Maintenance of remission following successful treatment of papulopustular rosacea with ivermectin 1% cream vs. metronidazole 0.75% cream: 36-week extension of the ATTRACT randomized study.

BACKGROUND: There are a limited number of approved treatments for papulopustular rosacea (PPR) and remission is difficult to maintain after successful treatment. OBJECTIVES: To investigate remission over a 36-week extension period in patients with moderate to severe PPR successfully treated with 16 weeks' treatment with ivermectin 1% cream once daily (QD) or metronidazole 0.75% cream twice daily (BID) in a randomized, parallel-group Phase III study. METHODS: Treatment was discontinued in patients initially successfully treated [Investigator's Global Assessment (IGA) score of 0 or 1] with ivermectin 1% cream QD (n = 399) or metronidazole 0.75% cream BID (n = 365; Part A) and patients were followed every 4 weeks for up to 36 weeks (Part B). Treatment with the same study treatment as used in Part A was only re-initiated if patients relapsed (IGA ≥ 2). Efficacy assessments were: time to first relapse; relapse rate; and number of days free of treatment. Safety assessments included incidence of adverse events and local cutaneous signs and symptoms. RESULTS: The median time to first relapse was significantly longer (115 days vs. 85 days) and relapse rates at the end of the study period significantly lower (62.7% vs. 68.4%) for patients initially successfully treated with ivermectin 1% compared with metronidazole 0.75%; Kaplan-Meier plot demonstrated a statistically significant difference between the two arms (P = 0.0365). The median number of days free of treatment was higher for ivermectin compared with metronidazole (196 days vs. 169.5 days; P = 0.026). The percentage of patients who experienced a related adverse event was equally low in both groups. CONCLUSION: The results of this relapse study showed that an initial successful treatment with ivermectin 1% cream QD significantly extended remission of rosacea compared with initial treatment with metronidazole 0.75% cream BID following treatment cessation.

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

BACKGROUND: Few therapeutic alternatives currently exist in the treatment of papulopustular rosacea (PPR). OBJECTIVES: To demonstrate superiority of once-daily ivermectin 1% cream (IVM 1%) once daily vs. twice-daily metronidazole (MTZ 0·75%) cream, regarding percentage reduction of inflammatory lesions in subjects with moderate to severe PPR. METHODS: In this Phase 3, investigator-blinded, randomized, parallel-group study, subjects received IVM 1% once daily, or MTZ 0·75% twice daily over 16 weeks. Efficacy assessments were inflammatory lesion counts and Investigator's Global Assessment (IGA). Safety assessments included incidence of adverse events (AEs) and local tolerance parameters. Subjects evaluated their disease following a 5-grade scale and completed questionnaires. RESULTS: A total of 962 subjects were randomized to receive IVM 1% (n = 478) or MTZ 0·75% (n = 484). At week 16, IVM 1% was significantly superior to MTZ 0·75% in terms of reduction from baseline in inflammatory lesions (83·0% vs. 73·7%; P < 0.001), observed as early as week 3 (Last Observation Carried Forward, LOCF). IGA results (subjects 'clear' or 'almost clear') also favoured IVM 1%: 84·9% vs. 75·4%, respectively (P < 0.001). Incidence of AEs was comparable between groups and local tolerability was better for IVM 1%. More subjects receiving IVM rated their global improvement as 'excellent' or 'good.' CONCLUSIONS: Ivermectin 1% cream was significantly superior to MTZ 0·75% cream and achieved high patient satisfaction.

Human papillomavirus typing of warts and response to cryotherapy.

BACKGROUND: Cutaneous warts are common and caused by a number of different types of human papillomaviruses (HPVs). OBJECTIVE: The aim of this study was to investigate the HPV types causing common warts and to determine any association between the HPV type and the duration of warts and response to cryotherapy. METHODS: Eighty wart samples from 76 immunocompetent patients were taken from warts by paring prior to cryotherapy and analysed by in situ hybridization (ISH) with HPV probes specific to HPV 1, 2, 3, 4, 7, 10 and 57 and PCR analysis using degenerate cutaneous HPV primers with subsequent DNA sequencing. Each patient's details, including site, duration and response of the wart to cryotherapy were recorded. Cryotherapy was performed at 2 week intervals for a maximum of 12 weeks. RESULTS: An HPV type was identified in 65 samples. The majority of warts (58 samples) were typed as HPV 2/27/57 by ISH and/or PCR. Three of the 18 samples that were HPV negative with ISH were HPV positive by PCR. Response to treatment did not correlate with HPV type, duration or location. In the 21 wart parings taken from patients aged 16 and under, response to treatment did not correlate with HPV type but warts of shorter duration were more likely to resolve with cryotherapy treatment than longer standing lesions. CONCLUSION: This study demonstrates that HPV type can be determined from wart parings. HPV-2 related viruses are the prevalent HPV types causing common warts on the hands and feet in this population.

A randomized controlled trial of R-salbutamol for topical treatment of discoid lupus erythematosus.

BACKGROUND: In a recent open pilot trial, R-salbutamol sulphate, a well-known molecule with anti-inflammatory effects, was tested successfully on patients with therapy-resistant discoid lupus erythematosus (DLE). OBJECTIVES: To compare the efficacy and safety of R-salbutamol cream 0.5% vs. placebo on DLE lesions in a multicentre, double-blinded, randomized, placebo-controlled phase II trial. METHODS: Thirty-seven patients with at least one newly developed DLE lesion were randomized - 19 to the R-salbutamol cream 0.5% and 18 to placebo - and treated twice daily for 8 weeks. Efficacy was evaluated through scores of erythema, scaling/hypertrophy and induration as well as pain and itching; general improvement scored by the investigator and global improvement scored by patients' assessment were also evaluated. RESULTS: The mean area under the curve of improvement for scaling/hypertrophy, pain, itching and global patient assessment was significantly better for the actively treated patients as compared with placebo (scaling/hypertrophy, P = 0.0262; pain, P = 0.0238; itching, P = 0.0135; global patient assessment, P = 0.045). Moreover, the percentage of patients without induration was significantly higher in the active group compared with the placebo group (P = 0.013), and a statistically significantly greater decrease in the size of the lesional area was also seen in the overall analysis of the R-salbutamol-treated patients (P = 0.0197). No serious adverse events were reported. CONCLUSIONS: Application of R-salbutamol cream 0.5% was safe and well tolerated. Statistically significant effects were seen on scaling/hypertrophy, induration, pain and itching as well as patient global assessment, suggesting that R-salbutamol could be a promising new topical therapy alternative for DLE.

A study examining inter-rater and intrarater reliability of a novel instrument for assessment of psoriasis: the Copenhagen Psoriasis Severity Index.

BACKGROUND: There is a perceived need for a better method for clinical assessment of the severity of psoriasis vulgaris. The most frequently used system is the Psoriasis Area and Severity Index (PASI), which has significant disadvantages, including the requirement for assessment of the percentage of skin affected, an inability to separate milder cases, and a lack of linearity. The Copenhagen Psoriasis Severity Index (CoPSI) is a novel approach which comprises assessment of three signs: erythema, plaque thickness and scaling, each on a four-point scale (0, none; 1, mild; 2, moderate; 3, severe), at each of 10 sites: face, scalp, upper limbs (excluding hands and wrists), hands and wrists, chest and abdomen, back, buttocks and sacral area, genitalia, lower limbs (excluding feet and ankles), feet and ankles. OBJECTIVES: To evaluate the inter-rater and intrarater reliability of the CoPSI and to provide comparative data from the PASI and a Physician's Global Assessment (PGA) used in recent clinical trials on psoriasis vulgaris. METHODS: On the day before the study, 14 dermatologists (raters) with an interest in psoriasis participated in a detailed training session and discussion (2.5 h) on use of the scales. On the study day, each rater evaluated 16 adults with chronic plaque psoriasis in the morning and again in the afternoon. Raters were randomly assigned to assess subjects using the scales in a specific sequence, either PGA, CoPSI, PASI or PGA, PASI, CoPSI. Each rater used one sequence in the morning and the other in the afternoon. The primary endpoint was the inter-rater and intrarater reliability as determined by intraclass correlation coefficients (ICCs). RESULTS: All three scales demonstrated 'substantial' (a priori defined as ICC > 80%) intrarater reliability. The inter-rater reliability for each of the CoPSI and PASI was also 'substantial' and for the PGA was 'moderate' (ICC 61%). The CoPSI was better at distinguishing between milder cases. CONCLUSIONS: The CoPSI and the PASI both provided reproducible psoriasis severity assessments. In terms of both intrarater and inter-rater reliability values, the CoPSI and the PASI are superior to the PGA. The CoPSI may overcome several of the problems associated with the PASI. In particular, the CoPSI avoids the need to estimate a percentage of skin involved, is able to separate milder cases where the PASI lacks sensitivity, and is also more linear and simpler. The CoPSI also incorporates more meaningful weighting of different anatomical areas.

A 4-year follow-up study of atopic dermatitis therapy with 0.1% tacrolimus ointment in children and adult patients.

BACKGROUND: For the treatment of a chronic disease like atopic dermatitis, sustained tolerability and efficacy of the applied medication are essential. OBJECTIVES: The present open-label, noncomparative study was conducted to obtain information on the long-term safety and efficacy of 0.1% tacrolimus ointment. METHODS: Patients aged 2 years or older with an affected body surface area of more than 5%, who previously participated in a clinical trial on tacrolimus ointment, were eligible for this study. The treatment area was defined by the investigator at study entry. Both children and adults applied continuously or intermittently 0.1% tacrolimus ointment twice daily during episodes of active disease plus an additional week after remission over a follow-up period of up to 4 years. RESULTS: The intent-to-treat population comprised 782 patients, with a median age of 22 years (range 2-72). Patients remained in the study for up to 4 years. Approximately half of the patients discontinued the study prematurely; the median follow-up was 1422 days. Median tacrolimus ointment use was 31.2 g during the first week; ointment use decreased during the first year and then remained stable for the remainder of the study. The median cumulative tacrolimus use was 271.5 g at month 6, 462.5 g at month 12, 739.9 g at month 24, 1029.3 g at month 36 and 1320.8 g at month 48. Altogether 51.8% of patients discontinued the study prematurely; the main reasons were withdrawal of consent (13.3%), loss to follow-up (11.3%) and lack of efficacy (9.4%). Adverse events led to study discontinuation in 3.7% of the patients. The most frequent application site events were skin burning and pruritus. These events were most often reported in adult patients during the initial treatment period; prevalence decreased after the first week and remained at a low level throughout the study. Nonapplication site events occurred with stable incidences throughout the study period. In general, calculated daily hazard rates did not indicate an increased risk of adverse events with prolonged treatment. The total affected body surface area decreased substantially upon onset of treatment and efficacy of treatment was maintained until the end of the study with smaller but continuous improvements throughout the follow-up period. Overall, 75% of the patients and 76% of the investigators rated their satisfaction with the treatment as excellent, very good or good at the end of the study or at the time of premature discontinuation. CONCLUSIONS: The safety profile of intermittent or continuous long-term application of 0.1% tacrolimus ointment for up to 4 years was consistent with that which has been established from shorter studies and gave no reason for concern. In addition, 0.1% tacrolimus ointment demonstrated sustained efficacy as reflected by the expression of high satisfaction with treatment by both patients and investigators.

Treatment of disseminated superficial actinic porokeratosis with topical diclofenac gel: a case series.

Disseminated superficial actinic porokeratosis (DSAP) is the most common of the of five clinical variants of porokeratosis. These are disorders of keratinization and the distinctive pathological feature is the cornoid lamella at the margin. DSAP usually manifests in the third or fourth decades of life with a female preponderance and with multiple lesions over sun-exposed areas. A diverse range of treatments is employed though evidence of efficacy remains largely anecdotal. We report a series of eight patients with DSAP treated with 3% diclofenac gel (Solaraze gel).

Mutations of keratin 9 in two families with palmoplantar epidermolytic hyperkeratosis.

The hereditary palmoplantar keratodermas are a heterogeneous group of diseases unified by thickening of the stratum corneum of the palms and soles with consequent painful fissuring, discomfort on pressure, and resultant disability. One of the histologic patterns underlying palmoplantar hyperkeratosis is that of epidermolytic hyperkeratosis. Because that histologic pattern has been found in its generalized form to be due to keratin gene mutations, we assessed the inheritance of the form localized to the palms and soles. In each of two families studied, the mutant gene causing the disease is linked strongly to the chromosome 17 cluster of genes encoding type I keratins, and mutations are present in the conserved helix initiation region of keratin 9 in affected members of both kindreds. These data, as well as those generated recently by others, indicate that keratin gene mutations may underlie not only the generalized phenotype but also this more localized phenotype of epidermolytic hyperkeratosis and suggest one mechanism by which skin diseases can achieve their characteristic localization.

Successful treatment of recalcitrant psoriasis with a combination of infliximab and hydroxyurea.

We report the use of a combination of the tumour necrosis factor alpha (TNF alpha) inhibitor infliximab and hydroxyurea to achieve control of disabling psoriasis and psoriatic arthritis. Our patient had psoriasis that proved resistant to conventional therapy including vitamin D analogues, topical steroids, dithranol, crude coal tar, narrow band UVB, bath PUVA and acitretin. She subsequently responded to hydroxyurea 1 g daily combined with infliximab infusions repeated at three monthly intervals which led to satisfactory control of her psoriasis and psoriatic arthritis. She has not reported any side-effects from this treatment regimen and her full blood count has remained normal.

Cyclosporin in childhood psoriasis.

BACKGROUND: Cyclosporin is known to be highly effective in the treatment of psoriasis in adults. It has also proved effective and well tolerated in the treatment of severe childhood atopic dermatitis. Psoriasis in childhood is relatively unusual but by no means rare and on occasions the disease can be very difficult to control in this age group. The use of cyclosporin for psoriasis in childhood has received scarcely any attention and in the few cases that have been reported the results have been inconsistent. Three children aged from 7 to 11 years with severe psoriasis resistant to topical agents were treated with cyclosporin. The highest dose required was 3.5 mg/kg per day. The duration of treatment ranged from 6 weeks to 4 months. Cyclosporin was effective and generally well tolerated. Treatment was interrupted in one case due to nausea and diarrhoea. None of the patients developed hypertension or renal impairment. The potential role of cyclosporin in severe childhood psoriasis is discussed.

Double-blind, randomised, multicentre, parallel group study comparing a 1% coal tar preparation (Exorex) with a 5% coal tar preparation (Alphosyl) in chronic plaque psoriasis.

BACKGROUND: Exorex lotion is a novel formulation of prepared coal tar indicated for the treatment of psoriasis. OBJECTIVES: To compare the efficacy and tolerability of 1% prepared coal tar lotion versus 5% coal tar extract in patients with mild to moderate plaque psoriasis. PATIENTS AND METHODS: This was a double-blind, randomised controlled study. Patients initially entered a 7-day washout period, during which they applied a yellow soft paraffin plus emulsifying wax ointment used as an emollient three times a day to their plaques. They were then randomised to receive treatment with 1% coal tar (Exorex) lotion or 5% conventional coal tar lotion (Alphosyl), three times a day for 12 weeks. Both treatment groups continued to apply the emollient throughout the duration of the study. Two target plaques were selected at entry for assessment. The clinical measures used were: 1) Total Sign Score (TSS), the sum of 5-point rating scores for erythema, induration and scaling averaged for the two target plaques (range 0-12), 2) the Psoriasis Area and Severity Index (PASI), and 3) patient and investigator 7-point global assessments of improvement at 12 weeks. Patients were assessed at 0, 4, 8 and 12 weeks during the treatment period or at the point of withdrawal. Spontaneously reported and observed adverse events were noted. RESULTS: Three hundred and twenty four of 338 randomised patients were evaluable (ITT analysis): 158 patients received 1% coal tar lotion and 166 patients received conventional coal tar. Both groups showed decreases from baseline to end of treatment in mean TSS (decrease of 2.4 points from 5.6 to 3.2 with 1% coal tar lotion and 1.8 points from 5.5 to 3.7 with conventional coal tar), and mean PASI (decrease of 2.4 points with 1% coal tar lotion and 1.5 points with conventional coal tar). Two hundred and twenty eight patients completed the full course of treatment. There was a statistically significant treatment difference in the percentage change in mean TSS at week 12, in favour of 1% coal tar lotion (-10.6%, 95% CI -20.6% to -0.5%, p=0.04). There was also a difference between treatments in the change in mean PASI in favour of 1% coal tar that was of borderline statistical significance (-11.7%, 95% CI -23.8% to 0.4%, p=0.06). Investigator global assessments also favoured 1% coal tar lotion (38% vs. 27% of patients showed clearance or marked improvement). The 1% coal tar lotion had a similar safety profile to 5% conventional coal tar lotion with the majority of treatment-related events being mild to moderate in severity. CONCLUSIONS: 1% coal tar lotion is more effective than a conventional coal tar lotion in mild to moderate psoriasis and may be preferred for first-line topical treatment.

Calcium homeostasis remains unaffected after 12 weeks' therapy with calcitriol 3 microg/g ointment; no correlation with extent of psoriasis.

OBJECTIVE: To assess the systemic safety of calcitriol 3 microg/g ointment (Silkis) ointment) in relation to body surface area (BSA) affected by chronic plaque psoriasis. METHODS: In this open-label, multicentre study, patients were divided into three parallel groups: 5% to <15% (n=23), 15% to <25% (n=18), 25% to 35% (n=18) based on BSA involvement. Ointment was applied topically twice daily for 12 weeks; patients were followed up for a further 8 weeks. RESULTS: There was no alteration of calcium homeostasis: the mean values of albumin-adjusted serum total calcium, as well as 24-hour urinary calcium and serum calcitriol levels, remained within normal ranges throughout treatment. No changes in calcium or phosphate homeostasis related to the area of psoriasis being treated with calcitriol ointment were detected. CONCLUSIONS: Reductions in the global severity score and BSA involvement, as well as results of the assessment of improvement, attested to the clinical efficacy of calcitriol 3 microg/g ointment in psoriasis. The study confirms the systemic safety of calcitriol 3 microg/g in psoriatic patients with 5-35% BSA involvement.

Treatment of basal cell carcinoma with intralesional interferon alpha-2b.

We report a series of 11 basal cell carcinomas of various types treated with nine intra-lesional injections of 1.5 million units of interferon alpha-2b. The diagnosis was confirmed histologically in each case. After 3 months' follow-up six tumours had resolved both clinically and histologically. In three cases the tumour size was reduced. One tumour grew larger. Side effects were well tolerated except by one subject who was withdrawn. Those cases which responded have now been followed-up for between 12 and 26 months with no clinical or histological evidence of tumour recurrence. This is the longest period of follow-up so far reported for this novel treatment. The results are encouraging and, if maintained in future series, may indicate a useful role for interferon alpha in the management of this common cutaneous malignancy.

Erythroderma: 90% skin failure.

Erythroderma is a life-threatening state of skin failure. This dermatological emergency often presents to an acute medical unit or accident and emergency department. Effective initial management is vital.