The efficacy of intravenous immunoglobulin for the treatment of toxic epidermal necrolysis: a systematic review and meta-analysis

Background Quantitative analysis of intravenous immunoglobulin (IVIg) treatment against toxic epidermal necrolysis (TEN) is lacking. Objectives To provide a meta‐analysis evidence‐based examination of IVIg efficacy against TEN. Methods A systematic review and meta‐analysis of literature published before 31 July 2011 was conducted. In observational controlled studies with at least eight patients with TEN receiving IVIg treatment, a pooled estimate of mortality risk was determined, comparing IVIg and supportive care. Statistical analyses were performed on raw data to compare the clinical differences between (i) high‐dose and low‐dose IVIg treatment in adult patients and (ii) paediatric and adult patients treated with IVIg. Results Seventeen studies met inclusion criteria. Overall mortality rate of patients with TEN treated with IVIg was 19·9%. The pooled odds ratio (OR) for mortality from six observational controlled studies comparing IVIg and supportive care was 1·00 [95% confidence interval (CI) 0·58–1·75; P = 0·99]. The pooled OR for mortality in patients treated with high‐dose IVIg vs. supportive care was 0·63 (95% CI 0·27–1·44; P = 0·27). Adults treated with high‐dose IVIg exhibited significantly lower mortality than those treated with low‐dose IVIg (18·9% vs. 50%, respectively; P = 0·022); however, multivariate logistic regression model adjustment indicated that IVIg dose does not correlate with mortality (high vs. low dose: OR 0·494; 95% CI 0·106–2·300; P = 0·369). Paediatric patients treated with IVIg had significantly lower mortality than adults (0% vs. 21·6%; P = 0·001). Conclusions Although high‐dose IVIg exhibited a trend towards improved mortality and children treated with IVIg had a good prognosis, the evidence does not support a clinical benefit of IVIg. Randomized controlled trials are necessary.     

A randomized, double-blind, placebo-controlled study to evaluate the addition of methotrexate to etanercept in patients with moderate to severe plaque psoriasis

Background Etanercept plus methotrexate combination therapy has not been adequately investigated in psoriasis. Objectives To evaluate etanercept plus methotrexate vs. etanercept monotherapy in patients with moderate to severe plaque psoriasis who had not failed prior methotrexate or tumour necrosis factor‐inhibitor therapy. Methods Patients received etanercept 50 mg twice weekly for 12 weeks followed by 50 mg once weekly for 12 weeks and were randomized 1 : 1 to receive methotrexate (7·5–15 mg weekly) or placebo. The primary endpoint was the proportion of patients achieving ≥75% improvement in Psoriasis Area and Severity Index (PASI 75) at week 24. Results In total, 239 patients were enrolled in each arm. PASI 75 was significantly higher at week 24 for the combination therapy group compared with the monotherapy group (77·3% vs. 60·3%; P < 0·0001). Other PASI improvement scores at week 12 [PASI 75, 70·2% vs. 54·3% (P = 0·01); PASI 50, 92·4% vs. 83·8% (P = 0·01); and PASI 90, 34·0% vs. 23·1% (P = 0·03)] showed similar results as did week 24 PASI 50 (91·6% vs. 84·6%; P = 0·01) and PASI 90 (53·8% vs. 34·2%; P = 0·01). Significantly more patients receiving combination therapy than monotherapy had static Physician’s Global Assessment of clear/almost clear at week 12 (65·5% vs. 47·0%; P = 0·01) and week 24 (71·8% vs. 54·3%; P = 0·01). Adverse events (AEs) were reported in 74·9% and 59·8% of combination therapy and monotherapy groups, respectively; three serious AEs were reported in each arm. Conclusions Combination therapy with etanercept plus methotrexate had acceptable tolerability and increased efficacy compared with etanercept monotherapy in patients with moderate to severe psoriasis.     

Filaggrin loss-of-function mutations are associated with early-onset eczema, eczema severity and transepidermal water loss at 3 months of age

Background Filaggrin loss‐of‐function (FLG) mutations are associated with eczema and skin barrier impairment, but it is unclear whether skin barrier impairment precedes phenotypic eczema in FLG mutation carriers. Objectives To study the association between FLG mutations, skin barrier impairment and clinical eczema at 3 months of age. Methods A total of 88 infants were examined for eczema. Disease severity was determined by the SCORAD eczema severity score. Transepidermal water loss (TEWL) was measured on unaffected forearm skin. Venous blood samples were screened for the four most common FLG mutations found in the U.K. white population (R501X, 2282del4, R2447X and S3247X). Median SCORAD and TEWL measurements in children with and without eczema and FLG mutations were compared. Results Thirty‐three per cent (29/88) of children had clinical eczema. Median SCORAD was 10·6 (range 3·5–31·0). TEWL (g m^?2 h^?1) was higher in children with eczema compared with unaffected infants (median TEWL 14·24 vs. 11·24, P < 0·001). Higher TEWL was associated with more severe disease (r = 0·59, P < 0·001, median TEWL, SCORAD < 15, 13·1 vs. 29·6, SCORAD ≥ 15, P = 0·029). Clinically dry skin was associated with higher TEWL, even in the absence of eczema (median TEWL 17·55 vs. 11·08, P = 0·008). Seventeen per cent (15/88) of children carried at least one FLG mutation. FLG mutation carriers were significantly more likely to have clinically dry skin, even in the absence of eczema [odds ratio (OR) 8·50, 95% confidence interval (CI) 1·09–66·58, P = 0·042]. FLG mutation carriers were also more likely to have eczema by 3 months of age (OR 4·26, 95% CI 1·34–13·57, P = 0·014). FLG mutations were significantly associated with higher median TEWL (all children, FLG‘yes’ 21·59 vs. FLG‘no’ 11·24, P < 0·001), even without clinical eczema (FLG‘yes’ 15·99 vs. FLG‘no’ 10·82, P = 0·01). Conclusions By the age of 3 months, FLG mutations are associated with an eczema phenotype, dry skin and TEWL. The observation that TEWL is elevated in unaffected FLG mutation carriers suggests that skin barrier impairment precedes clinical eczema.     

Association between atopic dermatitis and obesity in adulthood

Background Obesity in early childhood is associated with increased risk for and severity of atopic dermatitis (AD). Objective  To determine whether obesity in adulthood is associated with risk of AD. Methods This was a retrospective case–control study of 2090 adults using questionnaire, height and weight, and skin‐prick testing between January 1994 and December 2003. Results  Obesity in adults was associated with increased AD [multinomial logistic regression: adjusted odds ratio (aOR) 1·43, 95% confidence interval (CI) 1·08–1·89; P = 0·01], but not nonatopic dermatitis (aOR 0·59, 95% CI 0·21–1·68; P = 0·32). Obesity was also associated with increased atopic asthma (aOR 1·98, 95% CI 1·47–2·66, P < 0·0001), but not associated with nonatopic asthma (P = 0·20), atopic or nonatopic rhinoconjunctivitis (P = 0·08 and 0·31, respectively), food allergies (P = 0·67 and 0·35, respectively) or atopy (P = 0·40). The association between obesity and AD remained significant even when controlling for history of asthma, rhinoconjunctivitis and food allergies (aOR 1·40, 95% CI 1·05–1·86; P = 0·02) or in subset analyses of subjects with AD alone (aOR 1·96, 95% CI 1·02–3·75; P = 0·04) and with comorbid asthma, rhinoconjunctivitis and/or food allergies (aOR 1·40, 95% CI 1·03–1·91; P = 0·03). Conclusion Obesity in adulthood is associated with AD. Further studies are warranted to determine if weight loss may prevent or mitigate AD in adults.     

Histological regression in primary melanoma: not a predictor of sentinel lymph node metastasis in a cohort of 397 patients

Background Regression has been proposed as a potential marker of dissemination in thin melanomas. Previous studies have shown conflicting results. Objective To determine if regression in melanoma is associated with an increased risk of sentinel lymph node (SLN) metastasis. Methods A cohort analysis was conducted. Data on all patients were collected on a standardized case report form during 10 years. A total of 397 consecutive patients with melanoma who underwent a SLN biopsy were analysed. All cases of melanoma and SLN biopsies were examined by the same two pathologists. Differences between melanomas with and without SLN metastasis were compared using Fisher’s exact test or the two‐sample t‐test and the χ² test. Multivariable logistic regression was used to adjust for possible confounding factors. Results We analysed 397 patients (411 melanomas) who underwent a SLN biopsy. The median Breslow index was 1·8 mm (interquartile range 1·1–3). Regression was observed in 23% (n = 94). SLN metastases were observed in 26% (n = 106). The frequency of SLN metastasis was 16% in melanomas with regression and 29% without regression (P = 0·012). The adjusted odds ratio (OR) for regressive melanoma was 0·9 [95% confidence interval (CI) 0·4–1·9; P = 0·777]. The risk of SLN metastasis was increased in melanoma cases with a Breslow index from 1·5 to < 2·0 mm (adjusted OR 3·1; 95% CI 1·4–7·1; P = 0·006) and ≥ 2·0 mm (adjusted OR 3·5; 95% CI 1·7–7·4; P = 0·001) and ulceration of the melanoma (adjusted OR 1·8; 95% CI 1·1–3·2; P = 0·03). Conclusion Regression is not an independent predictor of the risk of SLN metastasis in melanoma.     

Impact of glucocorticoid‐induced adverse events on adherence in patients receiving long‐term systemic glucocorticoid therapy

Summary Background Factors influencing adherence to long‐term (i.e. ≥ 3 months) systemic glucocorticoid therapy are poorly understood. Objective To evaluate the relationship between glucocorticoid‐induced adverse events and therapeutic adherence in patients on long‐term glucocorticoid treatment. Methods A cross‐sectional survey was conducted in three departments of dermatology/internal medicine between April and September 2008. Patients were asked to provide data regarding symptoms they attributed to glucocorticoids, and adherence to treatment was measured using the four‐item Morisky–Green adherence scale. Logistic regression analyses were used to assess the association between reported adverse events and adherence to glucocorticoids. Results A total of 255 questionnaires were completed and analysed [women 78%; median age 48 years (interquartile range (IQR) 34–65); connective tissue diseases 59%; median duration of treatment 24 months (IQR 8–72); median daily dose 10 mg (IQR 6–20)]. Among these 255 patients, 199 (78%) reported themselves as ‘good adherents’ and 56 (22%) as ‘poor adherents’ to treatment. Poor adherence was associated with younger age [odds ratio (OR) 0·97, 95% confidence interval (CI) 0·95–0·99, per increasing year; P < 0·01], presence of glucocorticoid‐induced epigastralgia (OR 4·02, 95% CI 2·00–8·09; P < 0·01) and presence of glucocorticoid‐induced morphological changes (OR 2·49, 95% CI 1·19–5·21; P = 0·02). Moreover, patients with poor adherence were likely to report concomitantly poor adherence to dietary advice associated with glucocorticoid therapy (OR 2·44, 95% CI 1·12–5·26; P = 0·02). Conclusions As with other chronic therapies, the presence of glucocorticoid‐induced adverse events is associated with an altered self‐reported adherence to glucocorticoids. Patients who report epigastric pain or morphological changes that they associate with glucocorticoid therapy are particularly at risk of poor adherence. Adherence to dietary advice associated with glucocorticoid therapy may be an indirect measure of treatment adherence.     

Probiotics in pregnant women to prevent allergic disease: a randomized,double‐blind trial

Background Previous reports have suggested that certain probiotics given to mothers and children at risk of atopy halves the incidence of atopic dermatitis (AD) at 2 years of age. Objectives To examine if probiotics given to pregnant women in a nonselected population could prevent atopic sensitization or allergic diseases during the child’s first 2 years. Methods In a randomized, double‐blind trial of children from a nonselected maternal population (ClinicalTrials.gov identifier: NCT00159523), women received probiotic milk or placebo from 36 weeks of gestation to 3 months postnatally during breastfeeding. The probiotic milk contained Lactobacillus rhamnosus GG, L. acidophilus La‐5 and Bifidobacterium animalis subsp. lactis Bb‐12. Children with an itchy rash for more than 4 weeks were assessed for AD. At 2 years of age, all children were assessed for atopic sensitization, AD, asthma and allergic rhinoconjunctivitis. The intention‐to‐treat (ITT) analysis was enabled by multiple imputations. Results Four hundred and fifteen pregnant women were computer randomized. At 2 years, 138 and 140 children in the probiotic and the placebo groups, respectively, were assessed. In the ITT analysis, the odds ratio (OR) for the cumulative incidence of AD was 0·51 in the probiotic group compared with the placebo [95% confidence interval (CI) 0·30–0·87; P = 0·013]. There were no significant effects on asthma (OR 0·68, 95% CI 0·26–1·80; P = 0·437) or atopic sensitization (OR 1·52, 95% CI 0·74–3·14; P = 0·254). Conclusions Probiotics given to nonselected mothers reduced the cumulative incidence of AD, but had no effect on atopic sensitization.     

Efficacy and safety of bexarotene combined with psoralen-ultraviolet A (PUVA) compared with PUVA treatment alone in stage IB-IIA mycosis fungoides: final results from the EORTC Cutaneous Lymphoma Task Force phase III randomized clinical trial (NCT00056056)

Background Psoralen plus ultraviolet A (PUVA) is the standard treatment for early stages of mycosis fungoides. There have been no adequate randomized controlled trials with sufficient power comparing this modality with other therapies. Objective To assess disease response and to compare the response rates of patients treated with PUVA alone or PUVA and bexarotene. Methods EORTC 21011 (NCT 00056056) was a randomized phase III study comparing combined bexarotene (Targretin^®) and PUVA vs. PUVA alone in patients with stage IB and IIA mycosis fungoides (MF). The primary endpoint was the overall response rate [complete clinical response (CCR) plus partial response (PR)]. Results The study was prematurely closed due to low accrual after 93 of 145 required patients (65%) were randomized. Of the 93 randomized patients, 87 started treatment, 41 received PUVA and 46 received PUVA + bexarotene. Total UVA doses received were 107 J cm^?2 (range 1·4–489·9) in the PUVA arm vs. 101·7 J cm^?2 (0·2–529·9) in the combination arm. The safety profile was acceptable with few grade 3–4 toxicities observed in either arm. More drop‐outs due to toxicity were observed in the combination arm compared with the PUVA‐alone arm. The best overall response (CCR + PR) rate was 71% for PUVA alone and 77% for the combination arm (P = 0·57). The median duration of response was 9·7 months for PUVA vs. 5·8 months for the combination arm (P = 0·33). CCR was seen in 25 patients of whom 10 received PUVA alone (CCR 22%) and 15 received combination therapy (CCR 31%) (P = 0·45). CCR was sustained in 25% of patients regardless of therapy. There was a trend towards fewer PUVA sessions needed to achieve CCR in the combination arm (median 22) compared with the PUVA arm (median 27·5) (P = 0·11). Similarly, a trend towards lower UVA dose required to achieve CCR in the combination arm (median 55·8 J cm^?2) compared with the PUVA arm alone (median 117·5 J cm^?2) (P = 0·5) was observed. Conclusions No significant difference in response rate or response duration was observed in this study. However, there was a trend towards fewer PUVA sessions and lower UVA dose required to achieve CCR in the combination arm (PUVA + bexarotene) but this did not achieve statistical significance due to insufficient power.     

Ulcer recurrence after in‐hospital treatment for recalcitrant venous leg ulceration

Background Leg ulceration caused by chronic venous disease occurs in 1% of the adult Western population. A majority of these patients is successfully treated in the outpatient setting. A minority of patients is hospitalized, most frequently because of the lack of healing tendency. The literature provides recurrence rates for ulcer disease, but lacks specific data on recurrence rates after in‐hospital treatment of recalcitrant venous leg ulcers. Objectives To investigate time to ulcer recurrence after in‐hospital treatment of venous leg ulceration. Methods A multicentre, retrospective cohort study of patients admitted for leg ulceration between 1996 and 2007 was conducted. Results Data could be collected for 107 of the patients. Of these, 27 had conservative treatment (bed rest, local wound care, pain management) and 48 patients underwent surgical ulcer treatment with (n = 19) or without (n = 29) initial vacuum‐assisted closure (VAC) treatment. The treatment method was ‘miscellaneous’ in the remaining 32 patients. Median admission time was 30 days, median percentage of closure at discharge was 95%, and median time to ulcer recurrence 60 days. The Mann–Whitney U‐test showed significant differences between the conservative group and the surgery group, the latter having a longer length of hospital stay (P < 0·0001) and a higher percentage of ulcer closure (P < 0·0001), but there was no difference in time to ulcer recurrence (P = 0·273). Comparable differences were demonstrated between the conservative group and the VAC plus surgery group. No significant differences could be demonstrated between the surgically treated patients and those treated by VAC and surgery. Conclusions Hospital stay is significantly shorter in cases of surgical treatment of recalcitrant venous leg ulcers. Most ulcers recur within 2 months after hospital discharge. Recurrence of venous leg ulcers after hospital admission is independent of the method of treatment and cause of ulceration.     

Polymorphisms in human histamine receptor H4 gene are associated with atopic dermatitis

Background Atopic dermatitis (AD) is a chronic skin disease affecting more than 15% of children and 2% of adults. A strong connection between genetic factors and AD has been described for a long time. Histamine receptor H4 (HRH4) has been shown to be related to different kinds of allergic and autoimmune disorders. However, an association between HRH4 and AD has not yet been reported. Objectives To examine a possible association between HRH4 and AD. Methods Genomic DNA from 301 patients with AD and 313 healthy controls was extracted and three exons of HRH4 were sequenced. Results We found three new single nucleotide polymorphisms (SNPs) in HRH4 which were significantly associated with AD: ss142022671 [odds ratio (OR) 1·87, 95% confidence interval (CI) 1·24–2·81; P = 0·002], ss142022677 (OR 4·40, 95% CI 2·42–8·00; P = 1·5 × 10^?7) and ss142022679 (OR 4·26, 95% CI 2·38–7·61; P = 1·3 × 10^?7). The SNPs ss142022677 and ss142022679 were found to be in strong linkage disequilibrium (D’ = 0·98; r² = 0·92). Two‐SNP haplotype analysis (ss142022677 and ss142022679) showed that the major AA haplotype was protective against AD (OR 0·22, 95% CI 0·12–0·40; P = 3·1 × 10^?8) and the minor TT haplotype was significantly associated with AD (OR 4·13, 95% CI 2·27–7·54; P = 6·6 × 10^?7). In addition, in a three‐SNP haplotype analysis (ss142022671, ss142022677 and ss142022679), the major TAA haplotype was protective against AD (OR 0·46, 95% CI 0·31–0·69; P = 0·0001), while the complementary ATT haplotype was found to be significantly associated with AD (OR 3·81, 95% CI 2·03–7·14; P = 8·3 × 10^?6). Conclusions Polymorphisms of ss142022671, ss142022677 and ss142022679 in HRH4 are associated with AD.     

Genetic association of HLA-DQB1 and HLA-DRB1 polymorphisms with alopecia areata in the Italian population

Background Alopecia areata (AA) is a multifactorial disease characterized by hair loss especially from the scalp. As for other autoimmune conditions, the major histocompatibility complex (HLA) region is associated with AA susceptibility. Objective To provide evidence for the association of specific HLA‐DQB1 and HLA‐DRB1 alleles with AA in an Italian population, using a case–control approach. Methods We performed a case–control study to investigate whether HLA‐DQB1 and ‐DRB1 alleles predispose to AA in the Italian population. HLA class II typing was performed in 85 patients with AA and 210 healthy controls from the same ethnic group. Results An increased frequency of DQB1*03, coding for DQ7 heterodimers, and a decreased rate of the DQB1*06 allele were observed in patients when compared with controls; the greatest and significant difference was in the group of cases with a more severe phenotype [AA > 50% patients (more than 50% hair loss) vs. controls, P = 4·5 × 10^?3, P_c = 0·031, odds ratio (OR) 2·01, 95% confidence interval (CI) 1·22–3·31 and P = 2·5 × 10^?3, P_c = 0·017, OR 0·22, 95% CI 0·07–0·72, respectively]. DQB1*03, serologically related to DQ8 or coding for DQ9 molecules, was not associated with AA susceptibility. Out of all patients, 65·9% carried DQ7 heterodimers compared with 49·5% of the controls (P = 7·3 × 10^?3, OR 1·97, 95% CI 1·17–3·32) and DQ7 prevalence rose to 76·3% in patients with AA > 50% (P = 1·7 × 10^?3, OR 3·28, 95% CI 1·48–7·27). No significant difference was found in the distribution of DRB1 variants or phenotypes among cases and controls. Conclusion Our data show a correlation between the HLA‐DQB1 locus and the occurrence of AA in Italy supporting DQB1*03(DQ7) as a predisposing allele for the disease and the relevance of the HLA genetic test in the clinical management of AA.     

Randomized controlled trial comparing the effectiveness of 308-nm excimer laser alone or in combination with topical hydrocortisone 17-butyrate cream in the treatment of vitiligo of the face and neck

Background Vitiligo is a pigmentary disorder which may have disfiguring consequences. Its treatment remains a challenge. Objectives We designed a parallel‐group randomized controlled trial to compare the effectiveness of 308‐nm excimer laser alone or in combination with topical hydrocortisone 17‐butyrate cream in patients with vitiligo unresponsive to previous treatment with topical steroids or narrow‐band ultraviolet (UV) B phototherapy. Methods Consecutive patients aged 18–75 years with nonsegmental vitiligo localized on the face and/or neck lacking response to previous conventional treatment were eligible. In total, 84 patients (44 women and 40 men, mean age 44 years) were randomized to 308‐nm excimer laser phototherapy twice weekly alone or in combination with topical hydrocortisone 17‐butyrate cream twice daily for three periods of 3 weeks followed by a 1‐week steroid‐free interval. The primary outcome was a reduction of at least 75% of the overall lesional areas as judged by automatic image analysis on reflected UV photographs, conducted blind to treatment assignment, at 12 weeks compared with baseline. Secondary outcomes were clearance, and improvements on Physician’s Global Assessment (PGA) and Skindex‐29 scores. Results A total of 76 (90%) patients completed the study. In an intention‐to‐treat analysis, seven [16·6%; 95% confidence interval (CI) 5·3–27·8%] patients in the excimer monotherapy arm and 18 (42·8%; 95% CI 27·8–57·8%) in the combination arm showed ≥ 75% reduction of vitiligo lesions at 12 weeks (χ² test 6·89, P = 0·0087). Clearance was observed in two (4·7%; 95% CI 1·6–11·2%) and nine (21·4%; 95% CI 9·0–33·8%) patients, respectively (Fisher’s exact test P = 0·04). A significant difference also emerged for PGA scores, while no difference was documented for Skindex‐29. Conclusions Recalcitrant vitiligo of the face and neck may benefit from the combination of excimer laser phototherapy with topical hydrocortisone 17‐butyrate cream.     

What causes flares of eczema in children?

Summary Background Although eczema affects 2–20% of children worldwide, there is little direct evidence on the role of environmental factors in disease flares. Objectives We sought to identify which environmental factors might worsen eczema. Methods Sixty children aged 0–15 years with eczema were studied intensively for up to 9 months. Daily electronic diaries and portable data loggers were used to record indoor exposures, and external meteorological data were obtained from a local monitoring centre. The primary outcome was a daily ‘bother’ score. Autoregressive moving average models were used to study the impact of exposures on eczema severity for individuals. Random effects modelling pooled estimated regression coefficients across participants. Results Increased severity was associated with nylon clothing [pooled regression coefficient 0·23, 95% confidence interval (CI) 0·03–0·43], dust (0·53, 0·23–0·83), unfamiliar pets (0·22, 0·10–0·34), sweating (0·24, 0·09–0·39) and shampoo (0·07, 0·01–0·14). The latter was enhanced in cold weather (0·30, 0·04–0·57). Body‐site specificity was observed for nylon clothing, (trunk P =0·02, limbs P = 0·03), wool clothing (trunk P = 0·03, but not limbs P = 0·62) and unfamiliar pets (hands P < 0·001). A combination of any three of seven likely variables was associated with disease worsening (pooled regression coefficient 0·41, 95% CI 0·20–0·63). Conclusions This exploratory study suggests that nylon clothing, dust, unfamiliar pets, sweating and shampoos may play a direct role in worsening eczema in children with eczema. Combinations of exposures acting in concert may also be important. Such knowledge may be useful to families with eczema and could lead to better strategies for preventing flares.     

The association between porphyria cutanea tarda and diabetes mellitus: analysis of a long-term follow-up cohort

Background An association between porphyria cutanea tarda (PCT) and diabetes mellitus (DM) is widely reported, but the pathogenetic link remains unknown. Objectives To investigate the natural history of DM in the setting of PCT and to determine which PCT features and risk factors may be associated with the development of DM. Methods This retrospective longitudinal study included 81 Spanish patients with PCT with at least 10 years of strict follow‐up. Patients attended our Porphyria Unit for follow‐up visits and the data were collected in the period 2004–2008. We classified patients into two groups: patients with glucose metabolism alterations (GMA: DM or impaired fasting glucose), and patients without. PCT features and PCT and DM risk factors were retrieved from clinical charts and compared between groups. Results We identified 33 patients (41%) with GMA, of whom 27 (82%) developed GMA a long time after the diagnosis of PCT (mean 12·7 years). In bivariate analysis, these patients had significantly higher mean serum ferritin at diagnosis (651 vs. 405 ng mL^?1; P = 0·005), a higher prevalence of persistently elevated serum ferritin (52% vs. 15%; P < 0·001 for trend) and a higher prevalence of family history of DM (48% vs. 19%; P = 0·004). In multivariate analysis, persistently elevated serum ferritin [odds ratio (OR) 10·66, 95% confidence interval (CI) 1·95–58·19; P = 0·006] and family history of DM (OR 4·82, 95% CI 1·34–17·33; P = 0·016) remained significantly associated with the presence of GMA. Conclusions GMA are highly prevalent in patients with PCT and mostly develop a long time after the diagnosis of PCT. Persistent hyperferritinaemia seems to be a risk biomarker of GMA in patients with PCT, probably in the setting of chronic iron overload and hepatic inflammation. Strict long‐term monitoring of glucose metabolism and serum ferritin may be advisable in the routine follow‐up of patients with PCT.     

Conradi–Hünermann–Happle syndrome with abnormal lamellar granule contents

Background Long‐term maintenance treatment with 0·1% tacrolimus ointment for the prevention of flares has been demonstrated to be well tolerated and effective in adults for the treatment of atopic dermatitis (AD) but its impact on health‐related utility has not been reported. Objectives The purpose of this study was to estimate utility changes associated with the use of tacrolimus ointment in the maintenance treatment of adults with AD. Methods Data were collected from a clinical trial investigating long‐term maintenance treatment with 0·1% tacrolimus ointment in adults with AD. All patients were treated with twice‐daily tacrolimus ointment during an open‐label period (OLP) of up to 6 weeks, with subsequent randomization to a double‐blind disease‐control period (DCP) of 12 months comparing tacrolimus ointment, used twice weekly as maintenance treatment, vs. the emollient vehicle as standard treatment. Health‐related utility (EQ‐5D_index) was estimated by Monte Carlo simulation from SF‐12 responses by application of a published response mapping algorithm and the U.K. tariff for EQ‐5D responses and SF‐6D responses, respectively. Results Evaluable data were available for 257 patients stratified into mild, moderate or severe AD with a median age at screening of 28 years [interquartile range (IQR) 22–38] and 40% male. At screening the median EQ‐5D_index across the strata was 0·848 units (IQR 0·704–0·882) for mild cases, 0·796 (0·737–0·876) for moderate cases, and 0·760 (0·661–0·823, P < 0·001) for those with severe disease. At the end of the OLP, mean utility improvement across all strata was 0·027 [95% confidence interval (CI) −0·011 to 0·065, P = 0·165] for mild cases, 0·046 (95% CI 0·015–0·064, P = 0·002) for moderate cases and 0·076 (95% CI 0·035–0·118, P < 0·001) for those with severe disease. At the end of the blinded DCP, repeated measures analysis showed an age‐ and sex‐adjusted mean change of 0·045 units (P < 0·001) for subjects treated with tacrolimus ointment over those treated with emollient vehicle. Conclusions Patients with AD of all severities showed considerable decrements in health‐related utility. However, treatment with 0·1% tacrolimus ointment was associated with clinically significant improvement in health‐related utility for patients with moderate and severe AD, which was sustained over a 12‐month maintenance period compared with those using standard treatment with an emollient vehicle.     

P-cadherin expression in Merkel cell carcinomas is associated with prolonged recurrence-free survival

Background Merkel cell carcinoma (MCC) is a highly aggressive skin cancer, associated with advanced age, immunosuppression and Merkel cell polyomavirus (MCV) infections. As development and progression of cancer can be promoted by changes in cell adhesion proteins, we have previously analysed homo‐ and heterotypic cell–cell contacts of normal Merkel cells and MCCs and obtained indications for cadherin switching. Objectives To examine the prevalence and prognostic relevance of E‐, N‐ and P‐cadherin in MCCs. Methods Paraffin‐embedded MCC samples (n = 148) from 106 different patients were analysed by double‐label immunostaining and immunofluorescence microscopy. MCV status was determined by real‐time polymerase chain reaction. The cadherin repertoire and MCV status were correlated to clinical data, including tumour stage and recurrence‐free survival. Results Ninety‐one per cent of all MCC were positive for N‐cadherin whereas only 61·6% and 70·3% expressed E‐ and P‐cadherin, respectively. P‐cadherin was significantly more frequent in primary tumours than in lymph node metastases (81·9% vs. 40·9%, P = 0·0002). Patients with P‐cadherin‐positive primary tumours were in earlier tumour stages at initial diagnosis (P = 0·0046). Both in log‐rank tests (P = 0·0474) and in multiple Cox regression analysis including age, sex, immunosuppression, stage at initial diagnosis and MCV status (hazard ratio 0·193, P = 0·0373), patients with P‐cadherin‐positive primary MCCs had significantly prolonged recurrence‐free survival (mean 25·2 vs. 10·6 months; median 9·0 vs. 4·0 months). MCV DNA was detected in 78·2% of all MCC, more frequently in P‐cadherin‐positive MCC (P = 0·0008). Conclusion P‐cadherin expression in MCCs predicts prolonged recurrence‐free survival and may therefore indicate favourable prognosis.     

Prospective study of skin surgery in smokers vs. nonsmokers

Background Smoking may increase complications following minor surgery leading many clinicians to urge patients to refrain from smoking before and after surgery. Objective To study the association between smoking and complications following skin surgery. Methods In a 5‐year prospective observational study 7224 lesions were excised on 4197 patients. Patients were not instructed regarding smoking. All complications were recorded. Results A total of 439 smokers (10·5%) underwent 646 procedures (9%), 3758 nonsmokers (89·5%) underwent 6578 procedures (91%). Smokers were younger (55 ± 16 years) than nonsmokers (66 ± 17 years) (P < 0·001). Infection incidence was not significantly different, 1·9% (12/646) in smokers compared with 2·2% (146/6578) in nonsmokers (P = 0·55). There were two bleeds with smokers (0·3%) vs. 50 in nonsmokers (0·8%) (P = 0·2). The incidence of wound dehiscence in nonsmokers (three) was not different from nonsmokers (21) (P = 0·54). However, the incidence of scar contour distortion in smokers (three) was greater than in nonsmokers (two) (odds ratio 15·3; 95% confidence interval 2·5–92). Total complication incidence was similar, 3·6% in smokers vs. 4·0% in nonsmokers (P = 0·58). Out of 2371 flaps there were 14 (0·6%) cases of end‐flap necrosis but smokers were not at increased risk. The case–control analysis compared each smoker with two nonsmokers matched for age, sex, postal code and outdoor occupational exposure. This again demonstrated no difference in infection, scar complication, bleed, dehiscence, end‐flap necrosis or total complication incidence. Conclusions Smokers and nonsmokers suffer skin surgery complications similarly. The increased risk of contour distortion identified was difficult to interpret. Advice to cease smoking in the short term to improve outcomes with skin cancer surgery is not supported by these data.     

A phase IIIb,multicentre, randomized,double‐blind,vehicle‐controlled study of the efficacy and safety of adalimumab with and without calcipotriol/betamethasone topical treatment in patients with moderate to severe psoriasis: the BELIEVE study

Background Data are lacking on the use of topical therapies in combination with tumour necrosis factor blockers for the treatment of psoriasis. Objectives To assess the efficacy and safety of adalimumab (ADA) with topical calcipotriol/betamethasone (C/B) in patients with psoriasis resembling those treated in routine clinical practice. Methods A 16‐week, randomized, vehicle‐controlled trial was conducted in patients with moderate to severe psoriasis and previous failure, intolerance or contraindications to two or more systemic treatments. All patients received ADA (80 mg, week 0; 40 mg every other week, weeks 1–15) in addition to either topical C/B or drug‐free vehicle applied once daily for 4 weeks, and as needed thereafter. The primary endpoint was 75% improvement from baseline in Psoriasis Area and Severity Index (PASI 75) at week 16. Results A total of 730 patients received either ADA + C/B (n = 366) or ADA + vehicle (n = 364). PASI 75 response was initially higher with the combination therapy [14·8% for ADA + C/B vs. 5·8% for ADA + vehicle at week 2 (P < 0·001); and 40·7% vs. 32·4%, respectively, at week 4 (P = 0·021)]. After week 4, the trend was towards a higher response with ADA monotherapy, with no statistical difference in the PASI 75 response at week 16 (64·8% for ADA + C/B vs. 70·9% for ADA monotherapy, P = 0·086). Safety findings were consistent with previous ADA trials. Conclusions ADA + C/B resulted in more rapid and higher efficacy within the first 4 weeks; thereafter, the trend was towards a higher response with ADA monotherapy. There was no statistical difference in the PASI 75 response at week 16. Both treatment regimens were well tolerated.     

Pain evaluation and control during and following the treatment of hypertrophic scars and keloids by contact and intralesional cryosurgery – a preliminary study

Background Intralesional cryosurgery effectively treats hypertrophic scars and keloids (HSK), but pain experienced by the patient during treatment can limit the application of cryosurgery. Objectives  To characterize the pain response during cryosurgical treatment of HSK, and to evaluate the pain experienced during contact and intralesional cryosurgery that employs a pain‐control protocol. Methods  Twenty‐nine patients (17 women, 12 men) aged 17 years and older (mean ages 31.9 ± 12.5 and 38.9 ± 18.6 years, respectively, P = 0.24), who were treated for a total of 36 HSKs by intralesional (n = 20; 22 cryotreatments) or contact (n = 9; 14 cryotreatments) cryosurgery were evaluated. The pain‐control protocol involved oral pain‐relief tablets (Dipyrone) and translesional local anaesthesia with Bupivacaine hydrochloride 0.5%. Pain evaluation according to the Visual Analogue Scale (VAS) (0–10 cm) was compared between the two groups at three time points: during cryosurgery, immediately after it, and 4 h later. Scores ≤3 cm were considered to define the ‘zone of analgesic success’. These results were compared with control data (contact cryosurgery without a pain‐control protocol; n = 56). Results  Pain in the intralesional group was significantly lower than that in the contact group during and immediately after cryotreatment. During: mean VAS = 1.68 ± 2.21 vs. 5.07 ± 4.01 cm; median VAS = 0.5 vs. 5.5 cm, respectively; P < 0.0001. Immediately after: mean VAS = 1.22 ± 1.77 vs. 5.38 ± 3.81 cm; median VAS = 0 vs. 6.0 cm, respectively; P = 0.001. The control group had more pain during treatment (mean VAS = 5.34 ± 2.31, median = 6.0) and 4 h later (mean = 3.79 ± 2.35, median = 4.0) than the intralesional group (P < 0.0001 and P = 0.988, respectively). The pain level in the control group during the cryotreatment did not differ from that in the contact group (P = 0.988). In the intralesional, contact and control groups analgesic success (VAS ≤3 cm) was achieved in 77.3%, 35.7% and 33.9%, respectively, of cases (P = 0.002) during cryotreatment, and in 54.5%, 42.9% and 33.9%, respectively, of cases 4 h after treatment (P = 0.24). Conclusions  The pain‐control protocol significantly reduced pain severity to tolerable levels (VAS ≤3 cm) during and following intralesional and contact cryosurgery. Intralesional cryosurgery caused the least pain during and immediately after treatment.