Michael Weichenthal

Publications of Michael Weichenthal

• Combined Analysis of Genome-wide Association Studies for Crohn Disease and Psoriasis Identifies Seven Shared Susceptibility Loci.

  Authors: David Ellinghaus, Eva Ellinghaus, Rajan P Nair, Philip E Stuart, Tõnu Esko, Andres Metspalu, Sophie Debrus, John V Raelson, Trilokraj Tejasvi, Majid Belouchi [......] Richard C Trembath, Christopher G Mathew, Gonçalo R Abecasis, Stephan Weidinger, Susanna Nikolaus, Stefan Schreiber, James T Elder, Michael Weichenthal, Michael Nothnagel, Andre Franke

  American journal of human genetics. 04/2012; 90(4):636-47.

  Psoriasis (PS) and Crohn disease (CD) have been shown to be epidemiologically, pathologically, and therapeutically connected, but little is known about their shared genetic causes. We performedPsoriasis (PS) and Crohn disease (CD) have been shown to be epidemiologically, pathologically, and therapeutically connected, but little is known about their shared genetic causes. We performed meta-analyses of five published genome-wide association studies on PS (2,529 cases and 4,955 controls) and CD (2,142 cases and 5,505 controls), followed up 20 loci that showed strongest evidence for shared disease association and, furthermore, tested cross-disease associations for previously reported PS and CD risk alleles in additional 6,115 PS cases, 4,073 CD cases, and 10,100 controls. We identified seven susceptibility loci outside the human leukocyte antigen region (9p24 near JAK2, 10q22 at ZMIZ1, 11q13 near PRDX5, 16p13 near SOCS1, 17q21 at STAT3, 19p13 near FUT2, and 22q11 at YDJC) shared between PS and CD with genome-wide significance (p < 5 × 10(-8)) and confirmed four already established PS and CD risk loci (IL23R, IL12B, REL, and TYK2). Three of the shared loci are also genome-wide significantly associated with PS alone (10q22 at ZMIZ1, p(rs1250544) = 3.53 × 10(-8), 11q13 near PRDX5, p(rs694739) = 3.71 × 10(-09), 22q11 at YDJC, p(rs181359) = 8.02 × 10(-10)). In addition, we identified one susceptibility locus for CD (16p13 near SOCS1, p(rs4780355) = 4.99 × 10(-8)). Refinement of association signals identified shared genome-wide significant associations for exonic SNPs at 10q22 (ZMIZ1) and in silico expression quantitative trait locus analyses revealed that the associations at ZMIZ1 and near SOCS1 have a potential functional effect on gene expression. Our results show the usefulness of joint analyses of clinically distinct immune-mediated diseases and enlarge the map of shared genetic risk loci.

• IL-12 and IL-23 Affect Photocarcinogenesis Differently.

  Authors: Christian Jantschitsch, Michael Weichenthal, Ehrhardt Proksch, Thomas Schwarz, Agatha Schwarz

  The Journal of investigative dermatology. 02/2012;

  Induction of DNA damage by UVR is the key event in photocarcinogenesis. IL-12 and IL-23 are related heterodimeric cytokines consisting of a common p40 unit and a p35/IL-12 and a p19/IL-23 chain,Induction of DNA damage by UVR is the key event in photocarcinogenesis. IL-12 and IL-23 are related heterodimeric cytokines consisting of a common p40 unit and a p35/IL-12 and a p19/IL-23 chain, respectively. Both exert immunomodulatory activities but are also found to reduce UVR-induced DNA damage presumably via induction of DNA repair. As both cytokines are also produced in the skin, they may mitigate the risk to develop UVR-induced skin cancer. This appears to be the case as mice lacking p40 were previously shown to be at higher risk for skin tumors upon chronic UVR exposure. As these mice express neither IL-12 nor IL-23, the individual effects of IL-12 or IL-23 could not be evaluated. Thus, mice lacking p35 (IL-12p35-/-) or p19 (IL-23p19-/-) were subjected to chronic UVR exposure. The Kaplan-Meier analysis indicated a significantly increased probability of tumor development in IL-23p19-/- but not in IL-12p35-/- mice. Taken together, in our model, loss of IL-23, but not of IL-12, enhances development of UVR-induced skin tumors, indicating that IL-23 but not IL-12 may counteract photocarcinogenesis. This may have impact on the development of future strategies utilizing antibodies against IL-12 and IL-23, respectively, for the treatment of inflammatory dermatoses.Journal of Investigative Dermatology advance online publication, 2 February 2012; doi:10.1038/jid.2011.469.

• Leptin, adiponectin, visfatin and retinol-binding protein-4 - mediators of comorbidities in patients with psoriasis?

  Authors: Sascha Gerdes, Svetlana Osadtschy, Martin Rostami-Yazdi, Norbert Buhles, Michael Weichenthal, Ulrich Mrowietz

  Experimental dermatology. 01/2012; 21(1):43-7.

  White adipose tissue is known to be involved in numerous physiological processes such as insulin-mediated functions, lipid and glucose metabolism, vascular changes and coagulation. These processesWhite adipose tissue is known to be involved in numerous physiological processes such as insulin-mediated functions, lipid and glucose metabolism, vascular changes and coagulation. These processes are mainly mediated by adipokines that are secreted either from adipocytes or cells of the stromal-vascular fraction of adipose tissue. In obesity, a shift in the production of adipokines can mediate the development of associated diseases, such as metabolic syndrome, and vascular complications, such as artherosclerosis, myocardial infarction or stroke, which are known comorbidities of psoriasis too. As obesity is a frequently seen comorbidity in psoriasis patients, adipokines could be involved in the pathogenesis of psoriasis and/or its comorbidities either dependently or independently from obesity. Therefore, this study investigates the levels of four major adipokines in psoriasis patients compared with a control group of healthy volunteers without chronic inflammatory diseases in relation to body composition. Leptin, adiponectin (high molecular weight (HMW) and total adiponectin), visfatin and retinol-binding protein 4 (RBP4) have been analysed in 79 psoriasis patients and in 80 healthy volunteers. It was shown that HMW adiponectin (OR 1.3755; P = 0.0094) and visfatin (OR 1.1267; P = 0.0472) are independently increased, and RBP4 (OR 0.9884; P < 0.0001) is independently decreased in psoriasis. In conclusion, increased levels of HMW adiponectin and decreased levels of RBP4 could be a mechanism in a chronic inflammatory state that helps to protect against vascular and metabolic disorders, whereas the increase of the pro-inflammatory adipokine visfatin could lead to atherosclerosis and vascular disorders found in psoriasis.

• Genome-Wide Meta-Analysis of Psoriatic Arthritis Identifies Susceptibility Locus at REL.

  Authors: Eva Ellinghaus, Philip E Stuart, David Ellinghaus, Rajan P Nair, Sophie Debrus, John V Raelson, Majid Belouchi, Trilokraj Tejasvi, Yanming Li, Lam C Tsoi [......] Külli Kingo, Christian Gieger, H Erich Wichmann, Ulrich Mrowietz, Stephan Weidinger, Stefan Schreiber, Gonçalo R Abecasis, James T Elder, Michael Weichenthal, Andre Franke

  The Journal of investigative dermatology. 12/2011;

  Psoriatic arthritis (PsA) is a chronic inflammatory musculoskeletal disease affecting up to 30% of psoriasis vulgaris (PsV) cases and approximately 0.25 to 1% of the general population. To identifyPsoriatic arthritis (PsA) is a chronic inflammatory musculoskeletal disease affecting up to 30% of psoriasis vulgaris (PsV) cases and approximately 0.25 to 1% of the general population. To identify common susceptibility loci, we performed a meta-analysis of three imputed genome-wide association studies (GWAS) on psoriasis, stratified for PsA. A total of 1,160,703 single-nucleotide polymorphisms (SNPs) were analyzed in the discovery set consisting of 535 PsA cases and 3,432 controls from Germany, the United States, and Canada. We followed up two SNPs in 1,931 PsA cases and 6,785 controls comprising six independent replication panels from Germany, Estonia, the United States, and Canada. In the combined analysis, a genome-wide significant association was detected at 2p16 near the REL locus encoding c-Rel (rs13017599, P=1.18 × 10(-8), odds ratio (OR)=1.27, 95% confidence interval (CI)=1.18-1.35). The rs13017599 polymorphism is known to associate with rheumatoid arthritis (RA), and another SNP near REL (rs702873) was recently implicated in PsV susceptibility. However, conditional analysis indicated that rs13017599, rather than rs702873, accounts for the PsA association at REL. We hypothesize that c-Rel, as a member of the Rel/NF-κB family, is associated with PsA in the context of disease pathways that involve other identified PsA and PsV susceptibility genes including TNIP1, TNFAIP3, and NFκBIA.Journal of Investigative Dermatology advance online publication, 15 December 2011; doi:10.1038/jid.2011.415.

• Prospective evaluation of supportive care with or without CVD chemotherapy as a second-line treatment in advanced melanoma by patient's choice: a multicentre Dermatologic Cooperative Oncology Group trial.

  Authors: Maja A Hofmann, Axel Hauschild, Peter Mohr, Claus Garbe, Michael Weichenthal, Uwe Trefzer, Ulrike Drecoll, Wolfgang Tilgen, Dirk Schadendorf, Martin Kaatz, Jens Ulrich

  Melanoma research. 12/2011; 21(6):516-23.

  This prospective, nonrandomized multicentre, phase III study compared best supportive care (BSC) alone with cisplatin, vindesine and dacabazine-based (CVD) chemotherapy and BSC in patients withThis prospective, nonrandomized multicentre, phase III study compared best supportive care (BSC) alone with cisplatin, vindesine and dacabazine-based (CVD) chemotherapy and BSC in patients with advanced melanoma. A total of 117 pretreated patients with metastatic melanoma were evaluated, 34 patients in arm A (BSC) and 83 in arm B (BSC and CVD). Primary endpoint was overall survival and secondary endpoints were disease control rate and quality of life (European Organisation for Research and Treatment of Cancer QLQ-C30). Owing to sparse recruitment of patients for randomization, the protocol has been changed based on patients' choice. Baseline characteristics were imbalanced with respect to the Karnofsky Performance Index (P=0.001), the existence of brain metastases (P=0.035) and earlier application of chemoimmunotherapy (P=0.038). Disease control was observed in 8.8% of patients in arm A and in 28.9% of patients in arm B (P=0.028). Median overall survival time was 137 days in arm A and 229 days in arm B (P=0.014). Multivariate analyses could not ascribe this prognostic benefit to CVD treatment. No significant difference in the quality of life could be found. This study could not detect clear survival benefits for polychemotherapy with CVD compared with BSC alone in patients with advanced metastatic melanoma. Interestingly, having the choice of chemotherapy or BSC alone in a second-line situation, more than 70% of patients chose polychemotherapy.

• Comparative study of YKL-40, S-100B and LDH as monitoring tools for Stage IV melanoma.

  Authors: Friederike Egberts, Eva Maria Kotthoff, Sascha Gerdes, Jan Hendrik Egberts, Michael Weichenthal, Axel Hauschild

  European journal of cancer (Oxford, England : 1990). 09/2011;

  BACKGROUND: Serum markers can be important tools for the prognostic classification and the treatment monitoring in cancer patients. Recently, the potential new serum marker YKL-40 has been introducedBACKGROUND: Serum markers can be important tools for the prognostic classification and the treatment monitoring in cancer patients. Recently, the potential new serum marker YKL-40 has been introduced for patients with malignant melanoma. The purpose of this study was to assess the prognostic value of YKL-40 in stage IV melanoma patients regarding treatment outcome and survival compared to the established markers LDH and serum S-100B and to evaluate their ability to discriminate between different stages of the disease. METHODS: YKL-40, LDH and S-100B were measured in serum samples of 50 patients with stage I/II melanoma and 61 patients with metastatic melanoma before and after treatment. Univariate and multivariate analyses were performed to determine prognostic factors. RESULTS: YKL-40, S-100B and LDH correlated significantly with the stage of disease. In stage IV melanoma patients, only the baseline serum levels of S-100B were significantly associated with treatment response (p=0.031), but not those of LDH (p=0.193) or YKL-40 (p=0.186). We found a strong correlation between treatment response and unchanged or declining S-100B levels over time (p=0.003, OR: 9.52, 95%-CI: 1.87-47.62), but no significant correlation between treatment response and serum changes for LDH (p=0.534) and YKL-40 (p=0.306), respectively. In the Cox Regression analysis, only the serum levels of S-100B proved to have a significant prognostic impact on survival (p<0.0001). CONCLUSION: In melanoma patients, serum levels of YKL-40, S-100B and LDH correlate significantly with the stage of disease. In stage IV melanoma, S100-B significantly correlates with treatment response and survival and is superior to LDH and YKL-40.

• Infrared radiation does not enhance the frequency of ultraviolet radiation-induced skin tumors, but their growth behaviour in mice.

  Authors: Christian Jantschitsch, Michael Weichenthal, Akira Maeda, Ehrhardt Proksch, Thomas Schwarz, Agatha Schwarz

  Experimental dermatology. 04/2011; 20(4):346-50.

  There is increasing concern about the interaction between infrared radiation (IR) and ultraviolet radiation (UVR) with regard to carcinogenesis because prolonged solar exposure is associated with anThere is increasing concern about the interaction between infrared radiation (IR) and ultraviolet radiation (UVR) with regard to carcinogenesis because prolonged solar exposure is associated with an increased cumulative load not only of UVR but also of IR. We recently demonstrated that IR-pretreatment reduces UVR-induced apoptosis. As this might support the survival of UVR-damaged cells and thus carcinogenesis, we performed an in vivo photocarcinogenesis study. One group of mice were treated with IR prior to each UVR exposure; additional groups were treated with IR or UVR alone. IR alone did not induce skin cancer. UVR-induced tumor formation was not enhanced in IR-pretreated mice, but, in contrast, seemed to occur with delay. This correlated with a reduction of p53 mutated clones in the skin. However, once developed, tumors in IR-pretreated mice grew faster which was confirmed by their enhanced Ki-67 expression. The enhanced aggressiveness of tumors derived from IR-pretreated mice was associated with a higher prevalence of sarcomas than epithelial tumors. Hence, the impact of IR on UVR-induced carcinogenesis has to be interpreted with caution. Although IR may delay the onset of UVR-induced tumors, it might contribute to a worse outcome by shifting these tumors into a more aggressive phenotype.

• Gene expression in skin and lymphoblastoid cells: Refined statistical method reveals extensive overlap in cis-eQTL signals.

  Authors: Jun Ding, Johann E Gudjonsson, Liming Liang, Philip E Stuart, Yun Li, Wei Chen, Michael Weichenthal, Eva Ellinghaus, Andre Franke, William Cookson, Rajan P Nair, James T Elder, Gonçalo R Abecasis

  American journal of human genetics. 12/2010; 87(6):779-89.

  Psoriasis, an immune-mediated, inflammatory disease of the skin and joints, provides an ideal system for expression quantitative trait locus (eQTL) analysis, because it has a strong genetic basis andPsoriasis, an immune-mediated, inflammatory disease of the skin and joints, provides an ideal system for expression quantitative trait locus (eQTL) analysis, because it has a strong genetic basis and disease-relevant tissue (skin) is readily accessible. To better understand the role of genetic variants regulating cutaneous gene expression, we identified 841 cis-acting eQTLs using RNA extracted from skin biopsies of 53 psoriatic individuals and 57 healthy controls. We found substantial overlap between cis-eQTLs of normal control, uninvolved psoriatic, and lesional psoriatic skin. Consistent with recent studies and with the idea that control of gene expression can mediate relationships between genetic variants and disease risk, we found that eQTL SNPs are more likely to be associated with psoriasis than are randomly selected SNPs. To explore the tissue specificity of these eQTLs and hence to quantify the benefits of studying eQTLs in different tissues, we developed a refined statistical method for estimating eQTL overlap and used it to compare skin eQTLs to a published panel of lymphoblastoid cell line (LCL) eQTLs. Our method accounts for the fact that most eQTL studies are likely to miss some true eQTLs as a result of power limitations and shows that ∼70% of cis-eQTLs in LCLs are shared with skin, as compared with the naive estimate of < 50% sharing. Our results provide a useful method for estimating the overlap between various eQTL studies and provide a catalog of cis-eQTLs in skin that can facilitate efforts to understand the functional impact of identified susceptibility variants on psoriasis and other skin traits.

• Genome-wide association analysis identifies three psoriasis susceptibility loci.

  Authors: Philip E Stuart, Rajan P Nair, Eva Ellinghaus, Jun Ding, Trilokraj Tejasvi, Johann E Gudjonsson, Yun Li, Stephan Weidinger, Bernadette Eberlein, Christian Gieger [......] Anne M Bowcock, Ulrich Mrowietz, Henry W Lim, John J Voorhees, Gonçalo R Abecasis, Michael Weichenthal, Andre Franke, Proton Rahman, Dafna D Gladman, James T Elder

  Nature genetics. 11/2010; 42(11):1000-4.

  We carried out a meta-analysis of two recent psoriasis genome-wide association studies with a combined discovery sample of 1,831 affected individuals (cases) and 2,546 controls. One hundred and twoWe carried out a meta-analysis of two recent psoriasis genome-wide association studies with a combined discovery sample of 1,831 affected individuals (cases) and 2,546 controls. One hundred and two loci selected based on P value rankings were followed up in a three-stage replication study including 4,064 cases and 4,685 controls from Michigan, Toronto, Newfoundland and Germany. In the combined meta-analysis, we identified three new susceptibility loci, including one at NOS2 (rs4795067, combined P = 4 × 10⁻¹¹), one at FBXL19 (rs10782001, combined P = 9 × 10⁻¹⁰) and one near PSMA6-NFKBIA (rs12586317, combined P = 2 × 10⁻⁸). All three loci were also associated with psoriatic arthritis (rs4795067, combined P = 1 × 10⁻⁵; rs10782001, combined P = 4 × 10⁻⁸; and rs12586317, combined P = 6 × 1⁻⁵) and purely cutaneous psoriasis (rs4795067, combined P = 1 × 10⁻⁸; rs10782001, combined P = 2 × 10⁻⁶; and rs12586317, combined P = 1 × 10⁻⁶). We also replicated a recently identified association signal near RNF114 (rs495337, combined P = 2 × 10⁻⁷).

• Association analyses identify six new psoriasis susceptibility loci in the Chinese population.

  Authors: Liang-Dan Sun, Hui Cheng, Zai-Xing Wang, An-Ping Zhang, Pei-Guang Wang, Jin-Hua Xu, Qi-Xing Zhu, Hai-Sheng Zhou, Eva Ellinghaus, Fu-Ren Zhang [......] Li-Mei Shao, Jian-Lan Liu, Feng-Yu Zhang, Wei-Dong Du, Andre Franke, Anne M Bowcock, James T Elder, Jian-Jun Liu, Sen Yang, Xue-Jun Zhang

  Nature genetics. 11/2010; 42(11):1005-9.

  We extended our previous genome-wide association study for psoriasis with a multistage replication study including 8,312 individuals with psoriasis (cases) and 12,919 controls from China as well asWe extended our previous genome-wide association study for psoriasis with a multistage replication study including 8,312 individuals with psoriasis (cases) and 12,919 controls from China as well as 3,293 cases and 4,188 controls from Germany and the United States and 254 nuclear families from the United States. We identified six new susceptibility loci associated with psoriasis in the Chinese study containing the candidate genes ERAP1, PTTG1, CSMD1, GJB2, SERPINB8 and ZNF816A (combined P < 5 × 10⁻⁸) and replicated one locus, 5q33.1 (TNIP1-ANXA6), previously reported (combined P = 3.8 × 10⁻²¹) in the European studies. Two of these loci showed evidence for association in the German study at ZNF816A and GJB2 with P = 3.6 × 10⁻³ and P = 7.9 × 10⁻³, respectively. ERAP1 and ZNF816A were associated with type 1 (early onset) psoriasis in the Chinese Han population (test for heterogeneity P = 6.5 × 10⁻³ and P = 1.5 × 10⁻³, respectively). Comparisons with the results of previous GWAS of psoriasis highlight the heterogeneity of disease susceptibility between the Chinese and European populations. Our study identifies new genetic susceptibility factors and suggests new biological pathways in psoriasis.

• Genome-wide association study identifies a psoriasis susceptibility locus at TRAF3IP2.

  Authors: Eva Ellinghaus, David Ellinghaus, Philip E Stuart, Rajan P Nair, Sophie Debrus, John V Raelson, Majid Belouchi, Hélène Fournier, Claudia Reinhard, Jun Ding [......] Tom H Karlsen, Gabriele Mayr, Mario Albrecht, Dieter Kabelitz, Ulrich Mrowietz, Gonçalo R Abecasis, James T Elder, Stefan Schreiber, Michael Weichenthal, Andre Franke

  Nature genetics. 11/2010; 42(11):991-5.

  Psoriasis is a multifactorial skin disease characterized by epidermal hyperproliferation and chronic inflammation, the most common form of which is psoriasis vulgaris (PsV). We present a genome-widePsoriasis is a multifactorial skin disease characterized by epidermal hyperproliferation and chronic inflammation, the most common form of which is psoriasis vulgaris (PsV). We present a genome-wide association analysis of 2,339,118 SNPs in 472 PsV cases and 1,146 controls from Germany, with follow-up of the 147 most significant SNPs in 2,746 PsV cases and 4,140 controls from three independent replication panels. We identified an association at TRAF3IP2 on 6q21 and genotyped two SNPs at this locus in two additional replication panels (the combined discovery and replication panels consisted of 6,487 cases and 8,037 controls; combined P = 2.36 × 10⁻¹⁰ for rs13210247 and combined P = 1.24 × 10⁻¹⁶ for rs33980500). About 15% of psoriasis cases develop psoriatic arthritis (PsA). A stratified analysis of our datasets including only PsA cases (1,922 cases compared to 8,037 controls, P = 4.57 × 10⁻¹² for rs33980500) suggested that TRAF3IP2 represents a shared susceptibility for PsV and PsA. TRAF3IP2 encodes a protein involved in IL-17 signaling and which interacts with members of the Rel/NF-κB transcription factor family.

• Efficacy of low-dose interferon {alpha}2a 18 versus 60 months of treatment in patients with primary melanoma of >= 1.5 mm tumor thickness: results of a randomized phase III DeCOG trial.

  Authors: Axel Hauschild, Michael Weichenthal, Knuth Rass, Ruthild Linse, Carola Berking, Jörg Böttjer, Thomas Vogt, Konstanze Spieth, Thomas Eigentler, Norbert H Brockmeyer, Annette Stein, Helmut Näher, Dirk Schadendorf, Peter Mohr, Martin Kaatz, Michael Tronnier, Rüdiger Hein, Gerold Schuler, Friederike Egberts, Claus Garbe

  Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 02/2010; 28(5):841-6.

  PURPOSE Low-dose (LD) interferon (IFN) alfa (LDI) has demonstrated a consistent disease-free survival benefit for patients with clinically lymph node-negative melanoma in clinical trials. However,PURPOSE Low-dose (LD) interferon (IFN) alfa (LDI) has demonstrated a consistent disease-free survival benefit for patients with clinically lymph node-negative melanoma in clinical trials. However, the optimal duration of treatment is still under discussion, and no previous trial has evaluated this question specifically. A prolongation of LDI from 18 months to 60 months might be of clinical benefit for patients with intermediate or high-risk melanoma. PATIENTS AND METHODS Eight hundred fifty patients with resected cutaneous melanoma of at least 1.5 mm tumor thickness were included in this prospective randomized, multicenter trial in Germany and Austria. Patients had to be clinically lymph node-negative, and sentinel node biopsy (SLNB) was performed in a majority of cases. They were randomly assigned to receive 3 MU IFNalpha2a three times a week subcutaneously for either 18 months (arm A) or 60 months (arm B). Results Of 850 randomly assigned patients, 840 were eligible for evaluation after a median follow-up of 4.3 years. Tumor thickness and other relevant prognostic factors were well balanced between both groups. SLNB was performed in 635 patients (75.6%), with a positivity rate of 18.0% in arm A and 17.5% in arm B. Neither relapse-free survival (arm A, 75.6% v arm B, 72.6%; P = .72; hazard ratio, 1.05; 95% CI, 0.80 to 1.39) nor distant-metastasis-free survival (81.9% v 79.7%; P = .56; HR, 1.10; 95% CI, 0.80 to 1.52) or overall survival (85.9% v 84.9%; P = .86; HR, 1.03; 95% CI, 0.71 to 1.50) showed significant differences. CONCLUSION A prolongation of conventional LDI therapy from 18 to 60 months showed no clinical benefit in patients with intermediate and high-risk primary melanoma.

• Different effects of pimecrolimus and betamethasone on the skin barrier in patients with atopic dermatitis.

  Authors: Jens-Michael Jensen, Stephan Pfeiffer, Magdalena Witt, Matthias Bräutigam, Claudia Neumann, Michael Weichenthal, Thomas Schwarz, Regina Fölster-Holst, Ehrhardt Proksch

  The Journal of allergy and clinical immunology. 10/2009; 124(3 Suppl 2):R19-28.

  BACKGROUND: Genetic defects leading to skin barrier dysfunction were recognized as risk factors for atopic dermatitis (AD). It is essential that drugs applied to patients with AD restore the impairedBACKGROUND: Genetic defects leading to skin barrier dysfunction were recognized as risk factors for atopic dermatitis (AD). It is essential that drugs applied to patients with AD restore the impaired epidermal barrier to prevent sensitization by environmental allergens. OBJECTIVES: We investigated the effect of 2 common treatments, a calcineurin inhibitor and a corticosteroid, on the skin barrier. METHODS: In a randomized study 15 patients with AD were treated on one upper limb with pimecrolimus and on the other with betamethasone twice daily for 3 weeks. RESULTS: Stratum corneum hydration and transepidermal water loss, a marker of the inside-outside barrier, improved in both groups. Dye penetration, a marker of the outside-inside barrier, was also reduced in both drugs. Electron microscopic evaluation of barrier structure displayed prevalently ordered stratum corneum lipid layers and regular lamellar body extrusion in pimecrolimus-treated skin but inconsistent extracellular lipid bilayers and only partially filled lamellar bodies after betamethasone treatment. Both drugs normalized epidermal differentiation and reduced epidermal hyperproliferation. Betamethasone was superior in reducing clinical symptoms and epidermal proliferation; however, it led to epidermal thinning. CONCLUSION: The present study demonstrates that both betamethasone and pimecrolimus improve clinical and biophysical parameters and epidermal differentiation. Because pimecrolimus improved the epidermal barrier and did not cause atrophy, it might be more suitable for long-term treatment of AD.

• Quality of Life in Patients Receiving High-Dose Interferon Alfa-2b After Resected High-Risk Melanoma.

  Authors: Peter Mohr, Axel Hauschild, Uwe Trefzer, Michael Weichenthal

  Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 08/2009;

• Prospective Randomized Multicenter Adjuvant Dermatologic Cooperative Oncology Group Trial of Low-Dose Interferon Alfa-2b With or Without a Modified High-Dose Interferon Alfa-2b Induction Phase in Patients With Lymph Node-Negative Melanoma.

  Authors: Axel Hauschild, Michael Weichenthal, Knuth Rass, Ruthild Linse, Jens Ulrich, Rudolf Stadler, Matthias Volkenandt, Stephan Grabbe, Ulrike Proske, Dirk Schadendorf, Norbert Brockmeyer, Thomas Vogt, Rainer Rompel, Roland Kaufmann, Martin Kaatz, Helmut Näher, Peter Mohr, Thomas Eigentler, Elisabeth Livingstone, Claus Garbe

  Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 06/2009;

  PURPOSE: Interferon alfa (IFN-alpha) has shown clinical efficacy in the adjuvant treatment of patients with high-risk melanoma in several clinical trials, but optimal dosing and duration of treatmentPURPOSE: Interferon alfa (IFN-alpha) has shown clinical efficacy in the adjuvant treatment of patients with high-risk melanoma in several clinical trials, but optimal dosing and duration of treatment are still under discussion. It has been argued that in high-dose IFN-alpha (HDI), the intravenous (IV) induction phase might be critical for the clinical benefit of the regimen. PATIENTS AND METHODS: In an attempt to investigate the potential role of a modified high-dose induction phase, lymph node-negative patients with resected primary malignant melanoma of more than 1.5-mm tumor thickness were included in this prospective randomized multicenter Dermatologic Cooperative Oncology Group trial. Six hundred seventy-four patients were randomly assigned to receive 4 weeks of a modified HDI scheme. This schedule consisted of 5 times weekly 10 MU/m(2) IFN-alpha-2b IV for 2 weeks and 5 times weekly 10 MU/m(2) IFN-alpha-2b administered subcutaneously (SC) for another 2 weeks followed by 23 months of low-dose IFN-alpha-2b (LDI) 3 MU SC three times a week (arm A). LDI 3 MU three times a week was given for 24 months in arm B. RESULTS: Of 650 assessable patients, there were 92 relapses among the 321 patients receiving high-dose induction as compared with 95 relapses among the 329 patients receiving LDI only. Five-year relapse-free survival rates were 68.0% (arm A) and 67.1% (arm B), respectively. Likewise, melanoma-related fatalities were similar between both groups, resulting in 5-year overall survival rates of 80.2% (arm A) and 82.9% (arm B). CONCLUSION: The addition of a 4-week modified HDI induction phase to a 2-year low-dose adjuvant IFN-alpha-2b treatment schedule did not improve the clinical outcome.

• The Angiogenesis Inhibitor Thrombospondin-1 Inhibits Acute Cutaneous Hypersensitivity Reactions.

  Authors: Paula Velasco, Rainer Huegel, Jochen Brasch, Jens M Schröder, Michael Weichenthal, Eggert Stockfleth, Thomas Schwarz, Jack Lawler, Michael Detmar, Bernhard Lange-Asschenfeldt

  The Journal of investigative dermatology. 03/2009;

  There is increasing evidence that vascular remodeling and endothelial cell activation promote acute and chronic inflammation. Thrombospondin 1 (TSP-1) is a potent endogenous angiogenesis inhibitorThere is increasing evidence that vascular remodeling and endothelial cell activation promote acute and chronic inflammation. Thrombospondin 1 (TSP-1) is a potent endogenous angiogenesis inhibitor thought to play an important role in maintaining cutaneous vascular quiescence. We first investigated TSP-1 expression in human and contact hypersensitivity (CHS) reactions and found that TSP-1 was upregulated in the inflamed skin of patients and in mice. To elucidate the function of TSP-1 in cutaneous inflammation, we induced CHS reactions in the skin of mice with targeted epidermal TSP-1 overexpression in TSP-1-deficient mice and in wild-type mice. We found decreased edema formation, angiogenesis, and inflammatory infiltrate in the inflamed skin of TSP-1 transgenic mice. Conversely, TSP-1-deficient mice exhibited an enhanced and prolonged inflammation, characterized by increased edema formation, enhanced vascular remodeling, and increased neutrophilic infiltrate, when compared with wild-type mice. Moreover, we found strong upregulation of the proinflammatory cytokines IL-1beta, macrophage inflammatory protein 2, and tumor necrosis factor-alpha in the inflamed skin of TSP-1-deficient mice. Our results indicate that TSP-1 downregulates cutaneous delayed-type hypersensitivity reactions by acting on several distinct pathways mediating skin inflammation.Journal of Investigative Dermatology advance online publication, 5 February 2009; doi:10.1038/jid.2008.447.

• Prospective monitoring of adjuvant treatment in high-risk melanoma patients: lactate dehydrogenase and protein S-100B as indicators of relapse.

  Authors: Friederike Egberts, Wolfgang Hitschler, Michael Weichenthal, Axel Hauschild

  Melanoma research. 01/2009;

  At present there is no international consensus on laboratory testing during the follow-up of melanoma patients. We carried out a prospective monitoring study on the usefulness of lactateAt present there is no international consensus on laboratory testing during the follow-up of melanoma patients. We carried out a prospective monitoring study on the usefulness of lactate dehydrogenase (LDH) and protein S-100B assessment in high-risk melanoma patients. Ninety-seven patients treated within prospective randomized trials on the adjuvant treatment of melanoma received quarterly clinical visits and blood examinations. During the median observation period of 30 months disease progression was observed in 52 of 97 patients (53.1%). The clinical course of melanoma was correlated to elevated LDH and S-100B serum concentrations. The comparative analysis revealed that (i) neither LDH nor S-100B were indicators of in-transit metastases, (ii) clinically apparent lymph nodes were rarely detected because of elevated S-100B (29.4%) or LDH (11.8%) only, and (iii) the S-100B assessment was superior to LDH in the identification of early distant metastasis (53.8 vs. 23.1%; P=0.008). The rate of false-positive (elevated) LDH-serum levels and S-100B-serum levels in clinically disease-free melanoma patients did not differ significantly (S-100B 1.9% vs. LDH 1.6%). Our data indicate that only protein S-100B might be used as a highly specific and relatively sensitive marker of early distant metastasis. Both markers, LDH and S-100B, are not able to identify loco-regional metastases with a low tumor load in high-risk melanoma patients.

• Genome-wide scan reveals association of psoriasis with IL-23 and NF-kappaB pathways.

  Authors: Rajan P Nair, Kristina Callis Duffin, Cynthia Helms, Jun Ding, Philip E Stuart, David Goldgar, Johann E Gudjonsson, Yun Li, Trilokraj Tejasvi, Bing-Jian Feng [......] Jennifer Gardner, Amy Perlmutter, Andrew Miner, Ravi Hiremagalore, Robert W Ike, Henry W Lim, Enno Christophers, Tilo Henseler, Andre Franke, C Wise

  Nature genetics. 01/2009;

  Psoriasis is a common immune-mediated disorder that affects the skin, nails and joints. To identify psoriasis susceptibility loci, we genotyped 438,670 SNPs in 1,409 psoriasis cases and 1,436Psoriasis is a common immune-mediated disorder that affects the skin, nails and joints. To identify psoriasis susceptibility loci, we genotyped 438,670 SNPs in 1,409 psoriasis cases and 1,436 controls of European ancestry. We followed up 21 promising SNPs in 5,048 psoriasis cases and 5,041 controls. Our results provide strong support for the association of at least seven genetic loci and psoriasis (each with combined P < 5 x 10(-8)). Loci with confirmed association include HLA-C, three genes involved in IL-23 signaling (IL23A, IL23R, IL12B), two genes that act downstream of TNF-alpha and regulate NF-kappaB signaling (TNIP1, TNFAIP3) and two genes involved in the modulation of Th2 immune responses (IL4, IL13). Although the proteins encoded in these loci are known to interact biologically, we found no evidence for epistasis between associated SNPs. Our results expand the catalog of genetic loci implicated in psoriasis susceptibility and suggest priority targets for study in other auto-immune disorders.

• Polymorphisms of the IL12B and IL23R genes are associated with psoriasis.

  Authors: Rajan P Nair, Andreas Ruether, Philip E Stuart, Stefan Jenisch, Trilokraj Tejasvi, Ravi Hiremagalore, Stefan Schreiber, Dieter Kabelitz, Henry W Lim, John J Voorhees, Enno Christophers, James T Elder, Michael Weichenthal

  The Journal of investigative dermatology. 08/2008; 128(7):1653-61.

  Psoriasis is a common inflammatory and hyperproliferative skin disease with a multifactorial genetic basis. A recent study reported that psoriasis was associated with the IL12B haplotype rs3212227Psoriasis is a common inflammatory and hyperproliferative skin disease with a multifactorial genetic basis. A recent study reported that psoriasis was associated with the IL12B haplotype rs3212227 (3'-untranslated region)-rs6887695 (60 kb, 5') and the IL23R haplotype rs7530511 (L310P)-rs11209026 (Q381R). We examined these four single-nucleotide polymorphisms (SNPs) for association with psoriasis in two groups of North American and German Caucasians: (1) 1,810 cases and 2,522 controls; and (2) 509 pedigrees. Both IL12B markers showed highly significant association with psoriasis in the case-control (rs3212227, odds ratio (OR)=1.62, P=1.7 x 10(-15); rs6887695, OR=1.49, P=2.7 x 10(-15)) and in the family-based analysis (rs3212227, P=2.2 x 10(-3); rs6887695, P=1.7 x 10(-3)). The IL23R SNPs also showed significant association in the cases and controls (rs7530511, OR=1.22, P=3.9 x 10(-3); rs11209026, OR=1.40, P=3.8 x 10(-4)). For both genes, common risk haplotypes were identified whose statistical significance approached (IL23R) or exceeded (IL12B) genome-wide criteria. We found no statistical evidence for interactions of these haplotypes with HLA-Cw6. Our results confirm associations between IL12B and IL23R and psoriasis in Caucasians, and provide a genetic basis for the clinical association between psoriasis and Crohn's disease.

• Long-term survival analysis in metastatic melanoma: serum S100B is an independent prognostic marker and superior to LDH.

  Authors: Friederike Egberts, Andrea Pollex, Jan-Hendrik Egberts, Katharina C Kaehler, Michael Weichenthal, Axel Hauschild

  Onkologie. 07/2008; 31(7):380-4.

  BACKGROUND: The prognosis of metastatic melanoma is poor. The purpose of this study was to perform a long-term survival analysis on patients with advanced melanoma to determine clinical andBACKGROUND: The prognosis of metastatic melanoma is poor. The purpose of this study was to perform a long-term survival analysis on patients with advanced melanoma to determine clinical and laboratory prognostic factors for treatment outcome and long-term survival. The prognostic importance of S100B serum levels on overall survival compared to lactate dehydrogenase (LDH) was evaluated. PATIENTS AND METHODS: The medical records of 105 AJCC (American Joint Committee on Cancer) stage IV melanoma patients from 1994 to 2001 were analyzed retrospectively. Median time to progression and overall survival were assessed. Univariate and multivariate analysis were performed to determine prognostic factors. RESULTS: 86 (81.9%) of the 105 patients died during the observation period. In univariate analysis, pre-therapeutic LDH and S100B levels in serum samples (p = 0.01 and p = 0.002, respectively), tumor stage (AJCC IVa-IVc, p = 0.005), and response to the firstline therapy (p < 0.001) were found to be significant prognostic markers. However, in the multivariate analysis, pre-therapeutic S100B serum levels (p = 0.005, odds ratio (OR): 2.22, confidence interval (CI): 1.22-4.1) as well as presence of brain metastases (p = 0.009, OR: 5.08, CI: 1.51-17.05) were the only independent prognostic factors for overall survival. CONCLUSION: In metastatic melanoma, S100B is a strong prognostic factor for overall and long-term survival, and superior to LDH.