Evidence and consensus-based (S3) guidelines for the treatment of actinic keratosis: International League of Dermatological Societies in cooperation with the European Dermatology Forum: short version

BACKGROUND: Actinic keratosis (AK) is a frequent health condition attributable to chronic exposure to ultraviolet radiation. Several treatment options are available and evidence based guidelines are missing. OBJECTIVES: The goal of these evidence- and consensus-based guidelines was the development of treatment recommendations appropriate for different subgroups of patients presenting with AK. A secondary aim of these guidelines was the implementation of knowledge relating to the clinical background of AK, including consensus-based recommendations for the histopathological definition, diagnosis and the assessment of patients. METHODS: The guidelines development followed a pre-defined and structured process. For the underlying systematic literature review of interventions for AK, the methodology suggested by the Cochrane Handbook for Systematic Reviews of Interventions, the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement and Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology was adapted. All recommendations were consented during a consensus conference using a formal consensus methodology. Strength of recommendations was expressed based on the GRADE approach. If expert opinion without external evidence was incorporated into the reasoning for making a certain recommendation, the rationale was provided. The Guidelines underwent open public review and approval by the commissioning societies.RESULTS: Various interventions for the treatment of AK have been assessed for their efficacy. The consenting procedure led to a treatment algorithm as shown in the guidelines document. Based on expert consensus, the present guidelines present recommendations on the classification of patients, diagnosis and histopathological definition of AK. Details on the methods and results of the systematic literature review and guideline development process have been published separately. CONCLUSIONS: International guidelines are intended to be adapted to national or regional circumstances (regulatory approval, availability and reimbursement of treatments).(AU)

Evidence- and consensus-based (S3) Guidelines for the Treatment of Actinic Keratosis - International League of Dermatological Societies in cooperation with the European Dermatology Forum - Short version.

BACKGROUND: Actinic keratosis (AK) is a frequent health condition attributable to chronic exposure to ultraviolet radiation. Several treatment options are available and evidence based guidelines are missing. OBJECTIVES: The goal of these evidence- and consensus-based guidelines was the development of treatment recommendations appropriate for different subgroups of patients presenting with AK. A secondary aim of these guidelines was the implementation of knowledge relating to the clinical background of AK, including consensus-based recommendations for the histopathological definition, diagnosis and the assessment of patients. METHODS: The guidelines development followed a pre-defined and structured process. For the underlying systematic literature review of interventions for AK, the methodology suggested by the Cochrane Handbook for Systematic Reviews of Interventions, the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement and Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology was adapted. All recommendations were consented during a consensus conference using a formal consensus methodology. Strength of recommendations was expressed based on the GRADE approach. If expert opinion without external evidence was incorporated into the reasoning for making a certain recommendation, the rationale was provided. The Guidelines underwent open public review and approval by the commissioning societies. RESULTS: Various interventions for the treatment of AK have been assessed for their efficacy. The consenting procedure led to a treatment algorithm as shown in the guidelines document. Based on expert consensus, the present guidelines present recommendations on the classification of patients, diagnosis and histopathological definition of AK. Details on the methods and results of the systematic literature review and guideline development process have been published separately. CONCLUSIONS: International guidelines are intended to be adapted to national or regional circumstances (regulatory approval, availability and reimbursement of treatments).

Daylight photodynamic therapy with methyl aminolevulinate cream as a convenient, similarly effective, nearly painless alternative to conventional photodynamic therapy in actinic keratosis treatment: a randomized controlled trial.

BACKGROUND: Daylight photodynamic therapy (DL-PDT) of actinic keratosis (AK) has shown preliminary efficacy and safety results comparable to conventional photodynamic therapy (c-PDT), using methyl aminolevulinate (MAL) cream. OBJECTIVES: To demonstrate the efficacy and safety of DL-PDT vs. c-PDT in treating mild facial/scalp AK. MATERIALS AND METHODS: This 24-week randomized, controlled, investigator-blinded, multicentre, intra-individual efficacy (non-inferiority) and safety (superiority regarding pain) study enrolled 100 subjects. AKs on the face/scalp were treated once, with DL-PDT on one side and c-PDT on the contralateral side. Primary end points for DL-PDT at week 12 were efficacy [non-inferiority regarding complete lesion response (mild AK)] and safety (superiority regarding subject's assessment of pain). Lesions with complete response 12 weeks after one treatment session were followed until week 24. The safety evaluation included incidence of adverse events. Subject satisfaction was classified using a questionnaire. RESULTS: At week 12, the complete lesion response rate with DL-PDT was non-inferior to c-PDT (89·2% vs. 92·8%, respectively; 95% confidence interval -6·8 to -0·3), confirmed by intention-to-treat analysis. Additionally, regardless of the treatment used, 96% of mild lesions were maintained in complete response 24 weeks after the PDT session. For DL-PDT, subject-reported pain was significantly lower (0·8 vs. 5·7, respectively; P < 0·001), with better tolerability and significantly higher subject satisfaction regarding convenience and outcome. CONCLUSIONS: Daylight-mediated PDT was not inferior in efficacy to Metvix c-PDT (mild AK response rate), better tolerated, nearly painless and more convenient for patients.

Effect of dosing frequency on the safety and efficacy of imiquimod 5% cream for treatment of actinic keratosis on the forearms and hands: a phase II, randomized placebo-controlled trial.

BACKGROUND: Clinical studies in cutaneous conditions other than actinic keratosis (AK) have revealed that the safety and efficacy profile of imiquimod is influenced by dosing frequency. OBJECTIVES: To evaluate dosing frequency response of imiquimod 5% for treatment of AK. METHODS: This was a phase II, multicentre, randomized, double-blind, placebo-controlled study. Adults with > or = 10 but < or = 50 clinical AKs, one of which was histologically confirmed, were randomized (4:1) to 2-6 packets of imiquimod or placebo cream applied to the dorsum of the forearms and hands once daily 2, 3, 5 or 7 times per week for 8 weeks. The primary endpoint was complete clearance of AKs in the treatment area at 8 weeks post-treatment. RESULTS: One hundred and forty-nine (94 men and 54 women) white subjects, with a mean +/- SD age of 71 +/- 10.2 years, were enrolled. Twenty-eight subjects (18.8%) discontinued from study: 0%, 3.1%, 6.9%, 30.0% and 33.3% withdrew for local skin reactions or adverse events in the combined placebo, and in the imiquimod 2, 3, 5 or 7 times per week groups, respectively. Seven serious adverse events occurred; none was related to the study drug. Median baseline lesions ranged from 38 to 40 for the treatment groups. Complete clearance was achieved in 0%, 3.2%, 6.9%, 3.3% and 6.7% of subjects, and partial clearance (> or = 75% lesion reduction) in 0%, 22.6%, 24.1%, 20.0% and 36.7% of subjects for the placebo and imiquimod 2, 3, 5 or 7 times per week regimens, respectively. CONCLUSIONS: Imiquimod 5% applied more frequently than 3 times per week to AKs was not well tolerated. Complete clearance rates were low; however, partial clearance rates increased with increased dosing frequency (P = 0.002).

Oral retinoids for chemoprevention of skin cancers in organ transplant recipients: results of a survey.

Systemic retinoid therapy is thought to be beneficial for chemosuppression of skin cancers in solid organ transplant recipients. We present the results of a survey of 28 dermatologists with experience managing transplant recipients to clarify when and how systemic retinoids are used in this population. Almost 80% of respondents use retinoids in some transplant recipients. Factors influencing the use of retinoids include the incidence and aggressiveness of cutaneous squamous cell carcinomas and the extent of concomitant actinic keratoses. Patients are monitored more closely during periods of dose adjustment than during the maintenance phase of therapy. Adverse effects are variably managed symptomatically, with dose adjustment, by discontinuation of retinoids, or by referral to another specialist for further evaluation. In the absence of large randomized controlled trials, the practice habits of experienced physicians serve as a useful guide for the use of oral retinoids in transplant recipients.

CLinical experience acquired with the efalizumab (Raptiva) (CLEAR) trial in patients with moderate-to-severe plaque psoriasis: results from a phase III international randomized, placebo-controlled trial.

BACKGROUND: Efalizumab (anti-CD11a), a humanized monoclonal antibody, blocks multiple T-cell-dependent functions implicated in the pathogenesis of psoriasis, including T-cell activation, migration to the skin, reactivation in psoriatic skin and interactions with keratinocytes. OBJECTIVES: This multinational, randomized, double-blind, placebo-controlled, parallel-group trial was designed to evaluate the safety and efficacy of subcutaneous efalizumab 1.0 mg kg-1 once weekly for 12 weeks compared with placebo in a population that included high-need patients, defined as those for whom at least two systemic therapies were unsuitable because of lack of efficacy, intolerance or contraindication. PATIENTS/METHODS: Patients with moderate-to-severe plaque psoriasis [involvement of >or=10% of total body surface area and Psoriasis Area and Severity Index (PASI)>or=12.0 at screening] were randomized in a 2:1 ratio to receive efalizumab or placebo. The primary efficacy endpoint was the proportion of patients achieving >or=75% PASI improvement (PASI-75 response) at week 12 in the intention-to-treat population; secondary endpoints included changes in PASI, static Physician's Global Assessment, Physician's Global Assessment of change from baseline and percentage of body surface area affected. Results We enrolled 793 patients (529 received efalizumab and 264 placebo), including 526 high-need patients (342 received efalizumab and 184 placebo). Week 12 PASI-75 rates were 29.5% for efalizumab compared with 2.7% for placebo among high-need patients (P<0.0001) and 31.4% for efalizumab compared with 4.2% for placebo in the full study population (P<0.0001). RESULTS: for all secondary efficacy endpoints showed superiority of efalizumab over placebo in both the high-need and the full populations. Efalizumab demonstrated a favourable safety profile, without evidence of systemic toxicity, in both the high-need group and the overall study population. CONCLUSIONS: The efficacy and safety of efalizumab therapy were comparable between high-need patients and the more general moderate-to-severe psoriasis patient population. In view of its demonstrated efficacy and safety profile, efalizumab represents a valuable option for the treatment of adult patients with moderate-to-severe plaque psoriasis, including high-need patients.

Oral retinoids for the prevention of skin cancers in solid organ transplant recipients: a systematic review of randomized controlled trials.

BACKGROUND: The increased incidence of skin cancers after solid organ transplantation is well recognized. Skin cancers developing in transplant recipients are more aggressive in behaviour. Therapeutic options to reduce and/or delay the development of cutaneous neoplasms are therefore of interest. OBJECTIVES: The objective of this review was to summarize the available medical literature from randomized controlled trials on the use of oral retinoids as a preventive agent for skin cancers in the solid organ transplant population. METHODS: Three electronic databases were searched for relevant trials: MEDLINE (1966-October 2003), EMBASE (1980-week 44, 2003) and the Cochrane Controlled Trials Register (third quarter 2003). Randomized or quasi-randomized controlled clinical trials on subjects of any age or ethnic background who had received a solid organ transplant (cardiac, renal, liver, etc.) were evaluated. All titles and abstracts found by the search strategy were independently reviewed by two researchers for inclusion into the review. RESULTS: Eighty-one abstracts were identified through the electronic databases for consideration. Review of the abstracts identified three eligible trials. One cross-over trial involving 23 subjects treated with acitretin 25 mg daily for 12 months reported 46 squamous cell carcinomas (SCCs) developing in six subjects during acitretin treatment vs. 65 SCCs developing in 15 subjects during the drug-free period. Another trial involving 44 subjects treated with acitretin 30 mg daily or placebo for 6 months reported two of 19 subjects developing two SCCs in the treatment group vs. nine of 19 subjects developing 18 new skin cancers (15 SCCs, one Bowen's disease, two basal cell carcinomas) in the placebo group. One dose comparison trial involving 26 renal transplant recipients treated with acitretin did not find a significant difference in numbers of skin cancers developing at the doses examined. The major limitation to the use of acitretin was poor tolerance due to adverse events. Headaches, rash, musculoskeletal symptoms and hyperlipidaemia were the most common causes of withdrawal from treatment. No alterations in renal or liver function were detected during the periods of treatment or follow-up. CONCLUSIONS: The available data from a small number of randomized controlled trials suggest that acitretin may have a role in the management of solid organ transplant recipients with skin cancers. Tolerability of the drug is a major factor limiting its use. Appropriate selection of patients may help improve the risk-benefit ratio.

Summary of actinic keratosis studies with imiquimod 5% cream.

Imiquimod is being investigated as a therapeutic option for the management of actinic keratosis. Three recent clinical trials have demonstrated a reasonable efficacy rate and high safety profile. 'Cycle' therapy may improve the safety profile while maintaining efficacy. 'Field' treatment with imiquimod may uncover and treat 'subclinical' actinic keratoses, which in turn may potentially result in fewer recurrences. Longer follow-up studies are required to investigate this possibility.

Epidemiology and aetiology of basal cell carcinoma.

Basal cell carcinoma is the most common malignancy among caucasians worldwide. Accurate epidemiological data can be difficult to obtain, but does suggest that the overall incidence is increasing. Risk factors include skin type, prior skin cancers and immunosuppression. Research in free radical-mediated cellular injury and innate defence mechanisms, and ultraviolet radiation-induced genetic mutations have improved our understanding of the development of this disorder.

Treatment of Bowen's disease using a cycle regimen of imiquimod 5% cream.

Bowen's disease (BD; intraepithelial squamous cell carcinoma) is a challenging condition to treat because lesions, which can be multiple, are often located at sites that heal poorly, such as the shin. The disease is usually persistent and progressive and appears as an enlarging, demarcated erythematous plaque. Two elderly female patients with Bowen's disease of the lower leg are presented. Imiquimod 5% cream was applied in a cycle of three times weekly for 3 weeks followed by a 4-week rest period. The treatment was successful after a second cycle of therapy, with both cases clinically clear at 2- and 3-month follow-up visits.

Progress in Australian teledermatology.

Because of their remoteness, the majority of rural towns in Australia are disadvantaged in terms of access to dermatological services. Telemedicine offers one solution. Since the mid-1990s, Australian dermatologists have experimented with telemedicine as an adjunct to clinical practice. The technical viability of teledermatology was first demonstrated in 1997. In 1999, the accuracy and reliability of teledermatology were demonstrated in a real-life urban setting. In 2001, Broken Hill (in western New South Wales), a location remote from dermatology services, served as a trial site for the institution of teledermatology as the primary method of accessing dermatological services. High patient and general practitioner acceptability and positive medical outcomes were demonstrated, but the study also revealed unexpected barriers and pitfalls in the effective operation of rural teledermatology.

Imiquimod 5% cream in the treatment of superficial basal cell carcinoma: results of a multicenter 6-week dose-response trial.

BACKGROUND: Superficial basal cell carcinoma (sBCC) is an increasingly common tumor in fair-skinned populations throughout the world. Imiquimod, an immune response modifier that induces cytokines including interferons, has been shown in preliminary studies to have an effect when applied topically to BCC. OBJECTIVE: We conducted a multicenter, randomized, open-label dose-response trial of imiquimod 5% cream in the treatment of primary sBCC assessing efficacy and safety of different dose regimens. METHODS: Ninety-nine patients were randomized to 6 weeks' application of imiquimod in 1 of 4 treatment regimens: twice every day, once every day, twice daily 3 times/week, once daily 3 times/week. The treatment site was excised and examined histologically 6 weeks after cessation of imiquimod. RESULTS: Intention-to-treat analysis revealed 100% (3/3) histologic clearance in the twice-daily regimen, 87.9% (29/33) clearance in the once every day regimen, 73.3% (22/30) clearance in the twice-daily 3 times/week regimen, and 69.7% (23/33) clearance in the once-daily 3 times/week regimen. Dose-related inflammatory skin reactions at the site of application were common. The majority were well tolerated and only 1 patient withdrew from the trial as a result of a medication-related skin reaction. CONCLUSION: Imiquimod 5% cream appears to have potential as a patient-administered treatment option in sBCC.

Subacute cutaneous lupus erythematosus associated with hepatocellular carcinoma.

A 63-year-old man with a 4-year history of metastatic hepatocellular carcinoma secondary to chronic hepatitis B developed a rash affecting his arms, legs, thorax and back. Both clinical and histological examination suggested a diagnosis of subacute cutaneous lupus erythematosus (SCLE). The association of SCLE and hepatocellular carcinoma has not previously been reported. The SCLE persisted without remission and was still present at his death from metastatic hepatocellular carcinoma 3 months later. We also review other reported cases of SCLE as paraneoplastic dermatoses and apply McLean's criteria for paraneoplastic dermatosis.

Accuracy and reliability of store-and-forward teledermatology: preliminary results from the St George Teledermatology Project.

Teledermatology is the practice of dermatology across distances (and time) and involves the transfer of electronic information. To be effective and safe, the teledermatology process needs to demonstrate an acceptable level of accuracy and reliability. Accuracy is reflected by the degree of concordance (agreement) between the teledermatology and face-to-face diagnoses. Reliability is dependent on how consistently a set of results can be reproduced across different operators. Mean concordance (primary diagnoses) achieved by four dermatologists studying 53 store-and-forward diagnostic cases, originating from 49 referred patients, was 79% (range 73-85%). When the differential diagnoses were taken into account, the variation across individual dermatologists narrowed further, with a mean of 86% (range 83-89%). In contrast, the mean general practitioner (GP; n=11) concordance (GP face-to-face vs reference dermatologist store-and-forward diagnoses) was 49%. An interim review of all 49 teledermatology patients showed no adverse outcome at the end of 3 months. The ability to request face-to-face visits by dermatologists, combined with GPs maintaining primary care of the referred patient, serve as additional safeguards for patients using a telemedicine system. Our results indicate that teledermatology management of referred skin complaints is both accurate and reliable.

Australian teledermatology: the patient, the doctor and their government.

Telemedicine is an emerging technology within Australia. We review the historical development of telemedicine and discuss the clinical and non-clinical issues surrounding its practice in this country. Teledermatology is one application of telemedicine. We discuss the potential impact of teledermatology on patients, doctors and third parties such as government. So far, teledermatology has received little attention from Australian dermatologists. By contrast, the Government and other organizations are showing keen interest in establishing infrastructure within this country. We believe it is time for dermatologists to become more involved in the practice and politics of telemedicine within Australia.

Pemphigoid gestationis occurring in a patient with HELLP syndrome.

A case of pemphigoid gestationis occurring in a 40 year old female who developed HELLP syndrome during her fourth pregnancy is reported. Seven days after emergency Caesarean section for pre-eclampsia, she developed a pruritic blistering eruption which clinically resembled pemphigoid gestationis. The diagnosis was supported by skin histology and immunofluorescence. She responded rapidly to oral corticosteroids, with no evidence of recurrence after 12 weeks of follow up. In the current case report, the previously unreported simultaneous occurrence of two uncommon conditions is described.

Managing HIV. Part 5: Treating secondary outcomes. 5.1 HIV and skin disease.

The skin is the largest and most visible organ of the body, and a perception of good health depends on its appearance as well as its function. As about 90% of HIV-infected patients develop cutaneous signs and symptoms, diagnosis and management are vital in recognising progression of HIV infection.