical trials have found lebrikizumab and tralokinumab to be effective, and the authors believe phase 3 trials are warranted. For paediatric atopic dermatitis, cyclosporin was found to provide the greatest decrease in clinical severity; no randomised controlled trials reporting the efficacy of biologic agents were found for this patient group.

Comment: The problem with assessing relative efficacy of systemic treatments is that there are no head-to-head trials and there is wide variation in study designs and outcome measures. Of the systemic treatments, cyclosporin, azathioprine and methotrexate were assessed, but not mycophenolate, and there were no placebo-controlled trials with methotrexate. They showed some benefit but not as much as cyclosporin and dupilumab. Other biologics were assessed including lebrikizumab, tralokinumab and nemolizumab, but these were phase 2 trials, so phase 3 trials will need to be done before these can be better compared. Montelukast, mepolizumab and omalizumab did not improve clinical severity. Cyclosporin has too many side effects to be used as a long-term treatment, so further trials on the new biologics, including head-to-head trials, as are happening for biologics in psoriasis, are needed.

Reference: J Am Acad Dermatol 2019;80:411–6Abstract

Local radiation and phototherapy are the most cost-effective treatments for stage IA mycosis fungoidesAuthors: Xia FD et al.Summary: These US researchers compared the cost effectiveness of treatment options for stage IA mycosis fungoides using a state-transition comparative decision analysis model constructed with health states of stage IA–IV disease, no mycosis fungoides and death, and data on treatment-specific remission and relapse rates obtained from the literature. They calculated lifetime costs by accounting for medications, office visits, laboratory monitoring, related procedures, work absences and travel. Local radiation was the most cost effective of the treatment options at $US225,399 for 15.40 life-years, followed by NB-UVB at $344,728 for 15.17 life-years, PUVA at $371,741 for 15.07 life-years, topical corticosteroids at $469,354 for 14.65 life-years, topical nitrogen mustard at $951,662 for 14.29 life-years and topical bexarotene at $11,892,496 for 13.55 life-years. These cost-effectiveness rankings were confirmed in sensitivity analyses.

Comment: The treatments compared in the cost-benefit analysis were topical bexarotene, topical nitrogen mustard, topical corticosteroids, local radiation, NB-UVB and PUVA. Local radiation was the most cost-effective treatment for limited disease because it had the highest chance of complete clearance (94%) and lowest chance of relapse (11%). NB-UVB was the most effective treatment for generalised disease and had the next highest chance for complete remission (78%) and with topical steroids had the third equal lowest chance of relapse (41%) after nitrogen mustard (34%). NB-UVB also had the second longest time to recurrence (22 months) after PUVA (32.5 months). Stage I mycosis fungoides is the most common stage (78%) and is managed by dermatologists, and this article informs us of the treatments used and cost benefits, although in an Australian setting the costs may be different.

Reference: J Am Acad Dermatol 2019;80:485–92Abstract

Epidermolysis bullosa simplex generalized severe induces a T helper 17 response and is improved by apremilast treatmentAuthors: Castela E et al.Summary: Skin inflammation in patients with the generalised severe type of EBS (epidermolysis bullosa simplex) was evaluated using retrospective immunohistochemical analyses of frozen skin samples obtained from 17 patients with the condition. The researchers also prospectively assessed ten patients with severe disease. Constant dermal perivascular CD4+ lymphocyte infiltration was seen in skin biopsies of blister (n=17) and rubbed skin (n=5), epidermal neutrophils and eosinophils infiltration was present in 70% of cases, and there was increased immunostaining for CXCL9 and CXCL10 in blistering skin. Lesional skin was also found to contain high T helper 17 cytokine levels. Three adults who received apremilast for generalised severe EBS exhibited a dramatic improvement of skin blistering with good tolerability.

Comment: This study shows that generalised severe EBS is not just a mechanical disease, but inflammatory mechanisms also play an important role. Keratin fragments have been shown to trigger inflammation leading to keratinocyte apoptosis. In generalised severe EBS, the immune infiltrate is a T helper 17 phenotype. Whether this applies to other forms of EBS remains to be proven. Apremilast was dramatically effective in three patients with adult generalised severe EBS, but the other T helper 17 biologic treatments we use for psoriasis may also show benefit. Even more broadly acting treatments such as steroids or calcineurin inhibitors could show a benefit. This study opens up potential for new ways of treating EBS.

Reference: Br J Dermatol 2019;180:357–64Abstract

Selection of papers and comments are provided by Dr Warren Weightman, who has practiced Dermatology for over 25 years and is currently Head of the Department of Dermatology at the Queen Elizabeth Hospital, Adelaide and a Senior Lecturer with Adelaide University. He has been Chief Censor and President of the Australasian College of Dermatologists. Dr. Weightman has been involved in clinical research and has a particular interest in treatment of actinic keratoses and superficial basal cell cancers with topical therapies including methyl aminolevulinate and photodynamic therapy, imiquimod, and ingenol mebutate. His other interests include the management of non-melanoma skin cancer in transplant patients, the use of biologics in psoriasis and other skin disorders, and the role of oral retinoids.

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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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Analysis of spin in the reporting of studies of topical treatments of photoaged skinAuthors: Motosko CC et al.

Summary: This systematic literature review of 20 placebo-controlled, double-blind clinical trials investigating topical treatments for photoaged skin surveyed ‘spin’ strategies that the trials’ authors employed for potentially distorting the interpretation of their findings. Various types of spin strategies were identified, which could be broadly classified as inappropriate statistical analyses or inappropriate interpretation of results, and the most frequently used were the use of multiple primary outcomes (95%), inappropriate extrapolation of results from specific outcomes to global improvements (95%), focus on within-group comparisons (75%) and focus on interim analyses to provide additional weight to nonsignificant findings (65%).

Comment: This article highlights the spin that authors can use to improve their findings. Several techniques were highlighted, and dermatologists should understand them when reading any trial, especially those to do with treatments for photoaging. Editors and peer reviewers also need to be aware of these findings. The most common strategies included use of multiple primary outcomes, inappropriate extrapolation of results from specific outcomes to global improvements, focus on within-group comparisons and focus on interim analyses to give more weight to nonsignificant findings.

Reference: J Am Acad Dermatol 2019;80:516–22Abstract

Dupilumab treatment for generalized prurigo nodularisAuthors: Beck KM et al.

Summary: These authors described the cases of three patients with longstanding generalised prurigo nodularis, which was refractory to other treatments including Goeckerman therapy, who were treated with subcutaneous dupilumab 600mg initially then 300mg every second week; all three patients continued concomitant topical and systemic medications. At 12 weeks, all three patients had experienced reductions in pruritus symptoms as well as decreases in the overall size and number of prurigo lesions. All three patients were able to reduce or completely discontinue ≥1 concurrent therapy, and they all reported subjective quality of life improvements, particularly with respect to social and occupational functioning. One of the patients developed herpes labialis, which was successfully treated with aciclovir.

Comment: There is a high need for an effective treatment for prurigo nodularis. This case series reported three patients with severe prurigo nodularis who were on systemic treatments including cyclosporin, thalidomide and gabapentin. After 12 weeks of dupilumab, there was clearance in one patient and a dramatic improvement in the other two. Dupilumab looks to be a promising agent for prurigo nodules, and larger, placebo-controlled trials should be done to determine efficacy.

Reference: JAMA Dermatol 2019;155:118–20Abstract

Long-term outcomes of laser treatment for congenital melanocytic neviAuthors: Oh Y et al.Summary: Long-term outcomes were reported for 67 patients with congenital melanocytic naevi treated with a variety of laser treatments only (n=52) versus combination treatments that included partial excision and lasers in this retrospective study. Among the 20 patients who experienced near total clearance during laser-only treatment, 11 were in a long-term follow-up group, of whom five experienced repigmentation. Repigmentation occurred in 15 patients, in a mean of 3.93 years from initial treatment, regardless of clearance. Patients who underwent combination partial excision and laser treatment had higher Investigator’s Global Assessment scores and required fewer laser treatments and shorter treatment periods than those who received laser-only treatment.

Comment: This article suggests that laser as a sole treatment for congenital melanocytic naevi was not the best treatment. Only about 40% showed near total clearance and of those followed almost 50% showed recurrence. This should not be unexpected when lasers only target superficial melanocytes and not those in the deep dermis. Combining partial excision and laser gave better results, and is worthwhile using if complete excision cannot be done. Complete excision if feasible would still be the treatment of choice. The risk of melanoma is mainly associated with giant congenital melanocytic naevi of diameters greater than 20cm or with multiple small congenital melanocytic naevi, so regular follow-up is needed in these patients.

Reference: J Am Acad Dermatol 2019;80:523–31Abstract

Hydrochlorothiazide use and risk for Merkel cell carcinoma and malignant adnexal skin tumorsAuthors: Pedersen SA et al.Summary: The impact of hydrochlorothiazide use on the risk of developing Merkel cell carcinoma or a malignant adnexal skin tumour was explored using data from Danish nationwide health registries. The analyses included registered patients with incident Merkel cell carcinomas or malignant adnexal skin tumours during 2004–2015, each matched to a control participant. The likelihood of developing Merkel cell carcinoma or a malignant adnexal skin tumour was significantly increased with cumulative hydrochlorothiazide use of ≥50,000mg (respective adjusted odds ratios 2.3 [95% CI 1.1–4.8] and 3.6 [1.9–7.0]), and the likelihood increased further with cumulative use of ≥100,000mg (3.3 [1.3–8.3] and 5.6 [2.4–13.3]). Drugs with similar indications as hydrochlorothiazide were not associated with any increased risk of these tumours, with the exception of a trend towards an increased risk of Merkel cell carcinoma with furosemide use (odds ratio 1.9 [95% CI 0.9–4.0]). No sun exposure data were available for analysis.

Comment: There have been several recent studies that have shown increased risks of basal cell carcinoma, squamous cell carcinoma and melanoma in patients taking hydrochlorothiazide. This study shows an increased risk of Merkel cell carcinomas and malignant adnexal tumours. There was no increased risk for these tumours with other antihypertensive drugs. Other studies have shown that calcium channel blockers increased the risk of nonmelanoma skin cancer and β-blockers increased the risk of melanoma, but not all studies have shown an increased risk of skin cancer with thiazide diuretics. However, the evidence is increasing that thiazides increase the risk of skin cancer, and patients with an increased skin cancer risk should be advised to have alternative antihypertensives. The evidence is not yet strong enough to advise against taking other antihypertensives.

Reference: J Am Acad Dermatol 2019;80:460–5Abstract