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 (R)) 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.

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.

BACKGROUND:Dysregulation of microRNA (miRNA) metabolism has been observed in a variety of human cancers. In this pilot study, we investigated expression profiles of the two most important enzymes of the miRNA machinery, Drosha and Dicer, in relation to epithelial skin cancer and its premalignant stage. METHODS:Patients with premalignant actinic keratoses (AK, n = 6), basal cell carcinomas (BCC, n = 15), and squamous cell carcinomas (SCC, n = 7) were included in the study. Punch biopsies were harvested from the center of the tumors (lesional) as well as from sites of healthy skin (intraindividual controls). Skin samples (n = 14) were also obtained from healthy subjects for additional controls. Dicer and Drosha mRNA levels were detected by quantitative real-time reverse transcriptase polymerase chain reaction. RESULTS:Drosha expression levels were significantly upregulated in both the BCC and SCC groups compared to those in the healthy controls (p < .01), while Dicer expression levels in the BCC group were significantly lower (p < .05). Dicer expression in the SCC group was significantly higher compared to intraindividual controls (p < .05), while Dicer expression levels in both the SCC and AK groups were not significantly different from healthy control samples (p > .05). In the premalignant AK group, we could not observe any significant difference in Drosha or Dicer expression levels compared to either healthy or intraindividual controls (p > .05). CONCLUSIONS:We observed dysregulation of Drosha and Dicer expression in epithelial tumors when compared to healthy control samples. Therefore, we favor the hypothesis that miRNAs are involved in the carcinogenesis of epithelial skin cancer.

Die Korrelation zwischen Anaphylaxie nach Fleischverzehr und dem Kohlenhydratepitop Galaktose-α-1-3-Galaktose (α-Gal) wurde erstmals nach dem Einsatz von Cetuximab bei onkologischen Patienten beschrieben. Ein Zusammenhang zu Zeckenbissen und Parasitosen wird vermutet. Wir berichten über einen Patienten, der aus völliger Gesundheit heraus plötzlich aufgetretene verzögerte anaphylaktische Reaktionen nach dem Verzehr von Fleisch erlebte. Die serologische Diagnostik und Hauttestungen wiesen eine Sensibilisierung gegenüber α-Gal nach. Unter Karenz von Säugetierfleisch konnte die Symptomfreiheit erzielt werden.

BACKGROUND:Previous studies on the therapy of insufficient saphenous veins mainly compare different treatment methods. Only a few investigate differences of a specific treatment option between the great (GSV) and the small saphenous vein (SSV). The aim of this study was to evaluate the efficacy, clinical improvement and patient satisfaction after radiofrequency-induced thermotherapy (RFITT®) with regard to the treated vein.PATIENTS AND METHODS:We included 65 patients (40 women, 25 men; mean age 54.75 years) who were treated with RFITT® for incompetent saphenous veins (n = 83: 62 GSV, 21 SSV). Occlusion rates were determined by duplex-sonography. Additionally, we performed a prospective analysis of venous symptoms and signs by means of a standardized questionnaire and of patient satisfaction using a semi-quantitative rating (1 = very good, 6 = insufficient).RESULTS:The GSV group showed a significantly greater reduction of venous symptoms in comparison to the SSV group (p = 0.005) despite no significant differences in long term occlusion rates (mean time after operation: 22 months) of 90 % in the GSV group and 81.8 % in the SSV group (p = 0.598). Following the procedure, detailed analysis revealed significantly more swelling (p = 0.022), feeling of heavy legs (p = 0.002) and nightly calf cramps (p = 0.001) in the SSV group. Additionally, RFITT® led to a significant improvement in patient satisfaction in the GSV group (from 1.93 at day 1 - 3 to 1.41 after 6 - 12 months, p = 0.009) but not in the SSV group (from 2.29 to 2.07, p = 0.43).CONCLUSIONS:With regard to the improvement of venous symptoms and patient satisfaction, the benefit of RFITT® is greater for patients with incompetent GSV compared to those with incompetent SSV.

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.

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.

Skin diseases on the nose are seen in a variety of medical disciplines. Dermatologists, otorhinolaryngologists, general practitioners and general plastic and dermatologic surgeons are regularly consulted regarding cutaneous lesions on the nose. This article is the second part of a review series dealing with cutaneous lesions on the head and face, which are frequently seen in daily practice by a dermatologic surgeon. In this review, we focus on those skin diseases on the nose where surgery or laser therapy is considered a possible treatment option or that can be surgically evaluated.

In September 2013, a 69-year-old Caucasian man who was anti–JC virus (JCV) antibody positive was admitted to our hospital with slowly progressing right hemiparesis and aphasia lasting for approximately 6 months. Medical history revealed arterial hypertension, biological aortic valve replacement, and psoriasis vulgaris, treated with 3–6 tablets daily of dimethylfumarate (DMF; 120 mg)/ethylhydrogenfumarate (EHF; 95 mg) (Fumaderm, Biogen Idec, Ismaning, Germany) since December 2008 (table e-1 at [Neurology.org/nn][1]). No other immunosuppressive pretreatment had been given. In April/May 2013, the patient recognized a steadily progressing weakness of the right leg. In June 2013, an external diagnosis of ischemic stroke was made. An MRI scan (figure e-1), which was performed after deterioration of clinical symptoms, revealed a subcortical left hemispheric lesion; biopsy demonstrated macrophage-dominated inflammation, dysmorphic astrocytes, simian virus 40 positivity, and several p53- and MiB1-positive cells, suggestive of a JCV encephalitis (figure e-2). JCV DNA was detected in CSF at 2 different time points using a highly sensitive PCR protocol (September 24, 2013, 16 copies/mL; October 7, 2013, 42 copies/mL),1 leading to the diagnosis of progressive multifocal leukoencephalopathy (PML) in September 2013. Further diagnostic workup (table e-2) unmasked toxic bone marrow damage (figure e-3) and an increased excretion of kappa light chains in urine without any evidence for a plasmocytoma. Taking into account the patient's initial presentation with a slowly progressive paresis since April/May 2013 as well as the initial MRI scan (figure e-1), which is compatible with the PML diagnosis, we believe that the onset of PML was in April/May without preexisting leukopenia and only moderate lymphopenia (grade 2 lymphopenia: 724–738 cells/µL, figure). Several weeks later, white blood cell count dropped to a minimum of 4,800 cells/µL with 288 cells/µL lymphocytes under continuous Fumaderm treatment. Fumaderm was discontinued, and treatment with mirtazapine (45 mg/day; Remergil, MSD Sharp und Dohme GmbH, Haar, Germany), mefloquine (250 mg/week; Lariam, Roche Pharma AG, Grenzach-Wyhlen, Germany), and levetiracetam (1,000 mg/day; Keppra, UCB Pharma GmbH, Monheim, Germany) was initiated.2 Acknowledgment: The authors thank Prof. Dr. med. Anke Reinacher-Schick for her great support in hemato-oncologic diagnostics and Prof. Dr. med. Andrea Tannapfel/Dr. med. M. Gruener for providing pictures of the bone marrow biopsy. [1]: http://Neurology.org/nn

Objective The first two authors contributed equally to this work. A prospective, randomized study to evaluate efficacy, safety, and comfort of thigh-high, round knitted medical compression stockings (MCSs) with different pressure six weeks after vein surgery. Methods Female patients undergoing vein surgery were randomized for a compression therapy with low (18–21 mmHg, group A) or moderate (23–32 mmHg, group B) pressure MCSs. Follow-up was done by a phlebological experienced, blinded physician (pressure control, clinical aspect, duplex scan, and questionnaire) one and six weeks after surgery. Results Totally, 88 patients (41 in group A and 47 in group B) were analyzed. One week after surgery, patients of group B had significantly lower edema scores than patients of group A either in the clinical assessment (0.7 vs. 0.3; p = 0.016) or in the B-mode scan (0.9 vs. 0.4; p = 0.013). Significant less patients of group B had a feeling of “tightness” ( p = 0.01) and significant more a reduction of discomfort ( p = 0.01) after week 1 but with no significance in week 6. There was no significant difference according to other clinical and ultrasound findings such as hematoma, infection, hyperpigmentation, cording, or thrombosis after one or six weeks. In week 1 and week 6, more patients suffered from pain in group A (week 1 p = 0.24, week 6 p = 0.063). Application of the MCSs was easier in group A in week 1 but similar in groups A and B in week 6. Muscle vein thrombosis occurred in one patient of group A. Conclusion Compression stockings with a pressure of 23–32 mmHg facilitate a faster resolution of clinical and ultrasound verified edema and the subjective feelings of pain, tightness, and discomfort of the leg in the early period after surgery but have no difference in the longer post-surgical period compared to stockings with a pressure of 18–21 mmHg.

ZusammenfassungHintergrund und Design: Prospektive Pilot-fallserie zur Beurteilung der Effektivität, Verträglichkeit und Einfachheit der Anwendung einer neuartigen Fußschlinge (Stimfeet) zur Behandlung von habituellen Beinödemen.Patienten und Methoden: Eingeschlossen wurden acht Patientinnen mit nachweisbarer prätibialer Dellenbildung bei habituellen Beinödemen. Hämodynamisch relevante Refluxe oder Obstruktionen der Beinvenen wurden duplexsonographisch ausgeschlossen. Die Patientinnen erhielten eine einwöchige ganztägige Behandlung mit medizinischen Kompressionsstrümpfen (MKS) bis zum Knie (18–23 mmHg) und nach zweitägiger Pause mit Stimfeet (maximal vier Stunden ohne Unterbrechung) oder umgekehrt. Vor und nach jeder Behandlungswoche erfolgten jeweils zwei wasserplethysmographische Volumenmessungen pro Bein. Mittels standardisierter Fragebögen wurden die Effektivität, Verträglichkeit und Einfachheit der Anwendung evaluiert. In einem Patiententagebuch wurden die Nebenwirkungen dokumentiert.Ergebnisse: MKS führten zu einer größeren Volumenreduktion (mittleres Δ rechts: 39,00 g, links: 24,44 g) verglichen mit Stimfeet (mittleres Δ rechts: 5,06 g, links: 2,81 g). Die Ergebnisse unterschieden sich jedoch nicht signifikant (t-test: rechts: p=0,55, links: p=0,63). In Bezug auf weniger Einschränkung (n=5), Komfort (n=6), Reduktion der Symptome (n=5), Verbesserung der Lebensqualität (n=5), Verbesserung der Arbeitsbedingungen (n=5) und den Erwartungen entsprechend (n=5) bevorzugten mehr Patientinnen den MKS. Die Einfachheit der Anwendung wurde gleich bewertet. Die am häufigsten dokumentierten Nebenwirkungen von Stimfeet waren Druck- und Schürfstellen (n=6) und Verrutschen/Notwendigkeit der Fixierung (n=5).Schlussfolgerung: MKS waren der neuartigen Fußschlinge in der Behandlung habitueller Beinödeme überlegen. Bei einer Minderheit der Patientinnen führte die neuartige Fußschlinge jedoch zur Besserung der Beschwerden und Ödemreduktion. Die Wirksamkeit wird möglicherweise durch eine Stimulation der Fußmuskelpumpe bedingt. Methoden zur Aktivierung der Fußmuskelpumpe stellen eine neue Therapieoption für die Behandlung von Beinödemen dar.

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.

Objectives: Therapeutic options in progressive forms of multiple sclerosis (MS) are still limited. Dimethyl fumarate (DMF) has immunomodulatory properties but may also exert antioxidative cytoprotective effects. Hence, it may be a therapeutic option for progressive MS. The aim of this observational study was to evaluate safety, adherence and efficacy of fumarates in patients with primary progressive MS (PPMS) or secondary progressive MS. Methods: Patients with progressive MS whose condition had failed to respond to standard therapies and had worsened received the fumarate mixture Fumaderm, licensed for psoriasis therapy in Germany, or DMF by pharmaceutical preparation (Bochum ethics approval no. 4797-13). At regular follow-up visits, tolerability and disease course were assessed. Results: Twenty-six patients [age 54 ± 7.8 years; female = 13 (50%); PPMS = 12 (46.2%); Expanded Disability Status Scale (EDSS) = 6.0 ± 0.4 (range 3.5–8.0); disease duration = 14.1 ± 8.7 years] were initiated on treatment with Fumaderm ( n = 18) or pharmacy-prepared DMF (n=8). During a mean follow-up period of 13.2 ± 7.5 months (range 6–30) only five patients (19.2%) reported minor complaints. In 15 patients (57.7%) EDSS remained stable. In five cases (19.2%) there was even a decrease in EDSS while in six patients (23.1%) there was an increase in EDSS of more than 0.5 points, reflecting deterioration. Laboratory values were controlled for lymphopenia, renal and hepatic values, without any safety problems. We observed no significant differences between the two pharmaceutical forms. Conclusion: Our pilot data indicate that fumarate therapy appears to be safe and well tolerated by patients with progressive MS. In more than 75% of cases no further disease progression was evident. However, controlled studies are warranted to evaluate the detailed therapeutic potential of fumarates and their long-term effects in progressive MS.