Fumaric acid ester-induced T-cell lymphopenia in the real-life treatment of psoriasis.

BACKGROUND: Fumaric acid esters (FAEs) are used to treat psoriasis and are known to cause lymphopenia in roughly 60% of the patients. Much remains to be elucidated about the biological effects of FAEs on lymphocytes. OBJECTIVE: To evaluate the influence of long-term FAE (Fumaderm® ) treatment on peripheral blood CD4+ and CD8+ T cells, CD19+ B cells and CD56+ natural killer (NK) cells in psoriasis. METHODS: In this single-centre retrospective observational subcohort study, we obtained leucocyte and lymphocyte subset counts before initiating FAE therapy in 371 psoriasis patients (mean age, 47.8 years; 63.3% males) and monitored them during treatment (mean treatment duration, 2.9 years). Multiparametric flow cytometry was used for immunophenotyping. RESULTS: FAEs significantly reduced the numbers of CD4+ T, CD8+ T, CD19+ B and CD56+ NK cells. Among lymphocyte subsets, the mean percentage reduction from baseline was always highest for CD8+ T cells, with a peak of 55.7% after 2 years of therapy. The risk of T-cell lymphopenia increased significantly with the age of the psoriasis patients at the time that FAE therapy was initiated. It was significantly decreased for the combination therapy with methotrexate and folic acid (vitamin B9) supplementation. Supporting evidence was found suggesting that T-cell lymphopenia enhances the effectiveness of FAE therapy. CONCLUSIONS: Monitoring distinct T-cell subsets rather than just absolute lymphocyte counts may provide more meaningful insights into both the FAE treatment safety and efficacy. We therefore suggest optimizing pharmacovigilance by additionally monitoring CD4+ and CD8+ T-cell counts at regular intervals, especially in patients of middle to older age. Thus, further prospective studies are needed to establish evidence-based recommendations to guide dermatologists in the management of psoriasis patients who are taking FAEs and who develop low absolute T-cell counts.

Long-term real-life safety profile and effectiveness of fumaric acid esters in psoriasis patients: a single-centre, retrospective, observational study.

BACKGROUND: Fumaric acid esters (FAEs) are an established systemic treatment for moderate-to-severe psoriasis. However, the long-term clinical safety and effectiveness of continuous FAE monotherapy and combination therapy have not been established. OBJECTIVE: To examine the long-term safety and effectiveness of FAEs as monotherapy and in combination with phototherapy or methotrexate in patients with psoriasis treated at a single centre in Germany. METHODS: This monocentric, retrospective observational study, with a follow-up period of up to 32.5 years, included 859 patients: 626 received FAE monotherapy, 123 received FAEs with concomitant phototherapy and 110 received FAEs with methotrexate. RESULTS: Approximately half of patients (49.0%) reported adverse events (566 total events), most of which involved the gastrointestinal tract. Serious adverse events were reported in 2.3% of patients, but none were deemed to have a causal relationship with any of the treatment regimens. Adverse events leading to treatment discontinuation were observed in 12.9% of patients. A median duration of 1 year was observed in all three treatment subcohorts (P = 0.70) from initiation of FAE treatment to a 50% response rate, where response was defined as achieving a cumulative static Physician's Global Assessment (PGA) score of 'light' and at least a 2-point reduction in baseline PGA. A 50% response rate for the cumulative Psoriasis Area and Severity Index 75 was achieved in the FAE monotherapy subcohort after a median of 3 years of treatment, in the FAEs + phototherapy subcohort after 6.7 years and in the FAEs + methotrexate subcohort after 8.1 years (P = 0.001). CONCLUSION: According to our data, FAEs as monotherapy or in combination with phototherapy or methotrexate are safe and beneficial for long-term clinical use. However, multicentre, randomized controlled trials are required to establish the clinical value of monotherapy versus combination therapy and the optimal treatment duration.

Neurological disorders in patients with bullous pemphigoid: clinical and experimental investigations.

BACKGROUND: Previous studies have shown that patients with bullous pemphigoid (BP) are more likely to have neurological diseases (ND). OBJECTIVES: To compare clinical findings in BP patients with and without ND and to investigate BP180 autoantibody binding in different neuronal tissues of mammalians. METHODS: Our database was searched for clinical findings of in-patients with the definitive diagnosis of BP. Moreover, brain tissue of mammalians was treated with serum of BP patients with elevated BP180 autoantibodies using biochip mosaics. RESULTS: Of 85/161 (52.8%) patients had a history of at least one ND (BP+ND). BP180 (P = 0.018), eosinophils (P = 0.043) and patients' accommodation in nursing homes (P < 0.0001) remained in the logistic regression model as significant independent predictors for the presence of ND in patients with BP. Subgroup analysis of community-dwelling BP patients revealed 25/93 (26.9%) patients with ND. In this population, the presence of ND also significantly correlated with BP180 (r = 0.26; P = 0.0003) and eosinophils (r = 0.19; P = 0.0087). In the animal model, no BP180-specific immunofluorescence could be detected. CONCLUSIONS: Our data support results of previous studies detecting significantly increased frequency of ND in BP patients. We have shown that raised BP180 titres and blood eosinophils are independent predictors for the presence of ND in BP patients. However, our experimental data do not support previous results indicating that specific binding of BP180 antibodies in neuronal tissue plays a pathogenetic role in ND.

[Delayed anaphylaxis after ingestion of meat. Carbohydrate epitope galactose-α-1,3-galactose as cause of severe anaphylactic reactions]. / Verzögerte Anaphylaxie nach Fleischverzehr. Kohlenhydratepitop Galaktose-α-1,3-Galaktose als Auslöser schwerer anaphylaktischer Reaktionen.

The correlation between anaphylaxis after consumption of meat and the carbohydrate epitope galactose-α-1,3-galactose (α-Gal) was first described in oncologic patients treated with cetuximab. An association with tick bites and parasitosis is suspected. We report on a healthy patient who developed sudden anaphylactic reactions after the ingestion of meat. Serologic and skin tests confirmed sensitization to α-Gal. Avoiding the consumption of mammalian meat led to a complete absence of symptoms.

Glutathione-S-transferase T1 genotyping and phenotyping in psoriasis patients receiving treatment with oral fumaric acid esters.

BACKGROUND: Glutathione S-transferases (GSTs) are involved in detoxification of xenobiotics such as fumaric acid esters (FAE). OBJECTIVES: To perform GSTT1 geno- and phenotyping in psoriasis patients treated with FAE to find out whether the responder status and/or occurrence of side-effects are associated with allelic variants and enzymatic activity of GSTT1. METHODS: We treated 106 psoriasis patients with FAE. GSTT1 genotyping was performed using PCR, phenotyping was carried out by means of a validated high performance liquid chromatography assay at baseline and under treatment. RESULTS: The distribution of GSTT1 genotypes was as follows: 31% *A/*A; 49% *A/*0; 20% *0/*0. GSTT1 phenotypes as expressed in enzyme activity significantly differed between conjugators classes. (P < 0.001). GSTT1 activity under treatment was significantly (P = 0.0001) increased when compared with baseline. There were no significant associations between the aforementioned GSTT1 pheno- and genotypes and clinical parameters such as psoriasis area and severity index (PASI)50, adverse effects and FAE dosage (P > 0.05), except for the frequent occurrence of reduction (>50%) of circulating lymphocytes in patients with *0/*0 GSTT1 status (P = 0.036; odds ratio: 6, 95% CI: 1.1-32). CONCLUSION: GSTT1 geno- and phenotypes significantly correlate in psoriasis patients and do not substantially differ from healthy controls. Response to FAE does likely not depend on GSTT1. However, *0/*0 GSTT1 status is a predictor for the occurrence of marked reduction of lymphocyte counts under FAE therapy. Notably, FAE seem to enhance GSTT1 enzyme activity in high and low conjugators.

[Phlebology in German departments of dermatology. An analysis on behalf of the German Society of Phlebology]. / Phlebologie an deutschen Hautkliniken. Eine Bestandsaufnahme im Auftrag der Deutschen Gesellschaft für Phlebologie.

BACKGROUND: Phlebologic diseases have become extremely common and have major socio-economic impact. However, the percentage of dermatologists working in phlebology appears to be decreasing according to the data of the German Society of Phlebology (DGP). METHODS: To investigate the reasons for this development, we--on behalf of the DGP--sent a questionnaire to 120 German Departments of Dermatology in autumn 2012. RESULTS: In 76 returned questionnaires, the number of physicians with additional fellowship training in phlebology averaged 1.5; the average number of those who fulfill the criteria for training fellows in phlebology was 0.9. In 71.1 % of the departments there was a phlebologist. A special phlebologic outpatient clinic existed in 73.7 % of the departments. Sonography with Doppler (89.5 %) and duplex (86.8 %) was used as the most frequent diagnostic tool. For therapy, compression (94.7 %), sclerotherapy (liquid 78.9 %, foam 63.2 %, catheter 18.4 %), endoluminal thermic procedures (radio wave 28.9 %, laser 17.1 %) and surgery (especially crossectomy and stripping 67.1 %, phlebectomy of tributaries 75 %) were used. The average number of treatments was very heterogenous in the different departments. CONCLUSIONS: Phlebology definitely plays an important role in dermatology. Most departments fulfill the formal criteria for the license to conduct advanced training in phlebology. A wide spectrum of phlebological diagnostic and therapeutic procedures is available.

Compression and venous ulcers.

Compression therapy is considered to be the most important conservative treatment of venous leg ulcers. Until a few years ago, compression bandages were regarded as first-line therapy of venous leg ulcers. However, to date medical compression stockings are the first choice of treatment. With respect to compression therapy of venous leg ulcers the following statements are widely accepted: 1. Compression improves the healing of ulcers when compared with no compression; 2. Multicomponent compression systems are more effective than single-component compression systems; 3. High compression is more effective than lower compression; 4. Medical compression stockings are more effective than compression with short stretch bandages. Healed venous leg ulcers show a high relapse rate without ongoing treatment. The use of medical stockings significantly reduces the amount of recurrent ulcers. Furthermore, the relapse rate of venous leg ulcers can be significantly reduced by a combination of compression therapy and surgery of varicose veins compared with compression therapy alone.

New concept: different types of insufficiency of the saphenofemoral junction identified by duplex as a chance for a more differentiated therapy of the great saphenous vein.

Even though the item 'saphenofemoral junction' (SFJ) is anatomically well defined, the incontinence of the SFJ is often incompetently described in clinical practice and studies. Especially with regard to the optimal therapy of the great saphenous vein, it might be of importance to have a more distinct regard to the SFJ as it is known that about 10-30% of the saphenous refluxes have no femoral origin. Considering the terminal and preterminal valve three types of incompetence of the SFJ may be differentiated: Type 1: Incompetent terminal, but competent preterminal valve; Type 2: Competent terminal, but incompetent preterminal valve; Type 3: Incompetent terminal and preterminal valve (complete incompetence). A review on prior studies and reports leads to the assumption that the differentiation of the distinct types of SFJ-incompetence allows a more individual and - perhaps - more effective therapy. Finally, studies are necessary to evaluate the here given new concept.

Polidocanol foam sclerotherapy of persisting postoperative seromas after varicose vein surgery: a series of six cases.

OBJECTIVE: The aim of our case series was to show the therapeutic effect and the safety of the use of polidocanol foam in ultrasound-guided sclerotherapy treatment of relatively small postoperative seromas after varicose vein surgery. METHODS: We treated six patients with postoperative seromas after varicose vein surgery that were refractory to conventional treatments including compression dressings, repeated needle aspirations and manual lymph drainage. RESULTS: A complete regression of the fluid collections was seen after one and two ultrasound-guided injections of polidocanol foam into the seroma cavity in two cases, respectively. Up to five treatment sessions and up to four further needle aspirations were necessary for the remaining two patients until complete regression of the seromas. No side-effects were reported. CONCLUSION: This is the first case series to report of the regression of postoperative seromas after varicose vein surgery induced by polidocanol foam sclerotherapy.

Sclerotherapy in an undetected pregnancy - a catastrophe?

According to the guidelines and the manufacturer's information, pregnancy is a contraindication for sclerotherapy with Polidocanol. However, in some cases sclerotherapy has been conducted in a period when the pregnancy is not known by the patient. When pregnancy is diagnosed, patients and gynecologists often ask the phlebologist if there is an indication for the interruption of pregnancy. Up to now, there is only rare information on sclerotherapy, polidocanol and pregnancy. Current knowledge is summed up in this article together with case reports. The existing case reports and mainly retrospective case series on intended or accidentally conducted sclerotherapy with common sclerosants and doses show no increased risk for the mother and the unborn child. However, in view of the limited literature data available and the high probability for spontaneous regression of varicose veins postpartum, sclerotherapy should be avoided in pregnancy, if possible. Conservative measures during pregnancy or an elimination of varicose veins before pregnancy should be preferred. In single cases e.g. painful genitoanal varices, the use of sclerotherapy can be helpful even during pregnancy. Thereby, a very thorough clarification of the mother with a final written consent and an implementation according to the guidelines are especially important. According to the current data, there is no reason for an interruption after a sclerotherapy that has been conducted during undetected pregnancy.

[Scleromyxedema. A chronic progressive systemic disease]. / Skleromyxödem. Eine chronisch progressive Systemerkrankung.

BACKGROUND: Scleromyxedema is a rare connective tissue disease that may affect numerous internal organs in addition to the skin. The disease is almost exclusively associated with monoclonal gammopathy. MATERIAL AND METHODS: This retrospective study summarizes the clinical characteristics of four patients with scleromyxedema. In all of the patients a systematic serological and apparative check-up was performed. RESULTS: The mean age of the four patients (three women and one man) was 51 years. In all cases, monoclonal gammopathy (3 cases of IgG lambda and 1 case of IgG kappa) was involved. In one patient, skin lesions were restricted to the upper part of the body and three patients had generalized disease. The internal organs of all patients were affected with fibrosis of the lungs, myositis and arthritis, peripheral polyneuropathy and hypomotility of the esophagus. The most effective forms of treatment in this patient collective were dexamethasone-pulse therapy, intravenous immunoglobulins and bortezomib. All patients had recurrences after finishing therapy. The mean observation period after the initial diagnosis of scleromyxedena was 6.25 years (range 2-11 years). CONCLUSION: Scleromyxedema is a rare multisystemic disease. The heterogeneous affection of internal organs necessitates a comprehensive check-up. The response to recently published treatment strategies is low and recurrences after finishing therapy are frequent.

Prevalence of human polyomaviruses in common and rare types of non-Merkel cell carcinoma skin cancer.

BACKGROUND: Little is known about the association of human polyomaviruses (HPyVs) other than Merkel cell polyomavirus (MCPyV) with nonmelanoma skin cancer. OBJECTIVES: To evaluate the presence of HPyV6, HPyV7, trichodysplasia spinulosa-associated polyomavirus (TSV), also called HPyV8, and the recently discovered HPyV9 in basal cell carcinoma (BCC), actinic keratosis (AK), squamous cell carcinoma in situ (SCCis), squamous cell carcinoma (SCC), keratoacanthoma (KA), microcystic adnexal carcinoma (MAC) and atypical fibroxanthoma (AFX). METHODS: Archival paraffin-embedded samples (n = 193: 41 BCC, 31 AK, 8 SCCis, 52 SCC, 42 KA, 5 MAC and 14 AFX) were analysed for the presence of the respective HPyV by polymerase chain reaction (PCR). HPyV DNA loads (HPyV DNA copies per ß-globin gene copy) were determined in all HPyV-positive samples by quantitative real-time PCR. Immunohistochemical analysis of MCPyV large T-antigen (LTA) expression was performed using the monoclonal antibody CM2B4. RESULTS: MCPyV DNA was found in 29% of BCC, 19% of AK, 25% of SCCis, 27% of SCC, 29% of KA, 0% of MAC and 29% of AFX. MCPyV DNA loads never exceeded 0·3 MCPyV DNA copies per ß-globin gene copy (median 0·004). In the immunohistochemical analysis of MCPyV LTA expression, all evaluated samples (32 MCPyV DNA-positive samples) were LTA negative. HPyV6 DNA was found in 7% of BCC, 3% of AK, 12% of SCCis, 4% of SCC, 5% of KA, and 0% of MAC and AFX. HPyV6 DNA loads never exceeded 0·7 HPyV6 DNA copies per ß-globin gene copy (median 0·015). None of the 193 samples was positive for HPyV7, TSV or HPyV9 DNA. CONCLUSIONS: Our findings argue against a pathogenic role for MCPyV, HPyV6, HPyV7, TSV and HPyV9 in the analysed types of non-Merkel cell carcinoma skin cancer.

A randomized, half-side comparative study of aminolaevulinate photodynamic therapy vs. CO(2) laser ablation in immunocompetent patients with multiple actinic keratoses.

BACKGROUND: Photodynamic therapy (PDT) and laser ablation (LA) are frequently used treatment options for multiple actinic keratoses (AK), yet they have not been compared head to head. OBJECTIVES: To compare PDT and carbon dioxide (CO(2) ) LA in the management of multiple AK using objective and subjective outcome measures. METHODS: A single-centre, randomized, two-treatment half-side comparative study of PDT vs. CO(2) LA was performed. Patients with at least four bilateral (e.g., scalp, forearms) AK were included. The primary outcome measure was the reduction of AK 3 months (v3) after therapy. Secondary outcome measures included the reduction of AK 4 weeks (v2) after therapy, decrease of epidermal p53 and Ki-67 protein expression, micromorphological changes as assessed by optical coherence tomography (OCT) in vivo, and investigators' and patients' satisfaction scoring. RESULTS: In total, 20 patients (18 men and 2 women) completed the study. Both treatments reduced AK quantity significantly. On v3, relative reduction of AK quantity was significantly higher following PDT (P = 0·0362). Ki-67 and p53 protein expression was reduced significantly from baseline (Ki-67, median 49·5%; p53, median 64·8%) to v2 by both procedures (PDT, median 18·5%, P < 0·0001; LA, median 16·2%, P < 0·0001). AK features as assessed by OCT imaging were also significantly reduced by both procedures. The investigators and patients rated the side-effects and inconveniences of PDT as more severe, but both overall preferred PDT due to the superior clinical outcome. CONCLUSIONS: CO(2) LA and PDT are both effective therapy options for multiple AK, yet PDT seems to be superior in terms of AK reduction and participants' and investigators' overall satisfaction.

Expression of microRNAs in basal cell carcinoma.

BACKGROUND: Perturbations in the expression profiles of microRNAs (miRNAs) have been reported for a variety of different cancers. Differentially expressed miRNAs have not been systematically evaluated in basal cell carcinoma (BCC) of the skin. OBJECTIVES: To initiate a microarray-based miRNA profiling study to identify specific miRNA candidates that are differentially expressed in BCC. METHODS: Patients with BCC (n = 7) were included in this study. Punch biopsies were harvested from the tumour centre (lesional, n = 7) and from adjacent nonlesional skin (intraindividual control, n = 7). Microarray-based miRNA expression profiles were obtained on an Agilent platform using miRBase 16 screening for 1205 Homo sapiens (hsa)-miRNA candidates. To validate the microarray data, the expression of seven dysregulated miRNAs was measured by TaqMan quantitative real-time reverse transcription polymerase chain reaction. RESULTS: We identified 16 significantly upregulated (hsa-miR-17, hsa-miR-18a, hsa-miR-18b, hsa-miR-19b, hsa-miR-19b-1*, hsa-miR-93, hsa-miR-106b, hsa-miR-125a-5p, hsa-miR-130a, hsa-miR-181c, hsa-miR-181c*, hsa-miR-181d, hsa-miR-182, hsa-miR-455-3p, hsa-miR-455-5p and hsa-miR-542-5p) and 10 significantly downregulated (hsa-miR-29c, hsa-miR-29c*, hsa-miR-139-5p, hsa-miR-140-3p, hsa-miR-145, hsa-miR-378, hsa-miR-572, hsa-miR-638, hsa-miR-2861 and hsa-miR-3196) miRNAs in BCC compared with nonlesional skin. Data mining revealed connections to many tumour-promoting pathways, such as the Hedgehog and the mitogen-activated protein kinase/extracellular signal-regulated kinase signalling cascades. CONCLUSIONS: This study identified several miRNA candidates that may play a role in the molecular pathogenesis of BCC.

Serum levels of antimicrobial peptides and proteins do not correlate with psoriasis severity and are increased after treatment with fumaric acid esters.

Overexpression of antimicrobial peptides and proteins (AMPs) such as human ß-defensin-2 (hBD2), LL37, and psoriasin has frequently been observed in lesional skin of psoriasis patients. We aimed to evaluate whether circulating AMP levels correlate with disease severity, and change under therapy with fumaric acid esters (FAE). We studied psoriasis patients who underwent systemic therapy using oral FAE (Fumaderm(®)). An enzyme-linked immunosorbent assay for the detection of serum protein expression of hBD2, LL37, and psoriasin was performed at baseline and after 12-week therapy. After 12-week FAE treatment of 28 patients, the median PASI significantly (P < 0.0001) decreased from 27.1 to 12.5. In psoriasis patients, mean ± SD serum hBD2, psoriasin, and LL37 levels at baseline were 295.6 ± 93.5 pg/ml, 79.4 ± 32.7 ng/ml, and 106.3 ± 90 ng/ml, respectively, which were significantly increased when compared to healthy controls (110 ± 53.7 pg/ml, P ≤ 0.0001; 3.1 ± 0.7 ng/ml, P ≤ 0.0001; 3.8 ± 0.9 ng/ml, P = 0.0004, respectively). After 12-week FAE treatment, a significant increase of serum hBD2 (339.7 ± 74.3 pg/ml; P = 0.0046), psoriasin (106 ± 58.9 ng/ml; P = 0.0014), and LL37 (136.6 ± 115.1 ng/ml; P = 0.0035) was observed. Correlation studies did not reveal significant relationships between serum AMP levels and PASI (r < 0.1; P > 0.05). In contrast to AMP expression in psoriatic skin serum, AMP levels seem not to correlate with disease severity. Increased serum AMP protein levels in psoriasis resolution are an unexpected observation that needs to be investigated more in detail in future studies.

Add-on diagnostic tool for allergic contact dermatitis: the strip patch test.

The "conventional" patch test (PT) is considered to be the "gold standard" in diagnosing allergic contact dermatitis. However, the method of patch testing has repeatedly been criticized for its limited diagnostic accuracy and it is therefore by no means uniformly accepted as a reliable test method. Basic idea of the "strip" patch test (SPT), a modification by repeated tape stripping prior to patch testing, is to increase the quantity of allergen reaching the deeper epidermal cell layers and, thus, to increase the test sensitivity. The SPT according to our proposed standardized protocol is promising to improve diagnosis of allergic contact dermatitis which is demonstrated exemplary in the field of occupational contact dermatitis.

Induction of fat cell necrosis in human fat tissue after treatment with phosphatidylcholine and deoxycholate.

BACKGROUND: Injections with phosphatidylcholine- and deoxycholate-containing substances are used to treat localized fat accumulation and lipomas. It is believed that the injected substances induce fat cell destruction with subsequent acute panniculitis followed by a repair process of the treated fat tissue. OBJECTIVES: We investigated whether necrosis or apoptosis of fat cells was induced by the injected substances. METHODS: Samples of fat tissue of lipoma were collected at various times after injection and evaluated by light and electron microscopy, by immunostaining for active caspase-3 and antideoxyribonuclease I, in situ end-labelling (TUNEL staining), and biochemical caspase-3 assays. RESULTS: Light and electron microscopy showed fat cell necrosis in all areas of the treated lipomas. Low levels of active caspase-3 indicated the absence of apoptosis. CONCLUSIONS: Injection of the lipolytic substances phosphatidylcholine and deoxycholate leads to fat cell necrosis rather than apoptosis. However, additional studies evaluating different dosing and further time points after treatment are necessary.