Lipocalin-2 is expressed by activated granulocytes and keratinocytes in affected skin and reflects disease activity in acne inversa/hidradenitis suppurativa.

BACKGROUND: Acne inversa (AI)/hidradenitis suppurativa is a chronic inflammatory disease characterized by painful axillary, inguinal and perianal skin lesions with deep-seated nodules, abscesses and fistulae. OBJECTIVES: This study aimed to identify and characterize the key players in AI pathogenesis. METHODS: Epidemiological and anamnestic data for patients with AI were collected, and blood and skin samples were also taken. Healthy participants and patients with psoriasis served as controls. Assessment of samples and cultures of primary cells was performed by enzyme-linked immunosorbent assay, quantitative polymerase chain reaction on reverse transcribed mRNA, and immunohistochemistry. RESULTS: Of 35 mediators quantified in the blood of patients with AI, lipocalin-2 (LCN2) appeared as one of the most significantly upregulated parameters compared with healthy participants [85·8 ± 12·2 (n = 18) vs. 41·8 ± 4·2 (n = 15); P < 0·001]. Strongly elevated LCN2 expression was present in AI lesions, with granulocytes and keratinocytes being sources of this expression. In vitro, these cells upregulated LCN2 production in response to tumour necrosis factor (TNF)-α, and a positive relationship between systemic TNF-α and LCN2 levels (rs = 0·55, P = 0·011; n = 20) was evident for AI. LCN2 blood levels correlated with AI disease severity (rs = 0·65, P < 0·001; n = 29), but not with disease duration, age, sex, body mass index or smoking habit. Detailed analyses revealed a link with the number of skin regions containing nodules and fistulae, but not scars. CONCLUSIONS: LCN2 might serve as a blood biomarker for the objective assessment of inflammatory activity in AI. We suggest a self-amplification loop comprising TNF-α, neutrophilic granulocytes and LCN2, which contributes to the recurrent skin neutrophil infiltration in AI, clinically evident as pus.

Dose-escalation study evaluating pegylated interferon alpha-2a in patients with cutaneous T-cell lymphoma.

BACKGROUND: This open-label, multicenter, dose-escalation study evaluated the safety, tolerability, and efficacy of subcutaneous pegylated (40 kD) interferon α-2a (PEG-IFN α-2a) in patients with cutaneous T-cell lymphoma (CTCL). PATIENTS AND METHODS: PEG-IFN α-2a was administered subcutaneously at 180 (n = 4), 270 (n = 6), or 360 µg (n = 3) once weekly for 12 weeks. Efficacy was assessed by the proportion of patients with complete response (CR) or partial response (PR). RESULTS: PEG-IFN α-2a was generally well tolerated, with a moderate number of reductions or withholding of doses because of adverse events (AEs) (25% (n = 1), 66% (n = 4), and 0% (n = 0) in the 180-, 270-, and 360-µg/week groups, respectively). The only dose-limiting toxicity was a grade 3 elevation of liver enzymes in the 270-µg dose group. The most common AEs were fatigue, acute flu-like symptoms, and hepatic toxicity. The major response rate (CR or PR) was 50% in the 180-µg group (CR, 50%; PR, 0%), 83% in the 270-µg group (CR, 67%; PR, 17%), and 66% in the 360-µg group (CR, 33%; PR, 33%). CONCLUSION: PEG-IFN α-2a at doses up to 360 µg once weekly was well tolerated in patients with CTCL up to the highest dose group and showed good response rates. Due to their good tolerance even in high doses, they might be an option for patients not tolerating standard IFN-α preparations. However, for this purpose and to evaluate comparability between standard and PEG-IFN larger clinical trials are needed, alone and in combination with oral photochemotherapy (PUVA).

The 2016 International League of Dermatological Societies' revised glossary for the description of cutaneous lesions.

BACKGROUND: In order to facilitate effective communication in dermatology, a clearly defined glossary with precise descriptions is essential. The International League of Dermatological Societies' (ILDS) 'Glossary of basic dermatology lesions' was first published in 1987. A quarter of a century later, the ILDS made the decision to revise and expand this nomenclature. OBJECTIVES: Revision and expansion of an international nomenclature for the description of cutaneous lesions. METHODS: The ILDS nominated a committee on nomenclature. Based on a review of the literature and major textbooks, the committee assembled a list of terms and definitions. National member societies of the ILDS were then invited to participate in a Delphi voting exercise (two rounds for basic descriptive terms, one round for additional terms). The committee reviewed and consolidated comments and consented the final version. RESULTS: The revised and expanded version of the ILDS nomenclature includes 13 basic terms and over 100 additional descriptive terms. Forty-six and then 34 national member societies participated in the first and second voting rounds, respectively. CONCLUSIONS: A unifying nomenclature is crucial for effective communication among dermatologists and those who care for skin diseases. The next step will be a roll-out programme to national member societies of the ILDS that will include translations into languages other than English and adaptations reflecting local circumstances.

Interleukin-10 receptor-1 expression in monocyte-derived antigen-presenting cell populations: dendritic cells partially escape from IL-10's inhibitory mechanisms.

Interleukin (IL)-10 is an important immunoregulatory cytokine that mediates its effects via a transmembrane receptor complex consisting of two different chains, IL-10R1 and IL-10R2. While IL-10R2 is ubiquitously expressed and does not bind IL-10 primarily, the expression of IL-10R1 determines cellular responsiveness. However, the current knowledge about the expression and regulation of IL-10R1 is still limited. Here we analyzed the expression of IL-10R1 on monocytic cells and demonstrated that human blood monocytes carried about 720 IL-10-binding sites on their surface. Compared with lymphocytes and various tissue cells and tissues, blood monocytes expressed the highest IL-10R1 levels. The in vitro differentiation of these cells into macrophages provoked a further increase of IL-10R1 surface expression. In contrast, their differentiation into myeloid dendritic cells (mDCs) resulted in reduced surface IL-10R1 levels. The different IL-10R1 levels expressed by monocyte-derived antigen-presenting cell populations were reflected in their different responsiveness toward IL-10. Importantly, also in vivo developed immature macrophages and mDCs showed different IL-10 sensitivity. These data suggest that, compared with monocytes and macrophages, mDCs partially escape from IL-10's inhibitory mechanisms by downregulating IL-10R1.

Pattern of response in patients with moderate-to-severe psoriasis treated with etanercept.

BACKGROUND: Etanercept (ETN) 50 mg once weekly (QW) or 50 mg twice weekly (BIW) for 12 weeks, followed by 50 mg QW in all subjects to Week 24 improved psoriasis in patients with concomitant psoriatic arthritis in the PRESTA trial. OBJECTIVES: To use data from PRESTA to evaluate the effect of ETN in the treatment of psoriasis by Psoriasis Area Severity Index (PASI) body-region and component, and determine if PASI responses correlate with the Dermatology Life Quality Index (DLQI). METHODS: Median time to 75% improvement in PASI (PASI75), body- and component-specific subscales over 24 weeks were estimated. Pearson correlation coefficients determined the association between DLQI score and PASI total score, body- and component-specific subscales with ETN treatment at baseline and up to Week 24. RESULTS: In total, 748 patients from PRESTA were included (ETN 50 mg QW/QW, n = 371; BIW/QW, n = 377). Patients achieved PASI75 total score and 75% improvements in all body regions and components faster on ETN 50 mg BIW/QW than QW/QW (all P < 0·05). Median time to 75% improvement was faster for the head and trunk followed by upper and lower extremities, and for induration and desquamation followed by erythema and total area. Weak to moderately positive correlations between improvements in DLQI and PASI total score (r = 0·223-0·463), all PASI body-specific (r = 0·114-0·432) and component-specific (r = 0·178-0·478) subscales were observed over 24 weeks. CONCLUSIONS: Etanercept treatment-response appears to occur in a body- and component-specific manner. Changes in quality of life are not captured by PASI or its subscales.

Guidelines on the use of extracorporeal photopheresis.

BACKGROUND: After the first investigational study on the use of extracorporeal photopheresis for the treatment of cutaneous T-cell lymphoma was published in 1983 with its subsequent recognition by the FDA for its refractory forms, the technology has shown significant promise in the treatment of other severe and refractory conditions in a multi-disciplinary setting. Among the major studied conditions are graft versus host disease after allogeneic bone marrow transplantation, systemic sclerosis, solid organ transplant rejection and inflammatory bowel disease. MATERIALS AND METHODS: In order to provide recognized expert practical guidelines for the use of this technology for all indications the European Dermatology Forum (EDF) proceeded to address these questions in the hands of the recognized experts within and outside the field of dermatology. This was done using the recognized and approved guidelines of EDF for this task. RESULTS AND CONCLUSION: These guidelines provide at present the most comprehensive available expert recommendations for the use of extracorporeal photopheresis based on the available published literature and expert consensus opinion.

Gain or loss? Sunscreen efficiency after cosmetic pretreatment of the skin.

Sunscreens are a key pillar of the multimodal protection strategy against short- and long-term impacts of intermittent and continuous UV exposure. Hitherto, an unanswered part of current scientific discourse is the question whether a cosmetic pretreatment has an impact on distribution and adhesiveness of sunscreens on the skin and therefore affects UV protection. In order to evaluate the homogeneity of sunscreen filter distribution, water resistance as a parameter of adhesiveness and effective UV protection of sunscreens after a pretreatment with cream or lotion was investigated in 18 volunteers who were examined before and after swimming, using the established combination of the tape stripping procedure and UV/VIS spectroscopy. It was shown that a cosmetic skin pretreatment affects neither filter homogeneity nor effective UV protection prior to water contact. However, compared to nonpretreated skin, a considerable loss of water resistance is caused. Therefore, using a cream or lotion before application of sunscreens is not to be recommended.

Cutaneous carotenoids: the mirror of lifestyle?

Carotenoids could serve as marker substances of the antioxidant status of the human skin. In the present study, an optical skin scanner was used to analyse the carotenoid concentration obtained from 4 volunteers over a period of 13 days. The measurements were taken daily at different time points. In addition, the volunteers were asked to keep track of their daily nutritional behaviour and stress situations in a diary. It was found that the carotenoid values reflect clearly the nutritional behaviour and stress situations of the volunteers. While a steady, increased intake of fruit and vegetables resulted in a gradual increase in the dermal carotenoid values for several days, stressful situations entailed an immediate decline in these values. Although the impact of healthy nutrition on the antioxidant protection system is generally known and notwithstanding the small number of cases, the present study clearly demonstrates that the avoidance and/or reduction of stress is similarly important in order not to counteract or nullify the results achieved by healthy nutrition.

Long-term outcome of intravenous therapy with rituximab in patients with primary cutaneous B-cell lymphomas.

BACKGROUND: The monoclonal antibody rituximab directed against the B-cell antigen CD20 was approved for the treatment of B-cell lymphomas and maintenance therapy in follicular lymphomas more than a decade ago. However, median follow-up in case series of intravenous rituximab therapy in primary cutaneous B-cell lymphomas (CBCL) lasts only up to 3 years. We retrospectively analysed a cohort of CBCL patients treated with rituximab to gain more long term information. PATIENTS AND METHODS: Eighteen patients, treated intravenously with rituximab for a primary cutaneous B-cell lymphoma [follicle centre lymphoma (PCFCL), n = 11; diffuse large B-cell lymphoma, leg type (PCLBCL, leg type), n = 5; marginal zone B-cell lymphoma (PCMZL), n = 2] were included. The response rate (RR), time to relapse (TTR), and course of the disease after treatment were analysed. RESULTS: The overall RR was 89% (16 of 18 patients). Within the median follow-up time of 52 months, 81% (13 of 16) of patients experienced a relapse; the median TTR was 25 months. The duration of remission was significantly shorter in patients presenting with generalized skin lesions at start of therapy. Both nonresponding patients suffered from PCLBCL, leg type, with extracutaneous manifestations. In responders severe adverse events, the occurrence of extracutaneous dissemination or nodal lymphomas were not observed during follow-up. CONCLUSIONS: Therapy with rituximab is effective and safe for the treatment of PCFCL, but relapses, in particular in patients with generalized skin involvement, are commonly observed. However, all patients with relapses responded well to treatment and therefore maintenance therapy does not seem to be indicated. Patients with PCLBCL, leg type, should receive chemotherapy in addition to rituximab.

Alcohol consumption decreases the protection efficiency of the antioxidant network and increases the risk of sunburn in human skin.

In recent years, epidemiological data has demonstrated that alcohol consumption is a risk factor for sunburn, melanoma and nonmelanoma skin cancer. We hypothesized that if the concentration of the antioxidants in the skin has already decreased due to alcohol consumption, then an adequate neutralization of the free radicals induced by ultraviolet light cannot be performed. Based on this hypothesis, we determined the carotenoid concentration in the skin and the minimal erythema dose (MED) of 6 male human volunteers before and after consumption of alcohol or alcohol and orange juice combined. The results showed a significant decrease in the carotenoid concentration in the skin and the MED after alcohol consumption, but no significant decrease after a combined intake of alcohol and orange juice.

Photoprotective properties of the fluorescent europium complex in UV-irradiated skin.

In this study, we compared the UV-protective abilities of the europium complex compared to titanium dioxide, which represents the most common physical filter for ultraviolet light in the broad-band spectral range. The UV absorption and light transformative capacities of the europium complex were evaluated using a spectrometer with a double-integrating sphere showing that the europium complex does not only absorb and reflect UV light, but transforms it into red and infrared light. It was found that the europium complex binds to the surface of Jurkat cells in vitro. Cells incubated with the europium complex showed a significantly higher viability after UVA and UVB irradiation as compared to untreated cells and cells incubated with titanium dioxide pointing out its photoprotective properties. The europium complex and titanium dioxide show similar penetration capacities into the stratum corneum as tested in human and porcine skin using tape stripping analysis. The europium complex has proved to be an efficient UV filter with a low cyto- and phototoxic profile and therefore represents a potential candidate for use in sunscreen formulations.

Methods for the evaluation of the protective efficacy of sunscreen products.

The objective of the present investigation was to examine the utilization of optical and spectroscopic methods for the noninvasive characterization of Anthelios XL Fluide Extreme (SPF 50+), an exemplary sunscreen, concerning its homogeneity of distribution on the skin, its spectroscopic properties and its overall protective efficacy. The homogeneity of the distribution of the sunscreen on the skin was investigated with a multiphoton tomography microscope. Additionally, the sum transmission spectrum was determined using tape stripping and spectroscopic measurements. The results revealed a very homogeneous distribution of the sunscreen on the skin surface and also in the deep furrows. The sum transmission spectrum reflects a high protective efficacy of the sunscreen in both the UVA and UVB ranges. The sunscreen Anthelios XL Fluide Extreme (SPF 50+) generates a comfortable feeling on the skin and can be easily distributed. The presented optical methods have been shown to be suitable to investigate the overall protective efficacy of sunscreen products objectively, noninvasively and quickly.

Drug delivery with topically applied nanoparticles: science fiction or reality.

The efficacy of topically applied drugs is determined by their action mechanism and their potential capacity of passing the skin barrier. Nanoparticles are assumed to be efficient carrier systems for drug delivery through the skin barrier. For flexible nanoparticles like liposomes, this effect has been well demonstrated. The penetration properties of solid nanoparticles are currently under intensive investigation. The crucial advantage of nanoparticles over non-particulate substances is their capability to penetrate deeply into the hair follicles where they can be stored for several days. There is no evidence, yet, that solid particles ≥40 nm are capable of passing through the healthy skin barrier. Therefore and in spite of the long-standing research efforts in this field, commercially available solid nanoparticle-based products for drug delivery through the healthy skin are still missing. Nevertheless, the prospects for the clinical use of nanoparticles in drug delivery are tremendous. They can be designed as transport systems delivering drugs efficiently into the hair follicles in the vicinity of specific target structures. Once deposited at these structures, specific signals might trigger the release of the drugs and exert their effects on the target cells. In this article, examples of such triggered drug release are presented.

[CD30-positive anaplastic large cell T-cell lymphoma developing during immunosuppressive therapy of pityriasis rubra pilaris with ustekinumab]. / CD30-positives anaplastisch großzelliges T-Zell-Lymphom unter immunsuppressiver Therapie einer Pityriasis rubra pilaris mit Ustekinumab.

The development of malignancies during therapy with biologics has been discussed controversially. A patient with extensive pityriasis rubra pilaris failed to respond to standard therapeutic approaches. While receiving immunomodulatory therapy, lastly with ustekinumab, the patient developed a CD30(+) anaplastic large cell lymphoma.

Evaluation of different methods in the follow-up of patients with indolent types of primary cutaneous lymphomas.

BACKGROUND: Primary cutaneous lymphomas (CLs) are a heterogeneous group of diseases arising from B or T lymphocytes. CLs are grouped according to their clinical behaviour into indolent, intermediate and aggressive types. Indolent CLs respond well to therapy but frequently relapse, resulting in prolonged periods of follow-up. OBJECTIVES: To evaluate the outcome of follow-up examinations in indolent CL. METHODS: We retrospectively analysed a cohort from a CL outpatient clinic at a tertiary referral centre. Seventy-five patients with indolent cutaneous T-cell lymphomas (CTCLs) and 34 patients with indolent cutaneous B-cell lymphomas (CBCLs) were included. The value of clinical examination, blood tests and imaging procedures for detection of recurrence or progression was assessed. RESULTS: In patients with CTCL all but one disease recurrences were detected by clinical examination. Lymph node or organ involvement was detected by imaging procedures in seven patients, of whom all but one had recurrent or persistent CL lesions. In CBCL all recurrences were detected by clinical examination. CONCLUSIONS: Patients with indolent CL confined to the skin should be followed primarily by clinical examination. However, in patients who are refractory to treatment regular screening of lymph nodes by ultrasound may enable earlier detection of disease recurrence or progression.

The tumour suppressor p53 is frequently nonfunctional in Sézary syndrome.

BACKGROUND: Primary cutaneous T-cell lymphomas (CTCLs) are a heterogeneous group with Sézary syndrome (SS) as one of the most aggressive variants. Recently, we identified a loss of E2A as a recurrent event in SS, which enhanced proliferation via upregulation of the proto-oncogene MYC. MYC-induced transformation usually requires deleterious alterations of key apoptotic genes including p53; however, p53 functionality and mutation status in SS are unclear. OBJECTIVES: We investigated functionality of p53 signalling by pharmacological treatment with the MDM2 antagonist nutlin-3, which might result in p53 activation. Furthermore, we analysed the TP53 mutation status in CTCL cell lines and highly purified tumour cells from patients with SS by mRNA and DNA sequencing. METHODS: We analysed the apoptosis induction due to nutlin-3 treatment in various SS cell lines and primary patient samples by annexin V/propidium iodide staining. Induction of p53 target genes was analysed by immunoblotting, and TP53 was sequenced at the mRNA and DNA level. RESULTS: We identified various TP53 mutations and an impaired p53 signalling in the vast majority of the investigated cell lines and primary SS cells. CONCLUSIONS: In accordance with the importance of MYC deregulation in SS, p53 signalling is frequently nonfunctional in SS. However, although most likely ineffective as exclusive treatment in SS, it remains possible that pharmacological p53 activation could be beneficial in combination with other approaches including classical chemotherapeutics.

In vivo investigations on the penetration of various oils and their influence on the skin barrier.

BACKGROUND: The skin represents a potent barrier to the environment, which can be enhanced by the topical application of skin care products, such as oil and oil-based formulations by moisturizing the skin. METHODS: The aim of this study was the investigation of the penetration behaviour of four vegetable oils and of paraffin oil into the stratum corneum by laser scanning microscopy. In addition, the occlusion capacity of these substances was assessed by transepidermal water loss (TEWL) measurements. Petrolatum served as a positive control for skin occlusion. The study was conducted in vivo and included six healthy volunteers. RESULTS: Paraffin oil, as well as the vegetable oils, penetrated only into the first upper layers of the stratum corneum. TEWL measurements indicated that the application of the vegetable oils (except jojoba oil) as well as paraffin oil, led to a similar occlusion of the skin surface. The most effective occlusion was found for petrolatum. CONCLUSION: For the investigated oils, a deeper penetration than into the first upper layers of the stratum corneum could be excluded. The decreased TEWL values indicate that the application of the oils leads to a semi-occlusion of the skin surface as it is intended by the use of oils to retain moisture in skin.

The influence of endurance exercise on the antioxidative status of human skin.

Oxidative stress is supposed to be responsible for a diversity of diseases. For protection purposes, the human organism exhibits a line-up of antioxidant substances functioning as radical catchers. As a result of neutralization of free radicals, antioxidants are destroyed. Therefore, the degradation of the antioxidants can be utilized as an indirect parameter for the measurement of free radical formation. As physical exercise may also induce oxidative stress, the aim of the present study was to determine the antioxidant substances, and more precisely, the carotenoid concentration in the skin of male volunteers during different sportive exposures (cycling and running with two different exercise intensities) with resonance Raman spectroscopic measurements. The results revealed that moderate and high intensity cycling and running decrease the carotenoid concentration of the skin, whereas both sport disciplines and both exercise intensities revealed similar results. It can be concluded that above a certain threshold, physical exercise leads to oxidative stress also in the skin associated with the decrease in the antioxidant concentration. This gives rise to the impairment of the first defence line of the skin and means an increase in the risk of sun exposure-induced damage, e.g., when exercise training is performed outside. Nevertheless, it has to be emphasized that sport in general applied at moderate loads has predominantly positive effects on the health of humans especially concerning cardiovascular and metabolic diseases.

Is 'class effect' relevant when assessing the benefit/risk profile of a biologic agent?

Psoriasis is a chronic, genetically predisposed skin disorder, characterised by thickened scaly plaques. Although no therapy is recognised as curative, therapies aimed at symptom control include biologic agents that are generally designed to block molecular activation of cellular pathways of a pathogenic immune response. Although biologics are often described as a class, they can be further sub-classified according to properties including structure and molecular target. For example, the two main groups of biologics for the treatment of psoriasis are those targeting cytokines and those targeting T-cells or antigen-presenting cells. Agents that inhibit cytokines can be broadly split into anti-p40 agents, which target the p40 subunit of IL-12 and IL-23 (such as ustekinumab), and anti-TNF agents. Anti-TNF agents may then be further divided into soluble receptors (etanercept) and monoclonal antibodies (adalimumab and infliximab). Even within the same subclass, agents may display variations in structure, function, route of administration and pharmacokinetics, which are reflected in their clinical profiles. For example, of the TNF antagonists, infliximab, provides a rapid onset of response, high efficacy, high peak serum concentrations, anti-granulomatous activity, potential for tuberculosis reactivation and frequent antibody formation; adalimumab provides a fast response, high efficacy, potential for tuberculosis reactivation and the possibility of antibody formation; and etanercept provides a slower response, good efficacy, rare antibody formation and is rarely linked to tuberculosis cases. This suggests that biologic agents exhibit unique properties, which appear to be more relevant than a 'class effect' in assessing risk-benefit profiles for this diverse group of drugs. With a range of agents available, studying the immunogenesis of psoriasis is likely to be useful in profiling individuals best suited to the characteristics of particular drugs. It should also be noted that because differences between agents may affect safety profiles, long-term patient registries are an important tool to assess tolerability and develop guidelines for the most effective use of these drugs.

Ethnic differences in skin physiology, hair follicle morphology and follicular penetration.

BACKGROUND/AIMS: Inconsistent evidence is available that different ethnic groups exhibit differences in skin physiological parameters. Recently, variations in hair follicle morphology have been described, although the influence of such variations on the follicular penetration process has not been investigated until now. METHODS: The aim of the present study was thus to investigate skin physiological parameters, follicle morphology and the penetration process in different ethnic groups. RESULTS AND CONCLUSION: Whereas no significant differences with regard to skin physiological parameters could be observed, morphological analysis of the hair follicles revealed, inter alia, that Caucasians had significantly larger terminal hair follicles than Asians and Africans. The surface of the hair follicle infundibulum was shown to be 3% in Caucasians, 2.6% in Africans and 2.4% in Asians. The investigations into penetration revealed no significant differences after a 30-min penetration time, whereas after 24 h, the Asian volunteers presented significantly larger amounts of sodium fluorescein in the hair follicles and the stratum corneum, which may be explained by cultural habits.