Mupirocin blocks imiquimod-induced psoriasis-like skin lesion by inhibiting epidermal isoleucyl-tRNA synthetase.

BACKGROUND: The Isoleucyl-tRNA synthetase (IARS) catalyzes isoleucine to the corresponding tRNA, maintaining the accuracy of gene translation. Its role in psoriasis has been not investigated so far. In this study, we aimed to investigate the mechanisms underlying the efficacy of IARS inhibitor, mupirocin, treatment for psoriasis. METHODS: The expression of IARS was determined by immunofluorescence, Western blot and qRT-PCR in normal healthy control- and psoriatic human skin. An imiquimod (IMQ) -induced psoriasis-like skin disease model was used to study the phenotypes changed by an IARS inhibitor, mupirocin (MUP). Endotypes were analyzed by RNA-seq, R&D Luminex multi-factor technique, ELISA, immunofluorescence and flow cytometry. Additionally, the effect of MUP on epidermal keratinocytes (KCs) were conducted in-vitro in primary cultured human KCs. RESULTS: We found the expression of IARS was higher in psoriatic skin than in healthy controls. In IMQ-induced psoriasis-like C57BL/6 J mouse model, MUP reversed IMQ-induced keratinocytes proliferation, expression of inflammatory cytokines and infiltration of immune cells. Furthermore, in cultured human keratinocytes, MUP inhibited proliferation, but promoted apoptosis, which may be related with STAT3 signaling pathway. CONCLUSION: Our finding of blocking the infiltration of immune cells by inhibiting the formation of IARS, could be one mechanism to explain the effect of MUP in the treatment of psoriasis. Developing strategies targeting suppression IARS should open new perspectives for the treatment of psoriasis. Video Abstract.

Biomarkers and personalized medicine: current status and further perspectives with special focus on dermatology.

Biomarkers are of increasingly high importance in medicine, particularly in the realm of 'personalized medicine'. They are valuable for predicting prognosis and dose selection. Moreover, they may be helpful in detecting therapeutic and adverse responses and in patient stratification based on efficacy or safety prediction. Thus, biomarkers are essential tools for the selection of appropriate patients for treatment with certain drugs to and enable personalized medicine, that is 'providing the right treatment to the right patient, at the right dose at the right time'. Currently, there are six drugs approved for dermatological indications with recommended or mandatory biomarker testing. Most of them are used to treat melanoma and human immunodeficiency virus infection. In contrast to the few fully validated biomarkers, many exploratory biomarkers and biomarker candidates have potential applications. Prognostic biomarkers are of particular significance for malignant conditions. Similarly, diagnostic biomarkers are important in autoimmune diseases. Disease severity biomarkers are helpful tools in the treatment for inflammatory skin diseases. Identification, qualification and implementation of the different kinds of biomarkers are challenging and frequently necessitate collaborative efforts. This is particularly true for stratification biomarkers that require a companion diagnostic marker that is co-developed with a certain drug. In this article general definitions and requirements for biomarkers as well as for the impact of biomarkers in dermatology are reviewed and opportunities and challenges are discussed.

The effect of epidermal levels of urocanic acid on 25-hydroxyvitamin D synthesis and inflammatory mediators upon narrowband UVB irradiation.

BACKGROUND/PURPOSE: Urocanic acid (UCA) absorbs ultraviolet (UV)B radiation in the epidermis which may interfere with phototherapy. Therefore, the influence of individual levels of UCA on immune reactivity and vitamin D synthesis induced by narrowband UVB radiation was assessed. METHODS: Twenty-eight subjects with irritant contact dermatitis of the hands were irradiated with suberythemal doses of narrowband UVB radiation on their unaffected lower forearms on three consecutive days. Stratum corneum tape strips and epidermal interstitial fluid (ISF) as well as blood samples were analyzed. RESULTS: Narrowband UVB irradiation led to the conversion of trans-UCA into its cis-isomer in the epidermis. The observed increase in 25-hydroxyvitamin D serum concentrations was inversely correlated with the baseline levels of trans-UCA. Furthermore, UVB irradiation induced significant changes in the levels of CXCL10/IP-10, CCL2/MCP-1, CCL4/MIP-1ß, and the IL-1RA/IL-1α ratio. The levels of IL-1α and CXCL9/MIG showed a trend toward increase. The changes in the levels of inflammatory and immunomodulatory mediators did not depend on baseline levels of trans-UCA. CONCLUSION: The results suggest that epidermal levels of trans-UCA affect vitamin D synthesis, but not cutaneous immune reactivity upon repeated exposure to suberythemal doses of narrowband UVB radiation. However, this requires further exploration.

Handling chemotherapy drugs-Do medical gloves really protect?

Due to their potential mutagenic, carcinogenic and teratogenic effects occupational exposure to chemotherapy drugs should be kept to a minimum. Utilization of personnel protective devices, especially the use of protective medical gloves, is a mainstay to avoid skin contact. The choice of appropriate gloves is of outstanding importance. For optimal protection in the oncology setting it is essential to establish general guidelines evaluating appropriate materials and defining quality standards. Establishing these guidelines can facilitate better handling and avoid potential hazards and late sequelae. In Europe there are no specific requirements or test methodologies for medical gloves used in the oncology environment. The implementation of uniform standards for gloves used while handling chemotherapy drugs would be desirable. In contrast, in the US medical gloves used to handle chemotherapy drugs have to fulfill requirements according to the ASTM International (American Society of Testing and Materials) standard D 6978-05. Nitrile or natural rubber latex is a preferred basic glove material, while vinyl is considered inappropriate because of its generally increased permeability. For extended exposure to chemotherapy drugs, double gloving, the use of thicker gloves and the frequent change of gloves increases their protective power.

Impaired nuclear translocation of glucocorticoid receptors: novel findings from psoriatic epidermal keratinocytes.

Psoriasis is a chronic proliferative skin disease and is usually treated with topical glucocorticoids, which act through the glucocorticoid receptor (GR), a component of the physiological systems essential for immune responses, differentiation, and homeostasis. To investigate the possible role of GR in the pathogenesis of psoriasis, normal and psoriatic lesional skin were recruited. Firstly, the immunolocalization of GR in the skin and cultured epidermal keratinocytes were determined by immunofluorescence. In normal skin and cultured human epidermal keratinocytes, intracellular GR is localized in the nuclei, while in psoriatic skin and cultured keratinocytes, GR is in the cytoplasm. Next, we investigated possible factors associated with the cytoplasmic distribution. We found that VEGF and IFN-γ led to impaired nuclear translocation of GR through p53 and microtubule-inhibitor, vincristine, and inhibited nuclear uptake of GR in normal keratinocytes. In addition to dexamethasone, interleukin (IL)-13 was also able to transfer GR into nuclei of psoriatic keratinocytes. Furthermore, discontinuation of dexamethasone induced cytoplasmic retention of GR in normal keratinocytes. In contrast, energy depletion of normal epidermal keratinocytes did not change the nuclear distribution of GR. To confirm our findings in vivo, an imiquimod-induced psoriasis-like skin mouse model was included. IL-13 ameliorated (but vincristine exacerbated) the skin lesions on the mouse. Taken together, our findings define that impaired nuclear translocation of GR is associated with VEGF, IFN-γ, p53, and microtubule. Therapeutic strategies designed to accumulate GR in the nucleus, such as IL-13, may be beneficial for the therapy of psoriasis.

Periorbital dermatitis in 4779 patients - patch test results during a 10-year period.

BACKGROUND: The thinness of the periorbital skin may facilitate allergen penetration, making this area particularly susceptible to sensitization. MATERIAL AND METHODS: For the cross-sectional study, data were collected by the 57 participating centres of the Information Network of Departments of Dermatology. A total of 101 403 patients patch tested between January 2001 and December 2010 were included. Of these, 4779 patients suffered from periorbital dermatitis. RESULTS: Two major subgroups with different general epidemiological data and sensitization to specific allergens have to be considered: (i) young females with increased rates of skin atopy and allergies, particularly from cosmetic and skin care products; and (ii) older subjects with allergy to topical medications. The prevalence of sensitization to ophthalmic allergens is generally less than that to environmental allergens. CONCLUSIONS: Allergic contact dermatitis is a leading cause of periorbital dermatitis. Patch testing should be considered in all patients with periorbital dermatitis when contact allergy is suspected, in order to identify and avoid offending allergens.

No remarkable differences in rates of sensitization to common type I and IV allergens between FLG loss-of-function mutation carriers and wild-type subjects.

BACKGROUND: Loss-of-function mutations in the filaggrin gene (FLG) have been associated with reduced skin barrier function, possibly allowing increased penetration of irritants and allergens. OBJECTIVES: To study whether FLG loss-of-function mutation carriers show different rates of sensitization to common type I and IV allergens among patients referred for occupational contact dermatitis of the hands. MATERIALS AND METHODS: Four hundred and ninety-six Caucasian patients were genotyped for four FLG null mutations and patch tested with the European baseline series. In addition, 431 patients underwent prick testing with common type I allergens. RESULTS: Overall, 67 patients showed a heterozygous mutation in the FLG alleles R501X, R2447X, S3247X, and/or 2282del4. Sensitization rates for type I allergens from a European prick test series did not show significant differences between FLG loss-of-function mutation carriers and wild-type subjects. For type IV allergens, significantly more FLG loss-of-function carriers were found to be sensitized to lanolin and p-tert-butylphenol-formaldehyde resin. CONCLUSIONS: Probably a variety of immunological mechanisms other than that resulting from the filaggrin system have an impact on allergic sensitization to a greater degree. Larger cohorts may be necessary to increase the statistical power of the findings presented regarding type I and IV sensitization.

Genotype-phenotype associations in filaggrin loss-of-function mutation carriers.

BACKGROUND: Loss-of-function mutations in the filaggrin gene (FLG) have been reported to be associated with specific phenotypic characteristics such as hyperlinearity and keratosis pilaris. OBJECTIVES: To study phenotypic features in patients with occupational irritant contact eczema of the hands in relation to FLG loss-of-function mutations. MATERIALS AND METHODS: In a prospective cohort study, genotype was determined for 459 study subjects for four FLG null alleles, and investigated for selected history, clinical and laboratory features. RESULTS: Overall, 68 patients showed a mutation in the FLG alleles R501X, R2447X, S3247X, and/or 2282del4. Flexural eczema, xerosis cutis, pityriasis alba, dirty neck, pulpitis sicca, hyperlinear palms, keratosis pilaris and family history of eczema were positively associated with FLG mutations (p < 0.05). Although we observed a statistically significant correlation with higher serum IgE in FLG mutation carriers, allergic rhinoconjunctivitis and allergic asthma were not over-represented in this group. CONCLUSION: This study shows further genotype-phenotype correlations in patients with occupational irritant contact eczema and FLG mutation carrier status. These features may help to identify those with FLG mutations on a specific phenotype basis.

UBE2L3 Reduces TRIM21 Expression and IL-1ß Secretion in Epidermal Keratinocytes and Improves Psoriasis-Like Skin.

Proinflammatory cytokines, such as IL-1ß, are important mediators of psoriasis. UBE2L3, an E2 enzyme, is thought to be an indirect target of IL-1ß secretion by binding to ubiquitin ligases such as TRIM21. However, its role in psoriasis remains unknown. In this study, we found that UBE2L3 expression was decreased in psoriatic epidermis, whereas caspase 1 and IL-1ß signaling were strongly activated. When normal human epidermal keratinocytes were stimulated with nigericin, adenosine triphosphate, and poly(dA:dT), downregulation of UBE2L3 and increased secretion of IL-1ß were observed. Treatment with a caspase 1 inhibitor reversed the decrease in the level of UBE2L3. In addition, UBE2L3 overexpression reduced TRIM21, decreased signal transducer and activator of transcription 3 pathway activity, and reduced the level of the IL-1ß precursor (pro‒IL-1ß). Consistently, silencing UBE2L3 enhanced TRIM21 expression, signal transducer and activator of transcription 3 activation, and pro‒IL-1ß production. Finally, in an imiquimod-induced mouse model, UBE2L3 reduction and caspase 1 activation were localized in the epidermis, whereas overexpression of UBE2L3 ameliorated psoriasis-like lesions and reduced pro‒IL-1ß and mature IL-1ß levels in the epidermis. Thus, UBE2L3 may be a protective biomarker that regulates IL-1ß and inhibits TRIM21 in the epidermis of psoriasis.

Impact of tumour necrosis factor-α polymorphisms on irritant contact dermatitis.

BACKGROUND: Genetic variations in genes coding for cytokines involved in skin inflammation may alter their expression, thus changing the susceptibility to irritant contact dermatitis (ICD). OBJECTIVES: To determine the prevalence of polymorphisms in the cytokine genes TNFA-238 and TNFA-308 in patients with occupational ICD, and to compare it with that in controls. METHODS: In a case-control study, 478 patients with occupational ICD of the hands were genotyped for TNFA-238 and TNFA-308 polymorphisms. The results were compared with those for 393 apprentices from the same high-risk occupations (controls). RESULTS: For a carrier of a variant TNFA-238A allele, the odds ratio (OR) of acquiring ICD was 0.57 [95% confidence interval (CI) 0.34-0.97], suggesting a protective effect of the A allele. The genotype distributions were 94.4% wild type (G/G), 5.6% heterozygous (G/A) and 0% homozygous for variant allele (A/A) in patients, and 90.9%, 8.5%, and 0.6%, respectively in controls. In contrast, carriers of the variant TNFA-308A allele had an increased risk of ICD [OR 1.33; 95% CI 1.05-1.74; G/G 66.4%, G/A 31.2%, and A/A 2.4% (patients) versus 73.5%, 24.6%, 1.9% in controls]. CONCLUSIONS: Individuals with a TNFA-238 polymorphism are less prone and those with a TNFA-308 polymorphism are more prone to develop ICD of the hands, suggesting a protective versus a detrimental effect of the A allele respectively.

Patch test characteristics of patients referred for suspected contact allergy of the feet--retrospective 10-year cross-sectional study of the IVDK data.

BACKGROUND: The warm und humid environment, friction and occlusion within shoes make the feet to a favorable body site to acquire allergic contact dermatitis. OBJECTIVES: To evaluate and compare patch test results in patients with suspected contact allergy of the feet with the results in those with concomitant involvement of the feet/legs, feet/hands, and all others tested (excluding secondary involvement of the feet in 'others'), with regard to specific patterns of clinical data and patch test results. METHODS: For the present cross-sectional study, data were collected by the 59 participating centres of the Information Network of Departments of Dermatology in Germany, Austria, and Switzerland, including 102 209 patients patch-tested between January 2001 and December 2010. RESULTS: Allergens that were significantly over-represented in the tested 2671 foot patients included potassium dichromate, colophonium, and p-tert-butylphenol-formaldehyde resin. Among materials brought in by the patients, shoe pieces (27.5%), topical medications/pharmaceutical products (24.4%) and cosmetics (16.8%) played a major role. The final diagnoses of vesicular and hyperkeratotic dermatitis, as well as psoriasis, were significantly more common among foot patients. CONCLUSIONS: Chromium compounds and adhesives were the most common causes of allergic contact dermatitis among our foot patients. Psoriasis should be considered, particularly when the hands are concomitantly affected.

Long-Term Treatment with Dimethyl Fumarate for Plaque Psoriasis in Routine Practice: Good Overall Effectiveness and Positive Effect on Impactful Areas.

INTRODUCTION: Dimethyl fumarate (DMF) is an oral compound to treat plaque psoriasis. Data on the treatment of patients with psoriasis affecting impactful areas are scarce. In this interim analysis of the prospective, noninterventional SKILL study, we summarized results of DMF treatment regarding effectiveness (overall and in impactful areas) and safety. METHODS: Data from 676 patients suffering from moderate-to-severe plaque psoriasis were analyzed after 52 weeks of DMF treatment. Of these, 257 had data available after 52 weeks. The considered impactful areas were nails, palms, soles, and scalp. Data analysis included observed cases (OC) and last observation carried forward (LOCF). RESULTS: All effectiveness parameters improved after 52 weeks. The Psoriasis Area and Severity Index score was reduced by 79.5% (OC) and 65.7% (LOCF). Compared with baseline, improvements were shown for 70.2% of the patients in their nail psoriasis [nail-Physician Global Assessment (PGA)] and for 57.3% in palmoplantar disease (palmoplantar-PGA). The proportion of patients with scalp-PGA 0/1 (clear/almost clear) increased significantly to 79.8% (OC) and 69.3% (LOCF, both p < 0.001) (versus 37.5% and 36.6% at baseline, respectively). Significant reduction of pruritus (p < 0.001) was also observed. No unexpected adverse drug reactions were observed. CONCLUSION: Long-term treatment with DMF in routine practice showed good overall effectiveness and safety, and a positive effect on plaque-psoriasis-affected impactful areas.

Sprouty1 exerts a preventive effect on the initiation of psoriasis by inhibiting innate immune antimicrobial peptide cathelicidin and immunocytes.

OBJECTIVES: Psoriasis is an immune-mediated skin disease dominated by the cutaneous immune system. Keratinocytes have been considered important triggers that initiate psoriasis. The key molecules and events of keratinocytes that link the innate immune system in psoriasis must be investigated in more detail. Human psoriasis skin and primary human keratinocyte were detected in vitro. Epidermis specific transgenic mouse strain (Krt14-Sprouty1 tg) was used to further investigate psoriasis-like skin inflammation in vivo. MATERIALS AND METHODS: Bulk RNA sequencing of primary human keratinocyte screened differentially expressed genes, which was confirmed by quantitative real time PCR and Western Blot (WB). Moreover, we concomitantly reviewed open-accessed published RNAseq datasets of human psoriatic skin from GEO database. Immunohistochemical staining and immunofluorescence were used to detect Sprouty1 (SPRY1) expression in human psoriatic skin with and without anti-psoriasis treatments. Krt14-Sprouty1 tg was used to further investigate psoriasis-like skin inflammation, and followed by Hematoxylin and Eosin (HE) Staining, enzyme linked immunosorbent assay (ELISA), Western Blot and flow cytometry. RESULTS: Our data showed that Sprouty1 was decreased in psoriatic skin and keratinocytes. In imiquimod-induced psoriasis-like skin inflammation, the production of cathelicidin (camp/LL37) was inhibited by suppressing signal transducer and activator of transcription3 (Stat3) activation when Sprouty1 overexpressed in mouse epidermal keratinocytes. Moreover, CD11b+CCR2+ dendritic cells, IL-17A+ γδT cells, and Ly6C+ CD11c+ monocyte-derived dendritic cells were decreased in Krt14-Sprouty1 tg (STG) imiquimod-induced cutaneous inflammation. CONCLUSIONS: These findings indicate that Sprouty1 expressed in keratinocytes has a suppressive role in imiquimod-induced skin inflammation mediated by inhibiting the production of cathelicidin. Collectively, Sprouty1 plays a preventive role in psoriatic skin. Our data provide new evidence for the pathogenesis of psoriatic keratinocytes, and the link cutaneous innate immunity, that indicated Sprouty1 is a potential novel therapeutic target.

Immunotherapy in psoriasis.

Over the past two decades, significant progress has been achieved in the treatment of psoriasis by targeting the human cytokine network. At present, 11 biologicals - antibodies, and a soluble receptor - are used to neutralize key inflammatory cytokines. Based on their targets, they can be grouped into the following four classes: TNF-α-, IL-12/23-, IL-17- and IL-23-inhibitors. The range of available substances, as well as their different modes of action can be challenging when selecting the right drug for an individual patient. In this article, we provide an overview of the approved biologicals for the treatment of psoriasis, including their advantages and limitations, and summarize criteria for therapy selection.

Antibacterial effects of a chitosan-containing spray: results of a pilot study.

Chitosan is a deacetylated derivate (> or =50%) of chitin, to which antimicrobial properties have been assigned. As bacterial resistances to antibiotics are increasing, alternative treatments have been gaining in importance. In the present study, the authors investigated the antimicrobial effect of a chitosan-containing spray in a randomized, double blind, placebo controlled clinical trial at the department of dermatology of the University of Osnabrueck. Twenty-nine healthy volunteers applied a chitosan-containing (1% concentration, low molecular chitosan, degree of deacetylation 87%) spray and a chitosan-free control (vehicle only) spray to the left and right foot respectively for five days. Before and after treatment swabs were taken for microbiological analysis. Bacterial count of the chitosan treated areas showed a significant decrease (P<0.001) compared to those areas treated with the chitosan-free spray. Thus, chitosan might serve as an alternative local antimicrobial agent in the future.

Safety, effectiveness and comparability of professional skin cleansers.

BACKGROUND: There are no widely-accepted methodical specifications with which to objectify cleansing effectiveness and skin compatibility of occuptional skin cleansing products in Europe. Therefore the German Social Insurance Agency (DGUV) initiated a study with the goal to evaluate such products in view of the potency and the safety of hand cleansers. A market analysis was a part of the project. METHODOLOGY: The product descriptions and safety data sheets of 120 products (5-20/manufacturer) of 11 manufacturers were evaluated between 02/2008 and 04/2008. RESULTS: The manufacturers used mainly ingredients of low irritancy. The declaration of the applied ingredients was in the majority of the cases correctly labeled according to the INCI Declaration. Although there was documentation of skin tolerability for most products, the manufacturers used widely differing tests of skin compatibility. Evidences for cleansing effectiveness were not declared or have not been provided. One manufacturer even promised medical effects of its products. There was no uniform general classification of products making it difficult to identify characteristics of cleansers and choose between them. CONCLUSIONS: Presently, there are no commonly accepted criteria to classify products in view of cleansing effectiveness und skin compatibility. Generally accepted criteria and test methods are needed for the evaluation of hand cleansers in order to provide the possibility of transparency and comparability.

Quantitative Proteomic Profile of Psoriatic Epidermis Identifies OAS2 as a Novel Biomarker for Disease Activity.

Psoriasis is a common chronic inflammatory systemic disease. Epidermal proteins are considered to be important in maintaining skin barrier function, innate immunity, and inflammation. To define more possible roles of the epidermis in the pathogenesis of psoriasis, quantified proteomic analysis was used to screen and analyze the differentially expressed epidermal proteins between 16 psoriasis patients and 15 healthy controls. Upregulated differential expression proteins (DEPs) include several significant functional protein clusters, including antimicrobial peptides (AMPs) and antiviral proteins (AVPs). The levels of 2-5-oligoadenylate synthase 2 (OAS2) in both epidermis and serum levels were significantly elevated in psoriasis and were also positively correlated with Psoriasis Area Severity Index (PASI) scores and Body Surface Area (BSA) scores. Moreover, OAS2 expression in psoriatic skin significantly decreased after IL-17R mono-antibody treatment. It has been clarified that inflamed keratinocytes were the main source of abnormally increased OAS2 in psoriasis skin by immunofluorescence and primary cell cultures. Keratinocyte-derived OAS2 can be induced by not only IFNß, but also psoriasis associated cytokines like IL-17A and IL-6. This study revealed that AMPs and AVPs are two important functional protein clusters altering innate immune in psoriatic epidermis. OAS2 is a novel potential sensitive biomarker, which could predict the severity and activity of psoriasis, and could also be used as an indicator to evaluate or monitor the efficacy of clinical treatment.

Suppressor of Fused Inhibits Skin Wound Healing.

Objectives: To investigate the effect of suppressor of fused (Sufu) on epidermal and dermal cellular properties and in wound healing. Approach: Transgenic (TG) mice overexpressing human Sufu (hSufu) in the epidermis were applied to investigate the effects of Sufu on epidermal and dermal cellular properties and in wound healing. Results: Histological staining revealed a reduction of epidermal and dermal thickness and an increase of hypodermal adipose tissue in homozygous K14-hSufu TG mice when compared with wild-type (WT) controls. TG mice exhibited significantly delayed skin wound healing. Moreover, the migratory and proliferative capabilities of cultured keratinocytes were decreased in K14-hSufuTG mice. Transforming growth factor-ß treatment increased the expression of α-smooth muscle actin more in WT than in TG fibroblasts. Sufu overexpression significantly decreased the expression of ß-catenin, glioma transcription factor 1 (Gli1), and matrix metalloproteinase-3 in wounds of K14-hSufu TG mice when compared with controls, probably indicating a delaying effect of Sufu on wound healing via blocking the hedgehog (Hh)/Gli and Wnt/ß-catenin pathway. Innovation: Our results indicate a new property of Sufu in the process of skin wound healing. It provides an important basis for Sufu as a potential target for skin wound healing. Conclusion: Our findings suggest that Sufu overexpression in the epidermis impairs wound healing via dampening the Hh/Gli and Wnt/ß-catenin signaling pathway. These data provide an important basis for further analyses of Sufu in skin wound healing.

Dimethyl fumarate (DMF) vs. monoethyl fumarate (MEF) salts for the treatment of plaque psoriasis: a review of clinical data.

Fumarates (fumaric acid esters, FAEs) are orally administered systemic agents used for the treatment of psoriasis and multiple sclerosis. In 1994, a proprietary combination of FAEs was licensed for psoriasis by the German Drug Administration for use within Germany. Since then, fumarates have been established as one of the most commonly used treatments for moderate-to-severe psoriasis in Germany and other countries. The licensed FAE formulation contains dimethyl fumarate (DMF), as well as calcium, zinc, and magnesium salts of monoethyl fumarate (MEF). While the clinical efficacy of this FAE mixture is well established, the combination of esters on which it is based, and its dosing regimen, was determined empirically. Since the mid-1990s, the modes of action and contribution of the different FAEs to their overall therapeutic effect in psoriasis, as well as their adverse event profile, have been investigated in more detail. In this article, the available clinical data for DMF are reviewed and compared with data for the other FAEs. The current evidence substantiates that DMF is the main active compound, via its metabolic transformation to monomethyl fumarate (MMF). A recent phase III randomized and placebo-controlled trial including more than 700 patients demonstrated therapeutic equivalence when comparing the licensed FAE combination with DMF alone, in terms of psoriasis clearance according to the Psoriasis Area and Severity Index (PASI) and Physician's Global Assessment (PGA). Thus, DMF as monotherapy for the treatment of psoriasis is as efficacious as in combination with MEF, making the addition of such fumarate derivatives unnecessary.

The role of Sprouty1 in the proliferation, differentiation and apoptosis of epidermal keratinocytes.

OBJECTIVES: Sprouty (SPRY) 1 is one of the SPRY proteins that inhibits signalling from various growth factors pathways and has also been known as a tumour suppressor in various malignancies. However, no study elucidates the role of SPRY1 in the skin. Our study was conducted to determine the function of SPRY1 in human keratinocytes and the epidermis. MATERIALS AND METHODS: In vitro primary cultured epidermal keratinocytes were used to investigate the proliferation, differentiation and apoptosis of these cells. We also established overexpression of SPRY1 in vitro and K14-SPRY1 transgenic mice. RESULTS: SPRY1 was mainly located in the cytoplasm of the epidermal keratinocytes from the granular epidermal layer of the skin and cultured cells. Overexpressed SPRY1 in keratinocytes resulted in up-regulation of P21, P27 and down-regulation of cyclin B1; decrease in MMP3 and integrin α6. SPRY1-overexpressed primary keratinocytes exhibited a lower proliferation and migration capability and higher rates of apoptosis. Epidermis of SPRY1-TG mice represented delayed wound healing. Proteomics analysis and GO enrichment showed DEPs of SPRY1 TG mice epidermis is significantly enriched in immune- and inflammatory-associated biological process. CONCLUSIONS: In summary, SPRY1 expression was inversely correlated with cell proliferation, migration and promote cell apoptosis of keratinocytes. SPRY1 maybe a negative feedback regulator in normal human epidermal keratinocytes and cutaneous inflammatory responses. Our study raised the possibility that enhancing expression of SPRY1 may have the potential to promote anti-inflammatory effects.