Quantitative intracellular oxygen availability before and after 5-aminolevulinic acid skin photodynamic therapy.

BACKGROUND: During photodynamic therapy (PDT) oxygen is transformed into reactive oxygen species (ROS) to induce cellular apoptosis in (pre)malignant cells. Real time oxygen availability measurement is clinically available with the Cellular Oxygen Metabolism (COMET) monitor. METHODS: Primary objective is to show that mitochondrial oxygen availability (mitoPO2) measurement is possible during clinical ALA-PDT. The secondary aim was to determine the pain sensation, because it is the most commonly reported side effect of PDT. Before and after the two fraction PDT treatment, with a 2-hour dark period, mitoPO2 was measured and reported pain was documented with a visual analog scale (VAS) 0-100. RESULTS: Nine patients were included. Before the first PDT session the median signal quality was [IQR] 55.0% [34.2-68.0], which decreased after session one to 0% [0.0-10.0]. MitoPO2 was 40.0 [17.7-53.8] mmHg and increased afterwards to 61.8 [38.2-64.8] mmHg. This likely the result of the delay time between the illumination stop and the mitoPO2 measurements in a vasodilated, visibly red lesion. Before session two signal quality was 10.4% [0-20.15], 40% lower than at the start. In 5 patients the signal quality after session 2 was too low because of photobleaching and insufficient regeneration of PpIX, median 0% [0-10]. Subjects reported low median VAS scores, all below 3, directly after the mitoPO2 measurements. CONCLUSION: With COMET we were able to reliably measure mitochondrial oxygen concentrations during photodynamic therapy. Signal quality drastically decreases after a PDT session because of PpIX deterioration during the illumination phase.

Adalimumab and infliximab survival in patients with hidradenitis suppurativa: a daily practice cohort study.

BACKGROUND: Biologics are often required for the treatment of hidradenitis suppurativa (HS). However, data on the drug survival of biologics in daily practice are currently lacking. OBJECTIVES: To assess the drug survival of antitumour necrosis factor biologics in a daily practice cohort of patients with HS and to identify predictors for drug survival. METHODS: A retrospective multicentre study was performed in two academic dermatology centres in the Netherlands. Adult patients with HS using biologics between 2008 and 2020 were included. Drug survival was analysed with Kaplan-Meier survival curves and predictors of survival with univariate Cox regression analysis. RESULTS: The overall drug survival of adalimumab (n = 104) at 12 and 24 months was 56·3% and 30·5%, respectively, which was predominantly determined by infectiveness. Older age (P = 0·02) and longer disease duration (P < 0·01) were associated with longer survival time. For infliximab (n = 44), overall drug survival was 58·3% and 48·6% at 12 and 24 months, respectively, and was predominantly determined by infectiveness and side-effects. Surgery during treatment was associated with a longer survival time (P = 0·01). CONCLUSIONS: Survival rates were comparable for adalimumab and infliximab at 12 months, and were mainly determined by ineffectiveness. Age, disease duration (adalimumab) and surgery (infliximab) are predictors for longer survival.

A novel nicastrin mutation in a three-generation Dutch family with hidradenitis suppurativa: a search for functional significance.

BACKGROUND: Mutations in the γ-secretase enzyme subunits have been described in multiple kindreds with familial hidradenitis suppurativa (HS). OBJECTIVE: In this study, we report a novel nicastrin (NCSTN) mutation causing HS in a Dutch family. We sought to explore the immunobiological function of NCSTN mutations using data of the Immunological Genome Project. METHODS: Blood samples of three affected and two unaffected family members were collected. Whole-genome sequencing was performed using genomic DNA isolated from peripheral blood leucocytes. Sanger sequencing was done to confirm the causative NCSTN variant and the familial segregation. The microarray data set of the Immunological Genome Project was used for thorough dissection of the expression and function of wildtype NCSTN in the immune system. RESULTS: In a family consisting of 23 members, we found an autosomal dominant inheritance pattern of HS and detected a novel splice site mutation (c.1912_1915delCAGT) in the NCSTN gene resulting in a frameshift and subsequent premature stop. All affected individuals had HS lesions on non-flexural and atypical locations. Wildtype NCSTN appears to be upregulated in myeloid cells like monocytes and macrophages, and in mesenchymal cells such as fibroblastic reticular cells and fibroblasts. In addition, within the 25 highest co-expressed genes with NCSTN we identified CAPNS1, ARNT and PPARD. CONCLUSION: This study reports the identification a novel NCSTN gene splice site mutation which causes familial HS. The associated immunobiological functions of NCSTN and its co-expressed genes ARNT and PPARD link genetics to the most common environmental and metabolic HS risk factors which are smoking and obesity.

Current and future treatment of hidradenitis suppurativa.

This scholarly review on the current and future treatment of hidradenitis suppurativa (HS) focuses on medical and surgical treatment options, while novel pipeline drugs are also discussed. Treatment goals are to limit the incidence and duration of flares, reducing inflammation and suppuration, achieving local cure after surgery and, most importantly, to improve the quality of life of patients with HS. The type of medication and/or surgery should be chosen based on the stage of the disease and the degree of inflammation. However, the lack of a simple scoring system and the lack of clear surgical outcome definitions hamper the interpretation of treatment efficacy and the comparison between different treatment strategies. The therapeutic pipeline for HS is gradually expanding, and will probably lead to a broader panel of more effective therapeutic options.

Conjunctivitis in dupilumab clinical trials.

BACKGROUND: Dupilumab blocks the shared receptor component for interleukin (IL)-4 and IL-13. It is approved in the U.S.A. for patients aged ≥ 12 years with moderate-to-severe atopic dermatitis (AD) uncontrolled by topical prescription medicines or who cannot use topical medicines, for patients in Japan whose AD is uncontrolled with existing therapies, for patients with moderate-to-severe AD in Europe who are candidates for systemic therapy and for patients aged ≥ 12 years for maintenance treatment of moderate-to-severe asthma uncontrolled with their current medicines. AD trials have reported increased incidence of conjunctivitis for dupilumab vs. placebo. OBJECTIVES: To characterize further the occurrence and risk factors of conjunctivitis in dupilumab clinical trials. METHODS: We evaluated randomized placebo-controlled trials of dupilumab in AD (n = 2629), asthma (n = 2876), chronic rhinosinusitis with nasal polyps (CRSwNP) (n = 60) and eosinophilic oesophagitis (EoE) (n = 47). RESULTS: In most AD trials, dupilumab-treated patients had higher conjunctivitis incidence than placebo controls. Higher baseline AD severity and previous history of conjunctivitis were associated with increased conjunctivitis incidence. Conjunctivitis was mostly mild to moderate. Most cases recovered or resolved during the treatment period; two patients permanently discontinued dupilumab due to conjunctivitis or keratitis. Common treatments included ophthalmic corticosteroids, antibiotics, and antihistamines or mast cell stabilizers. Most cases were diagnosed by the investigators. In asthma and CRSwNP trials, the incidence of conjunctivitis was lower for both dupilumab and placebo than in AD trials; dupilumab did not increase the incidence compared with placebo. In the EoE trial, no patients had conjunctivitis. CONCLUSIONS: Conjunctivitis was more frequent with dupilumab treatment in most AD trials. In dupilumab trials in other type 2 diseases, incidence of conjunctivitis was overall very low, and was similar for dupilumab and placebo. In AD, the incidence of conjunctivitis was associated with AD severity and prior history of conjunctivitis. The aetiology and treatment of conjunctivitis in dupilumab-treated patients require further study. What's already known about this topic? Ocular disorders, including allergic conjunctivitis, are common in patients with atopic dermatitis (AD). In most dupilumab AD trials, dupilumab-treated patients had higher conjunctivitis incidence than those receiving placebo. Most cases were mild to moderate and recovered or were recovering during study treatment; study treatment discontinuation due to conjunctivitis was rare. Conjunctivitis incidence was very low and similar for dupilumab and placebo in clinical trials in asthma, chronic rhinosinusitis with nasal polyps and eosinophilic oesophagitis. What does this study add? This analysis confirms and extends the results of the individual clinical trials. Baseline disease-related factors, including AD severity, prior conjunctivitis history and certain biomarkers (thymus and activation-regulated chemokine, IgE, eosinophils), were associated with increased incidence of conjunctivitis. Patients who responded well to dupilumab had reduced incidence of conjunctivitis. Further study is needed to elucidate the aetiology and treatment of conjunctivitis in dupilumab-treated patients with AD.

Adalimumab medium-term dosing strategy in moderate-to-severe hidradenitis suppurativa: integrated results from the phase III randomized placebo-controlled PIONEER trials.

BACKGROUND: Weekly adalimumab (Humira® ) is approved for the treatment of hidradenitis suppurativa (HS) based on the 12-week placebo-controlled periods of the two phase III PIONEER trials. OBJECTIVES: Using PIONEER integrated trial results, we aimed to evaluate the optimal medium-term adalimumab maintenance dosing strategy for moderate-to-severe HS. METHODS: Each trial had two double-blind periods; 12-week Period A and 24-week Period B. Patients randomized to adalimumab 40 mg every week (ADAew) (Period A), were rerandomized in Period B to ADAew (ADAew/ew), ADA every other week (ADAew/eow), or placebo (ADAew/pbo). Placebo-randomized patients were reassigned in Period B to ADAew (PIONEER I) or placebo (PIONEER II). The primary outcome was HS Clinical Response (HiSCR). Patients who lost response during Period B were discontinued from the study and offered an option to enter the open-label extension (OLE) to receive ADAew. Results are reported across the two study periods, and data were combined from the two study periods and the OLE. RESULTS: For week-12 HiSCR achievers, the HiSCR week-36 rate was 48·1% (ADAew/ew) vs. 46·2% (ADAew/eow) and 32·1% (ADAew/pbo). Combining (post hoc) these patients with week-12 partial responders further differentiated outcomes in Period B (ADAew/ew 55·7% vs. ADAew/eow 40·0% and ADAew/pbo 30·1%). Period-B adverse-event rates were ADAew/ew 59·6% vs. ADAew/eow 57·4% and ADAew/pbo 65·0%. One patient (ADAew/ew) reported a serious infection. CONCLUSIONS: Weekly adalimumab treatment, effective throughout 36 weeks, was the optimal maintenance medium-term dosing regimen for this population. At least partial response after 12 weeks with continued weekly dosing had better outcomes than dose reduction or interruption. Patients who do not show at least a partial response to weekly adalimumab by week 12 are unlikely to benefit from continued therapy. No new safety risks were identified. What's already known about this topic? Hidradenitis suppurativa (HS) is a chronic inflammatory disease, commonly misinterpreted as an infection and treated with long-term antibiotic regimens or surgical incisions. Based on the chronicity of HS and the lack of evidence for efficacious and safe long-term HS treatments, it is important to evaluate medium- to long-term therapies for HS. Weekly adalimumab (Humira® ) is approved for the treatment of moderate-to-severe HS based on the two phase III PIONEER trials. What does this study add? This study pooled data from the two PIONEER trials, providing a more robust assessment of outcomes. After at least partial treatment success with weekly adalimumab short-term therapy (12 weeks), continuing weekly dosing during the subsequent 24 weeks had better outcomes than dose reduction or treatment interruption. Patients who do not show at least a partial response to weekly adalimumab by week 12 are unlikely to benefit from continued therapy.

The anti-inflammatory potency of biologics targeting tumour necrosis factor-α, interleukin (IL)-17A, IL-12/23 and CD20 in hidradenitis suppurativa: an ex vivo study.

BACKGROUND: Biologics targeting inflammatory mediators can achieve clinical improvements in hidradenitis suppurativa (HS). However, their clinical efficacy shows great interpatient variability in daily practice. OBJECTIVES: To investigate the anti-inflammatory potency of a selection of currently available biologics and prednisolone for the treatment of HS in an ex vivo skin culture system using lesional HS biopsies. METHODS: Lesional skin samples from 10 patients with HS and skin samples from five healthy controls were cultured ex vivo and exposed to prednisolone or biologics targeting tumour necrosis factor (TNF)-α, interleukin (IL)-17A, IL-12/23p40 or CD20 (adalimumab, infliximab, secukinumab, ustekinumab and rituximab, respectively). Real-time quantitative polymerase chain reaction and cytokine bead arrays were used to measure the inhibitory effect of the biologics on cytokines and antimicrobial peptides (AMPs). RESULTS: The relative mRNA expression of all tested cytokines and AMPs was significantly downregulated by all anti-inflammatory agents (P < 0·001). The protein production of the proinflammatory cytokines TNF-α, interferon γ, IL-1ß, IL-6 and IL-17A was significantly inhibited by adalimumab, infliximab, ustekinumab, prednisolone (all P < 0·001) and rituximab (P = 0·0071), but not by secukinumab (P = 0·0663). On both mRNA and protein levels, adalimumab, infliximab and prednisolone reduced the levels of a broader mix of individual cytokines than secukinumab, ustekinumab and rituximab. Moreover, a significant inhibitory effect on mRNA expression levels of inflammatory markers in healthy control skin was observed only for TNF-α inhibitors (P < 0·001) and prednisolone (P = 0·0015). CONCLUSIONS: This ex vivo study suggests that TNF-α inhibitors and prednisolone are the most powerful inhibitors of proinflammatory cytokines and AMPs in HS lesional skin, which concurs with our clinical experience in patients with HS.

Hidradenitis suppurativa/acne inversa: a practical framework for treatment optimization - systematic review and recommendations from the HS ALLIANCE working group.

Hidradenitis suppurativa (HS)/acne inversa is a debilitating chronic disease that remains poorly understood and difficult to manage. Clinical practice is variable, and there is a need for international, evidence-based and easily applicable consensus on HS management. We report here the findings of a systematic literature review, which were subsequently used as a basis for the development of international consensus recommendations for the management of patients with HS. A systematic literature review was performed for each of nine clinical questions in HS (defined by an expert steering committee), covering comorbidity assessment, therapy (medical, surgical and combinations) and response to treatment. Included articles underwent data extraction and were graded according to the Oxford Centre for Evidence-based Medicine criteria. Evidence-based recommendations were then drafted, refined and voted upon, using a modified Delphi process. Overall, 5310 articles were screened, 171 articles were analysed, and 65 were used to derive recommendations. These articles included six randomized controlled trials plus cohort studies and case series. The highest level of evidence concerned dosing recommendations for topical clindamycin in mild disease (with systemic tetracyclines for more frequent/widespread lesions) and biologic therapy (especially adalimumab) as second-line agents (following conventional therapy failure). Good-quality evidence was available for the hidradenitis suppurativa clinical response (HiSCR) as a dichotomous outcome measure in inflammatory areas under treatment. Lower-level evidence supported recommendations for topical triclosan and oral zinc in mild-to-moderate HS, systemic clindamycin and rifampicin in moderate HS and intravenous ertapenem in selected patients with more severe disease. Intralesional or systemic steroids may also be considered. Local surgical excision is suggested for mild-to-moderate HS, with wide excision for more extensive disease. Despite a paucity of good-quality data on management decisions in HS, this systematic review has enabled the development of robust and easily applicable clinical recommendations for international physicians based on graded evidence.

Apremilast for moderate hidradenitis suppurativa: no significant change in lesional skin inflammatory biomarkers.

BACKGROUND: Treatment with apremilast has recently demonstrated clinically meaningful improvement in moderate hidradenitis suppurativa (HS). OBJECTIVE: To evaluate the change in expression of inflammatory markers in lesional skin of HS patients receiving apremilast 30 mg twice daily (n = 15) for 16 weeks compared with placebo (n = 5). METHODS: At baseline, 5-mm punch biopsies were obtained from an index lesion (HSL) and non-lesional (HSN) skin in the same anatomical area. Subsequent HSL samples were taken as close as possible to the previously biopsied site at week 4 and week 16. After sampling, biopsies were split; one half was processed for in vivo mRNA analysis using real-time quantitative PCR; the other half was cultured for ex vivo protein analysis using a proximity extension assay (Olink). Linear mixed effects models were calculated to compare the levels of inflammatory markers in HSL skin between apremilast and placebo over time. RESULTS: At baseline, 17 proteins with a fold change >2 in HSL vs. HSN skin were identified in 20 patients. The top five were IL-17A (5), S100A12, CST5, IL-12/23p40, CD6 (1) with fold changes ranging from 6.6 to 1638, respectively (FDR <0.044). Linear mixed effects models for 75 assays were calculated. Protein levels of S100A12 decreased during treatment in the apremilast group compared with the placebo group (p = 0.014, FDR = 0.186). None of the 14 genes exhibited significant changes in expression over time. However, an evident downward trend in relative mRNA expression of IL-17A and IL-17F was demonstrated in patients receiving apremilast. CONCLUSION: We did not detect statistically significant changes in inflammatory markers in HSL skin of HS patients receiving apremilast compared with placebo, despite clinical improvement in the apremilast group. Nonetheless, S100A12 and IL-17A were significantly elevated in HSL skin and showed a decrease in response to apremilast. The translational model in clinical trials involving HS clearly needs further improvement.

Hidradenitis suppurativa treated with wide excision and second intention healing: a meaningful local cure rate after 253 procedures.

BACKGROUND: Surgery is an important treatment modality for hidradenitis suppurativa (HS). Various methods of HS surgery have been described. Even though wide excision is a common surgical procedure for HS, data on the recurrence rate and patient satisfaction are scarce. OBJECTIVE: To determine the recurrence rate and patient satisfaction of HS lesional wide excision (complete excision) with secondary intention healing. METHODS: A single centre retrospective study. Hundred and twenty eligible patients were identified from our medical files, and an individualized questionnaire was sent. RESULTS: Eighty-six patents responded to our questionnaire (71.7%). Of whom, 84 patients underwent in total 253 procedures. The mean follow-up time per procedure was 36.2 months. In 37.6% of the procedures, recurrence occurred within a mean follow-up period of 3 years (after a median of 6.0 months). Total remission of an anatomical area was achieved in 49% of the procedures, whereas natural disease progression occurred in 13%. The genital region was the most prone to recurrence. The majority of the patients were glad that they had undergone the procedure and would recommend the surgical procedure to other HS patients. CONCLUSION: Lesional wide excision (complete excision) with secondary intention healing yields a meaningful local cure rate for HS and is well tolerated.

Optimizing adalimumab treatment in psoriasis with concomitant methotrexate (OPTIMAP): study protocol for a pragmatic, single-blinded, investigator-initiated randomized controlled trial.

BACKGROUND: The introduction of anti-tumor necrosis factor medications has revolutionized the treatment of psoriasis with achievement of treatment goals (Psoriasis Area and Severity Index score 75, remission) that are not usually met with conventional systemics. Nevertheless, some patients continue to experience persistent disease activity or treatment failure over time. Strategies to optimize treatment outcomes include the use of concomitant methotrexate, which has demonstrated beneficial effects on pharmacokinetics and treatment efficacy in psoriasis and other inflammatory diseases. METHODS: This is an investigator-initiated, multicenter randomized controlled trial (RCT) designed to compare the combination treatment of adalimumab and methotrexate with adalimumab monotherapy in patients with psoriasis. The primary outcome is adalimumab drug survival at week 49. Other outcomes include improvement in disease severity and quality of life, tolerability, and safety. Moreover, anti-adalimumab antibodies and adalimumab serum concentrations will be measured and correlations between genotypes and clinical outcomes will be assessed. Patient recruitment started in March 2014. Up to now, 36 patients have been randomized. Many more patients have been (pre)screened. A total of 93 patients is desired to meet an adequate sample size. In our experience, the main limitation for recruitment is prior adalimumab therapy and intolerability or toxicity for methotrexate in the past. DISCUSSION: OPTIMAP is the first RCT to examine combination therapy with adalimumab and methotrexate in a psoriasis population. With data derived from this study we expect to provide valuable clinical data on long-term treatment outcomes. These data will be supported by assessment of the impact of concomitant methotrexate on adalimumab pharmacokinetics. Furthermore, the influence of several single nucleotide polymorphisms on adalimumab response will be analyzed in order to support the development of a more personalized approach for this targeted therapy. TRIAL REGISTRATION: NTR4499 . Registered on 7 April 2014.

Non-invasive anaesthetic methods for dermatological laser procedures: a systematic review.

Pain is a common side-effect of dermatological laser procedures. Non-invasive anaesthetic drugs and anaesthetic procedures can be used to provide pain relief and increase patient satisfaction and treatment efficacy. However, it remains unclear which method provides the best pain relief. The objective of this systematic review was therefore to assess the efficacy and safety of non-invasive anaesthetic methods during dermatological laser procedures. A systematic literature search was conducted. Randomized and non-randomized controlled clinical trials (RCTs and CCTs) were included. Two authors independently assessed study eligibility, extracted data and assessed the risk of bias. The quality of evidence was rated using Grading of Recommendations Assessment, Development and Evaluation (GRADE). Twenty RCTs and 12 CCTs were included, involving nine different laser indications: hair removal (n = 9), resurfacing/rejuvenation (n = 5), port wine stains (n = 8), leg telangiectasia (n = 3), facial telangiectasia (n = 2), tattoo removal (n = 2), naevus of Ota (n = 1), solar lentigines (n = 1) and HPV lesions (n = 1). The non-invasive anaesthetic methods (i.e. topical anaesthetic drugs, skin cooling, and pneumatic skin flattening [PSF]), types of lasers, laser settings, application time, and types of pain scales varied widely among the included studies. All of the studies had an unclear or high risk of bias, and the overall quality of evidence was rated as low. In general, active non-invasive anaesthetic methods seemed to provide favourable results compared to placebo or no anaesthesia, and topical anaesthetic drugs and PSF seemed to result in a better pain reduction than skin cooling. However, the current evidence is insufficient to provide recommendations for daily clinical practice. There is a need for more high-quality (head-to-head) RCTs. Future studies should also evaluate sex differences in pain perception, have uniformity with regard to validated pain measurement scales and address clinically significant differences in pain reduction besides statistically significant differences.

Comparison of lidocaine/tetracaine cream and lidocaine/prilocaine cream for local anaesthesia during laser treatment of acne keloidalis nuchae and tattoo removal: results of two randomized controlled trials.

BACKGROUND: Pain is a common adverse effect of dermatological laser procedures. Currently, no standard topical anaesthetic cream exists for deeper dermal laser procedures. OBJECTIVES: To compare the efficacy of lidocaine/tetracaine cream and lidocaine/prilocaine cream in reducing self-reported pain during deeper dermal laser treatment of acne keloidalis nuchae (AKN) and tattoos. METHODS: We conducted two randomized, double-blind, controlled clinical trials with intrapatient, split-lesion designs: study A included patients with AKN (n = 15); study B included patients with black tattoos (n = 15). The primary end point was the patients' self-reported pain on a 10-cm visual analogue scale (VAS). Secondary objectives were the percentage of patients with adequate pain relief, willingness to pay €25 for the cream that provided the best pain relief and safety of the creams. RESULTS: In both studies, VAS scores were lower for lidocaine/prilocaine cream, with a mean VAS difference in study A of 1·9 [95% confidence interval (CI) 1·0-2·8] and in study B of 0·6 (95% CI -0·7 to 1·9). In study A, adequate pain relief was achieved in 13% (n = 2) with lidocaine/tetracaine cream vs. 73% (n = 11) with lidocaine/prilocaine cream (P = 0·004), and in study B in 53% (n = 8) vs. 80% (n = 12), respectively (P = 0·289). In study A, 47% (n = 7) were willing to pay an additional €25 vs. 73% (n = 11) in study B. No serious adverse events occurred. CONCLUSIONS: Lidocaine/prilocaine cream under plastic occlusion is the preferred topical anaesthetic during painful laser procedures targeting dermal chromophores.

Lentigo maligna - anatomic location as a potential risk factor for recurrences after non-surgical treatment.

BACKGROUND: A higher incidence of lentigo maligna (LM) recurrences on the nose was previously observed in our cohort after non-surgical treatment. OBJECTIVES: To determine histological parameters that might be related to the previously observed higher incidence of LM recurrences on the nose after non-surgical treatment. METHODS: We randomly selected 22 surgical specimens of LM on the nose and 22 on the cheek. Histopathological analysis was performed on haematoxylin and eosin stained and microphthalmia transcription factor immunohistochemically stained slides. The number of pilosebaceous units (PSU) per mm, maximum depth of atypical melanocytes along the skin appendages and maximum depth of the PSU itself were determined. RESULTS: The nose had a significantly higher density of PSU than the cheek. The atypical melanocytes extended deeper along the PSU on the nose with a mean (SD) depth of 1.29 mm (0.48) vs. a mean depth of 0.72 mm (0.30) on the cheek (P < 0.001). The maximum depth of the PSU on the nose was greater than on the cheek, mean (SD) depth of 2.28 mm (0.41) vs. 1.65 mm (0.82) (P = 0.003). CONCLUSIONS: The higher recurrence risk of LM on the nose after non-surgical treatment that we previously observed in our cohort is most likely based on a higher density of atypical melanocytes and also their deeper extension into the follicles. These results shed more light on our previous findings and learn that anatomical location is relevant for the risk of recurrence of LM after non-surgical treatment.

Recurrence rate of lentigo maligna after micrographically controlled staged surgical excision.

BACKGROUND: Lentigo maligna is a slowly growing melanoma in situ. Current guidelines advise wide local excision with a margin of 5 mm as the treatment of first choice, which has recurrence rates ranging from 6% to 20%. OBJECTIVES: To determine retrospectively the recurrence rate of lentigo maligna after staged surgical excision. METHODS: Records of all patients with lentigo maligna treated with our method of staged surgical excision between 2002 and 2011 were retrieved. To identify recurrences we used the computer program Sympathy, which is linked to PALGA, a nationwide network and registry of histo- and cytopathology in the Netherlands. RESULTS: We identified 100 patients, who were treated with staged surgical excision with 100% immunohistopathological control of lateral margins. Digital pictures were used to facilitate orientation during the several stages of surgery. After a mean follow-up of 60 months, four patients had a recurrence, after 37, 58, 74 and 77 months of follow-up. CONCLUSIONS: Staged surgical excision is superior in clearance and recurrence rates to wide local excision for lentigo maligna and should be considered as the treatment of first choice in national and international guidelines.

European S1 guideline for the treatment of hidradenitis suppurativa/acne inversa.

Hidradenitis suppurativa/acne inversa (HS) is a chronic, inflammatory, recurrent, debilitating skin disease of the hair follicle that usually presents after puberty with painful, deep-seated, inflamed lesions in the apocrine gland-bearing areas of the body, most commonly the axillae, inguinal and anogenital regions. A mean disease incidence of 6.0 per 100,000 person-years and an average prevalence of 1% has been reported in Europe. HS has the highest impact on patients' quality of life among all assessed dermatological diseases. HS is associated with a variety of concomitant and secondary diseases, such as obesity, metabolic syndrome, inflammatory bowel disease, e.g. Crohn's disease, spondyloarthropathy, follicular occlusion syndrome and other hyperergic diseases. The central pathogenic event in HS is believed to be the occlusion of the upper part of the hair follicle leading to a perifollicular lympho-histiocytic inflammation. A highly significant association between the prevalence of HS and current smoking (Odds ratio 12.55) and overweight (Odds ratio 1.1 for each body mass index unit) has been documented. The European S1 HS guideline suggests that the disease should be treated based on its individual subjective impact and objective severity. Locally recurring lesions can be treated by classical surgery or LASER techniques, whereas medical treatment either as monotherapy or in combination with radical surgery is more appropriate for widely spread lesions. Medical therapy may include antibiotics (clindamycin plus rifampicine, tetracyclines), acitretin and biologics (adalimumab, infliximab). A Hurley severity grade-relevant treatment of HS is recommended by the expert group following a treatment algorithm. Adjuvant measurements, such as pain management, treatment of superinfections, weight loss and tobacco abstinence have to be considered.

Risk factors, clinical course and long-term prognosis in hidradenitis suppurativa: a cross-sectional study.

BACKGROUND: Hidradenitis suppurativa (HS) causes considerable morbidity. The long-term prognosis is of obvious interest to both patients and physicians. We conducted this study to determine the prognosis and risk factors in patients diagnosed with HS. OBJECTIVES: To describe the long-term prognosis and the clinical course of HS and its association to known risk factors. METHODS: A postal follow-up survey with uncomplicated factual questions was conducted. As all of the patients were well acquainted with their long-standing disease, this was thought to be sufficient for meaningful results. All cases were diagnosed by a dermatologist. Overall, 212 patients diagnosed with HS between 1981 and 2001 were studied after a median follow-up period of 22 years (range 12-32). RESULTS: The overall response rate was 71.2%, with 60.8% (129/212) valid (fully completed) questionnaires. Remission was reported by 39.4% (50/127) and improvement by 31.5% (40/127). Unchanged severity was reported by 20.5% (26/127), and 8.7% (11/127) experienced worsening disease. Tobacco smoking was reported by 92.2% (119/129). Among nonsmokers, 40% (35/88) reported remission vs. 29% (17/59) of active smokers. A higher proportion of nonobese patients (45%) reported remission than obese patients (23%). CONCLUSIONS: We found that 39.4% of the sample reported remission of HS. Suspected risk factors appeared to influence the prognosis. Smoking and obesity were significantly linked to a lower rate of self-reported remission. The notion that lifestyle factors play a role in HS appears to be supported by this survey.

Regulated genes in psoriatic skin during treatment with fumaric acid esters.

BACKGROUND: Fumaric acid esters (FAEs) are widely used in Europe for the treatment of psoriasis because of their clinical efficacy and favourable safety profile. However, the mechanisms of action by which FAEs improve psoriasis remain largely unknown. OBJECTIVES: To identify pathways and mechanisms affected by FAE treatment and to compare these with pathways affected by treatment with the antitumour necrosis factor (anti-TNF)-α biologic etanercept. METHODS: In a prospective cohort study, 50 patients with plaque psoriasis were treated with FAEs for 20 weeks. Nine patients were randomly selected for gene expression profiling of plaque biopsies from week 0 and week 12. The groups consisted of FAE responders [> Psoriasis Area and Severity Index (PASI)-75 improvement] and nonresponders (< PASI-50 improvement). Changes in gene expression profiles were analysed using Ingenuity Pathway Analysis (IPA) and the outcome was compared with gene expression affected by etanercept. RESULTS: Response to FAE treatment was associated with a ≥ 2-fold change (P < 0.05) in the expression of 458 genes. In FAE responders the role of interleukin-17A in the psoriasis pathway was most significantly activated. Glutathione and Nrf2 pathway molecules were specifically induced by FAE treatment and not by etanercept treatment, representing an FAE-specific effect in psoriatic skin. In addition, FAE treatment specifically induced the transcription factors PTTG1, NR3C1, GATA3 and NFκBIZ in responding patients. CONCLUSIONS: FAE treatment induces glutathione and Nrf2 pathway genes in lesional skin of patients with psoriasis. In responders, FAEs specifically regulate the transcription factors PTTG1, NR3C1, GATA3 and NFκBIZ, which are important in normal cutaneous development, and the T-helper (Th)2 and Th17 pathways, respectively.