Diagnosis and treatment of venous leg ulcers: S2k Guideline of the German Society of Phlebology and Lymphology (DGPL) e.V.

This S2k guideline on venous leg ulcers was created on the initiative and under the leadership of the German Society of Phlebology and Lymphology (DGPL). The guideline group also consisted of representatives from the German Society for Phlebology and Lymphology, German Dermatological Society, German Society for General Medicine, German Society for Angiology, German Society for Vascular Surgery and Vascular Medicine, German Society for Surgery, German Society for Dermatosurgery, German Society for Wound Healing and Wound Treatment, Professional Association of Phlebologists and Lymphologists and Initiative Chronische Wunden. The aim of this guideline is to combine the different approaches and levels of knowledge of the respective professional groups on the basis of consensus, so that a basic concept for the best possible treatment of patients with venous leg ulcers can be provided. A total of 70 specific recommendations were formulated and agreed upon, divided into the subject areas of diagnostics, therapy, prevention of recurrences, and everyday challenges. The guideline thus reflects the current state of scientific knowledge and is intended to be widely used as the best available document for the treatment of patients with venous leg ulcers in everyday clinical practice.

Hypersensitivity reactions to non-steroidal anti-inflammatory drugs (NSAIDs) - a retrospective study.

BACKGROUND: The aim of this study was to verify the validity of clinical history and oral provocation challenges of patients with NSAID hypersensitivity and to identify safe alternatives. The COX-2 inhibitor etoricoxib, in particular, was studied. PATIENTS AND METHODS: In all, 104 patients with confirmed diagnoses of NSAID hypersensitivity treated at the Department of Dermatology, Frankfurt University Hospital, Germany between 2004 and 2012 were retrospectively studied. RESULTS: The medical history and hypersensitivity symptoms during oral provocation testing (OPT) largely coincided and were mostly mild to moderate. Acetylsalicylic acid (ASA) was the most frequent trigger both anamnestically (27.9 %) and during OPT (47.8 %). Etoricoxib caused the fewest reactions during OPT (4.2 %). Acetaminophen led to reactions in only 6.7 % of the cases studied although it was named more often in clinical histories (14 %). CONCLUSIONS: OPT should be the aim whenever possible as most symptoms are mild to moderate. To distinguish between selective and cross-hypersensitivity reactions, ASA should be part of the test protocol. Furthermore, the findings of this study indicate that etoricoxib and acetaminophen are safe treatment alternatives in case of NSAID hypersensitivity. However, these drugs should not be administered without prior OPT in an inpatient setting, as severe symptoms can occur.

Frontal fibrosing alopecia - review of recent case reports and case series in PubMed.

BACKGROUND: In his initial publication of frontal fibrosing alopecia (FFA) in 1994, Steven Kossard included six postmenopausal women. A type of cicatricial alopecia, FFA is clinically characterized by frontotemporal hairline recession and loss of eyebrows. In recent years, there has been an increasing number of case reports of FFA in both premenopausal women and men. STUDY OBJECTIVE: Review and analysis of the literature on FFA with regard to epidemiology, associated disorders, disease presentation, diagnosis and treatment. METHODS AND MATERIAL: We conducted a Pubmed database search for case reports and case series on FFA. Overall, we reviewed and analyzed data from 68 articles, including 932 patients. Apart from epidemiological data such as age, gender or ethnicity, we also assessed other aspects such as predilection sites, associated skin lesions, comorbidities, drugs and treatment response as well as the diagnostic significance of autoantibodies. RESULTS: While we were able to confirm and more accurately define some of the data published in the literature, we were unable to reproduce certain assumptions that had previously been made. The high coincidence of FFA and thyroid disease we found in our analysis is particularly significant. CONCLUSIONS: The present study provides the most comprehensive review to date of published cases of FFA.

Dimethylfumarate inhibits melanoma cell proliferation via p21 and p53 induction and bcl-2 and cyclin B1 downregulation.

Recent evidence suggests that dimethylfumarate (DMF), known as a highly potent anti-psoriatic agent, might have anti-tumorigenic properties in melanoma. It has recently been demonstrated that DMF inhibits melanoma proliferation by apoptosis and cell cycle inhibition and therefore inhibits melanoma metastasis. Nonetheless, the underlying mechanisms remain to be evaluated. To elucidate the effects of DMF on melanoma cell lines (A375, SK-Mel), we first performed cytotoxicity assays. No significant lactatedehydogenase (LDH) release could be found. In further analysis, we showed that DMF suppresses melanoma cell proliferation in a concentration-dependent manner. To examine whether these effects are conveyed by apoptotic mechanisms, we studied the amount of apoptotic nucleosomes and caspase 3/7 activity using ELISA analysis. Significant apoptosis was induced by DMF in both cell lines, and this could be paralleled with bcl-2 downregulation and PARP-1 cleavage. We also performed cell cycle analysis and found that DMF induced concentration-dependent arrests of G0/G1 as well as G2/M. To examine the underlying mechanisms of cell cycle arrest, we analyzed the expression profiles of important cell cycle regulator proteins such as p53, p21, cyclins A, B1, and D1, and CDKs 3, 4, and 6. Interestingly, DMF induced p53 and p21 yet inhibited cyclin B1 expression in a concentration-dependent manner. Other cell cycle regulators were not influenced by DMF. The knockdown of DMF induced p53 via siRNA led to significantly reduced apoptosis but had no influence on cell cycle arrest. We examined the adhesion of melanoma cells on lymphendothelial cells during DMF treatment and found a significant reduction in interaction. These data provide evidence that DMF inhibits melanoma proliferation by reinduction of important cell cycle inhibitors leading to a concentration-dependent G0/G1 or G2/M cell cycle arrest and induction of apoptosis via downregulation of bcl-2 and induction of p53 and PARP-1 cleavage. Hence, DMF might be an interesting agent in the treatment of melanoma and is worth further investigation in vivo.

Dimethylfumarate effectively inhibits lymphangiogenesis via p21 induction and G1 cell cycle arrest.

Different pathologies, such as lymphoedema, cancer or psoriasis, are associated with abnormal lymphatic vessel formation. Therefore, influencing lymphangiogenesis is an interesting target. Recent evidence suggests that dimethylfumarate (DMF), an antipsoriatic agent, might have antitumorigenic and antilymphangiogenic properties. To prove this assumption, we performed proliferation and functional assays with primary human dermal lymphendothelial cells (DLEC). We could demonstrated that DMF suppresses DLEC proliferation and formation of capillary-like structures. Underlying apoptotic mechanisms could be ruled out. Cell cycle analysis demonstrated a pronounced G1-arrest. Further evaluations revealed increases in p21 expression. In addition, DMF suppressed Cyclin D1 and Cyclin A expression in a concentration-dependent manner. p21 knockdown experiments demonstrated a p21-dependent mechanism of regulation. Further analysis showed an increased p21 mRNA expression after DMF treatment. This transcriptional regulation was enforced by post-transcriptional and post-translational mechanisms. In addition, we could demonstrate that the combination of a proteasomal inhibitor and DMF superinduced the p21 expression. Hence, DMF is a new antilymphangiogenic compound and might be used in various illnesses associated with increased lymphangiogenesis.

No More Venous Ulcers-What More Can We Do?

Venous leg ulcers (VLUs) are the most severe complication caused by the progression of chronic venous insufficiency. They account for approximately 70-90% of all chronic leg ulcers (CLUs). A total of 1% of the Western population will suffer at some time in their lives from a VLU. Furthermore, most CLUs are VLUs, defined as chronic leg wounds that show no tendency to heal after three months of appropriate treatment or are still not fully healed at 12 months. The essential feature of VLUs is their recurrence. VLUs also significantly impact quality of life and could cause social isolation and depression. They also have a significant avoidable economic burden. It is estimated that the treatment of venous ulceration accounts for around 3% of the total expenditure on healthcare. A VLU-free world is a highly desirable aim but could be challenging to achieve with the current knowledge of the pathophysiology and diagnostic and therapeutical protocols. To decrease the incidence of VLUs, the long-term goal must be to identify high-risk patients at an early stage of chronic venous disease and initiate appropriate preventive measures. This review discusses the epidemiology, socioeconomic burden, pathophysiology, diagnosis, modes of conservative and invasive treatment, and prevention of VLUs.

Ligand activation of peroxisome proliferator-activated receptor delta suppresses cathepsin B expression in human endothelial cells in a posttranslational manner.

Peroxisome proliferator-activated receptor (PPAR) delta agonists are known to have distinct anti-inflammatory and antitumor effects; though, the knowledge regarding their mode of action has thus far been limited. Different cathepsins have been shown to be upregulated in a broad range of pathological events, such as rheumatoid arthritis, psoriasis, atherosclerosis and diverse tumor entities, for example melanoma. Recent work demonstrated that cathepsin B in particular is an important pro-angiogenic protease in various pathological conditions. We therefore analysed whether cathepsins are a valid target for PPARδ agonists. This study reveals an inhibitory effect of two commonly used PPARδ agonists, GW501516 and L-165,041, on the protein expression and enzyme activity of cathepsin B in human endothelial cells. In contrast, no inhibitory effects were observed on cathepsin L and cathepsin D protein expression after treatment with PPARδ agonists. Furthermore, the results substantiate that PPARδ activators mediate their inhibitory action in a PPARδ-dependent manner and that the underlying regulatory mechanism is not based on a transcriptional but rather on a posttranslational mode of action, via the reduction in the cathepsin B protein half-life. Mechanisms conveying the suppressive effect by 5'-alternative splicing, a 3'-UTR-dependent way or by miRNA could be excluded. The data of this study explore cathepsin B as a new valid target for PPARδ agonists in endothelial cells. The results bolster other studies demonstrating PPARδ agonists as anti-inflammatory and anticarcinogenic agents and thus might have the potential to help to develop new pharmaceutical drugs.

Dimethyl fumarate - only an anti-psoriatic medication?

Fumaric acid esters have been used successfully in the therapy of psoriasis vulgaris since 1959. In the last 17 years, many of the underlying mechanisms of anti-psoriatic action, such as a Th1/Th2 shift, a suppression of important leukocyte adhesion molecules, the induction of pro-apoptotic pathways in T-cells and recently anti-angiogenic action, have been discovered. Based on the knowledge of these immunomodulatory characteristics, fumaric acid esters have been shown to be effective or potentially effective in a multitude of dermatological as well as non-dermatological diseases. The range of new therapeutic targets reaches from multiple sclerosis to illnesses such as necrobiosis lipoidica, granuloma annulare and sarcoidosis. Experimental approaches offer promising, although preliminary, results on the treatment of cancer, malaria, chronic inflammatory lung diseases, and Huntington disease, to name but a few. This valued and well-known drug mainly prescribed by dermatologists is now experiencing a renaissance far beyond dermatologic applications.

Benefits and limitations of sting challenge in hymenoptera venom allergy.

The prevalence of systemic reactions to hymenoptera stings is up to 7.5%. Venom-specific immunotherapy (VIT) is an established treatment for insect venom allergy. In order to monitor the allergic status and thus the success of the therapy, controlled sting challenge under VIT continues to be the gold standard. This review deals not only with useful indications and therapeutic consequences but also with critical aspects that should be considered when performing sting challenge.

Impact of specific immunotherapy and sting challenge on the quality of life in patients with hymenoptera venom allergy.

BACKGROUND: An experienced life-threating anaphylactic reaction to hymenoptera venom can sustainably impair patients' quality of life (QoL). Besides carrying emergency medication, venom-specific immunotherapy (VIT) exists as a causal treatment of allergy. OBJECTIVE: This study aimed to examine QoL, anxiety, depression, and physical and mental health in patients allergic to hymenoptera venom before and during VIT and the impact of a tolerated sting challenge (SC). METHODS: Between July 2017 and August 2017, 142 patients with venom allergy were analyzed using validated questionnaires as the: Vespid Allergy Quality for Life Questionnaire" (VQLQ-d), the "Hospital Anxiety and Depression Scale" (HADS-D) and the "Short Form 36" (SF-36). To evaluate the impact of VIT and SC on the QoL, patients were divided into 3 groups: (A) VIT and tolerated SC (n = 45), (B) VIT before carrying out SC (n = 73), and (C) therapy-naïve before VIT (n = 20). Further parameters like gender, age, insect species, and severity of the anaphylactic reaction were assessed. RESULTS: A significant correlation between the health-related QoL and the parameters of gender and state of treatment was seen. Especially male patients, as well as patients allergic to yellow jacket venom, benefit from a SC in terms of a significant increase in their QoL. In the total study cohort, a clear trend was observed towards a higher QoL in patients under VIT who tolerated a SC. Overall, neither the patients' age nor the insect species exerted a relevant influence on QoL, depression or anxiety. However, women showed a lower QoL combined with higher anxiety and depression scores than men. CONCLUSION: Immunotherapy leads to an improved QoL, which can be further increased by a SC. A tolerated SC conceivably reassures the patients by objectifying the treatment success. Female patients appear to have a stronger impaired QoL per se. Taken together, a SC can be performed during VIT to strengthen the patients' QoL.

Single-center analysis of patients with frontal fibrosing alopecia: evidence for hypothyroidism and a good quality of life.

OBJECTIVE: Frontal fibrosing alopecia (FFA) is an underestimated scarring alopecia. This study aimed to examine epidemiological information, as well as predilection sites, associated diseases, and responses to therapy of patients with FFA. We also aimed to determine whether the extent or duration of disease correlated with the quality of life (QoL). METHODS: Twelve outpatients with FFA for > 2 years were analyzed. The Erlanger atopic score and the Functional Assessment of Non-life-threatening Conditions (FANLTC) for QoL-assessment were used as scoring systems. RESULTS: All patients were women with a mean age of 70.3 years. Most patients did not have any symptoms during their disease progression and no therapy that was used showed any significant effects. FFA was associated with hypothyroidism. There were no correlations between hairline regression, duration of disease, atopic disposition, and QoL. The overall QoL was good. CONCLUSIONS: The present study shows that there is no correlation between the extent of FFA and QoL or atopic predisposition. There is a strong correlation between the incidence of thyroid disease and FFA.